CN109476640B - 双环脯氨酸化合物 - Google Patents
双环脯氨酸化合物 Download PDFInfo
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- CN109476640B CN109476640B CN201780044581.0A CN201780044581A CN109476640B CN 109476640 B CN109476640 B CN 109476640B CN 201780044581 A CN201780044581 A CN 201780044581A CN 109476640 B CN109476640 B CN 109476640B
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- Prior art keywords
- trifluoromethyl
- compound
- equiv
- alkyl
- pyrimidin
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Abstract
本发明涉及式I的化合物及其盐。此外,本发明还涉及制备和使用式I的化合物的方法以及含有这些化合物的药物组合物。所述化合物可以用于治疗由TRPA1介导的疾病和病症,例如疼痛。
Description
相关申请的交叉引用
本申请要求2016年7月20日提交的美国临时申请顺序号US 62/364,487的优先权,其通过引用完整地并入本文。
技术领域
本发明涉及2.1.1双环脯氨酸化合物,其制备,含有它们的药物组合物和它们作为瞬时受体电位(TRP)通道拮抗剂的用途。
背景技术
TRP通道是一类在多种人(和其它动物)细胞类型的质膜上发现的离子通道。存在至少28种已知的人TRP通道,基于序列同源性和功能,将其分成很多家族或组。TRPA1是非选择性阳离子传导通道,其通过钠、钾和钙流调节膜电位。已经显示TRPA1在人背根神经节神经元和外周感觉神经中高度表达。在人中,TRPA1被很多反应性化合物例如丙烯醛,异硫氰酸烯丙酯,臭氧以及非反应性化合物例如烟碱和薄荷醇激活并且因此被认为充当‘化学传感器’。
许多已知TRPA1激动剂是在人和其它动物中引起疼痛,刺激和神经原性炎症的刺激物。因此,将预期TRPA1拮抗剂或阻断TRPA1通道激活剂的生物学效应的试剂在疾病例如哮喘及其恶化、久咳和相关疾病的治疗中会是有用的,以及在急性和慢性疼痛的治疗中也是有用的。近来,也已经表明,组织损伤和氧化应激的产物,例如4-羟基壬烯醛和相关化合物激活TRPA1通道。该发现提供了小分子TRPA1拮抗剂在与组织损伤、氧化应激和支气管平滑肌收缩相关的疾病例如哮喘,慢性阻塞性肺病(COPD),职业性哮喘和病毒引起的肺部炎症的治疗中的功效的另外的理论基础。此外,近期的发现已将TRPA1通道的激活与增加的疼痛感受相关联(Kosugi等人,J.Neurosci 27,(2007)4443-4451;Kremayer等人,Neuron 66(2010)671-680;Wei等人,Pain 152(2011)582-591);Wei等人,Neurosci Lett 479(2010)253-256)),提供了小分子TRPA1抑制剂在治疗疼痛疾病方面功效的另外的理论基础。
发明内容
发明概述
在一些实施方案中,提供了下式(I)的化合物或其药学上可接受的盐:
R1选自芳基或杂芳基,其各自任选地被一个或多个基团取代,所述基团独立地选自卤素、-C1-6烷基和-C1-6卤代烷基。R2各自独立地选自-C1-6烷基,且m是0、1或2。R3是4-、5-、6-或7-元杂环、芳基或杂芳基,其任选地被一个或多个基团取代,所述基团独立地选自卤素、-C1-6烷基、-C1-6卤代烷基、-O-C1-6烷基和-CN。A选自A1、A2和A3,其中:A1是未取代或取代的5-元杂芳基,其包含一个或两个杂原子;A2是未取代或取代的芳基;且A3是未取代或取代的6-元杂芳基,其包含一个或两个氮杂原子。
在一些实施方案中,提供了药物组合物,其包含式(I)的化合物或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
在一些实施方案中,提供了用于医学疗法的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于治疗或预防呼吸病的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于制备治疗或预防呼吸病的药物的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于治疗哺乳动物呼吸病的方法,该方法包含对所述哺乳动物施用式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于调节TRPA1活性的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于治疗或预防由TRPA1活性介导的疾病或病症的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于制备治疗或预防由TRPA1活性介导的疾病或病症的药物的式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于调节TRPA1活性的方法,该方法包含使TRPA1接触式(I)的化合物或其药学上可接受的盐。
在一些实施方案中,提供了用于治疗由TRPA1活性介导的疾病或病症的方法,该方法包含对所述哺乳动物施用式(I)的化合物或其药学上可接受的盐。
发明详述
定义
除非另有说明,用于本说明书和权利要求书的以下具体术语和措辞定义如下:
术语“部分”是指化学键合的原子中的原子或基团,其通过一个或多个化学键连接于另一原子或分子,从而形成分子的部分。例如,式(I)的变量R1-R5是指通过共价键连接于式(I)的核心结构的部分。
关于具有一个或多个氢原子的特定部分,术语“取代的”是指该部分的至少一个氢原子被另一个取代基或部分替代的事实。例如,术语“被卤素取代的低级烷基”是指低级烷基(如下文定义)的一个或多个氢原子被一个或多个卤素原子替代的事实(例如,三氟甲基、二氟甲基、氟甲基、氯甲基等)。
术语“烷基”是指具有1-20个碳原子的脂族直链或支链饱和烃部分。在具体的实施方案中,烷基具有1-10个碳原子。在具体的实施方案中,烷基具有1-6个碳原子。
术语“碳环”、“碳环基”、“碳环”和“环烷基”是指一价非芳族饱和或部分不饱和环,其具有3-12个碳原子(C3-C12)作为单环或7-12个碳原子作为双环。
“芳基”意为具有6-16个碳环原子的单-、双-或三环芳环的环芳烃部分。芳基可以任选地如上文所定义的被取代。芳基部分的实例包括但不限于苯基、萘基、菲基、芴基、茚基、并环戊二烯基、薁基等。术语“芳基”还包括环芳烃部分的部分氢化衍生物,前提是环芳烃部分中至少一个环是芳族的,它们各自任选地被取代。在一个实施方案中,芳基具有6-14个碳环原子(即(C6-C14)芳基)。在另一个实施方案中,芳基具有6-10个碳环原子(即(C6-C10)芳基)。
术语“杂芳基”表示5至12个环原子的芳族杂环单-或双环环系,其包含选自N、O和S的1、2、3或4个杂原子,剩余的环原子是碳。杂芳基部分的实例包括吡咯基、呋喃基、噻吩基、咪唑基、唑基、噻唑基、三唑基、二唑基、噻二唑基、四唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基、三嗪基、异唑基、苯并呋喃基、异噻唑基、苯并噻吩基、吲哚基、异吲哚基、异苯并呋喃基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、苯并二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基或喹喔啉基。
术语“卤代”、“卤素”和“卤化物”,其可以交替使用,是指取代基氟、氯、溴或碘。
术语“卤代烷基”表示烷基,其中烷基的至少一个或多个氢原子已经被相同或不同卤素原子,特别是氟原子替代。卤代烷基的实例包括单氟-、二氟-或三氟-甲基、-乙基或-丙基,例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基或三氟甲基。
“环烷基”意为具有单-或双环(包括桥连双环)环和环上的3至10个碳原子的饱和或部分不饱和碳环部分。环烷基部分可以任选地被一个或多个取代基取代。在特定实施方案中,环烷基含有3至8个碳原子(即(C3-C8)环烷基)。在其它特定实施方案中,环烷基含有3至6个碳原子(即(C3-C6)环烷基)。环烷基部分的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基及其部分不饱和(环烯基)衍生物(例如环戊烯基、环己烯基和环庚烯基)。环烷基部分可以以“螺环烷基”方式连接,例如“螺环丙基”:
“杂环”或“杂环基”是指饱和或部分不饱和的4、5、6和7-元单环或7、8、9和10-元双环(包括桥连双环)杂环部分,并且在所述环中具有一个或多个(例如在环上1、2、3或4)个选自氧、氮和硫的杂原子,其余环原子为碳。当涉及杂环的环原子使用时,氮或硫也可以是氧化形式,且氮可以被一个或多个(C1-C6)烷基或基团取代。杂环可以连接至其任意杂原子或碳原子上的侧基,产生稳定的结构,并且任意的环原子可以任选地被取代。这类饱和或部分不饱和杂环的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吡咯啉基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、唑烷基、哌嗪基、二烷基、二氧杂环戊烷基、二氮杂基、氧氮杂基、硫氮杂基、吗啉基和奎宁环基。术语杂环还包括其中杂环稠合至一个或多个芳基、杂芳基或环烷基环的基团,例如二氢吲哚基、3H-吲哚基、色满基、2-氮杂二环[2.2.1]庚基、八氢吲哚基或四氢喹啉基。
除非另有说明,术语“氢(hydrogen)”或“氢(hydro)”是指氢原子(-H)的部分并且不是H2。
术语“呼吸病”包括慢性梗阻性肺病症(COPD)、哮喘、过敏性鼻炎、支气管痉挛和囊性纤维化。
除非另有说明,术语“所述式的化合物”或“某式的化合物”或“所述式的多个化合物”或“某式的多个化合物”是指选自由该式限定的一类化合物的任意化合物(如果不另外说明,包括其任意的实施方案,例如任何此种化合物的任意药学上可接受的盐或酯、立体异构体、几何异构体、互变体、溶剂合物、代谢物、同位素、药学上可接受的盐或前药)。
术语“药学上可接受的盐”是指保留游离碱或游离酸的生物学效用和性质的那些盐,其不是生物学上或另外不适宜的。盐可以由无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,优选盐酸,和有机酸例如乙酸,丙酸,乙醇酸、丙酮酸、草酸、马来酸、丙二酸、水杨酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸,N-乙酰基半胱氨酸等形成。此外,盐可以通过将无机碱或有机碱加入至游离酸来制备。源自无机碱的盐包括但不限于钠、钾、锂、铵、钙和镁盐等。源自有机碱的盐包括,但不限于伯、仲、叔胺,取代的胺包括天然存在的取代的胺、环胺和碱性离子交换树脂,例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚胺树脂等的盐。
本发明的化合物可以以药学上可接受的盐的形式存在。另一个实施方案提供了式I的化合物的非药学上可接受的盐,其可以用作分离或纯化式I化合物的中间体。本发明的化合物还可以以药学上可接受的酯(即,要用作前药的式(I)的酸的甲酯和乙酯)的形式存在。本发明的化合物还可以被溶剂化,即水合。溶剂化可以在制备方法的过程中进行或可以例如作为起初无水的式(I)的化合物的吸湿性质的结果而发生。
具有相同分子式但性质或它们的原子的结合的顺序不同或它们的原子在空间的排列不同的化合物被称为“异构体”。其原子在空间上的排布不同的异构体被称为“立体异构体”。非对映异构体是在一个或多个手性中心处具有相反构型的立体异构体,其不是对映异构体。带有一个或多个不对称中心的、彼此为不能重叠的镜像的立体异构体被称为“对映异构体”。当化合物具有不对称中心时,例如,如果碳原子结合于四个不同基团上,对映异构体对是可能的。对映异构体可以由其一个不对称中心或多个不对称中心的绝对构型表征并且用Cahn,Ingold和Prelog的R-和S排序规则描述,或用其中分子使偏振光平面旋转的方式描述,并且称为右旋或左旋(即,分别为(+)或(-)-异构体)。手性化合物可以作为个体对映异构体或作为其混合物存在。含有等比例对映异构体的混合物被称为“外消旋混合物”。在某些实施方案中,化合物富含以重量计至少约90%的单个非对映异构体或对映异构体。在其它实施方案中,所述化合物富含以重量计至少约95%、98%或99%的单个非对映异构体或对映异构体。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋物、非对映异构体、几何异构体、区域异构体和单个异构体(例如,分离的对映异构体)都意在包括在本发明的范围内。
术语“治疗有效量”的化合物意为有效预防、减轻或改善疾病的症状或延长要治疗的受试者的存活的化合物量。治疗有效量的确定在本领域技术范围内。根据本发明的化合物的治疗有效量或剂量可以在限度内改变并且可以以本领域已知的方式确定。将在各个特定情况中针对个体需求调节该剂量,所述特定情况包括施用的特定化合物、施用途径、治疗的病症以及治疗的患者。通常,在口服或肠胃外施用于重约70Kg的成人的情况中,约0.1mg至约5,000mg、1mg至约1,000mg或1mg至100mg的每日剂量可以是适当的,尽管当有迹象表明必要时可以低于下限和超过上限。可以以单个剂量或分开的多剂量施用每日剂量,或对于肠胃外施用,可以以连续注入施用它。
术语“药学上可接受的载体”意在包括与药物施用相容的任意和所有物质,包括溶剂、分散介质、包衣材料、抗细菌和抗真菌剂,等渗和吸收延缓剂,以及与药物施用相容的其它物质和化合物。除非到了某一常规介质或试剂与活性化合物不相容的程度,否则考虑其在本发明组合物中的用途。补充的活性化合物也可以加入组合物中。
用于制备本发明组合物的有用的药物载体可以是固体、液体或气体;因此,所述组合物可以为片剂、丸剂、胶囊、栓剂、粉末剂、肠包衣或其它保护的制剂(例如结合于离子交换树脂或包装在脂蛋白泡囊中)、缓释制剂、溶液、混悬剂、酏剂、气溶胶等形式。所述载体可以选自不同油,包括石油、动物油、植物油或合成来源的油,例如,花生油、大豆油、矿物油、芝麻油等。水、盐水、含水葡萄糖和二元醇是优选的液体载体,特别是(当与血液等渗时)用于可注射溶液。例如,用于静脉施用的制剂包括活性成分的无菌水溶液,其通过将固体活性成分溶解于水来产生水溶液,并使得所述溶液无菌来制备。合适的药物赋形剂包括淀粉、纤维素、滑石粉、葡萄糖、乳糖、滑石粉、明胶、麦芽、大米、面粉、白垩、硅石、硬脂酸镁,硬脂酸钠、甘油单硬脂酸酯、氯化钠、无水脱脂乳、甘油、丙二醇、水、乙醇等。组合物可以加入常规药物添加剂例如防腐剂、稳定剂、湿润剂或乳化剂、用于调节渗透压的盐、缓冲剂等。合适的药物载体和它们的制剂在E.W.Martin的Remington′s Pharmaceutical Sciences(雷明顿药物科学)中描述。在任何情况中,这些组合物将含有与合适的载体一起的有效量活性化合物,以制备适当剂型用于适当施用于接受者。
在本发明方法的实践中,有效量的本发明化合物中任一个或任何本发明化合物的组合或其药学上可接受的盐或酯,通过本领域已知的任何常用和可接受方法,或者单独或者组合施用。因此所述化合物或组合物可以通过包括但不限于下列方式施用:口服(例如,口腔)、舌下、肠胃外(例如,肌肉内、静脉内或皮下)、经直肠(例如,通过栓剂或洗剂)、经皮(例如,皮肤电穿孔)或通过吸入(例如,通过气溶胶),并且以固体、液体或气体剂型(包括片剂和悬浮液)施用。所述施用可以以单个单位剂型以连续治疗或以单个剂量随意治疗进行。治疗组合物也可以是连同亲脂性盐例如扑酸的油乳状液或分散液的形式,或是用于皮下或肌肉内施用的可生物降解的缓释组合物的形式。
化合物
在本公开的不同实施方案中,2.1.1双环脯氨酸化合物或其药学上可接受的盐具有下式(I):
R1选自芳基或杂芳基,它们各自任选地被一个或多个基团取代,所述基团独立地选自卤素、-CN、-C1-6烷基和-C1-6卤代烷基。在一些实施方案中,R1选自:(1)在任意环位置上被取代基取代的芳基,所述取代基选自Br、Cl、F、-CHF2、-CF3、-CHCl2和-CCl3;和(2)在任意环位置上被取代基取代的苯并呋喃,所述取代基选自Cl、F、-CHF2、-CF3、-CHCl2和-CCl3。在一些实施方案中,R1选自:
在一些可替代选择的实施方案中,F各自可以位于非指示位置上的环位置上,且F可以被-CHF2或-CF3替代。
R2各自独立地选自-C1-6烷基,且m是0、1或2。在一些实施方案中,R2选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2。在一些实施方案中,R2是-CH3。在一些实施方案中,m是0。在一些实施方案中,m是1。在一些实施方案中,m是2。
R3是4-、5-、6-或7-元杂环、碳环、芳基或杂芳基,其任选地被一个或多个基团取代,所述基团独立地选自卤素、-C1-6烷基、-C1-6卤代烷基、-O-C1-6烷基和-CN。在一些实施方案中,R3是5-或6-元任选取代的杂芳基,其包含一个或两个氮杂原子。在一些实施方案中,R3选自:
其中:Y1和Y2的至少一个是N;s各自独立地是0或1;R7选自卤素、-O-C1-6烷基和-C1-6卤代烷基;R8选自H、-C1-6烷基和-C1-6卤代烷基;且1位和2位上所示的虚线键为任选的双键,其中双键可以仅位于1位和2位之一上,并且,其中R8不存在,此时双键存在于2位上。在一些实施方案中,R7选自-CF3、-CF2H、-OCF3和-OCF2H。在一些实施方案中,R3选自:
在一些可替代选择的实施方案中,-CF3可以位于非指示位置的环位置上,且–CF3可以被F或-CHF2替代。
A选自A1、A2和A3。
在一些实施方案中,A是A1,其中A1选自未取代或取代的5-元杂芳基,其包含一个或两个氮杂原子。在一些实施方案中,A1选自:
其中n是0或1,且,其中R4选自卤素、-O-C1-6烷基和-C1-6卤代烷基。在一些实施方案中,A1选自:
在一些可替代选择的实施方案中,-CH3和-CF3可以位于非指示位置的环位置上,且可以被F或-CHF2替代。
在一些实施方案中,A是A2,其中A2选自未取代和取代的芳基。在一些实施方案中,A2具有下式:
其中p是0或1,且,其中R5选自卤素、CN、-O-C1-6烷基、-O-C1-6卤代烷基、-C1-6卤代烷基和-C3-7环烷基。在一些实施方案中,R5选自F,Cl、-CN、-CH2CN、-CF2H和-CF3。在一些实施方案中,A2选自:
在一些可替代选择的实施方案中,-CN和F可以位于非指示位置的环位置上,且可以被-CHF2或-CF3替代。
在一些实施方案中,A是A3,其中A3选自未取代和取代的6-元杂芳基,其包含一个或两个氮杂原子。在一些实施方案中,A3具有下式:
其中:(1)X1、X2和X3独立地选自C和N,其中(i)X1、X2和X3之一是N,且r是0、1或2,或(ii)X1和X3各自为N,且r是0或1;和(2)R6各自独立地选自卤素、-CN、-C3-7环烷基、-O-C1-6卤代烷基、-O-C1-6烷基和-C1-6卤代烷基。在一些实施方案中,R6选自F、Cl、-CN、-环丙基、Br、-OCF3、-CF3、-CFH和-O-CH2-CF3。在一些实施方案中,A3选自:
在一些可替代选择的实施方案中,F、Cl、Br、-环丙基、-CHF2、CF3、-OCF3和-O-CH2-CF3可以位于非指示位置的环位置上。
在一些实施方案中,2.1.1双环脯氨酸化合物选自下列化合物列表中的任一个,其中环取代可以位于非指示环位置的环位置上,并且所示的取代基可以可替代选择地被如本文另外部分中所述的取代基替代:
在本发明的另一个实施方案中,将式I的化合物通过使其中一个或多个原子被具有不同原子量或质量数的原子替代来同位素标记。这种同位素标记的(即,放射标记的)式I化合物被认为在本发明的范围内。可以结合入式I化合物的同位素的实例分别包括氢、碳、氮、氧、磷、硫、氟、氯、和碘的同位素,例如但不限于2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。这些同位素标记的化合物将可用于通过表征例如离子通道上的作用位点或模式,或对药理学重要的离子通道特别是TRPA1上作用位点的结合亲和性,确定或测量化合物的功效。某些同位素标记的式I的化合物,例如,结合了放射性同位素的那些,用于药物和/或基体组织分布研究。放射性同位素氚(即3H)和碳-14(即14C),鉴于其容易结合且现成的检测方法,对于该目的特别有用。例如,式I的化合物可以富含百分之1、2、5、10、25、50、75、90、95或99的给定同位素。
用更重的同位素例如氘(即2H)取代,可以提供由更好的代谢稳定性造成的某些治疗优势,例如,增加的体内半衰期或降低的剂量需求。
用正电子发射同位素(例如11C、18F、15O和13N)取代,可以在正电子发射断层摄影(PET)研究中使用,用于检测底物受体占有率。同位素标记的式I化合物通常可以通过本领域技术人员已知的常规技术或通过类似于下文阐述的实施例中描述的那些的方法,使用适当的同位素标记的试剂替代之前使用的非标记的试剂制备。
在另一个实施方案中,本发明提供一种药物组合物,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和药学上可接受的载体。
除了盐形式外,本发明提供前药形式的化合物。如本文使用的,术语“前药”是指在生理条件下易于经历化学变化以提供本发明的化合物的那些化合物。此外,前药可以通过化学或生物化学方法在离体环境被转化为本发明的化合物。例如,当置于透皮贴剂储器中时,前药可以以合适的酶或化学试剂缓慢转化为本发明的化合物。
本发明的前药包括这样的化合物,其中氨基酸残基或两个以上(例如,两个、三个或四个)氨基酸残基的多肽链通过酰胺或酯键共价连接于本发明化合物的游离氨基、羟基或羧酸基团。所述氨基酸残基包括但不限于20种天然存在的通常由三字母符号表示的氨基酸并且还包括磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、4-羟基脯氨酸、羟基赖氨酸、锁链赖氨素(demosine)、异锁链赖氨素(isodemosine)、γ-羧基谷氨酸盐、马尿酸、八氢吲哚-2-甲酸、抑胃酶氨酸、1,2,3,4-四氢异喹啉-3-甲酸、青霉胺、鸟氨酸、3-甲基组氨酸、降缬氨酸(norvaline)、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、甲基-丙氨酸、对苯甲酰基苯基丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸、蛋氨酸砜和叔丁基甘氨酸。
还包括其它类型的前药。例如,本发明的化合物的游离羧基可以衍生为酰胺或烷基酯。作为另一个实例,包含游离羟基的本发明的化合物可以通过将羟基转化为例如,但不限于,磷酸酯、半琥珀酸酯、二甲基氨基乙酸酯或磷酰基氧基甲氧基羰基的基团而衍生为前药,如在Fleisher,D.等人,(1996)Improved oral drug delivery:solubilitylimitations overcome by the use of prodrugs(改善的口服药物传递:通过使用前药解决溶解性限制),Advanced Drug Delivery Reviews,19:115中概述的。还包括羟基和氨基的氨基甲酸酯前药,同样的还有羟基的碳酸酯前药、磺酸酯和硫酸酯。还包括羟基衍生为(酰氧基)甲醚和(酰氧基)乙醚,其中酰基可以是任选地被包括但不限于醚,胺和羧酸官能团的基团取代的烷基酯,或其中酰基是如上文所述的氨基酸酯。该类型的前药在J.Med.Chem.,(1996),39:10中描述。更具体的实例包括用例如(C1-6)烷酰基氧基甲基、1-((C1-6)烷酰基氧基)乙基、1-甲基-1-((C1-6)烷酰基氧基)乙基、(C1-6)烷氧基羰氧基甲基、N-(C1-6)烷氧基羰基氨基甲基、琥珀酰基、(C1-6)烷酰基、α-氨基(C1-4)烷酰基、芳酰基和α-氨基酰基或α-氨基酰基-α-氨基酰基的基团替代醇基团的氢原子,其中各个α-氨基酰基独立地选自天然存在的L-氨基酸,P(O)(OH)2,-P(O)(O(C1-6)烷基)2或糖基(由去除碳水化合物的半缩醛形式的羟基得到的基团)。
对于前药衍生物的其它实例,参见,例如,a)Design of Prodrugs,H.Bundgaard编辑(Elsevier,1985)和Methods in Enzymology,第42卷,第309-396页,K.Widder等人编辑(Academic Press,1985);b)ATextbook of Drug Design and Development(药物设计和研发手册),Krogsgaard-Larsen和H.Bundgaard编辑,第5章“Design and Application ofProdrugs(前药的设计和应用),”H.Bundgaard,第113-191页(1991);c)H.Bundgaard,Advanced Drug Delivery Reviews(高级药物传递综述),8:1-38(1992);d)H.Bundgaard等人,Journal of Pharmaceutical Sciences,77:285(1988);和e)N.Kakeya等人,Chem.Pharm.Bull.,32:692(1984),上述文献各自特别地通过引用并入本文。
