CN111801322A - 用于治疗中枢和周边神经系统病症的激酶抑制剂 - Google Patents
用于治疗中枢和周边神经系统病症的激酶抑制剂 Download PDFInfo
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- CN111801322A CN111801322A CN201880084890.5A CN201880084890A CN111801322A CN 111801322 A CN111801322 A CN 111801322A CN 201880084890 A CN201880084890 A CN 201880084890A CN 111801322 A CN111801322 A CN 111801322A
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Abstract
本文提供通式(I)的化合物,其充当激酶抑制剂,例如ROCK、S6K和/或PKC抑制剂,且对神经突生长和轴突生长有用。
Description
背景技术
脊髓损伤(spinal cord injury;SCI)的恢复通过中枢神经系统(centralnervous system;CNS)神经元不能使其损伤轴突再生而受到限制。由于存在抑制轴突生长的两种机制:1)CNS神经元的固有再生能力的丧失和2)面对损伤轴突的抑制性CNS微环境,所以研发药物以治疗SCI变得复杂化。假设有效治愈可能是基于同时治疗两种再生失效的来源以便在损伤之后诱导有临床意义的轴突再生。
发明内容
本文提供式(I)化合物或其医药学上可接受的盐:(I),其中环A包括具有1、2或3个氮环原子的5到6元单环杂芳基环或8到11元双环杂芳基环;L1不存在或C1-2亚烷基;X1为-NH-、-CH2NH-、-NHCH2-、-CH2CH2NH-或-NHCH2CH2-;X2为NR2或O;X3为NR2或O;L2为C(O)、O、CH2或CHOH;R1为H或卤基;各R2独立地为H或C1-3烷基;R3为H、C1-3烷基、C3-6环烷基、芳基、C(O)C1-3烷基、C(O)C3-6环烷基或C(O)芳基;R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C1-4烷氧基-芳基、C(O)OC3-6环烷基或C(O)O芳基;以及R5为H、卤基、C1-4烷基或C1-4烷氧基。
进一步提供使用如本文中所公开的化合物或其盐以抑制Rho激酶(ROCK)或核糖体蛋白S6激酶(S6K)或PKC的方法。还提供用如本文中所公开的化合物或其盐抑制ROCK和S6K中的每一个的方法。
还提供通过使神经突与如本文中所公开的化合物或其盐接触来诱导神经突生长的方法。进一步提供通过以有效修复神经元和/或轴突损伤且由此治疗CNS病症的量给予如本文中所公开的化合物或其盐来治疗个体中与神经元和/或轴突损伤相关的CNS病症的方法。在一些情况下,CNS病症为麻痹、脊髓损伤、视神经损伤、青光眼、多发性硬化症、创伤性脑损伤、弥漫性轴突损伤、中风或退行性疾病(如帕金森病(Parkinson's disease))。
进一步提供通过以有效修复神经元和/或轴突损伤且由此治疗PNS病症的量给予如本文中所公开的化合物或其盐来治疗个体中与神经元和/或轴突损伤相关的周边神经系统(peripheral nervous system;PNS)病症的方法。在一些情况下,PNS病症为周边神经创伤、重复性应激、肌肉萎缩性侧索硬化(amyotrophic lateral sclerosis;ALS)、勃起功能障碍、与器官移植相关的病症、神经纤维瘤、血管疾病、糖尿病、自体免疫病症、与化学毒性相关的病症或肾病。
还提供治疗经受癌症治疗的个体的神经退化症的方法,其包括以有效治疗神经退化症的量给予如本文中所公开的化合物或其盐。
附图说明
图1示出RO480500-002和其酰胺衍生物RO4367842-001的结构以及显示两种化合物促进原代CNS神经元中的神经突生长的曲线。
图2示出选择性ROCK抑制剂(H-1152)和选择性S6K抑制剂(PF-4708761)对原代CNS神经元中的神经突生长的作用。组合ROCK和S6K的抑制剂协同促进神经突生长。
图3示出用激酶抑制剂化合物RO48(A92)、SBI-0799926(A-16)和SBI-0814654(A88)治疗促进CST轴突在脊髓中萌发。A)在单侧右锥体束切断术和将AAV8-GFP和化合物共注射到运动皮层中之后5周的颈脊髓的横向截面显示在用RO48(A92)、SBI-0799926(A-16)和SBI-0814654(A88)治疗的动物中更多GFP+轴突萌发到失神经灰质(denervated greymatter)中。B)曲线表示在用所指示化合物治疗的两只动物中萌发轴突指数的平均值。误差棒指示数据点的范围。N=2只动物(小鼠)。
具体实施方式
本文提供化合物或其医药学上可接受的盐,其具有式(I)结构:
其中环A包括具有1、2或3个氮环原子的5到6元单环杂芳基环或8到11元双环杂芳基环;L1不存在或C1-2亚烷基;X1为-NH-、-CH2NH-、-NHCH2-、-CH2CH2NH-或-NHCH2CH2-;X2为NR2或O;X3为NR2或O;L2为C(O)、O或CHOH;R1为H或卤基;各R2独立地为H或C1-3烷基;R3为H、C1-3烷基、C3-6环烷基、芳基、C(O)C1-3烷基、C(O)C3-6环烷基或C(O)芳基;R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C1-4烷氧基-芳基、C(O)OC3-6环烷基或C(O)O芳基;以及R5为H、卤基、C1-4烷基或C1-4烷氧基。
已知介导轴突生长的外在抑制的激酶,如Rho激酶(ROCK)和蛋白激酶C(PKC)。这些激酶在CNS微环境内存在抑制性分子的情况下抑制轴突生长。已知介导轴突生长的内在抑制的激酶,如核糖体蛋白S6激酶(S6K)。这些激酶抑制神经元的固有再生状态。用诱导神经突生长的ROCK和/或S6K的选择性抑制剂处理所培养的原代神经元。此外,用两种激酶的抑制剂共处理所培养的原代神经元对神经突生长具有强协同效应。用ROCK和S6K的双重抑制剂处理所培养的神经元诱导神经突生长增加(相对于对照的400%)。在SCI的小鼠模型中,ROCK和S6K的双重抑制(经由单次皮质注射)足以在损伤(背侧半切)之后诱导稳固性轴突再生。这种再生伴随感觉运动功能的显著恢复。在脊髓再生的第二模型(锥体束切断术)中测试RO48(A92),且发现将RO48递送到损伤动物的CSF增强备用轴突的补偿性萌发。执行使用CNS损伤的第三模型(视神经挤压)的初步实验,发现将RO40注射到动物的眼睛中增强视神经轴突的再生。
基于这些结果,启动药物化学程序且制备衍生物。几种衍生物显示在培养物中对神经突生长促进效果强(一些接近对照的700%)。
注意:除抑制ROCK、PKC和S6K以外,所公开的化合物还可抑制2种确定为促进神经突生长的潜在目标的其它激酶。这些是PKG和PKX。
本文中所公开的化合物可抑制一或多种激酶,例如Rho激酶(ROCK)、核糖体蛋白S6激酶(S6K)和/或蛋白激酶C。抑制这些激酶中的一种或多种可促进中枢神经系统(CNS)中的神经突生长和/或轴突生长。
式(I)化合物
本文公开了化合物或其医药学上可接受的盐,其具有式(I)结构:
其中环A包括具有1、2或3个氮环原子的5-6元单环杂芳基环或8-11元双环杂芳基环;L1不存在或C1-2亚烷基;X1为-NH-、-CH2NH-、-NHCH2-、-CH2CH2NH-或-NHCH2CH2-;X2为NR2或O;X3为NR2或O;L2为C(O)、O或CHOH;R1为H或卤基;各R2独立地为H或C1-3烷基;R3为H、C1-3烷基、C3-6环烷基、芳基、C(O)C1-3烷基、C(O)C3-6环烷基或C(O)芳基;R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C1-4烷氧基-芳基、C(O)OC3-6环烷基或C(O)O芳基;以及R5为H、卤基、C1-4烷基或C1-4烷氧基。在一些实施例中,X1为-NH-、-CH2NH-或-NHCH2-。在一些实施例中,R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C(O)OC3-6环烷基、C(O)O芳基;且R5为H、卤基、C1-4烷基或C1-4烷氧基。
如本文中所使用,术语“烷基”是指直链和分支链饱和烃基。术语Cn意指烷基具有“n”个碳原子。举例来说,C4烷基是指具有4个碳原子的烷基。C1-C7烷基是指具有涵盖整个范围的碳原子数(即,1到7个碳原子)以及所有亚组(例如1到6个、2到7个、1到5个、3到6个、1个、2个、3个、4个、5个、6个和7个碳原子)的烷基。烷基的非限制性实例包含甲基、乙基、正丙基、异丙基、正丁基、仲丁基(2-甲基丙基)、叔丁基(1,1-二甲基乙基)、3,3-二甲基戊基和2-乙基己基。除非另外指明,否则烷基可为未经取代的烷基或经取代的烷基。经取代的烷基的非限制性实例包含卤烷基(即,经一个或多个卤基取代的烷基)、羟烷基(即,经一个或多个羟基取代的烷基)等。
本文中所使用的术语“亚烷基”是指具有取代基的烷基。举例来说,术语“亚烷基芳基”是指经芳基取代的烷基。举例来说,亚烷基可为-CH2CH2-或-CH2-。术语Cn意指亚烷基具有“n”个碳原子。举例来说,C1-6亚烷基是指具有涵盖整个范围的碳原子数以及所有亚组的亚烷基,如先前对于“烷基”基团所描述。除非另外指示,否则亚烷基可为未经取代的亚烷基或经取代的亚烷基。
