CN114761406B - 用于治疗自身免疫性疾病的氢吡啶并[1,2-a]吡嗪化合物 - Google Patents
用于治疗自身免疫性疾病的氢吡啶并[1,2-a]吡嗪化合物 Download PDFInfo
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- CN114761406B CN114761406B CN202080083352.1A CN202080083352A CN114761406B CN 114761406 B CN114761406 B CN 114761406B CN 202080083352 A CN202080083352 A CN 202080083352A CN 114761406 B CN114761406 B CN 114761406B
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- Prior art keywords
- methyl
- pyrazin
- carbonitrile
- quinoline
- octahydropyrido
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- 238000011282 treatment Methods 0.000 title abstract description 10
- 208000023275 Autoimmune disease Diseases 0.000 title description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明涉及式(I)化合物及其药用盐。所述化合物充当toll样受体TLR7、TLR8和/或TLR9的拮抗剂,并因此可用于治疗全身性红斑狼疮(SLE)和狼疮肾炎。
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,并伴有非预期的毒性和副作用。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性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的公认诊断标记物,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激活。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的激活特别有助于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激活TLR9还会导致诱导I型干扰素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激活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
本发明涉及具有式(I)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((氨基(C1-6烷氧基)吡咯烷基)苯基)氮杂环丁烷基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基氧基、(氨基-1,4-氧氮杂环庚烷基)吡啶基、(氨基氮杂环丁烷基)吡啶基、(吗啉基C1-6烷基)苯基、(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、(哌嗪基苯基)C1-6烷基氨基、氨基卤代吡咯烷基、吗啉基苯基、吗啉基苯基氨基、哌嗪基苯基、哌嗪基吡啶基、哌嗪基吡啶基氧基、哌嗪基嘧啶基氧基或吡啶基哌嗪基;
或其药用盐。
本发明的另一目的涉及式(I)的新型化合物。其生产、基于根据本发明化合物的药物及其制备,以及式(I)化合物作为TLR7和/或TLR8和/或TLR9拮抗剂以及用于治疗或预防全身性红斑狼疮或狼疮肾炎的用途。式(I)化合物表现出优异的TLR7和TLR8和TLR9拮抗活性。另外,式(I)化合物还表现出良好的细胞毒性、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“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;3,4-二氢-1H-2,6-萘啶基;7,8-二氢-5H-1,6-萘啶基;4,5,6,7-四氢吡唑并[3,4-c]吡啶基;6,7-二氢-5H-吡咯并[3,4-b]吡啶基;2,9-二氮杂螺[5.5]十一烷基;3,8-二氮杂双环[3.2.1]辛烷基;7,8-二氢-5H-吡啶并[3,4-b]吡嗪基;5,6,7,8-四氢吡啶并[4,3-d]嘧啶基和3,4-二氢-1H-异喹啉基。单环或双环杂环基可进一步被氨基、羟基、卤素、C1-6烷基、C1-6烷氧基或杂环基取代。
术语“杂环基杂芳基”表示杂环基-杂芳基-。
术语“杂环基C1-6烷基芳基”表示杂环基-C1-6烷基-芳基-。
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((氨基(C1-6烷氧基)吡咯烷基)苯基)氮杂环丁烷基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基氧基、(氨基-1,4-氧氮杂环庚烷基)吡啶基、(氨基氮杂环丁烷基)吡啶基、(吗啉基C1-6烷基)苯基、(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、(哌嗪基苯基)C1-6烷基氨基、氨基卤代吡咯烷基、吗啉基苯基、吗啉基苯基氨基、哌嗪基苯基、哌嗪基吡啶基、哌嗪基吡啶基氧基、哌嗪基嘧啶基氧基或吡啶基哌嗪基;
或其药用盐。
本发明的又一实施例为(ii)根据(i)的式(I)化合物或其药用盐,其中
R1为其中R4为氰基;R5为H或氘。
本发明的又一实施例为(iii)根据(i)或(ii)的式(I)化合物或其药用盐,其中R3为((3-氨基-4-甲氧基-吡咯烷-1-基)苯基)氮杂环丁烷-1-基;(3-氨基-4-甲氧基-吡咯烷-1-基)-3-吡啶基;(3-氨基-4-甲氧基-吡咯烷-1-基)-3-吡啶基氧基;(3-氨基氮杂环丁烷-1-基)-3-吡啶基;(4-吗啉-2-基甲基)苯基;(4-吗啉-2-基甲基)苯基氨基;(4-哌嗪-1-基苯基)氮杂环丁烷-1-基;(4-哌嗪-1-基苯基)甲基氨基;(6-氨基-1,4-氧氮杂环庚烷-4-基)-3-吡啶基;2-哌嗪-1-基嘧啶-5-基氧基;3-氨基-4-氟-吡咯烷-1-基;4-吗啉-2-基苯基;4-吗啉-2-基苯基氨基;4-哌嗪-1-基苯基;4-吡啶基哌嗪-1-基;5-哌嗪-1-基-2-吡啶基氧基;5-哌嗪-1-基-3-吡啶基氧基;6-哌嗪-1-基-3-吡啶基或6-哌嗪-1-基-3-吡啶基氧基。
本发明的又一实施例为(iv)根据(i)至(iii)中任一项的式(I)化合物或其药用盐,其中R2为甲基。
本发明的又一实施例为(v)根据(i)之(iv)中任一项的式(I)化合物,其中R3为(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、吗啉基苯基、吗啉基苯基氨基、哌嗪基吡啶基氧基或哌嗪基嘧啶基氧基。
本发明的又一实施例为(vi)根据(i)至(v)中任一项的式(I)化合物或其药用盐,其中R3为(4-吗啉-2-基甲基)苯基氨基、(4-哌嗪-1-基苯基)氮杂环丁烷-1-基、4-吗啉-2-基苯基、4-吗啉-2-基苯基氨基、6-哌嗪-1-基-3-吡啶基氧基或2-哌嗪-1-基嘧啶-5-基氧基。
本发明的又一实施例为(vii)根据(i)至(vi)中任一项所述的式(I)化合物或其药用盐,其中
R1为其中R4为氰基;R5为H或氘;
R2为C1-6烷基;
R3为(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、吗啉基苯基、吗啉基苯基氨基、哌嗪基吡啶基氧基或哌嗪基嘧啶基氧基;
或其药用盐。
本发明的又一实施例为(viii)根据(i)至(vii)中任一项所述的式(I)化合物或其药用盐,其中
R1为其中R4为氰基;R5为H或氘;
R2为甲基;
R3为(4-吗啉-2-基甲基)苯基氨基、(4-哌嗪-1-基苯基)氮杂环丁烷-1-基、4-吗啉-2-基苯基、4-吗啉-2-基苯基氨基、6-哌嗪-1-基-3-吡啶基氧基或2-哌嗪-1-基嘧啶-5-基氧基;
或其药用盐。
本发明的另一实施例为式(I)化合物,其选自以下化合物:
5-[(4R,8R,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R)-4-甲基-8-(4-哌嗪-1-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3S,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-(3-氨基氮杂环丁烷-1-基)-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[3-(4-哌嗪-1-基苯基)氮杂环丁烷-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3S,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aR)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)氧基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(6S)-6-氨基-1,4-氧氮杂环庚烷-4-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-(4-吗啉-2-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2R)-吗啉-2-基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[4-(吗啉-2-基甲基)苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-8-[[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]氧基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2S)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]]-2-氘代-喹啉-8-甲腈;和
5-[(4R,8R,9aS)-4-甲基-8-[4-(4-吡啶基)哌嗪-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
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)和(VI)和(X)和(XV)和(XIX)化合物的一般合成路线如下所示:
方案1
其中X为卤素;R7为H;R8为杂环基杂芳基、杂环基C1-6烷基杂芳基、杂环基杂芳基C1-6烷基、杂环基C1-6烷基芳基、杂环基芳基C1-6烷基;或者R7和R8与它们所连接的氮一起形成杂环基。
上述化合物的合成起始于双环胺,即式(III)化合物与卤化物(II)通过在催化剂诸如Ruphos Pd-G2和碱诸如Cs2CO3存在下的Buchwald-Hartwig胺化反应进行反应,该反应提供式(IV)化合物(参考文献:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in Current Chemistry,2002,219,131-209;这些文献以引用方式并入本文)。替代性地,式IV化合物也可通过在碱诸如DIPEA、NaHCO3和K2CO3存在下卤化物(II)与式(III)化合物之间的亲核取代来获得。式(VI)和(VIII)化合物可以由式(IV)化合物在还原剂诸如NaCNBH3的存在分别与式(V)和(VII)化合物的胺进行Borsch还原胺化来获得。式(VIII)化合物与胺(V)的偶合可以在Buchwald-Hartwig胺化条件(参考文献:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in CurrentChemistry,2002,219,131-209;以及其中引用的参考文献)下使用催化剂诸如tBuXPhos PdG3、RuPhos Pd G2、BrettPhos Pd G3、XPhos Pd G3Pd2(dba)3/BINAP和Pd2(dba)3/XantPhos以及碱诸如Cs2CO3或t-BuONa实现,以提供式(X)化合物。
