CN114980899A - 离子通道调节剂 - Google Patents
离子通道调节剂 Download PDFInfo
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- CN114980899A CN114980899A CN202080093800.6A CN202080093800A CN114980899A CN 114980899 A CN114980899 A CN 114980899A CN 202080093800 A CN202080093800 A CN 202080093800A CN 114980899 A CN114980899 A CN 114980899A
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Abstract
本发明部分地涉及可用于预防和/或治疗与电压门控钠离子通道的异常功能例如异常晚钠电流/持续性钠电流相关的疾病或病症的稠合杂芳基化合物和组合物。本文还提供了治疗与钠离子通道的异常功能相关的疾病或病症的方法,所述疾病或病症包括神经障碍(例如,德拉韦综合征、癫痫)、疼痛和神经肌肉障碍。
Description
相关申请的交叉引用
本申请要求2019年11月26日提交的美国临时专利申请号62/940,500的权益,该临时专利申请的全部内容以引用的方式并入本文。
背景技术
钠离子(Na+)通道主要以瞬时方式打开并且迅速失活,从而生成快Na+电流以发起动作电位。晚钠电流或持续性钠电流(INaL)是心肌细胞和神经元的快Na+电流的持续分量。许多常见神经和心脏病症与异常INaL增强相关,该异常INaL增强导致哺乳动物中电功能障碍和收缩功能障碍的发病(参见例如Pharmacol Ther(2008)119:326-339)。因此,选择性地调节钠通道活性(例如,异常INaL)的药物化合物可用于治疗此类疾病状态。
发明内容
本文描述了可用于预防和/或治疗疾病、障碍或病症例如与钠离子通道异常功能例如异常晚钠电流/持续性钠电流(INaL)相关的疾病、障碍或病症的稠合杂芳基化合物和组合物。
因此,在一个方面,本文提供了具有式I的化合物:
或其药学上可接受的盐,其中Ra为C2-4烷基或单环C3-6环烷基;并且Rb为C1-4烷基。
在一些实施方案中,Ra为乙基、异丙基或环丙基。在一些实施方案中,Rb为甲基或乙基。
在一些实施方案中,式I的化合物选自:
在另一个方面,本文提供了具有式II的化合物:
或其药学上可接受的盐,其中Ra为C1-4烷基;Rb为C1-4烷基;并且Rc为氢或C1-4烷基。
在一些实施方案中,Ra为甲基。在一些实施方案中,Ra为甲基或乙基。在一些实施方案中,Rb为甲基。在一些实施方案中,Rb为甲基、乙基或异丙基。在一些实施方案中,Rc为氢或甲基。在一些实施方案中,Rc为氢。
在一些实施方案中,Rc为甲基。
在一些实施方案中,式II的化合物选自:
在另一个方面,本文提供了选自以下的化合物:
本文还提供了药物组合物,该药物组合物包含本文所述的化合物或其药学上可接受的盐;和药学上可接受的载剂。
在一个方面,本文提供了在有需要的受试者中治疗与钠离子通道的异常功能相关的病症的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,该病症是神经障碍或精神障碍。在一些实施方案中,该病症是癫痫或癫痫综合征。在一些实施方案中,该病症是遗传性癫痫或遗传性癫痫综合征。在一些实施方案中,该病症是小儿癫痫或小儿癫痫综合征。在一些实施方案中,该病症是癫痫性脑病。在一些实施方案中,该癫痫性脑病选自德拉韦综合征、婴儿痉挛或林-戈综合征。
在一些实施方案中,该病症选自癫痫性脑病、带SCN1A、SCN2A、SCN8A突变的癫痫性脑病、婴儿早期癫痫性脑病、德拉韦综合征、带SCN1A突变的德拉韦综合征、全身性癫痫伴热性惊厥、儿童难治性癫痫伴全身性强直阵挛发作、婴儿痉挛、良性家族性新生儿-婴儿癫痫发作、SCN2A癫痫性脑病、带SCN3A突变的局灶性癫痫、带SCN3A突变的儿童隐源性部分性癫痫、SCN8A癫痫性脑病、癫痫不明原因猝死、拉斯姆森脑炎、婴儿恶性游走性部分性发作、常染色体显性遗传夜间额叶癫痫、癫痫预期猝死(SUDEP)、KCNQ2癫痫性脑病以及KCNT1癫痫性脑病。
在另一个方面,本发明公开了治疗神经障碍或精神障碍的方法,其中该方法包括向有需要的受试者施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在另一个方面,本文提供了治疗疼痛的方法,其中该方法包括向有需要的受试者施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在另一个方面,提供了预防或治疗三叉神经自主神经性头痛(例如,阵发性偏头痛、持续性偏头痛、短暂单侧神经痛样头痛发作伴结膜充血和流泪(SUNCT)、短暂单侧神经痛样头痛发作伴颅自主神经症状(SUNA)以及长期自主神经症状伴偏头痛)的方法。本文还提供了预防或治疗颅神经病变(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹和第六神经麻痹)或多发性颅神经病变(MCN)的方法。在某些实施方案中,提供了预防或治疗偏头痛(例如,无先兆偏头痛、有先兆偏头痛、1型家族性偏瘫性偏头痛(FHM1)、2型家族性偏瘫性偏头痛(FHM2)、4型家族性偏瘫性偏头痛(FHM4)和散发性偏瘫性偏头痛(SHM))的方法。在一些其他实施方案中,本文提供了预防或治疗皮层扩散性抑制(CDC)的方法。
在一个方面,本公开提供了在有需要的受试者中治疗或预防三叉神经自主神经性头痛(TAC)的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物,其中TAC选自阵发性偏头痛、持续性偏头痛、短暂单侧神经痛样头痛发作伴结膜充血和流泪(SUNCT)、短暂单侧神经痛样头痛发作伴颅自主神经症状(SUNA)以及长期自主神经症状伴偏头痛。
在另一个方面,本文提供了在有需要的受试者中治疗或预防偏头痛的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物,其中偏头痛选自无先兆偏头痛、有先兆偏头痛、1型家族性偏瘫性偏头痛(FHM1)、2型家族性偏瘫性偏头痛(FHM2)、4型家族性偏瘫性偏头痛(FHM4)和散发性偏瘫性偏头痛(SHM)。
在另一个方面,本公开提供了在有需要的受试者中治疗或预防皮层扩散性抑制(CSD)的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在另一个方面,本公开提供了在有需要的受试者中治疗或预防颅神经病变或多发性颅神经病变(MCN)的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
本领域技术人员考虑随后的具体实施方式、实施例和权利要求会明白其他目的和优点。
具体实施方式
如本文一般性地描述,本发明提供了可用于预防和/或治疗本文所述的疾病、障碍或病症(例如与钠离子通道异常功能如异常晚钠电流(INaL)相关的疾病、障碍或病症)的化合物和组合物。示例性疾病、障碍或病症包括神经障碍(例如,癫痫或癫痫综合征、神经发育障碍或神经肌肉障碍)、精神障碍、疼痛或胃肠障碍。
定义
化学定义
下文更详细地描述特定官能团和化学术语的定义。根据元素周期表、CAS版本、化学和物理手册第75版、内封面来鉴别化学元素,并且特定官能团通常是如本文所述来定义。另外,有机化学的一般原理以及特定功能部分和反应性描述于Thomas Sorrell,有机化学(Organic Chemistry),University Science Books,Sausalito,1999;Smith及March,马奇的高等有机化学(March’s Advanced Organic Chemistry),第5版,John Wiley&Sons,Inc.,New York,2001;Larock,综合有机转化(Comprehensive OrganicTransformations),VCH Publishers,Inc.,New York,1989;和Carruthers,一些现代有机合成方法(Some Modern Methods of Organic Synthesis),第3版,Cambridge UniversityPress,Cambridge,1987。
本文所述的化合物可包括一个或多个不对称中心,且由此可以各种立体异构形式,例如对映异构体和/或非对映异构体形式存在。举例来说,本文所述的化合物可呈个别对映异构体、非对映异构体或几何异构体形式,或可呈立体异构体的混合物(包括外消旋混合物和富含一种或多种立体异构体的混合物)形式。异构体可以通过所属领域的技术人员已知的方法从混合物中分离,包括手性高压液相色谱(HPLC)和手性盐的形成和结晶;或优选异构体可以通过不对称合成物制备。参见例如Jacques等人,对映异构体、外消旋物和拆分物(Enantiomers,Racemates and Resolutions)(Wiley Interscience,New York,1981);Wilen等人,四面体(Tetrahedron)33:2725(1977))Eliel,碳化合物的立体化学(Stereochemistry of Carbon Compounds)(McGraw-Hill,NY,1962);和Wilen,拆分剂和光学拆分表(Tables of Resolving Agents and Optical Resolutions)第268页(E.L.Eliel编,Univ.of Notre Dame Press,Notre Dame,IN 1972)。本发明另外涵盖本文所述的呈基本上不含其他异构体的个别异构体形式且可替代地呈各种异构体的混合物形式的化合物。
如本文所用,纯对映异构化合物基本上不含化合物的其他对映异构体或立体异构体(即呈对映异构过量)。换句话说,化合物的“S”形式基本上不含化合物的“R”形式,并且因此呈“R”形式的对映异构过量。术语“对映异构纯”或“纯对映异构体”表示,化合物包括大于75重量%、大于80重量%、大于85重量%、大于90重量%、大于91重量%、大于92重量%、大于93重量%、大于94重量%、大于95重量%、大于96重量%、大于97重量%、大于98重量%、大于98.5重量%、大于99重量%、大于99.2重量%、大于99.5重量%、大于99.6重量%、大于99.7重量%、大于99.8重量%或大于99.9重量%的对映异构体。在某些实施方案中,重量基于化合物的所有对映异构体或立体异构体的总重量。
在本文提供的组合物中,对映异构纯化合物可以与其他活性或非活性成分一起存在。例如,包括对映异构纯R-化合物的药物组合物可以包括例如约90%赋形剂和约10%对映异构纯R-化合物。在某些实施方案中,此类组合物中的对映异构纯R-化合物可以例如包括按化合物总重量计至少约95重量%的R化合物和至多约5重量%的S-化合物。例如,包括对映异构纯S-化合物的药物组合物可以包括例如约90%赋形剂和约10%对映体纯S-化合物。在某些实施方案中,此类组合物中的对映异构纯S-化合物可以例如包括按化合物总重量计至少约95%重量的S-化合物和至多约5%重量的R-化合物。在某些实施方案中,活性成分可在极少或无赋形剂或载剂的情况下调配。
本文所述的化合物还可包括一个或多个同位素取代。举例来说,H可呈任何同位素形式,包括1H、2H(D或氘)和3H(T或氚);C可呈任何同位素形式,包括12C、13C和14C;O可呈任何同位素形式,包括16O和18O;F可呈任何同位素形式,包括18F和19F;等等。
以下术语旨在具有下文中呈现的含义,并且可用于理解本发明的描述和预期范围。当描述本发明时,本发明可以包括化合物和药学上可接受的盐、含有此类化合物的药物组合物和使用此类化合物和组合物的方法,除非另外指明,否则以下术语如果存在则具有以下含义。还应理解,当在本文中描述时,下文所定义的任何部分都可以被各种取代基取代,并且相应定义旨在包括如下文所阐述的其范围内的此类被取代部分。除非另有说明,否则术语“经取代”将如下文所阐述定义。还应理解,当在本文中使用时,术语“基团(group)”和“自由基(radical)”可视为可互换的。本文可以使用冠词“一(a/an)”来指代所述冠词的一个或多于一个(即,至少一个)语法宾语。作为实例,“类似物”意指一个类似物或多于一个类似物。
当列出值的范围时,预期涵盖所述范围内的每一值和子范围。例如,“C1-6烷基”旨在涵盖C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
如本文所用,“烷基”是指具有1至20个碳原子的直链或支链饱和烃基基团(“C1-20烷基”)。在一些实施方案中,烷基具有1至10个碳原子(“C1-10烷基”)。在一些实施方案中,烷基具有1至9个碳原子(“C1-9烷基”)。在一些实施方案中,烷基具有1至8个碳原子(“C1-8烷基”)。在一些实施方案中,烷基具有1至7个碳原子(“C1-7烷基”)。在一些实施方案中,烷基具有1至6个碳原子(“C1-6烷基”)。在一些实施方案中,烷基具有1至5个碳原子(“C1-5烷基”)。在一些实施方案中,烷基具有1至4个碳原子(“C1-4烷基”)。在一些实施方案中,烷基具有1至3个碳原子(“C1-3烷基”)。在一些实施方案中,烷基具有1至2个碳原子(“C1-2烷基”)。在一些实施方案中,烷基具有1个碳原子(“C1烷基”)。C1-6烷基的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基等。
如本文中使用的,“亚烷基”是指烷基的二价基。当为特定“亚烷基”提供了碳范围或数目时,应理解,该范围或数目是指直链碳二价链中的碳范围或数目。“亚烷基”可被如本文所述的一个或多个取代基取代或未取代。
如本文中使用的,“碳环基”或“碳环”是指在非芳香环系中具有3至10个环碳原子(“C3–10碳环基”)和零个杂原子的非芳香环烃基基团。在一些实施方案中,碳环基基团具有3至8个环碳原子(“C3-8碳环基”)。在一些实施方案中,碳环基具有3至7个环碳原子(“C3-7碳环基”)。在一些实施方案中,碳环基具有3至6个环碳原子(“C3-6碳环基”)。在一些实施方案中,碳环基具有5至10个环碳原子(“C5-10碳环基”)。示例性C3-6碳环基包括但不限于环丙基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。示例性C3-8碳环基包括但不限于前述C3-6碳环基以及环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)、双环[2.2.1]庚烯基(C7)、双环[2.2.2]辛烯基(C8)等。示例性C3-10碳环基包括但不限于前述C3-8碳环基以及环壬基(C9)、环壬烯基(C9)、环癸基(C10)、环癸烯基(C10)、八氢-1H-茚基(C9)、十氢萘基(C10)、螺[4.5]癸基(C10)等。如前述实例所说明,在某些实施方案中,碳环基为单环(“单环碳环基”)或含有稠合、桥连或螺环系统,如双环系统(“双环碳环基”)且可为饱和或可部分不饱和的。“碳环基”还包括环系统,其中如上所定义的碳环基环与一个或多个芳基或杂芳基稠合,其中连接点在碳环基环上,且在此类个例中,碳的数目继续表示碳环系统中碳的数目。
术语“环烷基”是指本文所提及的具有3至12个、3至8个、4至8个或4至6个碳的单价饱和环状、双环或桥连环状(例如金刚烷基)烃基,例如为衍生自环烷烃的“C4-8环烷基”。示例性环烷基包括但不限于环己烷、环戊烷、环丁烷和环丙烷。
如本文中使用的,“C3-6单环环烷基”或“单环C3-6环烷基”是指饱和的3至7元单环烃环系。3至7元单环环烷基包括但不限于环丙基、环丁基、环戊基和环己基。在被指定为任选取代或取代的情况下,环烷基上的取代基(例如,就任选取代的环烷基而言)可存在于任何可取代位置上并且包括例如连接环烷基的位置。
这些和其他示例性取代基更详细地描述在详细描述、实施例和权利要求中。本发明不旨在以任何方式受上述取代基的示例性列表的限制。
其他定义
如本文中使用的,“药学上可接受的载剂”是指不破坏与其一起调配的化合物的药理活性的无毒载剂、佐剂或媒剂。可在本文所述的组合物中使用的药学上可接受的载剂、佐剂或媒剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
如本文中使用的,“药学上可接受的盐”是指在合理的医疗判断范围内适用于与人类和低等动物的组织接触而没有不当毒性、刺激性、变态反应等并且与合理的效益/风险比相称的那些盐。药学上可接受的盐是本领域众所周知的。例如,Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述了药学上可接受的盐。本发明的化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和碱的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸和过氯酸)或有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸)形成的盐,或通过使用所属领域中所用的其他方法(如离子交换)形成的盐。其他药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、丁二酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。衍生自适当碱的药学上可接受的盐包括碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4盐。代表性的碱金属盐或碱土金属盐包括钠、锂、钾、钙、镁等。适当时,其他药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。
如本文所用,考虑施用的“受试者”包括但不限于人类(即,任何年龄组的男性或女性,例如儿童受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻人、中年任或老年人))和/或非人类动物,例如哺乳动物,如灵长类动物(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在某些实施方案中,受试者是人类。在某些实施方案中,所述受试者是非人动物。术语“人类”、“患者”和“受试者”在本文中可互换使用。
疾病、病症和病状在本文中可互换使用。
如本文中使用的,且除非另外指出,否则术语“治疗”和“处理”涵盖在受试者正在遭受特定疾病、障碍或病症时发生的动作,其降低疾病、障碍或病症的严重程度,或延缓或减慢疾病、障碍或病症的进展(“治疗性处理”),并且还涵盖在受试者开始遭受特定疾病、障碍或病症之前发生的动作(“预防性处理”)。
如本文中使用的,“有效量”的化合物是指足以诱发期望的生物反应的量。本领域普通技术人员会理解,本发明的化合物的有效量可以随诸如以下因素变化:期望的生物学终点、化合物的药代动力学、所治疗的疾病、施用模式以及受试者的年龄、健康和状况。有效量包括治疗性和预防性处理。
如本文中使用的,且除非另外指出,否则化合物的“治疗有效量”是这样的量:其足以在疾病、障碍或病症的治疗中提供治疗益处,或延迟或最小化与疾病、障碍或病症相关的一种或多种症状。化合物的治疗有效量是指单独的或与其他疗法组合的治疗剂的量,其在疾病、障碍或病症的治疗中提供治疗益处。术语“治疗有效量”可以包括这样的量:其改善总体治疗,减少或避免疾病或病症的症状或起因,或增强另一种治疗剂的治疗效果。
化合物
在一个方面,本文提供了具有式I的化合物:
或其药学上可接受的盐,其中Ra为C2-4烷基或单环C3-6环烷基;并且Rb为C1-4烷基。
在一些实施方案中,Ra为乙基、异丙基、正丙基、正丁基、异丁基、环丙基、环丁基、环戊基或环己基。在一些实施方案中,Ra为乙基、异丙基或环丙基。在一些实施方案中,Ra为乙基。在一些实施方案中,Ra为异丙基或环丙基。在一些实施方案中,Ra为异丙基。在一些实施方案中,Ra为环丙基。在一些实施方案中,Rb为甲基、乙基、异丙基、正丙基、正丁基或异丁基。在一些实施方案中,Rb为甲基或乙基。在一些实施方案中,Rb为甲基。在一些实施方案中,Rb为乙基。
在一些实施方案中,式I的化合物选自:
在另一个方面,本文提供了具有式II的化合物:
或其药学上可接受的盐,其中Ra为C1-4烷基;Rb为C1-4烷基;并且Rc为氢或C1-4烷基。
在一些实施方案中,Ra为甲基、乙基、正丙基、异丙基、正丁基或异丁基。在一些实施方案中,Ra为甲基或乙基。在一些实施方案中,Ra为甲基。在一些实施方案中,Ra为乙基。在一些实施方案中,Rb为甲基、乙基、正丙基、异丙基、正丁基或异丁基。在一些实施方案中,Rb为甲基、乙基或异丙基。在一些实施方案中,Rb为甲基。在一些实施方案中,Rb为乙基。在一些实施方案中,Rb为异丙基。在一些实施方案中,Rc为氢、甲基、乙基、异丙基、正丙基、异丁基或正丁基。在一些实施方案中,Rc为氢或甲基。在一些实施方案中,Rc为氢。在一些实施方案中,Rc为甲基。
在一些实施方案中,式II的化合物选自:
在另一个方面,本文提供了选自以下的化合物:
药物组合物和施用途径
根据本发明的化合物通常以药物组合物的形式施用。因此,本发明提供含有以下作为活性成分的药物组合物:所描述的一种或多种化合物或其药学上可接受的盐或酯以及一种或多种药学上可接受的赋形剂、载剂(包括惰性固体稀释剂和填充剂)、稀释剂(包括无菌水溶液和各种有机溶剂)、穿透增强剂、增溶剂以及佐剂。药物组合物可以单独或与其他治疗剂组合施用。此类组合物以医药领域中熟知的方式制备(参见例如雷明顿药物科学(Remington’s Pharmaceutical Sciences),Mace Publishing Co.,Philadelphia,Pa.第17版(1985);以及现代药剂学(Modern Pharmaceutics),Marcel Dekker,Inc.第3版(G.S.Banker和T.Rhodes编)。
药物组合物可以通过具有类似效用的任一种可接受的药剂施用模式单剂量或多剂量投与,所述药剂施用模式例如,如以引用的方式并入的那些专利和专利申请中所述,包括经直肠、经颊、鼻内以及经皮途径,通过动脉内注射、静脉内、腹膜内、肠胃外、肌内、皮下、经口、局部投与,作为吸入剂,或例如经由如支架的浸渍或涂布装置,或动脉插入圆柱形聚合物投与。
一种施用模式是肠胃外的,特别是通过注射施用。本发明的新颖组合物可以并入用于注射施用的形式包括水或油悬浮液或乳液,其具有芝麻油、玉米油、棉籽油或花生油,以及酏剂、甘露醇、右旋糖或无菌水溶液,以及类似医药媒剂。盐水溶液也通常用于注射,但在本发明的上下文中不优选使用。还可采用乙醇、丙三醇、丙二醇、液体聚乙二醇等(和其适合的混合物)、环糊精衍生物和植物油。可以例如通过使用涂层(如卵磷脂)、在分散液情况下通过维持所需粒径和通过使用表面活性剂来维持适当流动性。微生物作用的预防可以通过各种抗细菌剂和抗真菌剂(例如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来实现。
无菌可注射溶液是通过如下制备:将所需量的根据本发明的化合物视需要与上文列举的多种其他成分一起并入适当溶剂中,随后过滤灭菌。一般来说,通过将各种灭菌活性成分并入含有碱性分散介质和来自上文所列举的那些成分的所需其他成分的无菌媒剂中来制备分散液。在无菌粉末用于制备无菌可注射溶液的情况下,优选制备方法是真空干燥和冷冻干燥技术,其从先前的无菌过滤溶液得到活性成分加上任何其他所需成分的粉末。
经口施用是根据本发明的化合物的另一种施用途径。可以经由胶囊或肠溶衣片剂或类似物施用。在制造包括至少一种本文所述的化合物的药物组合物的过程中,通常通过赋形剂来稀释活性成分和/或将其包封在可以呈胶囊、药囊、纸或其他容器形式的所述载剂内。当赋形剂用作稀释剂时,其可以呈固体、半固体或液体材料(如上所述)形式,其充当活性成分的媒剂、载剂或介质。因此,组合物可以呈以下形式:片剂、丸剂、散剂、口含剂、药囊、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或于液体介质中)、含有例如高达10重量%的活性化合物的软膏、软及硬明胶胶囊、无菌可注射溶液以及无菌包装散剂。
适合的赋形剂的一些实例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、磷酸钙、海藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆以及甲基纤维素。调配物可另外包括:润滑剂,如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和悬浮剂;防腐剂,如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂;和调味剂。
本发明组合物可以经调配,以便在通过采用所属领域中已知的程序向患者施用之后,提供活性成分的快速、持续或延迟释放。用于口服施用的控释药物递送系统包括渗透泵系统和溶出系统,其含有聚合物包衣的储层或药物-聚合物基质调配物。控释系统的实例在美国专利第3,845,770号;第4,326,525号;第4,902,514号;和第5,616,345号中给出。供用于本发明方法中的另一种调配物采用经皮递送装置(“贴片”)。此类透皮贴片可用于以受控量提供本发明的化合物的连续或不连续输注。用于递送医药剂的经皮贴片的建构和使用是所属领域中所熟知的。参见例如美国专利第5,023,252号、第4,992,445号和第5,001,139号。可以建构此类贴片以连续、脉冲式或按需求递送医药剂。
所述组合物优选以单位剂型调配。术语“单位剂型”是指适用作人类受试者和其他哺乳动物的单位剂量的物理离散单元,各单位含有经计算产生所需治疗效果的预定量的活性材料,其与适合的医药赋形剂(例如片剂、胶囊、安瓿)结合。化合物一般以药学有效量投与。优选地,对于经口施用,每个剂量单位含有1mg至2g本文所述的化合物,并且对于肠胃外施用,优选0.1至700mg的本文所述的化合物。然而,应理解,化合物的实际施用量通常将由医生鉴于相关情形而决定,所述情形包括待治疗的病状;所选择的施用途径;实际施用化合物和其相对活性;个体患者的年龄、重量以及反应;患者症状严重程度等。
为了制备固体组合物(如片剂),将主要活性成分与医药赋形剂混合以形成含有本发明化合物的均匀混合物的固体预调配组合物。当提及这些预调配组合物是均匀的时,意味着活性成分通常均匀分散在整个组合物中,以便组合物可以容易地再分成同等有效的单位剂型,如片剂、丸剂以及胶囊。
本发明的片剂或丸剂可以经涂布或以其他方式混配以提供剂型,其具有作用时间长或保护免受胃的酸性条件的作用的优势。例如,片剂或丸剂可以包括内剂量组分和外剂量组分,后者在前者之上采用包膜的形式。两种组分可以通过肠溶层分开,所述肠溶层用于抵抗胃中的崩解并且允许内部组分完整地传递进入十二指肠或被延迟释放。多种材料可以用于此类肠溶层或包衣,此类材料包括许多聚合酸以及聚合酸与如虫胶、十六醇和乙酸纤维素等材料的混合物。
