CN112204032A - 杂环衍生物及其用途 - Google Patents
杂环衍生物及其用途 Download PDFInfo
- Publication number
- CN112204032A CN112204032A CN201980035540.4A CN201980035540A CN112204032A CN 112204032 A CN112204032 A CN 112204032A CN 201980035540 A CN201980035540 A CN 201980035540A CN 112204032 A CN112204032 A CN 112204032A
- Authority
- CN
- China
- Prior art keywords
- pyrazin
- pyrido
- bromo
- imidazo
- methylpiperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract
本发明涉及用于制备用于治疗与组胺4受体的各种功能有关的疾病的药物的新型杂环化合物。特别地,这些药物可用于预防或治疗炎性疾病,变态反应,疼痛,鼻息肉,鼻炎,慢性鼻窦炎,鼻充血,鼻痒,哮喘,慢性阻塞性肺疾病,类风湿性关节炎,特应性皮炎,银屑病,湿疹,瘙痒,皮肤发痒,荨麻疹,特发性慢性荨麻疹,硬皮病,结膜炎,角膜结膜炎,眼部炎症,干眼症,年龄相关性黄斑变性,心功能障碍,心律失常,动脉粥样硬化,多发性硬化,炎性肠病(结肠炎,克罗恩病,溃疡性结肠炎),炎性疼痛,神经性疼痛,骨关节炎性疼痛,自身免疫性甲状腺疾病,免疫介导的(也称为I型)糖尿病,狼疮,术后粘连,前庭疾病和癌症。
Description
技术领域
本发明涉及用于制备用于治疗与组胺4受体的各种功能有关的疾病的药物的新型杂环化合物。特别地,这些药物可用于预防或治疗:炎性疾病,变态反应,疼痛,鼻息肉,鼻炎,慢性鼻窦炎,鼻充血,鼻痒,哮喘,慢性阻塞性肺疾病,类风湿性关节炎,特应性皮炎,银屑病,湿疹,瘙痒,皮肤发痒(itchy skin),荨麻疹,特发性慢性荨麻疹,硬皮病,结膜炎,角膜结膜炎,眼部炎症,干眼症,年龄相关性黄斑变性,心功能障碍,心律失常,动脉粥样硬化,多发性硬化,炎性肠病(结肠炎,克罗恩病,溃疡性结肠炎),炎性疼痛,神经性疼痛,骨关节炎性疼痛,自身免疫性甲状腺疾病,免疫介导的(也称为I型)糖尿病,狼疮,术后粘连,前庭疾病和癌症。
背景技术
组胺是一种生物胺,在免疫和炎症反应中起着核心作用,同时也是一种神经递质。例如,组胺控制抗原呈递细胞(树突状细胞和巨噬细胞),T细胞,B细胞,上皮和内皮细胞的各种功能,以及树突状细胞和肥大细胞中T细胞的增殖或细胞因子分泌(W.等人,J.Dtsch.Dermatol.Ges.2010,8,495-504)。存在4种组胺受体(组胺1受体,组胺2受体,组胺3受体和组胺4受体)(M.E.Parsons等人,Br.J.Pharmacol.2006,147,S127-S135)。急性变态反应由广泛分布在体内的组胺1受体控制(A.S.F.Ash等人,Br.J.Pharmacol.Chemother.1966,27,427-439),而胃酸分泌受组胺2受体控制,所述组胺2受体也像组胺1受体一样广泛分布在体内(J.W.Black等人,Nature 1972,236,385-390)。众所周知,中枢神经系统中神经递质的分泌受神经元中表达的组胺3受体的控制(J.M.Arrang等人,Nature1983,302,832-837)。组胺4受体进一步解释了许多信号传导过程的生理功能,其仅由组胺1受体,组胺2受体和组胺3受体无法解释。组胺4受体在1994年首次被报道,其克隆仅从2000年才开始进行。组胺4受体是一种G蛋白偶联受体,由390个氨基酸组成,并且其通过与Gi/o蛋白结合而活化,从而增加钙浓度或抑制环磷酸腺苷(cAMP)(M.Shahid等人,The Open Immunology Journal,2009,2,9-41)。组胺4受体主要在骨髓或嗜酸性粒细胞,嗜碱性粒细胞,T细胞,肥大细胞,单核细胞和树突状细胞中表达,并且还在脾,胸腺,肺,心脏和肠中被观察到(R.L.Thurmond等人,Nat.Rev.Drug Discov.2008,7,41-53;T.Nakamura等人,Biochem.Biophys.Res.Commun.2000,279,615-620)。组胺4受体不仅在免疫应答中起着中心作用,而且还对各种免疫细胞的活化和迁移以及细胞因子和趋化因子的产生有影响(R.Gutzmer等人,J.Immunol.2005,174,5224-5232;C.L.Hofstra等人,J.Pharmacol.Exp.Ther.2003,305,1212-1221;D.Dijkstra等人,J.AllergyClin.Immunol.2007,120,300-307;M.O’Reilly等人,J.Recept.SignalTransduct.Res.2002,22,431-448)。
在各种体内实验中,众所周知,组胺4受体在炎症和瘙痒中起重要作用(P.J.Dunford等人,J.Allergy Clin.Immunol.2007,119,176-183;R.L.Thurmond等人,J.Pharmacol.Exp.Ther.2004,309,404-413)。具体地,作为研究结果,已经发现在变应性小鼠哮喘模型中,组胺4拮抗剂通过控制Th2(T辅助2型)反应减轻了肺部炎症,并证实了组胺4拮抗剂可以有效抑制组胺引起的瘙痒。这种对变应性炎症和瘙痒的双重作用是以下事实的基础:组胺4受体可能是治疗变应性皮肤病(如特应性皮炎)的良好靶标(J.M.Cowden等人,J.Invest.Dermatol.2010,130,1023-1033)。
在这种免疫细胞中,对组胺4受体各种功能的拮抗作用是炎性疾病,瘙痒,疼痛,变应性鼻炎,哮喘,类风湿性关节炎,特应性皮炎,特发性慢性荨麻疹,炎性疼痛,神经性疼痛和骨关节炎性疼痛的研究重点。最近,从研究结果中报道了作为治疗剂的可能性,其中通过组胺4受体拮抗剂抑制了年龄相关性黄斑变性中的脉络膜新生血管形成(H.Kaneko等人,Br.J.Pharmacol.2014,171,3754-3763)。
另外,已经宣布了与针对组胺4受体的激动剂的单一疗法或联合疗法的抗癌功效有关的最新研究,因此有望将其开发为抗癌药(W.K.Cai等人,Eur.J.Cancer 2014,50,1195-1206;N.A.Massari等人,Oncotarget 2017,8,26471-26491;A.M.B.Abiuso等人,Eur.J.Cancer 2018,91,125-135)。
发明公开
技术问题
因此,本发明的目的是提供一种调节组胺4受体的新型杂环化合物。
本发明的另一个目的是提供一种用于预防或治疗与组胺4受体的活化或抑制有关的疾病的药物组合物。
解决技术问题的技术方案
根据本发明,提供了下式1的杂环化合物或其药学上可接受的盐或异构体:
[式1]
其中
X1,X2,X3和X4中的每一个独立地为C或N;
R1为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-12元单或多杂环基,其中R1未被取代或被1-3个选自-C1-C6烷基和-氨基-C1-C6烷基的取代基取代;
R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-C3-C8环烷基,-卤素(-F,-Cl,-Br,-I),-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-C2-C7烯基,-C2-C8炔基,-氨基,-乙酰基,-酰氨基,-磺酰胺,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基(-COOH),-C1-C6酰基,-OH,-硝基(-NO2),-C6-C10芳基,-杂环基和-O-C1-C6烷基-杂环基,其中杂环基为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-6元杂环基;
前提是,当X1为N时,R2不存在;当X2为N时,R3不存在;当X3为N时,R4不存在;且当X4为N时,R5不存在;且当X1,X2,X3和X4全部为C时,R3不为氢或氟(F);
Y1和Y2中的每一个独立地为C或N;
A环为包含至少2个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的5或6元杂环;和
R6和R7中的每一个独立地为氧代(=O)或=NH,且R6和R7之一可以不存在;
其中烷基,环烷基,杂环基,烷氧基,烯基,炔基,酰基和芳基中的每一个可以独立地未被取代或被一个或多个取代基(例如1-3个取代基)取代,所述取代基选自:-C1-C4烷基,-卤素(-F,-Cl,-Br,-I),-CN,-C1-C4烷氧基,-氨基,-酰氨基,-羧基(-COOH),-C1-C6酰基,-OH,-硝基(-NO2),杂环基和苯基,其中杂环基为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-6元杂环基。
根据本发明的一个实施方案,在式1中,
X1,X2,X3和X4中的每一个独立地为C或N;
R1为含有1-3个选自N,O和S的杂原子的饱和或不饱和的3-10元单或多杂环基,其中杂环基未被取代或被1或2个选自-C1-C6烷基和-氨基-C1-C6烷基的取代基取代;
R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-C3-C8环烷基,-卤素,-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-氨基,-乙酰基,-磺酰氨基,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基,-OH,-硝基,-C6-C10芳基,-杂环基和-O-C1-C6烷基-杂环基,其中杂环基为含有1-3个选自N,O和S的杂原子的饱和或不饱和的3-6元杂环基;
Y1和Y2中的每一个独立地为C或N;
A环为饱和或不饱和的包含2-4个选自N,O和S的杂原子5或6元杂环;和
R6和R7中的每一个独立地为氧代或=NH,并且R6和R7之一可以不存在。
根据本发明的另一个实施方案,在式1中,X1和X2为C且X3和X4中的每一个为C或N。
根据本发明的又一实施方案,在式1中,X1和X2中的每一个独立地为C或N,且X3和X4为C。
根据本发明的又一个实施方案,在式1中,R1为含有1-3个选自N和O的杂原子的饱和或不饱和的3-10元单或多杂环基,其中杂环基未被取代1或2个选自-C1-C4烷基和-氨基-C1-C4烷基的取代基取代。
根据本发明的又一个实施方案,在式1中,R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-卤素,-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-氨基,-乙酰基,-磺酰氨基,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基,-OH,-硝基和-杂环基,其中杂环基为含有1-3个选自N,O和S的杂原子的饱和或不饱和的5或6元杂环基。
根据本发明的又一个实施方案,在式1中,A环为含有2或3个选自N和S的杂原子的饱和或不饱和的5元或6元杂环。
根据本发明的又一个实施方案,在式1中,R6是氧代或=NH,且R7不存在。
根据本发明的又一个实施方案,在式1中,R6和R7为氧代。
除非另有说明,否则本文所述的烷基取代基和本文所述的其他取代基(例如烷氧基)中的烷基残基可以是直链或支链的。此外,卤素包括氟(F),氯(Cl),溴(Br)和碘(I)。
作为根据本发明的式1的化合物的代表性实例,可以提及以下化合物,但不限于此:
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
(R)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
(S)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-a]吡嗪-1(2H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2(1H)-酮;
8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-7-氟-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
9-溴-5-(4-甲基哌嗪-1-基)-1H-[1,2,4]三嗪并[4,3-a]喹喔啉-2(3H)-酮;
8,9-二溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
N-(4-(3-(甲基氨基)氮杂环丁烷-1-基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-8-基)甲磺酰胺;
8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-氨基-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮盐酸盐;
3-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[4,3-e]吡嗪-8(9H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)-1H-吡啶并[2,3-e][1,2,4]噻二唑并[4,3-a]吡嗪2,2-二氧化物;
8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐;
2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;
2-溴-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;
2-氯-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;和
2-溴-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮。
上面列出的化合物名称是根据PerkinElmer的ChemDraw Professional(版本15.0.0.106)提供的命名方法来描述的。
因为根据本发明的式1的化合物可以具有不对称碳中心和不对称轴或平面,所以它们可以以E-或Z-异构体,R-或S-异构体,外消旋混合物或非对映异构体混合物以及每种非对映异构体的形式存在,所有这些都在本发明的范围内。
在根据本发明的式1的化合物为外消旋体的情况下,可通过使用常规的分离方法,例如正相或反相的手性柱色谱,并使用相应的溶剂,优选在正相中使用己烷,乙酸乙酯,二氯甲烷和甲醇的溶剂混合物,在反相中使用水和乙腈的溶剂混合物,可以将外消旋体分离为其各自的异构体。
根据本发明的式1的化合物还可以形成药学上可接受的盐。可用于制备此类药学上可接受的盐(例如酸加成盐)的代表性的酸包括但不限于盐酸,硫酸,硝酸,磷酸,氢溴酸,氢碘酸,甲酸,柠檬酸,乙酸,三氯乙酸或三氟乙酸,苯甲酸,富马酸,马来酸,甲磺酸,苯磺酸,对甲苯磺酸,2,2-二氯乙酸,酰化氨基酸,己二酸,海藻酸,抗坏血酸,L-天冬氨酸,4-乙酰氨基苯甲酸,(+)-樟脑酸,樟脑磺酸,(+)-(1S)-樟脑磺酸,癸酸,己酸,辛酸,肉桂酸,环己烷氨基磺酸,十二烷基硫酸,乙-1,2-二磺酸,乙磺酸,2-羟基乙磺酸,半乳糖酸,龙胆酸,葡糖庚酸(glucoheptanoic acid),D-葡糖酸,D-葡糖醛酸,L-谷氨酸,α-氧代-戊二酸,乙醇酸,马尿酸,(+)-L-乳酸,(±)-DL-乳酸,乳糖酸,(-)-L-苹果酸,丙二酸,(±)-DL-苦杏仁酸(mandelic acid),甲磺酸,萘-2-磺酸,萘-1,5-二磺酸,1-羟基-2-萘甲酸,烟酸,油酸,乳清酸,草酸,棕榈酸,帕莫酸(pamoic acid),L-焦谷氨酸,水杨酸,4-氨基-水杨酸,癸二酸,硬脂酸,琥珀酸,单宁酸,(+)-L-酒石酸,硫氰酸,十一碳烯酸等。另外,可以包括在本领域中已知和使用的胺衍生物的其他酸盐。它们可以通过常规已知的方法制备。
根据本发明的如上所定义的式1的化合物可以通过但不限于以下实施例中描述的方法来制备。
根据本发明的式1的化合物具有优异的调节人组胺4受体(hH4R)的活性。因此,本发明还提供了药物组合物,其包含治疗有效量的式1的化合物或其药学上可接受的盐或异构体作为活性成分以及药学上可接受的载体。根据本发明的式1的化合物可用于预防或治疗炎性疾病,自身免疫病,变应性疾病,眼病,皮肤病,呼吸系统疾病,疼痛性疾病,心脏病,和与人类组胺4受体(hH4R)相关的疾病。
因为根据本发明的式1的化合物显示出强的人组胺4受体(hH4R)抑制活性,所以它可用于预防或治疗炎性疾病,变态反应,疼痛,鼻息肉,鼻炎,慢性鼻窦炎,鼻充血,鼻痒,哮喘,慢性阻塞性肺疾病,类风湿性关节炎,特应性皮炎,银屑病,湿疹,瘙痒,发痒的皮肤,荨麻疹,特发性慢性荨麻疹,硬皮病,结膜炎,角膜结膜炎,眼部炎症,干眼症,心功能障碍,年龄相关性黄斑变性,心律失常,动脉粥样硬化,多发性硬化,炎性肠病(结肠炎,克罗恩病,溃疡性结肠炎),炎性疼痛,神经性疼痛,骨关节炎性疼痛,自身免疫性甲状腺疾病,免疫介导的(也称为I型)糖尿病,狼疮,术后粘连,前庭疾病和癌症。
本发明的药物组合物可以通过将治疗有效量的式1的化合物或其药学上可接受的盐或异构体作为活性成分与药学上可接受的载体,粘合剂,稳定剂和/或稀释剂混合来制备。另外,当将本发明的药物组合物制成注射液形式时,可将药学上可接受的缓冲剂,溶解助剂和/或等渗剂与式1的化合物或其药学上可接受的盐或异构体混合。
通过使用本领域技术人员已知或可获得的制备技术以及合适的药物赋形剂,可以将本发明的药物组合物制成包含一种或多种剂量单位药剂的药物组合物的递送形式。在本发明的方法中,可以通过合适的递送途径,例如口服或肠胃外,经皮,直肠,局部或眼内施用,或通过吸入来施用组合物。药物制剂可以是片剂,胶囊剂,小袋剂,糖衣丸剂,粉剂,颗粒剂,锭剂,用于重建的粉剂,液体制剂或栓剂的形式。例如,可以将组合物配制成用于静脉内注射,喷雾,局部或口服给药的形式。
在制备口服剂型的制剂的情况下,可以使用任何常规的药物载体。例如,在口服液体制剂例如悬浮液,糖浆、酏剂和溶液的情况下,水,二醇,油,醇等可用作载体;并且在固体制剂如粉剂,丸剂,胶囊剂和片剂的情况下,淀粉,糖,高岭土,润滑剂,粘合剂,崩解剂等可用作载体。由于易于给药,片剂和胶囊剂是最方便的剂型,优选将片剂和丸剂制成肠溶衣制剂。
在肠胃外制剂的情况下,通常使用无菌水,并且还可以包含其他成分,例如溶解助剂。可以根据已知技术通过使用合适的分散剂,润湿剂或悬浮剂来制备注射制剂,例如用于注射的无菌水基或油基悬浮液。可用于此目的的溶剂包括水,林格液和等渗NaCl溶液,并且无菌的固定化油也通常用作溶剂或悬浮介质。为此目的,可以使用任何非刺激性的固定化油,包括甘油单酯和甘油二酯,并且可以将脂肪酸例如油酸用于注射制剂。
在经皮制剂的情况下,渗透促进剂和/或合适的润湿剂可以用作载体,任选地与合适的对皮肤无刺激性的添加剂组合。作为这样的添加剂,可以选择有助于促进通过皮肤的给药和/或制备期望的组合物的那些。可以以各种方式施用经皮制剂,例如,透皮贴剂,点涂疗法或软膏剂。
根据患者的疾病,状况,年龄,体重和给药形式,可以适当地确定根据本发明的药物组合物的给药时间和剂量。对于成人,药物组合物可以单剂量或多剂量以每天0.1-2,000mg,优选每天1-200mg的量施用,但不限于此。
发明的有益效果
根据本发明的式1的杂环化合物或其药学上可接受的盐或异构体对活化或抑制组胺4受体表现出优异的作用,因此包含该化合物的药物组合物可用于预防或治疗与调节组胺4受体有关的疾病。另外,由于根据本发明的式1的杂环化合物或其药学上可接受的盐或异构体具有相对长的半衰期,因此,根据本发明的式1的杂环化合物或其药学上可接受的盐或异构体可以在相对长的时间内调节组胺4受体的活性,并且可以更有效地预防或治疗与调节组胺4受体相关的疾病。
发明模式
在下文中,通过以下实施例和实验更详细地解释本发明。然而,以下实施例和实验仅旨在促进对本发明的理解,并且本发明的保护范围不限于此。