方案2
其中X为卤素;R7为H;R8为杂环基杂芳基、杂环基C1-6烷基杂芳基、杂环基杂芳基C1-6烷基、杂环基C1-6烷基芳基、杂环基芳基C1-6烷基;或者R7和R8与它们所连接的氮一起形成杂环基;W为杂芳基或芳基。
式(IV)化合物可以与甲苯磺酰肼(XI)反应以得到式(XII)化合物。式(XIV)化合物可以通过式(XII)化合物与式(XIII)有机硼酸在碱诸如Cs2CO3、DIPEA、NaHCO3和K2CO3存在下的还原偶合来获得(参考文献:Chem.Eur.J.2016,22,6253–6257;J.Org.Chem.2014,79,328-338)。胺(V)与式(XIV)化合物的偶合可以在Buchwald-Hartwig胺化条件(参考文献:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in CurrentChemistry,2002,219,131-209;以及其中引用的参考文献)下使用催化剂诸如tBuXPhos PdG3、RuPhos Pd G2、BrettPhos Pd G3、XPhos Pd G3Pd2(dba)3/BINAP和Pd2(dba)3/XantPhos以及碱诸如Cs2CO3或t-BuONa实现,以提供式(XV)化合物
制备式XIX化合物的合成路线如方案3所示。
方案3
其中X为卤素;R7为H;R8为杂环基杂芳基、杂环基C1-6烷基杂芳基、杂环基杂芳基C1-6烷基、杂环基C1-6烷基芳基、杂环基芳基C1-6烷基;或者R7和R8与它们所连接的氮一起形成杂环基;W为杂芳基或芳基。
式(IV)化合物在还原试剂诸如NaBH4存在下的还原反应得到式(XVI)化合物,其可在偶氮二甲酸二乙酯(DEAD)或偶氮二甲酸二异丙酯(DIAD)和Ph3P存在下通过Mitsunobu反应转化为式(XVIII)化合物。胺(V)与式(XVIII)化合物的偶合可以在Buchwald-Hartwig胺化条件(参考文献:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics in Current Chemistry,2002,219,131-209;以及其中引用的参考文献)下使用催化剂诸如tBuXPhos Pd G3、RuPhos Pd G2、BrettPhos Pd G3、XPhos Pd G3Pd2(dba)3/BINAP和Pd2(dba)3/XantPhos以及碱诸如Cs2CO3或t-BuONa实现,以提供式(XIX)化合物。
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。
本发明还涉及用于制备式(I)化合物的方法,该方法包括以下步骤中的任一者:
a)式(VIII)化合物与胺(V)/> 之间的Buchwald-Hartwig胺化反应;/>
b)式(IV)化合物与胺(V)/>的还原性胺化;
c)式(XIV)化合物与胺(V)/>之间的Buchwald-Hartwig胺化反应;
d)式(XVIII)化合物与胺(V)/>之间的Buchwald-Hartwig胺化反应;
其中X为卤素;R7为H;R8为杂环基杂芳基、杂环基C1-6烷基杂芳基、杂环基杂芳基C1-6烷基、杂环基C1-6烷基芳基、杂环基芳基C1-6烷基;或者R7和R8与它们所连接的氮一起形成杂环基;W为杂芳基或芳基。
当根据上述方法制造时,式(I)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
DIAD 偶氮二甲酸二异丙酯
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
IC50: 半抑制浓度
IPA: 异丙醇
MS: 质谱
PPh3: 三苯膦
Pd(PPh3)4 肆(三苯基膦)钯
Pd/C 碳载钯
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
SFC: 超临界流体色谱
TEA: 三甲胺
TFA: 三氟乙酸
THF: 四氢呋喃
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 Alliance2020-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1:制备8-溴-5-氟喹啉(化合物A1.2)
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,10.5mmol)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。粗制物通过快速色谱纯化(硅胶,40g,0%至30%的EtOAc/PE),得到化合物A1.2(2.0g,84%收率)。MS:计算值226和228(MH+),测量值226和228(MH+)。
步骤2:5-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)在DMF(30mL)中的溶液中加入双氰锌(5.0g,43.4mmol)和RuPhos Pd G2(CAS:1375325-68-0,Sigma-Aldrich,目录号753246,842mg,1.1mmol)。将反应混合物在100℃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、过滤并真空浓缩。残余物通过快速色谱纯化(硅胶,40g,0%至70%EtOAc的PE溶液),得到中间体A1(3.0g,80%收率)。MS:计算值173(MH+),测量值173(MH+)。1H NMR(400MHz,甲醇-d4)δ9.11(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
2-氘代-5-氟-喹啉-8-甲腈
根据以下方案合成标题化合物:
步骤1:制备N-(2-溴-5-氟-苯基)-3,3-二甲氧基-丙酰胺(化合物A2.2)
在0℃,向2-溴-5-氟苯胺(化合物A2.1,50g,263mmol)和3,3-二甲氧基丙酸甲酯(45mL,316mmol)在THF(150mL)中的溶液中逐滴加入NaHMDS在THF(394mL,394mmol)中的溶液。将混合物在该温度搅拌10分钟,然后将其加热至15℃并搅拌18小时。用饱和NH4Cl水溶液猝灭反应,并浓缩至约300mL。用水稀释溶液,并用EtOAc萃取。有机层用Na2SO4干燥并浓缩,得到化合物A2.2(100g,90%收率)。MS:计算值306(MH+),测量值306(MH+)。
步骤2:8-溴-5-氟-1H-喹啉-2-酮(化合物A2.3)的制备
在0℃,将N-(2-溴-5-氟-苯基)-3,3-二甲氧基-丙酰胺(化合物A2.2,100g,238mmol)在DCM(500mL)中的溶液加入到浓硫酸(300mL)中。将混合物在15℃搅拌2小时。将混合物缓慢倒入2000mL冰水中,出现黄色沉淀。过滤混合物,并将湿饼用500mL水,200mL异丙醇和300mL PE洗涤。将固体在真空下干燥,得到化合物A2.3(50g,86.5%收率)。MS:计算值242(MH+),测量值242(MH+)。
步骤3:制备5-氟-2-氧代-1H-喹啉-8-甲腈(化合物A2.4)
将8-溴-5-氟-1H-喹啉-2-酮(化合物A2.3,50g,206mmol)、氰化锌(4820mg,412mmol)、Pd(PPh3)4(2428mg,21mmol)在DMF中的溶液在120℃搅拌5小时。将反应混合物用水稀释并用DCM萃取。将有机层干燥并浓缩以得到粗产物,将其通过快速柱纯化,得到化合物A2.4(29g,74.5%收率)。MS:计算值189(MH+),测量值189(MH+)。
步骤4:制备(8-氰基-5-氟-2-喹啉基)三氟甲磺酸盐(化合物A2.5)
在0℃,向5-氟-2-氧代-1H-喹啉-8-甲腈(化合物A2.4,17g,90mmol)和2,6-二甲基吡啶(39g,361mmol)在DCM中的溶液中逐滴加入三氟甲磺酸酐(51g,181mmol)。将混合物在0℃搅拌1小时,然后将反应物用水稀释,并且用DCM萃取。将合并的有机层干燥并浓缩。残余物通过快速柱纯化以得到化合物A2.5(23.0g,80%收率)。MS:计算321(MH+),测量321(MH+)。
步骤5:2-氘代-5-氟-喹啉-8-甲腈(中间体A2)的制备
向(8-氰基-5-氟-2-喹啉基)三氟甲磺酸酯(化合物A2.5,23g,72mmol)和氧化氘(100mL)的THF(230mL)溶液,加入碳酸钾(20g,144mmol)和Pd/C(6g)。将混合物在氘气氛(气球)下在40℃搅拌5小时。将混合物过滤,并将滤液浓缩并通过快速柱纯化,得到中间体A2(11g,87.8%收率),其不经进一步纯化即直接用于下一步。MS:计算174(MH+),测量174(MH+)。
中间体B
(4R)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮2,2,2-三氟乙酸盐
根据以下方案合成标题化合物:
步骤1: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
向N-[(1R)-2-氨基-1-甲基-乙基]氨基甲酸叔丁酯(化合物B1,135.0g,774.8mmol)在DCE(3.0L)中的溶液中加入苯甲醛(71.0mL,695.8mmol)。将所得混合物在室温搅拌2小时。将三乙酰氧基硼氢化钠(405.0g,1.9mol)加入到上述溶液中。在室温搅拌过夜后,将反应混合物用饱和Na2CO3水溶液中和至pH约为8,用水(1.0L)稀释,并用DCM(1.0L)萃取两次。合并的有机层用盐水(500mL)洗涤,经Na2SO4干燥并真空浓缩。残余物通过硅胶色谱纯化,得到化合物B2(163.6g,80%收率)。MS:计算265(MH+),测量265(MH+)。
步骤2:(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B2,185.0g,699.8mmol)在丙酮(2.0L)中的溶液中加入4-溴巴豆酸甲酯(135.0g,754.2mmol)和碳酸钾(290.0g,2.1mol)。在室温搅拌过夜后,将混合物通过硅藻土过滤并浓缩滤液。残余物通过硅胶色谱纯化,得到化合物B3(146.0g,57.6%收率)。MS:计算363(MH+),测量363(MH+)。
步骤3:2-[(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B3,132.0g,364.2mmol)和HCl/甲醇(1N,1.0L)加热回流2小时。将反应混合物冷却至室温并真空浓缩。残余物用饱和K2CO3水溶液中和至pH约10,用水(1.0L)稀释,并用DCM(1.0L)萃取三次。合并的有机层用盐水(1000mL)洗涤两次,用Na2SO4干燥并真空浓缩。残余物通过硅胶色谱纯化,得到化合物B4(90.0g,94.0%收率)。MS:计算263(MH+),测量263(MH+)。
步骤4:3-((6R)-4-苄基-2-(2-甲氧基-2-氧代乙基)-6-甲基哌嗪-1-基)丙酸甲酯(化合物B5)的制备
将2-((6R)-4-苄基-6-甲基哌嗪-2-基)乙酸甲酯(化合物B4,50g,191mmol)和丙烯酸甲酯(49.2g,51.5mL,572mmol)的溶液加热至100℃,持续12小时。然后将反应混合物浓缩并通过硅胶色谱(DCM/MeOH,1%至20%)纯化,得到化合物B5(12.7g,19.1%收率),为黄色油状物。MS:计算349(MH+),测量349(MH+)。
步骤5:(4R)-2-苄基-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮(化合物B6)的制备
向搅拌并冷却(冰水,0℃)的叔丁醇钾(8.18g,72.9mmol)在甲苯(40mL)中的悬浮液中缓慢加入3-((6R)-4-苄基-2-(2-甲氧基-2-氧代乙基)-6-甲基哌嗪-1-基)丙酸甲酯(化合物B5,12.7g,36.4mmol)在甲苯(5mL)中的溶液。将混合物在0℃搅拌2小时。然后将混合物用6N HCl(5mL)萃取三次。将水层在100℃搅拌3小时,然后将其重新冷却至0℃,用K2CO3中和并用EA(100mL)萃取三次。将有机层合并,用饱和NaCl(20mL)洗涤两次,经Na2SO4干燥并真空浓缩。粗制物通过快速色谱纯化(硅胶,80g,20%至80%的EtOAc/PE),得到化合物B6(6.6g,70.4%收率),为浅黄色油状物。MS:计算259(MH+),测量259(MH+)。
步骤6:(4R)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-甲酸叔丁酯(化合物B7)的制备