术语“烷氧基”是指经氧取代的烷基,例如烷基-O-。
如本文中所使用,术语“环烷基”是指脂族环状烃基。术语Cn意指环烷基具有“n”个碳原子。举例来说,C5环烷基是指在环中具有5个碳原子的环烷基。C3-C6环烷基是指具有涵盖整个范围的碳原子数(即,3至6个碳原子)以及所有亚组(例如3到5个、4到6个、5到6个、3个、4个、5个和6个碳原子)的环烷基。环烷基的非限制性实例包含环丙基、环丁基、环戊基和环己基。除非另外指示,否则环烷基可为未经取代的环烷基或经取代的环烷基。本文中所描述的环烷基可与另一环烷基、杂环烷基、芳基和/或杂芳基分离或稠合。
如本文中所使用,术语“芳基”是指单环或多环芳香族基团,优选地具有6到10个碳环原子的单环或双环芳香族基团,例如苯基或萘基。除非另外指明,否则芳基可未经取代或经一个或多个基团取代,且特别是经一个到四个独立地选自例如以下的基团取代:卤基、烷基、烯基、OCF3、NO2、CN、NC、OH、烷氧基、氨基、CO2H、CO2烷基、芳基和杂芳基。本文中所描述的芳基可与另一芳基、环烷基、杂环烷基和/或杂芳基分离或稠合。示例性芳基包含(但不限于)苯基、萘基、四氢萘基、氯苯基、甲基苯基、甲氧基苯基、三氟甲基苯基、硝基苯基、2,4-甲氧基氯苯基等。
如本文中所使用,“杂芳基”是指具有1、2或3个选自N、S和O的杂原子的5到6元单环芳香族环或具有1、2、3或4个选自N、S和O的杂原子的8到11元双环芳香族环。在一些实施例中,杂芳基环包括至少1个环氮或1、2或3个环氮。所涵盖的杂芳基的实例包含(但不限于)噻吩基(thienyl)、呋喃基、吡啶基、吡咯基、恶唑基、喹啉基、噻吩基(thiophenyl)、异喹啉基、吲哚基、三嗪基、三唑基、异噻唑基、异恶唑基、咪唑基、苯并噻唑基、吡嗪基、嘧啶基、噻唑基和噻二唑基。在一些情况下,杂芳基可为吡咯基、吡唑基、咪唑基、三唑基、吡啶基、吡嗪基、嘧啶基、吲哚基、吲唑基、苯并三唑基、苯并咪唑基、吡咯并吡啶基或咪唑并吡啶基(imidazopyrindinyl)。在不同情况下,杂芳基可为吡啶基、嘧啶基、吡咯并吡啶基、吲唑基或咪唑并吡啶基。
术语“卤基”是指氟、氯、溴和碘。
本公开特定涵盖的化合物包含下表中的那些。
在一些情况下,化合物为选自A1到A86的化合物或盐。
在一些情况下,本公开的化合物包含表A中所列的那些化合物或其医药学上可接受的盐:
表A
在一些情况下,化合物为如表B中所列的一种或其医药学上可接受的盐:
表B
在一些情况下,化合物为如表C中所列的一种或其医药学上可接受的盐:
表C
本文中所公开的化合物可作为医药学上可接受的盐。如本文中所使用,术语“医药学上可接受的盐”是指在合理医学判断范围内适用于与人类和低等动物的组织接触而无不当毒性、刺激、过敏反应等,且与合理的效益/风险比相称的那些盐。医药学上可接受的盐为所属领域中众所周知的。举例来说,S.M.Berge等人在《医药科学杂志(J.PharmaceuticalSciences)》,1977,66,1-19中详细描述了医药学上可接受的盐,所述文献以引用的方式并入本文中。本发明化合物的医药学上可接受的盐包含衍生自合适的无机和有机酸和碱的那些盐。医药学上可接受的无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或与有机酸(如乙酸(三氟乙酸)、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用所属领域中所使用的其它方法(如离子交换法)形成的盐。其它医药学上可接受的盐包含己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、丁二酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。含有羧酸或其它酸性官能团的化合物的盐可以通过与合适的碱反应来制备。这类盐包含(但不限于)碱金属、碱土金属、铝盐、铵、N+(C1-4烷基)4盐和有机碱的盐,如三甲胺、三乙胺、吗啉、吡啶、哌啶、甲基吡啶、二环己胺、N,N'-二苯甲基乙二胺、2-羟乙胺、双-(2-羟乙基)胺、三-(2-羟乙基)胺、普鲁卡因(procaine)、二苯甲基哌啶、脱氢枞胺(dehydroabietylamine)、N,N'-双脱氢枞胺、还原葡糖胺、N-甲基葡糖胺、三甲基吡啶、奎宁、喹啉和碱性氨基酸,如赖氨酸和精氨酸。本发明还设想本文中所公开的化合物的任何碱性含氮基团的季铵化。可通过这种季铵化获得水溶性或油溶性或可分散性产物。代表性的碱金属盐或碱土金属盐包含钠、锂、钾、钙、镁等。适当时,其它医药学上可接受的盐包含使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳数烷基磺酸根和芳基磺酸根的相对离子形成的无毒铵、季铵以及胺阳离子。
化合物的合成
本文中所公开的化合物可通过合成有机化学家可用的任何手段来合成。合成化合物的指南显示于实例中。
举例来说,式(I)化合物可通过根据以下合成流程选择适当的起始材料和试剂来制备:
流程
医药调配物、剂量和给药途径
进一步提供医药调配物,其包括如本文中所描述的化合物(例如,式(I)化合物或其医药学上可接受的盐)和医药学上可接受的赋形剂。
本文中所描述的化合物可以治疗有效量(例如,以足以抑制ROCK、S6K和/或PKC的量)给予个体。化合物可单独或作为医药学上可接受的组合物或调配物的一部分给予。另外,化合物可一次、多次全部给予或在一段时间内大体上均匀地递送。还应注意,化合物的剂量可随时间而变化。
针对特定个体的特定给药方案将部分取决于化合物、所给予化合物的量、给药途径以及任何副作用的起因和程度。根据本公开的给予个体(例如哺乳动物,如人类)的化合物的量应足以在合理的时间范围影响所需反应。剂量典型地取决于给药途径、时间和频率。因此,临床医师滴定剂量并修改给药途径以获得最优治疗效果,且常规测距技术为所属领域的普通技术人员所已知。
仅仅借助于说明,方法包括视上文所提及的因素而给予例如约0.1mg/kg高达约100mg/kg的化合物或更多。在其它实施例中,剂量在1mg/kg高达约100mg/kg;或5mg/kg高达约100mg/kg;或10mg/kg高达约100mg/kg的范围内。一些病状需要延长治疗,这可能需要或可能不需要多次给药后给予较低剂量的化合物。如果需要,则化合物的剂量在一整天适当的时间间隔下以二次、三次、四次、五次、六次或更多次亚剂量给予形式单独地给予,任选地以单位剂型给予。治疗时段将取决于特定病状和疼痛类型,且可持续一天到几个月。
给予生理学上可接受的组合物,如包括本文中所公开的化合物(例如,式(I)化合物)的医药组合物的合适方法为所属领域中众所周知的。虽然多于一个途径可用于给予化合物,但特定途径可比另一途径提供更即时和更有效的反应。根据情形,将包括化合物的医药组合物施加或滴注到体腔中,通过皮肤或黏膜而吸收,摄入、吸入和/或引入到循环中。举例来说,在某些情形中,期望将包括药剂的医药组合物经口递送,通过静脉内、腹膜内、脑内(实质内)、脑室内、肌肉内、眼内、动脉内、门静脉内、病灶内、髓内、鞘内、心室内、经皮、皮下、腹膜内、鼻内、经肠、局部、舌下、尿道、阴道或直肠方式经过注射递送,通过持续释放系统或通过植入装置递送。如果需要,则化合物经由鞘内给药、脑内(实质内)给药、脑室内给药或动脉内或静脉内给药区域性地给予,从而馈入所关注区域。可替代地,组合物经由植入膜、海绵体或已将所需化合物吸收或囊封于其上的另一适当材料来局部给药。当使用植入装置时,在一个方面,将装置植入到任何合适组织或器官中,且所需化合物的递送例如经由扩散、定时释放大丸剂或连续给药。
为有助于给药,在不同方面,将化合物调配成包括载剂(即,媒剂、佐剂或稀释剂)的生理学上可接受的组合物。所采用的特定载剂仅受到化学物理考量(如溶解度和缺少与化合物的反应性)和给药途径限制。生理学上可接受的载剂为所属领域中众所周知的。适合于可注射用途的说明性药物形式包含:无菌水溶液或分散液,和用于临时制备无菌可注射溶液或分散液的无菌散剂(例如参见美国专利第5,466,468号)。可注射调配物进一步描述于例如费城利平科特公司(J.B.Lippincott Co.)的《药剂学和药学实践(Pharmaceuticsand Pharmacy Practice)》中。Pa.,Banker和Chalmers编,第238-250页(1982)以及ASHP可注射药物手册(ASHP Handbook on Injectable Drugs),Toissel,第4版,第622-630页(1986))。在一个方面,将包括化合物的医药组合物连同提供关于使用这类医药组合物的说明书的封装材料一起放置于容器内。一般来说,这类说明包含描述试剂浓度的有形表达,以及在某些实施例中,复原医药组合物可能需要的赋形剂成分或稀释剂(例如,水、盐水或PBS)的相对量。
适合于非经肠注射的组合物可包括生理学上可接受的无菌水溶液或非水溶液、分散液、悬浮液或乳液以及用于复原成无菌可注射溶液或分散液的无菌散剂。合适的水性和非水性载剂、稀释剂、溶剂或媒剂的实例包含:水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其适合混合物、植物油(如橄榄油)以及可注射有机酯(如油酸乙酯)。可例如通过使用包衣(如卵磷脂)、通过在分散液情况下维持所需粒度和通过使用表面活性剂来维持适当流动性。