此外,本发明提供本发明的化合物的代谢产物。如本文使用的,″代谢产物″是指经指定化合物或其盐在体内的代谢产生的产物。这种产物可以例如从施用化合物的氧化、还原、水解、酰胺化、去酰胺化、酯化、去酯化、酶切割等产生。
代谢产物典型地通过制备本发明的化合物放射标记的(例如,14C或3H)同位素,将其以可检测剂量(例如,大于约0.5mg/kg)肠胃外施用于动物例如大鼠、小鼠、豚鼠、猴或施用于人,允许足够时间用于代谢发生(典型地约30秒到30小时)并从尿、血液或其它生物样本分离其转化产物来鉴定。这些产物容易被分离,因为它们被标记(其它的通过使用能够结合代谢产物中留存的表位的抗体来分离)。以常规模式,例如,通过MS,LC/MS或NMR分析确定代谢产物结构。通常,代谢产物的分析以与本领域技术人员公知的常规药物代谢研究相同的方式进行。代谢产物,只要它们未另外在体内发现,在用于治疗性剂量给药本发明的化合物的诊断测定中是有用的。
本发明的某些化合物可以以非溶剂化的形式以及溶剂化的形式,包括水合形式存在。通常,溶剂化形式等价于非溶剂化的形式,并且意在包括在本发明的范围内。本发明的某些化合物可以以多晶或无定形形式存在。通常,所有物理形式对于本发明考虑的用途而言均是等价的并且意在包括在本发明的范围内。
药物组合物和施用
除了一个或多个上文提供的化合物(包括立体异构体、几何异构体、互变异构体、溶剂化物、代谢产物、同位素、药学上可接受的盐或其前药)之外,本发明还提供包含式I化合物和至少一种药学上可接受的载体,稀释剂或赋形剂的组合物和药物或其实施方案。本发明的组合物可以用于选择性抑制患者(例如,人)中TRPA1。
如本文使用的术语“组合物”,意在包括包含指定量的指定成分的产物,以及直接或间接由指定量的指定成分的组合产生的任何产物。所谓“药学上可接受的”意为载体、稀释剂或赋形剂必须与制剂的其它成分相容并且对其接受者是无害的。
在一个实施方案中,本发明提供药物组合物或药物,其包含式I化合物或其实施方案(或其实施方案,包括立体异构体、几何异构体、互变异构体、溶剂化物、代谢产物、同位素、药学上可接受的盐或其前药)和药学上可接受的载体、稀释剂或赋形剂。在另一个实施方案中,本发明提供制备包含本发明的化合物的组合物(或药物)。在另一个实施方案中,本发明提供向需要它的患者(例如,人患者)施用式I的化合物或其实施方案和包含式I化合物或其实施方案的组合物。
以与良好医疗实践一致的方式配制、剂量给药和施用组合物。在这种情况下考虑的因素包括治疗的特定疾病、治疗的特定哺乳动物、个体患者的临床病症、疾病的原因、药剂的递送位点、施用方法、施用时间安排和执业医生已知的其它因素。要施用化合物的有效量将受此种考虑支配,并且是抑制TRPA1活性所需的最小量,如预防或治疗不希望的疾病或病症,例如,疼痛所需的。例如,此种量可以低于对正常细胞,或作为整体的哺乳动物有毒的量。
在一个实例中,肠胃外施用的本发明的化合物的治疗有效量每剂量将在约0.01-100mg/kg的范围内,备选地约例如,0.1-20mg/kg患者体重/天,使用的化合物的典型初始范围是0.3-15mg/kg/天。在某些实施方案中,每日剂量以单个每日剂量或以分开的剂量每天二到六次,或以缓释形式给出。在70kg成年人的情况中,总的每日剂量将通常是约7mg-约1,400mg。可以调节该剂量方案以提供最佳治疗响应。可以以每天1至4次,优选每天一次或两次的方案施用化合物。
可以以任何方便的施用形式施用本发明的化合物,例如,片剂、粉末剂、胶囊、溶液、分散液、混悬剂、糖浆、喷雾、栓剂、凝胶、乳状液、凝胶、贴片等。这种组合物可以含有药物制剂中常规的成分,例如,稀释剂、载体、pH调节剂、甜味剂、填充剂和其它活性剂。
本发明的化合物可以以任何合适的方式施用,例如口服(例如口腔)、局部、直肠、阴道、经皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内以及硬膜外和鼻内,并且,如果需要,用于局部治疗、病灶内的施用。肠胃外注入包括肌肉内、静脉内、动脉内、腹膜内、脑内、眼内、病灶内或皮下施用。
包含式I化合物(或其实施方案,包括立体异构体、几何异构体、互变体、溶剂合物、代谢物、同位素、药学上可接受的盐及其前药)的组合物通常根据标准药物实践配制为药物组合物。典型的制剂通过将本发明的化合物与稀释剂,载体或赋形剂混合来制备。合适的稀释剂,载体和赋形剂是本领域技术人员公知的并且详细描述在,例如,Ansel,Howard C.等人,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(安塞尔药物剂型和药物传递系统).Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.等人,Remington:The Science and Practice of Pharmacy(雷明顿:制药科学和实践).Philadelphia:Lippincott,Williams&Wilkins,2000;和Rowe,RaymondC.Handbook of Pharmaceutical Excipients(药用辅料手册).Chicago,PharmaceuticalPress,2005中。所述制剂还可以包括一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、混悬剂、防腐剂、抗氧化剂、遮盖剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂、稀释剂和其它已知的添加剂,以提供药物(即,本发明的化合物或其药物组合物)的雅致外观或在药物产物(即,药物)的制备中提供帮助。合适的载体、稀释剂和赋形剂是本领域技术人员公知的并且包括缓冲剂例如磷酸盐,柠檬酸盐以及其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化六烃季铵;苯扎氯胺、氯苄乙铵;苯酚、丁基或苄基醇;烷基对羟基苯甲酸酯例如甲基或丙基对羟基苯甲酸酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约10个残基)多肽;蛋白,例如血清白蛋白,明胶,或免疫球蛋白;亲水聚合物例如聚乙烯吡咯烷酮;氨基酸例如甘氨酸、谷氨酰胺、天冬氨酸、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂例如EDTA;糖例如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,例如钠;金属复合体(例如,Zn-蛋白复合体);和/或非离子型表面活性剂例如TWEENTM,PLURONICSTM或聚乙二醇(PEG)。本发明的活性药物成分(例如,式I化合物或其实施方案)还可以被包埋入例如,通过凝聚技术或通过界面聚合制备的微胶囊(例如,分别为羟甲基纤维素或明胶-微胶囊和聚-(甲基丙烯酸甲酯)微胶囊),胶状药物递送系统(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)或粗滴乳剂中。这种技术在Remington:The Scienceand Practice of Pharmacy:Remington the Science and Practice of Pharmacy(制药科学和实践:雷明顿制药科学和实践)(2005)第21版,Lippincott Williams&Wilkins,Philidelphia,PA中公开。使用的特定载体,稀释剂或赋形剂将依赖于施用本发明的化合物的方式和目的。通常基于本领域技术人员认为对于施用于哺乳动物安全(GRAS)的溶剂来选择溶剂。通常,安全溶剂是无毒水性溶剂例如水和可溶于水或在水中混溶的其它无毒溶剂。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG400、PEG300)等和其混合物。可接受的稀释剂、载体、赋形剂和稳定剂在使用的剂量和浓度对于接受者是无毒的,并且包括
可以制备本发明的化合物(例如,式I的化合物或其实施方案)的缓释制剂。缓释制剂的合适实例包括含有式I的化合物或其实施方案的固体疏水聚合物的半透性基质,所述基质是成形物品形式,例如,膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(美国专利号3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸酯的共聚物(Sidman等人,Biopolymers 22:547,1983)、不可降解的乙烯-醋酸乙烯酯(Langer等人,J.Biomed.Mater.Res.15:167,1981)、可降解的乳酸-乙醇酸共聚物例如LUPRONDEPOTTM(由乳酸-乙醇酸共聚物和亮氨酰脯氨酸醋酸酯构成的可注射微球)和聚-D-(-)-3-羟基丁酸(EP133,988A)。缓释组合物还包括脂质体包埋的化合物,其可以通过本身已知的方法制备(Epstein等人,Proc.Natl.Acad.Sci.U.S.A.82:3688,1985;Hwang等人,Proc.Natl.Acad.Sci.U.S.A.77:4030,1980;美国专利号4,485,045和4,544,545;以及EP102,324A)。通常,脂质体是小(约200-800埃)的单片型,其中脂含量大于约30mol%胆固醇,选择的比例被调节用于最佳治疗。
在一个实例中,式I的化合物或其实施方案可以通过在环境温度在适当的pH,并以所需纯度,与生理学可接受的载体,即,在用于盖伦制剂施用形式的剂量和浓度对接受者无毒的载体混合来配制。制剂的pH主要依赖于化合物的特定用途和浓度,但优选约3至约8范围内的任意处。在一个实例中,式I的化合物(或其实施方案)配制在pH 5的乙酸盐缓冲液中。在另一个实施方案中,式I的化合物或其实施方案是无菌的。化合物可以,例如,以固体或无定形组合物,以冻干制剂或以水溶液储存。
适于口服施用的本发明的化合物的制剂(例如,式I的化合物或其实施方案)可以制备为分离的单位例如丸剂、胶囊、扁囊药剂或片剂,各自含有预定量的本发明的化合物。
压制的片剂可以通过在合适的机器中将自由流动的形式例如粉末或颗粒的活性成分压制来制备,任选地与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性或分散剂混合。模制片剂可以通过在合适的机器中将用惰性液体稀释剂湿润的粉末状活性成分的混合物模制来制备。片剂可以任选地包衣或刻痕并且任选地配制从而提供活性成分的缓慢或控制释放。
片剂、药片、锭剂、水或油悬浮液、可分散粉末或颗粒、乳状液、硬或软胶囊(例如明胶胶囊)、糖浆或酏剂可以制备用于口服用途。意在用于口服用途的本发明的化合物(例如,式I的化合物或其实施方案)的制剂可以根据本领域已知的任意方法制备,用于制造药物组合物并且这种组合物可以含有包括甜味剂、芳香剂、着色剂和防腐剂的一种或多种试剂,从而提供合意的制剂。含有与适于制备片剂的无毒药用赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可以是,例如,惰性稀释剂,例如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的或可以通过包括微囊化的已知技术包衣,以延迟在胃肠道中的崩解和吸收,从而提供更长时间的缓释作用。例如,可以使用延时物质例如单独甘油单硬脂酸酯或甘油二硬脂酸酯或与蜡一起。
合适的口服施用形式的实例是含有与约90-30mg无水乳糖、约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁复合的约0.1mg、约1mg、约5mg、约10mg、约25mg、约30mg、约50mg、约80mg、约100mg、约150mg、约250mg、约300mg和约500mg的本发明化合物(或其实施方案)的片剂。首先将粉末化成分一起混合并随后与PVP的溶液混合。产生的组合物可以使用常规设备干燥,制粒,与硬脂酸镁混合并压制为片剂形式。气溶胶制剂的实例可以通过将化合物,例如5-400mg的本发明化合物溶解于合适的缓冲液,例如磷酸盐缓冲液,如果需要,加入等渗剂(tonicifier),例如盐如氯化钠来制备。可以例如使用0.2微米滤器将溶液过滤,以去除杂质和污染物。
为了治疗眼或其它外部组织(例如口和皮肤)疾病,制剂优选以含有例如,0.075至20%w/w量的活性成分的外用软膏或乳霜涂敷。当以软膏配制时,活性成分可以与石蜡族或水混溶性软膏基质一起使用。或者,活性成分可以以水包油乳霜基质的乳霜配制。如果需要,乳霜基质的水相可以包括多元醇,即,具有两个或多个羟基的醇例如丙二醇、丁1,3-二醇、甘露醇、山梨醇、甘油和聚乙二醇(包括PEG400)和其混合物。外用制剂可以根据需要包括增强活性成分经皮肤或其它受影响区域的吸收或穿透的化合物。这种透皮穿透增强剂的实例包括二甲亚砜和相关类似物。
对于局部制剂,期望施用有效量的本发明的药物组合物至目标区域,例如皮肤表面、粘膜等,其与待治疗的外周神经元相邻。该用量通常为每次施用约0.0001mg至约1g本发明化合物(或其实施方案),这取决于待治疗的区域,无论是诊断、预防还是治疗,症状的严重性和所用局部媒介物的性质。优选的局部制剂是软膏剂,其中每cc软膏剂基质使用约0.001-约50mg活性成分。可以将药物组合物配制成透皮组合物或透皮递送装置(“贴剂”)。这类组合物包括,例如裱褙材料、活性化合物储器、控制膜、衬垫和接触粘合剂。如果需要,这类透皮贴剂可以用于连续脉冲或根据要求递送本发明的化合物。
制剂可以包装在单位剂量或多剂量容器,例如密封的安瓿瓶和小瓶中,并且可以储存在冷冻干燥(冻干)条件,在即将使用前仅需要加入无菌液体载体(例如水)用于注射。临时的注射溶液和悬浮液从之前描述种类的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂是含有活性成分的每日剂量或单位每日亚剂量,如上文列举的,或其适当级分的那些。
当结合目标位于脑时,本发明的某些实施方案提供式I的化合物(或其实施方案)以穿过血脑屏障。某些神经变性疾病与血脑屏障渗透性的增加相关,从而式I的化合物(或其实施方案)可以容易被引入脑。当血脑屏障仍然完整时,存在多种本领域已知的用于将分子转运跨过它的方法,包括但不限于物理方法、基于脂质的方法以及基于受体和通道的方法。
将式I的化合物(或其实施方案)转运跨过血脑屏障的物理方法包括,但不限于,完全避开血脑屏障或通过在血脑屏障中产生开口。
避开方法包括,但不限于,直接注射于脑中(参见,例如,Papanastassiou等人,Gene Therapy 9:398-406,2002)、间质注入/对流增强递送(参见,例如,Bobo等人,Proc.Natl.Acad.Sci.U.S.A.91:2076-2080,1994)和在脑中植入递送装置(参见,例如,Gill等人,Nature Med.9:589-595,2003;和Gliadel WafersTM,GuildfordPharmaceutical)。
在屏障中产生开口的方法包括,但不限于,超声(参见,例如,美国专利公开号2002/0038086)、渗透压(例如,通过施用高渗甘露醇(Neuwelt,E.A.,Implication of theBlood-Brain Barried and its Manipulation,第1和2卷,Plenum Press,N.Y.,1989))和通过例如,缓激肽或渗透剂A-7的透化作用(参见,例如,美国专利号5,112,596、5,268,164、5,506,206和5,686,416)。
转运式I的化合物(或其实施方案)跨血脑屏障的基于脂质的方法包括,但不限于,将式I的化合物(或其实施方案)囊化入偶联于抗体结合片段的脂质体,所述抗体结合片段结合于血脑屏障的血管内皮上的受体(参见,例如,美国专利申请公开号2002/0025313)和将式I的化合物(或其实施方案)包衣在低密度脂蛋白颗粒(参见,例如,美国专利申请公开号2004/0204354)或阿朴脂蛋白E(参见,例如,美国专利申请公开号2004/0131692)中。
转运式I的化合物(或其实施方案)跨血脑屏障的基于受体和通道的方法包括,但不限于,使用糖肾上腺皮质激素阻断剂增加血脑屏障的渗透性(参见,例如,美国专利申请公开号2002/0065259、2003/0162695和2005/0124533);激活钾通道(参见,例如,美国专利申请公开号2005/0089473),抑制ABC药物转运剂(参见,例如,美国专利申请公开号2003/0073713);用转铁蛋白包衣式I的化合物(或其实施方案)并调节一个或多个转铁蛋白受体的活性(参见,例如,美国专利申请公开号2003/0129186),和阳离子化抗体(参见,例如,美国专利号5,004,697)。
为了脑内使用,在某些实施方案中,可以通过注入CNS的储液室连续施用化合物,尽管快速浓注可以是可接受的。抑制剂可以施用于脑室内或另外引入CNS或脊液中。施用可以通过使用留置导管和连续施用工具例如泵进行,或其可以通过植入施用,例如,脑内植入缓释载体。更具体地,抑制剂可以经长期植入套管注射或在渗透微泵的帮助下长期注入。皮下泵是可用的,其递送蛋白通过小管进入脑室。高度复杂的泵可以穿过皮肤再装满并且可以不用外科手术即设置其递送率。包括皮下泵装置或通过完全植入的药物递送系统连续脑室内灌注的合适的施用方案和递送系统的实例是用于施用多巴胺、多巴胺激动剂和胆碱能激动剂至阿尔茨海默病患者和帕金森病动物模型的那些,如Harbaugh,J.NeuralTransm.Suppl.24:271,1987;和DeYebenes等人,Mov.Disord.2:143,1987中所述。
适应证和治疗方法
代表性的本发明的化合物已经显示出调节TRPA1活性。因此,本发明的化合物(或其实施方案)可用于治疗TRPA1活性介导的疾病和病症。这种疾病或病症包括但不限于:疼痛(急性、慢性、炎性或神经性疼痛);痒病或不同炎性疾病;内耳疾病;发烧或其它体温调节病症;气管支气管或膈功能障碍;胃肠或尿道疾病;呼吸病,例如慢性阻塞性肺病;失禁;和与向CNS的血流量减少或CNS缺氧相关的疾病。
在特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法,以治疗疼痛,包括但不限于神经性和炎性疼痛等。疼痛的某些类型可以被认为是疾病或病症,而其它类型可以被认为是不同疾病或病症的症状,并且疼痛可以包括不同病因学。根据本发明可用TRPA1-调节剂治疗的示例性疼痛类型包括与以下疾病相关,由以下疾病引起,或由以下疾病导致的疼痛:骨关节炎、肌腱套疾病(rotatorcuffdisorders)、关节炎(例如,类风湿性关节炎或炎性关节炎;参见,Barton等人Exp.Mol.Pathol.2006,81(2),166-170)、纤维肌痛(fibromyalgia)、偏头痛(migraine)和头痛(例如丛集性头痛(clusterheadache)、窦性头痛(sinusheadache)或紧张性头痛(tensionheadache);参见,Goadsby Curr.Pain Headache Reports 2004,8,393)、鼻窦炎(sinusitis)、口腔黏膜炎(oralmucositis)、牙痛、牙外伤(dentaltrauma)、拔牙、牙感染、烧伤(Bolcskei等人,Pain2005,117(3),368-376)、晒伤、皮炎(dermatitis)、银屑病(psoriasis)、湿疹(eczema)、昆虫叮咬、肌骨骼病症、骨折、韧带扭伤(ligamentous sprains)、足底筋膜炎(plantarfasciitis)、肋软骨炎(costochondritis)、腱炎(tendonitis)、滑液囊炎(bursitis)、网球肘(tennis elbow)、投掷肘(pitcher′s elbow)、髌腱炎(patellar tendonitis)、重复性劳损(repetitive strain injury)、肌筋膜综合征(myofascial syndrome)、肌肉劳损(muscle strain)、肌炎(myositis)、颞颌关节疾病(temporomandibular jointdisorder)、截肢(amputation)、腰痛(low back pain)、脊髓损伤、颈痛、急性颈部扭伤(whiplash)、膀胱痉挛(bladder spasms)、Gl道疾病、膀胱炎(cystitis)、间质性膀胱炎(interstitial cystitis)、胆囊炎(cholecystitis)、尿道感染、尿道绞痛(urethralcolic)、肾绞痛(renal colic)、咽炎(pharyngitis)、唇疱疹(coldsores)、口腔炎(stomatitis)、外耳炎(external otitis)、中耳炎(otitis media)(Chan等人,Lancet,2003,361-385)、口腔烧灼综合征(burning mouth syndrome)、粘膜炎(mucositis)、食管痛(esophageal pain)、食管痉挛(esophageal spasms)、腹部疾病、胃食管返流疾病(gastroesophageal reflux disease)、胰腺炎(pancreatitis)、肠炎(enteritis)、肠易激症(irritable bowel disorder)、炎性肠病、克罗恩病(Crohn′s disease)、溃疡性结肠炎(ulcerative colitis)、结肠肿胀(colon distension)、腹缢(abdominal constriction)、肠憩室病(diverticulosis)、憩室炎(diverticulitis)、肠积气(intestinal gas)、痔疮(hemorrhoids)、肛裂(anal fissures)、肛门直肠疾病、前列腺炎(prostatitis)、附睾炎(epididymitis)、睾丸痛(testicular pain)、直肠炎(proctitis)、直肠痛、分娩(labor)、生产(childbirth)、子宫内膜异位(endometriosis)、经期痉挛(menstrual cramps)、骨盆痛(pelvicpain)、外阴痛(vulvodynia)、阴道炎(vaginitis)、口唇及生殖器感染(orolabial and genital infections)(例如单纯疱疹)、胸膜炎(pleurisy)、心包炎(pericarditis)、非心脏胸部疼痛(non-cardiacn chest pain)、挫伤(contusions)、擦伤(abrasions)、皮肤切口(skin incision)(Honore P.等人、J.Pharmacal Exp.Ther.,2005,314、410-21)、术后痛(postoperative pain)、外周神经病(peripheral neuropathy)、中枢神经病(central neuropathy)、糖尿病神经病变(diabetic neuropathy)、急性带状疱疹神经痛(acute herpetic neuralgia)、疱疹后神经痛(post-herpetic neuralgia)、三叉神经痛(trigeminal neuralgia)、舌咽神经痛(glossopharyngeal neuralgia)、非典型面部疼痛、神经根病(gradiculopathy)、HIV相关神经病、物理神经损伤、灼痛(causalgia)、反射交感性营养不良(reflex sympathetic dystrophy)、坐骨神经痛(sciatica)、颈椎、胸椎或腰椎神经根病(radiculopathy)、臂丛病(brachial plexopathy)、腰丛病(lumbarplexopathy)、神经变性病症、枕神经痛(occipital neuralgia)、肋间神经痛(intercostalneuralgia)、眶上神经痛(supraorbital neuralgia)、腹股沟神经痛(inguinalneuralgia)、感觉异常性股痛(meralgia paresthetica)、生殖股神经痛(genitofemoralneuralgia)、腕管综合征(carpal tunnel syndrome)、莫顿神经瘤(Morton′s neuroma)、乳房切除术后综合征(post-mastectomy syndrome)、开胸术后综合征(post-thoracotomysyndrome)、小儿麻痹症后期综合症(post-polio syndrome),古兰-巴雷综合征(Guillain-Barre syndrome)、雷诺综合征(Raynaud′s syndrome)、冠状动脉痉挛(coronary arteryspasm)(Printzmetal′s或变异型心绞痛(variant angina))、内脏痛觉过敏(visceralhyperalgesia)(Pomonis,J.D.等人J.Pharmacal.Exp.Ther.2003,306,387;Walker,K.M.等人,J.Pharmacal.Exp.Ther.2003,304(1),56-62)、丘脑性疼痛(thalamic pain)、癌症(例如由癌症引起的疼痛,包括溶骨肉瘤(osteolytic sarcoma),由放射或化疗的癌症治疗引起的疼痛,或与癌症相关的神经或骨损伤引起的疼痛(参见,Menendez,L.等人,Neurosci.Lett.2005,393(1),70-73;Asai,H.等人,Pain2005,117,19-29),或骨破坏疼痛(参见,Ghilardi,J.R.等人,J.Neurosci.2005,25,3126-31)),感染,或代谢疾病。此外,所述化合物可以用于治疗疼痛适应症例如内脏痛(visceral pain)、眼痛(ocular pain)、热痛(thermal pain)、牙痛(dental pain)、辣椒素引起的疼痛(以及其它由辣椒素引起的有症状的病症例如咳嗽、流泪和支气管痉挛)。