用于吸入或吹入的组合物包括药学上可接受的水性或有机溶剂或其混合物中的溶液和悬浮液,以及散剂。液体或固体组合物可以含有如上所述的合适的药学上可接受的赋形剂。优选地,所述组合物通过经口或鼻呼吸道途径施用,用于局部或全身效应。优选药学上可接受的溶剂中的组合物可以通过使用惰性气体来雾化。雾化溶液可以直接从雾化装置吸入或所述雾化装置可以连接到面罩托上或间歇性正压呼吸机上。可以优选地以适当的方式经口或经鼻从递送调配物的装置施用溶液、悬浮液或散剂组合物。
在一些实施方案中,药物组合物包含所公开的化合物或其药学上可接受的盐和药学上可接受的载剂。
治疗方法
本文所述的化合物和组合物一般可用于调节钠通道的活性并且可用于治疗与钠通道离子通道异常功能例如异常晚钠(INaL)电流相关的病症。在一些实施方案中,本发明所提供的化合物能有效治疗癫痫或癫痫综合征、神经发育障碍、疼痛或神经肌肉障碍。在一些实施方案中,本发明所提供的化合物能有效治疗神经病变(如颅神经病变)和疼痛(如偏头痛、三叉神经自主神经性头痛和皮层扩散性抑制)。所提供的化合物、其药学上可接受的盐或组合物还可调节所有钠离子通道,或可特定于仅一种或多种钠离子通道,例如NaV1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8和/或1.9。
在典型实施方案中,本发明旨在涵盖本文所公开的化合物以及此类化合物的药学上可接受的盐、药学上可接受的酯、互变异构形式、多晶型物和前药。在一些实施方案中,本发明包括本文所述的化合物(例如,式I或II的化合物)的药学上可接受的加成盐、药学上可接受的酯、加成盐的溶剂化物(例如,水合物)、互变异构形式、多晶型物、对映异构体、对映异构体的混合物、立体异构体或立体异构体的混合物(纯的或作为外消旋或非外消旋混合物)。
癫痫和癫痫综合征
本文所述的化合物可用于治疗癫痫和癫痫综合征。癫痫是脑中的神经细胞活动被破坏而引起癫痫发作或持续一段时间的异常行为、感觉及有时意识丧失的CNS障碍。癫痫发作症状差异很大,从简单的空白凝视几秒钟到在癫痫发作期间其手臂或腿的反复抽搐。
癫痫可能涉及全身性癫痫发作或部分或局灶性癫痫发作。全身性癫痫发作涉及脑的所有区域。经历全身性癫痫发作的人可能大声呼喊或发出一些声音,僵直几秒至一分钟,然后进行四肢的节律性运动。眼睛大致睁开,该人可能看起来不能呼吸并且实际上可能发青。意识的恢复是渐进的,并且这个人可能感到困惑几分钟到几小时。全身性癫痫发作有如下六种主要类型:强直阵挛、强直、阵挛、肌阵挛、失神和失张力发作。在部分或局灶性癫痫发作中,仅涉及脑的一部分,因此仅影响身体的一部分。根据具有异常电活动的脑部分,症状可能会有所不同。
如本文所述,癫痫包括全身性、部分性、复杂部分性、强直阵挛、阵挛、强直、难治性癫痫发作、癫痫持续状态、失神发作、热性惊厥或颞叶癫痫。
本文所述的化合物(例如,式I或II的化合物)还可用于治疗癫痫综合征。至少部分地由癫痫的某些方面引起的伴有弥散性脑功能障碍的严重综合征也称为癫痫性脑病。这些与对治疗有抗性的频繁癫痫发作和严重认知功能障碍(例如韦斯特综合征)有关。
在一些实施方案中,癫痫综合征包括癫痫性脑病,如德拉韦综合征、安格曼综合征、CDKL5障碍、额叶癫痫、婴儿痉挛、韦斯特综合征、青少年肌阵挛性癫痫、兰道-克莱夫纳综合征、林-戈综合征、大田原综合征、PCDH19癫痫或Glut1缺乏症。
在某些实施方案中,所述癫痫或癫痫综合征是遗传性癫痫或遗传性癫痫综合征。在一些实施方案中,癫痫或癫痫综合征包括癫痫性脑病、带SCN1A、SCN2A、SCN8A突变的癫痫性脑病、婴儿早期癫痫性脑病、德拉韦综合征、带SCN1A突变的德拉韦综合征、全身性癫痫伴热性惊厥、儿童难治性癫痫伴全身性强直阵挛发作、婴儿痉挛、良性家族性新生儿-婴儿癫痫发作、SCN2A癫痫性脑病、带SCN3A突变的局灶性癫痫、带SCN3A突变的儿童隐源性部分性癫痫、SCN8A癫痫性脑病、癫痫不明原因猝死、拉斯姆森脑炎、婴儿恶性游走性部分性发作、常染色体显性遗传夜间额叶癫痫、癫痫预期猝死(SUDEP)、KCNQ2癫痫性脑病或KCNT1癫痫性脑病。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物(例如,式I或II的化合物)之前鉴别患有癫痫或癫痫综合征(例如,癫痫性脑病、带SCN1A、SCN2A、SCN8A突变的癫痫性脑病、婴儿早期癫痫性脑病、德拉韦综合征、带SCN1A突变的德拉韦综合征、全身性癫痫伴热性惊厥、儿童难治性癫痫伴全身性强直阵挛发作、婴儿痉挛、良性家族性新生儿-婴儿癫痫发作、SCN2A癫痫性脑病、带SCN3A突变的局灶性癫痫、带SCN3A突变的儿童隐源性部分性癫痫、SCN8A癫痫性脑病、癫痫不明原因猝死、拉斯姆森脑炎、婴儿恶性游走性部分性发作、常染色体显性遗传夜间额叶癫痫、癫痫不明原因猝死(SUDEP)、KCNQ2癫痫性脑病或KCNT1癫痫性脑病)的受试者。
在一个方面,本发明的特征在于治疗癫痫或癫痫综合征(例如,癫痫性脑病、带SCN1A、SCN2A、SCN8A突变的癫痫性脑病、婴儿早期癫痫性脑病、德拉韦综合征、带SCN1A突变的德拉韦综合征、全身性癫痫伴热性惊厥、儿童难治性癫痫伴全身性强直阵挛发作、婴儿痉挛、良性家族性新生儿-婴儿癫痫发作、SCN2A癫痫性脑病、带SCN3A突变的局灶性癫痫、带SCN3A突变的儿童隐源性部分性癫痫、SCN8A癫痫性脑病、癫痫不明原因猝死、拉斯姆森脑炎、婴儿恶性游走性部分性发作、常染色体显性遗传夜间额叶癫痫、癫痫预期猝死(SUDEP)、KCNQ2癫痫性脑病或KCNT1癫痫性脑病)的方法,该方法包括向有需要的受试者施用式(I)的化合物或式(II)的化合物。
本发明的化合物(例如,式I或II的化合物)还可用于治疗癫痫性脑病,其中受试者在如下一者或多者中具有突变:ALDH7A1、ALG13、ARHGEF9、ARX、ASAH1、CDKL5、CHD2、CHRNA2、CHRNA4、CHRNB2、CLN8、CNTNAP2、CPA6、CSTB、DEPDC5、DNM1、EEF1A2、EPM2A、EPM2B、GABRA1、GABRB3、GABRG2、GNAO1、GOSR2、GRIN1、GRIN2A、GRIN2B、HCN1、IER3IP1、KCNA2、KCNB1、KCNC1、KCNMA1、KCNQ2、KCNQ3、KCNT1、KCTD7、LGI1、MEF2C、NHLRC1、PCDH19、PLCB1、PNKP、PNPO、PRICKLE1、PRICKLE2、PRRT2、RELN、SCARB2、SCN1A、SCN1B、SCN2A、SCN8A、SCN9A、SIAT9、SIK1、SLC13A5、SLC25A22、SLC2A1、SLC35A2、SLC6A1、SNIP1、SPTAN1、SRPX2、ST3GAL3、STRADA、STX1B、STXBP1、SYN1、SYNGAP1、SZT2、TBC1D24和WWOX。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物(例如,式I或II的化合物)之前鉴别在如下一者或多者中具有突变的受试者:ALDH7A1、ALG13、ARHGEF9、ARX、ASAH1、CDKL5、CHD2、CHRNA2、CHRNA4、CHRNB2、CLN8、CNTNAP2、CPA6、CSTB、DEPDC5、DNM1、EEF1A2、EPM2A、EPM2B、GABRA1、GABRB3、GABRG2、GNAO1、GOSR2、GRIN1、GRIN2A、GRIN2B、HCN1、IER3IP1、KCNA2、KCNB1、KCNC1、KCNMA1、KCNQ2、KCNQ3、KCNT1、KCTD7、LGI1、MEF2C、NHLRC1、PCDH19、PLCB1、PNKP、PNPO、PRICKLE1、PRICKLE2、PRRT2、RELN、SCARB2、SCN1A、SCN1B、SCN2A、SCN8A、SCN9A、SIAT9、SIK1、SLC13A5、SLC25A22、SLC2A1、SLC35A2、SLC6A1、SNIP1、SPTAN1、SRPX2、ST3GAL3、STRADA、STX1B、STXBP1、SYN1、SYNGAP1、SZT2、TBC1D24和WWOX。
神经发育障碍
本文所述的化合物可用于治疗神经发育障碍。在一些实施方案中,神经发育障碍包括孤独症、孤独症伴癫痫、结节性硬化症、脆性X染色体综合征、雷特综合征、安格曼综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利综合征、腭心面综合征、史密斯-莱姆利-奥普兹综合征或神经发育障碍伴癫痫。在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物(例如,式I或II的化合物)之前鉴别患有神经发育障碍(例如,孤独症、孤独症伴癫痫、结节性硬化症、脆性X染色体综合征、雷特综合征、安格曼综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利综合征、腭心面综合征、史密斯-莱姆利-奥普兹综合征或神经发育障碍伴癫痫)的受试者。
在一个方面,本发明的特征在于治疗神经发育障碍(例如,孤独症、孤独症伴癫痫、结节性硬化症、脆性X染色体综合征、雷特综合征、安格曼综合征、Dup15q综合征、22q13.3缺失综合征、普拉德-威利综合征、腭心面综合征、史密斯-莱姆利-奥普兹综合征或神经发育障碍伴癫痫)的方法,该方法包括向有需要的受试者施用式(I)的化合物或式(II)的化合物。
疼痛
本文所述的化合物可用于治疗疼痛。在一些实施方案中,疼痛包括神经病理性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、3型家族性偏瘫性偏头痛、丛集性头痛、三叉神经痛或相关头痛障碍。在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物(例如,式I或II的化合物)之前鉴别患有疼痛(例如,神经病理性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、3型家族性偏瘫性偏头痛、丛集性头痛、三叉神经痛或相关头痛障碍)的受试者。
在一个方面,本发明的特征在于治疗疼痛(例如,神经病理性疼痛、三叉神经痛、偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛、3型家族性偏瘫性偏头痛、丛集性头痛、三叉神经痛或相关头痛障碍)的方法,该方法包括向有需要的受试者施用式(I)的化合物或式(II)的化合物。
神经肌肉障碍
本文所述的化合物可用于治疗神经肌肉障碍。在一些实施方案中,神经肌肉障碍包括肌萎缩侧索硬化症、多发性硬化、肌强直、先天性副肌强直、钾加重性肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或带SCN4A突变的喉痉挛。在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物(例如,式I或II的化合物)之前鉴别患有神经肌肉障碍(例如,肌萎缩侧索硬化症、多发性硬化、肌强直、先天性副肌强直、钾加重性肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或带SCN4A突变的喉痉挛)的受试者。
在一个方面,本发明的特征在于治疗神经肌肉障碍(例如,肌萎缩侧索硬化症、多发性硬化、肌强直、先天性副肌强直、钾加重性肌强直、周期性麻痹、高钾性周期性麻痹、低钾性周期性麻痹或带SCN4A突变的喉痉挛)的方法,该方法包括向有需要的受试者施用式(I)的化合物或式(II)的化合物。
三叉神经自主神经性头痛
本文所述的化合物可用于治疗三叉神经自主神经性头痛(TAC)。TAC是以疼痛单侧性、相对较短症状持续时间和相关同侧颅自主体征为特征的一组原发性头痛。TAC可包括丛集性头痛(CH)、阵发性偏头痛(PH)、持续性偏头痛(HC)、短暂单侧神经痛样头痛发作伴结膜充血和流泪(SUNCT)、短暂单侧神经痛样头痛发作伴颅自主神经症状(SUNA)以及长期自主神经症状伴偏头痛(LASH)。这些三叉神经自主神经性头痛尽管拥有共同要素,但例如在发作持续时间和频率及对治疗的反应方面有所不同。
在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗PH、HC、SUNCT、SUNA和/或LASH的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗SUNCT的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗SUNA的方法。
在一些实施方案中,本发明提供了治疗TAC(例如,PH、HC、SUNCT、SUNA或LASH)的方法,该方法包括向有需要的受试者施用治疗有效量的本文所述的化合物(例如,式(I)的化合物或式(II)的化合物)或其药学上可接受的盐或本文所述的药物组合物。
在一个方面,本文提供了在有需要的受试者中治疗或预防三叉神经自主神经性头痛(TAC)的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物,其中TAC选自阵发性偏头痛、持续性偏头痛、短暂单侧神经痛样头痛发作伴结膜充血和流泪(SUNCT)、短暂单侧神经痛样头痛发作伴颅自主神经症状(SUNA)以及长期自主神经症状伴偏头痛。
在一些实施方案中,受试者可能对用于治疗TAC(例如,PH、HC、SUNCT、SUNA或LASH)的至少一种药物(例如,利多卡因、曲普坦类、拉莫三嗪、托吡酯或加巴喷丁或它们的任何组合)的反应不充分。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物之前鉴别患有TAC(例如,PH、CH、SUNCT、SUNA或LASH)的受试者。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于在受试者中治疗TAC(例如,PH、HC、SUNCT、SUNA或LASH)的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于制造适用于在受试者中治疗TAC(例如,PH、HC、SUNCT、SUNA或LASH)的药剂的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
偏头痛
本文所述的化合物可用于治疗偏头痛。偏头痛是以中度至重度的反复头痛为特征的原发性头痛障碍。如本文所述,偏头痛可以是无先兆偏头痛、有先兆偏头痛、偏瘫性偏头痛、家族性偏瘫性偏头痛(FHM)、1型家族性偏瘫性偏头痛(FHM1)、2型家族性偏瘫性偏头痛(FHM2)、3型家族性偏瘫性偏头痛(FHM3)、4型家族性偏瘫性偏头痛(FHM4)和散发性偏瘫性偏头痛(SHM)。
在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗无先兆偏头痛、有先兆偏头痛、偏瘫性偏头痛、FHM、FHM1、FHM2、FHM3、FHM4和/或SHM的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4和/或SHM的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗无先兆偏头痛的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗有先兆偏头痛的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗FHM1、FHM2和/或FHM4的方法。在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗SHM的方法。
在一些实施方案中,本发明提供了治疗偏头痛(例如,无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4或SHM)的方法,该方法包括向有需要的受试者施用治疗有效量的本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物。
在另一个方面,本公开提供了在有需要的受试者中治疗或预防偏头痛的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物,其中偏头痛选自无先兆偏头痛、有先兆偏头痛、1型家族性偏瘫性偏头痛(FHM1)、2型家族性偏瘫性偏头痛(FHM2)、4型家族性偏瘫性偏头痛(FHM4)和散发性偏瘫性偏头痛(SHM)。
在一些实施方案中,受试者对用于治疗偏头痛(例如,无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4或SHM)的至少一种药物的反应不充分。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物之前鉴别患有偏头痛(例如,无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4或SHM)的受试者。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于在受试者中治疗偏头痛(例如,无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4或SHM)的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于制造适用于在受试者中治疗偏头痛(例如,无先兆偏头痛、有先兆偏头痛、FHM1、FHM2、FHM4或SHM)的药剂的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
皮层扩散性抑制
本文所述的化合物可用于治疗皮层扩散性抑制(CSD)。CSD是穿过完整脑组织并参与例如脑缺血、有先兆偏头痛和癫痫发作的一阵持续去极化(神经元失活)。
在一些实施方案中,本发明提供了使用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物治疗CSD的方法。在一些实施方案中,本发明提供了治疗CSD的方法,该方法包括向有需要的受试者施用治疗有效量的本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物。
在另一个方面,本文提供了在有需要的受试者中治疗或预防皮层扩散性抑制(CSD)的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,受试者可能对用于治疗CSD的至少一种药物的反应不充分。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物之前鉴别患有CSD的受试者。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于在受试者中治疗CSD的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于制造适用于在受试者中治疗CSD的药剂的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
颅神经病变
本文所述的化合物可用于治疗颅神经病变。神经病变是神经损伤障碍并且影响感觉和行动的能力。当脑或脑干中的神经受到影响时,这即称为颅神经病变。颅神经是直接起于脑或脑干并且通常影响如面部和眼睛之类的区域的那些神经。颅神经病变包括贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹和第六神经麻痹。当若干不同颅神经受影响时,这即称为多发性颅神经病变(MCN)。
在一些实施方案中,本发明提供了治疗颅神经病变(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹或第六神经麻痹)或MCN的方法,该方法包括向有需要的受试者施用治疗有效量的本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物。
本文还提供了在有需要的受试者中治疗或预防颅神经病变的方法,该方法包括向受试者施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物,其中颅神经病变选自贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹和第六神经麻痹。
在一些实施方案中,受试者可能对用于治疗颅神经病变(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹或第六神经麻痹)或MCN的至少一种药物的反应不充分。
在一些实施方案中,本文所述的方法还包括在施用本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物之前鉴别患有颅神经病变(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹或第六神经麻痹)或MCN的受试者。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于在受试者中治疗(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹或第六神经麻痹)或MCN的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
在一些实施方案中,本发明提供了本文所述的化合物(例如,式I或式II的化合物)或其药学上可接受的盐或本文所述的药物组合物用于制造适用于在受试者中治疗(例如,贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹或第六神经麻痹)或MCN的药剂的用途,其中该治疗包括施用治疗有效量的本文所述的化合物或其药学上可接受的盐或本文所述的药物组合物。
其他障碍
在一些实施方案中,本发明的化合物(例如,式I或II的化合物)可具有适当的药代动力学特性,使得它们对于中枢和/或周围神经系统可能有活性。在一些实施方案中,本文提供的化合物用于治疗心血管疾病如房性和室性心律失常(包括心房纤颤)、普氏(变异型)心绞痛、稳定型心绞痛、不稳定型心绞痛、心脏、肾、肝和脑缺血和再灌注损伤、运动诱发心绞痛、肺高压、充血性心脏病(包括舒张性与收缩性心力衰竭)、复发缺血、脑缺血、卒中、肾缺血、与器官移植相关的缺血、急性冠脉综合征、外周动脉疾病、间歇性跛行以及心肌梗死。在一些实施方案中,本文提供的化合物可用于治疗影响神经肌肉系统而导致瘙痒、癫痫发作或麻痹的疾病,或可用于治疗糖尿病或胰岛素敏感性降低以及与糖尿病相关的疾病状态,如糖尿病性周围神经病变。在一些实施方案中,所公开的方法包括施用药物组合物。
在一些实施方案中,本文提供了治疗神经障碍或精神障碍的方法,其中该方法包括向有需要的受试者施用本文所公开的化合物或其药学上可接受的盐或本文所公开的药物组合物。
联合疗法
本文所述的化合物或组合物(例如,用于调节钠离子通道,例如晚钠(INaL)电流)可与另一种药剂或疗法联合施用。要施用本文公开的化合物的受试者可能患有将受益于用另一种药剂或疗法治疗的疾病、障碍或病症或其症状。这些疾病或病症可涉及癫痫或癫痫综合征、神经发育障碍、疼痛或神经肌肉障碍。
抗癫痫剂
抗癫痫剂包括布瓦西坦、卡马西平、氯巴占、氯硝西泮、地西泮、双丙戊酸、艾司利卡西平、乙琥胺、依佐加滨、非尔氨酯、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、劳拉西泮、奥卡西平、吡仑帕奈、苯巴比妥、苯妥英、普瑞巴林、扑米酮、卢非酰胺、噻加宾、托吡酯、丙戊酸、氨己烯酸、唑尼沙胺和大麻二酚。
心血管药剂联合疗法
可受益于本发明的钠通道阻滞剂与其他治疗剂的联合治疗的心血管相关疾病或病症包括但不限于心绞痛(包括稳定型心绞痛、不稳定型心绞痛(UA)、运动诱发心绞痛、变异型心绞痛)、心律失常、间歇性跛行、心肌梗死(包括非ST段抬高型心肌梗死(NSTEMI))、肺高压(包括肺动脉高压)、心力衰竭(包括充血性(或慢性)心力衰竭和舒张性心力衰竭及射血分数保留型心力衰竭(舒张功能障碍)、急性心力衰竭)或复发缺血。
适用于治疗心血管相关疾病或病症的治疗剂包括抗心绞痛药、心力衰竭药剂、抗血栓形成剂、抗心律失常剂、抗高血压剂和降脂剂。
本发明的钠通道阻滞剂与适用于治疗心血管相关病症的治疗剂的联合施用允许增强患者当前接受的标准护理疗法。
抗心绞痛药
抗心绞痛药包括β阻滞剂、钙通道阻滞剂和硝酸酯类。β阻滞剂通过减轻心脏的工作负荷使心率降低且心脏收缩不那么有力来减少心脏对氧的需求。β阻滞剂的实例包括醋丁洛尔(Sectral)、阿替洛尔(Tenormin)、倍他洛尔(Kerlone)、比索洛尔/氢氯噻嗪(Ziac)、比索洛尔(Zebeta)、卡替洛尔(Cartrol)、艾司洛尔(Brevibloc)、拉贝洛尔(Normodyne、Trandate)、美托洛尔(Lopressor、Toprol XL)、纳多洛尔(Corgard)、普萘洛尔(Inderal)、索他洛尔(Betapace)和噻吗洛尔(Blocadren)。
硝酸酯类扩张动脉和静脉,从而增加冠脉血流并降低血压。硝酸酯类的实例包括硝酸甘油、硝酸酯贴片、二硝酸异山梨酯和5-单硝酸异山梨酯。
钙通道阻滞剂防止正常钙流进入心脏和血管的细胞,造成血管舒张,从而增加对心脏的血液和氧气供应。钙通道阻滞剂的实例包括氨氯地平(Norvasc、Lotrel)、苄普地尔(Vascor)、地尔硫卓(Cardizem、Tiazac)、非洛地平(Plendil)、硝苯地平(Adalat、Procardia)、尼莫地平(Nimotop)、尼索地平(Sular)、维拉帕米(Calan、Isoptin、Verelan)和尼卡地平。
心力衰竭药剂
用于治疗心力衰竭的药剂包括利尿剂、ACE抑制剂、血管扩张剂和强心苷。利尿剂排出组织和循环中的多余流体,从而减轻心力衰竭的许多症状。利尿剂的实例包括氢氯噻嗪、美托拉宗(Zaroxolyn)、呋塞米(Lasix)、布美他尼(Bumex)、螺内酯(Aldactone)和依普利酮(lnspra)。
血管紧张素转化酶(ACE)抑制剂通过扩张血管并减小血流阻力来减轻心脏的工作负荷。ACE抑制剂的实例包括贝那普利(Lotensin)、卡托普利(Capoten)、依那普利(Vasotec)、福辛普利(Monopril)、赖诺普利(Prinivil、Zestril)、莫西普利(Univasc)、培哚普利(Aceon)、喹那普利(Accupril)、雷米普利(Altace)和群多普利(Mavik)。
血管扩张剂通过使血管舒张和扩张来降低对血管的压力。血管扩张剂的实例包括肼屈嗪、二氮嗪、哌唑嗪、可乐定和甲基多巴。ACE抑制剂、硝酸酯类、钾通道激活剂和钙通道阻滞剂也充当血管扩张剂。
强心苷是增大心脏收缩力的化合物。这些化合物增强心脏的泵血能力并且改善不规律的心跳活动。强心苷的实例包括洋地黄、地高辛和洋地黄毒苷。
抗血栓形成剂
抗血栓形成剂抑制血液的凝血能力。抗血栓形成剂有三种主要类型--血小板抑制剂、抗凝血剂和溶栓剂。
血小板抑制剂抑制血小板的凝血活性,从而减少动脉的凝血。血小板抑制剂的实例包括乙酰水杨酸(阿司匹林)、噻氯匹定、氯吡格雷(plavix)、双嘧达莫、西洛他唑、潘生丁、磺吡酮、双嘧达莫、吲哚美辛以及糖蛋白IIb/IIIa抑制剂,如阿昔单抗、替罗非班和依替巴肽(Integrelin)。β阻滞剂和钙通道阻滞剂也具有血小板抑制效应。
