CN114599652B - 用于治疗自身免疫性疾病的氢吡嗪并[1,2-d][1,4]二氮杂䓬化合物 - Google Patents
用于治疗自身免疫性疾病的氢吡嗪并[1,2-d][1,4]二氮杂䓬化合物 Download PDFInfo
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- CN114599652B CN114599652B CN202080074407.2A CN202080074407A CN114599652B CN 114599652 B CN114599652 B CN 114599652B CN 202080074407 A CN202080074407 A CN 202080074407A CN 114599652 B CN114599652 B CN 114599652B
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- Prior art keywords
- methyl
- diaza
- carbonitrile
- octahydropyrazino
- quinoline
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及式(I)化合物,其中R1至R3和n如本文所述,及其药用盐,并且涉及包含所述化合物的组合物和使用所述化合物的方法。
Description
本发明涉及可用于哺乳动物的治疗和/或预防的有机化合物,尤其涉及可用于治疗系统性红斑狼疮或狼疮肾炎的TLR7和/或TLR8和/或TLR9的拮抗剂。
技术领域
自身免疫性结缔组织病(CTD)包括典型的自身免疫综合征,诸如系统性红斑狼疮(SLE)、原发性干燥综合征(pSjS)、混合性结缔组织病(MCTD)、皮肌炎/多发性肌炎(DM/PM)、类风湿关节炎(RA)和系统性硬化症(SSc)。除RA以外,对患者来说,没有真正有效且安全的疗法。SLE代表典型的CTD,其患病率为20-150/100,000,并在不同器官引起广泛的炎症和组织损伤,从皮肤和关节的常见症状到肾、肺或心力衰竭。传统上,SLE已使用非特异性抗炎药或免疫抑制剂进行治疗。但是,长期使用免疫抑制药物(例如皮质类固醇)仅部分有效,并伴有不良的毒性和副作用。贝利尤单抗是过去50年中唯一获得FDA批准的用于狼疮的药物,尽管仅对部分SLE患者具有适度延迟的疗效(Navarra,S.V.等人,Lancet 2011,377,721.)。其他生物制剂,诸如抗CD20 mAb、抗特定细胞因子的mAb或其可溶受体,在大多数临床研究中均失败了。因此,需要新型疗法,其在更大比例的患者群组中提供持续改善,并且对于在许多自身免疫以及自身炎症性疾病中的长期使用而言更安全。
Toll样受体(TLR)是模式识别受体(PRR)的重要家族,可以引发多种免疫细胞产生广泛的免疫应答。核内体TLR 7、TLR8和TLR9作为天然的宿主防御传感器,可识别衍生自病毒、细菌的核酸;具体地,TLR7/TLR8和TLR9分别识别单链RNA(ssRNA)和单链CpG-DNA。然而,TRL7、TRL8、TRL9的异常核酸传感被认为是广泛的自身免疫和自身炎性疾病的关键节点(Krieg,A.M.等人,Immunol.Rev.2007,220,251.Jiménez-Dalmaroni,M.J.等人,AutoimmunRev.2016,15,1.Chen,J.Q.等人,Clinical Reviews in Allergy&Immunology 2016,50,1.)。抗RNA和抗DNA抗体是SLE的公认诊断标志,这些抗体可以将自身RNA和自身DNA两者传递至内体。自身RNA复合物可以被TLR7和TLR8识别,而自身DNA复合物可以触发TLR9活化。实际上,在SLE(系统性红斑狼疮)患者中,自身RNA和自身DNA从血液和/或组织中的缺陷清除很明显。据报道,TLR7和TLR9在SLE组织中被上调,并分别与狼疮性肾炎的慢性和活性有关。在SLE患者的B细胞中,TLR7表达与抗RNP抗体的产生相关,而TLR9表达与IL-6和抗dsDNA抗体水平相关。一致地,在狼疮小鼠模型中,抗RNA抗体需要TLR7,抗核小体抗体需要TLR9。另一方面,小鼠中TLR7或人TLR8的过度表达会促进自身免疫和自身炎症。此外,TLR8的活化特别有助于mDC/巨噬细胞的炎症性细胞因子分泌,嗜中性粒细胞胞外捕网过程(NETosis),Th17细胞的诱导和Treg细胞的抑制。除了描述的TLR9在促进B细胞自身抗体产生中的作用外,pDC中通过自身DNA活化TLR9还会导致诱导I型IFN和其他炎症性细胞因子。考虑到pDC和B细胞两者中TLR9的这些作用,它们都是自身免疫性疾病发病机理的关键因素,而且在许多自身免疫性疾病患者中大量存在可轻易活化TLR9的自身DNA复合物,在抑制TLR7和TLR8途径基础之上,它对于进一步阻断自身DNA介导的TLR9途径可能具有额外益处。总之,TLR7、TLR8和TLR9途径代表了治疗自身免疫性疾病和自身炎症性疾病的新治疗靶点,针对这些疾病,不存在有效的不含类固醇和无细胞毒性的口服药物,并且从非常上游就抑制了所有这些途径可能会带来令人满意的治疗效果。因此,我们发明了靶向和抑制TLR7、TLR8和TLR9的口服化合物,用于治疗自身免疫性疾病和自身炎症性疾病。
发明内容
本发明涉及式(I)或(Ia)的新型化合物,
其中
R1为 其中R4为C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤素、硝基或氰基;R4a为C1-6烷基或C3-7环烷基;R5、R5a和R5b独立地选自H和氘;R6为H或卤素;
R2为C1-6烷基;
R3为5元至7元单环芳基或杂芳基;或7元至12元双环杂环基;
n为0、1或2;
或其药用盐。
本发明的另一目的涉及式(I)或(Ia)的新型化合物。其制备、基于根据本发明化合物的药物及其生产以及式(I)或(Ia)化合物作为TLR7和/或TLR8和/或TLR9拮抗剂的用途,及用于治疗或预防系统性红斑狼疮或狼疮肾炎。式(I)或(Ia)化合物显示出优异的TLR7和TLR8和TLR9拮抗活性。另外,式(I)或式(Ia)的化合物还显示出良好的细胞毒性、光毒性、溶解性、hPBMC、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
具体实施方式
定义
术语“C1-6烷基”表示含有1至6个,特别是1至4个碳原子的饱和、直链或支链烷基,例如,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。特别地,“C1-6烷基”基团为甲基、乙基和正丙基。
术语“卤素”和“卤基”在本文中可互换使用,表示氟、氯、溴或碘。
术语“卤代吡咯烷基”表示被卤素取代一次、两次或三次的吡咯烷基。卤代吡咯烷基的实例包括但不限于二氟吡咯烷基和氟吡咯烷基。
术语“芳基”表示具有5至12个环原子的芳族烃单价或双环体系。芳基的实例包括但不限于苯基和萘基。芳基可进一步被取代基取代,这些取代基包括但不限于C1-6烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;1,4-二氮杂环庚烷基;被C1-6烷基取代的2,6-二氮杂螺[3.3]庚烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基-1,4-氧氮杂环庚烷基;被一个或两个独立地选自氨基和C1-6烷基的取代基取代的氮杂环丁烷基;未被取代或被C1-6烷基取代的哌嗪基;以及被一个或两个独立地选自氨基、C1-6烷氧基和卤素的取代基取代的吡咯烷基。
术语“杂芳基”表示具有5个至12个环原子的芳族杂环的单环或双环体系,其包含1、2、3或4个选自N、O和S的杂原子,剩余的环原子是碳。杂芳基部分的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、三唑基、噁二唑基、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、异噁唑基、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、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基或喹噁啉基。杂芳基可进一步被取代基取代,这些取代基包括但不限于C1-6烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;1,4-二氮杂环庚烷基;被C1-6烷基取代的2,6-二氮杂螺[3.3]庚烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基-1,4-氧氮杂环庚烷基;被一个或两个独立地选自氨基和C1-6烷基的取代基取代的氮杂环丁烷基;未被取代或被C1-6烷基取代的哌嗪基;以及被一个或两个独立地选自氨基、C1-6烷氧基和卤素的取代基取代的吡咯烷基。
术语“杂环基”或“杂环”表示具有3至12个环原子的单价饱和或部分不饱和的单环或双环体系,其包含1至5个选自N、O和S的杂原子,剩余的环原子是碳。在特定的实施例中,杂环基是4至7个环原子的单价饱和的单环系统,其包含1、2或3个选自N、O和S的环杂原子,剩余的环原子为碳。单环饱和杂环基的实例为氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚烷基、二氮杂环庚烷基、高哌嗪基、氧氮杂环庚烷基。双环饱和杂环的实例为氮杂双环[3.2.1]辛基、奎宁环基、氧氮杂双环[3.2.1]辛烷基、氮杂双环[3.3.1]壬烷基、氧氮杂-双环[3.3.1]壬烷基、氮杂双环[3.1.0]己烷基、氧代二氮杂螺[3.4]辛烷基、乙酰氧代二氮杂螺[3.4]辛烷基、噻氮杂双环[3.3.1]壬烷基、氧代氮杂螺[2.4]庚烷基、氧代氮杂螺[3.4]辛烷基、氧代氮杂双环[3.1.0]己烷基和二氧代四氢吡咯并[1,2-a]吡嗪基。双环杂环基的实例包括但不限于:1,2,3,4-四氢异喹啉基;5,6,7,8-四氢-1,6-萘啶基;5,6,7,8-四氢-1,7-萘啶基;5,6,7,8-四氢-2,6-萘啶基;5,6,7,8-四氢-2,7-萘啶基;异吲哚啉基。
术语“药用盐”表示在生物学上或其他方面不是不期望的盐。“药用盐”包括酸加成盐和碱加成盐两者。
“药用酸加成盐”是指与无机酸和有机酸形成的那些药用盐,所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可以选自脂肪族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,诸如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸、和水杨酸等。
术语“药用碱加成盐”表示与有机或无机碱形成的那些药用盐。可接受的无机碱的示例包括钠、钾、铵、钙、镁、铁、锌、铜、锰和铝盐。衍生自药用有机无毒碱的盐包括伯胺、仲胺和叔胺,取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、氨丁三醇、二环己胺,赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶和多胺树脂)的盐。
术语“药物活性代谢物”表示通过特定化合物或其盐在体内的代谢产生的药理活性产物。进入人体后,大多数药物均是化学反应的底物,可能改变其物理性质和生物学效应。这些通常影响本发明化合物极性的代谢转化改变了药物在体内分布和从体内排泄的方式。然而,在某些情况下,药物代谢是治疗效果所必需的。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,给药途径和形式,主治医学或兽医的判断和其他因素。
术语“药物组合物”表示包含治疗有效量的活性药物成分和一起施用于有此需要的哺乳动物(例如人)的药用赋形剂的混合物或溶液。
TLR7和/或TLR8和/或TLR9的拮抗剂
本发明涉及(i),其是式(I)化合物,
其中
R1为 其中R4为C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤素、硝基或氰基;R4a为C1-6烷基或C3-7环烷基;R5、R5a和R5b独立地选自H和氘;R6为H或卤素;
R2为C1-6烷基;
R3为5元至7元单环芳基或杂芳基;或7元至12元双环杂环基;
n为0、1或2;
或其药用盐。
本发明的另一个实施例为(ii),其为根据(i)所述的式(I)化合物,其中R3为1,2,3,4-四氢异喹啉基;
5,6,7,8-四氢-1,6-萘啶基;
5,6,7,8-四氢-1,7-萘啶基;
5,6,7,8-四氢-2,6-萘啶基;
5,6,7,8-四氢-2,7-萘啶基;
被吗啉基取代的苯基;
被哌嗪基取代的吡嗪基;
被一个或两个独立地选自以下项的取代基取代的吡啶基:卤素、哌嗪基、氨基卤代吡咯烷基、氨基-1,4-氧氮杂环庚烷基和氨基(C1-6烷氧基)吡咯烷基;或
被哌嗪基或氨基(C1-6烷氧基)吡咯烷基取代的嘧啶基。
本发明的另一实施例是(iii),其是式(Ia)化合物,
其中
R1为 其中R4为C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤素、硝基或氰基;R4a为C1-6烷基或C3-7环烷基;R5、R5a和R5b独立地选自H和氘;R6为H或卤素;
R2为C1-6烷基;
R3为1,2,3,4-四氢异喹啉基;
5,6,7,8-四氢-1,6-萘啶基;
5,6,7,8-四氢-1,7-萘啶基;
5,6,7,8-四氢-2,6-萘啶基;
5,6,7,8-四氢-2,7-萘啶基;
被吗啉基取代的苯基;
被哌嗪基取代的吡嗪基;