在另一特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法用于治疗痒病,所述痒病可以由多种来源产生,例如皮肤病或炎性疾病。
在另一特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗炎性疾病,包括选自由以下各项组成的组的病症:肾脏或肝胆病症、免疫病症、药物反应和未知的/突发病症。可用本发明药剂治疗的炎性疾病包括,例如,炎性肠病(IBO)、克罗恩病和溃疡性结肠炎(ulcerative colitis)(Geppetti,P.等人,Br.J.Pharmacal.2004,141,1313-20;Yiangou,Y.等人,Lancet 2001,357,1338-39;Kimball,E.S.等人,Neurogastroenterol.Motif.,2004,16,811)、骨关节炎(Szabo,A.等人,J.Pharmacal.Exp.Ther.2005,314,111-119)、银屑病、银屑病关节炎、类风湿关节炎、重症肌无力(myasthenia gravis)、多发性硬化(multiples clerosis)、硬皮病(scleroderma)、肾小球性肾炎(glomerulonephritis)、胰腺炎、炎性肝炎、哮喘、慢性阻塞性肺病、变应性鼻炎、葡萄膜炎(uveitis)、和炎症的心血管表现,包括动脉粥样硬化(atherosclerosis)、心肌炎、心包炎和脉管炎(vasculitis)。
在另一特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗内耳疾病。这种病症包括,例如,听觉过敏(hyperacusis)、耳鸣(tinnitus)、前庭超敏性(vestibular hypersensitivity)和发作性眩晕(episodic vertigo)。
例如,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗气管支气管和膈功能障碍,包括,例如,哮喘和过敏相关的免疫应答(Agopyan,N.等人,Am.J.Physiol.Lung Cell Mol.Physiol.2004,286,L563-72;Agopyan,N.等人,Toxicol.Appl.Pharmacal.2003,192,21-35)、咳嗽(例如,急性或慢性咳嗽,或来自胃食管返流疾病的刺激引起的咳嗽;参见,Lalloo,U.G.等人,J.Appl.Physiol.1995,79(4),1082-7)、支气管痉挛(bronchospasm)、慢性阻塞性肺病、慢性支气管炎、肺气肿(emphysema)、和嗝(打嗝、呃逆(singultus))。
另一特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗胃肠和尿道疾病例如,膀胱过度活动症(bladder overactivity)、炎性痛觉过敏(inflammatory hyperalgesia)、膀胱的内脏反射亢进(visceral hyperreflexia oftheurinary bladder)、出血性膀胱炎(hemorrhagic cystitis)(Dinis,P.等人,JNeurosci.,2004,24,11253-11263)、间质性膀胱炎(Sculptoreanu,A.等人,NeurosciLett.,2005,381,42-46)、炎性前列腺疾病、前列腺炎(prostatitis)(Sanchez,M.等人,Eur J Pharmacal.,2005,515,20-27)、恶心(nausea)、呕吐、肠痉挛(intestinalcramping)、肠胀气(intestinal bloating)、膀胱痉挛(bladder spasms)、尿急(urinaryurgency)、排便急迫(defecation urgency)和欲望性尿失禁(urge in continence)。
在另一特定实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗与向CNS的血流量减少或CNS缺氧相关的病症。这种病症包括,例如,头部创伤(headtrauma)、脊髓损伤(spinal injury)、血栓栓塞或出血性中风(thromboembolic orhemorrhagic stroke)、短暂性脑缺血发作(transient ischaemic attacks)、脑血管痉挛(cerebral vasospasm)、低血糖(hypoglycaemia)、心脏停搏(cardiac arrest)、癫痫持续状态(status epilepticus)、围产期窒息(perinatal asphyxia)、阿尔茨海默病和亨廷顿病。
在其它实施方案中,可以施用本发明的化合物(或其实施方案)作为医学疗法以治疗通过TRPA1活性介导的其它疾病,病症或病状,例如:焦虑症(anxiety);学习或记忆病症;眼相关病症(例如青光眼(glaucoma)、视力丧失(vision loss)、眼内压增加(increasedintraocular pressure)和结膜炎(conjunctivitis));秃发(例如,通过刺激毛发生长);糖尿病(包括胰岛素抗性糖尿病或由胰岛素敏感性或分泌介导的糖尿病);肥胖症(例如,通过食欲抑制);消化不良(dyspepsia);胆绞痛;肾绞痛;膀胱疼痛综合征(painful bladdersyndrome);食管炎(inflamed esophagus);上呼吸道疾病;尿失禁;急性膀胱炎;和毒液螫入(例如海物、蛇或昆虫叮或咬,包括水母、蜘蛛或黄貂鱼(stingray)毒液螫入)。
在一个特定实施方案中,施用本发明的化合物(或其实施方案)作为医学疗法以治疗疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、关节炎、痒病、咳嗽、哮喘或炎性肠病。
在另一个实施方案中,本发明提供治疗神经性疼痛或炎性疼痛的方法,所述方法包括向需要其的受试者施用治疗有效量的如本文另外部分中所述的式I的化合物(或其实施方案)的步骤。
在另一个实施方案中,本发明提供如本文另外部分所述的式I的化合物(或其实施方案),用于调节TRPA1活性。在一些实施方案中,本发明提供用于调节TRPA1活性的式I的化合物的药学上可接受的盐。
在另一个实施方案中,本发明提供如本文另外部分中所述的式I的化合物或其实施方案,例如其药学上可接受的盐,用于医学疗法。
在另一个实施方案中,本发明提供治疗选自慢性阻塞性肺病(COPD)、哮喘、变应性鼻炎和支气管痉挛的呼吸病的方法,所述方法包括向需要其的受试者施用治疗有效量的如本文另外部分所述的式I的化合物(或其实施方案)的步骤。
在另一个实施方案中,本发明提供如本文另外部分所述的式I的化合物(或其实施方案),例如其药学上可接受的盐,用于治疗或预防呼吸病。
在另一个实施方案中,本发明提供如本文另外部分所述的式I的化合物或其实施方案,例如其药学上可接受的盐,用于制备治疗或预防呼吸病的药物。
在另一个实施方案中,本发明提供用于治疗哺乳动物(例如人)呼吸病的方法,包含对所述哺乳动物施用如本文另外部分中所述的式I的化合物或其实施方案,例如其药学上可接受的盐。
在另一个实施方案中,本发明提供用于调节TRPA1活性的方法,包含使TRPA1接触如本文另外部分中所述的式I的化合物或其实施方案,例如其药学上可接受的盐。
在另一个实施方案中,本发明提供上述描述的式(I)的化合物或其实施方案,例如其药用盐,用于治疗或预防由TRPA1活性介导的疾病或病症。在该实施方案的方面内,所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、痒病、炎性疾病、内耳疾病、发烧或另一体温调节疾病、气管支气管或膈功能障碍、胃肠或尿道疾病、慢性阻塞性肺病、失禁或与向CNS的血流量减少或CNS缺氧相关的疾病。在该实施方案的某些方面内,其中所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳疾病。
在另一个实施方案中,本发明提供如本文另外部分中所述的式I化合物或其实施方案例如其药学上可接受的盐用于制备药物的用途,所述药物用于治疗或预防由TRPA1活性介导的疾病或病症。在该实施方案的方面内,所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、痒病、炎性疾病、内耳疾病、发烧或另一体温调节疾病、气管支气管或膈功能障碍、胃肠或尿道疾病、慢性阻塞性肺病、失禁或与向CNS的血流量减少或CNS缺氧相关的疾病。在该实施方案的方面内,所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳疾病。
在另一个实施方案中,本发明提供治疗哺乳动物(例如人)中由TRPA1活性介导的疾病或病症的方法,所述方法包括向哺乳动物施用如本文另外部分中所述的式I化合物或其实施方案,例如其药学上可接受的盐。在该实施方案的某些方面内,所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、痒病、炎性疾病、内耳疾病、发烧或另一体温调节疾病、气管支气管或膈功能障碍、胃肠或尿道疾病、慢性阻塞性肺病、失禁或与向CNS的血流量减少或CNS缺氧相关的疾病。在该实施方案的某些方面内,所述疾病或病症是疼痛(包括但不限于急性、慢性、神经性和炎性疼痛)、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳疾病。
在一个方面,本发明的化合物与其它类似物相比显示更高的效能。同样在本发明范围内的这类有代表性的化合物如下表1中所示,其中“IC50”表示hTRPA1CHO Ca2+AUC EVO(IC50),以微摩尔为单位:
表1
组合治疗
在离子通道介导的疾病和病症的治疗中,本发明的化合物(或其实施方案)可以有用地与一种或多种其它本发明的化合物或一种或多种其它治疗剂组合或作为其任意组合。例如,本发明的化合物可以与一种或多种共治疗剂组合同时、顺序或分开施用。
在一些实施方案中,所述共治疗剂是阿片类镇痛药。阿片类镇痛药的实例包括吗啡、海洛因、可卡因、氧化吗啡、羟甲左吗喃、烯丙左吗喃(levallorphan)、氧可酮、可待因、二氢可待因、丙氧芬、纳美芬、芬太尼(fentanyl)、氢可酮、氢吗啡酮、meripidine、美沙酮、纳洛芬(nalorphine)、纳洛酮(naloxone)、纳曲酮(naltrexone)、丁丙诺啡(buprenorphine)、布托啡诺(butorphanol)、纳布啡(nalbuphine)和戊唑辛(pentazocine)及其组合。
在一些实施方案中,所述共治疗剂是非阿片类镇痛药,例如,对乙酰氨基酚(acetomeniphen)和/或水杨酸盐(例如,阿司匹林)。
在一些实施方案中,所述共治疗剂是非甾类抗炎药物(NSAIDs)。非甾类抗炎药物的实例包括布洛芬(ibuprofen)、萘普生(naproxen)、非诺洛芬(fenoprofen)、酮洛芬(ketoprofen)、塞来考昔(celecoxib)、双氯芬酸(diclofenac)、二氟尼柳(diflusinal)、依托度酸(etodolac)、芬布芬(fenbufen)、非诺洛芬(fenoprofen)、氟苯沙酸(flufenisal)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮洛芬、酮洛酸(ketorolac)、甲氯芬那酸(meclofenamicacid)、甲芬那酸(mefenamicacid)、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、萘普生、尼美舒利(nimesulide)、硝基氟吡洛芬(硝基flurbiprofen)、奥撒拉嗪(olsalazine)、噁丙嗪(oxaprozin)、苯基丁氮酮、吡罗昔康、柳氮磺胺吡淀(sulfasalazine)、舒林酸(sulindac)、托美丁(tolmetin)和佐美酸(zomepirac)及其组合。
在一些实施方案中,所述共治疗剂是抗痉挛剂。抗痉挛剂的实例包括氨甲酰氮杂、奥卡西平(oxcarbazepine)、拉莫三嗪(lamotrigine)、丙戊酸钠(valproate)、托吡酯(topiramate)、加巴喷丁(gabapentin)和普加巴林(pregabalin)及其组合。
在一些实施方案中,所述共治疗剂是抗抑郁药。抗抑郁药的实例包括阿密曲替林(amitriptyline)、氯米帕明(clomipramine)、脱甲丙咪嗪(despramine)、丙咪嗪(imipramine)和去甲替林(nortriptyline)及其组合。
在一些实施方案中,所述共治疗剂是COX-2选择性抑制剂。COX-2选择性抑制剂的实例包括塞来考昔(celecoxib)、罗非考昔(rofecoxib)、帕瑞考昔(parecoxib)、伐地考昔(valdecoxib)、地拉考昔(deracoxib)、艾托考昔(etoricoxib)、罗美西布(lumiracoxib)及其组合。
在一些实施方案中,所述共治疗剂是α-肾上腺素能物质。α-肾上腺素能物质的实例包括多沙唑嗪(doxazosin)、坦索罗辛(tamsulosin)、氯压定(clonidine)、胍法新(guanfacine)、dexmetatomidine、莫达非尼(modafinil)和4-氨基-6,7-二甲氧基-2-(5-甲磺酰胺基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉及其组合。
在一些实施方案中,所述共治疗剂是巴比妥类镇静药。巴比妥类镇静药的实例包括异戊巴比妥(amobarbital)、阿普巴比妥(aprobarbital)、仲丁巴比妥(butabarbital)、布他比妥(butabital)、甲苯巴比妥(mephobarbital)、美沙比妥(metharbital)、美索比妥(methohexital)、戊巴比妥(pentobarbital)、苯巴比妥(phenobartital)、司可巴比妥(secobarbital)、他布比妥(talbutal)、theamylal和戊硫代巴比妥(thiopental)及其组合。
在一些实施方案中,所述共治疗剂是速激肽(tachykinin)(NK)拮抗剂。速激肽拮抗剂的实例包括NK-3、NK-2或NK-1拮抗剂,例如(7R,9R)-7-[3,5-双(三氟甲基)苄基)]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮芳辛并[2,1-g][1,7]-萘啶-6-13-二酮(TAK-637)、5-[[2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]-甲基]-1,2-二氢-3H-1,2,4-三唑-3-酮(MK-869)、阿瑞匹坦(aprepitant)、拉奈匹坦(lanepitant)、达匹坦(dapitant)或3-[[2-甲氧基5-(三氟甲氧基)苯基]-甲基氨基]-2-苯基哌啶(2S,3S)及其组合。
在一些实施方案中,所述共治疗剂是煤焦油止痛药,特别是扑热息痛。
在一些实施方案中,所述共治疗剂是血清素(serotonin)再摄取抑制剂(SRI)。SRI的实例包括帕罗西汀(paroxetine)、舍曲林(sertraline)、诺氟西汀(norfluoxetine)(氟西汀(fluoxetine)去甲基代谢产物)、代谢产物去甲基舍曲林、′3氟戊肟胺(fluvoxamine)、帕罗西汀(paroxetine)、西酞普兰(citalopram)、西酞普兰代谢产物去甲基西酞普兰、依他普仑(escitalopram)、d,l-芬氟拉明(fenfluramine)、非莫西汀(femoxetine)、伊福西汀(ifoxetine)、氰基度硫平(cyanodothiepin)、利托西汀(litoxetine)、达泊西汀(dapoxetine)、萘法唑酮(nefazodone)、西克拉明(cericlamine)、曲唑酮(trazodone)和氟西汀(fluoxetine)及其组合。
在一些实施方案中,所述共治疗剂是去甲肾上腺素(noradrenaline)再摄取抑制剂。去甲肾上腺素(noradrenaline)再摄取抑制剂的实例包括马普替林(maprotiline)、洛非帕明(lofepramine)、米氮平(mirtazapine)、羟丙替林(oxaprotiline)、非唑拉明(fezolamine)、托莫西汀(tomoxetine)、米安舍林(mianserin)、安非他酮(buproprion)、安非他酮代谢产物羟基安非他酮、诺米芬新(nomifensine)和维洛沙秦(viloxazine)特别是选择性去甲肾上腺素再摄取抑制剂例如瑞波西汀(reboxetine),尤其是(S,S)-瑞波西汀、文拉法辛(venlafaxine)、度洛西汀(duloxetine)抗精神病镇静药/抗焦虑药及其组合。
在一些实施方案中,所述共治疗剂是双重血清素-去甲肾上腺素再摄取抑制剂。这类双重血清素-去甲肾上腺素再摄取抑制剂的实例包括文拉法辛代谢产物O-去甲文拉法辛、氯米帕明(clomipramine)、氯米帕明代谢产物去甲氯米帕明、度洛西汀(duloxetine)、米那普仑(milnacipran)和丙米嗪(imipramine)及其组合。
在一些实施方案中,所述共治疗剂是乙酰胆碱酯酶抑制剂,例如多奈哌齐(donepezil)。
在一些实施方案中,所述共治疗剂是5-HT3拮抗剂,例如昂丹司琼。
在一些实施方案中,所述共治疗剂是代谢型谷氨酸受体(mGluR)拮抗剂。
在一些实施方案中,所述共治疗剂是局部麻醉剂。局部麻醉剂的实例包括美西律(mexiletine)和利多卡因(lidocaine)。
在一些实施方案中,所述共治疗剂是皮质甾类,例如地塞米松(dexamethasone)。
在一些实施方案中,所述共治疗剂是抗心律失常药。抗心律失常药的实例包括美西律和苯妥英(phenytoin)。
在一些实施方案中,所述共治疗剂是毒蕈碱拮抗剂。毒蕈碱拮抗剂的实例包括托特罗定(tolterodine)、丙哌维林(propiverine)、曲司氯铵(tropsiumtchloride)、达非那新(darifenacin)、索利那新(solifenacin)、替米维林(temiverine)和异丙托铵(ipratropium)及其组合。
在一些实施方案中,所述共治疗剂是大麻素类。
在一些实施方案中,所述共治疗剂是辣椒素受体激动剂,例如,超强辣素(resiniferotoxin))或拮抗剂,例如,辣椒平(capsazepine)。
在一些实施方案中,所述共治疗剂是镇静剂。镇静剂的实例包括格鲁米特(glutethimide)、甲丙氨酯(meprobamate)、甲喹酮(methaqualone)、二氯醛安替比林(dichloralphenazone)及其组合。
在一些实施方案中,所述共治疗剂是抗焦虑药例如苯并二氮杂类。
在一些实施方案中,所述共治疗剂是抗抑郁药,例如米尔塔扎平(mirtazapine)。
在一些实施方案中,所述共治疗剂是局部活性剂。局部活性剂的实例包括利多卡因(lidocaine)、辣椒素(capsacin)和超强辣素及其组合。
在一些实施方案中,所述共治疗剂是肌肉松弛剂。肌肉松弛剂的实例包括苯并二氮杂类、巴氯芬(baclofen)、卡立普多(carisoprodol)、氯唑沙宗(chlorzoxazone)、环苯扎林(cyclobenzaprine)、美索巴莫(methocarbamol)和orphrenadine及其组合。
在一些实施方案中,所述共治疗剂是抗组胺或H1拮抗剂。
在一些实施方案中,所述共治疗剂是NMDA受体拮抗剂。
在一些实施方案中,所述共治疗剂是5-HT受体激动剂/拮抗剂。
在一些实施方案中,所述共治疗剂是PDEV抑制剂。
在一些实施方案中,所述共治疗剂是胆碱能(烟碱性)止痛药。
在一些实施方案中,所述共治疗剂是α-2-δ配体。
在一些实施方案中,所述共治疗剂是前列腺素E2亚型拮抗剂。
在一些实施方案中,所述共治疗剂是白三烯B4拮抗剂。
在一些实施方案中,所述共治疗剂是5-脂氧合酶抑制剂。
在一些实施方案中,所述共治疗剂是5-HT3拮抗剂。
如本文使用的“组合”是指一种或多种本发明的化合物(或其实施方案)和一种或多种其它本发明的化合物或一种或多种另外的治疗剂的任意混合物或排列。除非本文另有澄清,“组合”可以包括同时或顺序地与一种或多种治疗剂一起递送本发明的化合物。除非本文另有澄清,“组合”可以包括本发明的化合物与另一种治疗剂的剂型。除非本文另有澄清,“组合”可以包括本发明的化合物与另一种治疗剂的施用途径。除非本文另有澄清,“组合”可以包括本发明的化合物与另一种治疗剂的制剂。剂型、施用途径和药物组合物包括,但不限于,本文中描述的那些。
在另一个实施方案中,提供的是上文描述的发明。
式I化合物的一般制备
用于制备这些化合物的起始材料和试剂通常可以从商业供应商例如AldrichChemical Co.获得,或由本领域技术人员已知的方法,按照在下列参考文献例如Fieserand Fieser’s Reagents for Organic Synthesis(费舍尔和费氏有机合成试剂);Wiley&Sons:New York,1991,第1-15卷;Rodd’s Chemistry of Carbon Compounds(Rodd碳化合物化学),Elsevier Science Publishers,1989,第1-5卷和增刊;和Organic Reactions(有机反应),Wiley&Sons:New York,1991,第1-40卷中阐述的步骤制备。
以下合成反应方案仅说明一些可以合成本发明的化合物(或其实施方案)的方法,并且这些合成反应方案的各种改进是可以进行的并且将对参考本申请中含有的公开内容的本领域技术人员是有暗示的。
如果需要,可以使用常规技术,包括但不限于过滤、蒸馏、结晶、色谱等来分离和纯化合成反应方案的起始材料和中间体。这种物质可以使用常规方法表征,所述常规方法包括物理常数和光谱数据。
除非有相反指示,本文所述反应优选在惰性气氛下在大气压,在约-78℃至约150℃,更优选约0℃至约125℃,并且最优选和方便地在约室温(或环境温度),例如,约20℃的反应温度进行。
实施例
尽管在本文描述和叙述了某些示例性实施方案,本发明的化合物(或其实施方案)可以使用适当的起始材料根据本文中一般性描述的方法和/或通过本领域普通技术人员可获得的方法制备。
中间体和最终化合物通过快速色谱和/或通过反相制备型HPLC(高效液相色谱)和/或超临界流体色谱法纯化。除非另有说明,否则使用来自ISCO的预填充的硅胶柱或SiliCycle应用ISCO色谱仪(来自Teledyne Isco,Inc.)进行快速色谱。反相制备型HPLC使用(1)Polaris C-185μM柱(50×21mm)或(2)XBridge Prep C-18OBD 5μM柱(19×150mm)进行。超临界流体色谱法使用Chiral Technologies、Chiralpak AD、Chiralpak AS、Chiralpak IA、Chiralpak IB、Chiralpak IC、Chiralcel OD或ChiralcelOJ的填充柱进行,其中柱尺寸例如(1)4.6cm×5cm,3μM,(2)4.6cm×5cm,5μM,或(3)15cm×21.2mm,5μM。
使用如下仪器进行质谱(MS):(1)Sciex 15质谱仪,以ES+模式;或(2)Shimadzu液相色谱-质谱(LCMS)2020光谱仪,以ESI+模式。质谱数据通常仅表明母离子,另有描述的除外。对表明的特定中间体或化合物提供MS或HRMS数据。
使用如下仪器进行核磁共振光谱法(NMR):(1)Bruker AV III 300NMR光谱仪;(2)Bruker AV III 400NMR光谱仪;或(3)Bruker AV III 500NMR光谱仪并且参比四甲基硅烷。对表明的特定中间体或化合物提供NMR数据。
所有涉及空气敏感试剂的反应在惰性气氛下进行。除非另有标注,直接使用从商业供应商获得的试剂。
实施例1:制备1:2-(叔丁氧羰基)-2-氮杂双环[2.1.1]己烷-3-甲酸.
