CN114728988A - 用于治疗自身免疫性疾病的螺(异苯并呋喃氮杂环丁烷)化合物 - Google Patents
用于治疗自身免疫性疾病的螺(异苯并呋喃氮杂环丁烷)化合物 Download PDFInfo
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- CN114728988A CN114728988A CN202080080901.XA CN202080080901A CN114728988A CN 114728988 A CN114728988 A CN 114728988A CN 202080080901 A CN202080080901 A CN 202080080901A CN 114728988 A CN114728988 A CN 114728988A
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- Prior art keywords
- methyl
- morpholin
- azetidine
- carbonitrile
- spiro
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- 125000003003 spiro group Chemical group 0.000 title claims description 51
- 238000011282 treatment Methods 0.000 title claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 title description 4
- DPBLTZNZZBPTBR-UHFFFAOYSA-N azetidine;2-benzofuran Chemical class C1CNC1.C1=CC=CC2=COC=C21 DPBLTZNZZBPTBR-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 170
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 16
- -1 heptanyl group Chemical group 0.000 claims description 73
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 238000002360 preparation method Methods 0.000 claims description 48
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 32
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 30
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 29
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 29
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 25
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 18
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 16
- 229910052805 deuterium Inorganic materials 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
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- 208000005777 Lupus Nephritis Diseases 0.000 claims description 10
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- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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- KIDIJBYYGAEULX-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound N#CC1=CC=CC2=CC=NN12 KIDIJBYYGAEULX-UHFFFAOYSA-N 0.000 claims description 4
- QOLBPJHTZXJFLH-BWKNWUBXSA-N 4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-2-benzofuran-3,3'-azetidine]-1'-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](O1)CN1CC2(C1)OCC1=CC(=CC=C12)N1CC2(C1)CN(C2)C)C=1C=2N(C(=CC=1)C#N)N=CC=2 QOLBPJHTZXJFLH-BWKNWUBXSA-N 0.000 claims description 3
- BUIIAEXZBNKVJL-XXBNENTESA-N 4-[(2S,6R)-2-[[6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-2-benzofuran-3,3'-azetidine]-1'-yl]methyl]-6-methylmorpholin-4-yl]-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound C1N(CC11CNC1)C1=CC=C2C(=C1)COC21CN(C1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2F BUIIAEXZBNKVJL-XXBNENTESA-N 0.000 claims description 3
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- NNKXTCHEMZUFDJ-NQIIRXRSSA-N NC1(CN(C1)C1=CC2=C(C=N1)C1(CN(C1)C[C@H]1CN(C[C@H](O1)C)C=1C=3N(C(=CC=1)C#N)N=CC=3)OC2)C Chemical compound NC1(CN(C1)C1=CC2=C(C=N1)C1(CN(C1)C[C@H]1CN(C[C@H](O1)C)C=1C=3N(C(=CC=1)C#N)N=CC=3)OC2)C NNKXTCHEMZUFDJ-NQIIRXRSSA-N 0.000 claims description 3
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- OUCKAXOYNAKDEB-GCJKJVERSA-N NC1CN(C1)C1=CC=C2C(=C1)COC21CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=CC(N(C2=NC=CC=C12)C)=O Chemical compound NC1CN(C1)C1=CC=C2C(=C1)COC21CN(C1)C[C@H]1CN(C[C@H](O1)C)C1=CC(N(C2=NC=CC=C12)C)=O OUCKAXOYNAKDEB-GCJKJVERSA-N 0.000 claims description 3
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- YYNBINNMUMOEHR-VGSWGCGISA-N NC1CN(C1)C1=CC=C2C(=C1)COC21CN(C1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2F Chemical compound NC1CN(C1)C1=CC=C2C(=C1)COC21CN(C1)C[C@H]1CN(C[C@H](O1)C)C=1C=2N(C(=CC=1)C#N)N=CC=2F YYNBINNMUMOEHR-VGSWGCGISA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical class C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
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- 239000013543 active substance Substances 0.000 claims 1
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 3
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- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 40
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
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Abstract
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,Lancet2011,377,721.)。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.Jim é nez-Dalmaroni,M.J.等人,Autoimmun Rev.2016,15,1.Chen,J.Q.等人,Clinical Reviews in Allergy&Immunology2016,50,1.)。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、8和9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)和式(Ia)的新型化合物,