以下实施例中使用的缩写定义如下。
实施例1:8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)7-溴-2-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪的合成
将7-溴-2,3-二氯吡啶并[2,3-b]吡嗪(10.0g,35.9mmol)和1-甲基哌嗪(3.78mL,34.1mmol)溶于DCM(359mL),并在0℃下向其中缓慢添加TEA(15.0mL,108mmol)。将反应混合物在室温下搅拌15小时,向其中添加H2O(250mL),并用DCM(250mL)萃取。将有机层用盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:EtOAc=2:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,7-溴-2-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(8.50g,69%),为褐色。
LC/MS ESI(+):342(M+1)
1H NMR(400MHz,CDCl3)δ=8.94(d,J=2.4Hz,1H),8.33(d,J=2.4Hz,1H),3.81-3.79(m,4H),2.65-2.62(m,4H),2.38(s,3H)
(b)N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将7-溴-2-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(500mg,1.46mmol)和2-羟基乙酰胺(131mg,1.75mmol)溶于DMF(14.6mL),并在室温下向其中添加无水K2CO3(303mg,2.19mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=70:30)和胺二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(351mg,63%),为黄色。
LC/MS ESI(+):381(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.69(d,J=2.3Hz,1H),8.19(d,J=2.3Hz,1H),7.59(br s,1H),7.30(br s,1H),4.94(s,2H),3.88-3.86(m,4H),2.50-2.47(m,4H),2.23(s,3H)
(c)8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(351mg,0.921mmol)溶于DMF(18.4mL),并在室温下向其中添加甲磺酰氯(2.15mL,27.6mmol)和TEA(3.85mL,27.6mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=65:35)和胺二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(207mg,62%),为褐色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.77(d,J=2.4Hz,1H),8.34(d,J=2.4Hz,1H),5.40(s,2H),3.82-3.79(m,4H),2.50-2.47(m,4H),2.24(s,3H)
实施例2:8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
7-溴-2,3-二氯吡啶并[2,3-b]吡嗪(10.0g,35.9mmol)和氮杂环丁烷-3-基(甲基)氨基甲酸叔丁酯(6.68g,35.9mmol)溶于甲苯(179mL),并在0℃下向其中缓慢添加TEA(9.99mL,71.7mmol)。将反应混合物在0℃下搅拌1小时,向其中添加H2O(250mL),并用DCM(250mL)萃取。将有机层用盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:乙酸乙酯=4:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(7.00g,46%),为黄色。
LC/MS ESI(+):428(M+1)
1H NMR(400MHz,CDCl3)δ=8.86(d,J=2.4Hz,1H),8.25(d,J=2.4Hz,1H),5.17-4.92(m,1H),4.76(br s,2H),4.57-4.53(m,2H),2.98(s,3H),1.48(s,9H)
(b)(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(500mg,1.17mmol)和2-羟基乙酰胺(105mg,1.40mmol)溶于DMF(5.83mL),并在室温下向其中添加无水K2CO3(242mg,1.75mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=60:40)和胺二氧化硅柱色谱(DCM:MeOH=50:1)纯化。收集含有产物级分的级分并蒸发,得到固体化合物,(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(330mg,61%),为黄色。
LC/MS ESI(+):467(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.62(d,J=2.3Hz,1H),8.14(d,J=2.3Hz,1H),7.55(s,1H),7.35(s,1H),4.99-4.27(m,7H),2.91(s,3H),1.42(s,9H)
(c)(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(330mg,0.706mmol)溶于DMF(7.06mL),并在室温下向其中添加甲磺酰氯(1.65mL,21.2mmol)和TEA(2.95mL,21.2mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=65:35)和胺二氧化硅柱色谱(DCM:MeOH=50:1)纯化。收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(33.0mg,10%),为褐色。
LC/MS ESI(+):449(M+1)
1H NMR(400MHz,CDCl3)δ=8.73(d,J=2.4Hz,1H),8.15(d,J=2.3Hz,1H),5.14(s,3H),4.65(br s,2H),4.49(br s,2H),2.97(s,3H),1.48(s,9H)
(d)8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(33.0mg,0.0730mmol)溶于DCM(0.294mL),并向其中添加TFA(0.169mL)。将反应混合物在室温下搅拌1小时。在0℃下将DIPEA(0.300mL)添加到反应混合物中,并将溶剂在减压下蒸发。将残留物通过胺二氧化硅柱色谱(DCM:MeOH=50:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(18.0mg,70%),为黄色。
LC/MS ESI(+):349(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.60(d,J=2.4Hz,1H),8.16(d,J=2.4Hz,1H),5.28(s,2H),4.70-3.77(m,4H),3.57-3.51(m,1H),2.20(s,3H)
实施例3:(R)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)(R)-(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将7-溴-2,3-二氯吡啶并[2,3-b]吡嗪(600mg,2.15mmol)和(R)-甲基(吡咯烷-3-基)氨基甲酸叔丁酯(392mg,1.96mmol)溶于DCM(19.6mL),并在0℃下向其中缓慢添加TEA(0.818mL,5.87mmol)。将反应混合物在25℃下搅拌1小时,向其中添加H2O(25.0mL),并用DCM(25.0mL)萃取。将有机层用盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:EtOAc=50:50)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(R)-(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(582mg,67%),为黄色。
LC/MS ESI(+):442(M+1)
1H NMR(400MHz,CDCl3)δ=8.86(d,J=2.4Hz,1H),8.25(d,J=2.4Hz,1H),4.84(brs,1H),4.15-4.06(m,2H),4.00-3.86(m,2H),2.86(s,3H),2.21-2.10(m,2H),1.49(s,9H)
(b)(R)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将(R)-(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(582mg,1.32mmol)和2-羟基乙酰胺(118mg,1.58mmol)溶于DMF(6.57mL),并在室温下向其中添加无水K2CO3(273mg,1.97mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=55:45)和胺二氧化硅柱色谱(DCM:MeOH=50:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(R)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(460mg,73%),为黄色。
LC/MS ESI(+):481(M+1)
1H NMR(400MHz,CDCl3)δ=8.68(d,J=2.4Hz,1H),8.07(d,J=2.4Hz,1H),6.10(brs,1H),5.59(br s,1H),5.06-4.96(m,2H),4.79(br s,1H),4.18-4.13(m,2H),3.91-3.79(m,2H),2.85(s,3H),2.22-2.04(m,2H),1.48(s,9H)
(c)(R)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将(R)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(460mg,0.956mmol)溶于DMF(9.56mL),并在室温下向其中添加甲磺酰氯(0.371mL,4.78mmol)和TEA(0.666mL,4.78mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=40:60)和胺二氧化硅柱色谱(DCM:MeOH=90:10)纯化。收集含有产物级分的级分并蒸发,得到固体化合物,(R)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(125mg,28%),为褐色。
LC/MS ESI(+):463(M+1)
1H NMR(400MHz,CDCl3)δ=8.72(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H),5.15(s,2H),4.85(br s,1H),4.18-4.08(m,2H),3.91-3.84(m,1H),3.79(dd,J=12.2,8.1Hz,1H),2.85(s,3H),2.23-2.03(m,2H),1.49(s,9H)
(d)(R)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将(R)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(125mg,0.270mmol)溶于DCM(1.08mL),并向其中添加TFA(0.620mL)。将反应混合物在室温下搅拌1小时。在0℃下将DIPEA(1.20mL)添加到反应混合物中,并将溶剂在减压下蒸发。将残留物通过胺二氧化硅柱色谱(DCM:MeOH=100:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(R)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(81.0mg,83%),为黄色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.65(d,J=2.4Hz,1H),8.20(d,J=2.4Hz,1H),5.36(s,2H),3.89(br s,2H),3.65(br s,1H),3.26-3.22(m,1H),2.31(s,3H),2.08-2.00(m,2H),1.87-1.80(m,1H)
实施例4:(S)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)(S)-(1-(7-溴-2-氯吡啶并[2,3-b]-吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将7-溴-2,3-二氯吡啶并[2,3-b]吡嗪(300mg,1.08mmol)和(S)-甲基(吡咯烷-3-基)氨基甲酸叔丁酯(196mg,0.978mmol)溶于DCM(9.78mL),并在0℃下向其中缓慢添加TEA(0.409mL,2.93mmol)。将反应混合物在25℃下搅拌1小时,向其中添加H2O(10.0mL),并用DCM(10.0mL)萃取。将有机层用盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:乙酸乙酯=2:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(S)-(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(303mg,70%),为黄色。
LC/MS ESI(+):442(M+1)
1H NMR(400MHz,CDCl3)δ=8.86(d,J=2.4Hz,1H),8.25(d,J=2.4Hz,1H),4.91-4.75(m,1H),4.15-4.05(m,2H),4.00-3.93(m,1H),3.88(dd,J=11.6,8.3Hz,1H),2.86(s,3H),2.23-2.09(m,2H),1.49(s,9H)
(b)(S)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将(S)-(1-(7-溴-2-氯吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(303mg,0.684mmol)和2-羟基乙酰胺(61.6mg,0.821mmol)溶于DMF(3.42mL),并在室温下向其中添加无水K2CO3(142mg,1.03mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(DCM:MeOH=60:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(S)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(240mg,73%),为黄色。
LC/MS ESI(+):481(M+1)
1H NMR(400MHz,CDCl3)δ=8.68(d,J=2.3Hz,1H),8.07(d,J=2.3Hz,1H),6.05(brs,1H),5.55(br s,1H),5.05-4.97(m,2H),4.79(br s,1H),4.19-4.14(m,2H),3.92-3.80(m,2H),2.85(s,3H),2.22-2.07(m,2H),1.48(s,9H)
(c)(S)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的合成
将(S)-(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(240mg,0.499mmol)溶于DMF(4.99mL),并在室温下向其中添加甲磺酰氯(0.387mL,4.99mmol)和TEA(0.695mL,4.99mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=40:60)和二氧化硅柱色谱(DCM:MeOH=19:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(S)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(117mg,51%),为褐色。
LC/MS ESI(+):463(M+1)
1H NMR(400MHz,CDCl3)δ=8.72(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H),5.15(s,2H),4.84(br s,1H),4.17-4.08(m,2H),3.92-3.84(m,1H),3.81-3.76(m,1H),2.85(s,3H),2.21-2.08(m,2H),1.49(s,9H)
(d)(S)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将(S)-(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(115mg,0.248mmol)溶于DCM(0.993mL),并向其中添加TFA(0.570mL)。将反应混合物在室温下搅拌1小时。在0℃下将DIPEA(1.20mL)添加到反应混合物中,并将溶剂在减压下蒸发。将残留物通过胺二氧化硅柱色谱(DCM:MeOH=100:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(S)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(75.0mg,83%),为黄色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.65(d,J=2.4Hz,1H),8.20(d,J=2.4Hz,1H),5.36(s,2H),3.87(br s,2H),3.64(br s,1H),3.26-3.21(m,1H),2.31(s,3H),2.08-2.00(m,2H),1.87-1.81(m,1H)
实施例5:8-溴-4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)7-溴-2-氯-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪的合成
将7-溴-2,3-二氯吡啶并[2,3-b]吡嗪(300mg,1.08mmol)和八氢吡咯并[1,2-a]吡嗪(123mg,0.978mmol)溶于DCM(9.78mL),并在0℃下缓慢添加TEA(0.409mL,2.93mmol)。将反应混合物在25℃下搅拌1小时,向其中添加H2O(10.0mL),并用DCM(10.0mL)萃取。将有机层用盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:乙酸乙酯=2:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,7-溴-2-氯-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪(165mg,46%),为黄色。