实施例1的总体反应方案如下:
实施例1,步骤1:2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向冷却至0℃的2-氮杂双环[2.1.1]己烷盐酸盐(20.0g,159mmol)在1,4-二噁烷(300mL)和水(300mL)中的溶液中加入氢氧化钠(1mol/L)的水(318mL,318mmol)溶液。然后通过加液漏斗添加二碳酸二-叔丁酯(75mL,318mmol),历时30min。将该反应体系在0℃搅拌30min,然后温热至室温,搅拌18h。真空浓缩该反应混合物,以除去二噁烷,用石油醚(3×)萃取水性残余物。用硫酸钠干燥合并的有机层,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-50%EtOAc的庚烷溶液纯化,得到标题化合物,为淡黄色固体(25.7g,88%)。1H NMR(400MHz,CDCl3)δ4.34(s,1H),3.29(s,2H),2.86–2.77(m,1H),1.92–1.83(m,2H),1.47(s,9H),1.42–1.31(m,2H)。
实施例1,步骤2:3-甲酰基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤2按照如下方案进行:
向冷却至-78℃的2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(9.67g,50.7mmol)和N,N,N',N'-四甲基乙二胺(9.93mL,65.9mmol)在乙醚(200mL)中的溶液中滴加在环己烷(47mL,65.9mmol)中的仲丁基锂(1.4mol/L)。将该反应混合物在-78℃搅拌2h,然后通过加液漏斗缓慢地加入N,N-二甲基甲酰胺(29.4mL,380mmol)在乙醚(70mL)中的溶液,历时30min。将该反应混合物搅拌30min,温热至室温。通过添加60mL饱和氯化铵水溶液使该反应混合物猝灭,分离各层。用水(2×)洗涤有机层,用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物,为白色固体(2.97g,28%)。
实施例1,步骤3:2-(叔丁氧羰基)-2-氮杂双环[2.1.1]己烷-3-甲酸的制备
步骤3按照如下方案进行:
向2-甲酰基-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯(2.97g,14.1mmol)在叔丁醇(120mL)和水(28mL)中的溶液中加入2-甲基-2-丁烯(15mL,140.8mmol)、磷酸二氢钠(8.45g,70.4mmol)和次氯酸钠(6.37g,70.4mmol)。将该反应混合物在室温搅拌1h。然后用200mL乙酸乙酯和200mL饱和氯化铵水溶液稀释该反应混合物。分离各层,用EtOAc(200mL)萃取水层。用硫酸钠干燥有机层,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与10-80%3:1iPrOAc:MeOH的庚烷溶液纯化,得到期望的化合物,为无色油状物,其随时间固化,得到白色固体(3.07g,96%)。1H NMR(400MHz,CDCl3-d)δ4.36–4.29(m,1H),4.24(s,1H),3.19–3.10(m,1H),2.08–2.03(m,1H),2.03–1.97(m,1H),1.65–1.55(m,1H),1.51(s,9H),1.49–1.39(m,1H)。
实施例2:2-(叔丁氧羰基)-1-甲基-2-氮杂双环[2.1.1]己烷-3-甲酸的制备
实施例2的总体反应方案如下:
实施例2,步骤1:1-甲基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向冷却至-30℃的2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.00g,5.24mmol)在四氢呋喃(37mL)中的溶液中加入在环己烷(7.5mL,6.81mmol)中的仲丁基锂(1.4mol/L),将该反应混合物在-30℃搅拌10min。然后加入碘甲烷(0.65mL,10.5mmol),将该反应体系在-30℃搅拌10min,然后温热至室温,历时15min。通过添加饱和氯化铵水溶液使反应停止,分离各层,用乙醚(3×)萃取水层。用硫酸钠干燥合并的有机层,真空浓缩粗产物。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-50%EtOAc的庚烷溶液纯化,得到标题化合物,为白色固体(775mg,75%)。
实施例2,步骤2:3-甲酰基-1-甲基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤2按照如下方案进行:
将4-甲基-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯(670mg,3.4mmol)和N,N,N',N'-四甲基乙二胺(0.67mL,4.4mmol)在乙醚(25mL,239mmol)中的溶液冷却至-78℃,然后滴加在环己烷(3.2mL,4.4mmol)中的仲-丁基锂(1.4mol/L)。将该反应混合物在-78℃搅拌2h。将该反应混合物通过插套管导入-78℃的N,N-二甲基甲酰胺(2.0mL,25mmol)在乙醚(15mL)中的溶液,搅拌30min,温热至室温。通过添加饱和氯化铵水溶液使该反应混合物猝灭,然后分离各层。用水(2×)洗涤有机层,用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物,为白色固体(324mg,42%)。
实施例2,步骤3:2-(叔丁氧羰基)-1-甲基-2-氮杂双环[2.1.1]己烷-3-甲酸的制备
步骤3按照如下方案进行:
向2-甲酰基-4-甲基-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯(324mg,1.44mmol)在叔丁醇(12.0mL)和水(2.9mL)中的溶液中加入2-甲基-2-丁烯(1.5mL,14.4mmol)、磷酸二氢钠(864mg,7.2mmol)和次氯酸钠(651mg,7.2mmol)。将该反应混合物在室温搅拌1h,然后用乙酸乙酯和饱和氯化钠水溶液稀释该反应混合物。分离各层,用饱和氯化铵水溶液洗涤有机层。用硫酸钠干燥有机层,过滤并真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-80%(90:10)DCM:MeOH的DCM溶液纯化,得到期望的化合物,为澄清油状物,随时间固化为白色固体(242mg,70%)。
实施例3:(5-氟-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺的制备
实施例3的总体反应方案如下:
实施例3,步骤1:2-溴-5-氟异烟酰醛的制备
步骤1按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中加入二异丙基胺(86.57g,1.50当量)在四氢呋喃(1500mL)中的溶液,然后滴加n-BuLi(2.4mol/L)(310mL,1.30当量),同时在-35℃搅拌。将得到的溶液在-30℃搅拌30min。在-75℃向该混合物中滴加2-溴-5-氟吡啶(100g,568.23mmol,1.00当量)在四氢呋喃(200mL)中的溶液,同时搅拌。将得到的溶液在-75℃再搅拌2h。在-70℃向该混合物中滴加N,N-二甲基甲酰胺(83.4g,2.00当量),同时搅拌,将得到的溶液在-70℃再搅拌2h,通过添加4N HCl猝灭。用4N HCl溶液将该溶液到pH调整至6。用3×1000mL乙酸乙酯萃取得到的溶液。用1×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到125g(粗)2-溴-5-氟吡啶-4-甲醛,为黄色油状物。
实施例3,步骤2:(2-溴-5-氟吡啶-4-基)甲醇的制备
步骤2按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中加入2-溴-5-氟吡啶-4-甲醛(125g,612.75mmol,1.00当量)在甲醇(1000mL)中的溶液,然后在0℃滴加NaBH4(23.4g,635.44mmol,1.00当量),同时搅拌。将得到的溶液在室温搅拌1h,真空浓缩,用500mL H2O稀释,用3×800mL乙酸乙酯萃取。用1×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(1:4)洗脱,得到80g(63%)(2-溴-5-氟吡啶-4-基)甲醇,为白色固体。
实施例3,步骤3:2-溴-4-(氯甲基)-5-氟吡啶的制备
步骤3按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中加入(2-溴-5-氟吡啶-4-基)甲醇(80g,388.33mmol,1.00当量)在二氯甲烷(800mL)中的溶液,然后滴加亚硫酰氯(240mL),同时在0℃搅拌。将得到的溶液在40℃搅拌过夜,真空浓缩,得到90g(粗)2-溴-4-(氯甲基)-5-氟吡啶,为黄色油状物。
实施例3,步骤4:(2-溴-5-氟吡啶-4-基)甲基氨基甲酸双-叔丁酯的制备
步骤4按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中加入2-溴-4-(氯甲基)-5-氟吡啶(90g,400.97mmol,1.00当量)在N,N-二甲基甲酰胺(900mL)中的溶液、K2CO3(167g,1.20mol,2.99当量)和N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(103.7g,477.30mmol,1.19当量)。将得到的溶液在80℃搅拌4h,通过添加2000mL水/冰猝灭,用3×800mL乙酸乙酯萃取。用1×600mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1:10),得到110g(68%)N-[(2-溴-5-氟吡啶-4-基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯,为白色固体。
实施例3,步骤5:(5-氟-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基氨基甲酸双-叔丁酯的制备
步骤5按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中加入N-[(2-溴-5-氟吡啶-4-基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(105g,259.09mmol,1.00当量)在二噁烷(1500mL)中的溶液、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(142g,518.16mmol,2.00当量)、碳酸钾(107.5g,772.20mmol,2.98当量)和水(150mL)、Pd(dppf)Cl2(20g,27.33mmol,0.11当量)。将得到的溶液在75℃搅拌12h,冷却至室温,用2000mL乙酸乙酯稀释,过滤。用2×500mL水洗涤滤液,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1:8),得到60g(49%)N-[(叔丁氧基)羰基]-N-([5-氟-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯,为白色固体。
实施例3,步骤6:(5-氟-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺的制备
步骤6按照如下方案进行:
向1000-mL 4-颈圆底烧瓶中放入N-[(叔丁氧基)羰基]-N-([5-氟-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯(60g,127.00mmol,1.00当量)在二氯甲烷(600mL)中的溶液,然后导入氯化氢(足够的气体)。将得到的溶液在室温搅拌2h,真空浓缩,用水稀释。用碳酸钠水溶液(2mol/L)将溶液的pH值调整至9。用3×1000mL乙酸乙酯萃取得到的溶液。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(9:1)。使粗产物从1:10之比的EA:PE中重结晶,得到20g(58%)[5-氟-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺,为黄色固体。LCMS[M+H]+273;1H-NMR(300MHz,DMSO-d6)δ9.65(s,2H),8.67(d,J=1.5Hz,1H),8.43(d,J=6.0Hz,1H),3.88(s,2H),2.17(s,2H)。
实施例4:[5-溴-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
实施例4的总体反应方案如下:
实施例4,步骤1:2,5-二溴异烟醛的制备
步骤1按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的5-L 4-颈圆底烧瓶中放入DPA(138.5g,1.37mol,1.30当量)和四氢呋喃(1000mL),然后滴加丁基锂(1265mL,1.20当量),同时在-30℃搅拌。将该混合物在-30℃搅拌30min。向该溶液中滴加2,5-二溴吡啶(250g,1.06mol,1.00当量)在四氢呋喃(1000mL)中的溶液,同时在-78℃搅拌。将该混合物在-78℃搅拌2h。向该混合物中滴加DMF(151g,2.09mol,2.00当量),同时在-78℃搅拌。将得到的溶液在-78℃搅拌2h,然后用5L水/冰猝灭。用氯化氢水溶液(6N)将溶液的pH值调整至5,用3×2L乙酸乙酯萃取该反应混合物。用2×1.5L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到200g(72%)2,5-二溴吡啶-4-甲醛,为白色固体。
实施例4,步骤2:(2,5-二溴吡啶-4-基)甲醇的制备
步骤2按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 3-颈圆底烧瓶中放入2,5-二溴吡啶-4-甲醛(200g,755.00mmol,1.00当量)和甲醇(1800mL),然后在0℃分部分添加NaBH4(30.7g,811.53mmol,1.10当量)。将得到的溶液在室温搅拌2h,真空浓缩,通过添加1L水/冰猝灭。用3×800mL乙酸乙酯萃取得到的溶液。用2×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到180g(89%)(2,5-二溴吡啶-4-基)甲醇,为白色固体。
实施例4,步骤3:2,5-二溴-4-(溴甲基)吡啶的制备
步骤3按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的10-L 4-颈圆底烧瓶中放入(2,5-二溴吡啶-4-基)甲醇(180g,674.36mmol,1.00当量)和二氯甲烷(6L),然后滴加三溴磷杂环丙烷(180mL),同时搅拌。将该混合物在室温搅拌24h。向该混合物中再滴加三溴磷杂环丙烷(50mL),同时搅拌。将得到的溶液在室温搅拌3天,通过添加5L水/冰猝灭,用2×2L二氯甲烷萃取。用2×2L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到200g(90%)2,5-二溴-4-(溴甲基)吡啶,为白色固体。
实施例4,步骤4:(2,5-二溴吡啶-4-基)甲胺的制备
步骤4按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的10-L 4-颈圆底烧瓶中放入2,5-二溴-4-(溴甲基)吡啶(200g,606.40mmol,1.00当量)、1,4-二噁烷(4L)和胺水合物(400mL)。将得到的溶液在室温搅拌过夜,真空浓缩,得到220g(粗)(2,5-二溴吡啶-4-基)甲胺,为棕色油状物。
实施例4,步骤5:((2,5-二溴吡啶-4-基)甲基)氨基甲酸叔丁酯的制备
步骤5按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的5-L 3-颈圆底烧瓶中放入(2,5-二溴吡啶-4-基)甲胺(220g,827.28mmol,1.00当量)和二氯甲烷(3000mL),然后在水/冰浴中分别添加TEA(209g,2.07mol,2.50当量)和(Boc)2O(271g,1.24mol,1.50当量)。将得到的溶液在室温搅拌2h,通过添加3L水猝灭,用2×1.5L二氯甲烷萃取。用2×1L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(5/95),得到180g(59%)N-[(2,5-二溴吡啶-4-基)甲基]氨基甲酸叔丁酯,为白色固体。
实施例4,步骤6:((5-溴-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酸叔丁酯的制备
步骤6按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的1-L 3-颈圆底烧瓶中放入N-[(2,5-二溴吡啶-4-基)甲基]氨基甲酸叔丁酯(50g,136.59mmol,1.00当量)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(44.9g,1.20当量)、1,4-二噁烷(500mL)、水(50mL)、碳酸钾(56.6g,3.00当量)和Pd(dppf)Cl2(5g,0.05当量)。将得到的混合物在50℃搅拌4h,过滤。真空浓缩得到的滤液,用2L H2O稀释,用3×1.5L乙酸乙酯萃取。用2×1L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(10/90)洗脱,得到45g(25%)N-([5-溴-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯,为白色固体。
实施例4,步骤7:(5-溴-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺盐酸盐的制备
步骤7按照如下方案进行:
向1000-mL 3-颈圆底烧瓶中放入N-([5-溴-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯(45g,103.87mmol,1.00当量),甲醇(300mL)和二氯甲烷(300mL)。向上述反应系统中导入氯化氢(气体)。将得到的溶液在室温搅拌50min,真空浓缩,用400mL乙醚稀释,过滤。干燥滤饼,得到32g(83%)[5-溴-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐,为白色固体。LCMS[M-HCl+H]+333;1H NMR:(300CDCl3,DMSO-d6):δ4.26(s,2H),8.74(s,1H),8.95(s,3H),9.00(s,1H),9.74(s,2H)。
实施例5:(5-(三氟甲基)-2,4'-联嘧啶-6'-基)甲胺盐酸盐的制备
实施例5的总体反应方案如下:
实施例5,步骤1:6-羟基嘧啶-4-甲酸甲酯的制备
步骤1按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的5-L 4-颈圆底烧瓶中放入6-羟基嘧啶-4-甲酸(100g,713.79mmol,1.00当量)和甲醇(2000mL),然后滴加亚硫酰氯(210g,2.50当量),同时在0℃搅拌。将得到的溶液在30℃搅拌1天,真空浓缩,得到115g(粗)6-羟基嘧啶-4-甲酸甲酯,为黄白色固体。LCMS[M+H]+155。
实施例5,步骤2:6-氯嘧啶-4-甲酸甲酯的制备
向2000-mL4-颈圆底烧瓶中放入6-羟基嘧啶-4-甲酸甲酯(115g,746.16mmol,1.00当量)、CH3CN(1200mL)和POCl3(340g,2.22mol,3.00当量)。将得到的溶液在搅拌80℃过夜,冷却至室温,真空浓缩,用1000mL EA稀释,用1000mL水/冰猝灭。用3×500mL乙酸乙酯萃取得到的溶液。用1×1000mL水和1×1000mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1:4),得到76g(59%)6-氯嘧啶-4-甲酸甲酯,为白色固体。LCMS[M+H]+173。
实施例5,步骤3:(6-氯嘧啶-4-基)甲醇的制备
步骤3按照如下方案进行:
向3000-mL 4-颈圆底烧瓶中放入6-氯嘧啶-4-甲酸甲酯(80g,463.58mmol,1.00当量),四氢呋喃(1600mL)和乙醇(160mL),然后在0℃分几批添加NaBH4(48g,1.27mol,3.00当量)。将得到的溶液在0℃搅拌3h,通过添加1500mL水/冰猝灭,用3×800mL乙酸乙酯萃取。用1×800mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1:2),得到40g(60%)(6-氯嘧啶-4-基)甲醇,为黄色固体。LCMS[M+H]+145。
实施例5,步骤4:2-((6-氯嘧啶-4-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤4按照如下方案进行:
向3000-mL 4-颈圆底烧瓶中放入(6-氯嘧啶-4-基)甲醇(50g,345.88mmol,1.00当量)、四氢呋喃(1500mL)、2,3-二氢-1H-异吲哚-1,3-二酮(76.4g,519.27mmol,1.50当量)和PPh3(136g,518.51mmol,1.50当量),然后滴加DIAD(105g,519.26mmol,1.50当量),同时在0℃搅拌。将得到的溶液在室温搅拌过夜,真空浓缩,用1000mL EA稀释,再搅拌30min,过滤。用1×300mL EA洗涤滤饼,得到65g(69%)2-[(6-氯嘧啶-4-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮,为黄白色固体。LCMS[M+H]+274。
实施例5,步骤5:2-((5-(三氟甲基)-2,4'-联嘧啶-6'-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤5按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入2-[(6-氯嘧啶-4-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮(50g,182.70mmol,1.00当量)、1,4-二噁烷(1500mL)、水(70mL)、碳酸钾(50g,361.77mmol,2.00当量)、[2-(三氟甲基)嘧啶-5-基]硼酸(91g,474.20mmol,2.50当量)和Pd(dppf)Cl2(4g,5.47mmol,0.02当量)。将得到的溶液在70℃搅拌3h,冷却至室温,通过添加3L水猝灭,用3×1L乙酸乙酯萃取。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1:10),得到55g(78%)2-([6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮,为白色固体。LCMS[M+H]+386。
实施例5,步骤6:(5-(三氟甲基)-2,4'-联嘧啶-6'-基)甲胺的制备
步骤6按照如下方案进行:
向3000-mL 4-颈圆底烧瓶中放入2-([6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(55g,142.75mmol,1.00当量)、甲醇(1500mL)和NH2NH2·H2O(110g,15.00当量)。将得到的溶液在50℃搅拌过夜,冷却至室温,过滤。用1LH2O稀释滤液,用3×500mL乙酸乙酯萃取。用无水硫酸钠干燥合并的有机层,真空浓缩,得到35g(粗)[6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺,为棕色固体。
实施例5,步骤7:(5-(三氟甲基)-2,4'-联嘧啶-6'-基)甲基氨基甲酸叔丁酯的制备
步骤7按照如下方案进行:
向2000-mL 4-颈圆底烧瓶中放入[6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺(35g,137.15mmol,1.00当量)、二氯甲烷(700mL)、TEA(20g,197.65mmol,1.50当量)和(Boc)2O(44g,201.60mmol,1.50当量)。将得到的溶液在室温搅拌4h,用2L H2O稀释,用3×800mL二氯甲烷萃取。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(1:5)洗脱。这得到40g(82%)N-([6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯,为黄色固体。LCMS[M+H]+356。
实施例5,步骤8:(5-(三氟甲基)-2,4'-联嘧啶-6'-基)甲胺盐酸盐的制备步骤8按照如下方案进行:
向2000-mL 4-颈圆底烧瓶中放入N-([6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯(40g,112.58mmol,1.00当量)、二氯甲烷(800mL)和甲醇(400mL)。加入氯化氢气体。将得到的溶液在室温搅拌5h,真空浓缩,用200mL己烷稀释,过滤,得到26g(79%)[6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺盐酸盐,为淡黄色固体。LCMS[M+H]+256;1H-NMR(300MHz,DMSO)δ9.78(2H,s),9.45(1H,s),8.67-8.76(3H,ds),8.62(1H,s),4.33-4.37(2H,t)。