抗凝血剂防止血凝块长得更大并防止形成新凝块。抗凝血剂的实例包括比伐卢定(Angiomax)、华法林(Coumadin)、未分级肝素、低分子量肝素、达那肝素、来匹卢定和阿加曲班。
溶栓剂起到分解既有血凝块的作用。溶栓剂的实例包括链激酶、尿激酶和替奈普酶(TNK)及组织型纤溶酶原激活剂(t-PA)。
抗心律失常剂
抗心律失常剂用于治疗心率和心律紊乱。抗心律失常剂的实例包括胺碘酮、决奈达隆、奎尼丁、普鲁卡因胺、利多卡因和普罗帕酮。强心苷和β阻滞剂也用作抗心律失常剂。
考虑到最近发现了钠通道阻滞剂雷诺嗪与胺碘酮和决奈达隆的协同效应,与胺碘酮和决奈达隆联用受到格外关注。
抗高血压剂
抗高血压剂用于治疗高血压,即血压始终高于正常值的病症。高血压与心血管疾病的许多方面相关,包括充血性心力衰竭、动脉粥样硬化和推定的凝块(clot forillation)。抗高血压剂的实例包括α-1-肾上腺素拮抗剂,如哌唑嗪(Minipress)、甲磺酸多沙唑嗪(Cardura)、盐酸哌唑嗪(Minipress)、哌唑嗪、泊利噻嗪(Minizide)和盐酸特拉唑嗪(Hytrin);β-肾上腺素能拮抗剂,如普萘洛尔(Inderal)、纳多洛尔(Corgard)、噻吗洛尔(Blocadren)、美托洛尔(Lopressor)和吲哚洛尔(Visken);中枢α-肾上腺素受体激动剂,如盐酸可乐定(Catapres)、盐酸可乐定和氯噻酮(Clorpres、Combipres)、醋酸胍那苄(Wytensin)、盐酸胍法辛(Tenex)、甲基多巴(Aldomet)、甲基多巴和氯噻嗪(Aldoclor)、甲基多巴和氢氯噻嗪(Aldoril);复合α/β-肾上腺素能拮抗剂,如拉贝洛尔(Normodyne、Trandate)、卡维地洛(Coreg);肾上腺素能神经元阻滞剂,如胍乙啶(ismelin)、利血平(Serpasil);作用于中枢神经系统的抗高血压药,如可乐定(Catapres)、甲基多巴(Aldomet)、胍那苄(Wytensin);抗血管紧张素II药剂;ACE抑制剂,如培哚普利(Aceon)、卡托普利(Capoten)、依那普利(Vasotec)、赖诺普利(Prinivil、Zestril);血管紧张素-II受体拮抗剂,如坎地沙坦(Atacand)、依普沙坦(Teveten)、厄贝沙坦(Avapro)、氯沙坦(Cozaar)、替米沙坦(Micardis)、缬沙坦(Diovan);钙通道阻滞剂,如维拉帕米(Calan、Isoptin)、地尔硫卓(Cardizem)、硝苯地平(Adalat、Procardia);利尿剂;直接血管扩张剂,如硝普盐(Nipride)、二氮嗪(Hyperstat IV)、肼屈嗪(Apresoline)、米诺地尔(Loniten)、维拉帕米;以及钾通道激活剂,如阿普卡林、比卡林、克罗卡林、依马卡林、尼可地尔和吡那地尔。
降脂剂
降脂剂用于降低血液中存在的胆固醇或脂肪糖的量。降脂剂的实例包括苯扎贝特(Bezalip)、环丙贝特(Modalim)和他汀类,如阿托伐他汀(Lipitor)、氟伐他汀(Lescol)、洛伐他汀(Mevacor、Altocor)、美伐他汀、匹伐他汀(Livalo、Pitava)、普伐他汀(Lipostat)、瑞舒伐他汀(Crestor)和辛伐他汀(Zocor)。
在本发明中,呈现急性冠心病事件的患者经常患有继发性医学病症,如代谢障碍、肺障碍、外周血管障碍或胃肠障碍中的一种或多种。此类患者可受益于联合疗法的治疗,包括向该患者联合施用雷诺嗪和至少一种治疗剂。
肺障碍联合疗法
肺障碍是指与肺有关的任何疾病或病症。肺障碍的实例包括但不限于哮喘、慢性阻塞性肺病(COPD)、支气管炎和肺气肿。
用于治疗肺障碍的治疗剂的实例包括支气管扩张剂(包括β2激动剂和抗胆碱能类)、皮质类固醇和电解质补充剂。用于治疗肺障碍的治疗剂的具体实例包括肾上腺素、特布他林(Brethaire、Bricanyl)、沙丁胺醇(Proventil)、沙美特罗(Serevent、SereventDiskus)、茶碱、异丙托溴铵(Atrovent)、噻托溴铵(Spiriva)、甲泼尼龙(Solu-Medrol、Medrol)、镁和钾。
代谢障碍联合疗法
代谢障碍的实例包括但不限于糖尿病(包括I型和II型糖尿病)、代谢综合征、血脂异常、肥胖症、葡萄糖耐受不良、高血压、血清胆固醇升高和甘油三酯升高。
用于治疗代谢障碍的治疗剂的实例包括抗高血压剂和降脂剂,如以上部分“心血管药剂联合疗法”中所描述。用于治疗代谢障碍的额外治疗剂包括胰岛素、磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂和肠降血糖素类似物。
外周血管障碍联合疗法
外周血管障碍是与位于心脏和脑外部的血管(动脉和静脉)相关的障碍,包括例如外周动脉疾病(PAD),即当供应血液到内脏器官、臂和腿的动脉因为动脉粥样硬化而变得完全或部分堵塞时产生的病症。
胃肠障碍联合疗法
胃肠障碍是指与胃肠道相关的疾病或病症。胃肠障碍的实例包括胃食管反流病(GERD)、炎性肠病(IBD)、胃肠炎、胃炎和消化性溃疡病和胰腺炎。
用于治疗胃肠障碍的治疗剂的实例包括质子泵抑制剂,如泮托拉唑(Protonix)、兰索拉唑(Prevacid)、埃索美拉唑(Nexium)、奥美拉唑(Prilosec)、雷贝拉唑;H2阻滞剂,如西咪替丁(Tagamet)、雷尼替丁(Zantac)、法莫替丁(Pepcid)、尼扎替丁(Axid);前列腺素,如米索前列醇(Cytotec);硫糖铝;和抗酸药。
抗生素、镇痛药、抗抑郁药和抗焦虑剂联合疗法
呈现急性冠心病事件的患者可表现出受益于一种或多种治疗剂(其为抗生素、镇痛药、抗抑郁药和抗焦虑剂)与雷诺嗪的联合施用的病症。
抗生素
抗生素是杀死微生物(包括细菌和真菌)或使其停止生长的治疗剂。抗生素剂的实例包括β-内酰胺抗生素,包括青霉素(阿莫西林);头孢菌素,如头孢唑啉、头孢呋辛、头孢羟氨苄(Duricef)、头孢氨苄(Keflex)、头孢拉定(Velosef)、头孢克洛(Ceclor)、头孢呋辛酯(Ceftin)、头孢丙烯(Cefzil)、氯碳头孢(Lorabid)、头孢克肟(Suprax)、头孢泊肟酯(Vantin)、头孢布烯(Cedax)、头孢地尼(Omnicef)、头孢曲松(Rocephin)、碳青霉烯类和单内酰环类;四环素类,如四环素;大环内脂抗生素,如红霉素;氨基糖苷类,如庆大霉素、妥布霉素、阿米卡星;喹诺酮类,如环丙沙星;环肽类,如万古霉素、链阳菌素类、多粘菌素类;林可酰胺类,如克林霉素;噁唑烷酮类,如利奈唑胺;和磺胺类抗生素,如磺胺异噁唑。
镇痛药
镇痛药是用于缓解疼痛的治疗剂。镇痛药的实例包括阿片类和拟吗啡物质,如芬太尼和吗啡;扑热息痛;NSAID和COX-2抑制剂。考虑到本发明的钠通道阻滞剂通过抑制NaV1.7和1.8钠通道来治疗神经病理性疼痛的能力,特别设想了与镇痛药联用。参见美国专利申请公开20090203707。
抗抑郁药和抗焦虑剂
抗抑郁药和抗焦虑剂包括用于治疗焦虑障碍、抑郁的那些药剂以及用作镇静剂和安定剂的那些药剂。抗抑郁药和抗焦虑剂的实例包括苯二氮卓类,如地西泮、劳拉西泮和咪达唑仑;苯二氮卓类;巴比妥类;格鲁米特;水合氯醛;甲丙氨酯;舍曲林(Zoloft、Lustral、Apo-Sertral、Asentra、Gladem、Serlift、Stimuloton);艾司西酞普兰(Lexapro、Cipralex);氟西汀(Prozac、Sarafem、Fluctin、Fontex、Prodep、Fludep、Lovan);文拉法辛(Effexor XR、Efexor);西酞普兰(Celexa、Cipramil、Talohexane);帕罗西汀(Paxil、Seroxat、Aropax);曲唑酮(Desyrel);阿米替林(Elavil);和安非他酮(Wellbutrin、Zyban)。抗抑郁药和抗焦虑剂可包括神经活性类固醇和氯胺酮及相关NMDA受体拮抗剂。
因此,本发明的一个方面提供了包含本发明的钠通道阻滞剂和至少一种治疗剂的组合物。在一个替代实施方案中,该组合物包含本发明的钠通道阻滞剂和至少两种治疗剂。在另外的替代实施方案中,该组合物包含本发明的钠通道阻滞剂和至少三种治疗剂、本发明的钠通道阻滞剂和至少四种治疗剂、或本发明的钠通道阻滞剂和至少五种治疗剂。
联合疗法的方法包括:联合施用包含本发明的钠通道阻滞剂和一种或多种治疗剂的单一调配物,基本上同时施用包含本发明的钠通道阻滞剂和一种或多种治疗剂的超过一种调配物,以及以任何顺序相继施用本发明的钠通道阻滞剂和一种或多种治疗剂,其中优选地存在本发明的钠通道阻滞剂与一种或多种治疗剂同时发挥其治疗作用的时间段。
范例
下面的代表性实施例旨在帮助说明本发明,并非旨在限制本发明的范围,也不应将这些实施例解释为限制本发明的范围。
本文所提供的化合物可以使用以下通用方法和程序由容易获得的起始物质制备。应了解,除非另有说明,否则在给出典型或优选的工艺条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)的情况下,也可以使用其他工艺条件。最佳反应条件可能随使用的特定反应物或溶剂而变化,但这类条件可以由所属领域的技术人员通过例行优化来确定。
另外,对于所属领域的技术人员显而易见的是,常规保护基团对于防止某些官能团进行非期望反应可能是必需的。用于特定官能基的适合保护基的选择以及用于保护和去保护的适合条件为所属领域中众所周知的。例如,在T.W.Greene和P.G.M.Wuts,ProtectingGroups in Organic Synthesis,第二版,Wiley,New York,1991及其中引用的参考文献中描述了许多保护基以及它们的引入和去除。
本文提供的化合物可通过已知的标准程序分离和纯化。此类程序包括再结晶、过滤、快速色谱、湿磨、高压液相色谱(HPLC)或超临界流体色谱(SFC)。注意,快速色谱可以手动或通过自动化系统执行。本文所提供的化合物可以通过已知标准程序来表征,例如核磁共振光谱(NMR)或液相色谱质谱(LCMS)。NMR化学位移以百万分率(ppm)为单位报告且使用所属领域的技术人员众所周知的方法产生。
分析LCMS的示例性一般方法包括方法A(Xtimate C18(2.1mm x 30mm,3μm);A=H2O(0.04%TFA)并且B=CH3CN(0.02%TFA);50℃;1.2mL/min;10-80%B持续0.9分钟,然后80%B持续0.6分钟)和方法B(Chromolith Flash RP-18封端C18(2mm x 25mm);A=H2O(0.04%TFA)并且B=CH3CN(0.02%TFA);50℃;1.5mL/min;5-95%B持续0.7分钟,然后95%B持续0.4分钟)
缩写列表:
Pd(dppf)Cl2 [1,1′-双(二苯基膦)二茂铁]二氯钯(II)
MeOH 甲醇
EtOH 乙醇
THF 四氢呋喃
DCM 二氯甲烷
AcN或MeCN 乙腈
EtOAc 乙酸乙酯
PE 石油醚
DMSO 二甲亚砜
TFA 三氟乙酸
DEA 二乙胺
KOAc 乙酸钾
TBAF 四正丁基氟化铵
LAH 氢化铝锂
DAST 二乙氨基三氟化硫
实施例1.化合物1:(R)-3-(环丙氧基二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
A4:(R)-1,1,1-三氟丙-2-醇
在0℃下向(R)-2-(三氟甲基)环氧乙烷(2.2g,19.63mmol)在THF(20.0mL)中的溶液中逐滴添加LiAlH4(THF中的2.0M,4.91mL,9.82mmol)。将反应混合物缓慢升温至室温并搅拌3小时。将反应混合物冷却至0℃并用饱和Na2SO4溶液(2.0mL)处理。通过硅藻土过滤反应混合物。将滤液在Na2SO4上干燥并以THF中的溶液的形式用于下一步。
A5:(R)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶
在0℃下向(R)-1,1,1-三氟丙-2-醇(30.68mmol)在THF中的溶液中逐份添加NaH(1.84g,46mmol)并搅拌30min。在0℃下将5-溴-2-氟-吡啶(4.32g,24.55mmol)在搅拌下缓慢添加到反应混合物中。将反应混合物缓慢升温至室温并搅拌3小时。将反应混合物冷却至10℃,用冰水(10mL)处理,并用EtOAc(2×50mL)萃取。将有机层用盐水(40mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用20%EtOAc/PE纯化粗产物,得到液体形式的(R)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶(3.1g,11.5mmol,37%收率)。LCMS:270.0(M+H)+和272.0(M+2+H)+,Rt 2.78min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A6:(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶
向(R)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶(3.1g,11.5mmol)和双(频哪醇合)二硼(3.79g,14.92mmol)在1,4-二噁烷(35.0mL)中的搅拌溶液中添加乙酸钾(2.25g,22.96mmol)。将Pd(dppf)Cl2.DCM(1.41g,1.72mmol)在氮气氛下添加到反应混合物中并在90℃下加热12小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用6%EtOAc/PE纯化粗产物,得到固体形式的(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶(2.8g,8.83mmol,76%收率)。LCMS:318.0(M+H),Rt 4.04min;柱:ZORBAX Extend(50X 4.6mm),5μm;流动相:A:10mM乙酸铵水溶液,B:ACN;流速:1.2mL/min。
A7:(R)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶(0.5g,1.58mmol)和6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(0.45g,1.89mmol)在1,4-二噁烷(12.0mL)中的搅拌溶液中添加水(2.0mL)和Cs2CO3(1.03g,3.15mmol)。将Pd(dppf)Cl2.DCM(0.11g,0.16mmol)在氮气氛下添加到反应混合物中并在90℃下加热16小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用15%EtOAc/PE纯化粗产物,得到固体形式的(R)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(350mg,0.89mmol,56%收率)。LCMS:394.1(M+H),Rt 2.54min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
化合物1:(R)-3-(环丙氧基二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
在室温下向Cs2CO3(744mg,2.29mmol)在MeCN(10mL)中的搅拌悬浮液中添加环丙醇(0.29mL,4.57mmol)并搅拌15min。向反应混合物中逐滴添加(R)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(150mg,0.38mmol)的MeCN(5.0mL)溶液并搅拌2小时。将反应混合物用水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用20%EtOAc/PE纯化粗产物,得到固体形式的1(12mg,0.03mmol,7%收率)。pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.33min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:416.0(M+H),Rt 2.58min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。1H NMR(400MHz,DMSO-d6):δH=9.64(d,1H),8.84(d,1H),8.77(s,1H),8.42(dd,1H),7.06(d,1H),5.94-5.91(m,1H),4.18-4.15(m,1H),1.43(d,3H),0.88-0.85(m,2H),0.69-0.67(m,2H)。
实施例2.化合物2:(S)-3-(环丙氧基二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
A10:(S)-1,1,1-三氟丙-2-醇
在0℃下向(S)-2-(三氟甲基)环氧乙烷(4.0g,35.7mmol)在THF(20.0mL)中的溶液中逐滴添加LiAlH4(THF中的2.0M,8.92mL,17.85mmol)。将反应混合物缓慢升温至室温并搅拌3小时。将反应混合物冷却至0℃并用饱和Na2SO4溶液(2.0mL)处理。通过硅藻土过滤反应混合物,并将滤液在Na2SO4上干燥并以THF中的溶液的形式用于下一步。
A11:(S)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶
在0℃下向(S)-1,1,1-三氟丙-2-醇(26.3mmol)在THF中的溶液中逐份添加NaH(1.57g,39.45mmol)并搅拌30min。在0℃下将5-溴-2-氟-吡啶(3.7g,21.04mmol)缓慢添加到反应混合物中。将反应混合物缓慢升温至室温并搅拌3小时。将反应混合物冷却至10℃,用冰水(10mL)处理,并用EtOAc(2×50mL)萃取。将有机层用盐水(40mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用20%EtOAc/PE纯化粗产物,得到液体形式的(S)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶(1.6g,5.78mmol,27%收率)。LCMS:270.0(M+H)和272.0(M+2+H),Rt 2.78min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A12:(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶
向(S)-5-溴-2-((1,1,1-三氟丙-2-基)氧基)吡啶(0.5g,1.85mmol)和双(频哪醇合)二硼(0.52g,2.04mmol)在1,4-二噁烷(5.0mL)中的搅拌溶液中添加乙酸钾(0.36g,3.7mmol)。.将Pd(dppf)Cl2.DCM(0.15g,0.19mmol)在氮气氛下添加到反应混合物中并在80℃下加热12小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用10%EtOAc/PE纯化粗产物,得到(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶(302mg,0.95mmol,51%收率)。LCMS:318.1(M+H),Rt 3.04min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A14:(S)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟丙-2-基)氧基)吡啶(302mg,0.95mmol)和6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(0.25g,1.04mmol)在1,4-二噁烷(6.0mL)中的搅拌溶液中添加水(1.0mL)和Cs2CO3(0.62g,1.9mmol)。将Pd(dppf)Cl2.DCM(0.08g,0.09mmol)CS2CO3(0.62g,1.9mmol)在氮气氛下添加到反应混合物中并在80℃下加热12小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用20%EtOAc/PE纯化粗产物,得到(S)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(93mg,0.23mmol,24%收率)。LCMS:394.0(M+H),Rt 2.54min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
化合物2:(S)-3-(环丙氧基二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
在室温下向Cs2CO3(463mg,1.42mmol)在MeCN(6.0mL)中的搅拌悬浮液中添加环丙醇(165mg,2.84mmol)并搅拌15min。向反应混合物中逐滴添加(S)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(93mg,0.23mmol)的MeCN(6.0mL)溶液并搅拌2小时。将反应混合物用水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到固体形式的2(10mg,0.024mmol,10%收率)。制备型HPLC方法:Rt 10.42;柱:X-Bridge C8(150X 19mm),5.0μm;流动相:0.1%TFA水溶液/乙腈;流速:15.0mL/min。pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.32min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:416.1(M+H)+,Rt2.46min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。1H NMR(400MHz,DMSO-d6):δH=9.71(d,1H),8.91(dd,1H),8.85(d,1H),8.49(dd,1H),7.14(dd,1H),6.03-5.96(m,1H),4.26-4.21(m,1H),1.51(d,3H),0.97-0.93(m,2H),0.78-0.73(m,2H)。
实施例3.化合物3:(S)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
在室温下向Cs2CO3(463mg,1.42mmol)在MeCN(6.0mL)中的搅拌悬浮液中添加乙醇(0.17mL,2.84mmol)并搅拌30min。向反应混合物中逐滴添加(S)-3-(氯二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(100mg,0.24mmol)的MeCN(6.0mL)溶液并搅拌2小时。将反应混合物用水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到固体形式的3(17mg,0.042mmol,17%收率)。制备型HPLC方法:Rt 14.3;柱:X-Bridge C8(150X 19mm),5.0μm;流动相:0.1%TFA水溶液/乙腈;流速:15.0mL/min。pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.22min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:404.1(M+H)+,Rt2.54min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。手性方法:Rt 1.36min,SFC柱:Chiralcel OJ-H;流动相:60:40(A:B),A=液体CO2,B=含0.5%异丙胺的IPA;流速:3.0mL/min;波长:254nm。1H NMR(400MHz,DMSO-d6):δH=9.71(d,1H),8.92(s,1H),8.91(s,1H),8.50(dd,1H),7.14(d,1H),6.02-5.98(m,1H),4.32(q,2H),1.51(d,3H),1.39(t,3H)。
实施例4.化合物4:6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
A16:1-环丙基-2,2,2-三氟乙-1-醇
在0℃下向环丙甲醛(5.0g,71.34mmol)在THF(50.0mL)中的搅拌溶液中添加三甲基(三氟甲基)硅烷(11.16g,78.47mmol)和TBAF(THF中的1.0M,7.14mL,7.1mmol)。将反应混合物缓慢升温至室温并搅拌4小时。在室温下向反应混合物中添加TBAF(THF中的1.0M,142.6mL,142.6mmol)并搅拌30min。将反应混合物用水(50.0mL)处理并用二乙醚(2x100mL)萃取。将有机层用10%NaHCO3溶液(50.0mL)和盐水(50mL)洗涤。将有机层在无水Na2SO4上干燥并在30℃下浓缩,得到1-环丙基-2,2,2-三氟乙-1-醇(3.2g),将其用于下一步而不进一步纯化。
A17:5-溴-2-(1-环丙基-2,2,2-三氟乙氧基)吡啶
在0℃下向1-环丙基-2,2,2-三氟乙-1-醇(3.0g,21.41mmol)在THF(30.0mL)中的搅拌溶液中按小份添加NaH(矿物油中的60%,1.28g,32.12mmol)。将反应混合物搅拌10min并且添加5-溴-2-氟-吡啶(3.77g,21.41mmol)。将反应混合物缓慢升温至室温并搅拌1小时。将反应混合物冷却至10℃,并用冰水(100mL)处理。用EtOAc(2x 100mL)萃取反应混合物。将有机层用盐水(80mL)洗涤,在无水Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用PE纯化粗产物,得到5-溴-2-(1-环丙基-2,2,2-三氟乙氧基)吡啶(3.1g,10.47mmol,48%收率)。LCMS:296.0(M+H)+和298.0(M+2+H)+,Rt 2.90min;柱:ZORBAX XDBC-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A18:2-(1-环丙基-2,2,2-三氟乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