这些组合物还可含有佐剂,例如防腐剂、湿润剂、乳化剂和分散剂。微生物污染可通过添加多种抗菌和抗真菌试剂,例如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸等来防止。还可以期望包含等渗剂,例如糖、氯化钠等。可注射医药组合物的延长吸收可通过使用延迟吸收的药剂实现,例如单硬脂酸铝和明胶。
用于经口给药的固体剂型包含胶囊、片剂、散剂及颗粒。在这类固体剂型中,将活性化合物与至少一种惰性惯用赋形剂(或载剂),如柠檬酸钠或磷酸二钙;或(a)填充剂或补充剂,例如淀粉、乳糖、蔗糖、甘露醇和硅酸;(b)黏合剂,例如羧基甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如甘油;(d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些复合硅酸盐和碳酸钠;(a)溶液延迟剂,例如石蜡;(f)吸收加速剂,例如季铵化合物;(g)湿润剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如高岭土和膨润土;以及(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或其混合物混杂。就胶囊和片剂来说,剂型还可包括缓冲剂。类似类型的固体组合物还可用作软和硬填充明胶胶囊中的填充剂,所述胶囊使用如乳糖或奶糖以及高分子量聚乙二醇等赋形剂。
固体剂型,如片剂、糖衣药丸、胶囊、丸剂和颗粒可用包衣和外壳(如肠溶衣和所属领域中熟知的其它包衣)来制备。固体剂型还可含有遮光剂。此外,固体剂型可包埋组合物,使得其以延迟方式在肠道的某些部分释放一种或多种活性化合物。可使用的包埋组合物的实例为聚合物质和蜡。活性化合物还可呈微囊封形式,任选地具有一种或多种赋形剂。
用于经口给药的液体剂型包含医药学上可接受的乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物以外,液体剂型可含有所属领域中常用的惰性稀释剂,如水或其它溶剂;助溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻籽油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯或这些物质的混合物等。
除这类惰性稀释剂外,组合物还可包含佐剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。除活性化合物以外,悬浮液可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄芪或这些物质的混合物等。
用于直肠给药的组合物优选为栓剂,其可通过将本公开的化合物与合适的无刺激性赋形剂或载剂(如可可脂、聚乙二醇或栓剂蜡)混合来制备,所述栓剂在一般室温下为固体,但在体温下为液体,且因此在直肠或阴道腔中熔融并释放活性组分。
适当时,将化合物与其它物质(例如治疗剂)和/或其它治疗模态组合给予以达成额外(或扩增)生物作用。这些其它疗法/共治疗包含(例如)手术、辐射治疗、化学疗法、抗血管生成因子(例如,可溶生长因子受体(例如sflt)、生长因子拮抗剂(例如血管紧张素)等)、抗生素、激素疗法、抗炎剂(例如,非类固醇抗炎性药物(Non-Steroidal Anti-Inflammatory Drug;NSAID)或类固醇抗炎性物质)、抗病毒剂、抗细菌剂、咳嗽抑制剂、解充血剂或祛痰剂、疼痛缓解剂等。任选地,将化合物与有助于跨越血脑屏障运输的药剂和/或阻断从大脑流出的药剂组合给予。本文中未特定列出的额外组合疗法也在本公开的范围内。
因此,本公开包含向个体给予化合物以及一或多种额外合适物质,其各自根据适合于那种医药的方案来给予。这方面包含将药剂和一种或多种额外合适的药剂同时给予(即,大体上同时给予)和非同时给予(即,在不同时间以任何次序给予,无论是否重叠)。应了解,在某些方面,将不同组分以相同或不同组合物以及相同或不同给药途径给予。
在禁止授予对人体实践的方法的专利权的权限中,向人类个体“给予”组合物的含义应受限于开具人类个体将通过任何技术(例如,经口、吸入、局部施用、注射、插入等)自我给予的受控物质的处方。需要与界定可获专利主题的法律或法规一致的最广泛合理解释。在不禁止授予对人体实践的方法专利权的权限中,“给予”组合物包含对人体实践的方法以及前述活动两种。
使用方法
本文中所公开的化合物可抑制ROCK、S6K和PKC中的一种或多种。在一些情况下,化合物抑制ROCK、PKC和S6K。在一些情况下,化合物抑制ROCK、S6K和PKC中的每一个。
ROCK和S6K的共抑制协同促进原代神经元中的神经突生长。这种协同作用由于同时调节介导神经突生长的外在和内在抑制两种的机制而为可能的。
本文中所公开的化合物的抑制性活性可使用如实例中所描述的分析来评估。在一些情况下,针对ROCK的化合物的IC50为0.1到3000nM、0.1到1000nM、0.1到500nM、0.1到100nM、0.1到50nM、0.1到25nM、0.1到10nM、0.1到5nM、0.1到1nM、0.1到0.5nM、1000到2000nM、100到1000nM、10或100nM、5到50nM或1到10nM。在一些情况下,针对S6K的化合物的IC50为0.1到3000nM、0.1到1000nM、0.1到500nM、0.1到100nM、0.1到50nM、0.1到25nM、0.1到10nM、0.1到5nM、0.1到1nM、0.1到0.5nM、1000到2000nM、100到1000nM、10或100nM、5到50nM或1到10nM。在一些情况下,针对PKC的化合物的IC50为0.1到3000nM、0.1到1000nM、0.1到500nM、0.1到100nM、0.1到50nM、0.1到25nM、0.1到10nM、0.1到5nM、0.1到1nM、0.1到0.5nM、1000到2000nM、100到1000nM、10或100nM、5到50nM或1到10nM。
本文中所公开的化合物可诱导神经突生长。在一些情况下,本文中所公开的化合物可治疗与神经元和/或轴突损伤相关的CNS病症。举例来说,本文中所公开的化合物可治疗CNS病症,如麻痹、脊髓损伤、视神经损伤、青光眼、多发性硬化症、创伤性脑损伤、弥漫性轴突损伤、中风或退行性疾病(如帕金森病)。
在一些情况下,本文中所公开的化合物可治疗与神经元和/或轴突损伤相关的周边神经系统(PNS)病症。在一些情况下,PNS病症为周边神经创伤、重复性应激、肌肉萎缩性侧索硬化(ALS)、勃起功能障碍、与器官移植相关的病症、神经纤维瘤、血管疾病、糖尿病、自体免疫病症、与化学毒性相关的病症或肾病。
在一些情况下,本文中所公开的化合物可治疗经受癌症治疗的个体的神经退化症。
本文中所公开的化合物可适用于例如以下的疗法:(i)神经系统病症(例如神经退化性疾病)、(ii)继发于对神经系统外部具有原发性影响的疾病、病状或疗法的神经系统病状、(iii)由物理、机械或化学创伤造成的神经系统损伤、(iv)记忆丧失和(v)精神病症。
可通过根据本发明促进神经突生长来预防或治疗的神经退化性疾病和病状的实例包含肌肉萎缩性侧索硬化(ALS)、三叉神经痛、舌咽神经痛、贝尔氏麻痹(Bell's palsy)、重症肌无力、肌肉萎缩症、进行性肌肉萎缩、原发性侧索硬化(primary lateralsclerosis;PLS)、假性延髓麻痹、进行性延髓麻痹、脊髓性肌萎缩、进行性延髓麻痹、遗传性肌肉萎缩、椎间盘综合征(例如,突出盘、破裂盘和脱垂盘综合征)、颈椎病、神经丛病症、胸廓出口损坏综合征、周边神经病、紫质症(prophyria)、轻度认知障碍、阿尔茨海默氏病(Alzheimer's disease)、亨廷顿氏病(Huntington's disease)、帕金森病、帕金森叠加综合征(例如,多发性系统萎缩症、进行性核上麻痹和皮质基底核退化症)、路易体痴呆(dementia with Lewy bodies)、额颞叶型痴呆(frontotemporal dementia)、脱髓鞘疾病(例如,吉兰-巴雷综合征(Guillain-Barre syndrome)和多发性硬化症)、腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT;也称为遗传性运动和感觉神经病(HereditaryMotor and Sensory Neuropathy;HMSN)、遗传性感觉运动神经病(HereditarySensorimotor Neuropathy;HSMN)以及腓骨肌肉萎缩)、朊病毒病(例如克雅氏病(Creutzfeldt-Jakob disease)、格-斯二氏综合征(Gerstmann-Straussler-Scheinkersyndrome;GSS)、致命性家族性失眠症(fatal familial insomnia;FFI)和牛海绵状脑病(bovine spongiform encephalopathy;BSE,通常称为疯牛病))、皮克氏病(Pick'sdisease)、癫痫症以及AIDS痴呆复合征(也称为HIV痴呆、HIV脑病和HIV相关的痴呆)。
某些对神经系统外部具有原发性效应的疾疾病和病状可导致神经系统损伤,其可使用如本文中所公开的化合物治疗。这类病状的实例包含由例如糖尿病导致的周边神经病和神经痛、癌症、AIDS、肝炎、肾脏功能障碍、科罗拉多壁虱热(Colorado tick fever)、白喉、HIV感染、麻疯病、莱姆病(lyme disease)、结节性多动脉炎、类风湿性关节炎、结节病、休格连综合征(Sjogren syndrome)、梅毒、全身性红斑性狼疮症和淀粉样变性。