实施例6:[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺的制备实施例6的总体反应方案如下:
实施例6,步骤1:2,4-二氯-6-(氯甲基)嘧啶的制备
步骤1按照如下方案进行:
使6-(氯甲基)-1,2,3,4-四氢嘧啶-2,4-二酮(9.2g,57.30mmol,1.00当量)和POCl3(50mL)通过在100℃在油浴中搅拌12小时进行反应。然后将该反应体系倾入水/冰,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用石油醚洗脱,得到标题化合物(9.5g,84%),为淡黄色固体。LCMS[M+H+]197。
实施例6,步骤2:2-[(2,6-二氯嘧啶-4-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤2按照如下方案进行:
将2-钾(potassio)-2,3-二氢-1H-异吲哚-1,3-二酮(13g,70.19mmol,1.51当量)、2,4-二氯-6-(氯甲基)嘧啶(9.2g,46.59mmol,1.00当量)和N,N-二甲基甲酰胺(100mL)的混合物通过在室温搅拌3小时进行反应。将得到的溶液用水稀释。通过过滤采集固体,真空干燥,得到标题化合物(11.5g,80%),为黄色固体。LCMS[M+H+]308。
实施例6,步骤3:2-([2-氯-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤3按照如下方案进行:
将2-[(2,6-二氯嘧啶-4-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮(3.98g,12.91mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(2.81g,10.27mmol,0.80当量)、Pd(dppf)Cl2(945mg,1.29mmol,0.10当量)、碳酸钾(5.477g,39.63mmol,3.07当量)和N,N-二甲基甲酰胺(150mL)的混合物在70℃在氮气气氛中搅拌12h。然后过滤出固体。用盐水稀释得到的溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用二氯甲烷/乙酸乙酯(50/1)洗脱,得到标题化合物(1.75g,32%),为黄色固体。LCMS[M+H+]420。
实施例6,步骤4:2-([2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤4按照如下方案进行:
将2-([2-氯-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(190mg,0.45mmol,1.00当量)、环丙基硼酸(195mg,2.27mmol,5.02当量)、Pd(dppf)Cl2(33mg,0.045mmol,0.10当量)和碳酸钾(188mg,1.36mmol,3.01当量),1,4-二噁烷(10mL)的混合物在90℃在氮气气氛中搅拌12小时。过滤出固体。用盐水洗涤得到的溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱与二氯甲烷/乙酸乙酯(50/1)纯化残余物,得到标题化合物(175mg,91%),为黄色固体。LCMS[M+H+]426。
实施例6,步骤5:[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺的制备
步骤5按照如下方案进行:
将2-([2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(175mg,0.41mmol,1.00当量)、甲醇(20mL)、NH2NH2.H2O(206mg,41.1mmol,10.00当量)的混合物在油浴中加热至回流12小时。真空浓缩得到的混合物,溶于乙酸乙酯。过滤出沉淀的固体。真空浓缩得到的溶液,得到标题化合物(121mg),为黄色油状物。LCMS[M+H+]296。
实施例7:(2-氟-5-(2-(三氟甲基)嘧啶-5-基)苯基)甲胺的制备
实施例7的总体反应方案如下:
实施例7,步骤1:(5-溴-2-氟苯基)甲醇的制备
步骤1按照如下方案进行:
在0℃在氮气气氛中向BH3-THF(229mL,1M的THF溶液,5.00当量)中滴加5-溴-2-氟苯甲酸(10g,45.66mmol,1.00当量)在四氢呋喃(150mL)中的溶液。将得到的溶液在室温搅拌过夜,用水猝灭,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱色谱法与乙酸乙酯/石油醚(1:5)纯化残余物,得到标题化合物(9.5g),为淡黄色油状物。GCMS m/z=204,206。
实施例7,步骤2:2-[(5-溴-2-氟苯基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤2按照如下方案进行:
在0℃在氮气气氛中将DIAD(18.8g,92.97mmol,2.01当量)滴加到搅拌的(5-溴-2-氟苯基)甲醇(9.5g,46.34mmol,1.00当量)、2,3-二氢-1H-异吲哚-1,3-二酮(13.6g,92.44mmol,2.00当量)和PPh3(24.4g,93.03mmol,2.01当量)在四氢呋喃(300mL)中的混合物中。将得到的溶液在室温搅拌过夜,真空浓缩。通过硅胶柱与乙酸乙酯/石油醚(1:10)纯化残余物,得到标题化合物(9.5g,61%),为白色固体。LCMS[M+H+]334;1H NMR(300MHz,CDCl3)δ7.89-7.83(m,2H),7.78-7.70(m,2H),7.66-7.63(m,1H),7.40-7.35(m,1H),7.09-7.03(m,1H),4.78(s,2H)。
实施例7,步骤3:2-([2-氟-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤3按照如下方案进行:
将2-[(5-溴-2-氟苯基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮(2g,5.99mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(2.1g,7.66mmol,1.28当量)、Pd(dppf)Cl2(438mg,0.60mmol,0.10当量)和碳酸钾(1.65g,11.94mmol,2.00当量)在四氢呋喃(25mL)中的混合物在80℃搅拌过夜。真空浓缩得到的混合物,通过硅胶柱与乙酸乙酯/石油醚(1:100-1:10)纯化残余物。这得到标题化合物(1.7g,71%),为淡黄色固体。LCMS[M+H+]402。
实施例7,步骤4:[2-氟-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲胺的制备
步骤4按照如下方案进行:
将2-([2-氟-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(500mg,1.25mmol,1.00当量)和水合肼(623mg,12.45mmol,10.00当量)在甲醇(10mL)中的混合物在55℃搅拌过夜。真空浓缩得到的混合物。将残余物溶于乙酸乙酯。过滤出固体,真空浓缩液体。这得到标题化合物(300mg,粗),为淡黄色油状物。LCMS[M+H+]272。
实施例8:[5-(二氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
实施例8的总体反应方案如下:
实施例8,步骤1:(4,6-二氯吡啶-3-基)甲醇的制备
步骤1按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的5000-mL 4-颈圆底烧瓶中放入4,6-二氯吡啶-3-甲酸(95g,494.79mmol,1.00当量)和四氢呋喃(1000mL),然后滴加BH3.THF(1M)(2111mL,4.20当量),同时在0℃搅拌。将该反应混合物在0℃搅拌30min,在室温搅拌过夜,通过添加1000mL水/冰猝灭,用3×1000mL乙酸乙酯萃取。用无水硫酸钠干燥合并的有机层,真空浓缩,得到78.4g(89%)(4,6-二氯吡啶-3-基)甲醇,为白色固体。
实施例8,步骤2:4,6-二氯烟醛的制备
步骤2按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中放入(4,6-二氯吡啶-3-基)甲醇(78.4g,440.41mmol,1.00当量)、二氯甲烷(1000mL)、PCC(284.83g,1.32mol,3.00当量)和硅胶(235g)。将得到的混合物在室温搅拌4h,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(0:1-1:6),得到62g(80%)4,6-二氯吡啶-3-甲醛,为白色固体。
实施例8,步骤3:2,4-二氯-5-(二氟甲基)吡啶的制备
步骤3按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中放入4,6-二氯吡啶-3-甲醛(62g,352.27mmol,1.00当量)和二氯甲烷(1000mL),然后滴加DAST(113.7g,705.38mmol,2.00当量),同时在-20℃搅拌。将得到的溶液在-20℃搅拌30min,在室温再搅拌3h,通过滴加500mL水猝灭,同时搅拌,用3×500mL二氯甲烷萃取。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(0:1-1:0),得到36g(52%)2,4-二氯-5-(二氟甲基)吡啶,为淡黄色固体。
实施例8,步骤4:5-(4-氯-5-(二氟甲基)吡啶-2-基)-2-(三氟甲基)嘧啶的制备
步骤4按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入2,4-二氯-5-(二氟甲基)吡啶(36g,181.82mmol,1.00当量)、1,4-二噁烷(1800mL)、水(180mL)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(60g,218.94mmol,1.20当量)、碳酸钾(78g,564.36mmol,3.00当量)和Pd(dppf)Cl2.CH2Cl2(15g,18mmol,0.10当量)。将得到的溶液在80℃搅拌过夜,过滤。真空浓缩滤液。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(0:1-5:95),得到28g(50%)5-[4-氯-5-(二氟甲基)吡啶-2-基]-2-(三氟甲基)嘧啶,为白色固体。
实施例8,步骤5:((5-(二氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酸叔丁酯的制备
步骤5按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入5-[4-氯-5-(二氟甲基)吡啶-2-基]-2-(三氟甲基)嘧啶(20g,64.59mmol,1.00当量)、乙醇(2000mL)、水(400mL)、N-[(三氟-^4-硼烷基)甲基]氨基甲酸叔丁酯钾(20g,84.36mmol,1.30当量)、碳酸钠(22g,207.57mmol,3.20当量)和Pd(PPh3)2Cl2(5g,7.12mmol,0.11当量)。将该反应混合物首先在室温搅拌30min,然后在80℃搅拌过夜,然后过滤。真空浓缩滤液。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(0:1-1:6),得到14g(54%)N-[[5-(二氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基]氨基甲酸叔丁酯,为淡黄色固体。
实施例8,步骤6:(5-(二氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺盐酸盐的制备
步骤6按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的1000-mL 3-颈圆底烧瓶中放入N-[[5-(二氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基]氨基甲酸叔丁酯(30g,74.20mmol,1.00当量)和1,4-二噁烷(500mL)。向上述反应混合物中导入HCl(气体)。将得到的溶液在室温搅拌3h,真空浓缩,过滤。用1×300mL EA洗涤滤饼,干燥,得到20.37g(81%)[5-(二氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐,为黄色固体。LCMS[M-HCl+H+]305;1H NMR(300MHz,CD3OD)δ9.67(s,2H),9.10(s,1H),8.34(s,1H),7.39-7.03(t,1H),4.51(s,2H)。
实施例9:(2-溴-5-(2-(三氟甲基)嘧啶-5-基)苯基)甲胺盐酸盐的制备
实施例9的总体反应方案如下:
实施例9,步骤1:(2-溴-5-碘苯基)甲醇的制备
步骤1按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的5000-mL 4-颈圆底烧瓶中放入2-溴-5-碘苯甲酸(200g,611.78mmol,1.00当量)和四氢呋喃(1500mL),然后滴加硼烷(1834mL,3.00当量),同时在0℃搅拌。将得到的溶液在室温搅拌4h,通过添加4000mL水/冰猝灭,然后用2×2000mL乙酸乙酯萃取。用2×2000mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。用500mL PE稀释残余物。通过过滤采集固体,得到160g(84%)(2-溴-5-碘苯基)甲醇,为白色固体。
实施例9,步骤2:甲磺酸(2-溴-5-碘苯基)甲酯的制备
步骤2按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入(2-溴-5-碘基)甲醇(160g,511.30mmol,1.00当量)、二氯甲烷(1500mL)和TEA(103.2g,1.02mol,2.00当量),然后滴加甲磺酰氯(81.6g,712.35mmol,1.40当量),同时在0℃搅拌。将得到的溶液在室温搅拌30min,通过添加1000mL水/冰猝灭,然后用2×1500mL二氯甲烷萃取。用1×1000mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到200g(粗)甲磺酸(2-溴-5-碘苯基)甲酯,为淡黄色固体。
实施例9,步骤3:N-[(2-溴-5-碘苯基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯的制备
步骤3按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(105.4g,485.13mmol,0.95当量)和N,N-二甲基甲酰胺(1500mL),然后分部分添加氢化钠(24.5g,613.58mmol,1.20当量),搅拌40min。向其中滴加在N,N-二甲基甲酰胺(800mL)中的甲磺酸(2-溴-5-碘苯基)甲酯(200g,511.48mmol,1.05当量),同时搅拌。将得到的溶液在50℃搅拌3h,通过添加3000mL水/冰猝灭,用2×1500mL乙酸乙酯猝灭。用2×1000mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(5/95)洗脱,得到95g(36%)N-[(2-溴-5-碘苯基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯,为白色固体。
实施例9,步骤4:N-([2-溴-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲基)-N-[(叔丁氧基)羰基]氨基甲酸酯
步骤4按照如下方案进行:
向氮气惰性气氛吹扫并且维持在其中的1000-mL 3-颈圆底烧瓶中放入N-[(2-溴-5-碘苯基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(70g,136.67mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(52.5g,191.57mmol,1.40当量)、1,4-二噁烷(700mL)、K2CO3(37.8g,2.00当量)和Pd(dppf)Cl2二氯甲烷(10g,0.10当量)。将得到的溶液在80℃在油浴中搅拌24h,然后用700mL EA稀释。过滤出固体。真空浓缩得到的混合物。使残余物上硅胶柱,用乙酸乙酯/石油醚(5/95)洗脱,得到45g(62%)N-([2-溴-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲基)-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯,为白色固体。
实施例9,步骤5:[2-溴-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲胺盐酸盐的制备
步骤5按照如下方案进行:
向1000-mL 3-颈圆底烧瓶中放入N-([2-溴-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲基)-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(45g,84.53mmol,1.00当量)、二氯甲烷(300mL)和甲醇(300mL)。向上述体系中导入氯化氢(气体)。将得到的溶液在0-25℃在冰/盐浴中搅拌1h。真空浓缩得到的混合物。用300mL乙醚稀释残余物。通过过滤采集固体,得到30g(96%)[2-溴-5-[2-(三氟甲基)嘧啶-5-基]苯基]甲胺盐酸盐,为白色固体。LCMS[M-HCl+H+]332;1H NMR(300MHz,DMSO-d6)δ4.23(s,2H),7.88-7.94(m,2H),8.26-8.28(m,1H),8.64-8.76(m,3H),9.49(s,2H)。
实施例10:(5-(三氟甲氧基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺的制备
步骤1:2-氯-5-(三氟甲氧基)吡啶-4-甲醛的制备
在0℃在氮气气氛中将n-BuLi(20.2mL,2.5M的己烷溶液,2.00当量)滴加到i-Pr2NH(6.38g,63.05mmol,2.49当量)在四氢呋喃(100mL)中的溶液中。将得到的溶液在0℃搅拌15min。在-70℃向其中滴加2-氯-5-(三氟甲氧基)吡啶(5g,25.311mmol,1.00当量)。使得到的溶液再反应1h,同时将温度维持在-70℃。在-70℃向该混合物中滴加N,N-二甲基甲酰胺(9.22g,126.14mmol,4.98当量)。使得到的溶液再反应30min,同时将温度维持在-70℃。然后用饱和NH4Cl溶液使反应停止,用乙酸乙酯萃取,用氯化氢(1M)和盐水洗涤,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(4.5g,79%),为淡黄色油状物。LCMS[M+H+]226。
步骤2:[2-氯-5-(三氟甲氧基)吡啶-4-基]甲醇的制备
在0℃在氮气气氛中将NaBH4(757mg,20.01mmol,1.00当量)分部分加入到2-氯-5-(三氟甲氧基)吡啶-4-甲醛(4.5g,19.95mmol,1.00当量)在甲醇(100mL)中的溶液中。在0℃搅拌10min后,用饱和碳酸氢钠溶液使反应停止,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(4.6g,粗),为淡黄色油状物。LCMS[M+H+]228。
步骤3:甲磺酸2-氯-5-(三氟甲氧基)吡啶-4-基]甲酯的制备
将MsCl(2.8g,24.44mmol,1.21当量)滴加到[2-氯-5-(三氟甲氧基)吡啶-4-基]甲醇(4.6g,20.21mmol,1.00当量)和TEA(6.1g,60.28mmol,2.98当量)在二氯甲烷(100mL)中的溶液中。在0℃搅拌15min后,用水使反应停止,用乙酸乙酯萃取,用饱和NH4Cl溶液和盐水洗涤,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(7.2g,粗),为淡黄色油状物。LCMS[M+H+]306。
步骤4:N-[(叔丁氧基)羰基]-N-[[2-氯-5-(三氟甲氧基)吡啶-4-基]甲基]氨基甲酸叔丁酯的制备
将甲磺酸[2-氯-5-(三氟甲氧基)吡啶-4-基]甲酯(7.2g,23.56mmol,1.00当量)、N,N-二甲基甲酰胺(100mL)、NaI(3.5g,23.35mmol,0.99当量)和N-[(叔丁氧基)羰基]-N-钾氨基甲酸叔丁酯(9g,35.25mmol,1.50当量)的混合物在室温搅拌1h。用水稀释得到的溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/20)洗脱,得到标题化合物(7.1g,71%),为淡黄色油状物。LCMS[M+H+]427。
步骤5:N-[(叔丁氧基)羰基]-N-[[5-(三氟甲氧基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基]氨基甲酸叔丁酯的制备
在85℃在氮气气氛中将N-[(叔丁氧基)羰基]-N-[[2-氯-5-(三氟甲氧基)吡啶-4-基]甲基]氨基甲酸叔丁酯(5g,11.72mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(4.2g,15.33mmol,1.31当量)、Pd(dppf)Cl2(856mg,1.17mmol,0.10当量)和碳酸钾(4.8g,34.73mmol,2.96当量)在二噁烷(100mL)中的混合物搅拌12h。真空浓缩得到的混合物。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/10)洗脱,得到标题化合物(3.6g,57%),为黄色固体。LCMS[M+H+]539。
步骤6:[5-(三氟甲氧基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
将N-[(叔丁氧基)羰基]-N-[[5-(三氟甲氧基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基]氨基甲酸叔丁酯(3.6g,6.69mmol,1.00当量)和4N氯化氢的二噁烷溶液(30mL)的混合物在室温搅拌1h。通过过滤采集固体,减压干燥。这得到标题化合物(2.3g,92%),为淡黄色固体。LCMS[M+H+]339。
实施例11:(5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲胺的制备
实施例11的总体反应方案如下:
实施例11,步骤1:[2-氯-5-(三氟甲基)吡啶-4-基]甲醇的制备
步骤1按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的250-mL 3-颈圆底烧瓶中放入2-氯-5-(三氟甲基)吡啶-4-甲酸(4.5g,19.95mmol,1.00当量)在四氢呋喃(40mL)中的溶液,然后在0℃滴加BH3·THF(1M)(40mL,2.00当量),同时搅拌,历时10min。将得到的溶液在室温搅拌过夜,通过在0℃添加10mL甲醇猝灭,真空浓缩,用乙酸乙酯萃取。用盐水洗涤合并的有机层,用硫酸钠干燥,真空浓缩。通过硅胶柱与乙酸乙酯/石油醚(1:10)纯化残余物,得到3g(粗)[2-氯-5-(三氟甲基)吡啶-4-基]甲醇,为白色固体。
实施例11,步骤2:[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲醇的制备
步骤2按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的3-L 3-颈圆底烧瓶中放入[2-氯-5-(三氟甲基)吡啶-4-基]甲醇(75.6g,357.33mmol,1.00当量)、1,4-二噁烷(1.5L)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(110g,401.39mmol,1.20当量)、K2CO3(148g,1.06mol,3.00当量)和Pd(dppf)Cl2(13g,17.77mmol,0.05当量)。将得到的溶液在100℃在氮气气氛中搅拌6h,冷却至室温,过滤。用2×300mL EA洗涤滤饼。真空浓缩滤液。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1/5-1/2),得到90g(78%)[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲醇,为白色固体。
实施例11,步骤3:5-[4-(氯甲基)-5-(三氟甲基)吡啶-2-基]-2-(三氟甲基)嘧啶的制备
步骤3按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的2-L 3-颈圆底烧瓶中放入[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲醇(80g,247.53mmol,1.00当量)在四氢呋喃(800mL)中的溶液,然后在0℃滴加LiHMDS(1mol/L)(322mL,1.30当量),同时搅拌。将该混合物在0℃搅拌1h。在0℃在氮气气氛中向该混合物中分部分加入4-甲基苯-1-磺酰氯(61.2g,321.01mmol,1.30当量)。将得到的溶液在0℃-25℃搅拌24h,冷却至0℃,通过添加100mL水猝灭,用3×500mL乙酸乙酯萃取。用无水硫酸钠干燥合并的有机层,减压浓缩。通过硅胶柱色谱法纯化残余物,用乙酸乙酯/石油醚(1/10)洗脱,得到30g(35%)5-[4-(氯甲基)-5-(三氟甲基)吡啶-2-基]-2-(三氟甲基)嘧啶,为淡黄色固体。