将(4R)-2-苄基-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮(化合物B6,6.53g,25.3mmol)、boc-酸酐(11g,11.7mL,50.5mmol)和Pd-C(700mg,6.58mmol)在MeOH(30mL)中的溶液在室温在H2气氛下搅拌3小时。然后过滤并浓缩滤液。所得残余物通过硅胶色谱(DCM/MeOH,2%至10%)纯化,得到化合物B7(6.6g,97%收率),为白色固体。MS:计算269(MH+),测量269(MH+)。
步骤7:(4R)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮2,2,2-三氟乙酸盐(中间体B)的制备
在0℃向(4R)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-甲酸叔丁酯(化合物B7,6.6g,24.6mmol)在DCM(20mL)中的溶液中加入2,2,2-三氟乙酸(2.8g,20mL)。将反应混合物在室温搅拌12小时,然后浓缩,得到中间体B(6.8g,98%收率),为浅黄色油状物。MS:计算169(MH+),测量169(MH+)。
中间体C1
5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1)
根据以下方案合成标题化合物:
步骤1:(4R,8aS)-2-苄基-4-甲基-3,4,6,7,8,8a-六氢-1H-吡咯并[1,2-a]吡嗪-7-醇(中间体C1)的制备
向DIPEA(9.34g,12.6mL,72.3mmol)在DMSO(10mL)中的溶液中加入5-氟喹啉-8-甲腈(中间体A1,4.15g,24.1mmol和(4R)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮2,2,2-三氟乙酸盐(中间体B,6.8g,24.1mmol)。在120℃搅拌3小时后,将混合物冷却至室温,用水(10mL)猝灭,用EA萃取两次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过快速色谱(硅胶,20%至80%的PE/EtOAc)纯化,得到5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1,2g,25.9%收率),为黄色固体,以及5-((4R,9aR)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C2,400mg,5.18%收率),为黄色固体。中间体C1和C2的立体化学通过NOESY确认。
中间体C1:MS:计算321(MH+),测量321(MH+)。1H NMR(DMSO-d6,400MHz)δ9.04(dd,J=1.6,4.2Hz,1H),8.53(dd J=1.7,8.6Hz,1H,),8.24(d,J=8.1Hz,1H),7.67(dd,J=4.3,8.6Hz,1H),7.21(d,J=8.1Hz,1H),3.5-3.6(m,1H),3.3-3.4(m,2H),2.7-2.9(m,3H),2.5-2.7(m,2H),2.1-2.4(m,4H),1.1-1.2(m,3H)。
中间体C2:MS:计算321(MH+),测量321(MH+)。1H NMR(DMSO-d6,400MHz)δ9.05(dd,J=1.7,4.2Hz,1H),8.60(dd,J=1.6,8.6Hz,1H),8.25(d,J=8.1Hz,1H),7.70(dd,J=4.2,8.6Hz,1H),7.23(d,J=8.1Hz,1H),3.4-3.5(m,1H),3.28(br dd,J=2.7,11.5Hz,2H),3.20(br dd,J=5.5,11.6Hz,1H),3.06(br d,J=6.5Hz,1H),2.7-2.9(m,2H),2.6-2.7(m,1H),2.65(dt,J=6.1,13.5Hz,2H),2.23(td,J=2.6,14.2Hz,1H),2.13(br d,1H,J=13.7Hz),1.1-1.2(m,4H)。
中间体D1
2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)
根据以下方案合成标题化合物:
步骤1:2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)的制备
向DIPEA(9.34g,12.6mL,72.3mmol)在DMSO(10mL)中的溶液中加入2-氘代-5-氟喹啉-8-甲腈(中间体A2,300mg,1.73mmol和(4R)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-酮2,2,2-三氟乙酸盐(中间体B,537mg,1.90mmol)。在120℃搅拌3小时后,将混合物冷却至室温,用水(10mL)猝灭,用EA萃取两次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过快速色谱(硅胶,20%至80%的PE/EtOAc)纯化,得到2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1,500mg),为黄色固体。MS:计算322(MH+),测量322(MH+)。
实例1和17
5-[(4R,8R,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例1)
5-[(4R,8S,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例17)
根据以下方案制备标题化合物:
步骤1:4-(4-((((4R,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氨基)甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1b)
将5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1,32mg,99.9μmol)、4-(4-(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a,CAS:852180-47-3,供应商:Accela ChemBio Inc,29mg,99.9μmol)在MeOH(4mL)中的溶液在室温搅拌1小时。然后将反应混合物冷却至0℃并加入氰基三氢硼酸钠(12mg,200μmol)。将反应混合物在室温搅拌12小时。将混合物用水(10mL)猝灭,用EA萃取两次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩,得到粗制4-(4-((((4R,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氨基)甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1b,50mg),其不经纯化即用于下一步。MS:计算596(MH+),测量596(MH+)。
步骤2:5-[(4R,8R,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例1)
5-[(4R,8S,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例17)
在0℃,向4-(4-((((4R,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氨基)甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1b,50mg,83.9μmol)在DCM(4mL)中的溶液中加入TFA(0.5mL)。将反应混合物在室温搅拌2小时。然后将混合物浓缩成粗产物,将其通过制备型HPLC纯化,得到实例1(3mg),为浅黄色固体,以及实例17(4mg),为浅黄色固体。
实例1:立体化学由NOESY确认。MS计算496(MH+),测量496(MH+)。1H NMR(400MHz,甲醇-d4)δ8.99(dd,J=1.7,4.2Hz,1H),8.62(dd,J=1.7,8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.65(dd,J=4.2,8.6Hz,1H),7.26(dd,J=8.4,11.9Hz,3H),6.98(d,J=8.7Hz,2H),3.78(s,2H),3.46-3.37(m,2H),3.19-3.11(m,4H),3.03-2.97(m,4H),2.89-2.51(m,6H),2.15-1.92(m,3H),1.58-1.45(m,1H),1.33-1.23(m,1H),1.19(d,J=6.2Hz,3H)。
实例17:立体化学由NOESY确认。MS计算496(MH+),测量496(MH+)。1H NMR(400MHz,甲醇-d4)δ8.99(dd,J=1.7,4.2Hz,1H),8.62(dd,J=1.7,8.6Hz,1H),8.15(d,J=8.1Hz,1H),7.65(dd,J=4.2,8.6Hz,1H),7.29(d,J=8.6Hz,2H),7.22(d,J=8.1Hz,1H),6.97(d,J=8.7Hz,2H),3.81-3.70(m,2H),3.44-3.38(m,1H),3.29-3.23(m,1H),3.18-3.09(m,5H),3.04-2.94(m,6H),2.89-2.71(m,3H),2.50-2.41(m,1H),1.96-1.69(m,3H),1.59-1.50(m,1H),1.19(d,J=5.9Hz,3H)。
实例2
5-[(4R,8R)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
根据以下方案制备标题化合物:
步骤1:N'-((4R,E)-2-(8-氰基喹啉-5-基)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-亚基)-4-甲基苯磺酰肼(化合物2c)
向5-((4R)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1,387mg,1.21mmol)在乙醇(8mL)中的溶液中加入4-甲基苯磺酰肼(化合物2b,225mg,1.21mmol)。将反应混合物在25℃搅拌3小时。LCMS显示起始材料耗尽,将反应混合物浓缩,得到粗制N'-((4R,E)-2-(8-氰基喹啉-5-基)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-亚基)-4-甲基苯磺酰肼(化合物2c,400mg,48.8%收率),其可不经纯化即用于下一步,为黄色固体。MS计算值489(MH+);测量值489(MH+)。
步骤2:5-((4R)-8-(6-溴吡啶-3-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物2e)
向N'-((4R,E)-2-(8-氰基喹啉-5-基)-4-甲基八氢-8H-吡啶并[1,2-a]吡嗪-8-亚基)-4-甲基苯磺酰肼(化合物2c,300mg,614μmol)在1,4-二氧六环(2mL)中的溶液中加入(6-溴吡啶-3-基)硼酸(化合物2d,198mg,982μmol)和Cs2CO3(320mg,982μmol)。在120℃在rN2气氛下搅拌16小时后,将混合物浓缩,得到粗产物,将其通过硅胶柱(PE/EA=3/1)纯化,得到5-((4R)-8-(6-溴吡啶-3-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物2e,50mg,17.6%收率),为黄色油状物。MS计算463(MH+),测量463(MH+)。
步骤3:4-(5-((4R)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(化合物2g)