另外,本文中所公开的化合物可用于治疗如周边神经病的神经损伤,所述神经损伤是由暴露于以下毒性化合物导致的,包含:重金属(例如铅、砷和汞)和工业溶剂;以及药物,包含化学治疗剂(例如长春新碱(vincristine)和顺铂(cisplatin))、氨苯砜、HIV药物治疗(例如,齐多夫定(Zidovudine)、地达诺新(Didanosine)、司他夫定(Stavudine)、扎西他滨(Zalcitabine)、利托那韦(Ritonavir)和安普那韦(Amprenavir))、降胆固醇药物(例如洛伐他汀(Lovastatin)、吲达帕胺(Indapamid)和吉非罗齐(Gemfibrozil))、心脏或血压药物治疗(例如胺碘酮(Amiodarone)、肼酞嗪(Hydralazine)、哌克昔林(Perhexiline))以及甲硝哒唑(Metronidazole)。
本文中所公开的方法还可用于治疗由物理、机械或化学创伤造成的神经系统损伤。因此,方法可用于治疗由物理损伤(与例如烧伤、创伤、手术和事故相关)、局部缺血、长时间暴露于低温(例如冻伤)、化学创伤(例如,由于作为癌症治疗的化学疗法)造成的周边神经损伤以及由于例如中风或颅内出血(如脑出血)造成的中枢神经系统损伤。
此外,本文中所公开的化合物可用于预防或治疗记忆丧失,例如年龄有关的记忆丧失。可能受丧失影响的记忆类型包含情节记忆、语义记忆、短期记忆和长期记忆。与记忆丧失相关的疾病和病状的实例包含轻度认知障碍、阿尔茨海默氏病、帕金森病、亨廷顿氏病、化学疗法、应激、中风和创伤性脑损伤(例如,脑震荡)。
本文中所公开的化合物还可用于治疗精神病症,包含例如精神分裂症(schizophrenia)、妄想症、分裂情感性精神障碍、精神分裂症(schizopheniform)、共有型精神障碍、精神病、偏执型人格障碍、分裂性人格障碍、边缘型人格障碍、反社会型人格障碍、自恋型人格障碍、强迫症、谵妄、痴呆、情绪障碍、躁郁症、抑郁症、应激障碍、恐慌症、畏旷症、社交恐惧症、创伤后应激障碍、焦虑症和冲动控制障碍(例如,盗窃癖、病理性赌博、放火癖和拔毛癖)。
实例
一般程序1:在室温下,向小瓶中装入水杨醛(1.0当量)和DMF(0.25M)。接着添加(4-(甲氧羰基)苯基)硼酸(1.2当量),随后添加[RhCl2Cp*]2(0.04当量)和Cu(OAc)2(1.2当量)。使所得悬浮液升温到80℃持续3-4h。将混合物冷却到室温且过滤以去除不溶盐。溶液接着用EtOAc稀释且用水洗涤两次。浓缩有机部分以得到不经进一步纯化即可使用的粗中间物4-(2-羟基苯甲酰基)苯甲酸甲酯。将这种固体溶解于CH2Cl2(0.5M)中且用二异丙基乙胺(1.5当量)和(氯甲氧基)乙烷(1.5当量)处理。将这种溶液在室温下搅拌直到通过LCMS完成对苯酚的保护为止。反应接着用CH2Cl2稀释且用水洗涤三次。有机部分的浓缩和硅胶(己烷/EtOAc梯度)上的纯化得到4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸甲酯衍生物。将这种酯(1.0当量)溶解于THF(0.25M)和H2O(0.5M)中且用LiOH(4.0当量)处理。将混合物在室温下搅拌直到完成皂化为止,接着用EtOAc稀释并用10%柠檬酸溶液且接着水洗涤。浓缩有机部分得到4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸衍生物。
一般程序2:在室温下,向小瓶中装入4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸(1当量)、Et3N(1当量)和DMF(0.5M)。接着向这种溶液中添加HATU(1当量)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(1当量)和HCl(4.0M二恶烷溶液,2当量)于DMF(0.5M)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h以得到可直接就地使用的(3R,4R)-3-氨基-4-(4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯类似物。向这种溶液中添加杂芳基羧酸(1当量)、Et3N(2当量)和HATU(1当量)。将混合物在室温下搅拌1h,接着用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.2M)和1N HCl水溶液(0.1M)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。溶液接着经由HPLC纯化以得到呈甲酸盐形式的最终产物。
实例1:14-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.15(d,J=7.8Hz,2H),7.88(d,J=7.4Hz,2H),7.49(t,J=8.1Hz,1H),7.43(d,J=7.6Hz,1H),7.13(t,J=7.4Hz,1H),5.07(s,2H),3.49(m,2H),1.12(t,J=7.1Hz,3H)。
实例2:4-(5-氯-2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.16(d,J=8.9Hz,2H),7.87(d,J=8.0Hz,2H),7.44(dd,J=8.9,2.7Hz,1H),7.39(d,J=2.8Hz,1H),7.22(d,J=8.9Hz,1H),5.04(s,2H),3.48(q,J=6.9Hz,2H),1.12(t,J=7.0Hz,3H)。
实例3:4-(2-(乙氧基甲氧基)-5-甲基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.15(d,J=8.5Hz,2H),7.88(d,J=8.4Hz,2H),7.28(dd,J=8.6,2.4Hz,1H),7.23(d,J=2.3Hz,1H),7.14(d,J=8.5Hz,1H),5.02(s,2H),3.47(q,J=7.1Hz,2H),2.34(s,3H),1.11(t,J=7.1Hz,3H)。
实例4:4-(2-(乙氧基甲氧基)-5-甲氧基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.16(d,J=8.4Hz,2H),7.89(d,J=8.2Hz,2H),7.19(d,J=9.0Hz,1H),7.03(dd,J=9.1,3.1Hz,1H),6.96(d,J=3.1Hz,1H),4.97(s,2H),3.81(s,3H),3.48(q,J=7.0Hz,2H),1.12(t,J=7.1Hz,3H)。
实例5:4-(2-(乙氧基甲氧基)-4-甲基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.14(d,J=8.1Hz,2H),7.86(d,J=8.1Hz,2H),7.36(d,J=7.7Hz,1H),7.05(s,1H),6.93(d,J=7.8Hz,1H),5.04(s,2H),3.49(q,J=7.0Hz,2H),2.42(s,3H),1.13(t,J=7.1Hz,3H)。
实例6:4-(4-氯-2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.09(d,J=8.4Hz,2H),7.82(d,J=8.3Hz,2H),7.36(d,J=8.2Hz,1H),7.27(d,J=1.8Hz,1H),7.10(dd,J=8.1,1.8Hz,1H),5.04(s,2H),3.94(s,3H),3.48(q,J=7.1Hz,2H),1.13(t,J=7.1Hz,3H)。
实例7:4-(2-(乙氧基甲氧基)-4-甲氧基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.14(d,J=8.4Hz,2H),7.83(d,J=8.3Hz,2H),7.49(d,J=8.5Hz,1H),6.79(d,J=2.2Hz,1H),6.65(dd,J=8.6,2.3Hz,1H),5.03(s,2H),3.87(s,3H),3.49(q,J=7.1Hz,2H),1.13(t,J=7.1Hz,3H)。
实例8:4-(2-(乙氧基甲氧基)-3-甲基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.16(d,J=8.0Hz,2H),7.91(d,J=8.2Hz,2H),7.39(d,J=7.5Hz,1H),7.23(d,J=7.4Hz,1H),7.14(t,J=7.5Hz,1H),4.87(s,2H),3.46(q,J=7.0Hz,2H),2.37(s,3H),1.01(t,J=7.0Hz,3H)。
实例9:4-(3-氯-2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.17(d,J=8.1Hz,2H),7.91(d,J=8.1Hz,2H),7.60(d,J=7.9Hz,1H),7.31(d,J=7.7Hz,1H),7.20(t,J=7.9Hz,1H),5.01(s,2H),3.44(q,J=7.0Hz,2H),1.05-0.93(m,3H)。