LC/MS ESI(+):368(M+1)
1H NMR(400MHz,CDCl3)δ=8.93(d,J=2.4Hz,1H),8.33(d,J=2.4Hz,1H),4.51-4.40(m,2H),3.31-3.24(m,1H),3.19-3.13(m,2H),2.96(dd,J=12.5,10.5Hz,1H),2.49(td,J=11.4,3.1Hz,1H),2.27-2.20(m,2H),1.96-1.86(m,2H),1.83-1.72(m,1H),1.56-1.46(m,1H)
(b)N-(7-溴-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将7-溴-2-氯-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪(163mg,0.442mmol)和2-羟基乙酰胺(39.8mg,0.531mmol)溶于DMF(4.42mL),并在室温下向其中添加无水K2CO3(92.0mg,0.663mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=75:25)和胺二氧化硅柱色谱(DCM:MeOH=30:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(7-溴-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(75.0mg,42%),为黄色。
LC/MS ESI(+):407(M+1)
1H NMR(400MHz,CDCl3)δ=8.75(d,J=2.3Hz,1H),8.15(d,J=2.4Hz,1H),6.09-5.99(m,1H),5.58-5.47(m,1H),5.05(d,J=1.7Hz,2H),4.80-4.75(m,1H),4.71-4.65(m,1H),3.32-3.24(m,1H),3.19-3.12(m,2H),2.93(dd,J=12.6,10.5Hz,1H),2.41(td,J=11.5,3.1Hz,1H),2.24-2.13(m,2H),1.95-1.84(m,2H),1.82-1.72(m,1H),1.52-1.47(m,1H)
(c)8-溴-4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将N-(7-溴-3-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(74.0mg,0.182mmol)溶于DMF(3.63mL),并在室温下向其中添加甲磺酰氯(0.282mL,3.63mmol)和TEA(0.507mL,3.63mmol)。将反应混合物在80℃下搅拌15小时,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=70:30)和二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(14.0mg,20%),为黄色。
LC/MS ESI(+):389(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.77(d,J=2.3Hz,1H),8.34(d,J=2.4Hz,1H),5.40(s,2H),4.65(d,J=12.6Hz,1H),4.55(d,J=12.7Hz,1H),3.18-3.01(m,3H),2.83(t,J=11.4Hz,1H),2.30-2.24(m,1H),2.13-2.05(m,2H),1.87-1.81(m,1H),1.78-1.67(m,2H),1.45-1.35(m,1H)
实施例6:8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-a]吡嗪-1(2H)-酮的合成
(a)7-溴-2-肼基-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪的合成
将实施例1的步骤(a)中获得的7-溴-2-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(250mg,0.730mmol)和肼一水合物(0.142mL,2.92mmol)溶于EtOH(1.46mL)中,在室温下搅拌30分钟,并在减压下蒸馏。将Et2O添加到残留物中,并将所得混合物过滤并在减压下干燥,得到固体化合物,7-溴-2-肼基-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(247mg,100%),为黄色。
LC/MS ESI(+):338(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.01-7.45(m,1H),7.09(br s,4H),3.96-3.74(m,4H),2.43(br s,4H),2.21(s,3H)
(b)8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-a]吡嗪-1(2H)-酮的合成
将7-溴-2-肼基-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(100mg,0.296mmol)溶于DMF(1.48mL),并向其中添加CDI(96.0mg,0.591mmol)和TEA(0.0820mL,0.591mmol)。将反应混合物在65℃下搅拌1小时,然后在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O=100)和胺二氧化硅柱色谱(DCM:MeOH=80:20)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-a]吡嗪-1(2H)-酮(5.80mg,5.4%),为白色。
LC/MS ESI(+):364(M+1)
1H NMR(400MHz,DMSO-d6)δ=13.16(br s,1H),8.96(d,J=2.3Hz,1H),8.47(d,J=2.2Hz,1H),4.19(br s,4H),2.49-2.47(m,4H),2.24(s,3H)
实施例7:8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2(1H)-酮的合成
(a)3-肼基-2-硝基吡啶盐酸盐的合成
将3-氟-2-硝基呋喃(5.56g,39.1mmol)和肼一水合物(2.28mL,47.0mmol)溶于THF(78.0mL),并在室温下搅拌13小时。向反应混合物中加入一水合肼(0.569mL,11.7mmol),并将所得混合物在室温下搅拌9小时并在减压下蒸馏。将Et2O添加到残留物中,并将该残留物过滤并在减压下干燥。得到固体化合物,3-肼基-2-硝基吡啶盐酸盐(6.55g,96%),为红色。
LC/MS ESI(+):155(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.89(br s,1H),8.12(dd,J=8.7,1.5Hz,1H),7.78(dd,J=3.9,1.5Hz,1H),7.61(dd,J=8.7,3.9Hz,1H),4.68(s,2H)
(b)2-(2-硝基吡啶-3-基)肼-1-甲酰胺的合成
将3-肼基-2-硝基吡啶(3.19g,20.7mmol)和KOCN(2.52g,31.0mmol)溶于H2O(20.7mL),并向其中添加1N HCl(41.4mL,41.4mmol)。将反应混合物在室温下搅拌30分钟,并向其中添加H2O。将得到的固体过滤并在减压下干燥,得到固体化合物,2-(2-硝基吡啶-3-基)肼-1-甲酰胺(3.79g,93%),为黄色。
LC/MS ESI(+):198(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.07(s,1H),8.17(s,1H),7.94(dd,J=3.8,1.7Hz,1H),7.70-7.64(m,2H),6.24(br s,2H)
(c)1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮的合成
将2-(2-硝基吡啶-3-基)肼-1-甲酰胺(3.79g,19.2mmol)和对甲苯磺酸(0.366g,1.92mmol)溶于三乙氧基甲烷(80.0mL,481mmol),并在120℃下搅拌1小时。将EtOH添加到反应混合物中,并将该混合物过滤并在减压下干燥。得到固体化合物,1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮(3.05g,77%),为黄色。
LC/MS ESI(+):208(M+1)
1H NMR(400MHz,DMSO-d6)δ=11.78(br s,1H),8.86(s,1H),8.63(dd,J=4.6,1.3Hz,1H),8.52(dd,J=8.1,1.4Hz,1H),8.02(dd,J=8.2,4.6Hz,1H)
(d)2-(4-甲氧基苄基)-1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮的合成
将1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮(3.05g,14.7mmol)溶于DMF(147mL),并在0℃缓慢添加60%NaH(0.589g,14.7mmol)并搅拌30分钟。将4-甲氧基苄基氯(2.31g,14.7mmol)溶于DMF(147mL),并在0℃下缓慢添加到反应混合物中,并在室温下搅拌19小时。向反应混合物中加入水,并将该混合物用EtOAc(500mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:3)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-(4-甲氧基苄基)-1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮(3.48g,72%),为橙色。
LC/MS ESI(+):328(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.01(s,1H),8.67(dd,J=4.6,1.3Hz,1H),8.57(dd,J=8.2,1.5Hz,1H),8.05(dd,J=8.2,4.6Hz,1H),7.43-7.39(m,2H),6.97-6.94(m,2H),5.19(s,2H),3.33(s,3H)
(e)1-(2-氨基吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮的合成
将2-(4-甲氧基苄基)-1-(2-硝基吡啶-3-基)-1,2-二氢-3H-1,2,4-三唑-3-酮(3.48g,10.6mmol)溶于EtOH(53.2mL)和H2O(4.02mL),并在室温下向其中添加Fe(5.94g,106mmol)和浓HCl(0.404mL,13.3mmol)。将反应混合物回流1小时并冷却至室温。将MeOH添加到反应混合物中,并将该混合物用C盐过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(EtOAc=100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,1-(2-氨基吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮(2.33g,74%),为黄色。
LC/MS ESI(+):298(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.62(s,1H),8.06(dd,J=4.9,1.7Hz,1H),7.64(dd,J=7.7,1.6Hz,1H),7.44-7.41(m,2H),6.98-6.95(m,2H),6.69(dd,J=7.6,4.9Hz,1H),6.28(s,2H),5.25(s,2H),3.77(s,3H)
(f)1-(2-氨基-5-溴吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮的合成
将1-(2-氨基吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮(2.33g,7.84mmol)溶于CH3CN(78.0mL),并向其中添加N-溴琥珀酰亚胺(1.40g,7.84mmol)。将反应混合物在0℃下搅拌30分钟,并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,1-(2-氨基-5-溴吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮(2.27g,77%),为象牙色。
LC/MS ESI(+):376(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.68(s,1H),8.15(d,J=2.3Hz,1H),7.95(d,J=2.2Hz,1H),7.44-7.40(m,2H),6.98-6.95(m,2H),6.56(s,2H),5.26(s,2H),3.33(s,3H)
(g)8-溴吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2,4(1H,5H)-二酮的合成
1-(2-氨基-5-溴吡啶-3-基)-2-(4-甲氧基苄基)-1,2-二氢-3H-1,2,4-三唑-3-酮(1.10g,2.92mmol)溶于1,2-二氯苯(29.2mL),并向其中添加CDI(1.90g,11.7mmol)。将反应混合物在170℃下搅拌1小时,并冷却至室温。将H2O添加到反应混合物中,并将通过过滤获得的固体化合物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=85:15)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2,4(1H,5H)-二酮(181mg,22%),为深褐色。
LC/MS ESI(+):282(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.92(br s,1H),12.54(br s,1H),8.56(d,J=2.2Hz,1H),8.35(d,J=2.1Hz,1H)
(h)8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2(1H)-酮的合成
8-溴吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2,4(1H,5H)-二酮(50.0mg,0.177mmol)溶于POCl3(0.496mL,5.32mmol),并在100℃搅拌3.5小时。将反应混合物冷却至0℃,并向其中缓慢添加1-甲基吡嗪(2.96mL,26.6mmol)。将反应混合物在室温下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=80:20)纯化,收集含有产物的级分并蒸发以获得8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2(1H)-酮(7.60mg,12%),为褐色。
LC/MS ESI(+):364(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.59(br s,1H),8.32(br s,1H),4.22(br s,4H),2.51-2.47(m,4H),2.18(br s,3H)
实施例8:8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)5-溴-6-氯-3-硝基吡啶-2-胺的合成
将6-氯-3-硝基吡啶-2-胺(1.00g,5.76mmol)溶于DMF(19.2mL),并在室温下加入N-溴琥珀酰亚胺(1.13g,6.34mmol)。将反应混合物在室温下搅拌3小时,并向其中添加H2O(19.2mL)。将得到的固体过滤并在减压下干燥,得到固体化合物,5-溴-6-氯-3-硝基吡啶-2-胺(1.27g,87%),为黄色。
LC/MS ESI(+):252(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.64(s,1H),8.51-8.18(m,2H)
(b)5-溴-6-氯吡啶-2,3-二胺的合成
将5-溴-6-氯-3-硝基吡啶-2-胺(1.27g,5.03mmol)溶于EtOH(4.02mL)和H2O(1.01mL),并在在室温下向其中添加Fe(2.81g,50.3mmol)和浓HCl(0.0760mL,2.52mmol)。将反应混合物在100℃下搅拌1小时,并冷却至室温。将反应混合物用C盐过滤,并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,5-溴-6-氯吡啶-2,3-二胺(1.03g,92%),为灰色。
LC/MS ESI(+):222(M+1)
1H NMR(400MHz,DMSO-d6)δ=6.93(s,1H),6.06(s,2H),5.09(s,2H)
(c)7-溴-6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮的合成
将5-溴-6-氯吡啶-2,3-二胺(1.03g,4.63mmol)溶于草酸二乙酯(9.26mL,4.63mmol),并在130℃下搅拌20小时。将反应混合物冷却至室温。将获得的固体过滤,用Et2O洗涤,并在减压下干燥,得到固体化合物,7-溴-6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(1.19g,93%),为褐色。
LC/MS ESI(+):276(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.65(s,1H),12.09(s,1H),7.67(s,1H)
(d)7-溴-2,3,6-三氯吡啶并[2,3-b]吡嗪的合成
向7-溴-6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(506mg,1.83mmol)中添加POCl3(6.10mL,1.83mmol),并将该混合物在130℃下搅拌15小时。将反应混合物冷却至0℃下,并向其中缓慢添加冰水(12.0mL)。将获得的固体过滤,用H2O洗涤并在减压下干燥,得到固体化合物,7-溴-2,3,6-三氯吡啶并[2,3-b]吡嗪(417mg,73%),为褐色。
LC/MS ESI(+):312(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.20(s,1H)
(e)7-溴-2,6-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪的合成
将7-溴-2,3,6-三氯吡啶并[2,3-b]吡嗪(417mg,1.33mmol)溶于DMF(4.44mL),并在0℃下向其中缓慢添加1-甲基哌嗪(0.295mL,2.66mmol)。将反应混合物在25℃下搅拌1小时,向其中添加H2O(5.00mL),并用EtOAc(10.0mL)萃取。将有机层用H2O和盐水洗涤,用无水MgSO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,7-溴-2,6-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(195mg,39%),为褐色。
LC/MS ESI(+):376(M+1)
1H NMR(400MHz,CDCl3)δ=8.41(s,1H),3.84-3.82(m,4H),2.64-2.62(m,4H),2.37(s,3H)
