CN114369095A - 适用作ssao抑制剂的氨基嘧啶化合物及其制备方法 - Google Patents
适用作ssao抑制剂的氨基嘧啶化合物及其制备方法 Download PDFInfo
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本申请涉及适用作SSAO抑制剂的氨基嘧啶化合物及其制备方法。本发明提供下式化合物
Description
本申请为申请日2018年2月7日,申请号201880000825.X,名称为“适用作SSAO抑制剂的氨基嘧啶化合物”的发明专利申请的分案申请。
技术领域
本发明涉及氨基嘧啶化合物、所述化合物的医药学上可接受的盐以及所述化合物和其盐的治疗用途。
背景技术
氨基脲-敏感性氨基氧化酶/血管粘附蛋白-1(SSAO/VAP-1)以膜结合同种型和血浆可溶性同种型两种形式存在。其主要从内皮细胞表面、血管平滑肌和脂肪细胞表达。SSAO/VAP-1参与许多细胞过程,包括葡萄糖处置、炎症反应和相关疼痛以及白细胞募集。此酶的高活性水平与糖尿病、动脉粥样硬化、中风、慢性肾病和阿尔茨海默氏病(Alzheimer'sdisease)以及其它病症相关。SSAO/VAP-1已涉及肝病,如脂肪肝的发病机理。(韦斯顿C.J.(Weston C.J.)等人,《神经传递杂志(J.Neural.Transm.)》,2011,118,1055。)脂肪肝(fatty liver disease;FLD)涵盖一系列疾病病况,其特征为脂肪在肝脏中过量积累,常常伴有炎症。FLD可引起特征在于胰岛素抗性的非酒精性脂肪肝病(non-alcoholic fattyliver disease;NAFLD)。如果不经治疗,NAFLD会发展为持续性发炎性反应或非酒精性脂肪性肝炎(non-alcoholic steatohepatitis;NASH)、进行性肝纤维化并最终发展为肝硬化。目前需要提供肝病(如NAFLD和/或NASH)的替代治疗疗法。
据认为,SSAO/VAP-1抑制剂将减少肝脏炎症和纤维化并进而提供针对肝病的治疗,尤其针对NAFLD和/或NASH的治疗。另外,因为SSAO/VAP-1的活化涉及炎症和相关疼痛,所以SSAA/VAP-1酶的抑制可能适用于治疗疼痛和尤其与骨关节炎相关的疼痛。(路易斯M.(Luis M.)等人,《药理学与实验治疗学杂志(J of Pharm and ExperimentalTherapeutics)》,2005,315,553)。
美国专利8,426,587公开适用作SSAO/VAP1抑制剂的卤基烯丙基胺化合物。
目前,尚无批准用于治疗NASH的药物;NASH的护理标准由饮食控制和/或生活方式变化组成。另外,目前疼痛的护理标准由非类固醇消炎药物(NSAIDS)和***制剂主导。两种药物类别都仅建议短期使用。期望具有更多治疗选择来控制疼痛、尤其慢性疼痛。本发明提供抑制SSAO/VAP-1酶并可解决这些需求中的一或多种的化合物。
发明内容
本发明提供一种下式1化合物:
其中R1选自: 以及R2选自:H、-C(O)NH2、-C(O)NH(CH3)、-C(O)NH(CH3)2、以及R3是H或CH3,R4是H或R5选自:H、-C1-4烷基、-C3-4环烷基、-CH2-C3-4环烷基;且n是1或2;或其药学上可接受的盐。
说明为的到氟的键指示氟原子和甲氧基嘧啶基团相对于彼此可以是Z(同侧,在一起)或E(异侧,相对)。(参见布雷彻J.(Brecher J.)等人,“立体化学构型的图形表示(Graphical Representation of Stereochemical Configuration)”,《理论和应用化学(Pure and Appl.Chem)》,2006,78(10)1897,第1959页)。通过式1说明的结构包括围绕双键展现Z立体化学构型或E立体化学构型的化合物;或单独展现Z或E立体化学构型的化合物的混合物。本发明的优选化合物具有围绕双键的E立体化学构型。
本发明还提供式2化合物:
其中R1选自: 以及R2选自:H、-C(O)NH2、-C(O)NH(CH3)、-C(O)NH(CH3)2、以及R3是H或CH3;R4是H或R5选自:H、-C1-4烷基、-C3-4环烷基和-CH2-C3-4环烷基;且n是1或2;或其药学上可接受的盐。
在另一形式中,本发明提供根据式1或2的化合物,其中R1选自: 以及且其中R2、R3、R4、R5和n如上文所提供;或其药学上可接受的盐。在一个优选实施例中,R1是且R5和n如上文所提供。在另一优选实施例中,R1是且R5选自:H、-CH3、更优选地R5是-CH3。
在另一形式中,本发明提供根据式1或2的化合物,其中R1是R2选自:H、-C(O)NH2、-C(O)NH(CH3)、-C(O)NH(CH3)2、以及且R3和R4如上文所提供,或其医药学上可接受的盐。在一个优选实施例中,R3是H且R4如上所提供,或其医药学上可接受的盐。在另一优选实施例中,R3是H并且R4是H。
在另一形式中,本发明提供根据下式3的化合物:
或其医药学上可接受的盐。
在又一形式中,本发明提供下式4化合物:
或其医药学上可接受的盐。在一种形式中,式4化合物以游离碱形式提供。
在另一形式中,式4化合物以医药学上可接受的盐形式提供。优选地,式4化合物以单或二盐酸加成盐形式提供。
在另一形式中,本发明提供医药组合物,其包含根据式1到4中的任一个的化合物,或其医药学上可接受的盐和医药学上可接受的载剂、稀释剂或赋形剂。医药组合物可以用于治疗患有肝脏病症的患者。
在另一形式中,本发明提供治疗有需要的患者的肝脏病症的方法。所述方法包含向患者施用有效量的根据式1到4的化合物,或其医药学上可接受的盐。在某些实施例中,方法包含治疗需要治疗的患者的肝脏病症,其中肝脏病症选自:肝纤维化、醇诱导的纤维化、醇脂肪变性、非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。在特别优选的实施例中,方法包含治疗需要NASH治疗的患者。优选地,方法包含施用有效量的式4化合物或其医药学上可接受的盐,以用于治疗NASH。
在另一形式中,本发明提供根据式1到4中的任一个的化合物,或其医药学上可接受的盐,以用于疗法。在优选实施例中,本发明提供根据式1到4中的任一个的化合物,或其医药学上可接受的盐,以用于治疗肝脏病症。肝脏病症可选自:肝纤维化、醇诱导纤维化、醇脂肪变性、NAFLD和NASH。在一个实施例中,疗法是用于治疗肝纤维化。在另一实施例中,疗法是用于NAFLD。在再又另一个实施例中,疗法是用于NASH。
在又一形式中,本发明提供根据式1到4的化合物或其医药学上可接受的盐在制造供治疗肝脏病症用的药剂中的用途。在优选实施例中,肝脏病症选自:肝纤维化、醇诱导纤维化、醇脂肪变性NAFLD和NASH。
如本文所用的术语“医药学上可接受的盐”是指被认为是临床和/或兽用可接受的本发明的化合物的盐。医药学上可接受的盐和其常见制备方法的实例可发现于“医药盐手册:特性、选择和用途(Handbook of Pharmaceutical Salts:Properties,Selection andUse)”P.斯塔尔(P.Stahl)等人,第2次修订版,约翰威立国际出版公司(Wiley-VCH),2011和S.M.贝尔奇(S.M.Berge),等人,“医药盐(Pharmaceutical Salts)”,《医药科学杂志(Journal of Pharmaceutical Sciences)》,1977,66(1),1-19中。
用于本发明的医药组合物可使用医药学上可接受的添加剂制备。如本文所用的用于医药组合物的术语“医药学上可接受的添加剂”指代一或多种与组合物或调配物的其它添加剂相容并对患者无害的载剂、稀释剂和赋形剂。医药组合物和其制备方法的实例可发现于“雷明顿:药学的科学和实践(Remington:The Science and Practice ofPharmacy)”,劳埃德V.(Loyd,V.)等人编,第22版,马克出版公司(Mack Publishing Co.),2012。