其中
R2为C1-6烷基;
R3为未取代的或经取代的杂环基;
Y和A独立地选自CH和N;
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、其生产、基于根据本发明化合物的药物及其制备以及式(I)或(Ia)的化合物作为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的用途。式(I)或(Ia)的化合物显示出优异的TLR7和/或TLR8和/或TLR9拮抗活性。另外,式(I)或(Ia)的化合物还显示出良好的hPBMC、细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制。
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“C3-7环烷基”表示含有3至7个碳原子、特别是3至6个碳原子的饱和碳环,例如环丙基、环丁基、环戊基、环己基、环庚基等。特别的“C3-7环烷基”基团是环丙基、环戊基和环己基。
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“C1-6烷氧基”表示C1-6烷基-O-。
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“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。在特定的实施方案中,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、氧杂氮杂双环[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。杂环基的实例可进一步被氨基、C1-6烷基、C3-7环烷基、卤素、羟基或C1-6烷氧基取代。
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
R2为C1-6烷基;
R3为未取代的或经取代的杂环基;
Y和A独立地选自CH和N;
或其药用盐。
本发明的进一步的实施方案为(ii),其为根据(i)所述的式(I)化合物,其中
R2为C1-6烷基;
R3为2,6-二氮杂螺[3.3]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)吡咯烷基;氨基(C1-6烷氧基)吡咯烷基;氨基(羟基)吡咯烷基;氨基氮杂环丁烷基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;卤代吡咯烷基氨基或哌嗪基;
Y和A独立地选自CH和N,前提条件是Y和A不同时为N;
或其药用盐。
本发明的另一实施方案为(iii),其为式(Ia)化合物,
其中
R2为C1-6烷基;
R3为2,6-二氮杂螺[3.3]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)吡咯烷基;氨基(C1-6烷氧基)吡咯烷基;氨基(羟基)吡咯烷基;氨基氮杂环丁烷基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;卤代吡咯烷基氨基或哌嗪基;
Y和A独立地选自CH和N,前提条件是Y和A不同时为N;
或其药用盐。
本发明的进一步的实施方案为(vi),其为根据(i)至(v)中任一者所述的式(I)或(Ia)的化合物或其药用盐,其中Y为CH并且A为N;或Y为N并且A为CH。
本发明的进一步的实施方案为(vii),其为根据(i)至(vi)中任一者所述的式(I)或(Ia)的化合物或其药用盐,其中R3为氨基(C1-6烷基)氮杂环丁烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基或氨基(C1-6烷氧基)吡咯烷基。
本发明的进一步的实施方案为(viii),其为根据(i)至(vii)中任一者所述的式(I)或(Ia)的化合物或其药用盐,其中R3为3-氨基-3-甲基-氮杂环丁烷-1-基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基或3-氨基-4-甲氧基-吡咯烷-1-基。
本发明的进一步的实施方案为(ix),其为根据(i)至(viii)中任一者所述的式(I)或(Ia)的化合物,其中
R2为C1-6烷基;
R3为氨基(C1-6烷基)氮杂环丁烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基或氨基(C1-6烷氧基)吡咯烷基;
Y为CH并且A为N;或Y为N并且A为CH;
或其药用盐。
本发明的进一步的实施方案为(x),其为根据(i)至(ix)中任一者所述的式(I)或(Ia)的化合物,其中
R2为甲基;
R3为3-氨基-3-甲基-氮杂环丁烷-1-基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基或3-氨基-4-甲氧基-吡咯烷-1-基;
Y为CH并且A为N;或Y为N并且A为CH;
或其药用盐。
本发明的另一实施方案为(ix),其为选自以下项的式(I)或(Ia)的化合物:
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-氟吡咯烷-3-基]氨基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-[(3S)-3-氨基-3-甲基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-[(3S,4S)-3-氨基-4-羟基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-1-甲基-1,8-萘啶-2-酮;
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
2-氘代-5-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
2-氘代-5-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[3-(3-氨基氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[3-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;和
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
或其药用盐、对映体或非对映体。
专利US20150105370中公开了多种用作本文参比的化合物,其显示了表1中汇总的TLR7和TLR9效能数据(未获得TLR8数据)。表1中的所有化合物均在末端位置具有芳香环(苯基或吡啶基)。然而,根据公开的效能数据,表1中仅一些化合物显示出良好的TLR7效能,而所有这些化合物均缺乏TLR9效能。US20150105370中公开的具有相同结构特征的更多实例证实了这种趋势,这表明末端芳基/杂芳基环不利于TLR9活性。
同时,合成了US20150105370中公开的化合物的更多类似物,诸如在末端芳基环上带有一些取代基的化合物R1、化合物R2,以确认SAR(结构-活性-关系)。但是根据表2所示的效能数据,末端芳基环上的取代基不一定能提高TLR9的效能。因此,本领域技术人员不会从US20150105370公开的信息中获得任何启发来进一步优化这种化学结构。
令人惊讶地,本发明的化合物显著改善了TLR9效能(与ER-888286相比>8倍),同时保持了优异的TLR7和TLR8效能。在另一实施方案中,与来自US20150105370的参考化合物以及本文合成的参考化合物R1和R2相比,hERG特征和安全性比大大提高(参见表3)。式(I)或式(Ia)的化合物还显示出良好hPBMC、细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制作用。
表1.US20150105370中公开的化合物的TLR7和TLR9效能
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至R6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)化合物的一般合成路线在以下流程1中显示。
方案1
其中X为卤素;LG为离去基团,诸如OTf、OT和OM;PG为保护基团,诸如Boc和Cbz。
式(II)化合物与R1-X的偶联可在碱(诸如DIPEA或K2CO3)存在下或在Buchwald-Hartwig胺化条件下(参见: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),使用催化剂(诸如RuPhos Pd G2)和碱(诸如Cs2CO3)来实现,以提供式(III)化合物。随后,在碱性条件(诸如DIPEA、TEA、K2CO3)和2,6-二甲基吡啶下使用Tf2O、TsCl或MsCl,使式(III)化合物的羟基基团转变为离去基团(诸如OTf、OT和OM)。式(V)化合物的保护基团可在高温或在酸性条件(诸如TFA)下,或在氢化条件下,使用催化剂(诸如Pd/C和Pd(OH)2/C)除去。在碱(诸如K2CO3、DIPEA和Cs2CO3)存在下,将式(IV)化合物进一步被式(VI)化合物取代,以得到式(VII)化合物。式(VII)化合物与式(VIII)化合物的偶联可在Buchwald-Hartwig胺化条件下(参见:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics inCurrent Chemistry,2002,219,131-209;以及其中引用的参考文献),使用催化剂(诸如tBuXPhos Pd G3、RuPhos Pd G2、BrettPhos Pd G3、XPhos Pd G3、Pd2(dba)3/BINAP和Pd2(dba)3/XantPhos)和碱(诸如Cs2CO3或t-BuONa)来实现,以提供式(I)化合物。在一些实施方案中,式(VII)化合物与胺(VIII)的偶联可得到含有源自(VIII)的保护基团(例如Boc或Cbz)的产物,该保护基团将在获得最终的式(I)化合物之前除去。