向微波管中加入5-((4R)-8-(6-溴吡啶-3-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物2e,50mg,108μmol)、哌嗪-1-甲酸叔丁酯(化合物2f,26.2mg,141μmol)、叔丁醇钠(162μl,324μmol)和1,4-二氧六环(5mL),用N2将悬浮液鼓泡5分钟并加入tBuXPhos PD G3(8.59mg,10.8μmol)。在100℃搅拌12小时后,将混合物冷却至室温,用饱和NaHCO3(5mL)溶液猝灭,并用EtOAc(10mL)萃取三次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过快速色谱(硅胶,0%至15%DCM的MeOH溶液)纯化,得到4-(5-((4R)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(化合物2g,30mg,52.8μmol),为橙色固体。MS:计算值568(MH+),测量值568(MH+)。
步骤4:5-[(4R,8R)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例2)
在0℃,向4-(5-((4R)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(化合物2g,30mg,52.8μmol)在DCM(4mL)中的溶液中加入TFA(0.5mL)。然后将混合物浓缩为粗产物,将其通过制备型HPLC纯化,得到实例2(2mg),为浅黄色固体。MS计算值468(MH+),测量值468(MH+)。1H NMR(400MHz,甲醇-d4)δ8.90(dd,J=1.7,4.3Hz,1H),8.56(dd,J=1.6,8.6Hz,1H),8.06(d,J=7.9Hz,1H),7.96(d,J=2.2Hz,1H),7.56(dd,J=4.3,8.7Hz,1H),7.47(dd,J=2.5,8.7Hz,1H),7.16(d,J=8.1Hz,1H),6.76(d,J=8.7Hz,1H),3.50-3.43(m,4H),3.37-3.29(m,2H),3.00-2.93(m,4H),2.82-2.74(m,2H),2.70-2.64(m,2H),2.18-2.08(m,1H),1.91-1.84(m,1H),1.78-1.67(m,2H),1.52-1.40(m,1H),1.23-1.21(m,1H),1.20-1.17(m,1H),1.14(d,J=6.0Hz,3H)。
实例3
5-[(4R,8R)-4-甲基-8-(4-哌嗪-1-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用(4-溴苯基)硼酸代替(6-溴吡啶-3-基)硼酸(化合物2d)来制备标题化合物。获得实例3(17mg),为浅灰色固体。立体化学由NOESY确认。MS:计算467(MH+),测量467(MH+)。1H NMR(400MHz,甲醇-d4)δ9.07-9.00(m,1H),8.71(dd,J=1.7,8.6Hz,1H),8.26-8.18(m,1H),7.76-7.66(m,1H),7.38(d,J=8.1Hz,1H),7.29-7.22(m,2H),7.08-7.00(m,2H),4.26-4.05(m,1H),4.03-3.80(m,2H),3.79-3.64(m,2H),3.63-3.49(m,1H),3.48-3.34(m,8H),3.24(br d,J=11.7Hz,4H),2.31-1.98(m,3H),1.93-1.84(m,1H),1.84-1.78(m,1H),1.54(d,J=6.5Hz,1H)。
实例4
5-[(4R,8R,9aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用(6-溴吡啶-3-基)硼酸代替(6-溴吡啶-3-基)硼酸(化合物2d)来制备标题化合物。获得实例4(8mg),为棕色固体。立体化学由NOESY确认。MS:计算468(MH+),测量468(MH+)。1H NMR(400MHz,甲醇-d4)δ8.91(dd,J=1.6,4.3Hz,1H),8.59(dd,J=1.7,8.6Hz,1H),8.09(d,J=7.9Hz,1H),8.00(d,J=2.3Hz,1H),7.67(dd,J=2.3,9.0Hz,1H),7.59(dd,J=4.3,8.7Hz,1H),7.27(d,J=8.1Hz,1H),7.01(d,J=8.9Hz,1H),4.03-3.96(m,1H),3.86-3.78(m,1H),3.77-3.69(m,5H),3.67-3.54(m,2H),3.30-3.24(m,4H),3.18-3.08(m,3H),3.08-2.97(m,1H),2.19-2.07(m,2H),2.03-1.91(m,1H),1.86-1.75(m,1H),1.43(d,J=6.4Hz,3H)。
实例6
5-[(4R,8R,9aS)-8-[6-[(3S,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用N-[(3S,4S)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1627185-88-9,PharmaBlock,目录号PBZ4724)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例6(21mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ9.00(dd,J=1.5,4.3Hz,1H),8.68(dd,J=1.6,8.7Hz,1H),8.18(d,J=7.9Hz,1H),8.03(dd,J=2.0,9.3Hz,1H),7.93(d,J=2.0Hz,1H),7.68(dd,J=4.3,8.6Hz,1H),7.36(d,J=8.1Hz,1H),7.12(d,J=9.3Hz,1H),4.30-4.23(m,1H),4.14-3.99(m,4H),3.92(br s,1H),3.88-3.79(m,2H),3.79-3.62(m,3H),3.49(s,3H),3.29-3.12(m,4H),2.31-2.19(m,2H),2.16-2.04(m,1H),2.01-1.89(m,1H),1.53(d,J=6.5Hz,3H)。
实例7
5-[(4R,8R,9aS)-8-[6-(3-氨基氮杂环丁烷-1-基)-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用N-[(3S,4S)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1627185-88-9,PharmaBlock,目录号PBZ4724)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例7(14mg),为浅黄色固体。立体化学由NOESY确认。MS:计算454(MH+),测量454(MH+)。1H NMR 1H NMR(400MHz,甲醇-d4)δ9.05(dd,J=4.3,1.6Hz,1H),8.70(dd,J=8.6,1.6Hz,1H),8.23(d,J=7.9Hz,1H),7.98(d,J=2.0Hz,1H),7.90(dd,J=9.0,2.2Hz,1H),7.72(dd,J=8.6,4.3Hz,1H),7.39(d,J=8.1Hz,1H),6.84(d,J=9.0Hz,1H),4.58(dd,J=9.8,7.2Hz,2H),4.37–4.22(m,3H),4.16–4.08(m,1H),3.98–3.80(m,2H),3.80–3.64(m,2H),3.27–3.07(m,4H),2.21(br s,2H),2.13–1.99(m,1H),1.90(br d,J=14.1Hz,1H),1.54(d,J=6.5Hz,3H)。
实例9
5-[(4R,8R,9aS)-4-甲基-8-[3-(4-哌嗪-1-基苯基)氮杂环丁烷-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
根据以下方案制备标题化合物:
步骤1:5-[(4R,8R,9aS)-8-[3-(4-溴苯基)氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(化合物9b)
将5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1,30mg,93μmol)、3-(4-溴苯基)氮杂环丁烷(化合物9a,20mg,93μmol)在MeOH(10mL)中的溶液在室温搅拌1小时。然后将反应混合物冷却至0℃并加入氰基三氢硼酸钠(17mg,281μmol)。在室温搅拌12小时后,将混合物用水(10mL)猝灭,用EA萃取两次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩,得到粗产物,将其通过制备型HPLC纯化,得到5-[(4R,8R,9aS)-8-[3-(4-溴苯基)氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(化合物9b,20mg)。MS:计算值517(MH+),测量值517(MH+)。立体化学由NOESY确认。
步骤2:4-[4-[1-[(4R,8R,9aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-8-基]氮杂环丁烷-3-基]苯基]哌嗪-1-甲酸叔丁酯(化合物9d)
用N2充填5-[(4R,8R,9aS)-8-[3-(4-溴苯基)氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(化合物9b,20mg,38.7μmol)、哌嗪-1-甲酸叔丁酯(化合物9c,9.38mg,50.3μmol)、tBuXPhos Pd G3(1.54mg,1.94μmol)和叔丁醇钠(18.6mg,194μmol)在1,4-二氧六环(10mL)中的混合物。在90℃搅拌过夜后,将混合物冷却至室温,滤出固体并用EA(10mL)洗涤两次。将滤液浓缩为粗产物4-[4-[1-[(4R,8R,9aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-8-基]氮杂环丁烷-3-基]苯基]哌嗪-1-甲酸叔丁酯(化合物9d,25mg),其可不经纯化即用于下一步。MS:计算622(MH+),测量622(MH+)。
步骤3:5-[(4R,8R,9aS)-4-甲基-8-[3-(4-哌嗪-1-基苯基)氮杂环丁烷-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例9)
在0℃,向4-[4-[1-[(4R,8R,9aS)-2-(8-氰基-5-喹啉基)-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-8-基]氮杂环丁烷-3-基]苯基]哌嗪-1-甲酸叔丁酯(化合物9d,25mg)在DCM(4mL)中的溶液中加入TFA(0.5mL)。将反应混合物在室温搅拌2小时。然后将混合物浓缩成粗产物,将其通过制备型HPLC纯化,得到实例9(11mg),为浅黄色固体。MS:计算522(MH+),测量522(MH+)。1H NMR(400MHz,甲醇-d4)δ8.92(dd,J=4.3,1.6Hz,1H),8.55(dd,J=8.6,1.7Hz,1H),8.09(d,J=7.9Hz,1H),7.58(dd,J=8.6,4.3Hz,1H),7.25(t,J=8.4Hz,3H),6.92-7.04(m,2H),4.35-4.51(m,2H),4.11-4.30(m,2H),3.80-4.07(m,2H),3.38-3.71(m,5H),3.26-3.37(m,6H),2.90-3.12(m,2H),2.69-2.85(m,1H),2.18-2.42(m,2H),1.47-1.81(m,2H),1.32ppm(d,J=6.4Hz,3H)。
实例11
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
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根据以下方案制备标题化合物:
步骤1:5-((4R,8R)-8-羟基-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11a)