如本文所用,术语“有效量”指代有效治疗病症的作为剂量的量,所述病症如包括肝脏炎症、纤维化和脂肪性肝炎的肝病。护理医师作为本领域技术人员可容易通过使用常规技术和通过观察在类似情况下获得的结果来确定有效量。在确定化合物的有效量或剂量时所考虑的因素包括:将施用所述化合物还是其盐;其它试剂(如果使用的话)的共同施用;哺乳动物的物种;其尺寸、年龄和一般健康状况;病症的涉及程度或严重程度;个体患者的反应;施用模式;所施用制剂的生物可用性特征;所选择的剂量方案;其它附随药剂的使用;以及其它相关情况。
如本文所用,术语“治疗(treating/to treat/treatment)”包括减缓、减少或逆转现有症状、病症、病状或疾病的进展或严重程度,其可包括治疗肝病,如肝脏炎症、纤维化和脂肪性肝炎。
如本文所用,术语“患者”指代哺乳动物,优选地患者是人类或伴侣哺乳动物,如狗或猫。
治疗医师、兽医或其它医疗人员将能够确定用于治疗有需要患者的化合物的有效量。优选的医药组合物可以配制为用于口服施用的片剂或胶囊、用于口服施用的溶液或可注射溶液。片剂、胶囊或溶液可以包括呈有效治疗需要治疗的患者的量的本发明的化合物。
本文中所用的缩写根据道布G.H.(Daub G.H.)等人,“首字母缩略词在有机化学中的使用(The Use of Acronyms in Organic Chemistry)”《奥德里奇化学公司杂志(Aldrichimica Acta)》,1984,17(1),6-23定义。其它缩写定义如下:“Boc”指代叔丁氧基羰基;“DBAD”指代偶氮二羧酸二苯甲酯;“DCM”指代二氯甲烷;“DIPEA”指代N,N-二异丙基乙胺;“DMF”指代二甲基甲酰胺;“DMSO”指代二甲亚砜;“EDTA”指代乙二胺四乙酸;“EGTA”指代乙二醇四乙酸;“ES/MS”指代电喷质谱分析;“EtOH”指代乙酸乙酯;“EtOH”指代乙醇或乙基醇;“HATU”指代(二甲氨基)-N,N-二甲基(3H-[1,2,3]***并[4,5-b]吡啶-3-基氧基)甲亚胺六氟磷酸酯;“HEPES”指代4-(2-羟乙基)-1-哌嗪乙磺酸;“hr或hrs”指代小时(hour/hours);“IC50”指代产生所述试剂的可能的最大抑制反应的50%的试剂浓度(相对IC50),或相比于安慰剂对照产生目标活性的50%抑制的试剂浓度(绝对IC50);“IU”指代国际单位;“LCMS”指代液体色谱质谱分析;“MAOa和MAOb”分别指代单胺氧化酶a和b同种型;“MeOH”指代甲基醇或甲醇;“min”或mins指代分钟;“MTBE”指代甲基叔丁基醚;“NASH”指代非酒精性脂肪性肝炎;“NMP”指代N-甲基-吡咯烷酮或1-甲基-2-吡咯烷酮;PE指代石油醚;t(R)=滞留时间;“sat”指代饱和溶液;“SSAO”指代氨基脲敏感性胺氧化酶;“hSSAO”指代人类SSAO;且“TG”指代三酸甘油酯;“THF”指代四氢呋喃。
在本文中所描述的制备中,羟基和氨基官能团可以加以保护以促进本文所描述的化合物的合成。保护官能团的实例可以发现于“格林氏有机合成中的保护基团(Greene'sProtective Groups in Organic Synthesis),”乌兹P.G.M.(Wuts P.G.M.)等人编第5版,《约翰·威利父子出版公司(John Wiley and Sons)》,2014。可以使用可以容易转化为羟基或氨基的其它官能团。这些基团的这类官能团、制备和转化可以发现于拉洛克R.C.(Larock.R.C.),约翰威立国际出版公司(Wiley VCH),1999的“综合有机转化:官能团制备指导(Comprehensive Organic Transformations:A Guide to Functional GroupPreparations)”和“玛奇氏高级有机化学:反应、机制和结构(March's Advanced OrganicChemistry:Reactions,Mechanisms and Structure),”史密斯M.B.(Smith M.B.)编,第7版,《威利-国际学科(Wiley-Interscience)》,2013中。
具体实施方式
本发明的化合物或其盐可以通过多种程序制备,所述程序中的一些说明于下文流程、制备和实例中。下文流程中的每个步骤的产物可以通过常规方法回收,所述方法包括萃取、蒸发、沉淀、色谱、过滤、研磨和结晶。此外,个体异构体、对映异构体和非对映异构体可以通过如选择性结晶技术或手性色谱法分离或溶解(参见例如,J.雅克(J.Jacques)等人,“对映异构体、外消旋体和解析度(Enantiomers,Racemates,and Resolutions)”,约翰·威利父子公司,1981和E.L.伊莱尔(E.L.Eliel)和S.H.威伦(S.H.Wilen),“有机化合物的立体化学(Stereochemistry of Organic Compounds)”,《威利-国际科学》,1994)。在下文流程中,除非另外指示,否则全部取代基都如先前所定义。试剂和起始物质容易地可供本领域的技术人员使用。
流程1
流程1描绘式1化合物的通用合成,其中“PG”是羟基的保护基团。具体地说,在步骤1,子步骤1中,化合物A的氯可以被经环胺取代的R1的氮置换以得到化合物B。在步骤1,子步骤2中,羟基的脱保护可以根据特定保护基团通过多种方法实现。在步骤2,子步骤1中,所得化合物B的羟基可以用受适当保护的胺2-溴-3-氟-丙基-2-烯-胺烷基化,以得到式1化合物。烷基化通常可以在碱性条件下实现。受保护胺可以经脱保护以得到式1化合物。
制备和实例
以下制备和实例进一步说明本发明并表示本发明的化合物的典型合成。
制备1
4-(5-溴-2-吡啶基)-2-氧代-哌嗪-1-甲酸叔丁酯
将三乙胺(2.4mL,17mmol)、DMAP(160mg,1.30mmol)和碳酸叔丁氧基羰基叔丁酯(1.87g,1.1当量,8.59mmol)添加到4-(5-溴-2-吡啶基)哌嗪-2-酮(2.00g,7.81mmol)于DCM(45mL)中的溶液中。在25℃下将反应混合物搅拌3天以得到黄色悬浮液。将DCM(50mL)添加到反应物并用盐水(5×50mL)洗涤混合物。浓缩有机层以得到呈黄色固体状的粗产物。使材料经受用0到50%EtOAc/PE的梯度洗脱的硅胶色谱以得到呈白色固体状的标题化合物(1.57g,55%)。
制备2
2-氧代-4-[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-吡啶基]哌嗪-1-甲酸叔丁酯
在25℃下向4-(5-溴-2-吡啶基)-2-氧代-哌嗪-1-甲酸叔丁酯(1.57g,4.41mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,2-二氧杂硼杂环戊烷(1.23g,1.1当量,4.85mmol)和乙酸钾(1.29g,3.00当量,13.2mmol)于1,4-二噁烷(30mL)中的悬浮液中添加Pd(dppf)Cl2)(0.32g,0.1当量,0.441mmol)。在100℃下搅拌的同时在N2下将反应混合物脱气1hr。过滤反应混合物并浓缩滤液以得到呈黄色油状的粗产物。使材料经受用0到50%EtOAc/PE的梯度洗脱的硅胶色谱以得到呈淡黄色固体状的标题化合物(1.70g,96%)。
制备3
4-(5-羟基-2-吡啶基)-2-氧代-哌嗪-1-甲酸叔丁酯
在0℃下将氢氧化钠(水溶液2mL,1M)和过氧化氢(水溶液2mL,30质量%)添加到2-氧代-4-[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-吡啶基]哌嗪-1-甲酸叔丁酯(500mg,1.24mmol)于THF(5mL,61.6mmol)中的悬浮液中。在25℃下将反应混合物搅拌2小时。用饱和Na2SO3溶液淬灭反应物并用1M HCl将pH值调节到6-7。用EtOAc(3×20mL)萃取混合物并浓缩经合并的有机萃取物以得到呈黄色油状的粗产物。使粗产物经受用PE中的0到70%EtOAc的梯度洗脱的硅胶色谱以得到呈黄色固体状的标题化合物(120mg,33%)。LCMS(m/z):294.0[M+H]+。
制备4
1-甲基-3-(4-吡啶氧基)吡咯烷-2-酮