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。在另一个实施方案中,式(Ia)化合物可根据上述方案使用相应的手性起始材料来获得。
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)、(Ia)的化合物的方法,该方法包括以下步骤:
a)式(VII)化合物,
与胺HR3(VIII)通过Buchwald-Hartwig胺化发生反应;
其中,X为卤素,Y和A独立地选自CH和N。
根据上述方法采用非手性或手性原料制造式(I)或(Ia)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。
另一实施方案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)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
Boc2O: 二碳酸二叔丁酯
Tf2O: 三氟甲磺酸酐
DCM: 二氯甲烷
DDI 药物-药物相互作用
DIPEA 二乙基异丙基胺
EA或EtOAc: 乙酸乙酯
FA: 甲酸
HLM 人肝微粒体
hr 小时
hrs 小时
IC50: 半抑制浓度
LCMS 液相色谱-质谱
LYSA 冻干溶解度测定
MS: 质谱
PE: 石油醚
prep-HPLC: 制备型高效液相色谱
rt: rt
RT: 保留时间
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)第二代
SFC: 超临界流体色谱
TFA: 三氟乙酸
v/v 体积比
一般实验条件
使用以下仪器中的一个仪器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,否则试剂按从商业供应商处获得的原样使用,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E
[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯
根据以下方案制备标题化合物:
步骤1:制备4-氯-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(化合物E1)
向4-氯吡唑并[1,5-a]吡啶-7-甲腈(CAS:1268520-74-6,供应商:Pharmablock,600mg,3.38mmol)在乙腈(50mL)中的溶液加入选择性氟试剂(2.39g,6.76mmol)。在室温下搅拌24小时后,将混合物浓缩并且用水(30mL)稀释,用DCM(30mL)萃取两次。将有机层用NH4Cl和盐水洗涤,经Na2SO4干燥,并且浓缩,以得到粗产物,将其通过硅胶层析法纯化,以得到化合物E1(419mg),其为淡黄色粉末。MS:计算196(MH+),测量196(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.17(d,J=3.5Hz,1H),7.55(d,J=7.6Hz,1H),7.35(d,J=7.7Hz,1H)。
步骤2:制备3-氟-4-[(2R,6R)-2-(羟基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈(化合物E2)
在N2下,向4-氯-3-氟吡唑并[1,5-a]吡啶-7-甲腈(化合物E1,419mg,2.14mmol)、[(2R,6R)-6-甲基吗啉-2-基]甲醇;2,2,2-三氟乙酸(化合物A1,526mg,2.14mmol)和Cs2CO3(2.79g,8.57mmol)在1,4-二噁烷(10mL)中的溶液加入RuPhos Pd G2(116mg,0.15mmol)。将反应混合物在90℃下加热2小时。冷却后,将混合物用EtOAc稀释并且通过硅藻土过滤。浓缩滤液,以得到棕色油状物,将其通过硅胶层析法纯化,以得到化合物E2(325mg),其为黄色油状物。MS:计算291(MH+),测量291(MH+)。
步骤3:制备(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)
在室温下,向3-氟-4-[(2R,6R)-2-(羟基甲基)-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈(化合物E2,325mg,1.12mmol)在DCM(3mL)中的溶液中加入2,6-二甲基吡啶(240mg,258μL,2.24mmol)和Tf2O(474mg,284μL,1.68mmol)。搅拌1.5小时后,将混合物用DCM稀释,用饱和NH4Cl和盐水洗涤。有机层经Na2SO4干燥并浓缩,得到粗产物,将其通过硅胶层析法纯化,以得到中间体E(180mg),其为黄色固体。MS:计算423(MH+),测量423(MH+)。
中间体F
[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯
类似于中间体E的制备方法,使用4-氯吡唑并[1,5-a]吡啶-7-甲腈(CAS:1268520-74-6,供应商:PharmaBlock)代替4-氯-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(化合物E1)制备标题化合物。获得中间体F(166mg),其为白色固体。MS:计算405(MH+),测量405(MH+)。
中间体L
[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯
根据以下方案制备中间体L:
步骤1:制备N-(2-溴-5-氟-苯基)-3,3-二甲氧基-丙酰胺(化合物L1)
在0℃下,向2-溴-5-氟苯胺(CAS:1003-99-2,供应商:TCI,50g,263.14mmol)和3,3-二甲氧基丙酸甲酯(CAS:7424-91-1,供应商:Accela,45mL,315.77mmol)在THF(150mL)中的溶液逐滴加入在THF中的NaHMDS(1M,394mL,394.72mmol)。在0℃下搅拌10min后,将混合物温热至15℃并且搅拌18小时。通过加入100mL饱和NH4Cl猝灭反应,并且将其浓缩至约300mL。将溶液用500mL水稀释,并且用200mL EA萃取三次。将合并的有机层用200mL水洗涤两次,并且用100mL盐水洗涤,经Na2SO4干燥,并且浓缩,以得到粗产物L1(100g),其为棕色油状物。MS计算值321(MH+),实测值321(MH+)。
步骤2:制备8-溴-5-氟-1H-喹啉-2-酮(化合物L2)
在0℃下,将N-(2-溴-5-氟-苯基)-3,3-二甲氧基-丙酰胺(化合物L1,100g,238.46mmol)在DCM(500mL)中的溶液加入浓硫酸(300mL)中。在15℃下搅拌2小时后,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。在真空中干燥固体,以得到化合物L2(50g),其为黄色固体。MS计算值242(MH+),实测值242(MH+)。
步骤3:制备5-氟-2-氧代-1H-喹啉-8-甲腈(化合物L3)
将8-溴-5-氟-1H-喹啉-2-酮(化合物L2,50g,206.58mmol)、氰化锌(48.50g,413.15mmol)、Pd(PPh3)4(24.29g,21.02mmol)在DMF(1000mL)中的溶液在120℃下搅拌5小时。冷却后,将反应混合物用300mL饱和NH4Cl猝灭,用2000mL水稀释,并且用500mL DCM萃取三次。将合并的有机层用500mL水洗涤两次,并且用200mL盐水洗涤一次,经Na2SO4干燥,并且浓缩,以得到粗产物,将其通过硅胶层析法(PE/EA=3/1)纯化,以得到化合物L3(29g),其为黄色固体。MS计算值189(MH+),实测值189(MH+)。
步骤4:制备(8-氰基-5-氟-2-喹啉基)三氟甲磺酸酯(化合物L4)
在0℃下,向5-氟-2-氧代-1H-喹啉-8-甲腈(化合物L3,17g,90.35mmol)、2,6-二甲基吡啶(38.7g,361mmol)在DCM(500mL)中的溶液加入三氟甲磺酸酐(51g,181mmol)。在0℃下搅拌1h后,将混合物用500mL水稀释并且用200mL DCM萃取三次。将合并的有机层用200mL水洗涤两次,并且用100mL盐水洗涤一次,经Na2SO4干燥,并且浓缩,以得到粗产物,将其通过硅胶层析法(PE/EA=5/1)纯化,以得到化合物L4(23g),其为黄色固体。MS计算值321(MH+),实测值321(MH+)。
步骤5:制备2-氘代-5-氟-喹啉-8-甲腈(化合物L5)
向(8-氰基-5-氟-2-喹啉基)三氟甲磺酸酯(化合物L4,23g,71.83mmol)在THF(230mL)和氧化氘(100mL)的溶液中加入碳酸钾(19.8g,1.44mol)和Pd/C(10重量%,6g)。将混合物在氘气氛下于40℃下搅拌5小时。然后过滤混合物,然后将滤液浓缩并且利用硅胶层析法(PE/EA=5/1)进行纯化,以得到化合物L5(11.4g),其为淡黄色固体。MS计算值174(MH+),实测值174(MH+)。
步骤6:制备5-((2R,6R)-2-(羟基甲基)-6-甲基吗啉代)喹啉-8-甲腈-2-d(化合物L7)
将5-氟喹啉-8-甲腈-2-d(化合物L5,611mg,3.53mmol)、((2R,6R)-6-甲基吗啉-2-基)甲醇盐酸盐(化合物L6,710mg,4.23mmol)、N-乙基-N-异丙基丙烷-2-胺(1.37g,10.6mmol)在DMSO(3mL)中的混合物于120℃下搅拌16小时。然后将溶液用EA稀释,并且用水和盐水洗涤。将合并的有机层干燥并浓缩。利用硅胶层析法(EA/PE为20%至80%)纯化残余物,以得到5-((2R,6R)-2-(羟基甲基)-6-甲基吗啉代)喹啉-8-甲腈-2-d(化合物L7,990mg),其为黄色固体。MS:计算285(MH+),测量285(MH+)。
步骤7:制备((2R,6R)-4-(8-氰基喹啉-5-基-2-d)-6-甲基吗啉-2-基)三氟甲磺酸甲酯(中间体L)
在0℃下,向5-((2R,6R)-2-(羟基甲基)-6-甲基吗啉代)喹啉-8-甲腈-2-d(化合物L7,3g)和2,6-二甲基吡啶(3.39g,3.77ml,31.7mmol)在CH2Cl2(20ml)中的溶液中逐滴加入三氟甲磺酸酐(4.47g,2.67ml,15.8mmol)。将混合物在0℃下搅拌1h,然后用DCM稀释,并且用饱和NH4Cl溶液和盐水洗涤。有机层经Na2SO4干燥并浓缩。利用硅胶层析法(EA/PE为20%至60%)纯化残余物,以得到((2R,6R)-4-(8-氰基喹啉-5-基-2-d)-6-甲基吗啉-2-基)三氟甲磺酸甲酯(中间体L 4.087g),其为黄色固体。MS:计算417(MH+),测量417(MH+)。