向5-((4R)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1,500mg,1.56mmol)在MeOH(10mL)中的溶液中加入四氢硼酸钠(70.8mg,1.87mmol)。在室温搅拌2小时后,用10%HCl溶液小心地猝灭反应。所得混合物用K2CO3中和并用EtOAc(30mL)萃取两次。合并的有机层用盐水洗涤并经Na2SO4干燥,过滤并浓缩,得到5-((4R,8R)-8-羟基-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11a,500mg),其不经进一步纯化即直接用于下一步。立体化学由NOESY确认。MS:计算323(MH+),测量323(MH+)。1H NMR(DMSO-d6,400MHz)δ9.03(dd,1H,J=1.6,4.2Hz),8.51(dd,1H,J=1.5,8.6Hz),8.22(d,1H,J=8.1Hz),7.67(dd,1H,J=4.3,8.6Hz),7.18(d,1H,J=8.2Hz),4.69(d,1H,J=4.6Hz),3.48(dt,1H,J=5.6,10.4Hz),3.2-3.3(m,1H),3.20(br d,1H,J=11.4Hz),2.6-2.8(m,2H),2.3-2.4(m,1H),1.7-1.9(m,3H),1.3-1.5(m,1H),1.0-1.1(m,1H),1.0-1.1(m,3H)。
步骤2:5-((4R,8S,9aS)-8-((5-氯吡啶-2-基)氧基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11c)
将5-((4R,9aS)-8-羟基-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11a,60mg,186μmol)、5-氯吡啶-2-醇(化合物11b,24mg,186μmol)和PPh3(98mg,372μmol)在THF(4mL)中的溶液在0℃用DIAD(72μL,372μmol)处理,在室温搅拌1小时。在70℃搅拌1小时后,将混合物冷却至室温,用EtOAc稀释,用水和盐水洗涤,经Na2SO4干燥并浓缩。残余物通过硅胶柱色谱(20%至100%的EtOAc/PE)纯化,得到5-((4R,8S,9aS)-8-((5-氯吡啶-2-基)氧基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11c,40mg),为淡黄色固体。MS:计算434(MH+),测量434(MH+)。立体化学由NOESY确认。
步骤3:4-(6-(((4R,8S,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氧基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(化合物11e)
向微波管中加入5-((4R,8S,9aS)-8-((5-氯吡啶-2-基)氧基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物11c,40mg,92.2μmol)、哌嗪-1-甲酸叔丁酯(化合物11d,22mg,120μmol)、叔丁醇钠(138μL,277μmol,2M,在THF中)和1,4-二氧六环(5mL),用N2将悬浮液鼓泡5分钟并加入tBuXPhos PD G3(7mg,9.22μmol)。在100℃搅拌12小时后,将混合物冷却至室温,用饱和NaHCO3(5mL)溶液稀释,并用EtOAC(10mL)萃取三次。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到4-(6-(((4R,8S,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氧基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(化合物11e,20mg),为橙色固体,其可不经纯化即用于下一步。MS:calc’d 584(MH+),测得584(MH+)。
步骤4:5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例11)
在0℃,向4-(6-(((4R,8S,9aS)-2-(8-氰基喹啉-5-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-8-基)氧基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(化合物11e,20mg)在DCM(2mL)中的溶液中加入TFA(0.5mL)。将反应混合物在室温搅拌2小时。然后将混合物浓缩成粗产物,将其通过制备型HPLC纯化,得到实例11(16mg),为浅棕色固体。MS计算484(MH+),测量484(MH+)。1H NMR(400MHz,甲醇-d4)δ9.02(dd,J=4.2,1.7Hz,1H),8.70(dd,J=8.6,1.7Hz,1H),8.20(d,J=8.1Hz,1H),7.89(d,J=2.9Hz,1H),7.69(dd,J=8.7,4.3Hz,1H),7.57(dd,J=9.0,3.1Hz,1H),7.38(d,J=8.1Hz,1H),6.93(d,J=8.9Hz,1H),5.45(br s,1H),4.17–4.09(m,1H),4.00–3.87(m,2H),3.78–3.71(m,1H),3.66–3.59(m,1H),3.45–3.34(m,9H),3.21(td,J=14.0,11.1Hz,2H),2.48–2.36(m,2H),2.27–2.16(m,1H),2.12–2.01(m,1H),1.52(d,J=6.5Hz,3H)。
实例12
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用((3R,4S)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:1932508-77-4,PharmaBlock)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例12(9mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ9.02(dd,J=4.3,1.6Hz,1H),8.70(dd,J=8.6,1.6Hz,1H),8.20(d,J=8.1Hz,1H),8.06(dd,J=9.4,2.0Hz,1H),7.99–7.94(m,1H),7.70(dd,J=8.6,4.3Hz,1H),7.38(d,J=8.1Hz,1H),7.14(d,J=9.4Hz,1H),4.36(dt,J=4.5,2.3Hz,1H),4.22–4.04(m,3H),3.99–3.65(m,7H),3.53(s,3H),3.31–3.14(m,4H),2.34–2.07(m,3H),2.05–1.92(m,1H),1.55(d,J=6.5Hz,3H)。
实例13
5-[(4R,8R,9aS)-8-[6-[(3S,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用((3S,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:1931911-57-7,PharmaBlock,目录号PBZ4730)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例13(15mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ9.02(dd,J=4.2,1.5Hz,1H),8.70(dd,J=8.6,1.6Hz,1H),8.20(d,J=7.9Hz,1H),8.06(dd,J=9.4,2.0Hz,1H),7.99–7.93(m,1H),7.70(dd,J=8.6,4.3Hz,1H),7.38(d,J=7.9Hz,1H),7.14(d,J=9.3Hz,1H),4.36(td,J=4.5,2.4Hz,1H),4.21–4.05(m,3H),3.99–3.90(m,2H),3.89–3.79(m,2H),3.78–3.65(m,3H),3.53(s,3H),3.31–3.14(m,4H),2.34–2.07(m,3H),2.04–1.92(m,1H),1.55(d,J=6.4Hz,3H)。
实例14
5-[(4R,8R,9aS)-8-[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用((3R,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:1932066-52-8,PharmaBlock,目录号PBZ4728)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例13(10mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.2,1.5Hz,1H),8.71(dd,J=8.6,1.7Hz,1H),8.22(d,J=7.9Hz,1H),8.01–7.95(m,2H),7.71(dd,J=8.6,4.2Hz,1H),7.39(d,J=7.9Hz,1H),7.06(d,J=10.0Hz,1H),4.26(dt,J=5.5,2.8Hz,1H),4.16–4.09(m,1H),4.09–3.99(m,3H),3.98–3.82(m,2H),3.82–3.66(m,4H),3.51(s,3H),3.30–3.13(m,4H),2.34–2.20(m,2H),2.16–2.03(m,1H),2.00–1.88(m,1H),1.55(d,J=6.4Hz,3H)。
实例15
5-[(4R,8R,9aR)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用5-((4R,8R,9aR)-8-(6-溴吡啶-3-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈代替5-((4R)-8-(6-溴吡啶-3-基)-4-甲基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(化合物2e)来制备标题化合物。获得实例15(4mg),为浅黄色固体。立体化学由NOESY确认。MS:计算468(MH+),测量468(MH+)。1H NMR(400MHz,甲醇-d4)δ8.99(dd,J=4.2,1.7Hz,1H),8.73(dd,J=8.6,1.7Hz,1H),8.16(d,J=8.1Hz,1H),8.03(d,J=2.3Hz,1H),7.66(dd,J=8.6,4.3Hz,1H),7.54(dd,J=8.7,2.4Hz,1H),7.27(d,J=8.1Hz,1H),6.83(d,J=8.7Hz,1H),3.52–3.35(m,8H),3.31–3.26(m,1H),3.25–3.14(m,1H),2.98–2.82(m,6H),2.80–2.65(m,2H),1.93–1.77(m,2H),1.65–1.49(m,1H),1.48–1.43(m,3H)。
实例16
5-[(4R,8S,9aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例11的制备,通过使用5-溴-2-甲基吡啶(PharmaBlock,CAS:13466-38-1)代替5-氯吡啶-2-醇(化合物11b)来制备标题化合物。获得实例16(50mg),为白色固体。立体化学由NOESY确认。MS:计算484(MH+),测量484(MH+)。1H NMR(400MHz,甲醇-d4)δ8.94(dd,J=4.2,1.6Hz,1H),8.57(dd,J=8.6,1.6Hz,1H),8.11(d,J=7.9Hz,1H),7.76(d,J=2.8Hz,1H),7.61(dd,J=8.6,4.2Hz,1H),7.45(dd,J=8.9,3.1Hz,1H),7.20(d,J=7.9Hz,1H),6.79(d,J=8.9Hz,1H),5.21(t,J=2.4Hz,1H),3.40(br d,J=11.2Hz,1H),3.26(brd,J=11.7Hz,1H),3.21–3.15(m,1H),3.07–3.01(m,4H),3.01–2.94(m,5H),2.85–2.72(m,3H),2.49–2.36(m,1H),2.14–2.06(m,1H),2.01–1.87(m,2H),1.70–1.61(m,1H),1.18(d,J=5.9Hz,3H)。
实例18