被一个或两个独立地选自以下项的取代基取代的吡啶基:卤素、哌嗪基、氨基卤代吡咯烷基、氨基-1,4-氧氮杂环庚烷基和氨基(C1-6烷氧基)吡咯烷基;或
被哌嗪基或氨基(C1-6烷氧基)吡咯烷基取代的嘧啶基;
n为0、1或2;
或其药用盐。
本发明的另一个实施例为(iv)根据(i)至(iii)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中R1为 其中R4为氰基;R4a为C1-6烷基;R5为H;R6为H或卤素;且n为0或1。
本发明的另一个实施例为(v)根据(i)至(iv)中任一者所述的式(I)或(Ia)化合物,其中
R1为其中R4为氰基;R4a为甲基;R5为H;R6为H或氟;
R2为甲基;
R3为1,2,3,4-四氢异喹啉-6-基;
1,2,3,4-四氢异喹啉-7-基;
5,6,7,8-四氢-1,6-萘啶-2-基;
5,6,7,8-四氢-1,6-萘啶-3-基;
5,6,7,8-四氢-1,7-萘啶-2-基;
5,6,7,8-四氢-2,6-萘啶-3-基;
5,6,7,8-四氢-2,7-萘啶-3-基;
5,6,7,8-四氢-2,7-萘啶-4-基;
吗啉-2-基苯基;
哌嗪-1-基吡嗪基;
被一个或两个独立地选自以下项的取代基取代的吡啶基:氟、哌嗪-1-基、3-氨基-4-氟-吡咯烷-1-基、6-氨基-1,4-氧氮杂环庚烷-4-基和3-氨基-4-甲氧基-吡咯烷-1-基;或
被哌嗪-1-基或3-氨基-4-甲氧基-吡咯烷-1-基取代的嘧啶基;
n为0或1;
或其药用盐。
本发明的另一个实施例为(vi)根据(i)至(v)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中R1为其中R4为氰基;R5为H。
本发明的另一实施例为(vii)根据(i)至(vi)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中R3为5,6,7,8-四氢-2,6-萘啶基;5,6,7,8-四氢-2,7-萘啶基;被氨基(C1-6烷氧基)吡咯烷基取代的吡啶基;或被哌嗪基取代的嘧啶基。
本发明的另一实施例为(viii)根据(i)至(vii)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中R3为5,6,7,8-四氢-2,7-萘啶-4-基;5,6,7,8-四氢-2,6-萘啶-3-基;哌嗪-1-基嘧啶基;或3-氨基-4-甲氧基-吡咯烷-1-基吡啶基。
本发明的另一个实施例为(ix)根据(i)至(viii)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中
R1为其中R4为氰基;R5为H;
R2为C1-6烷基;
R3为5,6,7,8-四氢-2,6-萘啶基;5,6,7,8-四氢-2,7-萘啶基;被氨基(C1-6烷氧基)吡咯烷基取代的吡啶基;或被哌嗪基取代的嘧啶基;
n为0或1;
或其药用盐。
本发明的另一个实施例为(x)根据(i)至(ix)中任一者所述的式(I)或(Ia)化合物或其药用盐,其中
R1为其中R4为氰基;R5为H;
R2为甲基;
R3为5,6,7,8-四氢-2,7-萘啶-4-基;5,6,7,8-四氢-2,6-萘啶-3-基;哌嗪-1-基嘧啶基;或3-氨基-4-甲氧基-吡咯烷-1-基吡啶基;
n为0或1;
或其药用盐。
本发明的另一个实施例为式(I)或(Ia)化合物,其选自以下化合物:
5-[(4R,10aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-4-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,7-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-6-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基嘧啶-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(2-哌嗪-1-基嘧啶-5-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基吡嗪-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[(3-氟-5-哌嗪-1-基-2-吡啶基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]吡嗪-2-基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;和
4-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮;
或其药用盐。
合成
本发明的化合物可以通过任何常规方法制备。在以下方案和示例中提供了合成这些化合物及其原料的合适方法。除非另有说明,否则所有取代基,特别是R1和R2如上所定义。此外,除非另有明确说明,否则所有反应、反应条件、缩写和符号均具有有机化学领域普通技术人员众所周知的含义。
制备式(I)、(VII)和(XI)化合物的一般合成路线如下所示。
方案1
其中n为0、1或2;X为卤素;Y为卤素或甲磺酸酯;R7和R8为芳基或杂芳基;R9和R10与它们所连接的氮原子一起形成杂环基。
本发明的化合物的合成从卤化物II开始。卤化物II和式III化合物与催化剂诸如Ruphos Pd-G2和碱诸如Cs2CO3之间发生布赫瓦尔德-哈特维希胺化反应,得到式IV化合物(参考:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics inCurrent Chemistry,2002,219,131-209;这些文献以引用方式并入本文)。替代性地,式IV化合物也可通过卤化物II与式III化合物在碱诸如DIPEA、NaHCO3和K2CO3存在下发生亲核取代来获得。式IV化合物在酸性条件下(诸如含HCl的EtOAc以及含TFA的DCM)发生Boc脱保护,得到化合物V,该化合物可通过与式VI化合物在碱诸如DIPEA NaHCO3和K2CO3存在下发生亲核取代或与式VI化合物发生布赫瓦尔德-哈特维希胺化反应并且随后经适当的脱保护,转化为式VII化合物。同时,式V化合物可与式VIII化合物通过亲核取代发生反应,以得到式IX化合物。式IX化合物与胺X之间发生布赫瓦尔德-哈特维希胺化反应或亲核取代,然后经适当的脱保护,可得到式XI化合物。
式(Ia)化合物可根据方案1使用手性起始材料来合成。
本发明的化合物可以以非对映体或对映体的混合物形式获得,它们可以通过本领域熟知的方法分离,例如,(手性)HPLC或SFC。
本发明还涉及制备式(I)或(Ia)的化合物的方法,该方法包括以下步骤中的任一者:
a)式(IX)化合物,与胺(X),
(X),之间发生Buchwald-Hartwig胺化反应或亲核取代;
b)式(V)化合物,与式(VI)化合物,之间发生Buchwald-Hartwig胺化反应或亲核取代;
其中n为0、1或2;X为卤素;Y为卤素或甲磺酸酯;R7和R8为芳基或杂芳基;R9和R10与它们所连接的氮原子一起形成杂环基。
式(Ia)化合物还可根据方案1通过使用手性中间体来合成。
根据上述方法生产的式(I)或(Ia)的化合物也是本发明的目的。
适应症和治疗方法
本发明提供了可以用作TLR7和/或TLR8和/或TLR9拮抗剂的化合物,其抑制通过TLR7和/或TLR8和/或TLR9通路的活化以及相应的下游生物学事件,包括但不限于通过产生所有类型的细胞因子和各种形式的自身抗体介导的先天性和适应性免疫应答。因此,本发明的化合物可用于在表达此类受体的所有类型的细胞中阻断TLR7和/或TLR8和/或TLR9,所述细胞包括但不限于浆细胞样树突细胞、B细胞、T细胞、巨噬细胞、单核细胞、中性粒细胞、角质形成细胞、上皮细胞。如此,该化合物可用作系统性红斑狼疮和狼疮肾炎的治疗剂或预防剂。
本发明提供了治疗或预防有需要的患者的系统性红斑狼疮和狼疮肾炎的方法。
另一实施例包括治疗或预防需要这种治疗的哺乳动物中系统性红斑狼疮和狼疮肾炎的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式(I)的化合物、其立体异构体、互变异构体、前药或药用盐。
实例
通过参考以下实施例将更全面地理解本发明。但是,它们不应被解释为限制本发明的范围。
缩写
通过参考以下实施例将更全面地理解本发明。但是,它们不应被解释为限制本发明的范围。
本文使用的缩写如下:
ACN: 乙腈
DCM: 二氯甲烷
DCE: 二氯乙烷
DIPEA或DIEA: N,N-二异丙基乙胺
DMF: N,N-二甲基甲酰胺
EA或EtOAc: 乙酸乙酯
FA: 甲酸
HATU: 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸盐
IC50: 半抑制浓度
IPA: 异丙醇
MS: 质谱
prep-HPLC: 制备型高效液相色谱
prep-TLC: 制备型薄层色谱
RuPhos Pd G2: 氯(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)第2代
选择性氟试剂 1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷双(四氟硼酸酯)
SFC: 超临界流体色谱
TEA: 三甲胺
TFA: 三氟乙酸
THF: 四氢呋喃
XantPhos: 4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽
v/v 体积比
一般实验条件
使用以下仪器之一通过快速色谱法纯化中间体和最终化合物:i)Biotage SP1系统和Quad 12/25Cartridge模块。ii)ISCO combi-flash色谱仪。硅胶品牌和孔径:i)KP-SIL粒径:40-60μm;ii)CAS登录号:硅胶:63231-67-4,粒径:47-60微米硅胶;iii)青岛海洋化学有限公司的ZCX,孔:200-300或300-400。
中间体和最终化合物在反相色谱柱上通过制备型HPLC纯化,反相色谱柱使用XBridgeTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱,SunFireTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱,Phenomenex Synergi-C18(10μm,25×150mm)或Phenomenex Gemini-C18(10μm,25×150mm)。Waters AutoP纯化系统(样品管理器2767,泵2525,检测器:Micromass ZQ和UV 2487,溶剂系统:乙腈和0.1%氢氧化铵在水中的溶液;乙腈和0.1%FA在水中的溶液,或乙腈和0.1%TFA在水中的溶液)。或Gilson-281纯化系统(泵322,检测器:UV 156,溶剂系统:乙腈和0.05%氢氧化铵在水中的溶液;乙腈和0.225%FA在水中的溶液;乙腈和0.05%HCl在水中的溶液;乙腈和0.075%TFA在水中的溶液;或乙腈和水)。
为了进行SFC手性分离,中间体分离通过手性柱(Daicel chiralpak IC,5μm,30×250mm)、AS(10μm,30×250mm)或AD(10μm,30×250mm),使用Mettler Toledo MultigramIII系统SFC、Waters 80Q制备型SFC或Thar 80制备型SFC,溶剂系统:CO2和IPA(0.5%TEA的IPA溶液)或CO2和MeOH(0.1%NH3·H2O的MeOH溶液),背压100bar,在254或220nm处检测UV。
使用LC/MS(WatersTM Alliance 2795-Micromass ZQ、Shimadzu Alliance 2020-Micromass ZQ或Agilent Alliance 6110-Micromass ZQ)获得化合物的LC/MS光谱,LC/MS条件如下(运行时间3或1.5分钟):
酸性条件I:A:0.1%TFA在H2O中的溶液;B:0.1%TFA在乙腈中的溶液;
酸性条件II:A:0.0375%TFA在H2O中的溶液;B:0.01875%TFA在乙腈中的溶液;
碱性条件I:A:0.1%NH3·H2O在H2O中的溶液;B:乙腈;
碱性条件II:A:0.025%NH3·H2O在H2O中的溶液;B:乙腈;
中性条件:A:H2O;B:乙腈。
质谱(MS):通常仅报告表示母体质量的离子,除非另有说明,否则所引用的质量离子为正质量离子(MH)+。
使用Bruker Avance 400MHz获得NMR谱。
微波辅助反应在Biotage Initiator Sixty微波合成仪中进行。所有涉及对空气敏感的试剂的反应均在氩气或氮气气氛下进行。除非另有说明,否则试剂按原样购自商业供应商,未经进一步纯化。
制备实例
以下实例旨在说明本发明的含义,但绝不代表对本发明含义的限制:
中间体A1
5-氟喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):8-溴-5-氟-喹啉(化合物A1.2)的制备
在100mL梨形烧瓶中,将2-溴-5-氟苯胺(化合物A1.1,2.0g,10.5mmol),丙烷-1,2,3-三醇(969mg,10.5mmol)和3-硝基苯磺酸钠(2.4g,10.5)与70%H2SO4(20mL)合并,得到深褐色溶液,将溶液加热至150℃并搅拌3小时。冷却至室温后,将反应混合物倒入冰水中,并用氢氧化钠溶液中和。过滤所得混合物。将滤饼溶解在EtOAc中并过滤。将得到的滤液真空浓缩。粗物质通过快速色谱法纯化(硅胶,40g,0%至30%EtOAc的PE溶液),得到化合物A1.2(2.0g,84%收率)。MS:计算值为226和228[(M+H)+],测量值为226和228[(M+H)+]。