中间体M
[(2R,6R)-6-甲基-4-(1-甲基-2-氧代-1,8-萘啶-4-基)吗啉-2-基]三氟甲磺酸甲酯
类似于中间体A的制备方法,使用4-溴-1-甲基-1,8-萘啶-2-酮(化合物M1)代替5-溴喹啉-8-甲腈(化合物A2)制备标题化合物。获得中间体M(140mg),其为黄色固体。MS:计算422(MH+),测量422(MH+)。
根据以下方案制备化合物M1:
制备4-溴-1-甲基-1,8-萘啶-2-酮(化合物M1)
向4-溴-1,8-萘啶-2(1H)-酮(CAS:72235-36-0,供应商:Accela,370mg,1.64mmol)在DMF(15mL)中的溶液加入碘甲烷(2.33g,16.40mmol)和Cs2CO3(1.07g,3.29mmol)。将反应混合物在80℃下搅拌过夜。冷却后,利用冰水(30mL)猝灭反应。通过过滤收集固体,以得到粗化合物M1(419mg),将其直接用于下一步。MS计算值239(MH+),实测值239(MH+)。1H NMR(400MHz,甲醇-d4)δ=8.72(dd,J=1.7,4.7Hz,1H),8.39(dd,J=1.7,7.9Hz,1H),7.43(dd,J=4.7,8.0Hz,1H),7.20(s,1H),3.83(s,3H)。
实例1
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
根据以下方案制备标题化合物:
步骤1:6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷](化合物1b)
向6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a,CAS:1398609-80-7,Pharmablock,260mg)在DCM(2mL)中的溶液中加入三氟乙酸(0.5mL)。在室温下搅拌3小时后,将混合物在真空中浓缩,以得到白色油状物,其可以直接使用而不经纯化。获得184mg 6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷](化合物1b)。MS计算值242(MH+),实测值242(MH+)。
步骤2:4-[(2S,6R)-2-[(6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(化合物1c)
将6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷](化合物1b,35mg,146μmol)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E,62mg,146μmol)和DIPEA(0.2mL)在CH2Cl2(20mL)中的混合物于室温下搅拌2小时。然后将该混合物用DCM稀释,并且用盐水洗涤。有机层经Na2SO4干燥并浓缩。利用硅胶层析法(EA/PE为0%至100%)纯化残余物,以得到4-[(2S,6R)-2-[(6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(化合物1c,52mg),其为黄色固体。MS:计算值513(MH+),实测值513(MH+)。
步骤3:N-[1-[1'-[[(2S,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]螺[3H-异苯并呋喃-1,3'-氮杂环丁烷]-5-基]-3-甲基-氮杂环丁烷-3-基]氨基甲酸叔丁酯(化合物1e)
向4-[(2S,6R)-2-[(6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(化合物1c,74mg,144μmol)在二噁烷(10mL)中的溶液中加入RuPhos-Pd-G2(11mg,14.4μmol)、(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d,40mg,217μmol)和K2CO3(100mg,722μmol)。将反应混合物在N2下于90℃搅拌过夜。然后过滤该混合物,并且在减压下浓缩滤液,以得到粗产物,其可以直接用于下一步而不经纯化(化合物1e,89mg)。MS:计算618(MH+),测量618(MH+)。
步骤4:4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈(实例1)
在0℃下,向N-[1-[1'-[[(2S,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]甲基]螺[3H-异苯并呋喃-1,3'-氮杂环丁烷]-5-基]-3-甲基-氮杂环丁烷-3-基]氨基甲酸叔丁酯(化合物1e,89mg)在DCM(10mL)中的溶液中加入TFA(2mL)。将反应混合物在室温搅拌2小时。然后浓缩该混合物,以得到粗产物,利用制备型HPLC纯化该粗产物,以得到实例1(7mg),其为黄色固体。MS计算值518(MH+),实测值518(MH+)。1H NMR(甲醇-d4,400MHz)δ7.91(d,J=3.7Hz,1H),7.46(d,J=8.3Hz,1H),7.35(d,J=7.9Hz,1H),6.42-6.56(m,2H),6.29-6.39(m,1H),5.00(s,2H),4.35-4.57(m,3H),3.98-4.13(m,2H),3.76-3.95(m,5H),3.36-3.61(m,4H),2.49-2.80(m,2H),1.57(s,3H),1.18ppm(d,J=6.2Hz,3H)。
实例2
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用2-甲基-2,6-二氮杂螺[3.3]庚烷代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例2(26mg),为黄色固体。MS:计算544(MH+),测量544(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.7Hz,1H),7.53(d J=8.2Hz,1H,),7.44(d,J=7.9Hz,1H),6.55(d,J=7.9Hz,2H),6.39(d,J=1.1Hz,1H),5.08(s,2H),4.53(br d,J=11.5Hz,5H),4.25(br d,J=11.1Hz,2H),4.0-4.2(m,6H),3.9-4.0(m,1H),3.5-3.7(m,4H),2.94(s,3H),2.7-2.8(m,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H)。
实例3
3-氟-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-氟吡咯烷-3-基]氨基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用(3S,4R)-3-氨基-4-氟吡咯烷-1-甲酸叔丁酯(CAS:1174020-30-4,供应商:PharmaBlock)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例3(19mg),其为淡棕色固体。MS:计算536(MH+),测量536(MH+)。1H NMR(甲醇-d4,400MHz)δ8.00(d,J=3.5Hz,1H),7.51(br d,J=8.3Hz,1H),7.44(d,J=7.9Hz,1H),6.85(br d,J=8.4Hz,1H),6.68(s,1H),6.55(d,J=7.9Hz,1H),5.2-5.4(m,1H),5.08(s,2H),4.4-4.6(m,4H),4.1-4.2(m,1H),3.9-4.0(m,1H),3.7-3.8(m,2H),3.59(br d,J=12.7Hz,6H),3.21(br t,J=11.2Hz,1H),2.79(br t,J=11.2Hz,1H),2.68(br t,J=11.3Hz,1H),1.28(d,J=6.2Hz,3H)。
实例4
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用2-氧杂-5,8-二氮杂螺[3.5]壬烷-8-甲酸叔丁酯(CAS:1367777-12-5,供应商:PharmaBlock)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例4(33mg),其为淡棕色固体。MS:计算560(MH+),测量560(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.7Hz,1H),7.54(d,J=8.3Hz,1H),7.44(d,J=7.8Hz,1H),6.59(br d,J=8.6Hz,1H),6.55(d,J=7.9Hz,1H),6.44(d,J=1.3Hz,1H),5.10(s,2H),4.6-4.8(m,1H),4.4-4.6(m,3H),4.1-4.2(m,1H),4.0-4.1(m,2H),3.9-4.0(m,3H),3.8-3.8(m,2H),3.5-3.7(m,4H),3.5-3.5(m,2H),3.2-3.3(m,2H),2.6-2.8(m,2H),1.28(d,J=6.2Hz,3H)。
实例5
4-[(2S,6R)-2-[[6-[(3S)-3-氨基-3-甲基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用(S)-(3-甲基吡咯烷-3-基)氨基甲酸叔丁酯(CAS:927652-04-8,供应商:PharmaBlock)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例5(13mg),其为白色固体。MS:计算532(MH+),测量532(MH+)。1H NMR(甲醇-d4,400MHz)δ7.89(d,J=3.7Hz,1H),7.32(dd,J=3.4,8.1Hz,2H),6.46(dd,J=1.9,8.4Hz,1H),6.41(d,J=7.9Hz,1H),6.27(s,1H),4.88(s,2H),3.7-3.8(m,2H),3.5-3.6(m,5H),3.4-3.4(m,2H),3.2-3.3(m,1H),3.09(s,2H),2.5-2.7(m,4H),1.8-1.9(m,2H),1.25(s,3H),1.13(d,J=6.4Hz,3H)。