实施例11,步骤4:[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
步骤4按照如下方案进行:
向200-mL密封试管中放入5-[4-(氯甲基)-5-(三氟甲基)吡啶-2-基]-2-(三氟甲基)嘧啶(20g,58.54mmol,1.00当量)在甲醇/NH3(140mL)中的溶液。将得到的溶液在80℃在油浴中搅拌5h。将该反应重复2次。将该反应混合物冷却至室温,真空浓缩。用饱和碳酸氢钠水溶液将水溶液的pH值调整至8。用3×300mL二氯甲烷萃取得到的溶液。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用10%-30%乙酸乙酯的石油醚溶液洗脱,得到5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺33g,为淡黄色固体。将残余物溶于800mL乙酸乙酯。通过添加乙酸乙酯/HCl(g)沉淀产物。真空浓缩得到的混合物。通过过滤采集固体。用3×2500mL乙醚洗涤滤饼,干燥,得到31g(49.5%)[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐,为白色固体。LCMS[M-HCl+H+]323;1HNMR(300MHz,D2O)δ9.48(s,2H),9.06(s,1H),8.21(s,1H),4.49(s,2H)。
实施例12:[5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
实施例12的总体反应方案如下:
实施例12,步骤1:(2,5-二氯吡啶-4-基)甲醇的制备
步骤1按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的10000-mL 4-颈圆底烧瓶中放入2,5-二氯吡啶-4-甲酸(200g,1.04mol,1.00当量)和四氢呋喃(2000mL),然后在0℃滴加BH3-THF(3140mL,3.00当量,1M),同时搅拌。将得到的溶液在室温搅拌2h,通过添加2000mL水猝灭,用3×1500mL乙酸乙酯萃取。用2×1500mL水、3×1500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到140g(75%)(2,5-二氯吡啶-4-基)甲醇,为白色固体。
实施例12,步骤2:甲磺酸(2,5-二氯吡啶-4-基)甲酯的制备
步骤2按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入(2,5-二氯吡啶-4-基)甲醇(100g,561.75mmol,1.00当量)、二氯甲烷(1400mL)和TEA(172g,1.70mol,3.00当量),然后在0℃滴加MsCl(77.3g,678.07mmol,1.20当量),同时搅拌。将得到的溶液在室温搅拌1h,通过添加500mL水猝灭。用无水硫酸钠干燥有机层,真空浓缩,得到129g(90%)甲磺酸(2,5-二氯吡啶-4-基)甲酯,为黄色油状物。
实施例12,步骤3:N-[(叔丁氧基)羰基]-N-[(2,5-二氯吡啶-4-基)甲基]氨基甲酸叔丁酯的制备
步骤3按照如下方案进行:
在室温分几批向用氮气惰性气氛吹扫并且维持在其中的5000-mL 4-颈圆底烧瓶中放入N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(104.3g,480.07mmol,0.95当量)和N,N-二甲基甲酰胺(1200mL),然后添加NaH(65%的矿物油溶液)(21.3g,576.87mmol,1.14当量)。将该混合物在室温搅拌4h。向该混合物中滴加甲磺酸(2,5-二氯吡啶-4-基)甲酯(129g,503.70mmol,1.00当量)在N,N-二甲基甲酰胺(200mL)中的溶液,同时搅拌。将得到的溶液在50℃搅拌2h,通过添加2kg冰猝灭,用2×1500mL乙酸乙酯萃取。用5×800mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(1:20)洗脱。使粗产物从石油醚中重结晶,得到80g(42%)N-[(叔丁氧基)羰基]-N-[(2,5-二氯吡啶-4-基)甲基]氨基甲酸叔丁酯,为白色固体。
实施例12,步骤4:N-[(叔丁氧基)羰基]-N-([5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯的制备
步骤4按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的2000-mL 4-颈圆底烧瓶中放入N-[(叔丁氧基)羰基]-N-[(2,5-二氯吡啶-4-基)甲基]氨基甲酸叔丁酯(70g,185.55mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(76.5g,279.15mmol,1.50当量)、1,4-二噁烷(700mL)、Cs2CO3(0mg,2.00当量),水(200mL)和(PPh3)4Pd(5.4g)。将得到的溶液回流5h,冷却至室温,用500mL H2O稀释,用3×500mL乙酸乙酯萃取。用无水硫酸钠干燥合并的有机层,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(1:10)洗脱,得到45g(50%)N-[(叔丁氧基)羰基]-N-([5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯,为白色固体。
实施例12,步骤5:[5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐的制备
步骤5按照如下方案进行:
向2000-mL圆底烧瓶中放入N-[(叔丁氧基)羰基]-N-([5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)氨基甲酸叔丁酯(42g,85.91mmol,1.00当量)和甲醇(600mL)。使氯化氢(气体)通过上述体系中起泡。将得到的溶液在室温搅拌3h,真空浓缩,用300mL乙醚稀释。通过过滤采集固体,用1×200mL乙醚冲洗,得到22.4329g(80%)[5-氯-2-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺盐酸盐,为白色固体。LCMS[M-HCl+H+]330;1H NMR(300MHz,DMSO-d6)δ9.73(s,2H),8.93(s,3H),8.91(s,1H),8.81-8.78(d,J=9.0Hz,1H),4.30(s,2H)。
实施例13:[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺盐酸盐的制备
实施例13的总体反应方案如下:
实施例13,步骤1:5-氟-2-甲基吡啶的制备
步骤1按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的10-L 4-颈圆底烧瓶放入6-甲基吡啶-3-胺(350g,3.24mol,1.00当量)和水(400mL),然后在0℃滴加氯化氢水溶液(1600mL,12N),同时搅拌。在0℃向其中滴加亚硝酸钠(450g,6.52mol,2.00当量)的水(600mL)溶液,同时搅拌。在0℃将得到的溶液在0℃搅拌30min。向该混合物中滴加HPF6(60%)(1750mL),同时搅拌。将得到的溶液在0℃搅拌1h,过滤。用2×300mL冰/水、2×300mL EtOH、2×300mLEt2O洗涤滤饼,真空干燥。在90℃将残余物分几批加入到正-辛烷(4L)中,同时搅拌。将得到的溶液在90℃再搅拌20min,冷却至室温,用3×3L氯化氢(2N)萃取。合并水层,用1×3L乙醚萃取。用氢氧化钠水溶液(40%)将该水溶液的pH调整至9~10。用3×3L DCM萃取得到的溶液。用无水硫酸钠干燥合并的有机层。将粗溶液直接用于下一步。
实施例13,步骤2:5-氟-2-甲基吡啶1-氧化物的制备
步骤2按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的10-L 4-颈圆底烧瓶中分部分加入来自步骤1的5-氟-2-甲基吡啶溶液和m-CPBA(671g,3.89mol,1.20当量)。将得到的溶液在室温搅拌过夜。用氢氧化钠(2N)将该溶液的pH值调整至11-12。用6×1L二氯甲烷萃取得到的溶液。用1×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到220g(53%,2步)5-氟-2-甲基吡啶1-氧化物,为黄色固体。
实施例13,步骤3:5-氟-2-甲基-4-硝基吡啶1-氧化物的制备
步骤3按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的5-L 4-颈圆底烧瓶中放入5-氟-2-甲基吡啶-1-鎓-1-醇化物(220g,1.73mol,1.00当量)和硫酸(800mL),,然后在90℃滴加在发烟硫酸(400mL)中的发烟HNO3(1040mL),同时搅拌。将得到的溶液在90℃搅拌2h,通过添加10L冰/盐猝灭,用3×3L二氯甲烷萃取。用1×1.5L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到210g(70%)5-氟-2-甲基-4-硝基吡啶1-氧化物,为黄色固体。
实施例13,步骤4:4-溴-5-氟-2-甲基吡啶1-氧化物的制备
步骤4按照如下方案进行:
向5-L 4-颈圆底烧瓶用氮气惰性气氛吹扫并且维持在其中的放入5-氟-2-甲基-4-硝基吡啶-1-鎓-1-醇化物(210g,1.22mol,1.00当量)和AcOH(1.05L),然后在50℃滴加乙酰溴(1.58L),同时搅拌。将得到的溶液在100℃搅拌3h,冷却至室温,真空浓缩。用水/冰使残余物猝灭。用碳酸氢钠水溶液将该溶液的pH值调整至9~10。用3×1L二氯甲烷萃取得到的溶液。合并有机层,用无水硫酸钠干燥,真空浓缩。通过从PE中重结晶纯化粗产物,得到170g(68%)4-溴-5-氟-2-甲基吡啶1-氧化物,为灰色固体。
实施例13,步骤5:2,2,2-三氟乙酸(4-溴-5-氟吡啶-2-基)甲酯的制备
步骤5按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的2-L 4-颈圆底烧瓶中放入4-溴-5-氟-2-甲基吡啶-1-鎓-1-醇化物(170g,825.19mmol,1.00当量)和二氯甲烷(800mL),然后在0℃滴加2,2,2-三氟乙酸三氟乙酰酯(866g,4.12mol,5.00当量),同时搅拌。将得到的溶液回流过夜,冷却至室温,真空浓缩,得到200g(粗)2,2,2-三氟乙酸(4-溴-5-氟吡啶-2-基)甲酯,为淡黄色油状物。
实施例13,步骤6:(4-溴-5-氟吡啶-2-基)甲醇的制备
步骤6按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的2-L 4-颈圆底烧瓶中放入2,2,2-三氟乙酸(4-溴-5-氟吡啶-2-基)甲酯(200g,662.21mmol,1.00当量)和二氯甲烷(400mL),然后在0℃滴加氢氧化钠(3M)(1100mL,5.00当量),同时搅拌。将得到的溶液在室温搅拌过夜,用2×2L二氯甲烷萃取。用1×1L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(3/7)洗脱,得到50g(37%)(4-溴-5-氟吡啶-2-基)甲醇,为黄色油状物。
实施例13,步骤7:甲磺酸(4-溴-5-氟吡啶-2-基)甲酯的制备
步骤7按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的1-L 4-颈圆底烧瓶中放入(4-溴-5-氟吡啶-2-基)甲醇(50g,242.70mmol,1.00当量)、二氯甲烷(500mL)和TEA(49g,484.24mmol,2.00当量),然后在0℃滴加甲磺酰氯(33.4g,291.57mmol,1.20当量),同时搅拌。将得到的溶液在室温搅拌30min,通过添加水/冰猝灭,用2×500mL二氯甲烷萃取。用1×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩,得到65g(94%)甲磺酸(4-溴-5-氟吡啶-2-基)甲酯,为黄色固体。
实施例13,步骤8:N-[(4-溴-5-氟吡啶-2-基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯的制备
步骤8按照如下方案进行:
在0℃向用氮气惰性气氛吹扫并且维持在其中的3-L 4-颈圆底烧瓶分部分放入N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(59.7g,274.78mmol,1.20当量)和N,N-二甲基甲酰胺(350mL),然后添加NaH(60%)(11g,1.20当量)。将得到的溶液在0℃搅拌2h。在0℃向其中滴加甲磺酸(4-溴-5-氟吡啶-2-基)甲酯(65g,228.79mmol,1.00当量)在N,N-二甲基甲酰胺(300mL)中的溶液,同时搅拌。将得到的溶液在60℃再搅拌2h,冷却至室温,通过添加1.2L水/冰猝灭,用3×500mL乙酸乙酯萃取。用2×400mL水、1×400mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚(1/19)洗脱,得到60g(65%)N-[(4-溴-5-氟吡啶-2-基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯,为黄色固体。
实施例13,步骤9:N-[(叔丁氧基)羰基]-N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯的制备
步骤9按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的2-L 4-颈圆底烧瓶中放入N-[(4-溴-5-氟吡啶-2-基)甲基]-N-[(叔丁氧基)羰基]氨基甲酸叔丁酯(60g,148.05mmol,1.00当量)、1,4-二噁烷(900mL)、水(90mL)、碳酸钾(61.3g,443.53mmol,3.00当量)、5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(60.8g,222mmol,1.5当量)和Pd(dppf)Cl2(5.4g,7.38mmol,0.05当量)。将得到的溶液在90℃搅拌1h,冷却至室温,过滤。用3×500mL乙酸乙酯萃取滤液。用1×500mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1/9),得到60g(86%)N-[(叔丁氧基)羰基]-N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯,为白色固体。
实施例13,步骤10:[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺的制备
步骤10按照如下方案进行:
向2-L圆底烧瓶中放入N-[(叔丁氧基)羰基]-N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯(60g,127.00mmol,1.00当量)、甲醇(600mL)和二氯甲烷(60mL),用冰/水浴冷却。向上述体系中导入氯化氢(气体)。将得到的溶液在0℃搅拌2h,真空浓缩。用DCM和Et2O冲洗残余物。通过过滤采集固体。用Et2O洗涤滤饼,减压烘箱干燥,得到45g(粗)[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺,为白色固体。
实施例13,步骤11:N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯的制备
步骤11按照如下方案进行:
在0℃向用氮气惰性气氛吹扫并且维持在其中的1-L 4-颈圆底烧瓶中放入[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺(45g,165.32mmol,1.00当量)和二氯甲烷(450mL),然后滴加TEA(66.9g,661.13mmol,4.00当量),同时搅拌。在0℃向其中滴加二碳酸二-叔丁酯(36g,164.95mmol,1.00当量),同时搅拌。将得到的溶液在室温搅拌2h,真空浓缩,用300mL水稀释,用3×300mL二氯甲烷萃取。用1×300mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上硅胶柱,用乙酸乙酯/石油醚洗脱(1/3),得到31g(50%)N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯,为白色固体。
实施例13,步骤12:[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺盐酸盐的制备
步骤12按照如下方案进行:
向1-L圆底烧瓶中放入N-([5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯(31g,83.26mmol,1.00当量)、甲醇(300mL)和二氯甲烷(30mL)。向上述体系中导入氯化氢(g)。将得到的溶液在0℃搅拌4h。真空浓缩得到的混合物,用2×300mL甲醇、2×300mL二氯甲烷和2×300mL乙醚洗涤。通过从乙醚中重结晶纯化粗产物,得到24g(93%)[5-氟-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲胺盐酸盐,为白色固体。LCMS[M-HCl+H+]273;1H NMR(300MHz,DMSO-d6)δ9.44(2H,s),8.89(1H,s),8.51–8.39(3H,m),8.07–8.05(1H,m),4.29–4.27(2H,m)。
实施例14:(5-氯-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲胺盐酸盐的制备
实施例14的总体反应方案如下:
实施例14,步骤1:5-(2,5-二氯吡啶-4-基)-2-(三氟甲基)嘧啶的制备
步骤1按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的3000-mL 4-颈圆底烧瓶中放入2,5-二氯-4-碘吡啶(120g,438.14mmol,1.00当量)、1,4-二噁烷(1800mL)、水(180mL)、碳酸钾(182g,1.32mol,3.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(132.6g,483.86mmol,1.10当量)和Pd(dppf)Cl2(6g,8.20mmol,0.02当量)。将得到的溶液在60℃搅拌3h,冷却至室温,通过添加4L水/冰猝灭,用2×2L乙酸乙酯萃取。用1×1L H2O和1×1L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上使用乙酸乙酯/石油醚(1:100)的硅胶柱,得到78g(61%)5-(2,5-二氯吡啶-4-基)-2-(三氟甲基)嘧啶,为白色固体。
实施例14,步骤2:N-([5-氯-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯的制备
步骤2按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的5000-mL 4-颈圆底烧瓶中放入5-(2,5-二氯吡啶-4-基)-2-(三氟甲基)嘧啶(75g,255.05mmol,1.00当量)、乙醇(2250mL)、水(450mL)、碳酸钠(82.5g,778.38mmol,3.00当量)、(((叔丁氧羰基)氨基)甲基)三氟硼酸钾(90g,379.64mmol,1.50当量)和Pd(PPh3)2Cl2(5g,7.12mmol,0.03当量)。将得到的溶液在85℃搅拌过夜,冷却至室温,真空浓缩,用2L EA稀释,用2×500mL乙酸乙酯萃取。用1×1L H2O和1×1L盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。使残余物上使用乙酸乙酯/石油醚(1:10)的硅胶柱。使粗产物从1:10之比的EA:PE中重结晶,得到36g(36%)N-([5-氯-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯,为黄色固体。
实施例14,步骤3:(5-氯-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲胺盐酸盐的制备
步骤3按照如下方案进行:
向1000-mL 4-颈圆底烧瓶中放入N-([5-氯-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)氨基甲酸叔丁酯(35g,90.03mmol,1.00当量)和二氯甲烷(600mL)。向上述体系中导入氯化氢(气体)。将得到的溶液在室温搅拌过夜。通过过滤采集固体,用1×2L DCM洗涤,得到25g(85%)(5-氯-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲胺盐酸盐,为黄白色固体。LCMS[M-HCl+H+]289;1H NMR(300MHz,DMSO-d6)δ9.33-9.41(2H,s),8.88-8.91(1H,s),8.79(3H,s),7.97-7.98(1H,s),4.23-4.29(2H,m)。
实施例15:[6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲胺盐酸盐的制备
实施例15的总体反应方案如下:
实施例15,步骤1:4-氯-6-[6-(三氟甲基)吡啶-3-基]嘧啶的制备
步骤1按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的1000-mL 3-颈圆底烧瓶中放入[6-(三氟甲基)吡啶-3-基]硼酸(50g,256.66mmol,1.00当量)在1,4-二噁烷(600mL)中的溶液、4,6-二氯嘧啶(58.51g,392.74mmol,1.50当量)、Pd(PPh3)2Cl2(9.18g,0.05当量)、碳酸钠(55.5g,2.00当量)和水(120mL)。将得到的溶液在50℃搅拌24h,用1.5L水稀释,用4×200mL乙酸乙酯萃取。用4×150mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。用硅胶柱与乙酸乙酯:石油醚(0:1-1:20)纯化残余物,得到38g(55%)4-氯-6-[6-(三氟甲基)吡啶-3-基]嘧啶,为黄白色固体。
实施例15,步骤2:6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-甲腈的制备
步骤2按照如下方案进行:
向5000-mL 3-颈圆底烧瓶中放入4-氯-6-[6-(三氟甲基)吡啶-3-基]嘧啶(230g,868.21mmol,1.00当量)在DMSO(2500mL)、NaCN(100g,2.20当量)、1,4-二氮杂双环[2.2.2]辛烷(49.69g,434.12mmol,0.50当量)和水(250mL)中的溶液。将得到的溶液在室温搅拌2h,用2000mL水稀释,用5×500mL乙酸乙酯萃取。用4×150mL盐水洗涤合并的有机层,用无水硫酸钠干燥,真空浓缩。用硅胶柱与乙酸乙酯:石油醚(1:10-1:5)纯化残余物,得到165g(74%)6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-甲腈,为淡黄色固体。
实施例15,步骤3:N-([6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯的制备
步骤3按照如下方案进行:
向用氮气惰性气氛吹扫并且维持在其中的5000-mL 4-颈圆底烧瓶中放入6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-甲腈(180g,697.90mmol,1.00当量)在甲醇(2500mL)中的溶液、(Boc)2O(188.22g,837.49mmol,1.20当量)和Pd/C(30g,10%)。向上述体系中导入H2(气体),将得到的溶液在室温搅拌20h。过滤出固体,真空浓缩滤液。用硅胶柱与乙酸乙酯:石油醚(1:10-1:3)纯化残余物,得到185g(73%)N-([6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯,为淡黄色固体。
实施例15,步骤4:[6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲胺盐酸盐的制备
步骤4按照如下方案进行:
向2000-mL 3-颈圆底烧瓶中放入N-([6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯(185g,511.67mmol,1.00当量)在乙酸乙酯(1500mL)中的溶液。向上述体系中导入氯化氢(气体),将得到的溶液在室温搅拌2h。通过过滤采集固体,用3×500mLEA洗涤,得到120g(80%)[6-[6-(三氟甲基)吡啶-3-基]嘧啶-4-基]甲胺盐酸盐,为浅红色固体。LCMS[M-HCl+H+]255;1H NMR(300MHz,D2O)δ9.17(1H,s),9.04(1H,s),8.47-8.49(1H,d),8.00(1H,s),7.86-7.89(1H,d),4.45(2H,d)。