实例10:4-(2-(乙氧基甲氧基)-3-甲氧基苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.15(d,J=8.3Hz,2H),7.93(d,J=8.3Hz,2H),7.19(t,J=7.9Hz,1H),7.10(dd,J=8.4,1.4Hz,1H),6.98(dd,J=7.7,1.5Hz,1H),5.01(s,2H),3.91(s,3H),3.38(q,J=7.1Hz,2H),0.98(t,J=7.0Hz,3H)。
实例11:2-氯-4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.02(d,J=8.1Hz,1H),7.87(d,J=1.5Hz,1H),7.77-7.72(m,1H),7.51(t,J=7.7Hz,1H),7.45(d,J=7.6Hz,1H),7.28(m,1H),7.14(t,J=7.6Hz,1H),5.08(s,2H),3.52(q,J=7.1Hz,2H),1.15(t,J=7.1Hz,3H)。
实例12:4-(2-(乙氧基甲氧基)苯甲酰基)-2-甲氧基苯甲酸。
根据一般程序1制备。1H NMR(500MHz,氯仿-d)δ8.21(d,J=8.0Hz,1H),7.66(d,J=1.3Hz,1H),7.53-7.48(m,1H),7.42(dd,J=7.5,1.7Hz,1H),7.39-7.35(m,1H),7.28(m,1H),7.13(dd,J=8.0,6.9Hz,1H),5.08(s,2H),4.15(s,3H),3.51(q,J=7.1Hz,2H),1.14(t,J=7.1Hz,3H)。
实例13:3-氯-4-(2-(乙氧基甲氧基)苯甲酰基)苯甲酸。
根据一般程序1制备。LCMS指示氯的一些损失。
实例14:4-(2-(乙氧基甲氧基)苯甲酰基)-3-甲基苯甲酸。
根据一般程序1,用频哪醇硼酸酯代替硼酸来制备。这种化合物含有杂质且不经进一步纯化即使用。1H NMR(500MHz,氯仿-d)δ8.00(s,1H),7.91(d,J=8.2Hz,1H),7.61(dd,J=7.6,1.6Hz,1H),7.52-7.46(m,1H),7.38(d,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),7.10(t,J=7.6Hz,1H),4.98(s,2H),3.39(q,J=7.0Hz,2H),2.48(s,3H),1.09(t,J=7.1Hz,3H)。
实例15:N-((3R,4R)-4-(4-(2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰 胺。
根据一般程序2制备。1H NMR(400MHz,甲醇-d4)δ8.76-8.66(m,2H),8.37(s,2H),8.00(d,J=8.0Hz,2H),7.85-7.77(m,4H),7.61-7.47(m,2H),7.04(d,J=8.4Hz,1H),6.94(t,J=7.8Hz,1H),4.75(m,2H),3.85(m,2H),3.47(m,2H)。针对C24H22N4O4[M+H]的LCMS(ESI+)预测值=431.17,实验值=431.53。
实例16:N-((3R,4R)-4-(4-(5-氯-2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.72(s,2H),8.37(d,J=4.1Hz,2H),8.00(t,J=5.7Hz,2H),7.82(t,J=5.3Hz,4H),7.50(dt,J=8.4,2.8Hz,1H),7.42(t,J=2.8Hz,1H),7.03(dd,J=8.9,4.5Hz,1H),4.74(s,2H),3.90-3.81(m,2H),3.50-3.41(m,2H)。针对C24H21ClN4O4[M+H]的LCMS(ESI+)预测值=465.13,实验值=465.52。
实例17:2-氨基-N-((3R,4R)-4-(4-(5-氯-2-羟基苯甲酰基)苯甲酰胺基)吡咯烷- 3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ7.99(m,2H),7.82(s,2H),7.50(m,1H),7.43(m,1H),7.21(s,1H),7.04(m,1H),4.67(m,2H),3.76(m,2H),3.35(m,2H)。针对C23H21ClN6O4[M+H]的LCMS(ESI+)预测值=481.13,实验值=481.57。
实例18:N-((3R,4R)-4-(4-(2-羟基-4-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3- 基)异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.71(d,J=5.2Hz,2H),8.48(s,1H),7.99(d,J=8.0Hz,2H),7.84-7.78(m,2H),7.73(d,J=7.9Hz,2H),7.46(d,J=9.0Hz,1H),6.56(d,J=2.4Hz,1H),6.49(dd,J=9.0,2.5Hz,1H),4.67(m,2H),3.88(s,3H),3.77-3.68(m,2H)。针对C25H24N4O5[M+H]的LCMS(ESI+)预测值=461.18,实验值=461.55。
实例19:2-氨基-N-((3R,4R)-4-(4-(2-羟基-4-甲氧基苯甲酰基)苯甲酰胺基)吡 咯烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.49(s,1H),8.46(d,J=5.0Hz,1H),7.98(d,J=8.4Hz,2H),7.73(d,J=8.0Hz,2H),7.46(d,J=9.0Hz,1H),7.21(d,J=5.0Hz,1H),6.56(d,J=2.4Hz,1H),6.49(dd,J=9.0,2.5Hz,1H),4.64(m,2H),3.88(s,3H),3.76-3.64(m,2H),3.26(m,2H)。针对C24H24N6O5[M+H]的LCMS(ESI+)预测值=477.18,实验值=477.58。
实例20:N-((3R,4R)-4-(4-(2-羟基-4-甲基苯甲酰基)苯甲酰胺基)吡咯烷-3-基) 异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.72(d,J=6.1Hz,2H),8.44(s,1H),7.99(d,J=8.1Hz,2H),7.81(d,J=6.1Hz,2H),7.76(d,J=8.0Hz,2H),7.41(d,J=8.2Hz,1H),6.88(s,1H),6.77(d,J=8.2Hz,1H),4.73-4.66(m,2H),3.74(dd,J=12.1,6.9Hz,2H),2.38(s,3H)。针对C25H24N4O4[M+H]的LCMS(ESI+)预测值=445.18,实验值=445.55。
实例21:2-氨基-N-((3R,4R)-4-(4-(2-羟基-4-甲基苯甲酰基)苯甲酰胺基)吡咯 烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.46(d,J=4.9Hz,1H),8.40(s,4H),7.99(d,J=8.3Hz,2H),7.76(d,J=8.2Hz,2H),7.40(d,J=8.2Hz,1H),7.22(d,J=4.9Hz,1H),6.88(s,1H),6.78-6.75(m,1H),4.72(m,2H),3.84(dd,J=11.8,7.5Hz,2H),3.49-3.41(m,2H),2.37(s,3H)。针对C24H24N6O4[M+H]的LCMS(ESI+)预测值=461.19,实验值=461.78。
实例22:N-((3R,4R)-4-(4-(4-氯-2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.76-8.67(m,2H),8.50(s,1H),7.99(d,J=8.1Hz,2H),7.83-7.78(m,4H),7.50(d,J=8.5Hz,1H),7.08(d,J=2.0Hz,1H),6.96(dd,J=8.5,2.1Hz,1H),4.74-4.68(m,2H),3.74(dd,J=12.0,7.0Hz,2H),3.33(m,2H)。针对C24H21ClN4O4[M+H]的LCMS(ESI+)预测值=465.13,实验值=465.52。
实例23:N-((3R,4R)-4-(4-(2-羟基-5-甲基苯甲酰基)苯甲酰胺基)吡咯烷-3-基) 异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.72(d,J=6.0Hz,2H),8.37(s,3H),8.00(d,J=8.1Hz,2H),7.82(d,J=6.1Hz,2H),7.78(d,J=8.1Hz,2H),7.38(dd,J=8.5,2.2Hz,1H),7.27(d,J=2.1Hz,1H),6.94(d,J=8.5Hz,1H),4.72(d,J=7.4Hz,2H),3.84(dd,J=12.0,6.8Hz,2H),3.48-3.40(m,2H),2.24(s,3H)。针对C25H24N4O4[M+H]的LCMS(ESI+)预测值=445.18,实验值=445.55。