实例6
3-氟-4-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用哌嗪-1-甲酸叔丁酯代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例6(33mg),为黄色固体。MS:计算518(MH+),测量518(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.5Hz,1H),7.63(d,J=8.4Hz,1H),7.44(d,J=7.9Hz,1H),7.12(dd,J=2.1,8.5Hz,1H),6.9-7.0(m,1H),6.55(d,J=7.9Hz,1H),5.13(s,2H),4.5-4.5(m,2H),4.1-4.2(m,1H),3.9-4.0(m,1H),3.5-3.6(m,4H),3.4-3.5(m,5H),3.4-3.4(m,5H),2.78(t,J=11.2Hz,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H)。
实例7
4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体F)和2-氧杂-5,8-二氮杂螺[3.5]壬烷-8-甲酸叔丁酯(CAS:1367777-12-5,供应商:PharmaBlock)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例7(7mg),其为白色固体。MS:计算542(MH+),测量542(MH+)。1H NMR(甲醇-d4,400MHz)δ7.93(d,J=2.3Hz,1H),7.4-7.4(m,1H),7.36(s,1H),6.77(d,J=2.4Hz,1H),6.50(d,J=8.1Hz,1H),6.43(dd,J=1.8,8.2Hz,1H),6.27(s,1H),4.89(s,2H),4.49(br s,2H),3.8-3.8(m,4H),3.6-3.6(m,6H),3.5-3.6(m,2H),2.93(s,2H),2.7-2.7(m,4H),2.5-2.6(m,2H),1.15(d,J=6.2Hz,3H)。
实例8
4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体F)和2-甲基-2,6-二氮杂螺[3.3]庚烷代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例8(25mg),其为白色固体。MS:计算526(MH+),测量526(MH+)。1H NMR(甲醇-d4,400MHz)δ8.02(d,J=2.3Hz,1H),7.47(d,J=4.9Hz,1H),7.45(d,J=5.1Hz,1H),6.86(d,J=2.4Hz,1H),6.59(d,J=7.9Hz,1H),6.48(dd,J=2.0,8.3Hz,1H),6.33(d,J=1.3Hz,1H),4.97(s,2H),3.8-3.9(m,7H),3.73(br d,J=12.1Hz,1H),3.6-3.7(m,4H),3.48(s,4H),2.7-2.8(m,3H),2.6-2.7(m,1H),2.36(s,3H),1.24(d,J=6.2Hz,3H)。
实例9
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用氮杂环丁烷-3-基氨基甲酸叔丁酯(CAS:91188-13-5,供应商:BePharm)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例9(7mg),其为白色固体。MS:计算504(MH+),测量504(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.7Hz,1H),7.55(d,J=8.3Hz,1H),7.45(d,J=7.8Hz,1H),6.5-6.6(m,2H),6.44(s,1H),5.10(s,2H),4.1-4.3(m,4H),3.9-4.0(m,3H),3.7-3.8(m,1H),3.5-3.7(m,4H),3.4-3.5(m,1H),2.6-2.8(m,2H),2.03(s,2H),1.28(d,J=6.2Hz,3H)。
实例10
4-[(2S,6R)-2-[[6-[(3S,4S)-3-氨基-4-羟基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用((3R,4R)-4-羟基吡咯烷-3-基)氨基甲酸叔丁酯盐酸盐(CAS:1820575-70-9,供应商:BePharm)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例10(8mg),其为淡黄色固体。MS:计算534(MH+),测量534(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.5Hz,1H),7.5-7.6(m,1H),7.44(d,J=7.9Hz,1H),6.7-6.8(m,1H),6.5-6.6(m,2H),5.11(br d,J=9.2Hz,2H),4.4-4.6(m,4H),4.38(d,J=3.8Hz,1H),4.1-4.2(m,2H),3.9-4.0(m,2H),3.7-3.8(m,2H),3.5-3.7(m,4H),3.4-3.5(m,2H),2.7-2.8(m,2H),1.28(d,J=6.2Hz,3H)。
实例11
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例11(13mg),为黄色固体。MS:计算512(MH+),测量512(MH+)。1H NMR(400MHz,甲醇-d4)δ8.66(d,J=8.7Hz,1H),8.17(d,J=8.1Hz,1H),7.65(d,J=8.7Hz,1H),7.55(d,J=8.3Hz,1H),7.28(d,J=8.1Hz,1H),6.59(dd,J=8.3,2.0Hz,1H),6.44(s,1H),5.08(s,2H),4.21-4.68(m,5H),4.07-4.18(m,1H),3.86-4.01(m,4H),3.37-3.58(m,4H),2.64-2.91(m,2H),1.67(s,3H),1.28(d,J=6.2Hz,3H)。
实例12
4-[(2S,6R)-2-[[6-(2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用2,6-二氮杂螺[3.3]庚烷-2-甲酸草酸叔丁酯(CAS:1041026-71-4,供应商:PharmaBlock)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例12(18mg),其为淡棕色固体。MS:计算530(MH+),测量530(MH+)。1H NMR(甲醇-d4,400MHz)δ8.01(d,J=3.5Hz,1H),7.52(d,J=8.3Hz,1H),7.44(d,J=7.8Hz,1H),6.55(d,J=7.9Hz,2H),6.39(d,J=1.3Hz,1H),5.08(s,2H),4.4-4.6(m,4H),4.30(s,4H),4.1-4.2(m,1H),4.06(s,4H),3.9-4.0(m,1H),3.5-3.6(m,4H),2.78(t,J=11.2Hz,1H),2.6-2.7(m,1H),1.28(d,J=6.2Hz,3H)。
实例13
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备方法,使用N-(氮杂环丁烷-3-基)氨基甲酸叔丁酯和[(2R,6R)-6-甲基-4-(1-甲基-2-氧代-1,8-萘啶-4-基)吗啉-2-基]三氟甲磺酸甲酯(中间体M)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例13(4mg),为黄色固体。MS:计算503(MH+),测量503(MH+)。1H NMR(400MHz,甲醇-d4)δ8.64(dd,J=4.6,1.8Hz,1H),8.25(dd,J=8.0,1.8Hz,1H),7.43(d,J=8.3Hz,1H),7.30(dd,J=8.0,4.6Hz,1H),6.48(dd,J=8.3,2.0Hz,1H),6.33(d,J=0.9Hz,1H),6.15(s,1H),4.96(s,2H),4.12(t,J=7.3Hz,2H),3.80-4.00(m,3H),3.72(d,J=2.9Hz,3H),3.45-3.51(m,3H),3.11-3.23(m,5H),2.48-2.82(m,4H),1.22(d,J=6.2Hz,3H)。
实例14
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用N-(氮杂环丁烷-3-基)氨基甲酸叔丁酯和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例14(19mg),为黄色固体。MS:计算498(MH+),测量498(MH+)。1H NMR(400MHz,甲醇-d4)δ8.66(d,J=8.6Hz,1H),8.17(d,J=7.9Hz,1H),7.65(d,J=8.6Hz,1H),7.56(br d,J=8.2Hz,1H),7.29(d,J=8.1Hz,1H),6.59(br d,J=8.1Hz,1H),6.45(d,J=1.5Hz,1H),5.11(s,2H),4.43-4.70(m,3H),4.08(m,5H),3.84-3.99(m,2H),3.38-3.72(m,5H),2.62-2.91(m,2H),1.29(d,J=6.2Hz,3H)。
实例15
2-氘代-5-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]喹啉-8-甲腈