实施例16:[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺的制备实施例16的总体反应方案如下:
实施例16,步骤1:(2-氯吡啶-4-基)甲醇的制备
步骤1按照如下方案进行:
在0℃将BH3THF溶液(190mL,2.21mol,2.99当量)滴加到2-氯吡啶-4-甲酸(10g,63.47mmol,1.00当量)在四氢呋喃(200mL)中的溶液中。在室温搅拌12h后,用甲醇使反应停止,真空浓缩。通过硅胶柱纯化残余物,用二氯甲烷/乙酸乙酯(50/1)洗脱,得到标题化合物(11.9g,粗),为棕色油状物。LCMS[M+H+]144。
实施例16,步骤2:4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-2-氯吡啶的制备
步骤2按照如下方案进行:
在氮气气氛中将TBSCl(14.9g,98.85mmol,1.19当量)分几批加入到(2-氯吡啶-4-基)甲醇(11.9g,82.89mmol,1.00当量)、N,N-二甲基甲酰胺(100mL)和咪唑(11.2g,164.52mmol,1.99当量)的混合物中。将得到的溶液在室温搅拌1h,然后用盐水稀释,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥。通过硅胶柱纯化残余物,用二氯甲烷/石油醚(2/1)洗脱。这得到标题化合物(18g,84%),为淡黄色固体。LCMS[M+H+]258。
实施例16,步骤3:4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-2-氯-6-碘吡啶的制备
步骤3按照如下方案进行:
在0℃在氮气气氛中将n-BuLi(46.5mL,2.5M的己烷溶液,5.99当量)滴加到2-(二甲基氨基)乙-1-醇(5.1g,57.22mmol,2.95当量)在己烷(50mL)中的溶液中,历时1小时。将得到的溶液在0℃搅拌40min。在-70℃向其中滴加4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-2-氯吡啶(5g,19.39mmol,1.00当量)在己烷(50mL)中的溶液,历时1小时。将得到的溶液搅拌1.5h,同时将温度维持在-70℃。在-70℃向该混合物中滴加I2(19.7g,77.62mmol,4.00当量)在四氢呋喃(200mL)中的溶液,历时1.5小时。在-70℃搅拌30min后,用5%Na2S2O3使反应停止,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用二氯甲烷/石油醚(1/2)洗脱,得到标题化合物(3.5g,47%),为黄色油状物。LCMS[M+H+]384。
实施例16,步骤4:5-(4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-6-氯吡啶-2-基)-2-(三氟甲基)嘧啶的制备
步骤4按照如下方案进行:
将4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-2-氯-6-碘吡啶(1g,2.61mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(642mg,2.34mmol,0.90当量)、Pd(dppf)Cl2(95mg,0.13mmol,0.05当量)和碳酸钾(1.08g,7.81mmol,3.00当量)在二噁烷(10mL)/水(1mL)的混合物在60℃在氮气气氛中搅拌4h。过滤出固体,用盐水洗涤得到的溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/50)洗脱,得到标题化合物(870mg,83%),为黄色固体。LCMS[M+H+]404。
实施例16,步骤5:5-(4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-6-环丙基吡啶-2-基)-2-(三氟甲基)嘧啶的制备
步骤5按照如下方案进行:
将5-(4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-6-氯吡啶-2-基)-2-(三氟甲基)嘧啶(870mg,2.15mmol,1.00当量)、Pd2(dba)3(111mg,0.12mmol,0.06当量)、Sphos(88mg,0.21mmol,0.10当量)、K3PO4(1.37g,6.45mmol,3.00当量)和环丙基硼酸(1.37g,15.95mmol,7.41当量)在甲苯(20mL)/水(2mL)中的混合物在100℃在氮气气氛中搅拌3h。过滤出固体,用盐水洗涤得到的溶液,用乙酸乙酯萃取,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/50)洗脱,得到标题化合物(830mg,94%),为白色固体。LCMS[M+H+]410。
实施例16,步骤6:[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲醇的制备
步骤6按照如下方案进行:
将TBAF(2.43mL,9.29mmol,1.20当量)滴加到5-(4-[[(叔丁基二甲基甲硅烷基)氧基]甲基]-6-环丙基吡啶-2-基)-2-(三氟甲基)嘧啶(830mg,2.03mmol,1.00当量)在四氢呋喃(20mL)中的溶液中。将得到的溶液在室温搅拌1h。用饱和NH4Cl溶液稀释该反应溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/5)洗脱,得到标题化合物(580mg,97%),为黄色固体。LCMS[M+H+]296。
实施例16,步骤7:2-([2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮的制备
步骤7按照如下方案进行:
在0℃在氮气气氛中将DIAD(794mg,3.92mmol,1.99当量)滴加到[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲醇(580mg,1.96mmol,1.00当量)、2,3-二氢-1H-异吲哚-1,3-二酮(578mg,3.93mmol,2.00当量)和PPh3(1.03g,3.93mmol,2.00当量)在四氢呋喃(50mL)中的溶液中。在室温搅拌12h后,真空浓缩该反应体系。通过硅胶柱纯化残余物,用二氯甲烷/石油醚(10/1)洗脱,得到标题化合物(600mg,72%),为淡黄色固体。LCMS[M+H+]425。
实施例16,步骤8:[2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲胺的制备
步骤8按照如下方案进行:
将2-([2-环丙基-6-[2-(三氟甲基)嘧啶-5-基]吡啶-4-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(120mg,0.28mmol,1.00当量)和水合肼(142mg,80%)在甲醇(20mL)中的溶液在50℃搅拌3h。真空浓缩得到的混合物。将残余物溶于乙酸乙酯。过滤出固体,真空浓缩滤液。这得到标题化合物(80mg,96%),为黄色固体。LCMS[M+H+]295。
实施例17:2-((6-环丙基-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)异二氢吲哚-1,3-二酮的制备
实施例17的总体反应方案如下:
实施例17,步骤1:4,6-二氯吡啶-2-基)甲醇的制备
步骤1按照如下方案进行:
在-78℃在N2气氛中将DIBAL-H(73mL,1M的己烷溶液,3.00当量)滴加到4,6-二氯吡啶-2-甲酸甲酯(5g,24.26mmol,1.00当量)在二氯甲烷(100mL)中的溶液中。将得到的溶液在室温搅拌过夜。用甲醇使反应停止,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/20)洗脱,得到标题化合物(9.5g,84%),为淡黄色固体。LCMS[M+H+]178。
实施例17,步骤2:2-((4,6-二氯吡啶-2-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤2按照如下方案进行:
在N2气氛中将DIAD(6.87g,33.97mmol,2.00当量)滴加到2,3-二氢-1H-异吲哚-1,3-二酮(2.50g,16.99mmol,1.00当量)、(4,6-二氯吡啶-2-基)甲醇(4.54g,25.50mmol,1.50当量)和PPh3(8.91g,33.97mmol,2.00当量)在干四氢呋喃(50mL)中的溶液中。将得到的溶液在0℃搅拌2h,真空浓缩,溶于乙酸乙酯。通过过滤采集固体,真空浓缩滤液。这得到标题化合物(2.8g,54%),为白色固体。LCMS[M+H+]307。
实施例17,步骤3:2-((4-氯-6-环丙基吡啶-2-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤3按照如下方案进行:
将2-[(4,6-二氯吡啶-2-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮(1g,3.25mmol,1.000当量)、环丙基硼酸(2.8g,32.59mmol,10.00当量)、Pd(dppf)Cl2.CH2Cl2(270mg,0.33mmol,0.10当量)和碳酸钾(1.4g,10.13mmol,3.11当量)在二噁烷(50mL)中的混合物在70℃在N2气氛中搅拌12h。过滤出固体,真空浓缩滤液。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/5)洗脱,得到标题化合物(700mg,69%),为白色固体。LCMS[M+H+]313。
实施例17,步骤4:2-((6-环丙基-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤4按照如下方案进行:
将2-[(4-氯-6-环丙基吡啶-2-基)甲基]-2,3-二氢-1H-异吲哚-1,3-二酮(700mg,2.23mmol,1.00当量)、5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(615mg,2.24mmol,1.00当量)、Pd(dppf)Cl2(183mg,0.25mmol,0.11当量)和碳酸钾(930mg,6.72mmol,3.00当量)在二噁烷(30mL)中的混合物在100℃在N2气氛中搅拌12h。过滤出固体,真空浓缩滤液。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/4)洗脱,得到标题化合物(600mg,63%),为白色固体。LCMS[M+H+]425。
实施例17,步骤5:2-((6-环丙基-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)异二氢吲哚-1,3-二酮的制备
步骤5按照如下方案进行:
将2-([6-环丙基-4-[2-(三氟甲基)嘧啶-5-基]吡啶-2-基]甲基)-2,3-二氢-1H-异吲哚-1,3-二酮(600mg,1.41mmol,1.00当量)和水合肼(881mg,80%)在甲醇(50mL)中的溶液在50℃搅拌2h。真空浓缩得到的混合物,溶于乙酸乙酯。过滤出沉淀的固体。真空浓缩滤液,得到标题化合物(400mg,96%),为黄色油状物。[M+H+]295。
实施例18:[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺盐酸盐的制备
实施例18的总体反应方案如下:
实施例18,步骤1:N-[[6-氯-2-(三氟甲基)嘧啶-4-基]甲基]氨基甲酸叔丁酯的制备
步骤1按照如下方案进行:
将4,6-二氯-2-(三氟甲基)嘧啶(500mg,2.30mmol,1.00当量)、N-[(三氟boranuidyl)甲基]氨基甲酸叔丁酯钾(546mg,2.30mmol,0.99当量),Pd(PPh3)2Cl2(162mg,0.23mmol,0.10当量)和碳酸钠(488mg,4.60mmol,1.99当量)在叔丁醇(10mL)/水(2mL)中的混合物在70℃在氮气气氛中搅拌2h。过滤出固体,用水稀释滤液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/5)洗脱,得到标题化合物(450mg,63%),为白色固体。LCMS[M+H+]312。
实施例18,步骤2:N-[[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基]氨基甲酸叔丁酯的制备
步骤2按照如下方案进行:
将5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(450mg,1.64mmol,1.00当量)、N-[[6-氯-2-(三氟甲基)嘧啶-4-基]甲基]氨基甲酸叔丁酯(396mg,1.27mmol,0.77当量)、Pd(dppf)Cl2(106mg,0.14mmol,0.08当量)和碳酸钾(400mg,2.89mmol,1.76当量)在二噁烷(15mL)中的混合物在80℃在氮气气氛中搅拌3h。过滤出固体。用水稀释滤液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/5)洗脱,得到标题化合物(400mg,58%),为白色固体。LCMS[M+H+]424。
实施例18,步骤3:[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺盐酸盐的制备
步骤3按照如下方案进行:
将N-[[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基]氨基甲酸叔丁酯(400mg,0.94mmol,1.00当量)和4N HCl的1,4-二噁烷溶液(10mL)的混合物在室温搅拌2h。真空浓缩得到的混合物,得到标题化合物(220mg),为黄色油状物。LCMS[M+H+]324。
实施例19:(2-(2,2,2-三氟乙氧基)-2'-(三氟甲基)-4,5'-联嘧啶-6-基)甲胺盐酸盐的制备
实施例19的总体反应方案如下:
实施例19,步骤1:N-[(叔丁氧基)羰基]-N-[(3,5-二氯苯基)甲基]氨基甲酸叔丁酯的制备
步骤1按照如下方案进行:
将2,4-二氯-6-(氯甲基)嘧啶(4g,20.25mmol,1.00当量)、NaI(6.4g,42.69mmol,2.10当量)和N-[(叔丁氧基)羰基]-N-氨基甲酸叔丁酯钾(8.4g,32.89mmol,1.62当量)在四氢呋喃(80mL)中的混合物在室温搅拌14h。用水稀释该反应溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/2)洗脱,得到标题化合物(3.2g,42%),为黄白色固体。LCMS[M+H+]378。
实施例19,步骤2:(2-氯-2'-(三氟甲基)-4,5'-联嘧啶-6-基)甲基氨基甲酸叔丁酯的制备
步骤2按照如下方案进行:
将N-[(叔丁氧基)羰基]-N-[(2,6-二氯嘧啶-4-基)甲基]氨基甲酸叔丁酯(3.0g,7.93mmol,1.00当量)、Pd(dppf)Cl2(562mg,0.76mmol,0.0当量),碳酸钾(3.3g,23.96mmol,3.02当量)和5-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-(三氟甲基)嘧啶(2.19g,7.99mmol,1.00当量)在二噁烷(100mL)/水(10mL)中的混合物在80℃在氮气气氛中搅拌14h。真空浓缩得到的混合物。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(2/3)洗脱,得到标题化合物(1.1g,36%),为黄色固体。LCMS[M+H+]390。
实施例19,步骤3:(2-(2,2,2-三氟乙氧基)-2'-(三氟甲基)-4,5'-联嘧啶-6-基)甲基氨基甲酸叔丁酯的制备
步骤3按照如下方案进行:
将2,2,2-三氟乙-1-醇(8g,79.96mmol,62.33当量)和Na(50mg,2.17mmol,1.69当量)的混合物在室温搅拌2h。向上述溶液中加入N-([2-氯-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基)氨基甲酸叔丁酯(500mg,1.28mmol,1.00当量),将该反应混合物在0℃搅拌15min。用水使反应停止,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1/2)洗脱,得到标题化合物(420mg,72%),为黄白色固体。LCMS[M+H+]454.
实施例19,步骤4:(2-(2,2,2-三氟乙氧基)-2'-(三氟甲基)-4,5'-联嘧啶-6-基)甲胺盐酸盐的制备
步骤4按照如下方案进行:
将N-[[2-(2,2,2-三氟乙氧基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基]氨基甲酸叔丁酯(400mg,0.88mmol,1.00当量)和饱和4N HCl的二噁烷溶液(15mL)的混合物在室温搅拌4h。将得到的混合物真空浓缩,得到标题化合物(320mg,93%),为黄白色固体。LCMS[M+H+]354。
实施例20:(3-甲氧基-1-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑-4-基)甲胺的制备
实施例20的总体反应方案如下:
实施例20,步骤1:3-甲氧基-1-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑-4-甲酸乙酯的制备
步骤1按照如下方案进行:
将CuI(88mg,0.46mmol,0.10当量)、L-脯氨酸(108mg,0.94mmol,0.20当量)、碳酸钾(1.3g,9.41mmol,2.00当量)、3-甲氧基-1H-吡唑-4-甲酸乙酯(800mg,4.70mmol,1.00当量)和5-溴-2-(三氟甲基)嘧啶(1.28g,5.64mmol,1.20当量)在DMSO(5mL)中的混合物在100℃在氮气气氛中搅拌过夜。用40mL水稀释该反应混合物,用乙酸乙酯萃取,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1:5)洗脱,得到标题化合物(580mg,39%),为白色固体。
实施例20,步骤2:3-甲氧基-1-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑-4-甲酸的制备
步骤2按照如下方案进行:
将3-甲氧基-1-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑-4-甲酸乙酯(150mg,0.47mmol,1.0当量)和LiOH(22mg,0.92mmol,2.0当量)在THF(5mL)/水(2mL)中的混合物在50℃搅拌2h,用30mL水稀释。用稀HCl将该溶液的pH值调整至2。用乙酸乙酯萃取得到的溶液,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(120mg,88%),为白色固体。
实施例20,步骤3:3-甲氧基-1-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑-4-甲酰胺的制备
步骤3按照如下方案进行:
将3-甲氧基-1-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑-4-甲酸(400mg,1.39mmol,1.0当量)、HATU(792mg,2.08mmol,1.5当量)、DIEA(540mg,4.18mmol,3.0当量)和NH4Cl(110mg,2.06mmol,1.5当量)在N,N-二甲基甲酰胺(20ml)中的混合物在室温搅拌1h。用30mL水稀释该反应体系,用乙酸乙酯萃取,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(1:3)洗脱。这得到标题化合物(300mg,75%),为白色固体。
实施例20,步骤4:3-甲氧基-1-[4-(三氟甲基)苯基]-1H-吡唑-4-甲腈的制备
步骤4按照如下方案进行:
将3-甲氧基-1-[4-(三氟甲基)苯基]-1H-吡唑-4-甲酰胺(300mg,1.05mmol,1.00当量)、吡啶(347mg,4.39mmol,4.00当量)和Tf2O(620mg,2.20mmol,2.00当量)在二氯甲烷(30mL)中的混合物在室温搅拌2h。用30mL水稀释该反应体系,用二氯甲烷萃取,用无水硫酸钠干燥,真空浓缩。这得到标题化合物170mg(60%),为棕色固体。
实施例20,步骤5:(3-甲氧基-1-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑-4-基)甲胺盐酸盐的制备
步骤5按照如下方案进行:
向用NH2气氛吹扫并且维持在其中的100-mL圆底烧瓶中放入3-甲氧基-1-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑-4-甲腈(170mg,0.63mmol,1.00当量)、甲醇(30mL)、氯化氢(0.5mL,13.71mmol,1.00当量)和披钯炭(40mg,0.38mmol,1.00当量)。在室温30min后,过滤出固体。真空浓缩液体,得到标题化合物(120mg,70%),为淡黄色固体。
实施例21:(3-甲氧基-1-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑-4-基)甲胺的制备
实施例21的总体反应方案如下:
实施例21,步骤1:3-(三氟甲基)-1-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑-4-甲酸乙酯的制备
步骤1按照如下方案进行:
将3-(三氟甲基)-1H-吡唑-4-甲酸乙酯(2.022g,9.71mmol,1.00当量)在N,N-二甲基甲酰胺(60mL)、5-溴-2-(三氟甲基)吡啶(2.25g,9.96mmol,1.00当量)、碳酸钾(4.14g,29.96mmol,3.10当量)、L-脯氨酸(230mg,2.00mmol,0.20当量)和CuI(190mg,1.00mmol,0.10当量)的混合物在100℃在油浴中在氮气气氛中搅拌过夜。过滤出固体。用盐水稀释得到的溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(5:100)洗脱,得到标题化合物(1.47g,43%),为白色固体。LC-MS(ESI):[M+H]+=354.1。
实施例21,步骤2:[3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-基]甲醇的制备
步骤2按照如下方案进行:
在0℃在氮气气氛中将LiAlH4(190mg,5.01mmol,1.20当量)分几批加入到3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-甲酸乙酯(1.47g,4.16mmol,1.00当量)在四氢呋喃(30mL)中的溶液中。在0℃在冰/盐浴中将得到的溶液搅拌30min。然后通过添加10mL NaOH(1moL/L)使反应停止。过滤出得到的混合物。用水稀释该溶液,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(1.257g,97%),为黄色固体。LC-MS(ESI):[M+H]+=312.0。
实施例21,步骤3:3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-甲醛的制备
步骤3按照如下方案进行:
将[3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-基]甲醇(1.257g,4.04mmol,1.00当量)在二氯甲烷(40mL)和DMP(2.06g,4.86mmol,1.20当量)的混合物在室温搅拌3h。用乙酸乙酯稀释得到的溶液,用饱和碳酸氢钠溶液和盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用乙酸乙酯/石油醚(7:100)洗脱。这得到标题化合物(1.13g,90%),为淡黄色固体。LC-MS(ESI):[M+H]+=310.0。
实施例21,步骤4:[3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-基]甲胺的制备
步骤4按照如下方案进行:
将3-(三氟甲基)-1-[6-(三氟甲基)吡啶-3-基]-1H-吡唑-4-甲醛(500mg,1.62mmol,1.00当量)在乙醇(40mL)、NH2OH·HCl(230mg,3.31mmol,2.00当量)和水(5mL)中的混合物在室温搅拌2h。将浓氯化氢(2mL)、Pd/C(100mg,10%)加入该混合物。将得到的混合物在室温在氢气气氛中搅拌1h。过滤出固体。用水稀释得到的溶液。用碳酸钠将该溶液的pH值调整至9。用乙酸乙酯萃取得到的溶液,用无水硫酸钠干燥,真空浓缩。这得到标题化合物(800mg,粗),为黄色固体,不经任何进一步纯化用于下一步。LC-MS(ESI):[M+H]+=311.1。
实施例22:(S)-2-((4-氟苯基)磺酰基)-N-((5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例22的总体反应方案如下:
实施例22,步骤1:2-[[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲基氨基甲酰基]-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向圆底烧瓶中加入3-叔丁氧羰基-3-氮杂双环[2.1.1]己烷-2-甲酸(82mg,0.36mmol)、[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲胺盐酸盐(136mg,0.38mmol)和HATU(154mg,0.40mmol)。加入二氯甲烷(3.0mL),然后加入N,N-二异丙基乙胺(0.22mL,1.26mmol),将该反应混合物在室温搅拌过夜。用饱和碳酸氢钠水溶液使反应停止,用DCM(3×)萃取。用水(1×)、盐水(1×)洗涤合并的有机萃取物,然后用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物(155mg,81%)。