步骤(b):5-氟喹啉-8-甲腈(中间体A1)的制备
向8-溴-5-氟喹啉(化合物A1.2,4.9g,21.7mmol)的DMF(30mL)溶液中加入双氰锌(5.0g,43.4mmol)和RuPhos Pd G2(CAS:1375325-68-0,西格玛奥德里奇,目录:753246,842mg,1.1mmol)。将反应混合物在100℃下搅拌3小时,然后冷却至室温。过滤反应混合物,然后用水(50mL)稀释滤液,并用EA(80mL)萃取3次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,40g,0%至70%的EtOAc的PE溶液)纯化,得到中间体A1(3.0g,80%产率)。MS:计算值为173[(M+H)+],测量值为173[(M+H)+]。1HNMR(400MHz,METHANOL-d4)δppm 9.11(dd,J=4.28,1.71Hz,1H),8.64(dd,J=8.56,1.71Hz,1H),8.29(dd,J=8.19,5.62Hz,1H),7.76(dd,J=8.56,4.28Hz,1H),7.49(dd,J=9.35,8.25Hz,1H).
中间体A2
4-氯-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤(a):2-(甲基氨基)吡啶-3-甲酸(化合物A2.2)的制备
将2-氯烟酸(化合物A2.1,1.0kg,6.3mmol)溶于33%单甲胺(386.3mol)的乙醇溶液中。将反应混合物在高压釜中在80℃搅拌80小时,然后在真空中浓缩得到化合物A2.2(1.4kg,粗品)。MS:计算值为153[(M+H)+],测量值为153[(M+H)+]。
步骤(b):(1-甲基-2-氧代-1,8-萘啶-4-基)乙酸酯(化合物A2.3)的制备
将2-(甲基氨基)吡啶-3-甲酸(化合物A2.2,1.4kg,粗品)在乙酸酐(10.0L,105789mmol)和乙酸(5.0L)的溶液加热至回流2小时。将反应混合物在真空中浓缩得到化合物A2.3(1.8kg,粗品)。MS:计算值为219[(M+H)+],测量值为219[(M+H)+]。
步骤(c):4-羟基-1-甲基-1,8-萘啶-2-酮(化合物A2.4)的制备
向(1-甲基-2-氧代-1,8-萘啶-4-基)乙酸酯(化合物A2.3,1.8kg,粗产物)在甲醇(12.0L)中的溶液中添加碳酸钾(1.9kg,13.75mol)在水(3.6L)中的水溶液。将混合物在25℃搅拌2小时。然后将反应混合物在减压下浓缩以除去MeOH。将残余物用HCl溶液(6N)酸化至pH 4-5,用EA(1500mL)萃取三次。将合并的有机层用饱和盐水(1500mL)洗涤,经Na2SO4干燥,并且在真空中浓缩,得到化合物A2.4(450g,40.2%产率)。MS:计算值为177[(M+H)+],测量值为177[(M+H)+];1H NMR(400MHz,DMSO-d6)δppm 11.68(s,1H),8.63(dd,J=4.60,1.80Hz,1H),8.22(dd,J=7.80,1.80Hz,1H),7.27(dd,J=7.80,4.60Hz,1H),5.93(s,1H),3.59(s,3H)
步骤(d):4-氯-1-甲基-1,8-萘啶-2-酮(中间体A2)的制备
将4-羟基-1-甲基-1,8-萘啶-2-酮(化合物A2.4,150g,0.85mol)的三氯氧磷(300mL)溶液在100℃搅拌2小时。将反应混合物在减压下浓缩以除去三氯氧磷。将残余物通过在室温下添加饱和NaHCO3溶液中和至pH 7-8,并将混合物用DCM(1000mL)萃取两次。将合并的有机层用饱和盐水(500mL)洗涤,经Na2SO4干燥,并且在真空中浓缩以给出粗产物,利用硅胶色谱法(PE/EtOAc=1:0至7:1)纯化该粗产物,得到中间体A2(39g,24%产率)。MS:计算值为195[(M+H)+],测量值为195[(M+H)+];1H NMR(400MHz,DMSO-d6)δppm 8.75(dd,J=4.60,1.60Hz,1H),8.32(dd,J=7.90,1.70Hz,1H),7.44(dd,J=8.00,4.60Hz,1H),7.03(s,1H),3.66(s,3H)。
中间体A3
4-氟吡唑并[1,5-a]吡啶-7-甲腈
根据以下方案合成标题化合物:
步骤(a):制备氨基2,4,6-三甲基苯磺酸盐(化合物A3.2)
在30min内向(1E)-N-(2,4,6-三甲基苯基)磺酰基氧基乙酰亚胺乙酯(化合物A3.1,CAS:38202-27-6,Bide Pharmatech,目录:BD129455,200g,700mmol)的1,4-二噁烷(500mL)溶液中逐滴添加高氯酸(110mL)并在0℃搅拌1小时。添加1000mL冰水并过滤混合物。将滤饼溶解在1.5L EtOAc中,然后搅拌30分钟。浓缩有机层(保持温度低于25℃),得到粗产物。将粗产物重结晶(石油/EtOAc=10/1),得到化合物A3.2(110g,73%产率)。MS:计算值为216[(M+H)+],测量值为216[(M+H)+]。
步骤(b):2-溴-5-氟-吡啶-1-鎓-1-胺;2,4,6-三甲苯磺酸盐(化合物A3.3)的制备
将氨基2,4,6-三甲基苯磺酸盐(化合物A3.2,110g,511mmol)和2-溴-5-氟吡啶(60g,341mmol)的DCM(1800mL)溶液在10℃搅拌18小时。浓缩混合物,残余物在EtOAc中重结晶,得到化合物A3.3(90g,92%产率)。MS:计算值为191[(M+H)+],测量值为191[(M+H)+]。
步骤(c):7-溴-4-氟-吡唑并[1,5-a]吡啶-3-甲酸乙酯(化合物A3.4)的制备
2-溴-5-氟吡啶-1-鎓-1-胺;2,4,6-三甲基苯磺酸盐(化合物A3.3,90g,230mmol)、K2CO3(64g,460mmol)和丙酸乙酯(28mL,276mmol)的DMF(1300mL)溶液在10℃搅拌18小时。将反应用水稀释,用EtOAc萃取。将有机层经Na2SO4干燥,过滤,并将滤液在真空下浓缩。残余物通过色谱柱纯化,得到化合物A3.4(11g,16.7%产率)。MS:计算值为287[(M+H)+],测量值为287[(M+H)+]。
步骤(d):7-溴-4-氟吡唑并[1,5-a]吡啶(化合物A3.5)的制备
向7-溴-4-氟-吡唑并[1,5-a]吡啶-3-甲酸乙酯(化合物A3.4,8.0g,26.7mmol)的乙酸(48mL)和水(48mL)的混合物中添加浓HCl(36mL,432mmol)。将混合物在100℃搅拌18小时。将混合物用水(200mL)稀释,用NaOH(1N)水溶液碱化至pH 8,并用EA(200mL)萃取三次。合并的有机层用盐水洗涤,经Na2SO4干燥,并在真空中浓缩,得到化合物A3.5(5g,86.9%产率),其直接用于下一步。
MS:计算值为215[(M+H)+],测量值为215[(M+H)+]。
步骤(e):4-氟吡唑并[1,5-a]吡啶-7-甲腈(中间体A3)的制备
将7-溴-4-氟-吡唑并[1,5-a]吡啶(化合物A3.5,1000mg,4.6mmol)、氰化锌(880mg,7.5mmol)、锌(31mg,0.5mmol)、XantPhos(1076mg,1.8mmol)和Pd(OAc)2(209mg,0.9mmol)在DMA(10mL)中的混合物脱气并用氩气吹扫3次,然后将混合物在氩气气氛下在120℃搅拌1小时。将混合物用EA(150mL)稀释,过滤,并将滤液用水(50mL)、盐水(50mL)洗涤三次,经Na2SO4干燥并在真空下浓缩。残余物通过Prep-TLC纯化(PE:EA=3:1)得到中间体A3(600mg,68%产率)。MS:计算值为162[(M+H)+],测量值为162[(M+H)+]。
中间体A4
3,4-二氟吡唑并[1,5-a]吡啶-7-甲腈
根据以下方案合成标题化合物:
步骤(a):7-溴-4-氟-吡唑并[1,5-a]吡啶-3-甲酸(化合物A4.1)的制备
将7-溴-4-氟-吡唑并[1,5-a]吡啶-3-甲酸乙酯(化合物A3.4,5.2g,18.1mmol)、NaOH(2.1g,54.3mmol)在EtOH(90.0mL)和水(70.0mL)中的混合物在60℃搅拌2小时。浓缩反应混合物,然后用水稀释。用1N HCl调节pH至4后,沉淀出灰色固体,将其通过过滤收集得到化合物A4.1(4.0g,85.6%产率)。MS:计算值为259[(M+H)+],测量值为259[(M+H)+]。
步骤(b):7-溴-3,4-二氟-吡唑并[1,5-a]吡啶(化合物A4.2)的制备
向7-溴-4-氟-吡唑并[1,5-a]吡啶-3-甲酸(化合物A4.1,4.0g,15.4mmol)和KF(3.6g,61.8mmol)在DCE(60.0mL)和水(50.0mL)中的溶液添加Selectfluor(10.9g,30.9mmol)。将反应在70℃下搅拌18小时。用水猝灭反应,用DCM萃取两次。将合并的有机层经Na2SO4干燥,过滤并将滤液真空浓缩,得到粗化合物A4.2(2.8g,78%产率)。MS:计算值为233[(M+H)+],测量值为233[(M+H)+]。
步骤(c):3,4-二氟吡唑并[1,5-a]吡啶-7-甲腈(中间体A4)的制备
向7-溴-3,4-二氟-吡唑并[1,5-a]吡啶(化合物A4.2,2.8g,12.0mmol)和氰化锌(5.6g,48.0mmol)的DMF(70.0mL)溶液中添加四(三苯基膦)钯(1.4g,1.2mmol)。将反应混合物在N2气氛下在120℃搅拌18小时。用水猝灭混合物,并用EtOAc萃取两次。将合并的有机层经Na2SO4干燥,过滤并将滤液在真空中浓缩。残余物通过纯化柱色谱法纯化得到中间体A4(810mg,37.7%产率)。MS:计算值为180[(M+H)+],测量值为180[(M+H)+]。1H NMR(400MHz,CHLOROFORM-d)δppm 8.00(d,J=3.6Hz,1H),7.31(dd,J=4.7,8.0Hz,1H),6.83(t,J=8.4Hz,1H).
中间体B
(4R,10aS)-4-甲基-2,3,4,6,7,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯
根据以下方案合成标题化合物:
步骤(a):N-[(1R)-2-(苄基氨基)-1-甲基-乙基]氨基甲酸叔丁酯(化合物B2)的制备
将(R)-(1-氨基丙-2-基)氨基甲酸叔丁酯(4.95g,28.40mmol)、苯甲醛(2.86g,27mmol)和DCE(80mL)的混合物在室温下搅拌30min。然后将NaBH(OAc)3(12.0g,56.80mmol)添加至混合物。将所得混合物在室温下搅拌2小时,然后用水(100mL)猝灭,用DCM(80mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,并在真空中浓缩。残余物通过快速色谱法(硅胶,80g,0%至30%的EtOAc的DCM溶液)纯化,得到化合物B2(5.10g,68%产率)。MS:计算值为265[(M+H)+],测量值为265[(M+H)+]。
步骤(b):(E)-4-[苄基-[(2R)-2-(-叔丁氧基羰基氨基)丙基]氨基]丁-2-烯酸甲酯(化合物B3)的制备
向N-[(1R)-2-(苄基氨基)-1-甲基-乙基]氨基甲酸叔丁酯(化合物B2,5.10g,19.30mmol)的丙酮(150mL)溶液中添加(E)-4-溴丁-2-烯酸甲酯(3.45g,19.3mmol)和K2CO3(5.33g,38.6mmol)。将反应混合物在室温下搅拌20小时,然后通过celite过滤并将滤液浓缩。残余物通过快速色谱法(硅胶,80g,0%至30%的EtOAc的PE溶液)纯化,得到化合物B3(4.20g,60%产率)。MS:计算值为363[(M+H)+],测量值为363[(M+H)+]。
步骤(c):2-[(6R)-4-苄基-6-甲基-哌嗪-2-基]乙酸甲酯(化合物B4)的制备
将(E)-4-[苄基-[(2R)-2-(叔丁氧基羰基氨基)丙基]氨基]丁-2-烯酸甲酯(化合物B3,4.20g,11.60mmol)和HCl/MeOH(1N,70mL,70mmol)的混合物在回流下加热2小时。冷却至室温后,将反应混合物用饱和K2CO3水溶液中和,并用DCM(80mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,40g,0%至20%的MeOH的DCM溶液)纯化,得到化合物B4(2.40g,79%产率)。MS:计算值为263[(M+H)+],测量值为263[(M+H)+]。
步骤(d):2-[(6R)-4-苄基-1-[2-(-叔丁氧基羰基氨基)-乙酰基]-6-甲基-哌嗪-2-基]乙酸甲酯(化合物B5)的制备
向(叔丁氧基羰基)甘氨酸(3.50g,20.0mmol)的DMF(40mL)溶液中添加2-[(6R)-4-苄基-6-甲基-哌嗪-2-基]乙酸甲酯(化合物B4,5.24g,20.0mmol)、DIEA(7.74g,60.0mmol)和HATU(7.60g,20.0mmol)。将所得混合物在室温下搅拌3小时。将反应用水(100mL)猝灭,用DCM(80mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并将滤液在真空中浓缩。残余物通过快速色谱法(硅胶,120g,0%至60%的EtOAc的PE溶液)纯化,得到化合物B5(7.2g,85.9%产率)。MS:计算值为420[(M+H)+],测量值为420[(M+H)+]。
步骤(e):(4R)-2-苄基-4-甲基-3,4,7,8,10,10a-六氢-1H-吡嗪并[1,2-d][1,4]二氮杂-6,9-二酮(化合物B6)的制备