5-[(4R,8S,9aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)氧基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例11的制备,通过使用2-氯-5-羟基嘧啶(Accela ChemBio Inc,CAS:4983-28-2)代替5-氯吡啶-2-醇(化合物11b)来制备标题化合物。获得实例18(27mg),为浅黄色固体。立体化学由NOESY确认。MS:计算485(MH+),测量485(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.2,1.7Hz,1H),8.71(dd,J=8.6,1.7Hz,1H),8.37(s,2H),8.22(d,J=7.9Hz,1H),7.71(dd,J=8.6,4.3Hz,1H),7.38(d,J=7.9Hz,1H),4.79(br s,1H),4.21–4.12(m,1H),4.06–4.00(m,4H),3.99–3.87(m,2H),3.79–3.72(m,1H),3.70–3.62(m,1H),3.50–3.40(m,1H),3.32–3.28(m,4H),3.21(td,J=13.7,11.2Hz,2H),2.42–2.35(m,2H),2.25–2.13(m,1H),2.10–2.00(m,1H),1.52(d,J=6.5Hz,3H)。
实例19
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用N-[(3R,4S)-4-氟吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1033718-91-0,PharmaBlock,目录号PB09204)代替哌嗪-1-甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例19(5mg),为浅黄色固体。立体化学由NOESY确认。MS:计算486(MH+),测量486(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.3,1.6Hz,1H),8.71(dd,J=8.6,1.6Hz,1H),8.22(d,J=7.9Hz,1H),8.05(dd,J=9.2,2.3Hz,1H),8.00(d,J=1.8Hz,1H),7.71(dd,J=8.6,4.3Hz,1H),7.39(d,J=7.9Hz,1H),7.12(d,J=9.3Hz,1H),5.69–5.51(m,1H),4.34–4.20(m,2H),4.17–4.03(m,3H),4.00–3.80(m,3H),3.79–3.65(m,3H),3.31–3.14(m,4H),2.34–2.21(m,2H),2.19–2.06(m,1H),2.03–1.91(m,1H),1.55(d,J=6.4Hz,3H)。
实例20
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例1的制备,通过在步骤1中使用(2S)-2-(4-氨基苯基)吗啉-4-甲酸叔丁酯代替4-(4-(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a)来制备标题化合物。获得实例20(7mg),为浅黄色固体。立体化学由NOESY确认。MS:计算483(MH+),测量483(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.3,1.6Hz,1H),8.71(dd,J=8.6,1.6Hz,1H),8.22(d,J=7.9Hz,1H),7.72(dd,J=8.6,4.3Hz,1H),7.38(d,J=8.1Hz,1H),7.20(d,J=8.6Hz,2H),6.75(d,J=8.6Hz,2H),4.60(dd,J=11.2,2.1Hz,1H),4.21(dd,J=12.9,3.1Hz,1H),3.60-4.12(m,7H),3.05-3.25(m,8H),2.44(br t,J=14.7Hz,2H),1.68-1.90(m,1H),1.45(s,3H)。
实例21
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例1的制备,通过在步骤1中使用(2R)-2-[(4-氨基苯基)甲基]吗啉-4-甲酸叔丁酯代替4-(4-(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a)来制备标题化合物。获得实例21(8mg),为浅黄色固体。立体化学由NOESY确认。MS:计算497(MH+),测量497(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.2,1.7Hz,1H),8.71(dd,J=8.6,1.7Hz,1H),8.22(d,J=7.9Hz,1H),7.72(dd,J=8.6,4.3Hz,1H),7.38(d,J=8.1Hz,1H),7.06(d,J=8.6Hz,2H),6.73(d,J=8.4Hz,2H),4.07(br dd,J=13.0,3.5Hz,2H),3.63-3.99(m,7H),3.03-3.27(m,6H),2.61-2.92(m,3H),2.32-2.54(m,2H),1.68-1.88(m,1H),1.56-1.60(m,1H),1.40(s,3H)。
实例22
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备,通过使用(R)-2-(4-氨基苄基)吗啉-4-甲酸叔丁酯和2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)代替4-(4(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a)和5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1)来制备标题化合物。获得实例22(39mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ8.67(d,J=8.7Hz,1H),8.17(d,J=8.1Hz,1H),7.68(d,J=8.6Hz,1H),7.31(d,J=7.9Hz,1H),7.04(d,J=8.4Hz,2H),6.69(d,J=8.6Hz,2H),4.06(dd,J=12.8,3.5Hz,1H),3.88–3.38(m,9H),3.28–3.19(m,2H),3.16–3.01(m,3H),2.87(dd,J=12.7,11.1Hz,1H),2.82–2.75(m,1H),2.71–2.63(m,1H),2.39–2.24(m,2H),1.75–1.62(m,1H),1.51–1.43(m,1H),1.40(d,J=6.4Hz,3H)。
实例23
5-[(4R,8R,9aS)-8-[6-[(6S)-6-氨基-1,4-氧氮杂环庚烷-4-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例2的制备,通过使用N-[(6S)-1,4-氧氮杂环庚烷-6-基]氨基甲酸叔丁酯(PharmaBlock,目录号PB97931)代替)代替哌嗪-1-氨基甲酸叔丁酯(化合物2f)来制备标题化合物。获得实例23(1mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ8.92(dd,J=4.2,1.5Hz,1H),8.59(dd,J=8.6,1.6Hz,1H),8.10(d,J=7.9Hz,1H),7.98(d,J=2.3Hz,1H),7.60(dd,J=8.6,4.3Hz,1H),7.51(dd,J=8.9,2.5Hz,1H),7.27(d,J=7.9Hz,1H),6.79(d,J=8.8Hz,1H),4.17–4.08(m,1H),4.02–3.88(m,3H),3.85–3.52(m,10H),3.17–3.07(m,2H),3.07–2.90(m,2H),2.18–2.05(m,2H),2.02–1.91(m,1H),1.83–1.71(m,1H),1.42(d,J=6.4Hz,3H)。
实例24和27
5-[(4R,8S,9aS)-4-甲基-8-(4-吗啉-2-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例24)
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2R)-吗啉-2-基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例27)
类似于实例2的制备,通过使用(R)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉-4-甲酸叔丁酯代替6-溴吡啶-3-基)硼酸(化合物2d)来制备标题化合物。获得实例24(11mg),为浅黄色固体,获得实例27(17mg),为浅黄色固体。
实例24立体化学由NOESY确认。MS:计算468(MH+),测量468(MH+)。1H NMR(400MHz,甲醇-d4)δ9.03–8.98(m,1H),8.70(dd,J=8.6,1.5Hz,1H),8.59(dd,J=8.6,1.4Hz,1H),8.73–8.56(m,1H),8.23–8.20(m,1H),8.18(br d,J=7.9Hz,1H),8.24–8.16(m,1H),7.71–7.63(m,1H),7.58–7.46(m,2H),7.45–7.33(m,2H),4.79(ddd,J=16.6,11.3,2.0Hz,1H),4.26(dt,J=12.6,4.2Hz,1H),4.44–4.20(m,1H),4.09–3.63(m,5H),3.60–3.41(m,3H),3.18–3.01(m,2H),2.74–2.60(m,1H),2.51–2.01(m,3H),1.52–1.43(m,3H)。
实例27立体化学由NOESY确认。MS:计算468(MH+),测量468(MH+)。1H NMR(400MHz,甲醇-d4)δ9.05–9.01(m,1H),8.71(dd,J=8.6,1.5Hz,1H),8.21(d,J=7.9Hz,1H),7.71(dd,J=8.6,4.3Hz,1H),7.45–7.36(m,5H),4.77(dd,J=11.2,2.3Hz,1H),4.26(dd,J=13.0,3.3Hz,1H),4.15–4.08(m,1H),4.05–3.81(m,3H),3.80–3.65(m,2H),3.46(br d,J=13.0Hz,1H),3.40–3.35(m,1H),3.31–3.05(m,6H),2.32–2.19(m,2H),2.16–2.02(m,1H),1.93(q,J=13.1Hz,1H),1.54(d,J=6.4Hz,3H)。
实例25和26
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例25)
5-[(4R,8S,9aS)-4-甲基-8-[4-(吗啉-2-基甲基)苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(实例26)
类似于实例2的制备,通过使用(R)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)吗啉-4-甲酸叔丁酯代替6-溴吡啶-3-基)硼酸(化合物2d)来制备标题化合物。获得实例25(15mg),为浅黄色固体,获得实例26(8mg),为浅黄色固体。
实例25:立体化学由NOESY确认。MS:计算482(MH+),测量482(MH+)。1H NMR(400MHz,甲醇-d4)δ9.02(dd,J=4.3,1.6Hz,1H),8.71(dd,J=8.6,1.7Hz,1H),8.20(d,J=8.1Hz,1H),7.70(dd,J=8.6,4.3Hz,1H),7.38(d,J=8.1Hz,1H),7.27(s,4H),4.14–4.02(m,2H),3.98–3.83(m,3H),3.83–3.64(m,3H),3.29–3.08(m,7H),2.97–2.77(m,3H),2.31–2.17(m,2H),2.15–2.01(m,1H),1.98–1.86(m,1H),1.54(d,J=6.5Hz,3H)。
实例26:立体化学由NOESY确认。MS:计算482(MH+),测量482(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04–8.99(m,1H),8.73–8.58(m,1H),8.21(dd,J=10.1,8.0Hz,1H),7.68(ddd,J=13.0,8.6,4.3Hz,1H),7.52–7.31(m,3H),7.25(s,2H),4.42–4.20(m,1H),4.10–3.65(m,7H),3.60–3.41(m,2H),3.30–3.22(m,2H),3.18–3.04(m,3H),2.98–2.81(m,3H),2.74–2.59(m,1H),2.48–1.98(m,3H),1.47(dd,J=14.2,6.7Hz,3H)。