向5-溴-2-(1-环丙基-2,2,2-三氟乙氧基)吡啶(3.1g,10.47mmol)和双(频哪醇合)二硼(3.46g,13.61mmol)在1,4-二噁烷(30mL)中的搅拌溶液中添加乙酸钾(1.72g,20.94mmol)。将Pd(dppf)Cl2.DCM(0.86g,1.05mmol)在氮气氛下添加到反应混合物中并在90℃下加热3小时。将反应混合物冷却至室温并通过硅藻土过滤。将反应混合物用冰水(50mL)处理,并用EtOAc(2×50mL)萃取。将有机层用盐水(30mL)洗涤,在无水Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用4%EtOAc/PE纯化粗产物,得到2-(1-环丙基-2,2,2-三氟乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(3.2g,9.3mmol,89%收率)。LCMS:344.1(M+H)+,Rt 3.18min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A19:3-(氯二氟甲基)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(2.0g,8.37mmol)和2-(1-环丙基-2,2,2-三氟乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(3.16g,9.2mmol)在1,4-二噁烷(36mL)中的搅拌溶液中添加Cs2CO3(5.45g,16.74mmol)和水(4.0mL)。将Pd(dppf)Cl2.DCM(0.68g,0.84mmol)在氮气氛下添加到反应混合物中并在90℃下加热3小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用13%EtOAc/PE纯化粗产物,得到3-(氯二氟甲基)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(1.39g,3.31mmol,39%收率)。LCMS:420.0(M+H)+,Rt 3.89min;柱:ZORBAX Extend C18(50X 4.6mm),5μm;流动相:A:10mM乙酸铵水溶液,B:ACN;流速:1.2mL/min。
化合物4:6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
在室温下向Cs2CO3(1.9g,5.85mmol)在MeCN(15mL)中的搅拌悬浮液中添加乙醇(1.14mL,19.5mmol)并搅拌15min。向反应混合物中逐滴添加3-(氯二氟甲基)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(500mg,0.98mmol)的MeCN(10mL)溶液并在室温下搅拌30min。将反应混合物用水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到固体形式的4(85mg,0.19mmol,20%收率)。制备型HPLC方法:Rt11.83;柱:X-Bridge C8(150X 19mm),5.0μm;流动相:0.1%TFA水溶液/乙腈;流速:15.0mL/min。pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.52min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:429.8(M+H)+,Rt 2.51min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液:ACN(95:5),B:含0.1%TFA的ACN;流速:1.5mL/min。1H NMR(400MHz,CD3OD):δH=9.55(d,1H),8.84(dd,1H),8.80(d,1H),8.42(dd,1H),7.04(dd,1H),5.54-5.50(m,1H),4.39(q,2H),1.49(t,3H),1.35-1.29(m,1H),0.80-0.75(m,1H),0.67-0.62(m,3H)。
实施例5.化合物5:(R)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(二氟(甲氧基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪和化合物6:(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(二氟(甲氧基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪的合成。注意,立体构型已被随机归属
向Cs2CO3(3.81g,11.7mmol)在MeCN(30mL)中的搅拌悬浮液中添加MeOH(1.58mL,38.99mmol)并搅拌10min。向反应混合物中添加3-(氯二氟甲基)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(1.0g,1.95mmol)的MeCN(20mL)溶液。将反应混合物在室温下搅拌30min并用冰水(50mL)处理。将反应混合物用EtOAc(2x50mL)萃取,用盐水(30mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用14%EtOAc/PE纯化粗产物,得到450mg的外消旋化合物。通过SFC纯化来分离外消旋混合物,得到固体形式的5(87mg,0.20mmol,10%收率)和6(50mg,0.12mmol,6%收率)。手性方法:SFC柱:Lux A1;流动相:80:20(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。5和6的立体构型被随机归属。
化合物5:pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.25min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:416.0(M+H)+,Rt2.47min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液:ACN(95:5),B:含0.1%TFA的ACN;流速:1.5mL/min。手性方法:Rt 4.35min,SFC柱:Lux A1;流动相:80:20(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。1H NMR(400MHz,CD3OD):δH=9.55(d,1H),8.85(dd,1H),8.81(d,1H),8.43(dd,1H),7.04(dd,1H),5.54-5.50(m,1H),3.99(s,3H),1.34-1.31(m,1H),0.79-0.77(m,1H),0.67-0.63(m,3H)。
化合物6:pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 5.25min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:415.9(M+H)+,Rt2.54min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。手性方法:Rt 4.85min,SFC柱:Lux A1;流动相:80:20(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。1H NMR(400MHz,CD3OD):δH=9.55(d,1H),8.85(dd,1H),8.81(d,1H),8.43(dd,1H),7.04(dd,1H),5.54-5.50(m,1H),3.99(s,3H),1.34-1.31(m,1H),0.79-0.76(m,1H),0.67-0.66(m,3H)。
实施例6.化合物7:3-(二氟(甲氧基)甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
A21:1,1,1-三氟-3-甲基丁-2-醇
在10℃下于氮气下向异丁醛(5.0g,69.34mmol)在THF(50.0mL)中的搅拌溶液中添加三甲基(三氟甲基)硅烷(10.85g,76.27mmol)和TBAF(1.81g,6.93mmol)。将反应混合物在室温下搅拌2小时。将TBAF(36.26g,138.68mmol)添加到反应混合物中并在室温下搅拌2小时。将反应混合物用水(200mL)处理并用二乙醚(2x 150mL)萃取。用二乙醚(100mL)洗涤水溶液。将有机层用盐水(30mL)洗涤,在无水Na2SO4上干燥并浓缩,得到1,1,1-三氟-3-甲基丁-2-醇(2.27g,16.0mmol,23%收率),将其用于下一步而不进一步纯化。
A22:5-溴-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶
在0℃下向1,1,1-三氟-3-甲基丁-2-醇(720mg,5.07mmol)在THF(15.0mL)中的搅拌溶液中逐份添加NaH(矿物油中的60%,0.41g,10.13mmol)并搅拌30min。在0℃下将5-溴-2-氟吡啶(0.89g,5.07mmol)的THF(2.0mL)溶液缓慢添加到反应混合物中。将反应混合物缓慢升温至室温并搅拌2小时。将反应混合物冷却至10℃,用冰水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(30mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用15%EtOAc/PE纯化粗产物,得到5-溴-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶(1.0g,3.35mmol,66%收率)。LCMS:297.8(M+H)+和299.8(M+2+H)+,Rt 3.04min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A23:5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶
向5-溴-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶(1.0g,3.35mmol)和双(频哪醇合)二硼(1.11g,4.36mmol)在1,4-二噁烷(10.0mL)中的搅拌溶液中添加乙酸钾(0.66g,6.71mmol)。将Pd(dppf)Cl2.DCM(356mg,0.44mmol)在氮气氛下添加到反应混合物中并在85℃下加热3小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用15%EtOAc/PE纯化粗产物,得到固体形式的5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶(0.9g,2.6mmol,77%收率)。1HNMR(400MHz,CD3OD):δH=8.46(dd,1H),8.02(dd,1H),6.88(dd,1H),5.92-5.85(m,1H),2.30-2.23(m,1H),1.36(s,12H),1.08(d,6H)。
A24:3-(氯二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(400mg,1.67mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶(570mg,1.65mmol)在1,4-二噁烷(3.6mL)中的搅拌溶液中添加Cs2CO3(1.09g,3.35mmol)和水(0.4mL)。将Pd(dppf)Cl2.DCM(136mg,0.17mmol)在氮气氛下添加到反应混合物中并在90℃下加热3小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用15%EtOAc/PE纯化粗产物,得到3-(氯二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(225mg,0.53mmol,31%收率)。LCMS:422.0(M+H)+,Rt 2.81min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
化合物7:3-(二氟(甲氧基)甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
在50mL密封管中,向MeOH(0.36mL,8.87mmol)在MeCN(3.0mL)中的搅拌溶液中添加Cs2CO3(866mg,2.66mmol)并将反应混合物搅拌20min。向反应混合物中逐滴添加3-(氯二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(185mg,0.44mmol)的MeCN(15.0mL)溶液并在室温下搅拌2h。将反应混合物用水(20mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用18%EtOAc/PE纯化粗产物,得到外消旋化合物。通过制备型HPLC纯化粗产物,得到固体形式的7(60mg,0.14mmol,32%收率)。制备型HPLC方法:Rt14.8;柱:Agilent C18(50X 50mm),5.0μm;流动相:0.1%TFA水溶液/乙腈;流速:25.0mL/min。HPLC:Rt 5.50min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:418.1(M+H)+,Rt 2.71min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。1HNMR(400MHz,CD3OD):δH=9.55(d,1H),8.88-8.87(m,1H),8.81(d,1H),8.44(dd,1H),7.06(dd,1H),5.97-5.92(m,1H),3.99(s,3H),2.35-2.30(m,1H),1.13-1.11(m,6H)。
实施例7.化合物8:3-[二氟(丙氧基)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A26:5-溴-2-(2,2,2-三氟乙氧基)吡啶
在0℃下向2,2,2-三氟乙醇(3.13g,31.25mmol)在THF(50mL)中的溶液中缓慢添加NaH(1.36g,34.09mmol,油中的60%)。将混合物在25℃下搅拌1小时。向所得混合物中添加5-溴-2-氟-吡啶(5g,28.41mmol)并将混合物在25℃下搅拌3.5小时。用饱和NH4Cl水溶液(50mL)淬灭混合物。分离有机相,并用EtOAc(30mL x 2)萃取水层。将合并的有机相用盐水(50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到油形式的粗产物(7g,27.34mmol)。1HNMR(400MHz,CDCl3)δH=8.20(s,1H),7.73(dd,1H),6.80(d,1H),4.73(q,2H)。
A27:5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(2,2,2-三氟乙氧基)吡啶
将1,4-二噁烷(80mL)中的5-溴-2-(2,2,2-三氟乙氧基)吡啶(7g,27.34mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(7.64g,30.08mmol)、KOAc(5.37g,54.68mmol)和Pd(dppf)Cl2(1g,1.37mmol)的混合物在85℃下于N2下搅拌12小时。在冷却至室温后,通过硅藻土过滤混合物,然后浓缩滤液。通过快速色谱在硅胶上(EtOAc/PE=0%至5%)纯化粗产物,得到油形式的产物(8g,26.4mmol,96%收率)。1H NMR(400MHz,CDCl3)δH=8.53(s,1H),8.00(dd,1H),6.84(d,1H),4.80(q,2H),1.35(s,12H)。
A28:2-氯-5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪
将1,4-二噁烷(80mL)和水(8mL)中的Pd(dppf)Cl2(0.97g,1.32mmol)、Cs2CO3(17.2g,52.79mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(2,2,2-三氟乙氧基)吡啶(8g,26.39mmol)和2-溴-5-氯-吡嗪(5.62g,29.03mmol)的混合物在25℃下于N2下搅拌16小时。将混合物通过硅藻土过滤,并浓缩滤液。添加水(150mL),并用EtOAc(150mL x 2)萃取水层。将合并的有机相用盐水(300mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至30%至60%)纯化粗产物,得到固体形式的产物(4g,13.55mmol,51%收率)。1H NMR(400MHz,CDCl3)δH=8.78-8.73(m,2H),8.64(s,1H),8.29(dd,1H),7.02(d,1H),4.85(q,2H)。LCMS Rt=0.92min(在1.5min色谱中),5-95AB,C11H8ClF3N3O[M+H]+的MS ESI计算值290.0,实测值289.8。
A29:[5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪-2-基]肼
在25℃下向2-氯-5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪(4g,13.55mmol)在MeCN(50mL)中的溶液中添加N2H4.H2O(6.77g,135.49mmol)。将混合物在80℃下搅拌16小时。在冷却至25℃后,将反应体系倒入水(200mL)中。过滤混合物,并用H2O(15mL x 2)洗提滤饼。减压干燥固体。用PE(150mL)和EtOAc(60mL)磨碎固体,得到固体形式的产物(2.8g,9.81mmol,72%收率)。1H NMR(400MHz,DMSO-d6)δH=8.74(s,1H),8.58(s,1H),8.31(dd,1H),8.24-8.10(m,2H),7.05(d,1H),5.03(q,2H),4.34(s,2H)。LCMS Rt=0.70min(在1.5min色谱中),5-95AB,C11H11F3N5O[M+H]+的MS ESI计算值286.1,实测值285.8。
A30:2-溴-N-(2-溴-2,2-二氟-乙酰基)-2,2-二氟-N'-[5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪-2-基]乙酰肼
向2-溴-2,2-二氟-乙酸(1g,5.72mmol)在THF(10mL)中的溶液中添加DMF(20.89mg,0.29mmol)和(COCl)2(0.58mL,6.86mmol)。将所得混合物在25℃下搅拌30min。将[5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪-2-基]肼(1g,3.51mmol)在THF(10mL)中的溶液添加到混合物中。将混合物在25℃下搅拌1小时。添加水(20mL),并用EtOAc(20mL×2)萃取水层。将合并的有机层用盐水(30mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到油形式的产物(1.7g,2.84mmol,80%收率)。LCMS Rt=1.49min(在2.0min色谱中),10-80AB,C16H9Br2F7N5O3[M+H]+的MS ESI计算值599.9,实测值600.1。
A31:3-[溴(二氟)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向2-溴-N-(2-溴-2,2-二氟-乙酰基)-2,2-二氟-N'-[5-[6-(2,2,2-三氟乙氧基)-3-吡啶基]吡嗪-2-基]乙酰肼(1.7g,2.84mmol)在甲苯(20mL)中的溶液中添加TsOH(146.6mg,0.85mmol)。将混合物在130℃下搅拌12小时。添加水(30mL),并用EtOAc(30mL x2)萃取水层。将合并的有机层用盐水(30mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE 0~20%)纯化粗产物,得到固体形式的产物(700mg,1.65mmol,58%收率)。1H NMR(400MHz,CDCl3)δH=9.59(s,1H),8.78(s,1H),8.42(s,1H),8.27(dd,1H),7.06(d,1H),4.87(q,2H)。LCMS Rt=0.89min(在1.5min色谱中),5-95AB,C13H8BrF5N5O[M+H]+的MS ESI计算值426.0,实测值425.7。
化合物8:3-[二氟(丙氧基)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(150mg,0.35mmol)在1-丙醇(2mL)中的溶液中添加AgBF4(137.23mg,0.71mmol)。将混合物在60℃下搅拌3小时。添加盐水(30mL),通过硅藻土过滤水层,并用EtOAc(10mL x2)洗提滤饼。分离滤液,并用EtOAc(20mL x 2)萃取水相。将合并的有机层用盐水(50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱(EtOAc/PE 0~20%)纯化粗产物,得到固体形式的产物(80.95mg,0.20mmol,56%收率)。1H NMR(400MHz,CDCl3)δH=9.53(s,1H),8.72(s 1H),8.47(d,1H),8.24(dd,1H),7.05(d,1H),4.86(q,2H),4.25(t,2H),1.94-1.83(m,2H),1.09(t,3H)。LCMS Rt=1.23min(在2.0min色谱中),10-80AB,C16H15F5N5O2[M+H]+的MS ESI计算值404.1,实测值404.1。
实施例8.化合物9:(R)-3-(二氟(甲氧基)甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪和化合物10:(S)-3-(二氟(甲氧基)甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成。
注意,立体构型被随机归属。
A33:1,1-二氟丙-2-醇
在0℃下向1,1-二氟丙-2-酮(2.0g,21.26mmol)在THF(20.0mL)中的搅拌溶液中添加LAH(THF中的1.0M,32.0mL,31.89mmol)。将反应混合物缓慢升温至室温并搅拌2小时。将反应混合物在0℃下用饱和Na2SO4水溶液(5mL)处理并搅拌30min。通过硅藻土过滤反应混合物,将滤液在Na2SO4上干燥并以THF中的溶液的形式用于下一步。
A34:5-溴-2-((1,1-二氟丙-2-基)氧基)吡啶
在0℃下向1,1-二氟丙-2-醇(21.2mmol)在THF中的搅拌溶液中逐份添加NaH(矿物油中的60%,1.25g,31.2mmol)并搅拌15min。在0℃下将5-溴-2-氟-吡啶(3.66g,20.82mmol)缓慢添加到反应混合物中。将反应混合物缓慢升温至室温并搅拌1小时。将反应混合物冷却至10℃,用冰水(30mL)处理,并用EtOAc(2×50mL)萃取。将有机层用盐水(40mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用2%EtOAc/PE纯化粗产物,得到5-溴-2-((1,1-二氟丙-2-基)氧基)吡啶(1.01g,4.03mmol,19%收率)。LCMS:252.0(M+H)+和254.0(M+2+H)+,Rt 2.44min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A35:2-((1,1-二氟丙-2-基)氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
向5-溴-2-((1,1-二氟丙-2-基)氧基)吡啶(1.01g,4.03mmol)和双(频哪醇合)二硼(1.33g,5.24mmol)在1,4-二噁烷(22.0mL)中的搅拌溶液中添加乙酸钾(0.79g,8.06mmol)。将Pd(dppf)Cl2.DCM(0.33g,0.40mmol)在氮气氛下添加到反应混合物中并在85℃下加热3小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用4%EtOAc/PE纯化粗产物,得到2-((1,1-二氟丙-2-基)氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(1.0g,3.34mmol,82%收率)。LCMS:300.1(M+H)+,Rt2.84min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A36:3-(氯二氟甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向2-((1,1-二氟丙-2-基)氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(1.0g,3.34mmol)和6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(0.88g,3.68mmol)在1,4-二噁烷(9.0mL)中的搅拌溶液中添加Cs2CO3(2.18g,6.69mmol)和水(1.0mL)。将Pd(dppf)Cl2.DCM(0.27g,0.33mmol)在氮气氛下添加到反应混合物中并在90℃下加热3小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用12%EtOAc/PE纯化粗产物,得到3-(氯二氟甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(252mg,0.67mmol,20%收率)。LCMS:375.8(M+H)+,Rt2.34min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
化合物9和10:(R)-3-(二氟(甲氧基)甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(二氟(甲氧基)甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