将2-[(6R)-4-苄基-1-[2-(-叔丁氧基羰基氨基)-乙酰基]-6-甲基-哌嗪-2-基]乙酸甲酯(化合物B5,5.0g,11.9mmol)和HCl/MeOH(7%HCl在MeOH中,80mL)的混合物在回流下搅拌2小时。将反应混合物浓缩,将残余物用MeOH(100mL)稀释,然后添加甲醇钠(3.22g,59.60mmol)。将所得混合物在回流下搅拌5小时。冷却至室温后,将反应用水(300mL)猝灭并用EA(100mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并将滤液在真空中浓缩。残余物通过快速色谱法纯化得到化合物B6(2.30g,67.3%产率)。MS:计算值为288[(M+H)+],测量值为288[(M+H)+]。
步骤(f):(4R,10aR)-2-苄基-4-甲基-3,4,7,8,10,10a-六氢-1H-吡嗪并[1,2-d][1,4]二氮杂-6,9-二酮(化合物B7a)和(4R,10aS)-2-苄基-4-甲基-3,4,7,8,10,10a-六氢-1H-吡嗪并[1,2-d][1,4]二氮杂-6,9-二酮(化合物B7b)的制备
通过SFC用25%甲醇/CO2(在OJ(5μm,250×30mm)柱上)解析化合物B7a(2.30g)以给出两种单独的异构体:化合物B7a(较快洗脱,0.63g,27.4%产率)和化合物B7b(较慢洗脱,1.56g,67.8%产率)。立体化学由NOESY确认。
化合物B7a:MS:计算值为288(M+H)+,测量值为288(M+H)+;1H NMR(400MHz,甲醇-d4)δppm 7.05-7.55(m,5H),4.82(ddd,J=1.71,4.03,6.85Hz,1H),4.04(s,2H),3.91-4.01(m,1H),3.54-3.64(m,1H),3.43-3.49(m,1H),2.95(dd,J=4.40,14.43Hz,1H),2.87(td,J=2.17,11.19Hz,1H),2.78(dd,J=7.76,14.49Hz,1H),2.72(td,J=1.71,11.49Hz,1H),2.14(dd,J=3.91,11.49Hz,1H),2.04(t,J=11.07Hz,1H),1.32(d,J=6.85Hz,3H)。
化合物B7b:MS:计算值为288(M+H)+,测量值为288(M+H)+;1H NMR(400MHz,甲醇-d4)δppm 7.38-7.42(m,2H),7.32-7.39(m,2H),7.05-7.71(m,1H),4.58(d,J=14.79Hz,1H),4.45(td,J=3.81,13.54Hz,1H),4.30-4.39(m,1H),3.52-3.65(m,2H),3.46(d,J=14.92Hz,1H),3.10(dd,J=13.45,18.46Hz,1H),2.75-2.82(m,1H),2.77(s,1H),2.53(dd,J=2.87,18.40Hz,1H),2.39(dd,J=5.26,12.10Hz,1H),2.27(dd,J=4.46,11.55Hz,1H),1.27(d,J=6.72Hz,3H)。
步骤(g):(4R,10aS)-2-苄基-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(化合物B8)的制备
将(4R,10aS)-2-苄基-4-甲基-3,4,7,8,10,10a-六氢-1H-吡嗪并[1,2-d][1,4]二氮杂-6,9-二酮(化合物B7b,1.56g,5.43mmol)和BH3溶液(1M在THF中,40mL,40mmol)的混合物在80℃加热伴随搅拌持续20小时。将反应混合物冷却至0℃,然后在相同温度下将HCl溶液(2N,10mL)缓慢添加至反应混合物。将所得混合物在回流下搅拌3小时,然后将混合物冷却回室温。在真空中除去有机溶剂后,将残余物用DCM(100mL)稀释。分别添加Boc酸酐(1.77g,8.12mmol)和TEA(2.74g,27.1mmol)。将所得混合物在室温下搅拌2小时。将反应用水(50mL)猝灭,并用DCM(50mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,80g,20%至80%的EtOAc的DCM溶液)纯化,得到化合物B8(1.8g,92.4%产率)。MS:计算值为360[(M+H)+],测量值为360[(M+H)+]。
步骤(h):(4R,10aS)-4-甲基-2,3,4,6,7,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(中间体B)的制备
将(4R,10aS)-2-苄基-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(化合物B8,1.8g,5.01mmol)和Pd-C(100mg)在MeOH(100mL)中的混合物在室温下用氢气球氢化5小时。滤出催化剂后,将滤液在真空中浓缩得到中间体B(1.2g,89%产率),其无需进一步纯化即可直接用于下一步。MS:计算值为270[(M+H)+],测量值为270[(M+H)+]。
中间体C1
5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐
根据以下方案合成标题化合物:
步骤(a):(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(化合物C1.1)的制备
向(4R,10aS)-4-甲基-2,3,4,6,7,9,10,10a-八氢-1H-吡嗪并
[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(中间体B,1.20g,4.45mmol)的DMSO(20mL)溶液中添加5-氟喹啉-8-甲腈(中间体A1,0.77g,4.45mmol)和DIEA(0.58g,4.45mmol)。将所得混合物在120℃搅拌5小时。冷却至室温后,将反应用水(100mL)猝灭并用EA(90mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,40g,0%至100%的EtOAc的PE溶液)纯化得到化合物C1.1(1.41g,75.1%产率)。MS:计算值为422[(M+H)+],测量值为422[(M+H)+]。
步骤(b):5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1)的制备
在0℃向(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-甲酸叔丁酯(化合物C1.1,1.41g,3.34mmol)的DCM(30mL)溶液中逐滴添加HCl/二噁烷(4N,8mL)。添加后,将混合物在室温搅拌2小时,然后将反应混合物浓缩。将残余物溶解于纯水(20mL),并通过冻干法干燥得到中间体C1(1.44g,100%产率)。MS:计算值为322[(M+H)+],测量值为322[(M+H)+]。
中间体C2
4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮;三盐酸盐
类似于中间体C1,通过用4-氯-1-甲基-1,8-萘啶-2-酮(中间体A2)替换5-氟喹啉-8-甲腈(中间体A1)且用DIEA替换CsF(在步骤(a)中)制备4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮;三盐酸盐(中间体C2)。MS:计算值为328[(M+H)+],测量值为328[(M+H)+]。
中间体C3
4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐
类似于中间体C1,通过用5-氟喹啉-8-甲腈(中间体A1)替换4-氟吡唑并[1,5-a]吡啶-7-甲腈(中间体A3)(在步骤(a)中)制备4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐(中间体C3)。MS:计算值为311[(M+H)+],测量值为311[(M+H)+]。
中间体C4
4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐
类似于中间体C1,通过用5-氟喹啉-8-甲腈(中间体A1)替换3,4-二氟吡唑并[1,5-a]吡啶-7-甲腈(中间体A4)(在步骤(a)中)制备4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐(中间体C4)。MS:计算值为329[(M+H)+],测量值为329[(M+H)+]。
实例1
5-[(4R,10aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):4-[5-[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]-2-吡啶基]哌嗪-1-甲酸叔丁酯(化合物1.1)的制备
向5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1,70mg,162μmol)的甲苯(5mL)溶液中添加4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(CAS:153747-97-8,BePharm,目录:BD94595,55.6mg,162μmol)、tBuONa(78.1mg,812μmol)和RuPhos Pd G2(CAS:1375325-68-0,ALDRICH,目录:753246,12.6mg,16.2μmol)。将所得混合物在100℃搅拌过夜。冷却至室温后,将混合物用水(20mL)稀释并用EA(20mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,20g,0%至100%的EtOAc的PE溶液)纯化得到化合物1.1(38mg,40.1%产率)。MS:计算值为583[(M+H)+],测量值为583[(M+H)+]。
步骤(b):5-[(4R,10aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(实例1)的制备
向4-[5-[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]-2-吡啶基]哌嗪-1-甲酸叔丁酯(化合物1.1,38mg,65.2μmol)的DCM(2mL)溶液中添加TFA(1mL)。将反应混合物在室温下搅拌2小时,然后浓缩得到粗产物将其通过制备型HPLC纯化,得到实例1(9.4mg,30.3%产率)。MS:计算值为483[(M+H)+],测量值为483[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.07-8.97(m,1H),8.76-8.62(m,1H),8.19(d,J=8.1Hz,1H),7.87(d,J=3.1Hz,1H),7.75-7.62(m,1H),7.40-7.28(m,2H),6.95(d,J=9.2Hz,1H),4.14-4.02(m,1H),3.89-3.52(m,12H),3.40-3.34(m,5H),3.23-3.09(m,2H),2.37-2.24(m,1H),2.20(br s,1H),1.53(d,J=6.5Hz,3H)。
实例2
5-[(4R,10aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(CAS:374930-88-8,BePharm,目录:BD28540)代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例2。MS:计算值为484[(M+H)+],测量值为484[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 9.11-9.02(m,1H),8.75-8.66(m,1H),8.32-8.20(m,3H),7.76-7.60(m,1H),7.39(d,J=8.1Hz,1H),4.22-4.09(m,1H),4.08-3.84(m,6H),3.84-3.65(m,4H),3.61-3.44(m,4H),3.31-3.26(m,3H),3.25-3.09(m,2H),2.45-2.13(m,2H),1.58(d,J=6.4Hz,3H)。
实例3
5-[(4R,10aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用(2S)-2-(4-溴苯基)吗啉-4-甲酸叔丁酯代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例3。MS:计算值为483[(M+H)+],测量值为483[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.08-8.99(m,1H),8.75-8.64(m,1H),8.22(d,J=7.9Hz,1H),7.73-7.63(m,1H),7.38(d,J=8.1Hz,1H),7.33(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),4.72-4.61(m,1H),4.27-4.13(m,2H),4.04-3.59(m,9H),3.54-3.45(m,1H),3.42-3.35(m,2H),3.29-3.07(m,4H),2.39-2.08(m,2H),1.57(d,J=6.2Hz,3H)。
实例4