在0℃下将DBAD(3.06g,13.0mmol)于THF(10mL)中的溶液逐滴添加到3-羟基-1-甲基-吡咯烷-2-酮(500mg,4.34mmol)、吡啶-4-醇(0.826g,8.69mmol)和(正丁基)3P(2.72g,13.0mmol)于DCM(9mL)和THF(15mL)中的溶液中并在室温下将反应混合物搅拌4小时。在真空下浓缩反应混合物并通过用DCM中的0.5%到10%MeOH的梯度洗脱的硅胶快速色谱纯化残余物以得到呈淡黄色油状的标题化合物(300mg,32%产率)。LCMS(m/z):193.0[M+H]+,1HNMR(400MHz,CDCl3)δ8.50-8.35(m,2H),7.00-6.87(m,2H),4.94(dd,J=6.0,7.6Hz,1H),3.56-3.46(m,1H),3.44-3.32(m,1H),2.93(s,3H),2.63-2.50(m,1H),2.21-2.09(m,1H).
制备5
3-(1-苄基吡啶-1-鎓-4-基)氧基-1-甲基-吡咯烷-2-酮溴化物
将溴甲基苯(0.534g,3.12mmol)添加到1-甲基-3-(4-吡啶氧基)吡咯烷-2-酮(5,300mg,1.56mmol)于DMF(8.0mL)中的混合物中并将反应混合物升温到55℃历时16小时。在真空下浓缩反应混合物,用水(20mL)稀释并用EtOAc(2×10mL)萃取。在真空下浓缩水层以得到呈白色固体状的标题化合物(450mg,71.4%)。1H NMR(400MHz,d6-DMSO)δ9.04(d,J=7.2Hz,2H),7.75(d,J=7.6Hz,2H),7.56-7.48(m,2H),7.47-7.33(m,3H),5.72(s,2H),5.61(t,J=8.0Hz,1H),3.42-3.37(m,5H),2.70-2.58(m,1H),2.17-2.00(m,1H)
制备6
3-[(1-苯甲基-3,6-二氢-2H-吡啶-4-基)氧基]-1-甲基-吡咯烷-2-酮
在0℃下将NaBH4(212mg,5.58mmol)添加到3-(1-苄基吡啶-1-鎓-4-基)氧基-1-甲基-吡咯烷-2-酮溴化物(450mg,1.12mmol)于MeOH(8.0mL)中的溶液中并在0℃下将反应混合物搅拌10min。用EtOAc(40mL)稀释反应混合物并用NaHCO3(饱和水溶液)(30mL)和盐水(30mL)洗涤。经无水Na2SO4干燥有机层,过滤并在真空下浓缩滤液。使粗产物经受用0-1%MeOH/DCM的梯度洗脱的硅胶快速色谱以得到呈无色胶状物的标题化合物(120mg,36%)。LCMS(m/z):287.1[M+H]+,1H NMR(400MHz,CDCl3)δ7.45-7.14(m,5H),4.71(t,J=3.2Hz,1H),4.62-4.50(m,1H),3.74-3.50(m,2H),3.50-3.40(m,1H),3.40-3.25(m,1H),3.18-3.06(m,1H),3.05-2.95(m,1H),2.89(s,3H),2.75-2.65(m,1H),2.55-2.47(m,1H),2.43-2.30(m,1H),2.25-2.15(m,2H),2.06-1.94(m,1H)
制备7
1-甲基-3-(4-哌啶基氧基)吡咯烷-2-酮
将钯/碳(50%水,10%w,20.0mg)添加到3-[(1-苯甲基-3,6-二氢-2H-吡啶-4-基)氧基]-1-甲基-吡咯烷-2-酮(120mg,0.40mmol)于EtOH(6.0mL)中的溶液中并在氢氛围下在室温下将反应混合物搅拌5小时。经由硅藻土过滤反应混合物并在真空下浓缩滤液以得到呈无色胶状物的标题化合物(85.0mg,96.9%)。1H NMR(400MHz,CDCl3)δ4.20-4.10(m,1H),3.90-3.80(m,1H),3.45-3.35(m,1H),3.30-3.18(m,1H),3.14-3.04(m,2H),2.85(s,3H),2.66-2.55(m,2H),2.36-2.28(m,1H),1.98-1.90(m,2H),1.55-1.35(m,2H)
制备8
2-环丙基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯
合并1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(161mg,0.60mmol)、乙酸铜(II)(110mg,0.61mmol)和碳酸铯(98mg,0.30mmol)。随后经由注射器添加吡啶(145mg,1.83mmol)、2-环丙基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(203mg,1.21mmol)和甲苯(1.2mL)。将混合物加热到110℃历时64小时。用EtOAc洗涤混合物并经由硅藻土过滤。浓缩滤液并使残余物经受用50%EtOAc/己烷洗脱的硅胶快速色谱以得到呈淡黄色油状的标题化合物。LCMS(m/z):317.3[M+Na]+
制备9
2-环丙基-2,8-二氮杂螺[4.5]癸-1-酮盐酸盐
将HCl中的2-环丙基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(172mg,0.555mmol)溶解于MeOH(6.0mL,3mmol,0.5mmol/mL)中且加热到80℃历时50min。在真空下浓缩混合物以得到呈淡棕色油状物的标题化合物,其不经进一步纯化即使用。LCMS(m/z):195.3[M+H]+
制备10
4-(2-溴乙基)哌啶-1,4-二羧酸O1-叔丁基O4-甲酯
在N2下在-78℃下将己烷中的二异丙胺基锂(9.70mL,19.396mmol,2mol/L)逐滴添加到哌啶-1,4-二羧酸O1-叔丁基O4-甲酯(3.146g,12.93mmol)于中THF(45mL)中的溶液中。在-78℃下将所得混合物搅拌30min且随后添加1,2-二溴乙烷(2.23mL,25.861mmol)。使所得混合物升温到室温并搅拌1hr。用饱和NH4Cl水溶液(20mL)淬灭反应物,且用EtOAc(2×30mL)萃取。合并有机萃取物,经Na2SO4干燥,过滤并浓缩至干燥。经由用20%EtOAc/己烷洗脱的硅胶快速色谱纯化粗物质以得到呈微黄色油状物的标题化合物(0.698g,15%)。LCMS(m/z):(79Br/81Br)372.2/374.2[M+Na]+
制备11
2-叔丁基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯
将4-(2-溴乙基)哌啶-1,4-二羧酸O1-叔丁基O4-甲酯(698mg,1.89mmol)溶解于MeOH(5mL)中且添加2-甲基丙-2-胺(1.59mL,15.1mmol)。经由微波照射将溶液加热到120℃历时16小时。浓缩溶液,随后经由用25%EtOAc/己烷洗脱的硅胶快速色谱纯化残余物以得到呈淡黄色油状的标题化合物(74mg,11%)。LCMS(m/z):333.3[M+Na]+
制备12
2-叔丁基-2,8-二氮杂螺[4.5]癸-1-酮盐酸盐
将HCl中的2-叔丁基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(74mg,0.21mmol)溶解于MeOH(5mL,2.5mmol,0.50mmol/mL)中且经由微波照射加热到80℃历时5min。浓缩溶液以得到呈淡黄色油状物的标题化合物(56mg,95%)。LCMS(m/z):211.2[M+H]+
制备13
2-甲基-2,8-二氮杂螺[4.5]癸-1-酮盐酸盐
将2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(45.2g,168mmol)冷却到0℃。添加MeOH(250mL,4.0M)中的HCl且将溶液剧烈搅拌30分钟。将混合物升温到室温,搅拌5小时,且随后浓缩至干燥以得到呈淡黄色固体状的标题化合物(34.6g,98.4%)。ES/MS(m/z)169.2(M+H)。
制备14
N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