实例24:N-((3R,4R)-4-(4-(2-羟基-5-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3- 基)异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.76-8.69(m,2H),8.45(s,1H),8.00(d,J=8.1Hz,2H),7.87-7.77(m,4H),7.19(dd,J=9.0,3.1Hz,1H),6.99(s,1H),6.98-6.95(m,1H),4.73-4.66(m,2H),3.75(dd,J=12.1,7.1Hz,2H),3.70(s,3H)。针对C25H24N4O5[M+H]的LCMS(ESI+)预测值=461.18,实验值=461.45。
实例25:2-氨基-N-((3R,4R)-4-(4-(2-羟基-5-甲氧基苯甲酰基)苯甲酰胺基)吡 咯烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.48-8.43(m,1H),7.99(d,J=8.1Hz,2H),7.82(d,J=8.1Hz,2H),7.22(d,J=4.9Hz,1H),7.19(dd,J=9.1,3.1Hz,1H),7.01-6.95(m,2H),4.67(dq,J=19.9,6.9Hz,2H),3.81-3.73(m,2H),3.69(s,3H),3.39-3.33(m,2H)。针对C24H24N6O5[M+H]的LCMS(ESI+)预测值=477.18,实验值=477.44。
实例26:N-((3R,4R)-4-(4-(2-羟基-3-甲基苯甲酰基)苯甲酰胺基)吡咯烷-3-基) 异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.75-8.68(m,2H),8.46(s,1H),8.00(d,J=7.9Hz,2H),7.85-7.79(m,2H),7.77(d,J=8.0Hz,2H),7.46(d,J=7.3Hz,1H),7.37(d,J=8.1Hz,1H),6.83(t,J=7.7Hz,1H),4.73-4.65(m,2H),3.73(dd,J=12.0,7.0Hz,2H),3.29(s,2H),2.30(s,3H)。针对C25H24N4O4[M+H]的LCMS(ESI+)预测值=445.18,实验值=445.44。
实例27:2-氨基-N-((3R,4R)-4-(4-(2-羟基-3-甲基苯甲酰基)苯甲酰胺基)吡咯 烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.49(s,2H),8.46(d,J=4.9Hz,1H),7.99(d,J=8.0Hz,2H),7.76(d,J=7.9Hz,2H),7.45(d,J=7.3Hz,1H),7.37(d,J=8.0Hz,1H),7.22(d,J=4.9Hz,1H),6.83(t,J=7.7Hz,1H),4.66(dq,J=22.0,7.0Hz,2H),3.78-3.67(m,2H),3.27(m,2H),2.30(s,3H)。针对C24H24N6O4[M+H]的LCMS(ESI+)预测值=461.19,实验值=461.42。
实例28:N-((3R,4R)-4-(4-(2-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3- 基)异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.75-8.68(m,2H),8.45(s,1H),7.97(d,J=7.9Hz,2H),7.85-7.77(m,4H),7.22(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),6.90(t,J=8.0Hz,1H),4.67(s,2H),3.91(s,3H),3.73(s,2H)。针对C25H24N4O5[M+H]的LCMS(ESI+)预测值=461.18,实验值=461.55。
实例29:2-氨基-N-((3R,4R)-4-(4-(2-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡 咯烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.48(s,2H),8.46(d,J=5.0Hz,1H),7.96(d,J=7.9Hz,2H),7.81(d,J=7.9Hz,2H),7.22(m,2H),7.06(d,J=8.0Hz,1H),6.91(t,J=8.0Hz,1H),4.67(s,2H),3.92(s,3H),3.71(s,2H),3.27(s,1H)。针对C24H24N6O5[M+H]的LCMS(ESI+)预测值=477.18,实验值=477.58。
实例30:N-((3R,4R)-4-(4-(3-氯-2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.74-8.69(m,2H),8.47(s,1H),8.01(dd,J=8.3,1.6Hz,2H),7.85-7.79(m,4H),7.67(d,J=7.8Hz,1H),7.49(d,J=7.9Hz,1H),6.95(dd,J=8.7,7.2Hz,1H),4.71(d,J=6.4Hz,2H),3.76(dd,J=12.0,6.8Hz,2H),3.35(d,J=6.3Hz,2H)。针对C24H21ClN4O4[M+H]的LCMS(ESI+)预测值=465.13,实验值=465.52。
实例31:2-氨基-N-((3R,4R)-4-(4-(3-氯-2-羟基苯甲酰基)苯甲酰胺基)吡咯烷- 3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.48(s,1H),8.46(d,J=4.9Hz,1H),7.99(d,J=7.9Hz,2H),7.81(d,J=7.9Hz,2H),7.71-7.64(m,1H),7.49(dd,J=7.9,1.5Hz,1H),7.21(d,J=5.0Hz,1H),6.95(t,J=8.0Hz,1H),4.63(m,2H),3.69(s,2H),3.25(m,2H)。针对C23H21ClN6O4[M+H]的LCMS(ESI+)预测值=481.13,实验值=481.51。
实例32:N-((3R,4R)-4-(4-(2-羟基苯甲酰基)-2-甲氧基苯甲酰胺基)吡咯烷-3- 基)异烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.76-8.69(m,2H),8.51(s,1H),7.96(d,J=7.8Hz,1H),7.86-7.79(m,2H),7.55(dd,J=8.9,7.4Hz,2H),7.43(d,J=1.4Hz,1H),7.33(d,J=7.9Hz,1H),7.04(d,J=8.4Hz,1H),6.94(t,J=7.6Hz,1H),4.69(q,J=7.3Hz,1H),4.60(q,J=7.2Hz,1H),4.01(s,3H),3.71(dd,J=11.8,7.8Hz,1H),3.65(dd,J=11.9,7.8Hz,1H),3.22(td,J=8.0,3.8Hz,2H)。针对C25H24N4O5[M+H]的LCMS(ESI+)预测值=461.18,实验值=461.60。
实例33:2-氨基-N-((3R,4R)-4-(4-(2-羟基苯甲酰基)-2-甲氧基苯甲酰胺基)吡 咯烷-3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.48(s,1H),8.47(d,J=5.0Hz,1H),7.97(d,J=7.9Hz,1H),7.55(t,J=8.1Hz,2H),7.43(s,1H),7.33(d,J=8.1Hz,1H),7.23(d,J=5.1Hz,1H),7.04(d,J=8.2Hz,1H),6.94(t,J=7.6Hz,1H),4.64(dt,J=22.6,7.3Hz,2H),4.01(s,3H),3.73(ddd,J=31.3,11.9,7.8Hz,2H),3.26(m,2H)。针对C24H24N6O5[M+H]的LCMS(ESI+)预测值=477.18,实验值=477.61。
实例34:N-((3R,4R)-4-(3-氯-4-(2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.75-8.69(m,2H),8.48(s,1H),8.04(d,J=1.6Hz,1H),7.94(d,J=7.8Hz,1H),7.83-7.79(m,2H),7.63-7.53(m,2H),7.22(d,J=7.9Hz,1H),7.05(d,J=8.4Hz,1H),6.89(t,J=7.6Hz,1H),4.66(t,J=5.7Hz,2H),3.68(dd,J=12.4,6.4Hz,2H),3.28-3.21(m,2H)。针对C24H21ClN4O4[M+H]的LCMS(ESI+)预测值=465.13,实验值=465.52。