(f)N-(7-溴-6-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将7-溴-2,6-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(195mg,0.517mmol)和2-羟基乙酰胺(46.6mg,0.621mmol)溶于DMF(5.17mL),并在室温下向其中添加无水K2CO3(107mg,0.776mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=70:30)和二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(7-溴-6-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(115mg,54%),为褐色。
LC/MS ESI(+):415(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.35(s,1H),7.61(s,1H),7.31(s,1H),4.93(s,2H),3.93-3.91(m,4H),2.48-2.46(m,4H),2.23(s,3H)
(g)8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
N-(7-溴-6-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(115mg,0.277mmol)溶于DMF(5.53mL),并在室温下向其中添加甲磺酰氯(0.645mL,8.30mmol)和TEA(1.16mL,8.30mmol)。将反应混合物在80℃下搅拌2小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=60:40)和二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(51.0mg,46%),为黄色。
LC/MS ESI(+):397(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.50(s,1H),5.39(s,2H),3.86-3.84(m,4H),2.48-2.47(m,4H),2.23(s,3H)
实施例9:8-溴-7-氟-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将实施例8中获得的8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(80.0mg,0.201mmol)溶于DMSO(2.01mL),并在室温下添加CsF(92.0mg,0.604mmol)。将反应混合物在90℃下搅拌1小时,并通过反相二氧化硅柱色谱(含0.1%TFA:CH3CN的H2O=65:35),二氧化硅柱色谱(DCM:MeOH=9:1),胺二氧化硅柱色谱(DCM:MeOH=100:1)纯化。收集含有产物的级分并蒸发,得到固体化合物,8-溴-7-氟-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(5.50mg,7.2%),为黄色。
LC/MS ESI(+):381(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.57(d,J=8.8Hz,1H),5.38(s,2H),3.85-3.83(m,4H),2.49-2.47(m,4H),2.23(s,3H)
实施例10:4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
(a)2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺的合成
将3-氯-2-(4-甲基哌嗪-1-基)-6-硝基喹喔啉(490mg,1.59mmol)和2-羟基乙酰胺(143mg,1.91mmol)溶于DMF(15.9mL),并在室温下向其中添加无水K2CO3(330mg,2.39mmol)。将反应混合物在70℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=70:30)和二氧化硅柱色谱(DCM:MeOH=20:1)纯化,并将含有产物的级分收集并蒸发,得到固体化合物,2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺(345mg,63%),为褐色。
LC/MS ESI(+):347(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.32(d,J=2.6Hz,1H),8.22(dd,J=9.0,2.6Hz,1H),7.72(d,J=9.0Hz,1H),7.63(br s,1H),7.30(br s,1H),4.96(s,2H),3.95-3.93(m,4H),2.50-2.48(m,4H),2.24(s,3H)
(b)4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺(345mg,0.996mmol)溶于DMF(9.96mL),并在室温下向其中添加甲磺酰氯(2.32mL,29.9mmol)和TEA(4.17mL,29.9mmol)。将反应混合物在80℃下搅拌2小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=60:40)和二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮(150mg,46%),为黄色。
LC/MS ESI(+):329(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.36(d,J=2.3Hz,1H),8.20(dd,J=9.0,2.4Hz,1H),7.69(d,J=9.0Hz,1H),5.36(s,2H),3.80-3.78(m,4H),2.43-2.41(m,4H),2.16(s,3H)
实施例11:8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将实施例10中获得的4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮(105mg,0.320mmol)溶于EtOH(2.56mL)和H2O(0.640mL),并在室温下向其中添加Fe(179mg,3.20mmol)和浓HCl(0.00486mL,0.160mmol)。将反应混合物在100℃下搅拌1小时,并冷却至室温。将反应混合物用C盐过滤,并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=10:1)和胺二氧化硅柱色谱(DCM:MeOH=10:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(85.0mg,89%),为黄色。
LC/MS ESI(+):299(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.44(d,J=8.8Hz,1H),6.93(dd,J=8.7,1.8Hz,1H),6.77(d,J=1.7Hz,1H),5.54(s,2H),5.32(s,2H),3.41-3.39(m,4H),2.49-2.47(m,4H),2.23(s,3H)
实施例12:8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
(a)3-氯-2-(4-甲基哌嗪-1-基)-6-硝基喹喔啉的合成
将2,3-二氯-6-硝基喹喔啉(2.40g,9.83mmol)溶于DCM(98.0mL),并向其中添加1-甲基哌嗪(2.74mL,24.6mmol)。将反应混合物在室温下搅拌2小时。将反应混合物过滤以除去不溶物。将饱和的NaHCO3水溶液添加至有机层,并将该层用DCM(250mL)萃取。将有机层用H2O和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:乙酸乙酯=2:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,3-氯-2-(4-甲基哌嗪-1-基)-6-硝基喹喔啉(2.06g,68%),为黄色。
LC/MS ESI(+):308(M+1)
1H NMR(400MHz,CDCl3)δ=8.75(s,1H),8.41(d,J=9.0Hz,1H),7.85(d,J=9.2Hz,1H),3.79(br s,4H),2.67-2.63(m,4H),2.39(s,3H)
(b)2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺的合成
将3-氯-2-(4-甲基哌嗪-1-基)-6-硝基将二氟喹啉(2.06g,6.69mmol)和2-羟基乙酰胺(0.603g,8.03mmol)溶于DMF(66.9mL),并在室温下向其中添加无水K2CO3(1.39g,10.0mmol)。将反应混合物在70℃下搅拌2小时。将H2O添加到反应混合物中,并将该混合物用EtOAc(160mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=93:7)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺(1.08g,47%),为褐色。
LC/MS ESI(+):347(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.31(d,J=2.6Hz,1H),8.22(dd,J=9.0,2.5Hz,1H),7.72(d,J=9.0Hz,1H),7.63(br s,1H),7.30(br s,1H),4.96(s,2H),3.95-3.93(m,4H),2.50-2.48(m,4H),2.23(s,3H)
(c)4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将2-羟基-N-(3-(4-甲基哌嗪-1-基)-7-硝基喹喔啉-2-基)乙酰胺(1.08g,3.12mmol)溶于DMF(31.2mL),并向其中添加TEA(4.35mL,31.2mmol)和甲磺酰氯(2.43mL,31.2mmol)。将所得混合物在80℃下搅拌3小时。向反应混合物中加入饱和NaHCO3水溶液,并将该混合物用EtOAc(170mL)萃取。将有机层用水和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=90:10)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮(539mg,53%),为褐色。
LC/MS ESI(+):329(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.43(d,J=2.4Hz,1H),8.27(dd,J=9.0,2.6Hz,1H),7.76(d,J=9.0Hz,1H),5.44(s,2H),3.88-3.86(m,4H),2.50-2.47(m,4H),2.24(s,3H)
(d)8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮(539mg,1.64mmol)溶解于EtOH(13.1mL)和H2O(3.28mL),并向其中添加Fe(917mg,16.4mmol)和浓HCl(0.0249mL,0.821mmol)。将反应混合物回流2小时并冷却至室温。将MeOH添加到反应混合物中,并将该混合物用C盐过滤并在减压下蒸馏。将饱和的NaHCO3水溶液添加到残留物中,并将该混合物用EtOAc(80.0mL)萃取。将有机层用H2O和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:EtOAc=1:2)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(312mg,64%),为黄色。
LC/MS ESI(+):299(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.43(d,J=8.7Hz,1H),6.93(dd,J=8.8,2.4Hz,1H),6.77(d,J=2.3Hz,1H),5.54(s,2H),5.32(s,2H),3.41-3.38(m,4H),2.49-2.46(m,4H),2.23(s,3H)
(e)8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(200mg,0.670mmol)溶于CH3CN(4.47mL),并向其中添加亚硝酸叔丁酯(0.177mL,1.34mmol)。将该混合物在室温下搅拌20分钟。向反应混合物中加入CuBr2(150mg,0.670mmol),并将该混合物在室温下搅拌2小时。将亚硝酸叔丁酯(0.177mL,1.34mmol)添加到反应混合物中,并将该混合物在室温下搅拌1.5小时。将反应混合物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=60:40)和胺二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(31.0mg,13%),为白色。
LC/MS ESI(+):362(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.88(d,J=1.8Hz,1H),7.68-7.61(m,2H),5.39(s,2H),3.68-3.65(m,4H),2.50-2.47(m,4H),2.24(s,3H)
实施例13:8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
(a)(1-(3-氯-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将2,3-二氯-6-硝基喹喔啉(2.40g,9.83mmol)溶于DCM(98.0mL),并向其中添加TEA(2.74mL,19.7mmol)和氮杂环丁烷-3-基-(甲基)氨基甲酸叔丁酯盐酸盐(4.38g,19.7mmol)。将该混合物在室温下搅拌2小时。将饱和的NaHCO3水溶液添加到反应混合物中,并将该混合物用DCM(120mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:乙酸乙酯=4:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(3-氯-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(1.66g,43%),为黄色。
LC/MS ESI(+):394(M+1)
1H NMR(400MHz,CDCl3)δ=8.69(s,1H),8.36(d,J=9.0Hz,1H),7.73(d,J=9.0Hz,1H),5.07(br s,1H),4.74(br s,2H),4.55(br s,2H),3.00(s,3H),1.49(s,9H)
(b)(1-(3-(2-羟基乙酰氨基)-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(3-氯-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(1.66g,4.22mmol)和2-羟基乙酰胺(0.380g,5.06mmol)溶于DMF(42.2mL),并向其中添加无水K2CO3(0.874g,6.32mmol)。将反应混合物在70℃下搅拌2小时,然后冷却至室温。向反应混合物中加水,并将该混合物用EtOAc(110mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(EtOAc=100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(3-(2-羟基乙酰氨基)-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(988mg,54%),为褐色。
LC/MS ESI(+):433(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.29(d,J=2.6Hz,1H),8.18(dd,J=9.0,2.6Hz,1H),7.65(d,J=9.0Hz,1H),7.58(s,1H),7.35(s,1H),5.07-4.15(m,7H),2.91(s,3H),1.42(s,9H)
(c)甲基(1-(8-硝基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯的合成
将(1-(3-(2-羟基乙酰氨基)-6-硝基喹喔啉-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(899mg,2.08mmol)溶于DMF(20.8mL),并向其中添加TEA(1.74mL,12.5mmol)和甲磺酰氯(0.583mL,7.48mmol)。将该混合物在50℃下搅拌22小时。向反应混合物中加入饱和NaHCO3水溶液,并将该混合物用EtOAc(120mL)萃取。将有机层用H2O和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=3:2)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,甲基(1-(8-硝基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(691mg,80%),为黄色。
LC/MS ESI(+):415(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.39(d,J=2.7Hz,1H),8.24(dd,J=9.0,2.7Hz,1H),7.70(d,J=9.0Hz,1H),5.40(s,2H),5.12-4.15(m,5H),2.90(s,3H),1.42(s,9H)
(d)(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将甲基(1-(8-硝基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(629mg,1.52mmol)溶于EtOH(12.1mL)和H2O(3.04mL)中,然后向其中添加Fe(848mg,15.2mmol)和浓HCl(0.0231mL,0.759mmol)。将反应混合物回流1小时40分钟,并冷却至室温。添加MeOH后,将反应混合物用C盐过滤,并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(436mg,75%),为黄色。
LC/MS ESI(+):385(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.37(d,J=8.8Hz,1H),6.88(d,J=9.7Hz,1H),6.76(s,1H),5.37(s,2H),5.28(s,2H),4.81(br s,1H),4.30(t,J=8.5Hz,2H),4.17-4.13(m,2H),2.87(s,3H),1.41(s,9H)
(e)(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(408mg,1.06mmol)溶解于CH3CN(7.08mL),并向其中添加亚硝酸叔丁酯(0.281mL,2.12mmol)。将该混合物在室温下搅拌20分钟。添加CuBr2(237mg,1.06mmol)后,将反应混合物在室温下搅拌1小时。将反应混合物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=35:65)和二氧化硅柱色谱(正己烷:EtOAc=7:2)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(61.0mg,13%),为白色。