实例28
5-[(4R,8S,9aS)-8-[[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]氧基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例11的制备,通过使用2-氯-5-甲基吡啶(CAS:41288-96-4)和((3R,4S)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:1932508-77-4,PharmaBlock)代替5-氯吡啶-2-醇(化合物11b)和哌嗪-1-甲酸叔丁酯(化合物11d)来制备标题化合物。获得实例28(6mg),为浅黄色固体。立体化学由NOESY确认。MS:计算514(MH+),测量514(MH+)。1HNMR(400MHz,甲醇-d4)δ8.88(dd,J=4.2,1.3Hz,1H),8.57(dd,J=8.5,1.3Hz,1H),8.06(d,J=7.9Hz,1H),7.84(dd,J=9.7,2.7Hz,1H),7.79(d,J=2.7Hz,1H),7.57(dd,J=8.6,4.2Hz,1H),7.24(d,J=7.9Hz,1H),6.99(d,J=9.7Hz,1H),4.76–4.72(m,1H),4.27–4.20(m,1H),4.09–3.98(m,2H),3.96–3.89(m,1H),3.88–3.74(m,3H),3.71–3.56(m,3H),3.55–3.49(m,1H),3.40(s,3H),3.36–3.26(m,1H),3.19–3.05(m,2H),2.31–2.22(m,2H),2.20–2.06(m,1H),2.05–1.94(m,1H),1.41(d,J=6.5Hz,3H)。
实例29
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例11的制备,通过使用3-溴-5-甲基吡啶(CAS:74115-13-2)代替5-氯吡啶-2-醇(化合物11b)来制备标题化合物。获得实例29(3mg),为浅黄色固体。立体化学由NOESY确认。MS:计算484(MH+),测量484(MH+)。1H NMR(400MHz,甲醇-d4)δ9.02(dd,J=1.6,4.3Hz,1H),8.70(dd,J=1.6,8.6Hz,1H),8.21(d,J=7.9Hz,1H),8.13(br d,J=19.7Hz,2H),7.69(dd,1H,J=4.3,8.6Hz),7.61(s,1H),7.38(d,J=7.9Hz,1H),5.14(br s,1H),4.16(br t,J=11.6Hz,1H),3.9-4.0(m,2H),3.7-3.8(m,1H),3.6-3.7(m,5H),3.4-3.5(m,5H),3.2-3.3(m,2H),2.4-2.5(m,2H),2.2-2.4(m,1H),2.1-2.2(m,1H),1.53(d,J=6.5Hz,3H)。
实例30
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于实例9的制备,通过使用((3R,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:1932066-52-8,PharmaBlock)代替哌嗪-1-甲酸叔丁酯(化合物9c)来制备标题化合物。获得实例30(4mg),为浅黄色固体。立体化学由NOESY确认。MS:计算552(MH+),测量552(MH+)。1H NMR(400MHz,甲醇-d4)δ8.87(dd,J=4.3,1.6Hz,1H),8.51(dd,J=8.6,1.6Hz,1H),8.04(d,J=8.1Hz,1H),7.53(dd,J=8.6,4.2Hz,1H),7.01-7.18(m,3H),6.49(m,2H),3.70-3.98(m,3H),3.41-3.66(m,4H),2.99-3.16(m,11H),2.37-2.81(m,5H),1.71-2.04(m,3H),0.90-1.38ppm(m,4H)。
实例32
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈
类似于是9的制备,通过使用((3R,4S)-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(化合物9c)来制备标题化合物。立体化学由NOESY确认。获得实例32(2mg),为浅黄色固体。MS:计算552(MH+),测量552(MH+)。1H NMR(400MHz,甲醇-d4)δ9.04(dd,J=4.2,1.5Hz,1H),8.67(dd,J=8.6,1.7Hz,1H),8.22(d,J=7.9Hz,1H),7.70(dd,J=8.6,4.3Hz,1H),7.34(dd,J=19.0,8.4Hz,3H),6.68(d,J=8.7Hz,2H),4.46-4.66(m,2H),4.20-4.39(m,3H),3.94-4.17(m,3H),3.40-3.83(m,10H),3.05-3.25(m,3H),2.78-3.01(m,2H),2.33-2.53(m,2H),1.59-1.99(m,2H),1.46(s,3H)。
实例34
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2S)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备,通过使用(S)-2-(4-氨基苄基)吗啉-4-甲酸叔丁酯和2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)代替4-(4(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a)和5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1)来制备标题化合物。获得实例34(34mg),为浅黄色固体。立体化学由NOESY确认。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ8.58(d,J=8.6Hz,1H),8.08(d,J=7.9Hz,1H),7.59(d,J=8.6Hz,1H),7.25(d,J=7.9Hz,1H),6.92(d,J=8.6Hz,2H),6.58(d,J=8.6Hz,2H),3.98–3.89(m,2H),3.82–3.50(m,7H),3.15–2.95(m,6H),2.78–2.64(m,2H),2.59–2.51(m,1H),2.36–2.23(m,2H),1.72–1.59(m,1H),1.50–1.41(m,1H),1.39(d,J=6.4Hz,3H)。
实例36
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]]-2-氘代-喹啉-8-甲腈
类似于实例9的制备,通过使用2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)和N-[(3R,4S)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1932508-77-4,PharmaBlock)代替5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1)和哌嗪-1-甲酸叔丁酯(化合物9c)来制备标题化合物。获得实例36(7mg),为浅黄色固体。MS:计算553(MH+),测量553(MH+)。1H NMR(400MHz,甲醇-d4)δ8.56(d,J=8.7Hz,1H),8.10(d,J=7.9Hz,1H),7.59(d,J=8.6Hz,1H),7.23(dd,J=18.5,8.3Hz,3H),6.61(d,J=8.8Hz,2H),4.48–4.38(m,2H),4.25–4.14(m,2H),4.04–3.94(m,3H),3.82–3.73(m,2H),3.70–3.63(m,1H),3.62–3.52(m,5H),3.38–3.36(m,3H),3.35–3.31(m,1H),3.18–3.01(m,3H),2.95–2.84(m,1H),2.40–2.27(m,2H),1.84–1.72(m,1H),1.67–1.56(m,1H),1.36(d,J=6.2Hz,3H)。
实例37
5-[(4R,8R,9aS)-4-甲基-8-[4-(4-吡啶基)哌嗪-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备,通过在步骤1中会用1-(吡啶-4-基)哌嗪和2-氘代-5-[(4R)-4-甲基-8-氧代-3,4,6,7,9,9a-六氢-1H-吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈(中间体D1)代替4-(4-(氨基甲基)苯基)哌嗪-1-甲酸叔丁酯(化合物1a)和5-((4R,9aS)-4-甲基-8-氧代八氢-2H-吡啶并[1,2-a]吡嗪-2-基)喹啉-8-甲腈(中间体C1)来制备标题化合物。获得实例37(3mg),为浅黄色固体。MS:计算469(MH+),测量469(MH+)。1H NMR(400MHz,甲醇-d4)δ8.52(d,J=8.6Hz,1H),7.96-8.11(m,3H),7.53(d,J=8.7Hz,1H),7.13(d,J=8.1Hz,1H),6.66-6.83(m,2H),3.26-3.45(m,9H),2.51-2.80(m,7H),1.74-2.04(m,3H),1.43-1.62(m,1H),1.18-1.35(m,1H),1.09(d,J=6.2Hz,3H)。
实例38
为了确定式(I)和(Ia)的化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行以下检测。
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激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方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激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方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激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR9拮抗剂。
式(I)化合物具有人类TLR7和/或TLR8抑制活性(IC50值)<0.5μM。此外,某些化合物还具有人TLR9抑制活性<0.5μM。表2显示了本发明化合物的活性数据。
表2.本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
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实例39
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激活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;Relationshipsbetween preclinical cardiac electrophysiology,clinical QT interval prolongationand torsade de pointes for a broad range of drugs:evidence for a provisionalsafety margin in drug development.Cardiovasc.Res.58:32-45,Sanguinetti MC,Tristani-Firouzi M.2006;hERG potassium channels and cardiac arrhythmia.Nature440:463-469,Webster R,Leishman D,Walker D.2002;Towards a drug concentrationeffect relationship for QT prolongation and torsades de pointes.Curr.Opin.DrugDiscov.Devel.5:116-26).