将碳酸钾(1.126g,8.14mmol)添加到2-氯嘧啶-5-醇(501mg,3.84mmol)和N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(507mg,1.89mmol)于DMF(10mL)中的溶液并在室温下搅拌所得混合物过夜。通过添加水和EtOAc淬灭反应物并用EtOAc(3×50mL)萃取水相。合并有机萃取物,经由Na2SO4干燥溶液,过滤并在真空下浓缩滤液。使材料经受具有EtOAc/己烷的硅胶快速色谱以得到呈白色固体状的标题化合物(658mg,87%)。LCMS(ESI):m/s 340.2[M+Na]+。
制备15
8-(5-苄基氧基嘧啶-2-基)-2,8-二氮杂螺[4.5]癸-1-酮
将DIPEA(1.7g,13mmol)和5-苯甲氧基-2-氯-嘧啶(0.61g,2.8mmol)添加到2-甲基-2,8-二氮杂螺[4.5]癸-1-酮盐酸盐(0.50g,2.6mmol)于NMP(10mL)中的混合物中。在100℃下将反应混合物搅拌20小时。随后用水(40mL)稀释反应混合物并用EtOAc(2×20mL)萃取。合并有机萃取物;用盐水洗涤(3×20mL);经由Na2SO4干燥;过滤;且在真空下浓缩滤液,得到残余物。使残余物经受用0-1%MeOH/DCM的梯度洗脱的快速色谱硅胶以得到呈淡黄色固体状的标题化合物(0.39g,42%)。1H NMR(400MHz,CDCl3)δ8.11(s,2H),7.45-7.30(m,5H),5.79(s,1H),5.02(s,2H),4.55-4.45(m,2H),3.38(t,J=6.8Hz,2H),3.21-3.10(m,2H),2.15(t,J=6.8Hz,2H),1.98-1.85(m,2H),1.55-1.43(m,2H)。
制备16
1-(5-苄基氧基嘧啶-2-基)哌啶-4-甲酰胺
在N2下在100℃下将5-苯甲氧基-2-氯-嘧啶(400mg,1.81mmol)、哌啶-4-甲酰胺(0.28g,1.2当量,2.18mmol)和DIPEA(2.0当量,3.63mmol)于DMF(6mL)中的混合物搅拌17小时。将反应混合物倾入水(60mL)中且过滤。用EtOAc(30mL)洗涤滤饼且将材料搅拌0.5hr。过滤溶液且在减压下干燥滤饼以得到呈粉色固体状的标题化合物(310mg,49%)。1H NMR:(400MHz,CD3OD)δ8.13(s,2H),7.47-7.28(m,5H),5.07(s,2H),4.67-4.60(m,2H),2.95-2.84(m,2H),2.50-2.40(m,1H),1.85-1.75(m,2H),1.68-1.60(m,2H)。
制备17
8-(5-苄基氧基嘧啶-2-基)-2-环丙基-2,8-二氮杂螺[4.5]癸-1-酮
一起添加5-苯甲氧基-2-氯-嘧啶(79mg,0.36mmol)和碳酸钾(164mg,1.19mmol)。将2-环丙基-2,8-二氮杂螺[4.5]癸-1-酮;盐酸盐(72mg,0.30mmol)溶解于EtOH(3.0mL)中且添加到反应混合物。经由微波照射将反应物加热到110℃历时62小时。用EtOAc稀释混合物且经由硅藻土过滤浆液。浓缩滤液且经由用55%EtOAc/己烷洗脱的硅胶快速色谱纯化粗混合物以得到呈白色固体状的标题化合物(40mg,35%)。LCMS(m/z):379.2[M+H]+。
制备18
8-(5-苄基氧基嘧啶-2-基)-2-叔丁基-2,8-二氮杂螺[4.5]癸-1-酮
将NMP(1mL)添加到2-叔丁基-2,8-二氮杂螺[4.5]癸-1-酮;盐酸盐(56mg,0.20mmol)、5-苯甲氧基-2-氯-嘧啶(54mg,0.25mmol)和碳酸钾(113mg,0.82mmol)。经由微波照射将混合物加热到120℃历时16小时。用EtOAc稀释混合物且经由硅藻土将其过滤。浓缩滤液,得到残余物且使残余物经受用25%EtOAc/己烷洗脱的硅胶快速色谱以得到呈白色固体状的标题化合物(16mg,19%产率)。LCMS(m/z):395.3[M+H]+
制备19
9-(5-苄基氧基嘧啶-2-基)-2,9-二氮杂螺[5.5]十一烷-1-酮
将1-氧代-2,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯(1.907g,6.96mmol)溶解于DCM(50mL)中且在搅拌下于室温下添加三氟乙酸(10mL)。将所得溶液搅拌4小时。浓缩溶液以得到呈淡黄色油状的中间产物2,9-二氮杂螺[5.5]十一烷-1-酮;2,2,2-三氟乙酸(2.096g,6.683mmol)。用DMF(10mL)添加到粗混合物5-苯甲氧基-2-氯-嘧啶(880mg,3.99mmol)、碘化亚铜(158mg,0.830mmol)、N,N'-双(2-苯氧基苯基)草酰胺(220mg,0.804mmol)和三元磷酸钾(2.612g,12.06mmol)。在N2下搅拌所得混合物且加热到100℃历时6小时。用EtOAc稀释混合物且经由硅藻土过滤。浓缩滤液且使所得粗物质经受用7%MeOH/DCM洗脱的硅胶快速色谱以得到呈黄色固体状的标题化合物(869mg,61%)。LCMS(m/z):353.2[M+H]+
制备20
8-(5-苄基氧基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮
将矿物油中的氢化钠(60质量%,66mg,1.6mmol)添加到8-(5-苄基氧基嘧啶-2-基)-2,8-二氮杂螺[4.5]癸-1-酮(0.39g,1.1mmol)于DMF(8.0mL)中的溶液中;在0℃下将混合物搅拌20min。将碘甲烷(0.31g,2.2mmol)添加到冷的(0℃)混合物。使混合物升温到环境温度且将混合物搅拌1hr。用水(30mL)淬灭反应物。用EtOAc(2×15mL)萃取所得混合物。合并有机萃取物且用盐水(2×20mL)洗涤;经由无水Na2SO4干燥;过滤;且在真空下浓缩滤液以得到呈黄色固体状的标题化合物(0.42g,98%),其可以不经进一步纯化使用。1H NMR(400MHz,CDCl3)δ8.04(s,2H),7.38-7.24(m,5H),4.95(s,2H),4.42(dt,J=4.0,13.6Hz,2H),3.27(t,J=6.8Hz,2H),3.15-3.02(m,2H),2.79(s,3H),1.96(t,J=6.8Hz,2H),1.90-1.78(m,2H),1.42-1.34(m,2H)。
替代制备20
8-(5-苄基氧基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮
将5-苯甲氧基-2-氯-嘧啶(24.824g,112.50mmol)、2-甲基-2,8-二氮杂螺[4.5]癸-1-酮盐酸盐(29.736g,145.27mmol)和碳酸钾(46.643g,337.50mmol)合并于NMP中。添加NMP(170mL)和三乙胺(23.5mL,168.75mmol)且将混合物加热到130℃历时30小时。冷却混合物,过滤以收集固体,随后用EtOAc洗涤固体。浓缩滤液且将浓缩溶液倾入碎冰(约1.2L)中。立刻出现浅褐色固体沉淀物。将混合物搅拌30min且随后使混合物静置在室温下过夜。过滤混合物以收集固体且用MTBE(400mL)洗涤固体。在50℃下在真空下干燥固体历经1.5天以得到呈淡褐色固体状的标题化合物(36.924g,88.48%),其可以不经进一步纯化使用。ES/MS(m/z)353.3(M+H)。
制备21
8-(5-苄基氧基嘧啶-2-基)-2-(环丙基甲基))-2,8-二氮杂螺[4.5]癸-1-酮
在0℃下将矿物油中的氢化钠(22mg,0.55mmol,60质量%)添加到8-(5-苄基氧基嘧啶-2-基)-2,8-二氮杂螺[4.5]癸-1-酮(60mg,0.18mmol)于DMF(5.0mL)中的搅拌溶液中。使混合物升温到室温并搅拌5min。添加(溴甲基)环丙烷(100mg,0.71mmol)且在室温下将所得混合物搅拌16小时。在减压下蒸发溶剂以得到粗产物。使材料经受用40%EtOAc/己烷洗脱的硅胶快速色谱以得到呈白色固体状的标题化合物(40mg,55%)。LCMS(m/z):392.2[M+H]+