在室温下向密封管(50mL)中Cs2CO3(1.01g,3.11mmol)在MeCN(5.0mL)中的搅拌悬浮液中添加MeOH(0.42mL,10.36mmol)并搅拌10min。向反应混合物中逐滴添加3-(氯二氟甲基)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(195mg,0.52mmol)的MeCN(5.0mL)溶液并搅拌30min。将反应混合物用水(20mL)处理并用EtOAc(2x30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用18%EtOAc/PE纯化粗产物,得到外消旋化合物。通过SFC纯化来分离外消旋混合物,得到固体形式的9(33mg,0.089mmol,17%收率)和10(31mg,0.083mmol,16%收率)。手性方法:SFC柱:Lux C3;流动相:90:10(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。9和10的立体构型被随机归属。
化合物9:pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 4.48min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:372.1(M+H)+,Rt2.15min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液:ACN(95:5),B:含0.1%TFA的ACN;流速:1.5mL/min。手性方法:Rt 5.5min,SFC柱:Lux C3;流动相:90:10(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。1H NMR(400MHz,CD3OD):δH=9.54(d,1H),8.87(d,1H),8.79(d,1H),8.39(dd,1H),6.99-6.97(m,1H),6.21-5.93(m,1H),5.58-5.50(m,1H),3.99(s,3H),1.44(d,3H)。
化合物10:pd(dppf)Cl2(27.35mg,0.0400mmol)HPLC:Rt 4.48min;柱:X-BridgeC8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:372.1(M+H)+,Rt2.15min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液:ACN(95:5),B:含0.1%TFA的ACN;流速:1.5mL/min。手性方法:Rt 6.2min,SFC柱:Lux C3;流动相:90:10(A:B),A=液体CO2,B=含0.5%异丙胺的甲醇;流速:3.0mL/min;波长:254nm。1H NMR(400MHz,CD3OD):δH=9.54(d,1H),8.88(d,1H),8.79(d,1H),8.40(dd,1H),7.00-6.98(m,1H),6.21-5.93(m,1H),5.58-5.51(m,1H),3.99(s,3H),1.44(d,3H)。
实施例9.化合物11:3-[二氟(异丙氧基)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
向IPA(10mL)中的3-[溴(二氟)甲基]-6-[6-(2,2,2-三氟乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(940.0mg,1.88mmol)和Na2CO3(599.02mg,5.65mmol)的混合物中添加AgBF4(1.1g,5.65mmol)。将混合物在70℃下于N2和黑暗下搅拌1小时。在冷却至室温后,将混合物倒入盐水(20mL)中。然后过滤混合物,并用H2O(10mL)稀释滤液。用EtOAc(10mL×2)萃取混合物。将合并的有机相用水(10mL)和盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并减压浓缩。通过快速色谱在硅胶上(EtOAc/PE=0至0%)纯化粗产物,得到固体形式的粗产物(500mg,1.24mmol)。然后将粗产物重新溶解于正己烷(10mL)和DCM(10mL)中。将所得溶液在60℃和15psi下搅拌30分钟以去除大部分DCM。在冷却至室温后,过滤混合物并用正己烷(5mL x 3)洗涤滤饼,干燥,得到固体形式的产物(282.75mg,0.70mmol,57%收率)。1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.71(d,1H),8.46(d,1H),8.24(dd,1H),7.05(d,1H),5.08-4.98(m,1H),4.85(q,2H),1.51(d,6H)。LCMS Rt=1.21min(在2.0min色谱中),10-80AB,C16H15F5N5O2[M+H]+的MS ESI计算值404.1,实测值404.0。
实施例10.化合物12:3-(二氟(甲氧基)甲基)-6-(6-(2,2,3,3-四氟环丁氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
A37:5-溴-2-(2,2,3,3-四氟环丁氧基)吡啶
在0℃下向2,2,3,3-四氟环丁醇(1.0g,6.94mmol)在THF(20mL)中的搅拌溶液中按小份添加NaH(矿物油中的60%,305mg,7.64mmol)。将反应混合物缓慢升温至室温并搅拌15min。将5-溴-2-氟-吡啶(1.22g,6.94mmol)逐滴添加到反应混合物中并搅拌2小时。将反应混合物冷却至10℃,并用冰水(50mL)处理。用EtOAc(2x 60mL)萃取反应混合物。将有机层用盐水(50mL)洗涤,在无水Na2SO4上干燥并浓缩,得到粗产物。通过柱色谱在硅胶上采用5%EtOAc/PE纯化粗产物,得到5-溴-2-(2,2,3,3-四氟环丁氧基)吡啶(900mg,2.99mmol,43%收率)。LCMS:300.0(M+H)+和302.0(M+2+H)+,Rt 2.65min;柱:ZORBAX XDB C-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A38:2-(2,2,3,3-四氟环丁氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
向5-溴-2-(2,2,3,3-四氟环丁氧基)吡啶(0.9g,3.0mmol)和双(频哪醇合)二硼(0.84g,3.3mmol)在1,4-二噁烷(15.0mL)中的搅拌溶液中添加乙酸钾(0.59g,6.0mmol)。将Pd(dppf)Cl2.DCM(0.24g,0.30mmol)在氮气氛下添加到反应混合物中并在80℃下加热12小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用10%EtOAc/PE纯化粗产物,得到2-(2,2,3,3-四氟环丁氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(765mg,2.2mmol,73%收率)。LCMS:348.1(M+H)+,Rt 2.92min
柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
A39:3-(氯二氟甲基)-6-(6-(2,2,3,3-四氟环丁氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向2-(2,2,3,3-四氟环丁氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(0.9g,2.59mmol)和6-氯-3-(氯二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(0.68g,2.85mmol)在1,4-二噁烷(6.0mL)中的搅拌溶液中添加水(1.0mL)和Cs2CO3(1.69g,5.19mmol)。将Pd(dppf)Cl2.DCM(0.21g,0.26mmol)在氮气氛下添加到反应混合物中并在80℃下加热12小时。将反应混合物冷却至室温,通过硅藻土过滤并减压浓缩。通过柱色谱在硅胶上采用40%EtOAc/PE纯化粗产物,得到3-(氯二氟甲基)-6-(6-(2,2,3,3-四氟环丁氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(233mg,0.55mmol,21%收率)。LCMS:423.8(M+H)+,Rt2.43min;柱:ZORBAX XDB C-18(50X 4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。
化合物12:3-(二氟(甲氧基)甲基)-6-(6-(2,2,3,3-四氟环丁氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
在室温下向Cs2CO3(463mg,1.42mmol)在MeCN(3.0mL)中的搅拌悬浮液中添加MeOH(0.12mL,2.84mmol)并搅拌30min。向反应混合物中逐滴添加3-(氯二氟甲基)-6-(6-(2,2,3,3-四氟环丁氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(100mg,0.24mmol)的MeCN(3.0mL)溶液并搅拌2小时。将反应混合物用水(30mL)处理,并用EtOAc(2×30mL)萃取。将有机层用盐水(20mL)洗涤,在Na2SO4上干燥并浓缩,得到粗产物。通过制备型HPLC纯化粗产物,得到固体形式的12(25mg,0.06mmol,24%收率)。制备型HPLC方法:Rt 12.62;柱:X-BridgeC18(150X 19mm),5.0μm;流动相:0.1%TFA水溶液/乙腈;流速:15.0mL/min。HPLC:Rt4.88min;柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相:A:0.1%TFA水溶液,B:含0.1%TFA的ACN;流速:2.0mL/min。LCMS:420.1(M+H)+,Rt 2.38min;柱:ZORBAX XDB C-18(50X4.6mm),3.5μm;流动相:A:0.1%HCOOH水溶液:ACN(95:5),B:ACN;流速:1.5mL/min。1H NMR(400MHz,DMSO-d6):δH=9.71(d,1H),8.98-8.96(m,2H),8.53(dd,1H),7.19(dd,1H),5.74-5.69(m,1H),3.93(s,3H),3.02-2.88(m,1H),2.61-2.48(m,1H)。
实施例11.化合物13:3-[二氟(甲氧基)甲基]-6-[6-[(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和化合物14:3-[二氟(甲氧基)甲基]-6-[6-[(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A41:1,1,1-三氟丁-2-醇
在0℃下向1,1,1-三氟丁-2-酮(30g,237.94mmol)在乙醚(300mL)和水(10mL)中的溶液中逐份添加NaBH4(9.0g,237.94mmol)的水(40mL)溶液。将混合物在32℃下搅拌16小时。添加0.5M HCl以酸化至pH 6。用EtOAc(100mL×3)萃取水层。将合并的有机层用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并减压浓缩。减压蒸馏粗产物(水泵,沸点75~80℃),得到油形式的产物(12g,67.45mmol,28%收率)。1H NMR(400MHz,CDCl3)δH=3.90-3.78(m,1H),2.80-2.60(m,1H),1.83-1.70(m,1H),1.60-1.55(m,1H),1.07(t,3H)。
A42:5-溴-2-[1-(三氟甲基)丙氧基]吡啶
在0℃下向1,1,1-三氟丁-2-醇(4g,22.48mmol)在THF(50mL)中的溶液中逐份添加NaH(0.99g,24.73mmol,油中的60%)。将混合物在0℃下搅拌30min。然后将5-溴-2-氟-吡啶(4.35g,24.73mmol)逐滴添加到上述混合物中。将混合物在75℃下搅拌16小时。添加水(50mL),并用EtOAc(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE 0至2%)纯化粗产物,得到油形式的产物(6.3g,22.18mmol,99%收率)。1H NMR(400MHz,CDCl3)δH=8.18(d,1H),7.75-7.67(m,1H),6.76(d,1H),5.80-5.67(m,1H),2.00-1.80(m,2H),1.01(t,3H)。
A43:5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-[1-(三氟甲基)丙氧基]吡啶
向5-溴-2-[1-(三氟甲基)丙氧基]吡啶(6.3g,22.18mmol)在1,4-二噁烷(70mL)中的溶液中添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(6.19g,24.4mmol)和KOAc(4.35g,44.36mmol)。然后将Pd(dppf)Cl2(811mg,1.11mmol)在N2下添加到上述混合物中。将所得混合物在100℃搅拌16小时。过滤混合物并减压浓缩滤液。添加水(100mL),并用EtOAc(100mL x 3)萃取水层。将合并的有机层用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(PE)纯化粗产物,得到油形式的产物(7.1g,21.44mmol,97%收率)。1H NMR(400MHz,CDCl3)δH=8.50(d,1H),7.98(dd,1H),6.80(d,1H),5.97-5.86(m,1H),2.00-1.80(m,2H),1.35(s,12H),1.00(t,3H)。
A44:2-氯-5-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪
向5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-[1-(三氟甲基)丙氧基]吡啶(6.3g,19.03mmol)在1,4-二噁烷(100mL)和水(10mL)中的溶液中添加2-溴-5-氯-吡嗪(4.05g,20.93mmol)和Cs2CO3(9.3g,28.54mmol)。将混合物在50℃下搅拌6小时。过滤混合物并浓缩滤液。添加水(50mL),并用EtOAc(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE 0至10%)纯化粗产物,得到固体形式的产物(4.2g,13.22mmol,69%收率)。1HNMR(400MHz,CDCl3)δH=8.80-8.73(m,2H),8.63(s,1H),8.27(dd,1H),6.98(d,1H),5.95-5.85(m,1H),2.06-1.87(m,2H),1.05(t,3H)。
A45:[5-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼
向2-氯-5-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪(4.2g,13.22mmol)在MeCN(40mL)中的溶液中添加水合肼(6.62g,132.2mmol)。将混合物在90℃下搅拌16小时。添加水(10mL),并用EtOAc(100mL x 3)萃取水层。将合并的有机层用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE 0至50%)纯化粗产物,得到固体形式的产物(3.1g,9.90mmol,75%收率)。1H NMR(400MHz,DMSO-d6)δH=8.70(d,1H),8.57(s,1H),8.29(dd,1H),8.19(s,1H),8.13(s,1H),7.02(d,1H),5.97-5.86(m,1H),4.34(brs,2H),2.00-1.77(m,2H),0.96(t,3H)。
A47:3-[溴(二氟)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向2-溴-2,2-二氟-乙酸(838mg,4.79mmol)在甲苯(10mL)中的溶液中添加(COCl)2(0.49mL,5.75mmol)和1滴DMF。将混合物在30℃下搅拌1小时。将[5-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼(1.0g,3.19mmol)添加到上述混合物中。将混合物在30℃下搅拌16小时。将TsOH(165mg,0.96mmol)添加到上述混合物中并将混合物在140℃下搅拌16小时。添加水(50mL),并用EtOAc(50mL x 3)萃取水层。将合并的有机层用盐水(50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上纯化粗产物,得到固体形式的产物(1.1g,2.43mmol,76%收率)。1H NMR(400MHz,CDCl3)δH=9.61(d,1H),8.75(d,1H),8.42(s,1H),8.26(dd,1H),7.03(d,1H),5.97-5.83(m,1H),2.05-1.87(m,2H),1.06(t,3H)。
A48:3-[二氟(甲氧基)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,1.11mmol)在甲醇(5mL)中的溶液中添加AgBF4(429mg,2.21mmol)和Na2CO3(234.4mg,2.21mmol)。将混合物在70℃下搅拌4小时。添加水(30mL),并用EtOAc(30mLx 3)萃取水层。将合并的有机层用盐水(30mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE 0至40%)纯化粗产物,得到固体形式的产物(300mg,0.74mmol,67%收率)。LCMS Rt=1.02min(在1.5min色谱中),5-95AB,C16H15F5N5O2[M+H]+的MS ESI计算值404.1,实测值404.0。
化合物13和14:3-[二氟(甲氧基)甲基]-6-[6-[(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[二氟(甲氧基)甲基]-6-[6-[(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
分析SFC:(Chiralpak OJ-3 150x 4.6mm I.D,3mm。流动相:A:CO2,B:乙醇(0.05%DEA)。梯度:在5min内从5%至40%的B以及在0.5min内从40%至5%,保持5%的B达1.5min。流速:2.5mL/min柱温:35℃。ABPR:1500psi)显示出2.45min(49.9%)和2.73min(50.1%)处的两个峰。通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm)A=CO2且B=Neu-EtOH;70mL/min;15%B,进样次数:80)纯化3-[二氟(甲氧基)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(300mg,0.74mmol),得到固体形式的对映异构体1(其被随机归属为3-[二氟(甲氧基)甲基]-6-[6-[(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪)(114.98mg,0.29mmol,26%收率)(峰1的Rt=2.552min)和对映异构体2(其被随机归属为3-[二氟(甲氧基)甲基]-6-[6-[(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪)(120.19mg,0.29mmol,26%收率)(峰2的Rt=2.833min)。13和14的立体构型被随机归属。
化合物13:1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.71(s,1H),8.43(s,1H),8.35-8.18(m,1H),7.10-6.95(m,1H),5.97-5.83(m,1H),3.97(s,3H),2.10-1.85(m,2H),1.15-0.95(m,3H)。LCMS Rt=1.29min(在2.0min色谱中),10-80AB,C16H15F5N5O2[M+H]+的MSESI计算值404.1,实测值404.2。
化合物14:1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.71(d,1H),8.43(s,1H),8.23(dd,1H),7.00(d,1H),5.97-5.83(m,1H),3.97(s,3H),2.07-1.87(m,2H),1.06(d,3H)。LCMSRt=1.28min(在2.0min色谱中),10-80AB,C16H15F5N5O2[M+H]+的MS ESI计算值404.1,实测值404.2。实施例12.化合物15:3-[二氟(甲氧基)甲基]-6-[6-[(1R)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和化合物16:3-[二氟(甲氧基)甲基]-6-[6-[(1S)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A50:3-[(5-溴-2-吡啶基)氧基]丁-2-酮
在0℃下向3-羟基丁-2-酮(20.0g,226.99mmol)在THF(500mL)中的溶液中逐份添加NaH(10.9g,272.39mmol,油中的60%)。将混合物在20℃下搅拌1小时。然后将5-溴-2-氟-吡啶(39.95g,226.99mmol)添加到上述混合物中并将所得混合物在80℃下搅拌16小时。将混合物倒入水(1L)中并用EtOAc(1L x 2)萃取水层。将合并的有机相用盐水(500mL x 2)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至5%至10%)纯化粗产物,得到油形式的产物(30.0g,122.91mmol,54%收率)。1H NMR(400MHz,CDCl3)δH=8.09(d,1H),7.67(dd,1H),6.75(d,1H),5.21(q,1H),2.18(s,3H),1.48(d,3H)。
A51:5-溴-2-(2,2-二氟-1-甲基-丙氧基)吡啶
在0℃下向3-[(5-溴-2-吡啶基)氧基]丁-2-酮(15.0g,61.45mmol)在DCM(60mL)中的溶液中添加DAST(40.93mL,307.26mmol)。将混合物在25下搅拌16小时。将混合物逐滴添加到水(300mL)中并用EtOAc(300mL x 2)萃取水层。将合并的有机相用盐水(300mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(DCM/PE=0%至2%至5%)纯化粗产物,得到油形式的产物(5.0g,18.79mmol,31%收率)。1H NMR(400MHz,CDCl3)δH=8.18(d,1H),7.69-7.64(m,1H),6.70(dd,1H),5.47-5.37(m,1H),1.66(t,3H),1.39(d,3H)。
A52:2-(2,2-二氟-1-甲基-丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
将1,4-二噁烷(30mL)中的5-溴-2-(2,2-二氟-1-甲基-丙氧基)吡啶(4.0g,15.03mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(3.82g,15.03mmol)、KOAc(2.95g,30.07mmol)和Pd(dppf)Cl2(550mg,0.75mmol)的混合物在90℃下于N2下搅拌3小时。在冷却至室温后,通过硅藻土过滤混合物。浓缩滤液并通过快速色谱在硅胶上(DCM/PE=0%至5%)纯化粗产物,得到油形式的产物(2.5g,7.98mmol,53%收率)。LCMS Rt=0.99min(在1.5min色谱中),5-95AB,C15H23BF2NO3[M+H]+的MS ESI计算值314.2,实测值314.2。
A53:2-氯-5-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]吡嗪
将1,4-二噁烷(30mL)和水(3mL)中的2-(2,2-二氟-1-甲基-丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(3.5g,11.18mmol)、2-溴-5-氯-吡嗪(2.16g,11.18mmol)、Cs2CO3(7.28g,22.35mmol)及Pd(dppf)Cl2(817.8mg,1.12mmol)的混合物在55℃下搅拌2小时。在冷却至室温后,将混合物通过硅藻土过滤并浓缩。添加水(100mL),并用EtOAc(100mL x 2)萃取混合物。将合并的有机相用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至15%至30%)纯化粗产物,得到固体形式的产物(1.8g,6.01mmol,53%收率)。1H NMR(400MHz,CDCl3)δH=8.82-8.70(m,2H),8.63(d,1H),8.24(dd,1H),6.92(d,1H),5.64-5.53(m,1H),1.70(t,3H),1.45(d,3H)。
A54:[5-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]吡嗪-2-基]肼
将MeCN(20mL)中的2-氯-5-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]吡嗪(1.8g,6.01mmol)和水合肼(3.01g,60.06mmol)的混合物在95℃下搅拌16小时。在冷却至室温后,添加水(100mL),并用EtOAc(100mL x 2)萃取混合物。将合并的有机相用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至50%至80%)纯化粗产物,得到固体形式的产物(1.5g,5.08mmol,84%收率)。1H NMR(400MHz,DMSO-d6)δH=8.70(d,1H),8.55(d,1H),8.25(dd,1H),8.19(d,1H),8.12(s,1H),6.93(d,1H),5.61-5.43(m,1H),4.33(s,2H),1.68(t,3H),1.35(d,3H)。