类似于实例1的制备方法,使用5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-甲酸叔丁酯和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例15(9mg),为黄色固体。MS:计算554(MH+),测量554(MH+)。1H NMR(400MHz,甲醇-d4)δ8.55(d,J=8.7Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8.7Hz,1H),7.36(d,J=8.2Hz,1H),7.15(d,J=8.1Hz,1H),6.42(dd,J=8.3,2.0Hz,1H),6.27(d,J=1.5Hz,1H),4.90(s,2H),3.88-4.08(m,2H),3.79(d,J=8.2Hz,2H),3.48-3.75(m,8H),3.27-3.44(m,2H),2.97(s,2H),2.71-2.84(m,4H),2.48-2.72(m,2H),1.15(d,J=6.2Hz,3H)。
实例16
5-[(2S,6R)-2-[[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1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(PharmaBlock,PBZ4728,CAS:1932066-52-8)和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例16(9mg),为黄色固体。MS:计算542(MH+),测量542(MH+)。1H NMR(400MHz,甲醇-d4)δ8.55(d,J=8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8.6Hz,1H),7.35(d,J=8.3Hz,1H),7.15(d,J=8.1Hz,1H),6.51(dd,J=8.4,2.0Hz,1H),6.34(d,J=1.6Hz,1H),4.90(s,2H),3.88-4.02(m,2H),3.70-3.80(m,1H),3.58-3.68(m,5H),3.37-3.52(m,2H),3.24-3.35(m,4H),3.02-3.20(m,2H),2.49-2.82(m,4H),1.15ppm(d,J=6.4Hz,3H)。
实例17
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用(4aR,7aR)-3,4a,5,6,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-4-甲酸叔丁酯(PharmaBlock,PBXA8123,CAS:1932337-68-2)和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例17(9mg),为黄色固体。MS:计算554(MH+),测量554(MH+)。1H NMR(400MHz,甲醇-d4)δ8.55(d,J=8.6Hz,1H),8.05(d,J=8.1Hz,1H),7.53(d,J=8.6Hz,1H),7.34(d,J=8.4Hz,1H),7.16(d,J=8.1Hz,1H),6.46(dd,J=8.5,1.9Hz,1H),6.29(d,J=1.5Hz,1H),4.91(s,2H),3.82-4.07(m,3H),3.62-3.80(m,5H),3.26-3.59(m,6H),2.82-3.12(m,6H),2.50-2.76(m,2H),1.15(d,J=6.2Hz,3H)。
实例18
2-氘代-5-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]喹啉-8-甲腈
类似于实例1的制备方法,使用哌嗪-1-甲酸叔丁酯和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例18(2mg),为黄色固体。MS:计算512(MH+),测量512(MH+)。1H NMR(400MHz,甲醇-d4)δ8.55(d,J=8.6Hz,1H),8.06(d,J=7.9Hz,1H),7.53(d,J=8.6Hz,1H),7.45(d,J=8.4Hz,1H),7.16(d,J=8.1Hz,1H),6.93(dd,J=8.3,2.2Hz,1H),6.79(d,J=1.3Hz,1H),4.92(s,2H),3.86-4.12(m,2H),3.72(m,4H),3.28-3.44(m,6H),3.08-3.17(m,4H),2.51-2.80(m,4H),1.14(d,J=6.2Hz,3H)。
实例19
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体F)和氮杂环丁烷-3-基氨基甲酸叔丁酯(CAS:91188-13-5,供应商:BePharm)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)制备标题化合物。获得实例19(12mg),其为淡黄色固体。MS:计算486(MH+),测量486(MH+)。1H NMR(甲醇-d4,400MHz)δ8.02(d,J=2.3Hz,1H),7.46(dd,J=6.0,8.1Hz,2H),6.87(d,J=2.3Hz,1H),6.59(d,J=7.9Hz,1H),6.49(dd,J=1.7,8.3Hz,1H),6.34(s,1H),4.97(s,2H),4.58(br s,3H),4.12(t,J=7.3Hz,2H),3.9-3.9(m,3H),3.73(brd,J=12.0Hz,1H),3.6-3.7(m,3H),3.5-3.5(m,2H),2.7-2.8(m,2H),2.6-2.7(m,1H),1.24(d,J=6.2Hz,3H)。
实例20
5-[(2S,6R)-2-[[3-(3-氨基氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用N-(氮杂环丁烷-3-基)氨基甲酸叔丁酯和3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-甲酸叔丁酯(CAS:1575836-59-7,目录号:PBU1967,供应商:Pharmablock)以及[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)以及[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例20(3mg),为黄色固体。MS:计算499(MH+),测量499(MH+)。1H NMR(400MHz,甲醇-d4)δ8.66(d,J=8.6Hz,1H),8.16(d,J=7.9Hz,1H),7.75(d,J=2.6Hz,1H),7.65(d,J=8.7Hz,1H),7.27(d,J=8.1Hz,1H),6.81(d,J=2.4Hz,1H),5.04(s,2H),4.22(t,J=7.4Hz,2H),3.91-4.12(m,3H),3.67-3.82(m,4H),3.60(dd,J=7.7,5.6Hz,2H),3.35-3.50(m,5H),2.55-2.92(m,4H)。
实例21
5-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-甲酸叔丁酯和[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)和[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例21(10mg),为黄色固体。MS:计算513(MH+),测量513(MH+)。1H NMR(400MHz,甲醇-d4)δ8.66(d,J=8.6Hz,1H),8.16(d,J=8.1Hz,1H),7.75(d,J=2.4Hz,1H),7.65(d,J=8.7Hz,1H),7.27(d,J=8.1Hz,1H),6.82(d,J=2.4Hz,1H),5.04(s,2H),3.95-4.18(m,2H),3.83-3.90(m,2H),3.61-3.80(m,6H),3.36-3.52(m,2H),2.56-2.93(m,4H),1.54(s,3H),1.24(d,J=6.2Hz,3H)。
实例22
3-氟-4-[(2R,6S)-2-甲基-6-[[3-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用2-甲基-2,6-二氮杂螺[3.3]庚烷和3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-甲酸叔丁酯代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例22(15mg),为黄色固体。MS:计算545(MH+),测量545(MH+)。1H NMR(400MHz,甲醇-d4)δ7.91(d,J=3.7Hz,1H),7.76(s,1H),7.35(d,J=7.9Hz,1H),6.75(d,J=2.4Hz,1H),6.46(d,J=7.9Hz,1H),5.02(s,2H),4.31-4.61(m,6H),4.00-4.23(m,7H),3.79-3.94(m,1H),3.41-3.67(m,4H),2.85(s,3H),2.48-2.74(m,2H),1.18(d,J=6.2Hz,3H)。
实例23
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)和叔-螺[氮杂环丁烷-3,3'(1'H)-呋喃并[3,4-c]吡啶]-1-甲酸,6'-氯-,1,1-二甲基乙酯(CAS:1575836-95-1,供应商:PharmaBlock)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例23(38mg),其为淡黄色固体。MS:计算513(MH+),测量513(MH+)。1HNMR(甲醇-d4,400MHz)δ8.63(d,J=8.7Hz,1H),8.54(s,1H),8.13(d,J=7.9Hz,1H),7.63(d,J=8.6Hz,1H),7.25(d,J=8.1Hz,1H),6.7-6.8(m,1H),5.17(s,2H),4.81(br d,J=8.4Hz,2H),4.63(br dd,J=12.0,17.2Hz,2H),4.4-4.4(m,2H),4.3-4.4(m,3H),4.1-4.2(m,1H),3.6-3.7(m,1H),3.5-3.6(m,1H),3.41(br t,J=11.5Hz,2H),2.79(t,J=11.1Hz,1H),2.70(dd,J=10.4,12.1Hz,1H),1.73(s,3H),1.28(d,J=6.2Hz,3H)。