制备22
9-(5-苄基氧基嘧啶-2-基)-2-甲基-2,9-二氮杂螺[5.5]十一烷-1-酮
将9-(5-苄基氧基嘧啶-2-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(183mg,0.51mmol)溶解于THF(8mL)中且将溶液冷却到0℃。一次性添加氢化钠(41mg,1.018mmol,60质量%)。在0℃下将溶液搅拌15min。在0℃下添加碘甲烷(0.064mL,1.02mmol),将混合物升温到室温且搅拌30min。将混合物冷却到0℃,进一步添加氢化钠(20mg,0.51mmol)且搅拌15min。添加碘甲烷(0.032mL,0.51mmol),将混合物升温到室温,且搅拌30min。添加饱和NH4Cl(水溶液)以淬灭反应物且用EtOAc稀释。分离有机相且用EtOAc萃取水相(2×)。合并有机萃取物,经由Na2SO4干燥,过滤、浓缩滤液,得到残余物。使残余物经受用75%EtOAc/己烷洗脱的硅胶快速色谱以得到标题化合物(158mg,83%)。LCMS(m/z):367.2[M+H]+
制备23
8-(5-羟基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮
将钯/碳(水中为50%,10%w,42mg)添加到8-(5-苄基氧基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮(0.42g,1.1mmol)于MeOH(40mL)中的溶液中。在氢氛围下在室温下将混合物搅拌4小时且随后在40℃下搅拌6小时。经由硅藻土垫过滤混合物。在真空下浓缩滤液以得到呈淡黄色固体状的标题化合物(0.34g,97%),其可以不经进一步纯化使用。1H NMR(400MHz,CDCl3)δ8.05(s,2H),4.54-4.44(m,2H),3.37(t,J=7.2Hz,2H),3.15-3.05(m,2H),2.88(s,3H),2.07(t,J=7.2Hz,2H),1.96-1.88(m,2H),1.45-1.40(m,2H),ES/MS(m/z)262.9(M+H)。
替代制备23
8-(5-羟基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮
将8-(5-苄基氧基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮(18.190g,49.04mmol)于EtOAc(100mL)和MeOH(100mL)中的悬浮液转移到高压反应器,向所述高压反应器添加5%活性碳上的钯(1.84g,0.865mmol)于MeOH(40mL)中的悬浮液。在ParrTM摇动器中在310kPa氢下将混合物氢化4小时。用MeOH稀释混合物且经由硅藻土过滤混合物。浓缩滤液至干燥以得到呈黄色固体状的标题化合物(12.9g,46.7mmol,95.3%),其不经进一步纯化即使用。ES/MS(m/z)263.3(M+H)。
制备24
2-环丙基-8-(5-羟基嘧啶-2-基)-2,8-二氮杂螺[4.5]癸-1-酮
将8-(5-苄基氧基嘧啶-2-基)-2-环丙基-2,8-二氮杂螺[4.5]癸-1-酮(39mg,0.10mmol)溶解于EtOAc(2.0mL)中。将活性碳上的钯(10mg,0.005mmol,5质量%)悬浮于MeOH(1.0mL)中且转移到上述溶液。添加1,4-环己二烯(0.096mL,1.01mmol)且在室温下搅拌所得混合物过夜。用EtOAc稀释混合物且经由硅藻土过滤。浓缩滤液以得到呈白色固体状的标题化合物(29mg,98%),其不经进一步纯化即直接使用。LCMS(m/z):289.1[M+H]+
制备25
2-(环丙基甲基))-8-(5-羟基嘧啶-2-基)-2,8-二氮杂螺[4.5]癸-1-酮
在室温下于H2氛围下使8-(5-苄基氧基嘧啶-2-基)-2-(环丙基甲基)-2,8-二氮杂螺[4.5]癸-1-酮(40mg,0.097mmol)和钯/碳(20mg,5质量%)在MeOH(10mL)中在一起搅拌16小时。经由硅藻土过滤混合物且在减压下浓缩滤液以得到粗产物,使所述粗产物经受用80%EtOAc和20%己烷洗脱的硅胶快速色谱以得到呈白色固体状的标题化合物(17mg,55%)。LCMS(m/z):303.3[M+H]+
制备26
9-(5-羟基嘧啶-2-基)-2,9-二氮杂螺[5.5]十一烷-1-酮
将活性碳上的钯(50mg,0.023mmol)悬浮于MeOH(15mL)中且添加到9-(5-苄基氧基嘧啶-2-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(97mg,0.27mmol)。配备氢气球,用氢抽空3次,且在室温下将所得混合物搅拌4小时。用MeOH稀释混合物且经由硅藻土过滤溶液。浓缩滤液以得到呈白色固体状的标题化合物(72mg,99%),其不经进一步纯化即直接使用。LCMS(m/z):263.1[M+H]+
基本根据制备26的方法制备以下化合物且将混合物搅拌1-5小时。
制备30
N-[(E)-3-氟-2-[[2-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸-8-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
将8-(5-羟基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮(0.14g,0.49mmol)、N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(0.11g,0.41mmol)和碳酸钾(0.17g,1.2mmol)合并于无水DMF(5.0mL)中。将所得混合物升温到50℃且搅拌1.5小时。用水(30mL)稀释混合物且用EtOAc(2×15mL)萃取。合并有机萃取物;用盐水洗涤(2×20mL);经由Na2SO4干燥;过滤;且在真空下浓缩滤液,得到残余物。使残余物经受用0-0.5%MeOH/DCM洗脱的快速色谱硅胶以得到呈白色固体状的标题化合物(0.16g,82%)。1H NMR(400MHz,CDCl3)δ8.09(s,2H),6.70(d,J=82.0Hz,2H),4.78(br s,1H),4.60-4.45(m,2H),4.39(s,2H),4.00(s,2H),3.41-3.28(m,2H),3.25-3.18(m,2H),2.94-2.76(m,3H),2.12-2.01(m,2H),2.00-1.85(m,2H),1.50-1.38(m,12H)。
替代制备30
N-[(E)-3-氟-2-[[2-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸-8-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
使8-(5-羟基嘧啶-2-基)-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮(12.9g,46.7mmol)、N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(13.2g,49.1mmol)和碳酸钾(19.4g,140mmol)与DMF(73mL)合并。在室温下将所得混合物搅拌5小时。用EtOAc稀释混合物且经由硅藻土过滤。浓缩滤液,得到残余物。使残余物经受用3%MeOH/DCM洗脱的硅胶快速色谱以得到呈黄色油状物的标题化合物(18.6g,40.6mmol,86.8%)。ES/MS(m/z)450.3(M+H)。
基本根据替代制备30的方法制备以下化合物且将反应物搅拌3小时到64小时。
a在室温下搅拌且将反应物加热到80℃历时1.5小时。
制备37