实例35:2-氨基-N-((3R,4R)-4-(3-氯-4-(2-羟基苯甲酰基)苯甲酰胺基)吡咯烷- 3-基)嘧啶-4-甲酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.49(s,1H),8.46(d,J=4.8Hz,1H),8.04(s,1H),7.93(d,J=8.0Hz,1H),7.63-7.54(m,2H),7.22(d,J=5.9Hz,2H),7.05(d,J=8.4Hz,1H),6.89(t,J=7.6Hz,1H),4.68-4.60(m,2H),3.67(m,2H),3.25(m,2H)。针对C23H21ClN6O4[M+H]的LCMS(ESI+)预测值=481.13,实验值=481.54。针对C25H24N4O4[M+H]的LCMS(ESI+)预测值=445.18,实验值=445.55。
实例36:N-((3R,4R)-4-(2-氯-4-(2-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.74-8.69(m,2H),8.46(s,1H),7.86-7.79(m,2H),7.78(d,J=1.4Hz,1H),7.69(d,J=7.7Hz,1H),7.63(d,J=7.9Hz,1H),7.55(dd,J=8.6,6.9Hz,1H),7.49(d,J=8.0Hz,1H),7.03(d,J=8.4Hz,1H),6.96(t,J=7.6Hz,1H),4.66(dq,J=25.7,7.2Hz,2H),3.65(ddd,J=30.6,11.9,7.4Hz,2H),3.23-3.15(m,2H)。针对C24H21ClN4O4[M+H]的LCMS(ESI+)预测值=465.13,实验值=465.52。
实例37:N-((3R,4R)-4-(4-(2-羟基苯甲酰基)-3-甲基苯甲酰胺)吡咯烷-3-基)异 烟酰胺。
根据一般程序2制备。1H NMR(500MHz,甲醇-d4)δ8.72(d,J=5.2Hz,2H),8.48(s,1H),7.86-7.76(m,4H),7.57(t,J=7.7Hz,1H),7.41(d,J=7.9Hz,1H),7.23(d,J=8.1Hz,1H),7.05(d,J=8.4Hz,1H),6.87(t,J=7.5Hz,1H),4.65(d,J=7.5Hz,2H),3.68(dd,J=12.6,6.7Hz,2H),3.26-3.20(m,2H),2.33(s,3H)。
实例38:4-(乙氧基甲氧基)-2-氟-1-甲氧基苯。
在室温下,向圆底烧瓶中装入3-氟-4-甲氧基苯酚(5.0g,0.035mol)和CH2Cl2(50mL)。将这种溶液冷却到0℃且接着添加二异丙基乙胺(12.2mL,0.070mol),随后添加(氯甲氧基)乙烷(6.52mL,0.070mol)。使所得溶液升温到室温且通过LC-MS监测。在24h之后,溶液依序用水和NaHCO3洗涤。将有机部分浓缩且在硅胶(40g,己烷/EtOAc梯度0%-20%)上纯化以得到不经进一步纯化即使用的4-(乙氧基甲氧基)-2-氟-1-甲氧基苯。1H NMR(500MHz,氯仿-d)δ6.93-6.81(m,2H),6.80-6.72(m,1H),5.14(s,2H),3.85(s,3H),3.72(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H)。
4-((6-(乙氧基甲氧基)-2-氟-3-甲氧基苯基)(羟基)甲基)苯甲酸甲酯。
在N2气氛下,向火焰干燥的圆底烧瓶中装入4-(乙氧基甲氧基)-2-氟-1-甲氧基苯(1.5g,7.49mmol)和无水THF(25mL)。将溶液在干冰/丙酮浴中冷却且接着用nBuLi(4.48mL的2.5M己烷溶液,11.2mmol)缓慢处理。在低温搅拌两小时之后,溶液用4-甲酰基苯甲酸甲酯(1.85mL,11.2mmol)于无水THF(5mL)中的溶液缓慢处理。使所得混合物缓慢升温到室温且通过LC-MS监测。完成后,溶液用乙酸乙酯稀释且依序用水和盐水洗涤。浓缩得到3.36g的黄色油状物,从而接着在硅胶(40g,己烷/EtOAc梯度12%-100%)上纯化以得到4-((6-(乙氧基甲氧基)-2-氟-3-甲氧基苯基)(羟基)甲基)苯甲酸甲酯。1H NMR(500MHz,氯仿-d)δ7.97(d,J=8.5Hz,2H),7.43(d,J=8.1Hz,2H),6.86(m,2H),6.25(d,J=11.2Hz,1H),5.08(d,J=6.9Hz,1H),4.98(d,J=6.9Hz,1H),3.89(s,3H),3.87(s,3H),3.53-3.29(m,2H),1.09(t,J=7.0Hz,3H)。
4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸甲酯。
在室温下,向圆底烧瓶中装入4-((6-(乙氧基甲氧基)-2-氟-3-甲氧基苯基)(羟基)甲基)苯甲酸甲酯(2.13g,5.85mmol)和CH2Cl2(40mL)。接着添加戴斯-马丁高碘烷(Dess-Martin Periodinane)(3.72g,8.77mmol)且将所得浅黄色悬浮液搅拌30min。溶液用二氯甲烷稀释且用NaHCO3洗涤。浓缩和硅胶(40g,己烷/EtOAc梯度6%-50%)上的纯化得到4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸甲酯。1H NMR(500MHz,氯仿-d)δ8.11(d,J=8.5Hz,2H),7.91(d,J=8.5Hz,2H),7.07-6.95(m,2H),5.05(s,2H),3.95(s,3H),3.89(s,3H),3.51(q,J=7.1Hz,2H),1.11(t,J=7.1Hz,3H)。
4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸。
向小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸甲酯(1.0g,2.76mmol)、THF(9mL)和水(3mL)。添加LiOH(264mg,11.0mmol)且将所得混合物在60℃下搅拌30min。溶液接着用乙酸乙酯稀释且用10%柠檬酸溶液洗涤。浓缩有机部分,得到4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸。1H NMR(500MHz,DMSO-d6)δ8.10(d,J=8.4Hz,2H),7.88(d,J=8.3Hz,2H),7.32(t,J=9.5Hz,1H),7.08(dd,J=9.2,1.4Hz,1H),5.11(s,2H),3.86(s,3H),3.36(通过溶剂遮挡,m,2H),0.98(t,J=7.1Hz,3H)。
实例39:N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)乙基)异烟酰胺。
在室温下,向反应小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(75mg,0.215mmol)和MeCN(2mL)。向这种溶液中依序添加三乙胺(60μL,0.430mmol)、(2-氨基乙基)氨基甲酸叔丁酯(35mg,0.215mmol)和HATU(82mg,0.215mmol)。在通过LCMS完成后,溶液用水稀释且用EtOAc萃取两次。将溶液在真空中浓缩,且接着溶解于THF(3mL)中。这种溶液接着用1N HCl(3mL)处理且使其升温到65℃。在通过LCMS完成后,将溶液冷却到室温且用EtOAc稀释。有机部分接着用水、NaHCO3和盐水溶液洗涤。EtOAc溶液经硫酸钠干燥且浓缩以得到131mg呈油状的N-(2-氨基乙基)-4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺,其不经进一步纯化即直接使用。将这种油状物溶解于DMF(2mL)中且在室温下用三乙胺(90μL,0.645mmol)处理。添加异烟酸(32mg,0.258mmol)、随后HATU(98mg,0.258mmol)并搅拌15min。LCMS指示苯酚的一些酰化,因此添加LiOH(20mg于1mL H2O中)并搅拌2h。水溶液在HPLC上直接纯化以得到N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)乙基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.98(s,1H),8.81(s,1H),8.72(d,J=6.3Hz,2H),7.90(m,4H),7.85-7.80(m,2H),7.13(t,J=9.3Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),3.84(s,3H),3.68-3.63(m,4H)。针对C23H20FN3O5[M+H]的LCMS(ESI+)预测值=438.14,实验值=438.36。
实例40:N-(2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)乙基)异烟酰胺。
在室温下,向小瓶中装入N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)乙基)异烟酰胺(4.4mg)和DMF(1mL)。溶液用碘甲烷(0.6μL,以DMF溶液形式添加)和过量碳酸钾处理。将溶液搅拌18h,用水淬灭且在HPLC上直接纯化以得到N-(2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)乙基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.75(d,J=5.1Hz,2H),7.92(d,J=8.2Hz,2H),7.86(d,J=8.3Hz,2H),7.68(d,J=5.1Hz,2H),7.54(s,1H),7.08-7.00(m,2H),6.69(dd,J=9.1,1.5Hz,1H),3.88(s,3H),3.80-3.71(m,4H),3.68(s,3H)。针对C24H22FN3O5[M+H]的LCMS(ESI+)预测值=452.16,实验值=452.39。