LC/MS ESI(+):448(M+1)
1H NMR(400MHz,CDCl3)δ=7.85(m,1H),7.54(m,2H),5.13(s,2H),5.09-4.83(m,1H),4.55(t,J=9.1Hz,2H),4.36(dd,J=10.1,6.2Hz,2H),2.97(s,3H),1.48(s,9H)
(f)8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(61.0mg,0.136mmol)溶于DCM(0.580mL),并向其中添加TFA(0.335mL)。将反应混合物在室温下搅拌21小时,并在0℃下添加DIPEA(0.760mL)并搅拌30分钟。将反应混合物通过胺二氧化硅柱色谱(EtOAc=100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(27.0mg,54%),为白色。
LC/MS ESI(+):348(M+1)
1H NMR(400MHz,CDCl3)δ=7.83(dd,J=1.8,0.7Hz,1H),7.53-7.52(m,2H),5.12(s,2H),4.52(dd,J=9.5,7.7Hz,2H),4.06(dd,J=10.1,4.6Hz,2H),3.76-3.70(m,1H),2.46(s,3H)
实施例14:9-溴-5-(4-甲基哌嗪-1-基)-1H-[1,2,4]三嗪并[4,3-a]喹喔啉-2(3H)-酮的合成
(a)6-溴-1,4-二氢喹喔啉-2,3-二酮的合成
将4-溴苯-1,2-二胺(3.68g,19.7mmol)溶于草酸二乙酯(85.0mL,620mmol),并在120℃下搅拌3小时。将反应混合物冷却至室温。添加EtOH后,将得到的固体减压干燥,得到固体化合物,6-溴-1,4-二氢喹喔啉-2,3-二酮(4.64g,98%),为褐色。
LC/MS ESI(+):241(M+1)
1H NMR(400MHz,DMSO-d6)δ=11.99(s,1H),11.96(s,1H),7.26-7.24(m,2H),7.07-7.05(m,1H)
(b)6-溴-2,3-二氯喹喔啉的合成
将6-溴-1,4-二氢喹喔啉-2,3-二酮(4.64g,19.3mmol)溶于POCl3(96.4mL,1.03mol),并向其中添加N,N-二甲基苯胺(3.52mL,27.8mmol)。将反应混合物在150℃下搅拌67小时,然后冷却至0℃下。缓慢添加H2O后,将所得固体用H2O洗涤,并将滤液减压干燥,得到固体化合物,6-溴-2,3-二氯喹喔啉(3.53g,66%),为黄色。
1H NMR(400MHz,DMSO-d6)δ=8.40(d,J=2.0Hz,1H),8.12-8.04(m,2H)
(c)6-溴-2-氯-3-肼基喹喔啉的合成
将6-溴-2,3-二氯喹喔啉(724mg,2.60mmol)溶于EtOH(26.0mL),并向其中添加肼一水合物(0.190mL,3.91mmol)。将反应混合物在室温下搅拌4小时并在减压下蒸馏。将DCM添加到残留物中,并将获得的固体过滤并用DCM洗涤。将滤液在减压下干燥。过滤的固体通过二氧化硅柱色谱(正己烷:EtOAc=3:2)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,6-溴-2-氯-3-肼基喹喔啉(179mg,25%),为黄色。
LC/MS ESI(+):273(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.17(br s,1H),7.83(s,1H),7.69(d,J=8.7Hz,1H),7.52(d,J=8.7Hz,1H),4.70(br s,2H)
(d)(Z)-N”-(7-溴-3-氯喹喔啉-2(1H)-亚基)-2-氯乙酰肼的合成
将6-溴-2-氯-3-氯基甲酸二甲苯(179mg,0.654mmol)溶于DMF(6.54mL),并向其中添加氯乙酰氯(0.0524mL,0.654mmol)。将反应混合物在室温下搅拌40分钟。将反应混合物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=50:50)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(Z)-N”-(7-溴-3-氯喹喔啉-2(1H)-亚基)-2-氯乙酰肼(215mg,94%),为象牙色。
LC/MS ESI(+):349(M+1)
1H NMR(400MHz,DMSO-d6)δ=10.53(br s,1H),9.82(br s,1H),7.88(s,1H),7.80(d,J=8.8Hz,1H),7.67(d,J=8.9Hz,1H),4.29(s,2H)
(e)9-溴-5-(4-甲基哌嗪-1-基)-1H-[1,2,4]三嗪并[4,3-a]喹喔啉-2(3H)-酮的合成
将(Z)-N”-(7-溴-3-氯喹喔啉-2(1H)-亚基)-2-氯乙酰肼(87.0mg,0.249mmol)溶于1,4-二噁烷(2.49mL),并向其中添加DBU(0.0187mL,0.124mmol)。将反应混合物在50℃下搅拌1.5小时并冷却至室温。添加1-甲基吡嗪(0.277mL,2.49mmol)后,将反应混合物在室温下搅拌30分钟。将反应混合物在减压下浓缩。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的水:CH3CN=60:40),二氧化硅柱色谱(DCM:MeOH=90:10),胺二氧化硅柱色谱(DCM:MeOH=97:3)和反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=60:40)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,9-溴-5-(4-甲基哌嗪-1-基)-1H-[1,2,4]三嗪并[4,3-a]喹喔啉-2(3H)-酮(1.10mg,1.1%),为白色。
LC/MS ESI(+):377(M+1)
1H NMR(400MHz,DMSO-d6)δ=10.96(s,1H),7.23(s,1H),7.16-7.08(m,2H),4.39(s,2H),3.68-3.65(m,4H),2.34-2.32(m,4H),2.13(s,3H)
实施例15:8,9-二溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
通过实施例12的纯化步骤获得标题化合物。
LC/MS ESI(+):440(M+1)
1H NMR(400MHz,CDCl3)δ=7.70(d,J=8.8Hz,1H),7.54(d,J=8.9Hz,1H),5.25(s,2H),3.87-3.74(m,4H),2.58(t,J=4.7Hz,4H),2.36(s,3H)
实施例16:N-(4-(3-(甲基氨基)氮杂环丁烷-1-基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-8-基)甲磺酰胺的合成
(a)甲基(1-(8-(甲磺酰氨基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯的合成
将(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(100mg,0.260mmol)溶于吡啶(867mL),并向其中添加甲磺酰氯(26.4mL,0.338mmol)。将反应混合物在室温下搅拌1小时。添加H2O(50.0mL)后,将反应混合物用EtOAc(50.0mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,甲基(1-(8-(甲磺酰氨基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(86.0mg,71%),为黄色。
LC/MS ESI(+):463(M+1)
1H NMR(400MHz,CDCl3)δ=7.66(d,J=8.8Hz,1H),7.57(s,1H),7.34-7.28(m,1H),6.50(s,1H),5.14(s,2H),5.09-4.71(m,1H),4.55(m,2H),4.35(dd,J=6.3,9.7Hz,2H),3.05(s,3H),2.98(s,3H),1.48(s,9H)
(b)N-(4-(3-(甲基氨基)氮杂环丁烷-1-基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-8-基)甲磺酰胺的合成
将甲基(1-(8-(甲磺酰氨基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(86.0mg,0.186mmol)溶于DCM(1.86mL),并向其中添加TFA(430mL,5.58mmol)。将反应混合物在室温下搅拌1.5小时。添加饱和NaHCO3水溶液后,将反应混合物用DCM(50.0mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(4-(3-(甲基氨基)氮杂环丁烷-1-基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-8-基)甲磺酰胺(44.0mg,65%),为象牙色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.58(d,J=8.8Hz,1H),7.48(d,J=2.4Hz,1H),7.34(dd,J=2.5,8.9Hz,1H),5.36(s,2H),4.36(m,2H),3.93(m,2H),3.57(s,1H),3.00(s,3H),2.25(s,3H)
实施例17:8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)2,7-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪的合成
将2,3,7-三氯吡啶并[2,3-b]吡嗪(200mg,0.853mmol)溶于DCM(4.26mL),并在室温下向其中添加TEA(238mL,1.70mmol)和1-甲基哌嗪(104mL,0.938mmol)。将反应混合物在室温下搅拌2小时。将反应混合物通过胺二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2,7-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(61.0mg,44%),为象牙色。
LC/MS ESI(+):298(M+1)
1H NMR(400MHz,CDCl3)δ=8.88(s,1H),8.19(s,1H),3.82(brs,4H),2.69-2.62(m,4H),2.40(s,3H)
(b)N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将2,7-二氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(61.0mg,0.250mmol)溶于DMF(2.05mL),并在室温下向其中添加2-羟基乙酰胺(23.0mg,0.307mmol)和无水K2CO3(42.4mg,0.307mmol)。将反应混合物在70℃下搅拌1.5小时。将反应混合物通过反相二氧化硅柱色谱(含0.1%的甲酸的H2O:CH3CN=80:20)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(55.0mg,70%),为象牙色。
LC/MS ESI(+):337(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.63(d,J=2.6Hz,1H),8.08(d,J=2.4Hz,1H),7.59(brs,1H),7.29(brs,1H),4.94(s,2H),3.87(brs,4H),3.39-3.33(m,4H),2.24(s,3H)
(c)8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-基)-2-羟基乙酰胺(55.0mg,0.163mmol)溶于DMF(1.63mL),并在室温下向其中添加甲磺酰氯(191mL,2.45mmol)和TEA(341mL,2.45mmol)。将反应混合物在70℃下搅拌6.5小时。添加饱和NaHCO3水溶液后,将反应混合物用EtOAc(50.0mL)萃取。将有机层用H2O和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(9.30mg,13%),为象牙色。
LC/MS ESI(+):319(M+1)
1H NMR(400MHz,CDCl3)δ=8.73(d,J=2.4Hz,1H),8.07(d,J=2.6Hz,1H),5.21(s,2H),4.00-3.92(m,4H),2.64-2.57(m,4H),2.38(s,3H)
实施例18:8-氨基-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(100mg,0.260mmol)溶于DCM(2.60mL),并向其中添加TFA(100mL,1.30mmol)。将反应混合物在室温下搅拌1小时。添加饱和NaHCO3水溶液后,将反应混合物用DCM(50.0mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氨基-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(40.0mg,54%),为黄色。
LC/MS ESI(+):285(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.34(d,J=8.8Hz,1H),6.86(dd,J=2.5,8.7Hz,1H),6.74(d,J=2.6Hz,1H),5.33(s,2H),5.29(s,2H),4.27-4.20(m,2H),3.82(dd,J=5.6,9.0Hz,2H),3.54(m,1H),2.24(s,3H)
实施例19:8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
(a)(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(8-氨基-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(300mg,0.780mmol)溶于CH3CN(7.80mL),并在室温下向其中添加亚硝酸叔丁酯(124mL,0.936mmol),对甲苯磺酸(178mg,0.936mmol),CuCl2(10.5mg,0.0780mmol)和TBAC(260mg,0.936mmol)。将反应混合物在40℃下搅拌22小时。将反应混合物通过反相二氧化硅柱色谱(含0.1%的甲酸的H2O:CH3CN=65:35)纯化,并收集含有产物的级分并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=3:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(60.0mg,19%),为白色。
LC/MS ESI(+):404(M+1)
1H NMR(400MHz,CDCl3)δ=7.71(d,J=2.3Hz,1H),7.62(d,J=8.8Hz,1H),7.44(dd,J=2.4,8.8Hz,1H),5.15(s,2H),5.11-4.81(m,1H),4.57(m,2H),4.38(dd,J=6.0,10.1Hz,2H),3.00(s,3H),1.50(s,9H)
(b)8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮的合成
将(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(60.0mg,0.194mml)溶于DCM(1.48mL),并向其中添加TFA(114mL,1.48mmol)。将反应混合物在室温下搅拌18小时。添加饱和NaHCO3水溶液后,将反应混合物用DCM(50.0mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(36.0mg,80%),为白色。
LC/MS ESI(+):304(M+1)
1H NMR(400MHz,CDCl3)δ=7.69(d,J=2.4Hz,1H),7.60(d,J=8.8Hz,1H),7.42(dd,J=2.3,8.8Hz,1H),5.15(s,2H),4.55(dd,J=7.5,9.3Hz,2H),4.08(dd,J=4.8,9.8Hz,2H),3.79-3.72(m,1H),2.49(s,3H)
实施例20:8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
(a)(1-(2,7-二氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将2,3,7-三氯吡啶并[2,3-b]吡嗪(267mg,1.13mmol)溶于DCM(11.4mL),并向其中添加TEA(0.952mL,6.83mmol)和氮杂环丁烷-3-基-(甲基)氨基甲酸叔丁酯盐酸盐(279mg,1.25mmol)。将反应混合物在室温下搅拌1小时。将反应混合物通过二氧化硅柱色谱(正己烷:乙酸乙酯=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(2,7-二氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(94.0mg,21%),为象牙色。
LC/MS ESI(+):384(M+1)
1H NMR(400MHz,CDCl3)δ=8.80(s,1H),8.12(s,1H),5.22-4.90(m,1H),4.90-4.70(m,2H),4.65-4.50(m,2H),3.00(s,3H),1.50(s,9H)
(b)(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(2,7-二氯吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(94.0mg,0.245mmol)溶于DMF(2.44mL),并在室温下向其中添加2-羟基乙酰胺(27.5mg,0.367mmol)和无水K2CO3(50.7mg,0.367mmol)。将反应混合物在70℃下搅拌1小时。将反应混合物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=45:55)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(66.0mg,63%),为象牙色。
LC/MS ESI(+):423(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.56(d,J=2.6Hz,1H),8.03(d,J=2.4Hz,1H),7.55(s,1H),7.35(s,1H),5.09-4.88(m,1H),4.86(s,2H),4.72-4.17(m,4H),2.91(s,3H),1.42(s,9H)
(c)(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(66.0mg,0.156mmol)溶于DMF(1.56mL),并在室温下向其中添加甲磺酰氯(182mL,2.34mmol)和TEA(326mL,2.34mmol)。反应混合物在70℃下搅拌3.5小时。添加饱和NaHCO3水溶液后,将反应混合物用EtOAc(50.0mL)萃取。将有机层用H2O和盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(11.0mg,17%),为白色。
LC/MS ESI(+):405(M+1)