4-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]-2-吡啶基]-2-氧代-哌嗪-1-甲酸叔丁酯
将N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(0.12g,1.1当量,0.450mmol)和碳酸钾(0.17g,3当量,1.23mmol)添加到4-(5-羟基-2-吡啶基)-2-氧代-哌嗪-1-羧酸叔丁酯(120mg,0.409mmol)于DMF(3mL,39mmol)中的溶液。在70℃下将混合物搅拌2小时以得到黄色悬浮液。将水(20mL)添加到混合物且用EtOAc(3×20mL)萃取混合物。合并萃取物且用盐水(2×20mL)洗涤经合并的有机萃取物。浓缩有机萃取物以得到呈黄色油状物的标题化合物(180mg),其不经进一步纯化即直接使用。LCMS(ESI):m/s 381.2[M+H]+。
制备39
N-[(E)-2-[[2-(4-胺甲酰基-1-哌啶基)嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
遵循基本根据制备38的方法的程序,但使用2当量碳酸钾。ES/MS(m/z)[M+H]+410.2
制备40
N-[(E)-3-氟-2-[[2-(3-甲基-2-氧代-咪唑烷-1-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
在N2氛围下在微波条件下将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(114mg,0.36mmol)、甲基咪唑烷酮(115mg,1.151mmol)、碘化亚铜(40.1mg,0.211mmol)、反-N,N'-二甲基环己烷-1,2-二胺(40μL)、碳酸铯(351mg,1.077mmol)和1,4-二噁烷(10mL)的混合物加热到160℃持续3小时。过滤反应混合物且在真空下浓缩。使残余物经受具有以下条件的制备型HPLC:LC柱:SunFire C1830×100mm 5μm;A:H2O(0.1%FA);B:ACN(0.1%FA),在11min内梯度24-39%CAN,在17min时停止;柱温室温;流动速率30mL/min.;t(R)=10.0分钟(UV)。获得呈白色固体状的标题产物。(137mg,27%)。LCMS(ESI):m/s 382.2[M+H]+。
制备41
N-[(E)-3-氟-2-[[2-(3-氧代-2,8-二氮杂螺[4.5]癸-8-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
在120℃下在微波照射下将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(65mg,0.20mmol)、2,8-二氮杂螺[4.5]癸-3-酮(67mg,0.41mmol)、DIPEA(0.11mL,0.63mmol)和1,4-二噁烷(5.0mL)的混合物搅拌12小时。在减压下蒸发溶剂以得到粗产物,使所述粗产物经受用0-5%MeOH/DCM的梯度洗脱的硅胶快速色谱以得到呈白色固体状的标题化合物(61mg,68.46%)。LCMS(ESI):m/s 436.3[M+H]。
基本根据制备41的方法制备以下化合物,从110到120℃加热历经3-12小时。
a参见下文纯化程序。
制备43的纯化
N-[(E)-3-氟-2-[[2-[4-(2-氧代吡咯烷-1-基)-1-哌啶基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
使粗物质经受具有以下条件的制备型HPLC:柱:SunFire C18 30×100mm 5μm;A:H2O(0.1%FA);B:ACN(0.1%FA),在11min内梯度:33-48%ACN,在18min时停止;柱温:室温;流动速率30mL/min.;t(R)=8.7分钟(UV),得到呈白色固体状的标题化合物(16mg,21%)。
制备45的纯化
N-[(E)-2-[[2-[(3S)-3-(环丙基胺甲酰基)-1-哌啶基]嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
使粗物质经受具有以下条件的制备型HPLC:柱:C18 30×150mm 5μm;A:H2O 10mM NH4HCO3;B:ACN,在11min内梯度:35-40%ACN,在17min时停止;柱温:室温;流动速率35mL/min.;t(R)=9.8分钟(UV),得到标题化合物(120mg,53%)。
制备47的纯化
N-[(E)-2-[[2-(3,3-二甲基-5-氧代-哌嗪-1-基)嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
使粗物质经受具有以下条件的制备型HPLC:柱:SunFire C18 30×100mm 5μm;A:H2O(0.1%FA);B:ACN(0.1%FA),在11min内梯度:29-44%ACN,在17min时停止;柱温:室温;流动速率:30mL/min.;t(R)=10.1分钟(UV),得到呈白色固体状的标题化合物(15mg,6%)。
制备51
N-[(E)-2-[[2-(4,4-二甲基-2-氧代-咪唑烷-1-基)嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
将N-[(E)-2-[[2-[(2-氨基-2-甲基-丙基)氨基]嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(151mg,0.41mmol)溶解于THF(10mL)中且一次性添加1,1'-羰基二咪唑(122mg,0.73mmol)。在室温下搅拌混合物过夜且随后将混合物加热到60℃持续5小时。在真空下浓缩反应混合物,不经进一步纯化使用粗混合物。
制备52
N-[(E)-3-氟-2-[[2-[4-(1-甲基-2-氧代-吡咯烷-3-基)氧基-1-哌啶基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
在100℃下在NMP(2.0mL)中搅拌1-甲基-3-(4-哌啶基氧基)吡咯烷-2-酮(85mg,0.386mmol)、N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(0.123g,0.386mmol)和DIPEA(0.102g,0.772mmol,0.135mL)的混合物,持续16小时。用水(30mL)稀释反应混合物且用EtOAc(3×15mL)萃取混合物。用盐水(3×30mL)洗涤经合并的有机萃取物,经由无水Na2SO4干燥,过滤且在真空下浓缩滤液。使残余物经受用0-0.5%MeOH/DCM洗脱的硅胶快速色谱以得到呈无色胶状物的标题化合物(85mg,41%)。LCMS(m/z):480.2[M+H]+,
1H NMR(400MHz,CDCl3)δ8.08(s,2H),6.70(d,J=81.6Hz,1H),4.77(br s,1H),4.39(d,J=3.6Hz,2H),4.38-4.25(m,2H),4.20-4.14(m,1H),4.13-4.05(m,1H),4.04-3.94(m,2H),3.45-3.36(m,1H),3.35-3.20(m,3H),2.87(s,3H),2.42-2.28(m,1H),2.06-1.94(m,3H),1.62-1.50(m,2H),1.43(s,9H)
制备53
1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-羧酸
将氢氧化锂(300mg,12.5mmol)添加到1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-羧酸甲酯(260mg,0.55mmol)于THF(8.0mL)和水(4.0mL)的混合物中的搅拌溶液中。在室温下将所得混合物搅拌16小时。过滤以去除固体且浓缩滤液以得到粗产物标题产物,所述标题产物可以不经进一步纯化即直接使用。LCMS(ESI):m/s 411.3[M+H]。