实施例22,步骤2:(S)-2-((4-氟苯基)磺酰基)-N-((5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤2按照如下方案进行:
向2-[[5-(三氟甲基)-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲基氨基甲酰基]-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯(155mg,0.29mmol)在二氯甲烷(5.0mL)中的溶液中加入盐酸(4mol/L)的1,4-二噁烷(1.2mL,4.8mmol)溶液。将该反应混合物在室温搅拌过夜。真空浓缩该反应混合物,然后溶于二氯甲烷(5.0mL)。加入4-氟苯磺酰氯(62mg,0.32mmol)和三乙胺(0.12mL,0.86mmol),将该反应混合物在室温搅拌2h。用DCM和水稀释该反应混合物,分离各层,用DCM(2×)萃取水层。用硫酸钠干燥合并的有机层,过滤,真空浓缩。通过手性SFC纯化残余物,得到标题化合物(70mg,41%),为白色固体。LCMS[M+H+]590.1;1H NMR(400MHz,DMSO-d6)δ9.72(s,2H),9.12(s,1H),9.01(t,J=6.1Hz,1H),8.37(s,1H),8.09–7.99(m,2H),7.57–7.48(m,2H),4.83(dd,J=17.3,6.8Hz,1H),4.50(dd,J=17.1,5.1Hz,1H),4.31–4.23(m,1H),4.03(s,1H),2.87–2.80(m,1H),1.97–1.90(m,1H),1.82(dd,J=10.6,8.0Hz,1H),1.77–1.69(m,1H),0.41(dd,J=10.6,8.3Hz,1H)。
实施例23:(S)-N-((5-环丙基-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例23的总体反应方案如下:
实施例23,步骤1:3-(((5-溴-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向圆底烧瓶中加入3-叔丁氧羰基-3-氮杂双环[2.1.1]己烷-2-甲酸(300mg,1.32mmol)、[5-溴-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲胺盐酸盐(537mg,1.45mmol)和HATU(563mg,1.45mmol)。加入二氯甲烷(10mL),然后加入N,N-二异丙基乙胺(0.81mL,4.62mmol),将该反应混合物在室温搅拌过夜。用饱和碳酸氢钠水溶液使反应停止,用DCM(3×)萃取。用水(1×),盐水(1×)洗涤合并的有机萃取物,然后用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物(572mg,80%)。
实施例23,步骤2:N-((5-溴-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤2按照如下方案进行:
向3-(((5-溴-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(572mg,1.06mmol)在二氯甲烷(15mL)中的溶液中加入盐酸(4mol/L)的1,4-二噁烷(6.0mL,24mmol)溶液。将该反应混合物在室温搅拌2h。真空浓缩该反应混合物,然后溶于二氯甲烷(12mL)。加入4-氟苯磺酰氯(226mg,1.16mmol)和三乙胺(0.44mL,3.16mmol),将该反应混合物在室温搅拌2h。用DCM和水稀释该反应混合物,分离各层,用DCM(2×)萃取水层。用硫酸钠干燥合并的有机层,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到期望的化合物,为白色固体(543mg,86%)。LCMS[M+H+]600.0;1H NMR(400MHz,DMSO-d6)δ9.65(s,2H),8.97–8.91(m,2H),8.18(s,1H),8.08–8.00(m,2H),7.56–7.47(m,2H),4.63(dd,J=17.3,6.9Hz,1H),4.33(dd,J=17.3,5.2Hz,1H),4.28–4.23(m,1H),4.03(s,1H),2.88–2.80(m,1H),1.97–1.90(m,1H),1.89–1.79(m,1H),1.76–1.70(m,1H),0.47–0.37(m,1H)。
实施例23,步骤3:(S)-N-((5-环丙基-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤3按照如下方案进行:
向微波小瓶中加入N-[[5-溴-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲基]-3-(4-氟苯基)磺酰基-3-氮杂双环[2.1.1]己烷-2-甲酰胺(100mg,0.17mmol)、环丙基硼酸(22mg,0.25mmol)、[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯环物二氯甲烷加合物(14mg,0.017mmol),磷酸三钾(90mg,0.42mmol)。加入四氢呋喃(4.0mL),用氮气给该反应混合物脱气,加热至80℃过夜。用DCM稀释该反应混合物,通过C盐过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%EtOAc的庚烷溶液纯化,得到期望的化合物,为棕色泡沫体。通过手性SFC纯化残余物,得到标题化合物(21.2mg,23%),为白色固体。LCMS[M+H+]562.1;1H NMR(400MHz,DMSO-d6)δ9.63(s,2H),8.82(t,J=6.0Hz,1H),8.45(s,1H),8.09(s,1H),8.08–7.98(m,2H),7.56–7.46(m,2H),4.79(dd,J=16.9,6.8Hz,1H),4.51(dd,J=16.9,5.3Hz,1H),4.29–4.21(m,1H),4.01(s,1H),2.87–2.79(m,1H),2.09–1.97(m,1H),1.96–1.89(m,1H),1.90–1.81(m,1H),1.77–1.69(m,1H),1.10–1.02(m,2H),0.91–0.80(m,2H),0.47–0.38(m,1H)。
实施例24:(S)-N-((5-氰基-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例24的总体反应方案如下:
向小瓶中加入N-[[5-氯-2-[2-(三氟甲基)嘧啶-5-基]-4-吡啶基]甲基]-3-(4-氟苯基)磺酰基-3-氮杂双环[2.1.1]己烷-2-甲酰胺(104mg,0.19mmol)、Zn(CN)2(44.mg,0.37mmol)、三(二亚苄基丙酮)二钯(17mg,0.019mmol)和dppf(31mg,0.056mmol)。加入脱气的DMF(2.0mL),使氮气通过该溶液起泡3min。将该溶液在150℃搅拌2h。使得到的溶液通过C盐过滤,真空浓缩。将残余物溶于EtOAc,用水(2×)和盐水(1×)洗涤,用硫酸钠干燥,过滤,真空浓缩。通过手性SFC纯化残余物,得到标题化合物(28.5mg,28%),为白色固体。LCMS[M+H+]547.1;1H NMR(400MHz,DMSO-d6)δ9.70(s,2H),9.22(s,1H),9.02(t,J=5.9Hz,1H),8.32(s,1H),8.07–7.97(m,2H),7.57–7.46(m,2H),4.78(dd,J=17.0,6.5Hz,1H),4.54(dd,J=17.0,5.2Hz,1H),4.29–4.21(m,1H),4.00(s,1H),2.88–2.80(m,1H),1.96–1.88(m,1H),1.88–1.78(m,1H),1.76–1.68(m,1H),0.46–0.36(m,1H)。
实施例25:(S)-N-(3-氟-5-(2-(三氟甲基)嘧啶-5-基)苄基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例25的总体反应方案如下:
实施例25,步骤1:3-((3-溴-5-氟苄基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向圆底烧瓶中加入3-叔丁氧羰基-3-氮杂双环[2.1.1]己烷-2-甲酸(150mg,0.66mmol)、(3-溴-5-氟苯基)甲胺(156mg,0.73mmol)和HATU(282mg,0.73mmol)。加入二氯甲烷(5.0mL),然后加入N,N-二异丙基乙胺(0.29mL,1.65mmol),将该反应混合物在室温搅拌过夜。用饱和碳酸氢钠水溶液使反应停止,用DCM(3×)萃取。用水(1×)、盐水(1×)洗涤合并的有机萃取物,然后用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物(246mg,90%)。
实施例25,步骤2:N-(3-溴-5-氟苄基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤2按照如下方案进行:
向2-[(3-溴-5-氟-苯基)甲基氨基甲酰基]-3-氮杂双环[2.1.1]己烷-3-甲酸叔丁酯(246mg,0.60mmol)在二氯甲烷(5.0mL)中的溶液中加入在1,4-二噁烷(2.0mL,8.0mmol)中的盐酸(4mol/L)。将该反应混合物在室温搅拌2h。真空浓缩该反应混合物,然后溶于二氯甲烷(5.0mL)。加入4-氟苯磺酰氯(127mg,0.65mmol)和三乙胺(0.25mL,1.79mmol),将该反应混合物在室温搅拌2h。用DCM和水稀释该反应混合物,分离各层,用DCM(2×)萃取水层。用硫酸钠干燥合并的有机层,过滤,真空浓缩,得到粗标题化合物(279mg,99%),为棕色固体,直接用于下一步。
实施例25,步骤3:(S)-N-(3-氟-5-(2-(三氟甲基)嘧啶-5-基)苄基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤3按照如下方案进行:
向微波小瓶中加入N-[(3-溴-5-氟-苯基)甲基]-3-(4-氟苯基)磺酰基-3-氮杂双环[2.1.1]己烷-2-甲酰胺(65mg,0.14mmol)、2-(三氟甲基)嘧啶-5-基硼酸(38mg,0.19mmol)、双(二-叔丁基(4-二甲基氨基苯基)膦)二氯钯(II)(7.8mg,0.011mmol)、碳酸钠(20mg,0.19mmol)和乙酸钾(19mg,0.19mmol)。加入乙腈(1.5mL)和水(0.30mL),使氮气通过该反应混合物起泡3min,然后在微波中加热至120℃15min。用二氯甲烷稀释该反应混合物,通过C盐过滤,用二氯甲烷洗脱,真空浓缩滤液。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%EtOAc的庚烷溶液纯化,得到期望的化合物,为黄色泡沫体。通过手性SFC进一步纯化残余物,得到标题化合物(28.4mg,38%),为白色固体。LCMS[M+H+]547.1;1H NMR(400MHz,DMSO-d6)δ9.43(s,2H),8.73(t,J=6.1Hz,1H),8.02–7.94(m,2H),7.77–7.68(m,2H),7.54–7.44(m,2H),7.36–7.27(m,1H),4.55(dd,J=16.0,6.5Hz,1H),4.41(dd,J=15.9,5.8Hz,1H),4.26–4.18(m,1H),3.95(s,1H),2.85–2.76(m,1H),1.91–1.86(m,1H),1.84–1.77(m,1H),1.75–1.67(m,1H),0.49–0.39(m,1H)。
实施例26:(S)-N-((2-氯-6-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例26的总体反应方案如下:
实施例26,步骤1:3-(((2-溴-6-氯吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向圆底烧瓶中加入3-叔丁氧羰基-3-氮杂双环[2.1.1]己烷-2-甲酸(108mg,0.48mmol)、(2-溴-6-氯吡啶-4-基)甲胺(129mg,0.57mmol)和HATU(203mg,0.52mmol)。加入二氯甲烷(3.0mL),然后加入N,N-二异丙基乙胺(0.21mL,1.19mmol),将该反应混合物室温搅拌过夜。用饱和碳酸氢钠水溶液使反应停止,用DCM(3×)萃取。用水(1×)、盐水(1×)洗涤合并的有机萃取物,然后用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-50%iPrOAc的庚烷溶液纯化,得到标题化合物(118mg,58%),为淡黄色固体。
实施例26,步骤2:3-(((2-氯-6-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤2按照如下方案进行:
向微波小瓶中加入3-(((2-溴-6-氯吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(118mg,0.27mmol),2-(三氟甲基)嘧啶-5-基硼酸(52mg,0.27mmol)和1,1'-双(二苯基膦基)二茂铁-钯(II)二氯化物二氯甲烷复合物(18mg,0.022mmol)。加入乙腈(3.6mL)和1M乙酸钾的水溶液(0.9mL,0.9mmol),使氮气通过该反应混合物气泡3min,然后在微波中加热至110℃30min。用二氯甲烷稀释该反应混合物,通过C盐过滤,用二氯甲烷洗脱,真空浓缩滤液。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-10%MeOH的DCM溶液纯化,得到期望的化合物,为棕色泡沫体(118mg,87%)。
实施例26,步骤3:(S)-N-((2-氯-6-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤3按照如下方案进行:
向3-(((2-氯-6-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(118mg,0.24mmol)在二氯甲烷(3.5mL)中的溶液中加入盐酸(4mol/L)的1,4-二噁烷(0.9mL,4.0mmol)溶液。将该反应混合物在室温搅拌2h。真空浓缩该反应混合物,然后溶于二氯甲烷(5.0mL)。加入4-氟苯磺酰氯(51mg,0.26mmol)和三乙胺(0.10mL,0.71mmol),将该反应混合物在室温搅拌2h。用DCM和水稀释该反应混合物,分离各层,用DCM(2×)萃取水层。用硫酸钠干燥合并的有机层,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-80%3:1iPrOAc:MeOH的庚烷溶液纯化,得到期望的化合物。通过手性SFC进一步纯化残余物,得到标题化合物(41.4mg,31%),为白色固体。LCMS[M+H+]556.1;1H NMR(400MHz,DMSO-d6)δ9.62(s,2H),8.87(t,J=6.1Hz,1H),8.19(d,J=1.2Hz,1H),8.06–7.96(m,2H),7.62(d,J=1.2Hz,1H),7.56–7.45(m,2H),4.62(dd,J=16.9,6.6Hz,1H),4.43(dd,J=16.8,5.5Hz,1H),4.28–4.21(m,1H),3.99–3.94(m,1H),2.86–2.78(m,1H),1.95–1.87(m,1H),1.84–1.77(m,1H),1.74–1.68(m,1H),0.47–0.37(m,1H)。
实施例27:(S)-N-((5-氟-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例27的总体反应方案如下:
实施例27,步骤1:3-(((5-氟-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
向圆底烧瓶中加入3-叔丁氧羰基-3-氮杂双环[2.1.1]己烷-2-甲酸(67mg,0.29mmol),[5-氟-4-[2-(三氟甲基)嘧啶-5-基]-2-吡啶基]甲胺盐酸盐(109mg,0.35mmol)和HATU(126mg,0.32mmol)。加入二氯甲烷(2.0mL),然后加入N,N-二异丙基乙胺(0.18mL,1.03mmol),将该反应混合物在室温搅拌过夜。用饱和碳酸氢钠水溶液使反应停止,用DCM(3×)萃取。用水(1×)、盐水(1×)洗涤合并的有机萃取物,然后用硫酸钠干燥,过滤,真空浓缩。使残余物吸附在硅胶上,通过闪蒸塔色谱法与0-100%iPrOAc的庚烷溶液纯化,得到标题化合物(141mg,99%)。
实施例27,步骤2:(S)-N-((5-氟-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤2按照如下方案进行:
向3-(((5-氟-4-(2-(三氟甲基)嘧啶-5-基)吡啶-2-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(142mg,0.30mmol)在二氯甲烷(3.0mL)中的溶液中加入在1,4-二噁烷(1.0mL,4.0mmol)中的盐酸(4mol/L)。将该反应混合物在室温搅拌2h。真空浓缩该反应混合物,然后溶于二氯甲烷(3.0mL)。加入4-氟苯磺酰氯(63mg,0.32mmol)和三乙胺(0.12mL,0.88mmol),将反应混合物在室温搅拌2h。用DCM和水稀释该反应混合物,分离各层,用DCM(2×)萃取水层。用硫酸钠干燥合并的有机层,过滤,真空浓缩。通过手性SFC纯化残余物,得到标题化合物(53.8mg,34%),为白色固体。LCMS[M+H+]540.1;1H NMR(400MHz,DMSO-d6)δ9.38(d,J=1.2Hz,2H),8.80–8.72(m,2H),8.03–7.93(m,2H),7.81(d,J=6.1Hz,1H),7.54–7.43(m,2H),4.61(dd,J=16.3,6.3Hz,1H),4.48(dd,J=16.2,5.6Hz,1H),4.25–4.17(m,1H),4.01–3.95(m,1H),2.86–2.78(m,1H),1.91–1.86(m,1H),1.85–1.79(m,1H),1.76–1.67(m,1H),0.51–0.41(m,1H)。
实施例28:(S)-N-((2,2'-双(三氟甲基)-[4,5'-联嘧啶]-6-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
实施例28的总体反应方案如下:
实施例28,步骤1:3-(((2,2'-双(三氟甲基)-[4,5'-联嘧啶]-6-基)甲基)氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯的制备
步骤1按照如下方案进行:
将2-[(叔丁氧基)羰基]-2-氮杂双环[2.1.1]己烷-3-甲酸(71mg,0.31mmol,1.00当量)、[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲胺(50mg,0.15mmol,0.49当量)、N,N-二甲基甲酰胺(10mL)、DIEA(85mg,0.65mmol,2.10当量)和HATU(125mg,0.32mmol,1.05当量)的混合物在室温搅拌2h。将该反应体系倾入水,用乙酸乙酯萃取,用盐水洗涤,用无水硫酸钠干燥,真空浓缩。通过硅胶柱纯化残余物,用石油醚/乙酸乙酯(3/1)洗脱,得到标题化合物(120mg,72%),为白色固体。LCMS[M+H+]533。
实施例28,步骤2:(S)-N-((2,2'-双(三氟甲基)-[4,5'-联嘧啶]-6-基)甲基)-2-((4-氟苯基)磺酰基)-2-氮杂双环[2.1.1]己烷-3-甲酰胺的制备
步骤2按照如下方案进行:
将3-([[2-(三氟甲基)-6-[2-(三氟甲基)嘧啶-5-基]嘧啶-4-基]甲基]氨基甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(110mg,0.21mmol)和HCl的1,4-二噁烷溶液(10mL,4M)的混合物在室温搅拌1h。用正己烷稀释得到的溶液。通过过滤采集固体,真空干燥,得到黄色固体。用二氯甲烷(10mL)稀释该固体,加入三甲胺(63mg,0.62mmol)和4-氟苯-1-磺酰氯(60mg,0.31mmol),将该混合物在室温搅拌3h。真空浓缩得到的混合物。通过硅胶柱色谱法纯化残余物,用石油醚/乙酸乙酯(3/1)洗脱。通过手性-制备型-HPLC用如下条件进一步纯化部分纯化的产物:柱,修复的IA,21.2*150mm,5um;流动相,己烷-和乙醇-(保持30.0%乙醇-18min);检测器,UV254/220nm,得到标题化合物(37.0mg 33%),为白色固体。LCMS[M+H+]591;1H NMR(300MHz,DMSO-d6)δ9.73(s,2H),9.01(m,1H),8.51(s,1H),8.05-8.00(m,2H),7.54-7.49(m,2H),4.78-4.57(m,2H),4.25(d,J=7.2,1H),4.01(s,1H),2.83(d,J=7.5,1H),1.91-1.86(m,2H),1.73(d,J=6.3,1H),0.46-0.39(m,1H)。
示例性化合物的IC50测定
化合物对人和大鼠TRPA1通道的IC50(有效浓度)使用FLIPR Tetra仪器确定。将表达TRPA1的CHO细胞铺板于384-孔板,在37℃孵育过夜,并用BD钙指示剂染料在37℃加载1hr,接着在室温加载15分钟。测定缓冲液是含有20mMHEPES(pH重调节至7.4)与0.02%BSA的Hank’s平衡盐溶液(HBSS)。
染料加载和平板冷却之后,使用FLIPR Tetra将化合物加入细胞。随后将平板与化合物在室温孵育20分钟,之后加入激动剂。此孵育之后,将~EC80浓度的桂皮醛(75uM,人TRPA1;和45uM,大鼠TRPA1)以活化通道并测量该桂皮醛诱导的钙流入的阻断。
将IC50值用标准Hill函数拟合,保持Hill系数(n)固定在1.5。固定Hill常数通常将降低IC50测定的可变性。各自检测IC50以保证正确设置最小和最大点,之后确认结果。
上述实施例1-6的化合物与使用上述方法制备或通过商品来源购买的另外的化合物如下表2中所示,其中:“Ex”表示实施例编号,且“LCMS”表示测定的分子量。
表2.
将表2中详细描述的化合物的IC50和质子1H NMR结果报道在下表3中,其中“IC50”表示以微摩尔单位计的hTRPA1 CHO Ca2+AUC EVO(IC50)。
表3
要理解,本发明不限于上文描述的本发明的特定实施方案,因为可以改变特定实施方案,并且仍然落在本申请权利要求的范围内。本文中引用或依赖的所有文件明确地通过引用并入本文中。
Claims (23)
1.式(I)的化合物或其药学上可接受的盐:
其中:
m是0、1或2;
R2各自独立地选自-C1-6烷基;
A-R3选自:
其中:
(1)X1、X2和X3独立地选自C和N,其中
(i)X1、X2和X3之一是N,且r是0、1或2,或
(ii)X1和X3各自是N,且r是0或1;且
(2)R6各自独立地选自卤素、-CN、-C3-7环烷基、-O-C1-6卤代烷基、-O-C1-6烷基和-C1-6卤代烷基;
其中R3是4-、5-、6-或7-元杂芳基,其任选地被一个或多个基团取代,所述基团独立地选自卤素、-C1-6烷基、-C1-6卤代烷基、-O-C1-6烷基和-CN。
2.权利要求1的化合物,其中m是0。
3.权利要求1的化合物,其中m是1或2。
17.药物组合物,该药物组合物包含如权利要求1-16中任一项所述的化合物或其药学上可接受的盐和药用载体、稀释剂或赋形剂。
18.如权利要求1-16中任一项所述的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗或预防呼吸病。
19.如权利要求1-16中任一项所述的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于调节TRPA1活性。
20.如权利要求1-16中任一项所述的化合物或其药学上可接受的盐在用于制备药物的用途,所述药物用于治疗或预防由TRPA1活性介导的疾病或病症。
21.权利要求20的用途,其中所述疾病或病症是疼痛、痒病、炎性疾病、内耳疾病、发烧或另一体温调节疾病、气管支气管或膈功能障碍、胃肠或尿道疾病、慢性阻塞性肺病、失禁或者与向CNS的血流量减少或CNS缺氧相关的疾病。
22.权利要求20的用途,其中所述疾病或病症是疼痛、关节炎、痒病、咳嗽、哮喘、炎性肠病或内耳疾病。
23.调节TRPA1活性的体外方法,所述方法包括将TRPA1与如权利要求1-16中任一项所述的化合物或其盐相接触。
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CN109803964A (zh) | 2016-08-12 | 2019-05-24 | 豪夫迈·罗氏有限公司 | 磺酰基吡啶基trp抑制剂 |
FR3114235A1 (fr) | 2020-09-18 | 2022-03-25 | Université Grenoble Alpes | Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d’alzheimer |
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