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-4-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用5-溴-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(CAS:1251012-16-4)代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例4。MS:计算值为454[(M+H)+],测量值为454[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.09-9.00(m,1H),8.79-8.69(m,1H),8.51(s,1H),8.38(s,1H),8.23(d,J=7.9Hz,1H),7.79-7.66(m,1H),7.41(d,J=8.1Hz,1H),4.55(s,2H),4.17(br s,2H),4.04-3.84(m,2H),3.79-3.53(m,7H),3.48-3.40(m,1H),3.31-3.18(m,4H),2.49-2.34(m,1H),2.28-2.12(m,1H),1.59(d,J=6.4Hz,3H)。
实例5
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,7-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用2-氯-6,8-二氢-5H-1,7-萘啶-7-甲酸叔丁酯(CAS:1211581-54-2,PharmaBlock,目录:PBLJ8189)代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例5。MS:计算值为454[(M+H)+],测量值为454[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.04-8.98(m,1H),8.70-8.62(m,1H),8.19(d,J=7.9Hz,1H),7.74-7.61(m,1H),7.47(d,J=8.7Hz,1H),7.35(d,J=7.9Hz,1H),6.71(d,J=8.7Hz,1H),4.57-4.45(m,1H),4.24(s,2H),4.11-3.99(m,1H),3.88-3.56(m,7H),3.54-3.44(m,2H),3.25(br t,J=12.0Hz,1H),3.20-3.07(m,2H),3.01(t,J=6.1Hz,2H),2.40-2.25(m,1H),2.20-2.08(m,1H),1.51(d,J=6.2Hz,3H)。
实例6
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用2-氯-5,6,7,8-四氢-1,6-萘啶-6-甲酸叔丁酯(CAS:1151665-15-4,PharmaBlock,目录:PB06675)代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例6。MS:计算值为454[(M+H)+],测量值为454[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.04-8.92(m,1H),8.80-8.70(m,1H),8.17(d,J=8.1Hz,1H),7.81(d,J=9.4Hz,1H),7.74-7.64(m,1H),7.34(d,J=7.9Hz,1H),7.24(d,J=9.7Hz,1H),4.26(s,2H),4.23-4.01(m,4H),3.99-3.78(m,3H),3.71-3.46(m,5H),3.30-3.23(m,4H),2.63-2.47(m,1H),2.27-2.10(m,1H),1.54(d,J=6.4Hz,3H)。
实例7
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例1的制备方法,使用6-氯-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯代替4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例7。MS:计算值为454[(M+H)+],测量值为454[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.06-8.98(m,1H),8.73-8.61(m,1H),8.19(d,J=7.9Hz,1H),8.05(s,1H),7.80-7.62(m,1H),7.35(d,J=7.9Hz,1H),6.62(s,1H),4.55-4.45(m,1H),4.32(s,2H),4.15-4.03(m,1H),3.86-3.66(m,6H),3.64-3.57(m,1H),3.51(t,J=6.5Hz,2H),3.31-3.25(m,1H),3.22-3.01(m,4H),2.42-2.26(m,1H),2.22-2.09(m,1H),1.52(d,J=6.4Hz,3H)。
实例8
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):6-(甲基磺酰基氧基甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(化合物8.2)的制备
向6-(羟甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(化合物8.1,40mg,151μmol)和DIEA(58.7mg,454μmol)的DCM(5mL)溶液中逐滴添加甲磺酰氯(19.1mg,166μmol)。将所得混合物在室温下搅拌2小时。将反应用NaHCO3水溶液猝灭,用DCM(20mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并将滤液浓缩得到化合物8.2(52mg,100%产率),其无需进一步纯化即可直接用于下一步。MS:计算值为343[(M+H)+],测量值为343[(M+H)+]。
步骤(b):6-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,
6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(化合物8.3)的制备
向5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1,80mg,186μmol)的乙腈(10mL)的溶液中添加6-(甲基磺酰基氧基甲基)-3,4-二氢-1H
-2,7-萘啶-2-甲酸叔丁酯(化合物8.2,52mg,152μmol)和DIEA(98.1mg,759μmol)。将所得混合物在回流下搅拌5小时,然后浓缩,残余物通过快速色谱法纯化得到化合物8.3(49mg,56.8%产率)。MS:计算值为568[(M+H)+],测量值为568[(M+H)+]。
步骤(c):5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(实例8)的制备
向6-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(化合物8.3,50mg,88.1μmol)的DCM(10mL)溶液中添加TFA(3mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例8(18mg,43.7%产率)。MS:计算值为468[(M+H)+],测量值为468[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.01-8.97(m,1H),8.67-8.59(m,1H),8.37(s,1H),8.16(d,J=8.1Hz,1H),7.74-7.61(m,1H),7.38(s,1H),7.25(d,J=8.1Hz,1H),4.22(s,2H),4.03(br s,2H),3.45-3.36(m,3H),3.29-3.24(m,1H),3.19-2.97(m,8H),2.92-2.70(m,4H),2.14-1.99(m,1H),1.90-1.78(m,1H),1.22(d,J=6.1Hz,3H)。
实例9
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例8的制备方法,使用7-(羟甲基)-3,4-二氢-1H-2,6-萘啶-2-甲酸叔丁酯代替6-(羟甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例9。MS:计算值为468[(M+H)+],测量值为468[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.06-8.98(m,1H),8.69-8.64(m,1H),8.62(s,1H),8.19(d,J=8.1Hz,1H),7.72-7.65(m,1H),7.43(s,1H),7.32(d,J=8.1Hz,1H),4.49(d,J=6.6Hz,4H),3.82-3.74(m,1H),3.67-3.48(m,10H),3.41-3.35(m,1H),3.21(t,J=6.2Hz,2H),3.13-3.06(m,1H),3.03-2.94(m,1H),2.31-2.11(m,2H),1.39(d,J=6.1Hz,3H)。
实例10
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例8的制备方法,使用3-(羟甲基)-7,8-二氢-5H-1,6-萘啶-6-甲酸叔丁酯代替6-(羟甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例10。MS:计算值为468[(M+H)+],测量值为468[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.07-8.98(m,1H),8.72-8.60(m,2H),8.19(d,J=8.1Hz,1H),7.95(d,J=1.7Hz,1H),7.72-7.62(m,1H),7.34(d,J=8.1Hz,1H),4.51(s,2H),4.35(s,2H),3.97-3.75(m,2H),3.73-3.40(m,10H),3.32-3.25(m,2H),3.19-3.00(m,2H),2.29-2.16(m,2H),1.43(d,J=6.2Hz,3H)。
实例11
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-6-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例8的制备方法,使用6-(溴甲基)-3,4-二氢-1H-异喹啉-2-甲酸叔丁酯代替6-(甲基磺酰基氧基甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(化合物8.2)(在步骤(b)中)制备标题化合物。得到实例11。MS:计算值为467[(M+H)+],测量值为467[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.05-8.95(m,1H),8.67-8.57(m,1H),8.15(d,J=8.1Hz,1H),7.72-7.60(m,1H),7.51-7.42(m,2H),7.36(d,J=7.8Hz,1H),7.24(d,J=8.1Hz,1H),4.43(s,2H),4.33(s,2H),3.61-3.48(m,3H),3.47-3.35(m,5H),3.30-3.08(m,5H),3.00-2.81(m,2H),2.74(t,J=11.2Hz,1H),2.30-2.14(m,1H),2.00-1.86(m,1H),1.23(d,J=6.1Hz,3H)。
实例12
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例8的制备方法,使用7-(羟甲基)-3,4-二氢-1H-异喹啉-2-甲酸叔丁酯代替6-(羟甲基)-3,4-二氢-1H-2,7-萘啶-2-甲酸叔丁酯(在步骤(a)中)制备标题化合物。得到实例12。MS:计算值为467[(M+H)+],测量值为467[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.04-8.96(m,1H),8.67-8.59(m,1H),8.15(d,J=8.1Hz,1H),7.67-7.58(m,1H),7.52-7.45(m,1H),7.42-7.35(m,2H),7.25(d,J=8.1Hz,1H),4.43(s,2H),4.34(s,2H),3.55(t,J=6.4Hz,3H),3.46-3.35(m,5H),3.28-3.10(m,5H),2.99-2.85(m,2H),2.74(t,J=11.2Hz,1H),2.33-2.15(m,1H),2.04-1.86(m,1H),1.23(d,J=6.1Hz,3H)。
实例13
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基嘧啶-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):5-[(4R,10aS)-8-[(5-溴嘧啶-2-基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物13.1)的制备