制备54
1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]-4-甲基-哌啶-4-羧酸
将氢氧化锂(19mg,0.79mmol)添加到1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]-4-甲基-哌啶-4-羧酸乙酯(35mg,0.077mmol)于THF(4.0mL)和水(2.0mL)的混合物中的搅拌溶液中。在室温下将所得混合物搅拌16小时。在微波照射下将混合物加热到100℃历时2小时。添加10%HCl以将pH值调节到约3且在减压下蒸发混合物以干燥从而得到呈白色固体状的粗产物标题产物,其不经进一步纯化即直接使用。LCMS(ESI):m/s 425.3[M+H]。
制备55
N-[(E)-2-[[2-[4-(二甲基胺甲酰基)-1-哌啶基]嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
将THF中的二甲胺(0.10mL,0.20mmol,2mol/L)添加到1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-羧酸(60mg,0.14mmol)于DMF(4.0mL)中的搅拌溶液中,之后添加HATU(0.10g,0.26mmol)和DIPEA(0.05mL,0.3mmol)。在室温下将混合物搅拌16小时。在减压下去除溶剂以得到粗产物,使用以下条件通过制备型HPLC纯化粗物质:柱:SunFire C18 30×100mm 5μm;A:H2O(0.1%FA);B:ACN(0.1%FA),在11min内梯度:31-46%ACN,在18min时停止;柱温:室温;流动速率:30mL/min.;t(R)=9.2分钟(UV)。分离呈白色固体状的标题产物(23mg,37%)。LCMS(ESI):m/s 438.4[M+H]。
制备56
N-[(E)-3-氟-2-[[2-[4-[(3S)-3-羟基吡咯烷-1-羰基]-1-哌啶基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
使用适当胺,吡咯烷-3-醇遵循基本根据制备55的方法的程序。
实例1
8-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮二盐酸盐
将N-[(E)-3-氟-2-[[2-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸-8-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(0.16g,0.34mmol)溶解于MeOH中的3M HCl(5.0mL)中。在室温下将所得混合物搅拌1hr。在真空下浓缩混合物以得到残余物。将残余物溶解于水(5mL)中;冻干混合物以得到呈淡黄色胶状物的标题化合物(0.13g,86%)。ES/MS(m/z)350.2(M+H)。
实例2
8-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮
将碳酸钾(100mL)和2-甲基-THF(200mL)的饱和水溶液添加到8-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2-甲基-2,8-二氮杂螺[4.5]癸-1-酮二盐酸盐(9.17g,21.2mmol)。使水层与有机层分离。用2-甲基-THF(200mL)洗涤水层且将有机萃取物添加到有机层。经由NaSO4干燥有机层;过滤;且在真空下浓缩滤液以得到标题化合物(85质量%,7.47g,18.2mmol,85.9%)。ES/MS(m/z)350.2(M+H)。
实例3
4-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]-2-吡啶基]哌嗪-2-酮
将HCl(3mL,在1,4-二噁烷中为4M)添加到4-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]-2-吡啶基]-2-氧代-哌嗪-1-羧酸叔丁酯(180mg,0.364mmol)于1,4-二噁烷(2mL)中的溶液中。在室温下将反应混合物搅拌2小时。在减压下去除溶剂以得到呈黄色固体状的粗产物。使用以下条件使材料经受制备型HPLC:柱:Kromasil C18 250*50mm*10μm,1-30%B以及A:水/0.05%NH4OH,B:ACN,流动速率:25mL/min以得到标题化合物(20.2mg,19%)。LCMS(ESI):m/s 280.9[M+H]+,1H NMR(400MHz,d4-MeOH 7.95(d,J=3.2Hz,1H),7.37(dd,J=9.2,3.2Hz,1H),6.97(d,J=84Hz,1H),6.83(d,J=8.0Hz,1H),4.57(d,J=3.2Hz,2H),4.03(s,2H),3.71(t,J=4.0Hz,2H),3.62-3.55(m,2H),3.44(t,J=4.0Hz,2H)。
实例4
3-[[1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-4-哌啶基]氧基]-1-甲基-吡咯烷-2-酮二盐酸盐
在室温下将HCl中的N-[(E)-3-氟-2-[[2-[4-(1-甲基-2-氧代-吡咯烷-3-基)氧基-1-哌啶基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(85mg,0.160mmol)于MeOH(4.0mL,4M)中的混合物搅拌1hr且随后在真空下浓缩反应混合物。使用以下条件使残余物经受制备型HPLC:柱:YMC-Actus Triart C18 150*30mm*5μm,0-30%B以及A:水/0.05%HCl,B:ACN,流动速率:25mL/min以得到呈黄色胶状物的标题化合物(45mg,61%)。LCMS(m/z):380.3[M+H]+,1H NMR(400MHz,d4-MeOH)δ6.86(s,2H),5.68(d,J=80.4Hz,1H),3.13(d,J=2.8Hz,2H),2.73(t,J=7.8Hz,1H),2.55-2.41(m,3H),2.29-2.14(m,4H),1.88-1.76(m,2H),1.29(s,3H),0.95-0.81(m,1H),0.52-0.15(m,5H)
实例5
1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-3-甲基-咪唑烷-2-酮盐酸盐
将N-[(E)-3-氟-2-[[2-(3-甲基-2-氧代-咪唑烷-1-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(35.1mg,0.0920mmol)溶解于HCl(10mL,EtOAc中为1M)且搅拌所得溶液过夜。在真空下浓缩悬浮液,溶解于水中且冻干溶液以得到呈灰白色固体状的标题化合物。(24mg,63%)。LCMS(ESI):m/s 282.2[M+H]+。
使用适当受BOC保护的烯丙基甲基胺基本类似于实例5的方法制备以下化合物。
a与MeOH中的1mL 0.5mol/L HCl预混合
b将混合物加热到80℃历时1hr。
实例8
1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-甲酰胺盐酸盐
在10℃下将N-[(E)-2-[[2-(4-胺甲酰基-1-哌啶基)嘧啶-5-基]氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(80.0mg,0.195mmol)于HCl(8mL,在MeOH中为4M)中的混合物搅拌2小时。在减压下浓缩反应混合物。通过用0.05%HCl洗脱的制备型HPLC纯化残余物以得到呈黄色固体状的标题化合物(43.0mg,62%)。LCMS(ESI):m/s 309.9[M+H],1H NMR(400MHz,d4-MeOH)δ8.49(s,2H),7.28(d,J=80.4Hz,1H),4.74(d,J=2.8Hz,2H),4.60-4.47(m,2H),3.86(s,2H),3.41-3.33(m,2H),2.78-2.60(m,1H),2.08-1.95(m,2H),1.87-1.72(m,2H)。