1H NMR(400MHz,CDCl3)δ=8.67(d,J=2.4Hz,1H),8.01(d,J=2.4Hz,1H),5.16(s,2H),4.68(brs,2H),4.51(brs,2H),4.17-4.02(m,1H),2.99(s,3H),1.50(s,9H)
(d)8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮的合成
将(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(11.0mg,0.0270mmol)溶于DCM(272mL),并向其中添加TFA(10.4mL,0.136mmol)。将反应混合物在室温下搅拌2.5小时。添加饱和NaHCO3水溶液后,将反应混合物用DCM(50.0mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮(5.90mg,70%),为白色。
LC/MS ESI(+):305(M+1)
1H NMR(400MHz,CDCl3)δ=8.65(d,J=2.6Hz,1H),7.99(d,J=2.4Hz,1H),5.16(s,2H),4.65(brs,2H),4.20(brs,2H),3.81-3.75(m,1H),2.49(s,3H)
实施例21:8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮盐酸盐的合成
将8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮(10.0mg,0.0290mmol)溶于CH3CN(0.500mL)和H2O(0.500mL),并向其中添加1N HCl(0.0290mL,0.0290mmol)。将反应混合物在室温下搅拌1小时并冷冻干燥,得到固体化合物,8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮盐酸盐(11.0mg,100%),为象牙色。
LC/MS ESI(+):348(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.48(brs,2H),7.85(d,J=2.2Hz,1H),7.67-7.63(m,1H),7.59-7.56(m,1H),5.39(s,2H),4.59-4.49(m,2H),4.40-4.35(m,2H),4.16-4.09(m,1H),2.60(brt,J=5.3Hz,3H)
实施例22:3-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[4,3-e]吡嗪-8(9H)-酮的合成
(a)7-氯-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮的合成
将6-氯吡啶-3,4-二胺(1.00g,6.97mmol)和草酸二乙酯(30.0mL,219mmol)的悬浮液在120℃下搅拌18小时。将反应混合物冷却至室温,并将获得的固体过滤,用EtOH和正己烷洗涤,并在减压下干燥,得到固体化合物,7-氯-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮(1.22g,89%),为褐色。
LC/MS ESI(+):198(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.26(s,1H),12.13(s,1H),8.08(s,1H),7.05(s,1H)
(b)3,7-二氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪的合成
向7-氯-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮(200mg,1.01mmol)和SOCl2(2.95mL,40.5mmol)的悬浮液中加入DMF(7.84μL,0.101mmol),并将该混合物在100℃下搅拌5小时。将反应混合物冷却至室温并浓缩以获得2,3,7-三氯吡啶并[3,4-b]吡嗪。将获得的2,3,7-三氯吡啶并[3,4-b]吡嗪溶于DCM(10.1mL)中,然后向其中添加1-甲基吡嗪(282μL,2.53mmol)。将反应混合物在室温下搅拌30分钟。将反应混合物通过二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,3,7-二氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪(220mg,73%),为淡黄色。
LC/MS ESI(+):298(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.98(s,1H),7.76(s,1H),3.70(brd,J=5.0Hz,4H),3.37-3.36(m,4H),2.24(s,3H)
(C)N-(7-氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-3-基)-2-羟基乙酰胺的合成
将3,7-二氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪(220mg,0.738mmol)溶于DMF(3.69mL),然后在室温下向其中添加2-羟基乙酰胺(66.5mg,0.885mmol)和K2CO3(153mg,1.11mmol)。将反应混合物在70℃下搅拌1小时。将反应混合物冷却至室温,并将获得的固体过滤,用H2O和Et2O洗涤,并在减压下干燥,得到固体化合物,N-(7-氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-3-基)-2-羟基乙酰胺(175mg,71%),为褐色。
LC/MS ESI(+):337(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.59(s,1H),7.61(brs,1H),7.53(s,1H),7.31(brs,1H),4.93(s,2H),4.01-3.90(m,4H),2.49-2.44(m,4H),2.22(s,3H)
(d)3-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[4,3-e]吡嗪-8(9H)-酮的合成
将N-(7-氯-2-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-3-基)-2-羟基乙酰胺(175mg,0.520mmol)溶于DMF(3.46mL),并在室温下向其中添加甲磺酰氯(607μL,7.79mmol)和TEA(1.09mL,7.79mmol)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,并向其中添加H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=30:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,3-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[4,3-e]吡嗪-8(9H)-酮(115mg,69%),为淡黄色。
LC/MS ESI(+):319(M+1)
1H NMR(400MHz,CDCl3)δ=8.79(s,1H),7.54(s,1H),5.20(s,2H),4.04-3.89(m,4H),2.59(brs,4H),2.38(s,3H)
实施例23:8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐的合成
(a)N-(3,7-二氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺的合成
在室温下将DMF(0.0780mL,1.01mmol)添加到7-氯-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮(1.00g,5.06mmol)和SOCl2(12.9mL,177mmol)的悬浮液中,并将该混合物在100℃下搅拌5小时。将反应混合物冷却至室温并浓缩以获得2,3,7-三氯吡啶并[3,4-b]吡嗪。将获得的2,3,7-三氯吡啶并[3,4-b]吡嗪和2-羟基乙酰胺(760mg,10.1mmol)溶于DMF(16.9mL),并向其中添加DIPEA(1.76mL,10.1mmol)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,向其中添加H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(3,7-二氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(140mg,10%),为淡黄色。
LC/MS ESI(+):273(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.16(s,1H),7.94(s,1H),7.60(brs,1H),7.41(brs,1H),5.01(s,2H)
(b)(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将N-(3,7-二氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(140mg,0.513mmol)和氮杂环丁烷-3-基(甲基)氨基甲酸叔丁酯盐酸盐(171mg,0.769mmol)溶于DMF(2.56mL),并在室温下向其中添加TEA(286μL,2.05mmol)。将反应混合物在室温下搅拌30分钟,并通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=95:5~0:100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(150mg,69%),为淡褐色。
LC/MS ESI(+):423(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.65(s,1H),7.57(s,1H),7.55(s,1H),7.37(s,1H),4.89(m,3H),4.67-4.14(m,4H),2.90(s,3H),1.41(s,9H)
(c)(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(7-氯-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(140mg,0.331mmol)和甲磺酰氯(387μL,4.97mmol)溶于DMF(2.21mL),并在室温下向其中添加吡啶(26.8μL)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,并通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=95:5~0:100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(72.0mg,54%),为白色。
LC/MS ESI(+):405(M+1)
1H NMR(400MHz,CDCl3)δ=8.81(s,1H),7.58(s,1H),5.17(s,2H),5.12-4.91(m,1H),4.60(t,J=8.3Hz,2H),4.51-4.36(m,2H),2.99(s,3H),1.49(s,9H)
(d)8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐的合成
将(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(70.0mg,0.173mmol)溶于DCM(1.73mL),并向其中添加TFA(265μL,3.46mmol)。将反应混合物在室温下搅拌40分钟。添加1N HCl后,反应混合物用EtOAc洗涤,用1N NaOH中和并用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐(13.0mg,22%),为白色。
LC/MS ESI(+):305(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.26(brs,2H),8.76(s,1H),7.73(s,1H),5.44(s,2H),4.71-4.49(m,2H),4.47-4.27(m,2H),4.21-4.08(m,1H),2.65-2.61(m,3H)
实施例24:8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮的合成
将(1-(8-氯-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(30.0mg,0.0740mmol)溶于DCM(741μL),并向其中添加TFA(113μL,1.48mmol)。将反应混合物在室温下搅拌30分钟。将反应混合物通过胺二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮(11.0mg,49%),为白色。
LC/MS ESI(+):305(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.68(s,1H),7.64(s,1H),5.39(s,2H),4.63-4.30(m,2H),4.17-3.87(m,2H),3.58(m,1H),2.25(s,3H)
实施例25:8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮的合成
(a)7-溴-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮的合成
将6-溴吡啶-3,4-二胺(1.00g,5.32mmol)和草酸二乙酯(22.9mL,168mmol)的悬浮液在120℃下搅拌14小时。将反应混合物冷却至室温。过滤获得的固体,用EtOH和正己烷洗涤,并在减压下干燥。得到固体化合物,7-溴-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮(1.10g,85%),为褐色。
LC/MS ESI(+):242(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.16(brs,2H),8.07(s,1H),7.17(s,1H)
(b)N-(7-溴-3-氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺的合成
在室温下将DMF(77.0μL,0.992mmol)添加到7-溴-1,4-二氢吡啶并[3,4-b]吡嗪-2,3-二酮(600mg,2.48mmol)和SOCl2(7.23mL,99.0mmol)的悬浮液中,并将该混合物在100℃下搅拌5小时。将反应混合物冷却至室温并浓缩以获得7-溴-2,3-二氯吡啶并[3,4-b]吡嗪。将获得的7-溴-2,3-二氯吡啶并[3,4-b]吡嗪和2-羟基乙酰胺(111mg,1.48mmol)溶于环丁砜(8.23mL),并向其中添加DIPEA(473μL,2.72mmol)。将反应混合物在60℃下搅拌2小时。将反应混合物冷却至室温,向其中添加H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(正己烷:EtOAc=1:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(7-溴-3-氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(105mg,14%),为淡黄色。
LC/MS ESI(+):317(M+1)
1H NMR(400MHz,DMSO-d6)δ=9.13(s,1H),8.08(s,1H),7.60(brs,1H),7.41(brs,1H),5.01(s,2H)
(C)N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将N-(7-溴-3-氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(40.0mg,0.126mmol)溶于DMF(630μL)中,然后向其中添加1-甲基哌嗪(28.0μL,0.252mmol)。将反应混合物在60℃下搅拌10分钟。将反应混合物冷却至室温,向其中添加H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏,得到固体化合物,N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(42.0mg,87%),为淡褐色。
LC/MS ESI(+):381(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.71-8.70(s,1H),7.72-7.71(s,1H),7.61(brs,1H),7.35-7.29(m,1H),4.98-4.96(m,2H),3.81-3.78(m,4H),2.48-2.46(m,4H),2.23(s,3H)
(d)8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮的合成
将N-(7-溴-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(42.0mg,0.110mmol)溶于DMF(551μL),并在室温下向其中添加甲磺酰氯(129μL,1.65mmol)和吡啶(267μL,3.31mmol)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,并通过反相二氧化硅柱色谱(含0.1%甲酸:CH3CN的H2O=95:5~0:100)纯化,收集含有产物的级分并蒸发,得到固体化合物,8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮(2.00mg,5%),为褐色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.70(s,1H),7.79(s,1H),5.35(s,2H),3.69-3.65(m,4H),2.51-2.46(m,4H),2.21-2.19(m,3H)
实施例26:8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮的合成
(a)(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将N-(7-溴-3-氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(66.0mg,0.208mmol)和氮杂环丁烷-3-基(甲基)氨基甲酸叔丁酯盐酸盐(69.4mg,0.312mmol)溶于DMF(1.04mL),并在室温下向其中添加TEA(116μL,0.831mmol)。将反应混合物在室温下搅拌30分钟,并通过反相二氧化硅柱色谱(含0.1%甲酸:CH3CN的H2O=95:5~0:100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(82.0mg,84%),为白色。
LC/MS ESI(+):467(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.63(s,1H),7.67(s,1H),7.57(brs,1H),7.36(brs,1H),4.89(m,3H),4.71-4.21(m,4H),2.90(s,3H),1.41(s,9H)