A56:3-[溴(二氟)甲基]-6-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向2-溴-2,2-二氟-乙酸(1.32g,7.55mmol)在甲苯(15mL)中的溶液中添加一滴DMF。然后在0℃下将乙二酰二氯(0.77mL,9.06mmol)添加到该溶液中。将所得混合物在25℃搅拌1小时。将[5-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]吡嗪-2-基]肼(1.5g,5.08mmol)添加到上述混合物中并将混合物在25℃下搅拌2小时。添加TsOH(262mg,1.52mmol)并将混合物在125℃下搅拌16小时。在冷却到室温之后,将混合物减压浓缩。添加水(100mL),并用EtOAc(100mL x 2)萃取混合物。将合并的有机相用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至20%至40%)纯化粗产物,得到固体形式的产物(1.3g,2.99mmol,59%收率)。LCMS Rt=1.30min(在2.0min色谱中),10-80AB,C15H13BrF4N5O[M+H]+的MS ESI计算值436.0,实测值435.9。
A57:3-[二氟(甲氧基)甲基]-6-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
将甲醇(20mL)中的3-[溴(二氟)甲基]-6-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(1.3g,2.99mmol)、Na2CO3(634.69mg,5.99mmol)和AgBF4(1.16g,5.99mmol)的混合物在70℃下于黑暗下搅拌2小时。在冷却至室温后,添加盐水(100mL)和EtOAc(100mL)并通过硅藻土过滤混合物。在分离各相后,将有机相用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物。通过快速色谱在硅胶上(EtOAc/PE=0%至15%至30%)及通过制备型HPLC(Phenomenex Gemini-NX(80mm x 30mm,3μm)A=H2O(10mM NH4HCO3)且B=CH3CN;46-56%B持续8分钟)纯化粗产物,得到固体形式的产物(600mg,1.56mmol,52%收率)。1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.72(d,1H),8.42(d,1H),8.20(dd,1H),6.95(d,1H),5.66-5.53(m,1H),3.97(s,3H),1.71(t,3H),1.46(d,3H)。
化合物15和16:3-[二氟(甲氧基)甲基]-6-[6-[(1R)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[二氟(甲氧基)甲基]-6-[6-[(1S)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
分析SFC:(Chiralcel OJ-3 150x 4.6mm I.D,3μm。流动相:A:CO2B:乙醇(0.05%DEA)。梯度:在5min内从5%至40%的B以及在0.5min内从40%至5%的B并保持5%的B达1.5min。流速:2.5mL/min。柱温:35℃。ABPR:1500psi)显示出3.57min(49.91%)和3.80min(50.09%)处的两个峰。通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm)A=CO2且B=0.1%NH3H2O-EtOH;60mL/min;25%B,进样次数:170)纯化3-[二氟(甲氧基)甲基]-6-[6-(2,2-二氟-1-甲基-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(600mg,1.56mmol),得到固体形式的对映异构体1(被随机归属为3-[二氟(甲氧基)甲基]-6-[6-[(1R)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪)(226.75mg,0.58mmol,37%收率)(峰1的Rt=3.566min)和对映异构体2(被随机归属为3-[二氟(甲氧基)甲基]-6-[6-[(1S)-2,2-二氟-1-甲基-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪)(229.52mg,0.60mmol,38%收率)(峰2的Rt=3.803min)。15和16的立体构型被随机归属。
化合物15:
1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.72(d,1H),8.42(d,1H),8.20(dd,1H),6.95(d,1H),5.20-5.05(m,1H),3.97(s,3H),1.71(t,3H),146(d,3H)。LCMS Rt=1.23min(在2.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.1,实测值386.0。
化合物16:
1H NMR(400MHz,CDCl3)δH=9.52(s,1H),8.72(d,1H),8.42(s,1H),8.20(dd,1H),6.95(d,1H),5.20-5.05(m,1H),3.97(s,3H),1.71(t,3H),146(d,3H)。LCMS Rt=1.23min(在2.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.1,实测值386.0。
实施例13.化合物17:3-[二氟(丙氧基)甲基]-6-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
化合物17:3-[二氟(丙氧基)甲基]-6-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-[外消旋-(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(100mg,0.23mmol)在1-丙醇(3mL)中的溶液中添加AgBF4(88.6mg,0.46mmol)。将混合物在60℃下搅拌1小时。在冷却至室温后,添加盐水(10mL)和EtOAc(10mL)。过滤混合物,并用EtOAc(10mL x 3)洗涤滤饼。分离滤液,并且将有机层用盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至30%的EtOAc/PE)纯化混合物。通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2且B=EtOH(0.1%NH3.H2O);15%B;60mL/min)纯化混合物;得到固体形式的产物(26.8mg,0.06mmol)。1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.70(d,1H),8.45(d,1H),8.21(dd,1H),7.02-6.94(m,1H),5.94-5.80(m,1H),4.24(t,2H),1.96-1.73(m,2H),1.55-1.53(m,3H),1.08(t,3H)。LCMS Rt=1.32min(在2.0min色谱中),10-80AB,C17H17F5N5O2[M+H]+的MS ESI计算值418.1,实测值418.1。
实施例14.化合物18:3-[二氟(异丙氧基)甲基]-6-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
化合物18:3-[二氟(异丙氧基)甲基]-6-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-[外消旋-(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(100mg,0.23mmol)在异戊醇(4mL)中的溶液中添加AgBF4(88.6mg,0.46mmol)。将混合物在60℃下搅拌1小时。在冷却至室温后,添加盐水(10mL)和EtOAc(10mL)。过滤混合物,并用EtOAc(10mL x 3)洗涤滤饼。分离滤液,并且将有机层用盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至30%的EtOAc/PE)纯化混合物。通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2且B=EtOH(0.1%NH3.H2O);15%B;60mL/min)纯化混合物;得到固体形式的产物(27.3mg,0.07mmol,68%收率)。1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.69(d,1H),8.45(d,1H),8.21(dd,1H),6.98(d,1H),5.99-5.73(m,1H),5.11-4.79(m,1H),1.55-1.53(m,3H),1.51(d,6H)LCMSRt=1.31min(在2.0min色谱中),10-80AB,C17H17F5N5O2[M+H]+的MS ESI计算值418.1,实测值418.1。
实施例15.化合物19和20:3-[乙氧基(二氟)甲基]-6-[6-[外消旋-(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[乙氧基(二氟)甲基]-6-[6-[外消旋-(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A59:3-[乙氧基(二氟)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(300mg,0.66mmol)在乙醇(10mL)中的溶液中添加AgBF4(257.4mg,1.33mmol)。将混合物在60℃下搅拌1小时。在冷却至室温后,添加盐水(10mL)和EtOAc(10mL)。过滤混合物,并用EtOAc(10mL x 3)洗涤滤饼。分离滤液,并且将有机层用盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至30%的EtOAc/PE)纯化混合物,得到油形式的产物(200mg,0.48mmol,72%收率)。1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.69(d,1H),8.45(d,1H),8.22(dd,1H),7.00(d,1H),5.99-5.82(m,1H),4.40-4.29(m,2H),2.10-1.82(m,2H),1.50(t,3H),1.05(t,3H)。
化合物19和20:3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和
3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪。注意,立体构型被随机归属。
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2 B=EtOH(0.1%NH3.H2O);15%B;60mL/min)纯化3-[乙氧基(二氟)甲基]-6-[6-[1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.48mmol)的混合物;得到固体形式的3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(峰1,52.1mg,0.12mmol)和固体形式的3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(峰2,44.3mg,0.10mmol)。
化合物19:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.69(d,1H),8.45(d,1H),8.22(dd,1H),7.00(d,1H),5.94-5.84(m,1H),4.40-4.29(m,2H),2.06-1.83(m,2H),1.50(t,3H),1.05(t,3H)LCMS Rt=1.33min(在2.0min色谱中),10-80AB,C17H17F5N5O2[M+H]+的MSESI计算值418.1,实测值418.1。
化合物20:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.69(d,1H),8.45(d,1H),8.22(dd,1H),7.00(d,1H),5.95-5.83(m,1H),4.44-4.25(m,2H),2.08-1.83(m,2H),1.50(t,3H),1.05(t,3H)Rt=1.34min(在2.0min色谱中),10-80AB,C17H17F5N5O2[M+H]+的MS ESI计算值418.1,实测值418.1。
实施例16.化合物21:(S)-3-(二氟(丙氧基)甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
化合物21:(S)-3-(二氟(丙氧基)甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向(S)-3-(溴二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.46mmol)在1-丙醇(5mL)中的溶液中添加AgBF4(177.1mg,0.91mmol)。在60℃下搅拌12小时后,将混合物冷却至25℃,用盐水(10mL)稀释,并用EtOAc(2x 10mL)萃取。将合并的有机层用盐水(20mL x 2)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至40%的EtOAc/PE)纯化残余物,得到固体形式的产物(117.6mg,0.28mmol,61%收率)。1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.70(d,1H),8.45(d,1H),8.24-8.16(m,1H),6.98(d,1H),5.95-5.75(m,1H),4.24(t,2H),1.94-1.79(m,2H),1.54(d,3H),1.08(t,3H)。LCMS Rt=1.072min(在1.5min色谱中),5-95AB,C17H17F5N5O2[M+H]+的MSESI计算值418.1,实测值418.1。
实施例17.化合物22:(S)-3-(二氟(异丙氧基)甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成
化合物22:(S)-3-(二氟(异丙氧基)甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪
向(S)-3-(溴二氟甲基)-6-(6-((1,1,1-三氟丙-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(200mg,0.46mmol)在iPrOH(5mL)中的溶液中添加AgBF4(177.1mg,0.91mmol)。在60℃下搅拌12小时后,将混合物冷却至25℃,并添加盐水(10mL)。用EtOAc(2x10mL)萃取混合物。将合并的有机层用盐水(2x 20mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至40%的EtOAc/PE)纯化残余物,得到固体形式的产物(109.4mg,0.26mmol,57%收率)。1H NMR(400MHz,CDCl3)δH=9.50(d,1H),8.69(d,1H),8.45(d,1H),8.26-8.16(m,1H),6.98(d,1H),5.97-5.77(m,1H),5.12-4.77(m,1H),1.54(d,3H),1.51(s,3H),1.50(s,3H)。LCMS Rt=1.061min(在1.5min色谱中),5-95AB,C17H17F5N5O2[M+H]+的MSESI计算值418.0,实测值418.0。
实施例18.化合物24和23:(S)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪和(R)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪的合成。注意,立体构型被随机归属。
A61:2-氯-5-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]吡嗪
将1,4-二噁烷(50mL)和水(5mL)中的2-溴-5-氯-吡嗪(2.49g,12.9mmol)、2-(2,2-二氟-1-甲基-乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(3.50g,11.7mmol)、Pd(dppf)Cl2(0.86g,1.17mmol)和Cs2CO3(7.62g,23.4mmol)的混合物在50℃下于N2下搅拌16小时。在冷却至25℃后,分离水相,并浓缩有机相以去除大部分二噁烷。然后将残余物倒入水(50mL)中,并用EtOAc(2x 30mL)萃取混合物。将合并的有机相用水(20mL)和盐水(20mL)洗涤,在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(EtOAc/PE=0至1%至3%至20%)纯化粗产物,得到固体形式的产物(2.50g,8.75mmol,75%收率)。1HNMR(400MHz,CDCl3)δH=8.76-8.72(m,2H),8.64-8.60(m,1H),8.24(dd,1H),6.91(d,1H),6.14-5.79(m,1H),5.60-5.46(m,1H),1.45(d,3H)。
A62:[5-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]吡嗪-2-基]肼
将肼(5.61g,175.0mmol)和2-氯-5-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]吡嗪(2.50g,8.75mmol)在MeCN(35mL)中的溶液在90℃下于N2下搅拌16小时,得到溶液。在冷却至室温后,浓缩溶液,得到残余物。向残余物中添加水(50mL),并用EtOAc(2x 50mL)萃取混合物。将合并的有机相用盐水(2x 50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(2.50g,8.89mmol,粗制)。1H NMR(400MHz,CDCl3)δH=8.69-8.57(m,1H),8.47-8.38(m,1H),8.34-8.25(m,1H),8.20-8.09(m,1H),6.92-6.80(m,1H),6.16-5.80(m,2H),5.59-5.42(m,1H),4.00-3.85(m,2H),1.50-1.40(m,3H)。
A64:2-溴-N'-[5-[6-(2,2-二氟-1-甲基-乙氧基)-5-氟-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼
向2-溴-2,2-二氟-乙酸(1.24g,7.09mmol)和1mL DMF在THF(10mL)中的溶液中添加(COCl)2(0.73mL,8.51mmol),并将混合物在0℃下搅拌1小时。然后将混合物在30℃下搅拌1小时,得到第一混合物。将2-溴-2,2-二氟-乙酰氯(1.35g,6.98mmol)的THF(20mL)溶液和[5-[6-(2,2-二氟-1-甲基-乙氧基)-5-氟-3-吡啶基]吡嗪-2-基]肼(1.90g,6.35mmol)的混合物在20℃下搅拌1小时,然后添加到第一混合物中,并将所得混合物在30℃下搅拌16小时。在冷却至室温后,将混合物倒入水(30mL)中并用EtOAc(20mL)萃取。将合并的有机相用盐水(2x 20mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到油形式的产物(2.00g,4.35mmol,68%收率)LCMS Rt=1.00min(在1.5min色谱中),5-95AB,C14H12BrF4N5O2[M+3H]+的MS ESI计算值439.8,实测值439.8。
A63:3-[溴(二氟)甲基]-6-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向2-溴-N'-[5-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼(2.00g,4.56mmol)在DCM(15mL)中的溶液中添加2-甲氧基吡啶(1.99g,18.3mmol)和Tf2O(1.54mL,9.13mmol)。在20℃下搅拌2小时后,将反应体系倒入水(10mL)中并用EtOAc(10mL x 3)萃取。将合并的有机相用饱和NaHCO3水溶液(30mL x 2)和盐水(30mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至30%的EtOAc/PE)纯化残余物,得到油形式的产物(1.00g,2.38mmol,52%收率)。1H NMR(400MHz,CDCl3)δH=9.56(d,1H),8.17(s,1H),7.50-7.25(m,1H),6.99(d,2H),5.23(s,2H),2.40(s,3H)。
A65:6-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,1.19mmol)在乙醇(5mL)中的溶液中添加AgBF4(461.7mg,2.38mmol)。将混合物在60℃下搅拌3小时。在冷却至室温后,添加盐水(10mL)和EtOAc(10mL)。过滤混合物,并用EtOAc(10mL x 3)洗涤滤饼。分离滤液,并且将有机层用盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到粗产物,通过快速柱色谱在硅胶上(EtOAc/PE=0至1%至3%至20%)纯化该粗产物,得到油形式的产物(100mg,0.26mmol,22%收率)。1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.70(d,1H),8.46-8.42(m,1H),8.20(dd,8.7Hz,1H),6.94(d,1H),6.15-5.82(m,1H),5.60-5.47(m,1H),4.35(q,2H),1.52-1.44(m,6H)。
化合物24和23:(S)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪和(R)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
通过制备型SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2且B=MeOH(0.1%NH3.H2O);15%B)纯化上述不纯产物;得到固体形式的(S)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(31.7mg,0.08mmol)和(R)-6-(6-((1,1-二氟丙-2-基)氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(23.9mg,0.06mmol)。
化合物24:1H NMR(400MHz,CDCl3)δH=9.57-9.47(m,1H),8.77-8.64(m,1H),8.44(d,1H),8.46-8.40(m,1H),8.20(dd,1H),6.94(d,1H),6.21-5.78(m,1H),5.61-5.42(m,1H),4.40-4.29(m,1H),1.52-1.45(m,6H)。LCMS Rt=1.95min(在3.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.2,实测值386.2。
化合物23:1H NMR(400MHz,CDCl3)δH=9.57-9.47(m,1H),8.77-8.64(m,1H),8.44(d,1H),8.46-8.40(m,1H),8.20(dd,8.8Hz,1H),6.94(d,1H),6.21-5.78(m,1H),5.61-5.42(m,1H),4.40-4.29(m,1H),1.52-1.45(m,6H)。LCMS Rt=1.95min(在3.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.2,实测值386.2。
实施例19.化合物25、26、27和28:(R)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪、(S)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪、(S)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪和(R)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪的合成。注意,立体构型被随机归属。
A70:2-氯-5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪
在N2下向2-[2-甲基-1-(三氟甲基)丙氧基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(8.5g,24.6mmol)在1,4-二噁烷(80mL)和水(8mL)中的溶液中添加2-溴-5-氯-吡嗪(4.76g,24.6mmol)、Cs2CO3(16.0g,49.2mmol)和Pd(dppf)Cl2(1.08g,1.48mmol)。将反应体系在25℃下搅拌16小时,得到混合物。在冷却至25℃后,通过硅藻土过滤混合物,并真空浓缩滤液。通过快速柱色谱(EtOAc/PE,0%至3%)纯化粗混合物,得到固体形式的产物(7.8g,95%收率)。1H NMR(400MHz,CDCl3)δH=8.72-8.63(m,2H),8.56(d,1H),8.19(dd,1H),6.91(d,1H),5.84-5.70(m,1H),2.32-2.15(m,1H),1.02(d,6H)。