实例9
8-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2,8-二氮杂螺[4.5]癸-3-酮二盐酸盐
在60℃下在微波照射下将N-[(E)-3-氟-2-[[2-(3-氧代-2,8-二氮杂螺[4.5]癸-8-基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(61mg,0.1401mmol,100质量%)和MeOH中的HCl(4.0mL,0.39mol/L)搅拌2小时。在减压下蒸发溶剂以得到呈黄色固体状的标题化合物(60mg,99%)。LCMS(ESI):m/s 336.3[M+H]。
基本类似于实例9的方法制备以下化合物,将反应物加热到在约60与80℃之间持续5分钟-2小时。
a将粗物质溶解于水中且冻干为固体。
b参见下文纯化方法。
实例12的纯化
7-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2,7-二氮杂螺[4.5]癸-3-酮
使粗物质经受具有以下条件的制备型HPLC:柱:C18 30×150mm 5μm;A:H2O 10mM NH4HCO3;B:ACN,梯度:在0-2min内0-5%ACN,在2-12min内10-20%ACN,在18min时停止;柱温:室温;流动速率35mL/min.;t(R)=10.7min.(UV),得到呈白色固体状的标题产物(8.5mg,36%)。
实例20的纯化
9-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-2-甲基-2,9-二氮杂螺[5.5]十一烷-1-酮
将粗物质溶解于水中且用NaHCO3制成碱性。使所得材料经受具有以下条件的制备型HPLC:柱:C18 30×100mm 5μm;A:H2O(10mM NH4HCO3);B:ACN,梯度:在9min内10-25%B,在14min时停止;柱温:室温;流动速率35mL/min.;t(R)=8.7min.(UV),得到呈淡黄色油状物的标题化合物(21mg,52%)。
实例22
1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]-N,N,4-三甲基-哌啶-4-甲酰胺二甲酸
将THF中的二甲胺(0.20mL,0.40mmol,2mol/L)添加到1-[5-[(E)-2-[(叔丁氧基羰基氨基)甲基]-3-氟-烯丙氧基]嘧啶-2-基]-4-甲基-哌啶-4-羧酸(32mg,0.075mmol)于DMF(2.0mL)中的搅拌溶液中,之后添加HATU(60mg,0.16mmol)和DIPEA(0.065mL,0.37mmol)。在室温下将混合物搅拌16小时。在减压下浓缩混合物以得到粗产物。使用以下条件使粗物质经受制备型HPLC:LC柱:SunFire C18 30×100mm 5μm;A:H2O(0.1%FA);B:ACN(0.1%FA),梯度:在0-3min内5-5%ACN,在3-13min内5-10%ACN,在19min时停止;柱温:室温;流动速率30mL/min.;t(R)=8.5min.(UV),得到呈白色固体状的标题化合物(15mg,43%)。LCMS(ESI):m/s352.2[M+H]。
生物分析
SSAO/VAP-1体外活性
使用来自普洛麦格(Promega)(V1402)的MAO-GloTM分析试剂盒测量重组hSSAO、hMAOa和hMAOb同种型的胺氧化酶活性。在室温下将测试化合物(使用DMSO作为媒剂,SSAO为0.5%v/v)和酶培育10分钟,随后添加发光底物。人类重组SSAO的底物浓度为10μM。分析在孔板中在pH 7.4缓冲液(50mM HEPES、120mM NaCl、5mM KCl、2mM CaCl2、1.4mM MgCl2、0.001%Tween-20)中进行。底物氧化进行2小时,随后根据制造商的方案添加检测试剂。测试化合物的IC50值通过使用4-参数非线性回归程序拟合剂量反应曲线计算。实例的化合物展现小于100nM的hSSAO抑制IC50值。实例1的化合物的IC50值是19.36±5.68,n=5(数据以平均值±标准偏差呈现)。
所测试实例的化合物分别显示超过15μM和180μM的IC50 hMAOa和hMAOb,表明实例的化合物相比于hMAOa或hMAOb对hSSAO具有选择性。
SSAO靶接合
使用来自普洛麦格(V1402)的MAO-GloTM分析试剂盒测量大鼠血浆和肝脏组织中的SSAO活性。在化合物治疗之后大鼠中的残余SSAO活性通过测量对MAO抑制剂氯吉兰(Clogyline)和帕吉林(Pargyline)的存在不敏感的血浆或肝脏溶解产物中的总胺氧化酶活性来估算。以15、3、0.6、0.12、0.025、0.005mg/kg的剂量向大鼠施用实例1的化合物。向对照组施用相同体积(2ml/kg)的给药媒剂(羟基乙基纤维素1%w/v,0.25%Tween 80)。收集化合物治疗2或24小时后的血浆和肝脏且储存在-78℃下直到分析。组织溶解产物通过在溶解缓冲液(20mM HEPES,pH 7.4;150mM NaCl、1mM EDTA、1mM EGTA、1%Triton X-100和1×罗氏完全蛋白酶抑制剂片剂(Roche Complete protease inhibitor tablet))中均质化来制备。组织颗粒通过在4℃下以12,000rpm离心30min移出。在室温下将40μl血浆或肝脏溶解产物与氯吉兰(10μM)和帕吉林(10μM)一起培育20分钟,之后添加发光底物(50μM),持续60min。根据制造商的程序定量所产生的产物。对MAO抑制剂的存在不敏感的活性部分用作针对残余SSAO活性的替代物。在基本上如上文所述的方案中评估以各种剂量施用的实例1的化合物。结果列于下表中。
实例1的SSAO靶接合
数据以平均值±SEM,n=6呈现。
结果表明实例1的化合物在大鼠血浆和肝脏组织中剂量依赖性地抑制SSAO活性。
Claims (22)
1.一种制备式1化合物或其医药学上可接受的盐的方法:
其中:
R1选自由以下组成的群组:
R2选自由以下组成的群组:
R3是H或CH3,
R5选自由以下组成的群组:H、-C1-4烷基、-C3-4环烷基以及-CH2-C3-4环烷基;且
n是1或2,
所述方法包括以下步骤:
a)将式A化合物:
其中Pg是保护基团,
与被取代的环胺反应,随后通过脱保护步骤以形成式B化合物:
其中R1如式1中所定义;
b)将所述式B化合物与适当的胺经保护的2-溴甲基-3-氟-丙基-2-烯-胺,随后通过脱保护步骤以形成所述式1化合物;以及
c)任选地将所述式1化合物转化为医药学上可接受的盐。
7.根据权利要求6所述的方法,其中R3是H。
11.根据权利要求10所述的方法,其中所述化合物是单或二盐酸盐。
13.根据权利要求1所述的方法,其中步骤a)在所述式A化合物与所述被取代的环胺反应期间中在碱的存在下进行。
14.根据权利要求13所述的方法,其中所述碱是N,N-二异丙基乙胺或碳酸钾。
15.根据权利要求1所述的方法,其中步骤a)中所述式A化合物的所述保护基团为苄基。
16.根据权利要求15所述的方法,其中步骤a)的所述脱保护步骤使用钯催化氢化。
17.根据权利要求1所述的方法,其中步骤b)的所述适当的胺经保护的2-溴甲基-3-氟-丙基-2-烯-胺是N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯。
18.根据权利要求17所述的方法,其中步骤b)的所述脱保护步骤使用酸。
19.根据权利要求18所述的方法,其中所述酸是HCl。
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