hERG的结果在表3中给出。安全比(hERG IC20/EC50)>30表示通过抑制TLR7/8/9通路与潜在的hERG相关心脏毒性来区分药理学的充分安全窗。根据hERG IC20/TLR7/8/9IC50的计算(以下作为评估hERG责任的早期选择性指标),显然参比化合物ER-887258、ER-888285、ER-888286、R1和R2与本发明的化合物相比,具有更窄的安全窗。
表3.hERG和安全比结果
实例40
预期这些化合物具有最小DDI指标。因此,确定了(Ia)的式(I)化合物对主要CYP同种型,例如CYP2C9、CYP2D6和CYP3A4的影响。
CYP抑制测定
这是一种高通量筛选测定,用于评估早期发现阶段人肝微粒体(HLM)中测试化合物对CYP2C9、CYP2D6和CYP3A4活性的可逆抑制。
表4.CYP抑制测定中使用的化学品和材料
程序
将供试化合物的10mM DMSO储备溶液在DMSO中稀释,以生成2mM中间储备溶液。将250nL中间储备溶液一式两份转移到3个单独的384孔微量滴定板(待测板)中。制备HLM和每种底物的混合物。然后将45μL HLM底物混合物转移到待测板的每个孔中并混合。阴性(溶剂)和阳性对照(各CYP的标准抑制剂)包括在每个待测板中。将待测板在培养箱中温热至37℃放置10分钟。向每个培养孔中加入5μL预热的NADPH再生系统以开始反应。最终孵育体积为50μL。然后将测定板放回37℃的培养箱中。孵育5分钟(CYP2D6为10分钟)后,通过添加50μL含有内标(400ng/mL 13C6-4'-OH-双氯芬酸、20ng/mL D3-右啡烷和20ng/mL D4-1'Oh-咪达唑仑)的100%乙腈来猝灭孵育物。收集上清液用于RapidFire/MS/MS分析。
使用RapidFire在线固相萃取/样品进样系统(Agilent)偶联API4000三重四极杆质谱仪(AB Sciex)进行样品分析。流动相由乙腈和补充0.1%甲酸的水组成。使用C4固相萃取柱体进行样品分离。MS检测在阳离子MRM模式下完成。
数据分析
使用RapidFire积分器软件(版本3.6.12009.12296)确定底物、代谢物和内标的峰面积。然后计算代谢物和内标(稳定标记的代谢物)的峰面积比(PAR)。然后定义每个实验的测量窗:
PAR(0%活性)=含有浓缩抑制剂的所有孵育的平均PAR;
Par(100%活性)=不包含抑制剂的所有孵育的平均PAR(DMSO对照);
活性%(供试抑制剂)=[PAR(供试抑制剂)-PAR(0%活性)]/[PAR(100%活性)-PAR(0%活性)];
抑制%(供试抑制剂)=100-活性%(供试抑制剂)。
发现在上述测定中确定的本发明化合物对CYP2D6具有低CYP抑制作用。
表5.本发明化合物对CYP2D6的CYP抑制作用
*抑制百分比<0:非抑制剂或弱抑制剂。
Claims (9)
1.一种式(I)化合物,
其中
R1为其中R4为氰基;R5为H或氘;
R2为C1-6烷基;
R3为((氨基(C1-6烷氧基)吡咯烷基)苯基)氮杂环丁烷基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基、(氨基(C1-6烷氧基)吡咯烷基)吡啶基氧基、(氨基-1,4-氧氮杂环庚烷基)吡啶基、(氨基氮杂环丁烷基)吡啶基、(吗啉基C1-6烷基)苯基、(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、(哌嗪基苯基)C1-6烷基氨基、吗啉基苯基、吗啉基苯基氨基、哌嗪基苯基、哌嗪基吡啶基、哌嗪基吡啶基氧基、哌嗪基嘧啶基氧基或吡啶基哌嗪基;
或其药用盐。
2.根据权利要求1所述的化合物,其中R3为((3-氨基-4-甲氧基-吡咯烷-1-基)苯基)氮杂环丁烷-1-基;(3-氨基-4-甲氧基-吡咯烷-1-基)-3-吡啶基;(3-氨基-4-甲氧基-吡咯烷-1-基)-3-吡啶基氧基;(3-氨基氮杂环丁烷-1-基)-3-吡啶基;(4-吗啉-2-基甲基)苯基;(4-吗啉-2-基甲基)苯基氨基;(4-哌嗪-1-基苯基)氮杂环丁烷-1-基;(4-哌嗪-1-基苯基)甲基氨基;(6-氨基-1,4-氧氮杂环庚烷-4-基)-3-吡啶基;2-哌嗪-1-基嘧啶-5-基氧基;4-吗啉-2-基苯基;4-吗啉-2-基苯基氨基;4-哌嗪-1-基苯基;4-吡啶基哌嗪-1-基;5-哌嗪-1-基-2-吡啶基氧基;5-哌嗪-1-基-3-吡啶基氧基;6-哌嗪-1-基-3-吡啶基或6-哌嗪-1-基-3-吡啶基氧基。
3.根据权利要求1或2中任一项所述的化合物,其中R2为甲基。
4.根据权利要求2所述的化合物,其中R3为(4-吗啉-2-基甲基)苯基氨基、(4-哌嗪-1-基苯基)氮杂环丁烷-1-基、4-吗啉-2-基苯基、4-吗啉-2-基苯基氨基、6-哌嗪-1-基-3-吡啶基氧基或2-哌嗪-1-基嘧啶-5-基氧基。
5.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或氘;
R2为C1-6烷基;
R3为(吗啉基C1-6烷基)苯基氨基、(哌嗪基苯基)氮杂环丁烷基、吗啉基苯基、吗啉基苯基氨基、哌嗪基吡啶基氧基或哌嗪基嘧啶基氧基;
或其药用盐。
6.根据权利要求5所述的化合物,其中
R1为其中R4为氰基;R5为H或氘;
R2为甲基;
R3为(4-吗啉-2-基甲基)苯基氨基、(4-哌嗪-1-基苯基)氮杂环丁烷-1-基、4-吗啉-2-基苯基、4-吗啉-2-基苯基氨基、6-哌嗪-1-基-3-吡啶基氧基或2-哌嗪-1-基嘧啶-5-基氧基;
或其药用盐。
7.一种化合物,其选自:
5-[(4R,8R,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(4-哌嗪-1-基苯基)甲基氨基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R)-4-甲基-8-(4-哌嗪-1-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3S,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-(3-氨基氮杂环丁烷-1-基)-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[3-(4-哌嗪-1-基苯基)氮杂环丁烷-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-2-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3S,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aR)-4-甲基-8-(6-哌嗪-1-基-3-吡啶基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(6-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-(2-哌嗪-1-基嘧啶-5-基)氧基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2S)-吗啉-2-基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[6-[(6S)-6-氨基-1,4-氧氮杂环庚烷-4-基]-3-吡啶基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-(4-吗啉-2-基苯基)-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[(2R)-吗啉-2-基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2R)-吗啉-2-基]甲基]苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[4-(吗啉-2-基甲基)苯基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-8-[[6-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]-3-吡啶基]氧基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8S,9aS)-4-甲基-8-[(5-哌嗪-1-基-3-吡啶基)氧基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]喹啉-8-甲腈;
5-[(4R,8R,9aS)-4-甲基-8-[4-[[(2S)-吗啉-2-基]甲基]苯胺基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
5-[(4R,8R,9aS)-8-[3-[4-[(3R,4S)-3-氨基-4-甲氧基-吡咯烷-1-基]苯基]氮杂环丁烷-1-基]-4-甲基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]]-2-氘代-喹啉-8-甲腈;和
5-[(4R,8R,9aS)-4-甲基-8-[4-(4-吡啶基)哌嗪-1-基]-1,3,4,6,7,8,9,9a-八氢吡啶并[1,2-a]吡嗪-2-基]-2-氘代-喹啉-8-甲腈;
或其药用盐。
8.一种药物组合物,其包含根据权利要求1至7中任一项所述的化合物以及治疗惰性载体。
9.根据权利要求1至7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TLR7和TLR8和TLR9拮抗剂。
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EP (1) | EP4069693B1 (zh) |
JP (1) | JP2023505159A (zh) |
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WO (1) | WO2021110614A1 (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100280001A1 (en) * | 2007-05-08 | 2010-11-04 | Roger Victor Bonnert | Imidazoquinolines with immuno-modulating properties |
WO2015057655A1 (en) * | 2013-10-14 | 2015-04-23 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
CN105992766A (zh) * | 2013-12-13 | 2016-10-05 | 武田药品工业株式会社 | 作为tlr抑制剂的吡咯并[3,2-c]吡啶衍生物 |
CN106414432A (zh) * | 2013-10-14 | 2017-02-15 | 卫材R&D管理有限公司 | 选择性取代的喹啉化合物 |
WO2018031434A1 (en) * | 2016-08-08 | 2018-02-15 | Merck Patent Gmbh | Tlr7/8 antagonists and uses thereof |
CN108699032A (zh) * | 2015-12-17 | 2018-10-23 | 默克专利有限公司 | 多环tlr7/8拮抗剂及其在治疗免疫失调中的用途 |
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US11952363B2 (en) * | 2018-07-23 | 2024-04-09 | Hoffmann-La Roche Inc. | Piperazine compounds for the treatment of autoimmune disease |
KR20210149163A (ko) * | 2019-04-09 | 2021-12-08 | 에프. 호프만-라 로슈 아게 | 자가면역 질환의 치료를 위한 헥사하이드로-1H-피라지노[1,2-a]피라진 화합물 |
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- 2020-12-01 JP JP2022533088A patent/JP2023505159A/ja active Pending
- 2020-12-01 US US17/780,161 patent/US20230022297A1/en active Pending
- 2020-12-01 EP EP20819661.8A patent/EP4069693B1/en active Active
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100280001A1 (en) * | 2007-05-08 | 2010-11-04 | Roger Victor Bonnert | Imidazoquinolines with immuno-modulating properties |
WO2015057655A1 (en) * | 2013-10-14 | 2015-04-23 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
CN106414432A (zh) * | 2013-10-14 | 2017-02-15 | 卫材R&D管理有限公司 | 选择性取代的喹啉化合物 |
CN105992766A (zh) * | 2013-12-13 | 2016-10-05 | 武田药品工业株式会社 | 作为tlr抑制剂的吡咯并[3,2-c]吡啶衍生物 |
CN108699032A (zh) * | 2015-12-17 | 2018-10-23 | 默克专利有限公司 | 多环tlr7/8拮抗剂及其在治疗免疫失调中的用途 |
WO2018031434A1 (en) * | 2016-08-08 | 2018-02-15 | Merck Patent Gmbh | Tlr7/8 antagonists and uses thereof |
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WO2021110614A1 (en) | 2021-06-10 |
EP4069693A1 (en) | 2022-10-12 |
EP4069693C0 (en) | 2024-03-20 |
JP2023505159A (ja) | 2023-02-08 |
EP4069693B1 (en) | 2024-03-20 |
CN114761406A (zh) | 2022-07-15 |
US20230022297A1 (en) | 2023-01-26 |
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