(b)(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(7-溴-2-(2-羟基乙酰氨基)吡啶并[3,4-b]吡嗪-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(80.0mg,0.171mmol)溶于DMF(856μL),并在室温下向其中添加甲磺酰氯(200μL,2.57mmol)和吡啶(415μL,5.14mmol)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,并在反相二氧化硅上通过柱色谱(含0.1%甲酸的H2O:CH3CN=95:5~0:100)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(64.0mg,83%),为白色。
LC/MS ESI(+):449(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.69(s,1H),7.78(s,1H),5.38(s,2H),5.03-4.73(m,1H),4.68-4.14(m,4H),2.89(s,3H),1.41(s,9H)
(c)8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮的合成
将(1-(8-溴-2-氧代-1,2-二氢咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-4-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(62.0mg,0.138mmol)溶于DCM(920μL),并向其中添加TFA(211μL,2.76mmol)。将反应混合物在室温下搅拌30分钟。将反应混合物通过胺二氧化硅柱色谱(DCM:MeOH=20:1)和二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮(32.0mg,66%),为白色。
LC/MS ESI(+):349(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.66(s,1H),7.77(s,1H),5.39(s,2H),4.60-4.27(m,2H),4.23-3.84(m,2H),3.63-3.54(m,1H),2.26(s,3H)
实施例27:8-溴-4-(4-甲基哌嗪-1-基)-1H-吡啶并[2,3-e][1,2,4]噻二唑并[4,3-a]吡嗪2,2-二氧化物的合成
(a)7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-胺的合成
在100℃下将7-溴-2-氯-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪(420mg,1.22mmol)和2M NH3 IPA溶液(6.13mL,12.2mmol)的悬浮液搅拌21小时。向反应混合物中加入正己烷,将所得固体过滤并在减压下干燥,得到固体化合物,7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-胺(372mg,94%),为白色。
LC/MS ESI(+):323(M+1)
1H NMR(400MHz,CDCl3)δ=8.70(d,J=2.4Hz,1H),8.08(d,J=2.3Hz,1H),5.13(brs,2H),3.57(brs,4H),2.67(brs,4H),2.41(s,3H)
(b)8-溴-4-(4-甲基哌嗪-1-基)-1H-吡啶并[2,3-e][1,2,4]噻二唑并[4,3-a]吡嗪2,2-二氧化物的合成
将7-溴-3-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-2-胺(270mg,0.835mmol)溶于吡啶(2.78mL),并在0℃下向其中添加氯甲磺酰氯(1.51mL,16.7mmol)。将反应混合物在室温下搅拌17小时。添加饱和NaHCO3水溶液后,将反应混合物用EtOAc(100mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过二氧化硅柱色谱(DCM:MeOH=9:1)纯化,收集含有产物的级分并蒸发。将残留物通过平板TLC(EtOAc:MeOH=9:1)纯化,收集含有产物的级分并蒸发。将残留物在Et2O中搅拌30分钟并过滤,得到固体化合物,8-溴-4-(4-甲基哌嗪-1-基)-1H-吡啶并[2,3-e][1,2,4]噻二唑并[4,3-a]吡嗪2,2-二氧化物(6.50mg,2%),为黄色。
LC/MS ESI(+):399(M+1)
1H NMR(400MHz,CDCl3)δ=8.56(d,J=2.0Hz,1H),7.39(d,J=2.1Hz,1H),4.86(s,2H),4.30(brs,4H),2.59(brt,J=4.8Hz,4H),2.36(s,3H)
实施例28:8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐的合成
(a)N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺的合成
将N-(3,7-二氯吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(190mg,0.696mmol)溶于DMF(2.32mL)中,然后向其中添加1-甲基哌嗪(155μL,1.39mmol)。将反应混合物在60℃下搅拌30分钟。将反应混合物冷却至室温,加入H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏,得到固体化合物,N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(220mg,94%),为淡褐色。
LC/MS ESI(+):337(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.73(s,1H),7.62(s,1H),7.59(s,1H),7.32(s,1H),4.97(s,2H),3.82-3.75(m,4H),2.49-2.45(m,4H),2.23(s,3H)
(b)8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐的合成
将N-(7-氯-3-(4-甲基哌嗪-1-基)吡啶并[3,4-b]吡嗪-2-基)-2-羟基乙酰胺(220mg,0.653mmol)溶于DMF(3.27mL),并在室温下向其中添加甲磺酰氯(764μL,9.80mmol)和吡啶(1.59mL,19.6mmol)。将反应混合物在80℃下搅拌1小时。将反应混合物冷却至室温,向其中添加H2O和EtOAc,并将该混合物用EtOAc萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤并在减压下蒸馏。将残留物通过胺二氧化硅柱色谱(DCM:MeOH=20:1)和二氧化硅柱色谱(DCM:MeOH=20:1)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐(26.0mg,11%),为白色。
LC/MS ESI(+):319(M+1)
1H NMR(400MHz,DMSO-d6)δ=10.87(brs,1H),8.87(s,1H),7.81(s,1H),5.44(s,2H),4.51(m,2H),3.59-3.38(m,4H),3.33-3.13(m,2H),2.81(s,3H)
实施例29:2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
(a)6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮的合成
将6-氯吡啶-2,3-二胺(2.00g,13.9mmol)溶于草酸二乙酯(27.9mL),并将该混合物在130℃下搅拌15小时。将反应混合物冷却至室温,并将获得的固体过滤,用Et2O洗涤并在减压下干燥,得到固体化合物,6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(2.70g,96%),为褐色。
LC/MS ESI(+):198(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.51(brs,1H),12.05(brs,1H),7.46(d,J=8.2Hz,1H),7.20(d,J=8.2Hz,1H)
(b)2,3,6-三氯吡啶并[2,3-b]吡嗪的合成
将POCl3(16.9mL)添加到6-氯-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(1.00g,5.10mmol),并在130℃下将该混合物搅拌24小时。将反应混合物冷却至0℃下。缓慢添加冰水(50.0mL)后,将获得的固体过滤,用水洗涤并在减压下干燥,获得固体化合物,2,3,6-三氯吡啶并[2,3-b]吡嗪(945mg,80%),为褐色。
LC/MS ESI(+):234(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.64(d,J=8.7Hz,1H),8.06(d,J=8.7Hz,1H)
(c)N-(2,6-二氯吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺
将2,3,6-三氯吡啶并[2,3-b]吡嗪(945mg,4.00mmol)和2-羟基乙酰胺(605mg,8.10mmol)溶于DMF(13.4mL),并在室温下向其中添加DIPEA(1.40mL,8.10mmol)。将反应混合物在80℃下搅拌2小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(2,6-二氯吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺(373mg,34%),为黄色。
LC/MS ESI(+):273(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.49(d,J=8.5Hz,1H),7.82(d,J=8.5Hz,1H),7.61(brs,1H),7.37(brs,1H),4.99(s,2H)
(d)N-(6-氯-2-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺的合成
将N-(2,6-二氯吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺(200mg,0.700mmol)溶于DMF(3.70mL),并在室温下向其中缓慢添加1-甲基哌嗪(162μL,1.50mmol)。将反应混合物在60℃下搅拌10分钟,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(6-氯-2-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺(215mg,87%),为黄色。
LC/MS ESI(+):337(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.05(d,J=8.5Hz,1H),7.61(brs,1H),7.53(d,J=8.5Hz,1H),7.29(brs,1H),4.95(s,2H),3.78(s,4H),2.50(s,4H),2.24(s,3H)
(e)2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
将N-(6-氯-2-(4-甲基哌嗪-1-基)吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺(210mg,0.600mmol)溶于DMF(6.20mL),并在室温下向其中添加甲磺酰氯(1.00mL,12.5mmol)和TEA(1.70mL,12.5mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮(142mg,71%),为黄色。
LC/MS ESI(+):319(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.12(d,J=8.5Hz,1H),7.62(d,J=8.5Hz,1H),5.42(s,2H),3.72-3.69(m,4H),2.50-2.46(m,4H),2.22(s,3H)
实施例30:2-溴-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
将2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮(95.0mg,0.300mmol)溶于CH3CN(3.00mL),并在室温下向其中添加溴三甲基硅烷(641μL,6.00mmol)。将反应混合物在80℃下搅拌3天,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-溴-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮(24.0mg,22%),为黄色。
LC/MS ESI(+):363(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.00(d,J=8.5Hz,1H),7.72(d,J=8.5Hz,1H),5.42(s,2H),3.72-3.70(m,4H),2.50-2.46(m,4H),2.22(s,3H)
实施例31:2-氯-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
(a)(1-(6-氯-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将N-(2,6-二氯吡啶并[2,3-b]吡嗪-3-基)-2-羟基将乙酰胺(164mg,0.600mmol)溶于DMF(3.00mL),并在室温下向其中缓慢添加氮杂环丁烷-3-基(甲基)氨基甲酸叔丁酯盐酸盐(201mg,0.900mmol)和TEA(335μL,2.40mmol)。将反应混合物在25℃下搅拌30分钟,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=50:50)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(6-氯-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(241mg,95%),为黄色。
LC/MS ESI(+):423(M+1)
1H NMR(400MHz,CDCl3)δ=7.90(d,J=8.5Hz,1H),7.36(d,J=8.5Hz,1H),6.31(brs,1H),5.81(brs,1H),5.10(s,2H),4.99(s,1H),4.64-4.60(m,2H),4.46-4.42(m,2H),2.97(s,3H),1.47(s,9H)
(b)(1-(2-氯-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(6-氯-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(600mg,1.40mmol)溶解于DMF(14.2mL),并在室温下向其中添加甲磺酰氯(1.10mL,14.2mmol)和TEA(2.40mL,17.0mmol)。将反应混合物在80℃下搅拌2小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=40:60)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(2-氯-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(138mg,24%),为褐色。
LC/MS ESI(+):405(M+1)
1H NMR(400MHz,CDCl3)δ=7.94(d,J=8.5Hz,1H),7.42(d,J=8.5Hz,1H),5.23(s,2H),5.08(s,1H),4.64-4.58(m,2H),4.44-4.40(m,2H),2.98(s,3H),1.48(s,9H)
(c)2-氯-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
将(1-(2-氯-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(100mg,0.300mmol)溶于DCM(1.20mL),并在0℃下向其中添加TFA(567μL,7.40mmol)。将反应混合物在室温下搅拌10分钟并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-氯-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮(65.0mg,86%),为白色。
LC/MS ESI(+):305(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.01(d,J=8.5Hz,1H),7.54(d,J=8.5Hz,1H),5.38(s,2H),4.56-4.33(m,2H),4.11-3.86(m,2H),4.61-3.55(m,1H),2.36(brs,1H),2.25(s,3H)
实施例32:2-溴-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
(a)6-溴-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮的合成
将6-溴吡啶-2,3-二胺(1.00g,5.20mmol)溶于草酸二乙酯(10.4mL),并将该混合物在130℃下搅拌15小时。将反应混合物冷却至室温,并将获得的固体过滤,用Et2O洗涤并在减压下干燥,得到固体化合物,6-溴-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(1.20g,98%),为褐色。
LC/MS ESI(+):242(M+1)
1H NMR(400MHz,DMSO-d6)δ=12.51(brs,1H),12.05(brs,1H),7.37(d,J=8.2Hz,1H),7.32(d,J=8.2Hz,1H)
(b)2,3,6-三溴吡啶并[2,3-b]吡嗪的合成
将6-溴-1,4-二氢吡啶并[2,3-b]吡嗪-2,3-二酮(1.10g,4.50mmol)和DMF(18.0μL,0.200mmol)溶于DCE(11.4mL),并在室温下向其中添加POBr 3(3.90g,13.6mmol)。将反应混合物在100℃下搅拌15小时,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=40:60)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2,3,6-三溴吡啶并[2,3-b]吡嗪(795mg,48%),为黄色。
LC/MS ESI(+):366(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.51(d,J=8.7Hz,1H),8.16(d,J=8.7Hz,1H)
(c)N-(2,6-二溴吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺的合成
将2,3,6-三溴吡啶并[2,3-b]吡嗪(838mg,2.30mmol)和2-羟基乙酰胺(342mg,4.60mmol)溶于DMF(9.10mL),并在室温下向其中添加DIPEA(0.800mL,4.60mmol)。将反应混合物在80℃下搅拌2小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,N-(2,6-二溴吡啶并[2,3-b]吡嗪-3-基)-2-羟基乙酰胺(230mg,28%),为黄色。