实例24
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用叔-螺[氮杂环丁烷-3,3'(1'H)-呋喃并[3,4-c]吡啶]-1-甲酸,6'-氯-,1,1-二甲基乙酯(CAS:1575836-95-1,供应商:PharmaBlock)代替6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例24(3mg),其为淡黄色固体。MS:计算519(MH+),测量519(MH+)。1H NMR(甲醇-d4,400MHz)δ8.47(s,1H),8.01(d,J=3.5Hz,1H),7.44(d,J=7.8Hz,1H),6.55(d,J=7.9Hz,1H),6.51(d,J=0.7Hz,1H),5.11(s,2H),4.6-4.7(m,2H),4.5-4.6(m,2H),4.2-4.2(m,2H),4.1-4.2(m,3H),3.9-4.0(m,1H),3.5-3.7(m,4H),2.6-2.8(m,2H),1.69(s,3H),1.3-1.3(m,3H)。
实例25
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体F)和叔-螺[氮杂环丁烷-3,3'(1'H)-呋喃并[3,4-c]吡啶]-1-甲酸,6'-氯-,1,1-二甲基乙酯(CAS:1575836-95-1,供应商:PharmaBlock)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例25(22mg),其为淡黄色固体。MS:计算501(MH+),测量501(MH+)。1H NMR(甲醇-d4,400MHz)δ8.52(s,1H),8.03(d,J=2.3Hz,1H),7.46(d,J=7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.71(s,1H),6.62(d,J=7.9Hz,1H),5.16(s,2H),4.7-4.8(m,2H),4.62(br dd,J=12.0,17.4Hz,2H),4.38(d,J=9.9Hz,2H),4.2-4.3(m,2H),4.2-4.2(m,1H),3.9-4.0(m,1H),3.7-3.8(m,2H),3.7-3.7(m,1H),3.5-3.6(m,1H),2.77(dd,J=10.8,11.9Hz,1H),2.70(dd,J=10.6,12.3Hz,1H),1.73(s,3H),1.29(d,J=6.2Hz,3H)。
实例26
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(7-氰基吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体F)和3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3-氮杂环丁烷]-1-甲酸叔丁酯(CAS:1575836-59-7,供应商:PharmaBlock)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例26(7mg),其为淡黄色固体。MS:计算501(MH+),测量501(MH+)。1H NMR(甲醇-d4,400MHz)δ8.04(d,J=2.3Hz,1H),7.92(d,J=1.5Hz,1H),7.49(d,J=8.1Hz,1H),6.9-6.9(m,2H),6.64(d,J=8.1Hz,1H),5.13(s,2H),4.6-4.7(m,1H),4.5-4.6(m,2H),4.1-4.2(m,1H),4.10(d,J=8.6Hz,2H),4.0-4.0(m,3H),3.7-3.9(m,3H),3.5-3.6(m,2H),2.7-2.8(m,2H),1.69(s,3H),1.30(d,J=6.1Hz,3H)。
实例28
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用(4aR,7aR)-3,4a,5,6,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-4-甲酸叔丁酯(PharmaBlock,PBXA8123,CAS:1932337-68-2)、[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)和叔-螺[氮杂环丁烷-3,3'(1'H)-呋喃并[3,4-c]吡啶]-1-甲酸,6'-氯-,1,1-二甲基乙酯(CAS:1575836-95-1,供应商:PharmaBlock)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)、[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例28(2mg),其为淡黄色固体。MS:计算555(MH+),测量555(MH+)。1HNMR(400MHz,甲醇-d4)δ8.67(d,J=8.7Hz,1H),8.34(s,1H),8.18(d,J=8.1Hz,1H),7.66(d,J=8.6Hz,1H),7.28(d,J=8.1Hz,1H),6.39(s,1H),4.99(s,2H),4.11–3.96(m,3H),3.83–3.72(m,3H),3.71–3.62(m,5H),3.52–3.44(m,1H),3.43–3.37(m,1H),3.17–3.12(m,1H),3.06–2.92(m,3H),2.80–2.77(m,2H),2.71–2.64(m,1H),2.24–2.18(m,1H),2.07–2.03(m,1H),1.26(d,J=6.4Hz,3H)。
实例29
5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用(4aR,7aR)-3,4a,5,6,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-4-甲酸叔丁酯(PharmaBlock,PBXA8123,CAS:1932337-68-2)和3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-甲酸叔丁酯(CAS:1575836-59-7,PBU1967,供应商:Pharmablock)以及[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)以及[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例29(13mg),为黄色固体。MS:计算555(MH+),测量555(MH+)。1H NMR(400MHz,甲醇-d4)δ8.54(d,J=8.6Hz,1H),8.04(d,J=8.1Hz,1H),7.73(d,J=2.4Hz,1H),7.53(d,J=8.6Hz,1H),7.15(d,J=8.1Hz,1H),6.76(d,J=2.4Hz,1H),4.94(s,2H),3.84-4.05(m,3H),3.43-3.78(m,8H),3.25-3.40(m,2H),2.48-3.15(m,9H),1.13ppm(d,J=6.2Hz,3H)。
实例31
5-[(2S,6R)-2-[[3-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1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(PharmaBlock,PBZ4728,CAS:1932066-52-8)和3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-甲酸叔丁酯(CAS:1575836-59-7,PBU1967,供应商:Pharmablock)以及[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)代替(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(化合物1d)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)以及[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)制备标题化合物。获得实例31(13mg),其为黄色固体。MS:计算值543(MH+),实测值543(MH+)。1H NMR(400MHz,甲醇-d4)δ8.54(d,J=8.7Hz,1H),8.05(d,J=7.9Hz,1H),7.75(d,J=2.4Hz,1H),7.53(d,J=8.7Hz,1H),7.15(d,J=8.1Hz,1H),6.79(d,J=2.4Hz,1H),4.94(s,2H),3.87-4.00(m,2H),3.57-3.78(m,6H),3.39-3.55(m,2H),3.23-3.38(m,6H),2.97-3.09(m,1H),2.44-2.81(m,4H),1.13ppm(d,J=6.2Hz,3H)。
实例32
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈
类似于实例1的制备方法,使用[(2R,6R)-4-(8-氰基-2-氘代-5-喹啉基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体L)和叔-螺[氮杂环丁烷-3,3'(1'H)-呋喃并[3,4-c]吡啶]-1-甲酸,6'-氯-,1,1-二甲基乙酯(CAS:1575836-95-1,供应商:PharmaBlock)代替[(2R,6R)-4-(7-氰基-3-氟-吡唑并[1,5-a]吡啶-4-基)-6-甲基-吗啉-2-基]三氟甲磺酸甲酯(中间体E)和6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例32(2mg),其为淡黄色固体。MS:计算499(MH+),测量499(MH+)。1HNMR(400MHz,甲醇-d4)δ8.65(d,J=8.6Hz,1H),8.32(s,1H),8.15(d,J=7.9Hz,1H),7.63(d,J=8.7Hz,1H),7.25(d,J=8.1Hz,1H),6.32(s,1H),4.96(s,2H),4.26(d,J=7.6Hz,1H),4.09–4.02(m,2H),3.78(dd,J=8.1,4.8Hz,2H),3.72–3.62(m,4H),3.49–3.41(m,2H),3.40–3.35(m,2H),2.81–2.71(m,3H),2.69–2.62(m,1H),1.24(d,J=6.2Hz,3H)。