向5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1,90mg,209μmol)的乙腈(8mL)溶液中添加5-溴-2-(溴甲基)嘧啶(CAS:1193116-74-3,BePharm,目录:BD266661,105mg,418μmol)和DIPEA(135mg,1.04mmol)。将混合物在回流下搅拌2小时。将反应混合物浓缩,残余物通过快速色谱法纯化得到化合物13.1(32mg,31.1%产率)。MS:计算值为492,494[(M+H)+],测量值为492,494[(M+H)+]。
步骤(b):4-[2-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]嘧啶-5-基]哌嗪-1-甲酸叔丁酯(化合物13.2)的制备
向5-[(4R,10aS)-8-[(5-溴嘧啶-2-基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物13.1,30mg,60.9μmol)的甲苯(5ml)溶液中添加哌嗪-1-甲酸叔丁酯(22.7mg,122μmol)、tBuONa(11.7mg,122μmol)和RuPhos Pd G2(4.73mg,6.09μmol)。将反应混合物在100℃搅拌过夜。将混合物冷却至室温,用水(20mL)稀释,并用EA(20mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法(硅胶,20g,0%至100%的EtOAc的PE溶液)纯化得到化合物13.2(20mg,54.9%产率)。MS:计算值为598[(M+H)+],测量值为598[(M+H)+]。
步骤(c):5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基嘧啶-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(实例13)的制备
向4-[2-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]嘧啶-5-基]哌嗪-1-甲酸叔丁酯(化合物13.2,20mg,33.5μmol)的DCM(5mL)溶液中添加TFA(2mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例13(11mg,66.0%产率)。MS:计算值为498[(M+H)+],测量值为498[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.11-8.94(m,1H),8.72-8.60(m,3H),8.16(d,J=7.9Hz,1H),7.77-7.61(m,1H),7.26(d,J=8.1Hz,1H),4.48(s,2H),3.65-3.36(m,15H),3.30-3.09(m,2H),3.06-2.96(m,1H),2.95-2.85(m,1H),2.84-2.71(m,1H),2.22(br d,J=7.2Hz,1H),1.98(br d,J=7.5Hz,1H),1.27(d,J=6.1Hz,3H)。
实例14
5-[(4R,10aS)-4-甲基-8-[(2-哌嗪-1-基嘧啶-5-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):5-[(4R,10aS)-8-[(2-氯嘧啶-5-基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物14.1)的制备
向5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1,90mg,209μmol)的乙腈(8mL)溶液中添加2-氯-5-(氯甲基)嘧啶(CAS:148406-13-7,BePharm,目录:BD223762,68.1mg,418μmol)和DIEA(135mg,1.04mmol)。将混合物在回流下搅拌2小时,然后浓缩,残余物通过快速色谱法纯化得到化合物14.1(25mg,26.7%产率)。MS:计算值为448,450[(M+H)+],测量值为448,450[(M+H)+]。
步骤(b):4-[5-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]嘧啶-2-基]哌嗪-1-甲酸叔丁酯(化合物14.2)的制备
向10mL微波小瓶中添加5-[(4R,10aS)-8-[(2-氯嘧啶-5-基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物14.1,20mg,44.6μmol)、哌嗪-1-甲酸叔丁酯(16.6mg,89.3μmol)和DIEA(5.77mg,7.8μl,44.6μmol)的乙腈(2ml)溶液。给小瓶加帽并在微波中在120℃加热8h。将混合物浓缩得到化合物14.2(26.7mg,100%产率),其直接用于下一步。598[(M+H)+],测量值为598[(M+H)+]。
步骤(c):5-[(4R,10aS)-4-甲基-8-[(2-哌嗪-1-基嘧啶-5-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(实例14)的制备
向4-[5-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]嘧啶-2-基]哌嗪-1-甲酸叔丁酯(化合物14.2,20mg,33.5μmol)的DCM(6mL)溶液中添加TFA(2mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例14(15mg,90.1%产率)。MS:计算值为498[(M+H)+],测量值为498[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.05-8.97(m,1H),8.65-8.60(m,1H),8.55(s,2H),8.16(d,J=7.9Hz,1H),7.68-7.60(m,1H),7.26(d,J=7.9Hz,1H),4.21(s,2H),4.18-4.11(m,4H),3.52-3.36(m,6H),3.31-3.13(m,5H),2.99-2.85(m,2H),2.81-2.71(m,1H),2.30-2.12(m,1H),2.02-1.84(m,1H),1.26(d,J=6.1Hz,3H)。
实例15
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基吡嗪-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例14的制备方法,使用2-(溴甲基)-5-氯吡嗪(CAS:1433707-80-2,BePharm,目录:BD00735886)代替2-氯-5-(氯甲基)嘧啶(在步骤(a)中)制备标题化合物。得到实例15。MS:计算值为498[(M+H)+],测量值为498[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm9.06-8.98(m,1H),8.70-8.63(m,1H),8.45(d,J=1.3Hz,1H),8.30(d,J=1.3Hz,1H),8.18(d,J=8.1Hz,1H),7.73-7.60(m,1H),7.31(d,J=8.1Hz,1H),4.45(s,2H),4.05-3.93(m,4H),3.82-3.42(m,10H),3.41-3.36(m,4H),3.09(d,J=11.9Hz,1H),3.01-2.92(m,1H),2.31-2.09(m,2H),1.37(d,J=6.2Hz,3H)。
实例16
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例13的制备方法,使用3-溴-5-(溴甲基)吡啶(CAS:145743-85-7,BePharm,目录:BD162034)代替5-溴-2-(溴甲基)嘧啶(在步骤(a)中)制备标题化合物。得到实例16。MS:计算值为497[(M+H)+],测量值为497[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm9.02-8.96(m,1H),8.70-8.60(m,1H),8.40(d,J=2.7Hz,1H),8.22(d,J=1.5Hz,1H),8.16(d,J=7.9Hz,1H),7.70-7.60(m,2H),7.27(d,J=8.1Hz,1H),4.28(s,2H),3.63-3.56(m,4H),3.55-3.36(m,10H),3.33-3.19(m,3H),3.11-3.01(m,1H),3.00-2.90(m,1H),2.89-2.74(m,1H),2.28-2.14(m,1H),2.08-1.94(m,1H),1.27(d,J=6.2Hz,3H)。
实例17
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例13的制备方法,使用2-氯-5-(氯甲基)吡啶(CAS:70258-18-3,TCI,目录:C1628)代替5-溴-2-(溴甲基)嘧啶(在步骤(a)中)制备标题化合物。得到实例17。MS:计算值为497[(M+H)+],测量值为497[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.04-8.99(m,1H),8.73-8.61(m,1H),8.33(d,J=2.2Hz,1H),8.18(d,J=7.9Hz,1H),7.91-7.78(m,1H),7.73-7.62(m,1H),7.32(d,J=8.1Hz,1H),7.04(d,J=8.9Hz,1H),4.37(s,2H),4.00-3.89(m,4H),3.84(br d,J=16.8Hz,1H),3.71-3.47(m,8H),3.46-3.34(m,5H),3.17-3.07(m,1H),3.06-2.97(m,1H),2.36-2.14(m,2H),1.39(d,J=6.1Hz,3H)。
实例18
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例13的制备方法,使用2-氯-6-(氯甲基)吡啶(CAS:78846-88-5,BePharm,目录:BD120582)代替5-溴-2-(溴甲基)嘧啶(在步骤(a)中)制备标题化合物。得到实例18。MS:计算值为497[(M+H)+],测量值为497[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm9.06-8.93(m,1H),8.68-8.58(m,1H),8.15(d,J=7.9Hz,1H),7.78-7.68(m,1H),7.68-7.58(m,1H),7.24(d,J=8.1Hz,1H),6.98(d,J=8.6Hz,1H),6.89(d,J=7.2Hz,1H),4.42(s,2H),3.99-3.86(m,4H),3.72-3.49(m,3H),3.47-3.34(m,8H),3.19-3.11(m,1H),3.09-3.01(m,1H),3.00-2.92(m,1H),2.91-2.81(m,1H),2.77-2.64(m,1H),2.35-2.17(m,1H),2.05-1.91(m,1H),1.23(d,J=6.1Hz,3H)。
实例19
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例13的制备方法,使用5-溴-2-(氯甲基)吡啶(CAS:168823-76-5,BePharm,目录:BD223172)代替5-溴-2-(溴甲基)嘧啶(在步骤(a)中)制备标题化合物。得到实例19。MS:计算值为497[(M+H)+],测量值为497[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm9.14-8.95(m,1H),8.71-8.62(m,1H),8.48(d,J=2.8Hz,1H),8.19(d,J=7.9Hz,1H),7.75-7.59(m,2H),7.52(d,J=8.7Hz,1H),7.31(d,J=8.1Hz,1H),4.40(s,2H),3.65(br s,1H),3.61-3.36(m,16H),3.28-3.17(m,1H),3.08-2.97(m,1H),2.96-2.84(m,1H),2.21(br s,1H),2.11(br s,1H),1.35(d,J=6.1Hz,3H)。
实例20
5-[(4R,10aS)-8-[[5-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例19的制备方法,使用N-[(3R,4S)-4-氟吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1033718-91-0,PharmaBlock,目录:PB09204)代替哌嗪-1-甲酸叔丁酯(在步骤(b)中)制备标题化合物。得到实例20。MS:计算值为515[(M+H)+],测量值为515[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.04-8.92(m,1H),8.66-8.58(m,1H),8.15(d,J=7.9Hz,1H),8.10(d,J=2.8Hz,1H),7.71-7.59(m,1H),7.45(d,J=8.6Hz,1H),7.25(d,J=8.1Hz,1H),7.19-7.10(m,1H),5.64-5.43(m,1H),4.37(s,2H),4.29-4.15(m,1H),3.95(t,J=8.9Hz,1H),3.89-3.84(m,1H),3.79(d,J=2.0Hz,1H),3.61-3.35(m,8H),3.30-3.22(m,1H),3.21-3.12(m,1H),3.07-2.87(m,2H),2.83-2.70(m,1H),2.31-2.17(m,1H),2.03-1.92(m,1H),1.26(d,J=6.1Hz,3H)。