A71:[5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼
将MeCN(80mL)中的2-氯-5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪(7.8g,23.5mmol)和N2H4.H2O(8.85g,235mmol)的混合物在100℃下搅拌16小时。在冷却至25℃后,将混合物倒入水(300mL)中,并通过滤纸过滤混合物。将滤饼重新溶解于EtOAc(200mL)中,并通过硅藻土过滤混合物。将滤液用盐水(200mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(7g,91%收率)。1H NMR(400MHz,DMSO-d6)δH=8.71(d,1H),8.57(d,1H),8.30(dd,1H),8.23-8.09(m,2H),7.03(d,1H),5.90-5.79(m,1H),4.34(br s,2H),2.32-2.19(m,1H),1.03(d,6H)。
A69:2-溴-2,2-二氟-乙酰氯
向2-溴-2,2-二氟-乙酸(5g,28.5mmol)和0.1mL DMF在THF(75mL)中的溶液中添加(COCl)2(2.7mL,31.4mmol),并将混合物在25℃下搅拌1小时。将该溶液直接用于下一步而不进行表征。
A72:2-溴-2,2-二氟-N'-[5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]乙酰肼
向[5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼(7g,21.3mmol)在THF(70mL)中的溶液中添加2-溴-2,2-二氟-乙酰氯(5.53g,28.5mmol)。将所得混合物在25℃搅拌2小时,然后添加水(100mL)。用EtOAc(100mL x 2)萃取混合物和水层。将合并的有机相用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤,并浓缩成油形式的产物(10g,97%收率),将其直接用于下一步。
A73:3-[溴(二氟)甲基]-6-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向DCM(100mL)中的2-溴-2,2-二氟-N'-[5-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]乙酰肼(10g,20.6mmol)的混合物添加2-甲氧基吡啶(14.2g,130mmol)和Tf2O(10.5mL,62.0mmol)。将混合物在25℃下搅拌16小时,然后用水(100mL)处理。用EtOAc(100mL x 2)萃取混合物和水层。将合并的有机相用饱和NaHCO3水溶液(100mL)和盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(EtOAc/PE=0%至20%)纯化粗产物,得到产物1H NMR(400MHz,CDCl3)δH=9.57(d,1H),8.73(d,1H),8.40(s,1H),8.24(dd,1H),7.02(d,1H),5.92-5.75(m,1H),2.41-2.22(m,1H),1.10(d,6H)。
化合物25和26:(R)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪和(S)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪。注意,立体构型被随机归属。
将EtOH(4mL)中的3-[溴(二氟)甲基]-6-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(400mg,0.86mmol)和AgBF4(334mg,1.72mmol)的混合物在60℃下于黑暗中搅拌3小时。在冷却至25℃后,将混合物用盐水(30mL)洗涤,用EtOAc(30mL x 2)萃取,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(EtOAc/PE=0%至20%)纯化粗产物,得到油形式的产物(275mg,74%收率),通过SFC(DAICELCHIRALPAK AD(250mm x 30mm,10μm);A=CO2且B=EtOH(0.1%NH3.H2O);15%B;60mL/min;80次进样)进一步纯化该产物,得到固体形式的(R)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(99.62mg)和固体形式的(S)-3-(乙氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(97.9mg)。
化合物25:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.68(d,1H),8.44(d,1H),8.22(dd,1H),7.01(d,1H),5.91-5.76(m,1H),4.35(q,2H),2.38-2.34(m,1H),1.50(t,3H),1.10(d,6H)。LCMS Rt=2.033min(在3min色谱中),30-90AB,C18H19F5N5O2[M+H]+的MS ESI计算值432.1,实测值432.1
化合物26:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.68(d,1H),8.44(d,1H),8.22(dd,1H),7.01(d,1H),5.91-5.76(m,1H),4.35(q,2H),2.38-2.34(m,1H),1.50(t,3H),1.10(d,6H)。LCMS Rt=2.024min(在3min色谱中),30-90AB,C18H19F5N5O2[M+H]+的MS ESI计算值432.1,实测值432.1。
化合物27和28:(S)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪和
(R)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪。注意,立体构型被随机归属
将MeOH(4mL)中的3-[溴(二氟)甲基]-6-[6-[2-甲基-1-(三氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(400mg,0.86mmol)和AgBF4(334mg,1.72mmol)的混合物在60℃下于黑暗中搅拌3小时。在冷却至25℃后,将混合物用盐水(30mL)洗涤,用EtOAc(30mL x 2)萃取,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(EtOAc/PE=0%至30%)纯化粗产物,得到油形式的产物(160mg,45%收率),通过SFC(DAICELCHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2且B=IPA(0.1%NH3.H2O);15%B;60mL/min;100次进样)进一步纯化该产物,得到油形式的(S)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(29.4mg)和油形式的(R)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(70mg)。
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm),A=CO2 B=IPA(0.1%NH3.H2O);15%B;60mL/min;100次进样)纯化不纯(R)-3-(甲氧基二氟甲基)-6-(6-((1,1,1-三氟-3-甲基丁-2-基)氧基)吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪(70mg,0.17mmol),得到油形式的产物(33.3mg)。
化合物28:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.70(d,1H),8.42(d,1H),8.23(dd,1H),7.01(d,1H),5.89-5.78(m,1H),3.96(s,3H),2.37-2.25(m,1H),1.10(d,6H)。LCMSRt=1.879min(在3min色谱中),30-90AB,C17H17F5N5O2[M+H]+的MS ESI计算值418.1,实测值418.1。
化合物27:1H NMR(400MHz,CDCl3)δH=9.51(d,1H),8.70(d,1H),8.42(d,1H),8.23(dd,1H),7.01(d,1H),5.89-5.78(m,1H),3.96(s,3H),2.37-2.25(m,1H),1.10(d,6H)。LCMSRt=1.891min(在3min色谱中),30-90AB,C17H17F5N5O2[M+H]+的MS ESI计算值418.1,实测值418.1。
实施例20.化合物29和30:(R)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪和
(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪的合成。注意,立体构型被随机归属
A76:6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
向100mL密封管中Cs2CO3(1906.18mg,5.85mmol)在MeCN(15mL)中的搅拌悬浮液中添加乙醇(1.14mL,19.5mmol)。将反应混合物搅拌10min并在室温下添加3-[氯(二氟)甲基]-6-[6-(1-环丙基-2,2,2-三氟-乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(500mg,0.98mmol)的MeCN(10mL)溶液。将反应混合物在室温下搅拌30min。将混合物用冰水(20mL)淬灭并用乙酸乙酯(30mL x 2)萃取。将有机层在Na2SO4上干燥并浓缩。通过柱色谱硅胶100-200目使用14%乙酸乙酯/PE纯化粗化合物,从而提供产物。通过制备型HPLC进一步纯化产物,得到固体形式的产物(85.26mg,0.20mmol,20%收率)。1H NMR(400MHz,CDCl3)δH=9.50(d,1H),8.65(d,1H),8.43(d,1H),8.20(dd,1H),7.61-7.42(m,1H),6.98(d,1H),5.41(dd,1H),4.34(d,2H),1.48(t,3H),0.99-0.89(m,1H),0.80-0.69(m,1H),0.66-0.55(m,2H)
化合物29和30:(R)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪和
(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A=CO2且B=EtOH(0.1%NH3.H2O);10%B)纯化6-[6-(1-环丙基-2,2,2-三氟-乙氧基)-3-吡啶基]-3-[乙氧基(二氟)甲基]-[1,2,4]三唑并[4,3-a]吡嗪(150mg,0.35mmol)的混合物,得到油形式的(R)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(2.44mg)和(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(30mg,0.07mmol)。
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm),A=CO2且B=EtOH(0.1%NH3.H2O);10%B)纯化不纯(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(30mg),得到油形式的(S)-6-(6-(1-环丙基-2,2,2-三氟乙氧基)吡啶-3-基)-3-(乙氧基二氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(4.12mg)。
化合物29:1H NMR(400MHz,CDCl3)δH=9.53-9.48(m,1H),8.68-8.63(m,1H),8.43(s,1H),8.24-8.17(m,1H),7.02-6.96(m,1H),5.47-5.37(m,1H),4.35(q,2H),1.54-1.46(m,2H),1.34-1.25(m,1H),0.80-0.72(m,1H),2.84-0.57(m,4H)LCMS Rt=1.985min(在3.0min色谱中),30-90AB,C18H17F5N5O2[M+H]+的MS ESI计算值430.1,实测值430.1。
化合物30:1H NMR(400MHz,CDCl3)δH=9.55-9.44(m,1H),8.68-8.64(m,1H),8.43(s,1H),8.24-8.18(m,1H),7.03-6.97(m,1H),5.47-5.37(m,1H),4.40-4.31(m,2H),1.53-1.46(m,3H),1.35-1.24(m,1H),0.81-0.73(m,1H),0.62(br t,3H)LCMS Rt=1.888min(在3.0min色谱中),30-90AB,C18H17F5N5O2[M+H]+的MS ESI计算值430.1,实测值430.1。
实施例21.化合物31和32:3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪。注意,立体构型被随机归属。
A83:2,2-二氟戊-3-醇
在0℃下向THF(50mL)中的2,2-二氟丙酸甲酯(5g,40.3mmol)的混合物中逐滴添加EtMgBr(26.9mL,80.6mmol)(Et2O中的3M)。将混合物升温至20℃并搅拌2小时。向混合物中添加饱和NH4Cl溶液(50mL),并用THF(10mL x 2)萃取水层。将合并的有机层用盐水(20mL)洗涤并在无水Na2SO4上干燥,得到油形式的2,2-二氟戊-3-醇(5g,12.1mmol,30.0%收率),将其直接用于下一步。
A78:5-溴-2-(1-乙基-2,2-二氟-丙氧基)吡啶
在0℃下在30分钟内向2,2-二氟戊-3-醇(5g,40.3mmol)在THF(50mL)中的溶液中添加NaH(3.22g,80.6mmol),然后添加5-溴-2-氟-吡啶(6.38g,36.3mmol)。将混合物在60℃下搅拌16小时。在冷却至室温后,将混合物用饱和NH4Cl溶液(100mL)稀释并用EtOAc(100mLx 2)萃取。将合并的有机相用盐水(30mL)洗涤,在Na2SO4上干燥,过滤并浓缩,得到粗产物,通过快速色谱在硅胶上(EtOAc/PE=0%至1%至2%)纯化该粗产物,得到油形式的产物(7.4g,24.2mmol,60%收率)。1H NMR(400MHz,CDCl3)δH=8.19-8.11(m,1H),7.70-7.63(m,1H),6.71(d,1H),5.55-5.39(m,1H),1.92-1.82(m,1H),1.81-1.70(m,1H),1.66-1.57(m,3H),0.95(t,3H)。
A79:2-(1-乙基-2,2-二氟-丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
将1,4-二噁烷(100mL)中的5-溴-2-(1-乙基-2,2-二氟-丙氧基)吡啶(7.4g,26.4mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(7.38g,29.1mmol)、Pd(dppf)Cl2(1.93g,2.64mmol)和KOAc(5.19g,52.8mmol)的混合物在90℃下于N2下搅拌16小时。将混合物冷却至室温,过滤并浓缩,得到粗产物,通过快速色谱在硅胶上(EtOAc/PE=0%至1%至2%)纯化该粗产物,得到油形式的产物(6.1g,18.6mmol,71%收率)。1H NMR(400MHz,CDCl3)δH=8.50(d,1H),7.97-7.91(m,1H),6.76(d,1H),5.73-5.57(m,1H),1.94-1.83(m,1H),1.82-1.73(m,1H),1.64(s,1H),1.60(s,2H),1.33(s,12H),0.95(t,3H)。
A80:2-氯-5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪
将1,4-二噁烷(50mL)和水(5mL)中的Pd(dppf)Cl2(0.85g,1.16mmol)、Cs2CO3(7.57g,23.2mmol)、2-溴-5-氯-吡嗪(2.47g,12.8mmol)和2-(1-乙基-2,2-二氟-丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(3.8g,11.6mmol)的混合物在50℃下于N2下搅拌2小时。在冷却至25℃后,分离水相,并浓缩有机相以去除大部分二噁烷。然后用水(30mL)稀释残余物,并用EtOAc(60mL x 2)萃取混合物。将合并的有机相用水(40mL)和盐水(40mL)洗涤,在Na2SO4上干燥,过滤并浓缩。通过快速色谱在硅胶上(EtOAc/PE=0%至1%至3%至20%)纯化粗产物,得到固体形式的产物(3g,9.56mmol,82%收率)。1H NMR(400MHz,CDCl3)δ=8.74(d,2H),8.62(d,1H),8.26-8.20(m,1H),6.93(d,1H),5.72-5.60(m,1H),1.97-1.75(m,2H),1.64(t,3H),0.99(t,3H)。
A81:[5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪-2-基]肼
将2-氯-5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪(3g,9.56mmol)和肼(6.13g,191mmol)在MeCN(50mL)中的溶液在90℃下于N2下搅拌16小时,得到棕色溶液。在冷却至室温后,将溶液浓缩,用水(50mL)稀释并用EtOAc(50mL x 2)萃取。将合并的有机相用盐水(50mL x 2)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(2.6g,8.41mmol,88%收率)。将粗残余物直接用于下一步。
A84:2-溴-N'-[5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼
向2-溴-2,2-二氟-乙酸(4g,22.9mmol)在THF(40mL)中的溶液中添加乙二酰氯(2.35mL,27.4mmol)和DMF(1mL)。将混合物在0℃下搅拌1小时。将该溶液直接用于下一步而不进行进一步纯化。
向2-溴-2,2-二氟-乙酰氯的上述溶液中添加[5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪-2-基]肼(2.60g,8.41mmol),并将所得混合物在0℃下搅拌2小时。在升温至室温后,将混合物倒入水(40mL)中并用EtOAc(40mL)萃取。将合并的有机相用盐水(20mL x2)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到油形式的产物(7.60g,16.3mmol)。LCMS Rt=0.980min(在1.5min色谱中),5-95AB,C16H17BrF4N5O2[M+H]+的MS ESI计算值468.0,实测值468.0。
A82:3-[溴(二氟)甲基]-6-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向DCM(40mL)中的2-溴-N'-[5-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼(4.40g,9.44mmol)的黄色混合物中添加2-甲氧基吡啶(4mL,37.8mmol)和Tf2O(3.19mL,18.9mmol),并且将所得混合物在20℃下于N2下搅拌1小时。然后将混合物用水(40mL)稀释并用DCM(40mL x 2)萃取。将有机层在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(20至30%的EtOAc/PE)纯化残余物,得到固体形式的产物(800mg,1.78mmol,19%收率)。1H NMR(400MHz,CDCl3)δH=9.58(d,1H),8.73(d,1H),8.45-8.37(m,1H),8.26-8.17(m,1H),7.01-6.93(m,1H),5.72-5.59(m,1H),1.72-1.59(m,3H),1.27-1.24(m,2H),1.03-0.97(m,3H)。LCMS Rt=1.035min(在4.0min色谱中),30-90AB,C16H15BrF4N5O[M+H]+的MS ESI计算值447.9,实测值447.9。
A85:3-[乙氧基(二氟)甲基]-6-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
将乙醇(4mL)中的3-[溴(二氟)甲基]-6-[6-(1-乙基-2,2-二氟-丙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(400mg,0.89mmol)和AgBF4(347.5mg,1.78mmol)的混合物在60℃下于黑暗中搅拌1小时。在冷却至25℃后,将混合物用盐水(10mL)洗涤并用EtOAc(10mL x 2)萃取。将有机层在无水Na2SO4上干燥,过滤并浓缩。通过快速色谱在硅胶上(EtOAc/PE=0%至30%)纯化粗产物,得到固体形式的产物(60mg,0.15mmol,16%收率)。1HNMR(400MHz,CDCl3)δH=9.51(d,1H),8.68(d,1H),8.44(d,1H),8.24-8.16(m,1H),6.96(d,1H),5.75-5.59(m,1H),4.40-4.31(m,2H),1.97-1.76(m,2H),1.72-1.61(m,3H),1.53-1.46(m,3H),1.04-0.97(m,3H)。
化合物31和32:3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm),A:CO2,B=MeOH 0.1%NH3.H2O,25%B,60mL/min)纯化残余物,得到油形式的3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(30mg,0.07mmol)和油形式的3-[乙氧基(二氟)甲基]-6-[6-[外消旋-(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(25mg,0.06mmol)。通过制备型TLC纯化不纯3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(30mg,0.07mmol),得到油形式的3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(8.02mg,0.02mmol)。通过制备型TLC纯化不纯3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(25mg,0.06mmol),得到固体形式的3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(22.57mg,0.05mmol)。
化合物31:1H NMR(400MHz,CDCl3)δH=9.50(s,1H),8.68(d,1H),8.44(s,1H),8.24-8.14(m,1H),6.96(d,1H),5.76-5.54(m,1H),4.41-4.29(m,2H),1.99-1.88(m,1H),1.86-1.76(m,1H),1.73-1.62(m,3H),1.54-1.44(m,3H),1.05-0.95(m,3H)。LCMS Rt=1.292min(在2.0min色谱中),10-80AB,C18H20F4N5O2[M+H]+的MS ESI计算值414.1,实测值414.1。
化合物32:1H NMR(400MHz,CDCl3)δH=9.51(s,1H),8.69(d,1H),8.44(s,1H),8.24-8.16(m,1H),6.96(d,1H),5.76-5.51(m,1H),4.41-4.29(m,2H),1.96-1.89(m,1H),1.86-1.76(m,1H),1.72-1.59(m,3H),1.53-1.45(m,3H),1.05-0.96(m,3H)。LCMS Rt=1.283min(在2.0min色谱中),10-80AB,C18H20F4N5O2[M+H]+的MS ESI计算值414.1,实测值414.1。
实施例22.化合物33和34:3-[乙氧基(二氟)甲基]-6-[6-[(1R)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[乙氧基(二氟)甲基]-6-[6-[(1S)-1-乙基-2,2-二氟-丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪。注意,立体构型被随机归属。
A86:3-[二氟(异丙氧基)甲基]-6-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
在N2下向3-[溴(二氟)甲基]-6-[6-(2,2-二氟-1-甲基-乙氧基)-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(100mg,0.24mmol)在IPA(3mL)中的溶液中添加AgBF4(92.4mg,0.48mmol)。在60℃下搅拌12小时后,将混合物冷却至25℃并用盐水(10mL)稀释。用EtOAc(2x 10mL)萃取混合物。将合并的有机层用盐水(2x 10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至40%的EtOAc/PE)纯化残余物,得到固体形式的产物(40mg,0.1mmol,42%收率)。1H NMR(400MHz,CDCl3)δH=9.58-9.46(m,1H),8.80-8.64(m,1H),8.44(d,1H),8.19(dd,1H),6.94(d,1H),6.16-5.78(m,1H),5.66-5.46(m,1H),5.08-4.90(m,1H),1.51(d,6H),1.47(d,3H)。