LC/MS ESI(+):361(M+1)
1H NMR(400MHz,DMSO-d6)δ=8.39(d,J=8.5Hz,1H),7.92(d,J=8.5Hz,1H),7.60(brs,1H),7.37(brs,1H),4.98(s,2H)
(d)(1-(6-溴-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将N-(2,6-二溴吡啶并[2,3-b]吡嗪-3-基)-2-羟基将乙酰胺(225mg,0.600mmol)溶于DMF(3.10mL),并在室温下向其中缓慢添加氮杂环丁烷-3-基(甲基)氨基甲酸叔丁酯盐酸盐(208mg,0.900mmol)和TEA(347μL,2.50mmol)。将反应混合物在25℃下搅拌10分钟,并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=50:50)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(6-溴-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(255mg,88%),为黄色。
LC/MS ESI(+):467(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.87(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),7.56(brs,1H),7.34(brs,1H),5.03-4.76(m,1H),4.87(s,2H),4.61-4.28(m,4H),2.89(s,3H),1.40(s,9H)
(e)(1-(2-溴-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯的合成
将(1-(6-溴-3-(2-羟基乙酰氨基)吡啶并[2,3-b]吡嗪-2-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(250mg,0.500mmol)溶于DMF(5.40mL),并在室温下向其中添加甲磺酰氯(0.400mL,5.40mmol)和TEA(0.900mL,6.40mmol)。将反应混合物在80℃下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=40:60)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,(1-(2-溴-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(67.0mg,28%),为黄色。
LC/MS ESI(+):449(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.93(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),5.37(s,2H),5.01-4.69(m,1H),4.59-4.26(m,4H),2.88(s,3H),1.40(s,9H)
(f)2-溴-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮的合成
将(1-(2-溴-8-氧代-8,9-二氢咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-6-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(60.0mg,0.130mmol)溶于DCM(0.700mL),并在0℃下向其中添加TFA(307μL,4.00mmol)。将反应混合物在室温下搅拌1小时并在减压下蒸馏。将残留物通过反相二氧化硅柱色谱(含0.1%甲酸的H2O:CH3CN=70:30)纯化,收集含有产物级分的级分并蒸发,得到固体化合物,2-溴-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮(43.0mg,92%),为白色。
LC/MS ESI(+):349(M+1)
1H NMR(400MHz,DMSO-d6)δ=7.90(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),5.38(s,2H),4.56-4.33(m,2H),4.11-3.86(m,2H),4.61-3.55(m,1H),2.41(brs,1H),2.25(s,3H)
实验例1:人组胺4受体(hH4R)的结合亲和力分析
将以上实施例中制备的化合物,国际公开号WO2010/030785的实施例55的化合物和国际公开号WO2013/048214的实施例4的化合物用DMSO稀释1000倍(v/w),然后将1mL的稀释化合物溶液与99mL的分析缓冲溶液(50mM tris-HCl pH 7.4,5mM EDTA)混合,以获得1μM的浓度。将20mL制备的化合物溶液转移到96孔板的每个孔中,然后将20mL用分析缓冲液和1%DMSO稀释的100μM组胺转移到每个孔中以计算非特异性结合和总结合度。将15μg人组胺4受体过表达的细胞膜(Multispan)稀释到160mL分析缓冲溶液中,然后转移到每个孔中。将[3H]标记的组胺(PerkinElmer)稀释至10nM浓度,在每个孔中分配20mL,然后将其在27℃下的培养箱中放置30分钟。反应后,将100mL的混合物转移至玻璃纤维板中,在玻璃纤维板中预先浸泡0.5%的聚乙烯胺,然后真空除去未结合的[3H]标记的组胺。用200mL洗涤缓冲液(50mM tris-HCl,pH 7.4)洗涤6次后,将板在37℃下的烤箱中干燥18小时。将100mLβScint鸡尾酒溶液添加到每个孔中,并在10分钟后使用Microβ2TM测量[3H]标记的组胺的CPM(每分钟计数)值。通过Excel程序分析人组胺4受体对本发明化合物的结合亲和力(%抑制),其分析结果示于表1。
[表1]
实验例2:药代动力学测试
[药物制备]
如同上述实施例中制备的化合物的小鼠给药溶液,将国际公开号WO2010/030785的实施例55的化合物和国际公开号WO2013/048214的实施例4的化合物,20%羟丙基-β-环糊精溶液(99.75%)和2N HCl(0.25%)依次加入,得到5mg/mL。前提是,在实施例10的化合物的情况下,添加99.5%的20%羟丙基-β-环糊精溶液和0.5%的2N HCl(0.25%)。
[实验]
每只ICR小鼠的体重适当地为20-30g。本发明化合物的剂量为10mL/kg,并使用Zonde口服。使用涂有抗凝剂的毛细管通过眼眶静脉采血在0.5、1、2、4、7和24小时进行采血,然后使用离心机分离血浆并保存在冰箱中。
[分析]
使用固相萃取对从动物和标准浓度物质中收集的血浆进行预处理,并使用液相色谱质谱仪(Agilent HPLC,API-4000Qtrap)测定本发明化合物的浓度。根据所得的浓度值,使用WinNonlin(版本7.0)找到药代动力学参数,并且将半衰期(t1/2),最大血药浓度(Cmax)和曲线下面积(AUCall)示于表2中。
[表2]
*NC:未计算
实验例3:组胺诱导的ICR小鼠瘙痒模型
[动物]
雌性ICR小鼠(8周大)购自OrientBio Co.,Ltd.将动物圈养在温度可控制(23±3℃下),湿度(50±5%)和可随意采食和饮水的条件下。实验前1小时停水和食物。
[实验:瘙痒的诱发与测量]
为了方便地在皮肤内注射pruritogen(组胺,溶于盐水注射溶液中,使浓度为300nmol/40μL),在使用异氟烷进行吸入麻醉的实验前24小时,使用修剪器(8000AD,THRIVE)将头发修剪至吻部。小鼠(每组n=10)分为5组(正常组,对照组和3个实验组)。将动物随机分配相似的体重分布。在组胺给药前30分钟,向正常组和对照组口服赋形剂(在二次蒸馏水中的20%环糊精),并将在实施例13中制备的化合物,国际公开号WO2010/030785的实施例55的化合物和国际公开号WO2013/048214的实施例4的化合物口服给予实验组(以50mg/kg的剂量溶于赋形剂中)。因为血液浓度保持24小时,所以在口服给药后7小时给药组胺。组胺给药后,立即将动物放在观察笼中,个体之间保持独立的空间,然后使用相机(PowerShot N2,Canon)拍摄20分钟的视频。拍摄结束时,使用录制的视频对在组胺给药后20分钟内测试动物的挠痒次数进行计数。挠痒的次数,计数从用动物的后脚挠痒到将后脚举到嘴上的时间的一系列动,作为一次(J.Allergy Clin.Immunol.2007,19(1),176-183)。使用Excel和Prism分析所有数据,每组的挠痒次数表示为平均值±S.E.M.。化合物的抑制效果以对组胺的最大响应百分数表示(对照组为100%)。使用单因素方差分析和Dunnett检验对统计分析进行分析。p<0.05的值被认为具有统计学意义。化合物的抑制效果示于表3中。
[表3]
Claims (14)
1.下式1的杂环化合物或其药学上可接受的盐或异构体:
[式1]
其中
X1,X2,X3和X4中的每一个独立地为C或N;
R1为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-12元单或多杂环基,其中R1未被取代或被1-3个选自-C1-C6烷基和-氨基-C1-C6烷基的取代基取代;
R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-C3-C8环烷基,-卤素(-F,-Cl,-Br,-I),-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-C2-C7烯基,-C2-C8炔基,-氨基,-乙酰基,-酰氨基,-磺酰胺,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基(-COOH),-C1-C6酰基,-OH,-硝基(-NO2),-C6-C10芳基,-杂环基和-O-C1-C6烷基-杂环基,其中杂环基为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-6元杂环基;
前提是,当X1为N时,R2不存在;当X2为N时,R3不存在;当X3为N时,R4不存在;且当X4为N时,R5不存在;且当X1,X2,X3和X4全部为C时,R3不为氢或氟(F);
Y1和Y2中的每一个独立地为C或N;
A环为包含至少2个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的5或6元杂环;和
R6和R7中的每一个独立地为氧代(=O)或=NH,且R6和R7之一可以不存在;
其中烷基,环烷基,杂环基,烷氧基,烯基,炔基,酰基和芳基中的每一个可以独立地未被取代或被一个或多个取代基(例如1-3个取代基)取代,所述取代基选自:-C1-C4烷基,-卤素(-F,-Cl,-Br,-I),-CN,-C1-C4烷氧基,-氨基,-酰氨基,-羧基(-COOH),-C1-C6酰基,-OH,-硝基(-NO2),杂环基和苯基,其中杂环基为含有1-3个杂原子(优选选自N,O和S的杂原子)的饱和或不饱和的3-6元杂环基。
2.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中
X1,X2,X3和X4中的每一个独立地为C或N;
R1为含有1-3个选自N,O和S的杂原子的饱和或不饱和的3-10元单或多杂环基,其中杂环基未被取代或被1或2个选自-C1-C6烷基和-氨基-C1-C6烷基的取代基取代;
R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-C3-C8环烷基,-卤素,-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-氨基,-乙酰基,-磺酰氨基,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基,-OH,-硝基,-C6-C10芳基,-杂环基和-O-C1-C6烷基-杂环基,其中杂环基为含有1-3个选自N,O和S的杂原子的饱和或不饱和的3-6元杂环基;
Y1和Y2中的每一个独立地为C或N;
A环为包含2-4个选自N,O和S的杂原子的饱和或不饱和的5或6元杂环;和
R6和R7各自独立地为氧代或=NH,且R6和R7之一可以不存在。
3.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中X1和X2为C,且X3和X4中的每一个独立地为C或N。
4.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中X1和X2中的每一个独立地为C或N,且X3和X4为C。
5.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中R1为含有1-3个选自N和O的杂原子的饱和或不饱和的3-10元单或多杂环基,其中杂环基未被取代或被1或2个选自-C1-C4烷基和-氨基-C1-C4烷基的取代基取代。
6.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中R2,R3,R4和R5可以相同或不同;并且它们中的每一个独立地选自-H,-C1-C6烷基,-C1-C6卤代烷基,-C1-C6全卤代烷基,-氨基-C1-C6烷基,-卤素,-CN,-C1-C6烷氧基,-C1-C6卤代烷氧基,-C1-C6全卤代烷氧基,-氨基,-乙酰基,-磺酰氨基,-磺酰基,-氨基磺酰基-C1-C6烷基,-C1-C6烷基羧基,-羧基,-OH,-硝基和-杂环基,其中杂环基为含有1-3个选自N,O和S的杂原子的饱和或不饱和的5或6元杂环基。
7.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中A环为含有2或3个选自N和S的杂原子的饱和或不饱和的5或6元杂环。
8.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中R6是氧代或=NH,且R7不存在。
9.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中R6和R7为氧代。
10.根据权利要求1的杂环化合物或其药学上可接受的盐或异构体,其中杂环化合物选自:
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
(R)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
(S)-8-溴-4-(3-(甲基氨基)吡咯烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-a]吡嗪-1(2H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-a]吡嗪-2(1H)-酮;
8-溴-7-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-7-氟-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
4-(4-甲基哌嗪-1-基)-8-硝基咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氨基-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
9-溴-5-(4-甲基哌嗪-1-基)-1H-[1,2,4]三嗪并[4,3-a]喹喔啉-2(3H)-酮;
8,9-二溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
N-(4-(3-(甲基氨基)氮杂环丁烷-1-基)-2-氧代-1,2-二氢咪唑并[1,2-a]喹喔啉-8-基)甲磺酰胺;
8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-氨基-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[2,3-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]喹喔啉-2(1H)-酮盐酸盐;
3-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[4,3-e]吡嗪-8(9H)-酮;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐;
8-氯-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮;
8-溴-4-(4-甲基哌嗪-1-基)-1H-吡啶并[2,3-e][1,2,4]噻二唑并[4,3-a]吡嗪2,2-二氧化物;
8-氯-4-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,4-e]吡嗪-2(1H)-酮盐酸盐;
2-氯-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;
2-溴-6-(4-甲基哌嗪-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;
2-氯-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮;和
2-溴-6-(3-(甲基氨基)氮杂环丁烷-1-基)咪唑并[1,2-a]吡啶并[3,2-e]吡嗪-8(9H)-酮。
11.药物组合物,包含作为活性成分的权利要求1至10中任一项所定义的杂环化合物或其药学上可接受的盐或异构体,和药学上可接受的载体。
12.根据权利要求11的药物组合物,其中所述组合物显示出人组胺4受体(hH4R)抑制活性。
13.根据权利要求11的药物组合物,其中所述组合物用于预防或治疗疾病,所述疾病选自炎性疾病,自身免疫病,变应性疾病,眼病,皮肤病,呼吸系统疾病,疼痛性疾病,心脏病和与人组胺4受体(hH4R)相关的疾病。
14.根据权利要求13的药物组合物,其中所述组合物用于预防或治疗疾病,所述疾病选自炎性疾病,变态反应,疼痛,鼻息肉,鼻炎,慢性鼻窦炎,鼻充血,鼻痒,哮喘,慢性阻塞性肺疾病,类风湿性关节炎,特应性皮炎,银屑病,湿疹,瘙痒,发痒的皮肤,荨麻疹,特发性慢性荨麻疹,硬皮病,结膜炎,角膜结膜炎,眼部炎症,干眼症,心功能障碍,年龄相关性黄斑变性,心律失常,动脉粥样硬化,多发性硬化,炎性肠病(结肠炎,克罗恩病,溃疡性结肠炎),炎性疼痛,神经性疼痛,骨关节炎性疼痛,自身免疫性甲状腺疾病,免疫介导的糖尿病,狼疮,术后粘连,前庭疾病和癌症。
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JP2023529867A (ja) | 2020-06-05 | 2023-07-12 | キネート バイオファーマ インク. | 線維芽細胞増殖因子受容体キナーゼの阻害剤 |
EP4067357A1 (en) * | 2021-03-30 | 2022-10-05 | JW Pharmaceutical Corporation | Novel crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-n-methylazetidin-3-amine hydrogen sulfate monohydrate |
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BR112020023946A2 (pt) | 2021-02-23 |
MX2020011955A (es) | 2021-01-15 |
TW202021969A (zh) | 2020-06-16 |
JP2021525738A (ja) | 2021-09-27 |
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