实例33
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈
类似于实例1的制备方法,使用3-溴螺[5H-呋喃并[3,4-b]吡啶-7,3-氮杂环丁烷]-1-甲酸叔丁酯(CAS:1575836-59-7,供应商:PharmaBlock)代替6-溴螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-甲酸叔丁酯(化合物1a)制备标题化合物。获得实例33(3mg),其为淡黄色固体。MS:计算519(MH+),测量519(MH+)。1H NMR(400MHz,甲醇-d4)δ7.9-8.0(m,1H),7.8-7.9(m,1H),7.35(d,1H,J=7.9Hz),6.82(d,1H,J=2.6Hz),6.3-6.5(m,1H),5.04(s,2H),3.9-4.1(m,5H),3.3-3.6(m,6H),2.5-2.8(m,2H),2.96–3.10(m,3H),1.59(s,3H),1.1-1.3(m,3H)。
实例34
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250,000450,000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620655nm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250,000450,000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620655nm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250,000450,000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620655nm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)或式(Ia)的化合物具有人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
实例35
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;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。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36
预期这些化合物具有最小DDI指标。因此,确定了具有式(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试验,用于评估早期发现阶段人肝微粒体(HLM)中供试化合物对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(每种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(对于CYP2D6,孵育时间为10分钟)后,加入含有内标(400ng/mL 13C6-4'-OH-双氯芬酸、20ng/mL D3-右啡烷和20ng/mLD4-1'OH-咪达唑仑)的50μL 100%乙腈以猝灭孵育物。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
实例编号 | CYP(%)2C9/2D6/3A4 |
ER-888286 | 29.5/52.5/5.5 |
7 | 0/-2/16.5 |
8 | -8.5/5/-8.5 |
11 | 4/5.5/12 |
17 | 3.5/18.5/14 |
20 | 13.5/13/40.5 |
21 | 4.5/5/12.5 |
24 | 21/3.5/-0.5 |
抑制百分比<0:非抑制剂或弱抑制剂
Claims (22)
6.根据权利要求4所述的化合物,其中Y为CH并且A为N;或Y为N并且A为CH。
7.根据权利要求6所述的化合物,其中R3为氨基(C1-6烷基)氮杂环丁烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基或氨基(C1-6烷氧基)吡咯烷基。
8.根据权利要求7所述的化合物,其中R3为3-氨基-3-甲基-氮杂环丁烷-1-基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基或3-氨基-4-甲氧基-吡咯烷-1-基。
11.一种化合物,其选自:
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-氟吡咯烷-3-基]氨基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-[(3S)-3-氨基-3-甲基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2R,6S)-2-甲基-6-[[6-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-[(3S,4S)-3-氨基-4-羟基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(2,6-二氮杂螺[3.3]庚烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-1-甲基-1,8-萘啶-2-酮;
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;2-氘代-5-[(2R,6S)-2-甲基-6-[[6-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
2-氘代-5-[(2R,6S)-2-甲基-6-[(6-哌嗪-1-基螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基)甲基]吗啉-4-基]喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-异苯并呋喃-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[3-(3-氨基氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
3-氟-4-[(2R,6S)-2-甲基-6-[[3-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[6-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]吡唑并[1,5-a]吡啶-7-甲腈;
5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[3-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;
5-[(2S,6R)-2-[[6-(3-氨基氮杂环丁烷-1-基)螺[1H-呋喃并[3,4-c]吡啶-3,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-2-氘代-喹啉-8-甲腈;和
4-[(2S,6R)-2-[[3-(3-氨基-3-甲基-氮杂环丁烷-1-基)螺[5H-呋喃并[3,4-b]吡啶-7,3'-氮杂环丁烷]-1'-基]甲基]-6-甲基-吗啉-4-基]-3-氟-吡唑并[1,5-a]吡啶-7-甲腈;
或其药用盐、对映体或非对映体。
13.根据权利要求1至11中任一项所述的化合物或药用盐、对映体或非对映体,其用作治疗活性物质。
14.一种药物组合物,其包含根据权利要求1至11中任一项所述的化合物以及治疗惰性载体。
15.根据权利要求1至11中任一项所述的化合物用于治疗或预防系统性红斑狼疮或狼疮肾炎的用途。
16.根据权利要求1至11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系统性红斑狼疮或狼疮肾炎。
17.根据权利要求1至11中任一项所述的化合物作为TLR7或TLR8或TLR9拮抗剂的用途。
18.根据权利要求1至11中任一项所述的化合物作为TLR7和TLR8和TLR9拮抗剂的用途。
19.根据权利要求1至11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。
20.根据权利要求1至11中任一项所述的化合物或药用盐、对映体或非对映体,其用于治疗或预防系统性红斑狼疮或狼疮肾炎。
21.根据权利要求1至11中任一项所述的化合物或药用盐、对映体或非对映体,其根据权利要求12所述的方法生产。
22.一种用于治疗或预防系统性红斑狼疮或狼疮肾炎的方法,所述方法包括施用治疗有效量的如权利要求1至11中任一项所定义的化合物。
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CN104662014A (zh) * | 2012-07-10 | 2015-05-27 | 阿雷斯贸易股份有限公司 | 嘧啶吡唑基衍生物 |
WO2015057659A1 (en) * | 2013-10-14 | 2015-04-23 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
WO2017106607A1 (en) * | 2015-12-17 | 2017-06-22 | Merck Patent Gmbh | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
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