化合物33和34:3-[二氟(异丙氧基)甲基]-6-[6-[(1R)-2,2-二氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[二氟(异丙氧基)甲基]-6-[6-[(1S)-2,2-二氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
通过SFC(DAICEL CHIRALCEL AY-H(250mm x 30mm,5μm);A:CO2 B=EtOH 0.1%NH3.H2O;15%B)纯化外消旋产物,得到固体形式的3-[二氟(异丙氧基)甲基]-6-[6-[(1R)-2,2-二氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(峰1,11.07mg)和3-[二氟(异丙氧基)甲基]-6-[6-[(1S)-2,2-二氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(峰2,7.39mg)的产物。
化合物33:1H NMR(400MHz,CDCl3)δH=9.51(s,1H),8.71-8.66(m,1H),8.44(s,1H),8.19(dd,1H),6.95(d,1H),6.18-5.80(m,1H),5.62-5.42(m,1H),5.11-4.90(m,1H),1.51(d,6H),1.47(d,3H)。LCMS Rt=1.95min(在3.0min色谱中),10-80AB,C17H18F4N5O2[M+H]+的MS ESI计算值400.2,实测值400.2。
化合物34:1H NMR(400MHz,CDCl3)δH=9.51(s,1H),8.70-8.67(m,1H),8.45(s,1H),8.19(dd,1H),6.95(d,1H),6.16-5.79(m,1H),5.63-5.46(m,1H),5.14-4.90(m,1H),1.50(d,6H),1.47(d,3H)。LCMS Rt=1.95min(在3.0min色谱中),10-80AB,C17H18F4N5O2[M+H]+的MS ESI计算值400.2,实测值400.2。
实施例23.化合物35和36:3-[二氟(甲氧基)甲基]-6-[6-[外消旋-(1R)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪和3-[二氟(甲氧基)甲基]-6-[6-[外消旋-(1S)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成。注意,立体构型被随机归属。
A93:1,1-二氟丁-2-醇
在0℃下向THF(30mL)中的2,2-二氟乙酸甲酯(5g,45.43mmol)的混合物中逐滴添加EtMgBr(30.3mL,90.9mmol)(Et2O中的3M)。将混合物升温至20℃并搅拌2小时。向混合物中添加饱和NH4Cl溶液(50mL),并用THF(2x 20mL)萃取水层。将合并的有机层用盐水(20mL)洗涤并在无水Na2SO4上干燥,得到油形式的1,1-二氟丁-2-醇(5g,13.6mmol),将其直接用于下一步。
A88:5-溴-2-[1-(二氟甲基)丙氧基]吡啶
在0℃下在30分钟内向1,1-二氟丁-2-醇(4.5g,40.89mmol)在THF(50mL)中的溶液中添加NaH(4.09g,102.22mmol)。然后将5-溴-2-氟-吡啶(10.8g,61.36mmol)添加到所得混合物中,并将混合物在60℃下搅拌16小时。在冷却至室温后,将混合物用饱和NH4Cl(50mL)稀释并用EtOAc(2x 50mL)萃取。将合并的有机相用盐水(30mL)洗涤,在Na2SO4上干燥,过滤并浓缩,得到粗产物,通过快速色谱在硅胶上(EtOAc/PE=0%至1%至2%)纯化该粗产物,得到油形式的产物(2g,6.89mmol)。1H NMR(400MHz,CDCl3)δH=8.20-8.11(m,1H),7.68(dd,1H),6.72(d,1H),6.08-5.72(m,1H),5.42-5.23(m,1H),1.94-1.73(m,2H),1.00(t,3H)。
A89:2-[1-(二氟甲基)丙氧基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
将1,4-二噁烷(25mL)中的Pd(dppf)Cl2(0.55g,0.75mmol)、KOAc(1.48g,15.03mmol)、5-溴-2-[1-(二氟甲基)丙氧基]吡啶(2g,7.52mmol)和双(频哪醇合)二硼(2.1g,8.27mmol)的混合物在90℃下于N2下搅拌16小时。将混合物冷却至室温,过滤并浓缩,得到粗产物,通过快速色谱在硅胶上(EtOAc/PE=0%至1%至2%)纯化该粗产物,得到油形式的产物(1.2g,3.83mmol)。1H NMR(400MHz,CDCl3)δH=8.49(s,1H),8.02-7.88(m,1H),6.76(d,1H),6.16-5.75(m,1H),5.61-5.33(m,1H),1.95-1.75(m,2H),1.33(s,12H),1.00(t,3H)。
A90:2-氯-5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪
将1,4-二噁烷(20mL)和水(2mL)中的Pd(dppf)Cl2(0.28g,0.38mmol)、Cs2CO3(2.5g,7.66mmol)、2-溴-5-氯-吡嗪(0.82g,4.22mmol)和2-[1-(二氟甲基)丙氧基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(1.2g,3.83mmol)的混合物在50℃下于N2下搅拌2小时。在冷却至25℃后,分离水相,并浓缩有机相以去除大部分二噁烷。然后将残余物倒入水(30mL)中并用EtOAc(2x 60mL)萃取。将合并的有机相用水(40mL)和盐水(40mL)洗涤,在Na2SO4上干燥,过滤并浓缩。通过快速色谱在硅胶上(EtOAc/PE=0%至1%至3%至20%)纯化粗产物,得到固体形式的产物(1g,3.34mmol,87%收率)。1H NMR(400MHz,CDCl3)δH=8.76-8.73(m,2H),8.65-8.60(m,1H),8.24(dd,1H),6.94(d,1H),6.17-5.77(m,1H),5.60-5.36(m,1H),1.98-1.79(m,2H),1.04(t,3H)。
A91:[5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼
将2-氯-5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪(1g,3.34mmol)和N2H4.H2O(3.34g,66.73mmol)在MeCN(15mL)中的溶液在90℃下于N2下搅拌16小时。在冷却至室温后,浓缩溶液,得到残余物。将残余物用水(50mL)稀释并用EtOAc(2x 50mL)萃取。将合并的有机相用盐水(2x 50mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(0.95g,3.22mmol,96%收率)。1H NMR(400MHz,CDCl3)δH=8.61-8.54(m,1H),8.40(d,1H),8.27(d,1H),8.16-8.09(m,1H),6.91-6.82(m,1H),6.13-5.80(m,1H),5.49-5.33(m,1H),4.55(s,3H),1.92-1.84(m,2H),1.08-0.96(m,3H)。
A94:2-溴-N'-[5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼
向2-溴-2,2-二氟-乙酸(620mg,3.54mmol)和DMF(0.5mL)在THF(5mL)中的溶液中添加(COCl)2(0.36mL,4.25mmol),并将混合物在0℃下搅拌1小时。向所得溶液中添加[5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]肼(0.95g,3.22mmol),并将混合物在20℃下搅拌1小时。在冷却至室温后,将混合物倒入水(30mL)中并用EtOAc(2x 20mL)萃取。将合并的有机相用盐水(2x 20mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到油形式的产物(0.95g,2.1mmol)。LCMS Rt=1.00min(在1.5min色谱中),5-95AB,C15H17BrF4N5O2[M+3H]+的MS ESI计算值454.0,实测值454.0。
A92:3-[溴(二氟)甲基]-6-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向2-溴-N'-[5-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]吡嗪-2-基]-2,2-二氟-乙酰肼(0.95g,2.1mmol)在DCM(15mL)中的溶液中添加2-甲氧基吡啶(0.92g,8.4mmol)和Tf2O(0.71mL,4.2mmol)。在20℃下搅拌2小时后,将反应体系倒入水(10mL)中并用EtOAc(3x10mL)萃取。将合并的有机相用饱和NaHCO3(2x 10mL)、盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速柱色谱(0至15%的EtOAc/PE)纯化残余物,得到油形式的产物(120mg,0.28mmol,13%收率)。1H NMR(400MHz,CDCl3)δH=9.57(d,1H),8.78-8.71(m,1H),8.43-8.37(m,1H),8.26-8.18(m,1H),6.99(d,1H),6.1-5.78(m,1H),5.56-5.40(m,1H),1.99-1.81(m,2H),1.06(t,3H)。
A95:3-[二氟(甲氧基)甲基]-6-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
向3-[溴(二氟)甲基]-6-[6-[1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(120mg,0.28mmol)在甲醇(5mL)中的溶液中添加NaOMe(29.86mg,0.55mmol),并将所得混合物在60℃下搅拌2小时。在冷却至室温后,将反应体系用水(10mL)淬灭并用EtOAc(2x 10mL)萃取。将合并的有机层用盐水(10mL)洗涤,在Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(90mg,0.19mmol,68%收率)。LCMS Rt=1.63min(在2.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.2,实测值386.2。
化合物35:3-[二氟(甲氧基)甲基]-6-[6-[(1R)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A:CO2 B=EtOH 0.1%NH3.H2O;15%B)纯化外消旋产物,得到固体形式的3-[二氟(甲氧基)甲基]-6-[6-[外消旋-(1R)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(8.51mg,0.0213mmol)的产物。1H NMR(400MHz,CDCl3)δH=9.57-9.46(m,1H),8.73-8.68(m,1H),8.44-8.40(m,1H),8.24-8.19(m,1H),6.97(d,J=8.8Hz,1H),6.14-5.83(m,1H),5.56-5.40(m,1H),3.96(s,3H),1.97-1.82(m,2H),1.05(t,J=7.6Hz,3H)。LCMS Rt=1.63min(在2.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.2,实测值386.2。
化合物36:3-[二氟(甲氧基)甲基]-6-[6-[(1S)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪
通过SFC(DAICEL CHIRALCEL OJ-H(250mm x 30mm,5μm);A:CO2 B=0.1%NH3.H2O;15%B)纯化外消旋产物,得到不纯产物,将其通过第二SFC(DAICEL CHIRALCEL OJ-H(250mmx 30mm,5μm);A:CO2 B=0.1%NH3.H2O;15%B)纯化,得到不纯产物。通过制备型TLC(PE:EA=2:1)纯化不纯产物,得到固体形式的3-[二氟(甲氧基)甲基]-6-[6-[外消旋-(1S)-1-(二氟甲基)丙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪(3.01mg,0.0076mmol)。1H NMR(400MHz,CDCl3)δH=9.57-9.46(m,1H),8.73-8.68(m,1H),8.44-8.40(m,1H),8.24-8.19(m,1H),6.97(d,1H),6.14-5.83(m,1H),5.56-5.40(m,1H),3.96(s,3H),1.97-1.82(m,2H),1.05(t,J=7.6Hz,3H)。LCMS Rt=1.63min(在2.0min色谱中),10-80AB,C16H16F4N5O2[M+H]+的MS ESI计算值386.2,实测值386.2。
实施例24:A58:3-[溴(二氟)甲基]-6-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]-[1,2,4]三唑并[4,3-a]吡嗪的合成
A96的合成:将1,4-二噁烷(2000mL)和水(500mL)中的5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-[(1R)-2,2,2-三氟-1-甲基-乙氧基]吡啶(200g,630.7mmol)、2-溴-5-氯-吡嗪(122g,630.7mmol)、Pd(dppf)Cl2(46.15g,63.07mmol)和Cs2CO3(513.7g,1.58mol)的混合物在50℃下于N2下搅拌2小时。在冷却至25℃后,分离混合物,并浓缩有机相以去除大部分二噁烷。将残余物倒入水(1L)中并用EtOAc(800mL x 2)萃取混合物。将合并的有机相用水(500mL)和盐水(500mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速色谱在硅胶上(EtOAc/PE=0%至1%至3%至20%)纯化粗产物,得到固体形式的产物(122g,401.75mmol,64%收率)。1H NMR(400MHz,CDCl3)δH=8.77-8.73(m,2H),8.63(d,1H),8.26(dd,1H),6.96(d,1H),5.93-5.82(m,1H),1.54(d,3H)。
A97的合成:在25℃下向2-氯-5-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]吡嗪(122g,401.75mmol)在MeCN(1000mL)中的溶液中添加肼(128.76g,4.02mol)。将混合物在90℃下搅拌16小时。在冷却至25℃后,将反应体系倒入水(2L)中并且通过过滤收集固体并用水(500mL x 2)洗涤固体。将固体溶解于EtOAc(1500mL)中,并且将混合物用盐水(500mL)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的粗产物(120g,401mmol)。LCMS Rt=0.96min(在2min色谱中),10-80AB,C12H13F3N5O[M+H]+的MS ESI计算值300.1,实测值299.9。
A98的合成:向2-溴-2,2-二氟-乙酸(91g,520.21mmol)在THF(1000mL)中的溶液中添加一滴DMF和(COCl)2(52.82mL,624.25mmol)。将混合物在20℃下搅拌30分钟。然后将[5-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]吡嗪-2-基]肼(120g,401mmol)添加到该溶液中。将混合物在20℃下搅拌1小时。将混合物倒入水(2L)中并用EtOAc(2L x 2)萃取水层。将合并的有机相用盐水(1L x 2)洗涤,在无水Na2SO4上干燥,过滤并浓缩,得到固体形式的产物(180g,293.6mmol)。
A58的合成:向2-溴-2,2-二氟-N'-[5-[6-[(1R)-2,2,2-三氟-1-甲基-乙氧基]-3-吡啶基]吡嗪-2-基]乙酰肼(180g,293.6mmol)在甲苯(1500mL)中的溶液中添加TsOH(5.18g,30.07mmol)。将混合物在125℃下搅拌16小时。在冷却至室温后,将混合物倒入水(1.5L)中并用EtOAc(1.5L x 2)萃取水层。将合并的有机相用盐水(500mL x 2)洗涤,在无水Na2SO4上干燥,过滤并浓缩。通过快速色谱在硅胶上(EtOAc/PE=10%至20%)纯化粗产物,得到固体形式的产物(55g,125.57mmol,31%收率)。1H NMR(400MHz,CDCl3)δH=9.59(d,1H),8.76(d,1H),8.41(d,1H),8.25(dd,1H),7.01(d,1H),5.96-5.80(m,1H),1.56(d,3H)。
实施例25:示例性化合物在调节晚钠电流(INaL)方面的功效
使用PatchXpressTM高通量电生理平台(Molecular Devices,Sunnyvale,CA)完成示例性化合物用于调节NaV1.6电压门控钠通道所表现的INaL的功能表征。使表达重组人NaV1.6(hNaV1.6)的HEK-293细胞生长于含10%FBS、2mM丙酮酸钠、10mM HEPES和400μg/mLG418的DMEM/高葡萄糖杜氏改良培养基中。在收获之前使细胞生长到50%–80%汇合度。洗涤胰蛋白酶处理的细胞,让其恢复1小时,然后以1x 106个细胞/ml的浓度重悬于胞外记录溶液中。PatchXpress的板载液体处理设施用于分配细胞和施加测试化合物。通过施加300nM ATX-II来诱发NaV晚电流。通过以0.1Hz的频率在200ms内将脉冲从非失活性钳制电位(例如,-120mV)去极化到0mV来诱发INaL。通过在测试脉冲的最后20ms内分析平均电流振幅来确定INaL振幅和稳定性。在用示例性化合物(例如,如本文所述)稳态阻断后,添加包含非通透性阳离子的无Na+溶液(例如,胆碱或NDMG)以确认钠电流的身份。INaL的稳态抑制百分比计算如下:[(INaL_化合物)/(INaL_对照)]*100,其中INaL_化合物和INaL_对照分别表示在存在或不存在化合物的情况下记录的INaL。
该测定得出的与hNaV1.6处的INaL抑制百分比相关的结果(使用与上述类似的程序但使用1μM表达重组人NaV 1.6(h NaV 1.6)的HEK-293细胞测得)总结于下表1中。在该表中,“A”指示小于30%的抑制率;“B”指示约30%至约70%之间的抑制率;并且“C”指示大于70%的抑制率。“N/A”指示不可用。
表1
虽然我们已经描述了许多实施方案,但是显而易见的是,可以改变我们的基本实例以提供利用本发明的化合物和方法的其他实施方案。因此,应理解,本发明的范围将由所附权利要求限定而不是由已以举例的方式表示的具体实施方案限定。
贯穿本申请引用的所有参考文献(包括文献引用、发布的专利、公开的专利申请和共同未决的专利申请)的内容在此明确以引用的方式整体地并入本文。除非另外定义,否则本文中使用的所有技术和科学术语都与本领域普通技术人员通常已知的含义一致。
Claims (38)
2.如权利要求1所述的化合物,其中Ra为乙基、异丙基或环丙基。
3.如权利要求1或2所述的化合物,其中Rb为甲基或乙基。
6.如权利要求5所述的化合物,其中Ra为甲基或乙基。
7.如权利要求5或6所述的化合物,其中Rb为甲基、乙基或异丙基。
8.如权利要求5至7中任一项所述的化合物,其中Rc为氢或甲基。
9.如权利要求5至8中任一项所述的化合物,其中Rc为氢。
10.如权利要求5至8中任一项所述的化合物,其中Rc为甲基。
13.一种药物组合物,所述药物组合物包含如权利要求1至12中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载剂。
14.一种在有需要的受试者中治疗与钠离子通道的异常功能相关的病症的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物。
15.如权利要求14所述的方法,其中所述病症是神经障碍或精神障碍。
16.如权利要求14或15所述的方法,其中所述病症是癫痫或癫痫综合征。
17.如权利要求14至16中任一项所述的方法,其中所述病症是遗传性癫痫或遗传性癫痫综合征。
18.如权利要求14至16中任一项所述的方法,其中所述病症是小儿癫痫或小儿癫痫综合征。
19.如权利要求14至16中任一项所述的方法,其中所述病症是癫痫性脑病。
20.如权利要求19所述的方法,其中所述癫痫性脑病选自德拉韦综合征、婴儿痉挛或林-戈综合征。
21.如权利要求14或15所述的方法,其中所述病症选自癫痫性脑病、带SCN1A、SCN2A、SCN8A突变的癫痫性脑病、婴儿早期癫痫性脑病、德拉韦综合征、带SCN1A突变的德拉韦综合征、全身性癫痫伴热性惊厥、儿童难治性癫痫伴全身性强直阵挛发作、婴儿痉挛、良性家族性新生儿-婴儿癫痫发作、SCN2A癫痫性脑病、带SCN3A突变的局灶性癫痫、带SCN3A突变的儿童隐源性部分性癫痫、SCN8A癫痫性脑病、癫痫不明原因猝死、拉斯姆森脑炎、婴儿恶性游走性部分性发作、常染色体显性遗传夜间额叶癫痫、癫痫预期猝死(SUDEP)、KCNQ2癫痫性脑病以及KCNT1癫痫性脑病。
22.一种治疗神经障碍或精神障碍的方法,其中所述方法包括向有需要的受试者施用如权利要求1至12中任一项所述的化合物或其所述药学上可接受的盐或如权利要求13所述的药物组合物。
23.一种治疗疼痛的方法,其中所述方法包括向有需要的受试者施用如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物。
24.一种在有需要的受试者中治疗或预防三叉神经自主神经性头痛(TAC)的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物,其中所述TAC选自阵发性偏头痛、持续性偏头痛、短暂单侧神经痛样头痛发作伴结膜充血和流泪(SUNCT)、短暂单侧神经痛样头痛发作伴颅自主神经症状(SUNA)以及长期自主神经症状伴偏头痛。
25.如权利要求24所述的方法,其中所述TAC是短暂单侧神经痛样头痛发作。
26.如权利要求24或25所述的方法,其中所述TAC是SUNCT。
27.如权利要求24或25所述的方法,其中所述TAC是SUNA。
28.如权利要求24至27中任一项所述的方法,其中所述受试者对用于治疗TAC的至少一种药物的反应不充分。
29.一种在有需要的受试者中治疗或预防偏头痛的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物,其中所述偏头痛选自无先兆偏头痛、有先兆偏头痛、1型家族性偏瘫性偏头痛(FHM1)、2型家族性偏瘫性偏头痛(FHM2)、4型家族性偏瘫性偏头痛(FHM4)和散发性偏瘫性偏头痛(SHM)。
30.如权利要求29所述的方法,其中所述偏头痛是无先兆偏头痛。
31.如权利要求29所述的方法,其中所述偏头痛是有先兆偏头痛。
32.如权利要求29所述的方法,其中所述偏头痛是FHM1。
33.如权利要求29所述的方法,其中所述偏头痛是FHM2。
34.如权利要求29所述的方法,其中所述偏头痛是FHM4。
35.如权利要求29所述的方法,其中所述偏头痛是SHM。
36.如权利要求29至35中任一项所述的方法,其中所述受试者对用于治疗偏头痛的至少一种药物的反应不充分。
37.一种在有需要的受试者中治疗或预防皮层扩散性抑制(CSD)的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物。
38.一种在有需要的受试者中治疗或预防颅神经病变或多发性颅神经病变的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐或如权利要求13所述的药物组合物,其中所述颅神经病变选自贝尔麻痹、微血管颅神经麻痹、第三神经麻痹、第四神经麻痹和第六神经麻痹。
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US11261188B2 (en) | 2016-11-28 | 2022-03-01 | Praxis Precision Medicines, Inc. | Fused heteroaryl compounds, and methods thereof for treating diseases, disorders, and conditions relating to aberrant function of a sodium channel |
US11492345B2 (en) | 2017-02-13 | 2022-11-08 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
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IL309843A (en) | 2018-05-30 | 2024-02-01 | Praxis Prec Medicines Inc | ion channel modulators |
US11773099B2 (en) | 2019-05-28 | 2023-10-03 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
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US11505554B2 (en) | 2019-05-31 | 2022-11-22 | Praxis Precision Medicines, Inc. | Substituted pyridines as ion channel modulators |
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