实例21
5-[(4R,10aS)-8-[[5-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例19的制备方法,使用N-[(6R)-1,4-氧氮杂环庚烷-6-基]氨基甲酸叔丁酯(PharmaBlock,目录:PB97932)代替哌嗪-1-甲酸叔丁酯(在步骤(b)中)制备标题化合物。得到实例21。MS:计算值为527[(M+H)+],测量值为527[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.06-8.91(m,1H),8.67-8.59(m,1H),8.34(d,J=2.8Hz,1H),8.15(d,J=7.9Hz,1H),7.75-7.59(m,1H),7.51-7.31(m,2H),7.25(d,J=8.1Hz,1H),4.36(s,2H),4.23-4.15(m,1H),4.12-4.05(m,1H),4.04-3.91(m,2H),3.88-3.75(m,2H),3.74-3.64(m,2H),3.63-3.54(m,2H),3.53-3.46(m,2H),3.45-3.35(m,4H),3.23-3.13(m,1H),3.12-3.04(m,1H),2.98-2.81(m,2H),2.79-2.68(m,1H),2.30-2.10(m,1H),1.99-1.89(m,1H),1.24(d,J=6.1Hz,3H)。
实例22
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例19的制备方法,使用N-[(3R,4R)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1932066-52-8,PharmaBlock,目录:PBZ4728)代替哌嗪-1-甲酸叔丁酯(在步骤(b)中)制备标题化合物。得到实例22。MS:计算值为527[(M+H)+],测量值为527[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 9.01-8.95(m,1H),8.65-8.59(m,1H),8.15(d,J=8.1Hz,1H),8.11(d,J=2.9Hz,1H),7.70-7.60(m,1H),7.44(d,J=8.6Hz,1H),7.25(d,J=8.1Hz,1H),7.19-7.11(m,1H),4.36(s,2H),4.24-4.16(m,1H),4.04-3.97(m,1H),3.95-3.86(m,1H),3.81-3.72(m,1H),3.61-3.35(m,6H),3.48(s,3H),3.30-3.22(m,1H),3.22-3.12(m,1H),3.06-2.86(m,2H),2.84-2.72(m,1H),2.33-2.12(m,1H),2.04-1.91(m,1H),1.26(d,J=6.2Hz,3H)。
实例23
5-[(4R,10aS)-8-[(3-氟-5-哌嗪-1-基-2-吡啶基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤(a):(5-溴-3-氟-2-吡啶基)甲基甲磺酸酯(化合物23.2)的制备
向(5-溴-3-氟吡啶-2-基)甲醇(CAS:1206968-92-4,BePharm,目录:BD264415,300mg,1.46mmol)和DIEA(565mg,4.37mmol)的DCM(40mL)溶液中逐滴添加甲磺酰氯(183mg,1.6mmol)。将所得混合物在室温下搅拌2小时,然后用NaHCO3水溶液猝灭,用DCM(20mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并将滤液浓缩得到化合物23.2(414mg,100%产率),其无需进一步纯化即可直接用于下一步。MS:计算值为284[(M+H)+],测量值为284[(M+H)+]。
步骤(b):5-[(4R,10aS)-8-[(5-溴-3-氟-2-吡啶基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物23.3)的制备
向5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1,320mg,743μmol)的乙腈(30mL)溶液中添加(5-溴-3-氟吡啶-2-基)甲基甲磺酸酯(化合物23.2,414mg,1.46mmol)和DIEA(480mg,3.71mmol)。将所得混合物在回流下搅拌5小时。将混合物浓缩,残余物通过快速色谱法纯化得到化合物23.3(220mg,58.1%产率)。MS:计算值为509,511[(M+H)+],测量值为509,511[(M+H)+]。
步骤(c):4-[6-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]-5-氟-3-吡啶基]哌嗪-1-甲酸叔丁酯(化合物23.4)的制备
向5-[(4R,10aS)-8-[(5-溴-3-氟-2-吡啶基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(化合物23.3,45mg,88.3μmol)的甲苯(8mL)溶液中添加哌嗪-1-甲酸叔丁酯(32.9mg,177μmol)、RuPhos Pd G2(6.86mg,8.83μmol)和tBuONa(17mg,177μmol)。将所得混合物在100℃搅拌过夜。然后将混合物冷却至室温,用水(20mL)稀释并用EA(20mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在真空中浓缩。残余物通过快速色谱法纯化得到化合物23.4(27mg,49.7%产率)。615[(M+H)+],测量值为615[(M+H)+]。
步骤(d):5-[(4R,10aS)-8-[(3-氟-5-哌嗪-1-基-2-吡啶基)甲基]-
4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈(实例23)的制备
向4-[6-[[(4R,10aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-8-基]甲基]-5-氟-3-吡啶基]哌嗪-1-甲酸叔丁酯(化合物23.4,27mg,43.9μmol)的DCM(8mL)溶液中添加TFA(4mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例23(20mg,88.6%产率)。MS:计算值为515[(M+H)+],测量值为515[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 9.09-8.94(m,1H),8.68-8.60(m,1H),8.33(d,J=1.3Hz,1H),8.16(d,J=7.9Hz,1H),7.70-7.61(m,1H),7.42-7.35(m,1H),7.26(d,J=8.1Hz,1H),4.45(s,2H),3.67-3.52(m,6H),3.52-3.36(m,9H),3.29-3.21(m,1H),3.20-3.07(m,1H),3.03-2.84(m,2H),2.82-2.66(m,1H),2.31-2.11(m,1H),2.03-1.84(m,1H),1.26(d,J=6.1Hz,3H)。
实例24
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈
类似于实例23的制备方法,使用N-[(3R,4R)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1932066-52-8,PharmaBlock,目录:PBZ4728)代替哌嗪-1-甲酸叔丁酯(在步骤(c)中)制备标题化合物。得到实例24。MS:计算值为545[(M+H)+],测量值为545[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 9.03-8.96(m,1H),8.65-8.59(m,1H),8.16(d,J=7.9Hz,1H),7.98(d,J=0.9Hz,1H),7.68-7.61(m,1H),7.25(d,J=8.1Hz,1H),7.00-6.94(m,1H),4.43(s,2H),4.22-4.14(m,1H),4.03-3.95(m,1H),3.94-3.85(m,1H),3.83-3.76(m,1H),3.66-3.36(m,6H),3.51(s,3H),3.25-3.17(m,1H),3.13-3.07(m,1H),2.99-2.84(m,2H),2.80-2.68(m,1H),2.30-2.13(m,1H),2.00-1.86(m,1H),1.24(d,J=6.1Hz,3H)。
实例25
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]吡嗪-2-基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例15的制备方法,使用4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐(中间体C3)代替5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1)(在步骤(a)中)并且使用N-[(3R,4R)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯代替哌嗪-1-甲酸叔丁酯(在步骤(b)中)制备标题化合物。得到实例25。MS:计算值为517[(M+H)+],测量值为517[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.23(d,J=1.3Hz,1H),8.12(d,J=1.3Hz,1H),8.04(d,J=2.4Hz,1H),7.47(d,J=7.9Hz,1H),6.85(d,J=2.4Hz,1H),6.59(d,J=8.1Hz,1H),4.38(s,2H),4.27-4.17(m,1H),4.04-3.91(m,3H),3.82-3.57(m,5H),3.56-3.45(m,2H),3.51(s,3H),3.10-2.88(m,3H),2.79-2.70(m,1H),2.33-2.20(m,1H),1.96(br d,J=2.2Hz,1H),1.24(d,J=6.0Hz,3H)。
实例26
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例24的制备方法,使用4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐(中间体C3)代替5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1)(在步骤(a)中)制备标题化合物。得到实例26。MS:计算值为534[(M+H)+],测量值为534[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm7.91(d,J=2.3Hz,1H),7.72(d,J=1.0Hz,1H),7.34(d,J=7.9Hz,1H),6.76-6.67(m,2H),6.45(d,J=8.1Hz,1H),3.95(s,2H),3.87-3.76(m,1H),3.70-3.63(m,1H),3.62-3.54(m,2H),3.55-3.46(m,1H),3.33(s,3H),3.19-2.86(m,5H),2.81-2.65(m,3H),2.64-2.55(m,2H),2.04-1.92(m,1H),1.77-1.67(m,1H),1.08(d,J=6.0Hz,3H)。
实例27
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例24的制备方法,使用4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;三盐酸盐(中间体C4)代替5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1)(在步骤(a)中)制备标题化合物。得到实例27。MS:计算值为552[(M+H)+],测量值为552[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm8.00(d,J=3.7Hz,1H),7.99-7.97(m,1H),7.43(d,J=8.1Hz,1H),6.97(s,1H),6.51(d,J=8.1Hz,1H),4.44(s,2H),4.20-4.13(m,1H),4.01-3.95(m,1H),3.93-3.85(m,1H),3.84-3.75(m,1H),3.67-3.42(m,6H),3.49(s,3H),2.99(br d,J=2.7Hz,1H),2.95-2.78(m,3H),2.74-2.61(m,1H),2.30-2.17(m,1H),2.02-1.91(m,1H),1.23(d,J=6.1Hz,3H)。
实例28
4-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例12的制备方法,使用4-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮;三盐酸盐(中间体C2)代替5-[(4R,10aS)-4-甲基-3,4,6,7,8,9,10,10a-八氢-1H-吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;三盐酸盐(中间体C1)(在步骤(a)中)制备标题化合物。得到实例28。MS:计算值为473[(M+H)+],测量值为373[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.66-8.57(m,1H),8.22-8.13(m,1H),7.32-7.25(m,1H),7.16-6.95(m,3H),6.09(s,1H),3.96(s,2H),3.74(s,3H),3.59(s,2H),3.23(br d,J=11.9Hz,1H),3.15-3.06(m,3H),2.95-2.48(m,12H),1.96-1.78(m,1H),1.72(br s,1H),1.13(d,J=6.1Hz,3H)。
实例29
为了确定具有式(I)或(Ia)或(Ib)的化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行了以下测试。
HEK293-Blue-hTLR-7细胞测定:
稳定的HEK293-Blue-hTLR-7细胞系购自InvivoGen(Cat.#:hkb-htlr7,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR7刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR7配体刺激HEK-Blue hTLR7细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如R848(Resiquimod))的刺激下孵育20小时,报告基因表达被TLR7拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,Ca,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)的96孔板中以170μL的体积将HEK293-Blue-hTLR7细胞以个细胞/mL的密度孵育,在上述DMEM中,在最终DMSO存在的条件下以1%的最终稀释度添加20μL供试化合物和10μL的20uM R848,在37℃的CO2培养箱中进行20小时的培养。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在下读取吸光度。TLR7活化导致下游NF-κB活化的信号传导途径已被广泛接受,因此对类似的报告基因测定法进行了修改以评估TLR7拮抗剂。
HEK293-Blue-hTLR-8细胞测定:
稳定的HEK293-Blue-hTLR-8细胞系购自InvivoGen(Cat.#:hkb-htlr8,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR8刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR8配体刺激HEK-Blue hTLR8细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如R848)的刺激下孵育20小时,报告基因表达被TLR8拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,Ca,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)的96孔板中以170μL的体积将HEK293-Blue-hTLR8细胞以个细胞/mL的密度孵育,在上述DMEM中,在最终DMSO存在的条件下以1%的最终稀释度添加20μL供试化合物和10μL的60uM R848,在37℃的CO2培养箱中进行20小时的培养。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在下读取吸光度。TLR8活化导致下游NF-κB活化的信号传导途径已被广泛接受,因此对类似的报告基因测定法进行了修改以评估TLR8拮抗剂。
HEK293-Blue-hTLR-9细胞测定:
稳定的HEK293-Blue-hTLR-9细胞系购自InvivoGen(Cat.#:hkb-htlr9,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR9刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR9配体刺激HEK-Blue hTLR9细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如ODN2006(Cat.#:tlrl-2006-1,Invivogen,San Diego,California,USA))的刺激下孵育20小时,报告基因表达被TLR9拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,California,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
HEK293-Blue-hTLR9细胞以细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20uMODN2006的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在处读取吸光度。TLR9活化导致下游NF-κB活化的信号传导途径已被广泛接受,因此对类似的报告基因测定法进行了修改以评估TLR9拮抗剂。
具有式(I)的化合物具有TLR7和/或TLR8抑制活性(IC50值)<0.1μM。此外,大多数化合物还具有<0.3μM的TLR9抑制活性。表1显示了本发明化合物的活性数据。
表1:本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
实例30
人微粒体稳定性测定
将人肝微粒体(目录号:452117,美国康宁)在37℃下于100mM磷酸钾缓冲液(pH7.4)中与受试化合物预孵育10分钟。通过添加NADPH再生系统来引发反应。最终的孵育混合物在100mM磷酸钾缓冲液(pH 7.4)中含1μM供试化合物、0.5mg/mL肝微粒体蛋白、1mMMgCl2、1mM NADP、1单位/mL异柠檬酸脱氢酶和6mM异柠檬酸。在37℃下孵育0、3、6、9、15和30分钟后,将300μL冷ACN(包括内标)添加到100μL孵育混合物中以终止反应。沉淀并离心后,取出100uL上清液并加入300uL水。通过LC-MS/MS测定样品中残留的化合物的量。还制备并分析了零和30分钟无NADPH再生系统的对照。结果分类为:低(<7.0mL/min/kg),中(7.0-16.2mL/min/kg)和高(16.2-23.2mL/min/kg)。测试结果汇总于表2中。
表2:人类微粒体稳定性结果
实例31
hERG通道抑制测定
hERG通道抑制测定是一种高度灵敏的测量,可鉴定表现出与体内心脏毒性相关的hERG抑制作用的化合物。将hERG K+通道克隆到人体内,并在CHO(中国仓鼠卵巢)细胞系中稳定表达。CHOhERG细胞用于膜片钳(电压钳,全细胞)实验。电压模式刺激细胞以活化hERG通道并传导IKhERG电流(hERG通道的快速延迟向外整流钾电流)。细胞稳定几分钟后,以0.1Hz(6bpm)的刺激频率记录IKhERG的振幅和动力学。此后,将测试化合物以增加的浓度加入制剂中。对于每种浓度,都试图达到稳态效果,通常在3-10分钟内达到此效果,此时施加下一个最高浓度。记录每种药物浓度下IKhERG的振幅和动力学,并将其与对照值进行比较(以100%计)(参考文献:Redfern WS,Carlsson L,Davis AS,Lynch WG,MacKenzie I,PalethorpeS,Siegl PK,Strang I,Sullivan AT,Wallis R,Camm AJ,Hammond TG.2003;Relationships between preclinical cardiac electrophysiology,clinical QTinterval prolongation and torsade de pointes for a broad range of drugs:evidence for a provisional safety margin in drugdevelopment.Cardiovasc.Res.58:32-45,Sanguinetti MC,Tristani-Firouzi M.2006;hERG potassium channels and cardiac arrhythmia.Nature 440:463-469,Webster R,Leishman D,Walker D.2002;Towards a drug concentration effect relationship forQT prolongation and torsades de pointes.Curr.Opin.Drug Discov.Devel.5:116-26).hERG的结果在表3中给出。
表3:hERG结果
Claims (5)
1.一种式(I)化合物,
或一种式(Ia)化合物,
其中
R1为其中R4为氰基;R5为H;
R2为C1-6烷基;
R3为5,6,7,8-四氢-2,6-萘啶基;5,6,7,8-四氢-2,7-萘啶基;被氨基(C1-6烷氧基)吡咯烷基取代一次的吡啶基;或被哌嗪基取代的嘧啶基;
n为0或1;
或其药用盐。
2.根据权利要求1所述的化合物,其中
R1为其中R4为氰基;R5为H;
R2为甲基;
R3为5,6,7,8-四氢-2,7-萘啶-4-基;5,6,7,8-四氢-2,6-萘啶-3-基;哌嗪-1-基嘧啶基;或3-氨基-4-甲氧基-吡咯烷-1-基吡啶基;
n为0或1;
或其药用盐。
3.一种化合物,其选自:
5-[(4R,10aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-4-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,7-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-2-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,7-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-2,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(5,6,7,8-四氢-1,6-萘啶-3-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-6-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基嘧啶-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(2-哌嗪-1-基嘧啶-5-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基吡嗪-2-基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(6-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)甲基]-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[(3-氟-5-哌嗪-1-基-2-吡啶基)甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
5-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]喹啉-8-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]吡嗪-2-基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(4R,10aS)-8-[[5-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-氟-2-吡啶基]甲基]-4-甲基-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;和
4-[(4R,10aS)-4-甲基-8-(1,2,3,4-四氢异喹啉-7-基甲基)-1,3,4,6,7,9,10,10a-八氢吡嗪并[1,2-d][1,4]二氮杂-2-基]-1-甲基-1,8-萘啶-2-酮;
或其药用盐。
4.根据权利要求1至3中任一项所述的化合物用于制备药物的用途,所述药物用于治疗或预防由TLR7/8/9介导的系统性红斑狼疮或狼疮肾炎。
5.根据权利要求1至3中任一项所述的化合物用于制备TLR7和TLR8和TLR9拮抗剂的药物的用途。
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