实例41:N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环庚基)异烟酰胺。
将HATU(114mg,0.300mmol)添加到((1R,2R)-2-氨基环庚基)氨基甲酸叔丁酯(69mg,0.300mmol)、异烟酸(37mg,0.300mmol)和三乙胺(84μL,0.600mmol)于乙腈(1.5mL)中的室温溶液中。5min之后,溶液用水淬灭且用EtOAc萃取。有机萃取物用水洗涤三次且在真空中浓缩。接着将残余物溶解于含4N HCl的二恶烷(2mL)中,从而形成沉淀物。浓缩得到不经进一步纯化即使用的固体。将由此形成的N-((1R,2R)-2-氨基环庚基)异烟酰胺(0.200mmol)溶解于乙腈(1.5mL)和DMF(1.0mL)的混合物中。添加三乙胺(167μL,1.2mmol),随后添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(70mg,0.200mmol)和HATU(76mg,0.200mmol)。将所得溶液在室温下搅拌30min且接着用水淬灭。溶液用EtOAc萃取两次且接着在真空中浓缩。随后使THF(1mL)和1N HCl(1mL)中的溶解液升温到55℃持续3h。接着将溶液冷却到室温且分配于水性NaHCO3与EtOAc之间。将有机部分浓缩且在硅胶(12g,己烷/EtOAc梯度25%-100%)上纯化以得到N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环庚基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ10.23(s,1H),8.70(d,J=5.5Hz,2H),7.76(d,J=8.2Hz,2H),7.71(dd,J=8.5,2.3Hz,2H),7.67(s,2H),7.21(t,J=9.2Hz,1H),6.83(dd,J=9.2,1.8Hz,1H),6.66(s,1H),4.18(m,2H),3.84(s,3H),2.06(m,2H),1.88-1.72(m,4H),1.60(m,4H)。针对C28H28FN3O5[M+H]的LCMS(ESI+)预测值=506.20,实验值=506.42。
实例42:N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环庚基)异烟酰胺。
在室温下,向小瓶中装入N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环庚基)异烟酰胺(5.0mg)和DMF(0.5mL)。溶液用碘甲烷(0.6μL,以DMF溶液形式添加)和过量碳酸钾处理。将溶液搅拌2h,用水淬灭且在HPLC上直接纯化以得到N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环庚基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.73-8.65(m,2H),7.86(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.61(d,J=5.5Hz,2H),7.21(d,J=7.6Hz,1H),7.02(t,J=9.2Hz,1H),6.71(d,J=8.2Hz,1H),6.68(dd,J=9.0,1.6Hz,1H),4.25-4.06(m,2H),3.88(s,3H),3.66(s,3H),2.03(m,2H),1.75(m,8H)。针对C29H30FN3O5[M+H]的LCMS(ESI+)预测值=520.22,实验值=520.47。
实例43:N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环庚基)异烟酰胺。
将由此形成的N-((1R,2R)-2-氨基环庚基)异烟酰胺(0.100mmol)溶解于乙腈(1.0mL)和DMF(1.0mL)的混合物中。添加三乙胺(84μL,0.6mmol),随后添加4-(苯甲酰基)苯甲酸(23mg,0.100mmol)和HATU(38mg,0.100mmol)。将所得溶液在室温下搅拌120min且接着用水淬灭。溶液在HPLC上直接纯化以得到N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环庚基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.69(d,J=6.1Hz,2H),7.80(q,J=8.4Hz,4H),7.77-7.73(m,2H),7.65-7.56(m,3H),7.48(t,J=7.8Hz,2H),7.32(d,J=7.6Hz,1H),6.95(d,J=8.0Hz,1H),4.24-4.06(m,2H),2.11-1.98(m,2H),1.86-1.66(m,4H),1.62(m,4H)。针对C27H27N3O3[M+H]的LCMS(ESI+)预测值=442.21,实验值=442.46。
实例44:N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环己基)异烟酰胺。
将HATU(114mg,0.300mmol)添加到((1R,2R)-2-氨基环己基)氨基甲酸叔丁酯(64mg,0.300mmol)、异烟酸(37mg,0.300mmol)和三乙胺(84μL,0.600mmol)于乙腈(1.5mL)中的室温溶液中。5min之后,溶液用水淬灭且用EtOAc萃取。有机萃取物用水洗涤三次且在真空中浓缩。接着,将残余物溶解于含4N HCl的二恶烷(4mL)中并搅拌20min。浓缩得到不经进一步纯化即使用的白色固体(152mg)。将由此形成的N-((1R,2R)-2-氨基环己基)异烟酰胺(0.150mmol)溶解于DMF(1.5mL)中。添加三乙胺(84μL,0.60mmol),随后添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(52mg,0.150mmol)和HATU(57mg,0.150mmol)。将所得溶液在室温下搅拌30min且接着用水淬灭。溶液用EtOAc萃取两次且接着在真空中浓缩。随后使THF(2mL)和1N HCl(2mL)中的溶解液升温到55℃持续2h。接着将溶液冷却到室温且分配于水性NaHCO3与EtOAc之间。将有机部分浓缩且在反相HPLC上纯化以得到N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环己基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ10.25(s,1H),8.71(d,J=5.2Hz,2H),7.79(d,J=8.3Hz,2H),7.76-7.71(m,2H),7.67(s,2H),7.21(t,J=9.1Hz,1H),6.83(dd,J=9.2,1.9Hz,1H),6.57(s,1H),4.01(m,2H),3.84(s,3H),2.31(m,1H),2.21(m,1H),1.89(m,2H),1.48(m,4H)。针对C27H26FN3O5[M+H]的LCMS(ESI+)预测值=492.19,实验值=492.43。
实例45:N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环己基)异烟酰胺。
在室温下,向小瓶中装入N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环己基)异烟酰胺(4.5mg)和DMF(0.5mL)。溶液用碘甲烷(以DMF溶液形式添加1当量)和过量碳酸钾处理。将溶液搅拌18h,用水淬灭且在HPLC上直接纯化以得到N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环己基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.70(s,2H),7.87(d,J=8.3Hz,2H),7.76(d,J=8.4Hz,2H),7.60(s,2H),7.11(d,J=7.5Hz,1H),7.02(t,J=9.2Hz,1H),6.68(dd,J=9.1,1.6Hz,1H),6.60(d,J=8.0Hz,1H),4.00(m,2H),3.88(s,3H),3.66(s,3H),2.32-2.15(m,2H),1.87(m,2H),1.44(m,4H)。针对C28H28FN3O5[M+H]的LCMS(ESI+)预测值=506.20,实验值=506.45。
实例46:N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环己基)异烟酰胺。
将N-((1R,2R)-2-氨基环己基)异烟酰胺(0.150mmol)溶解于DMF(1.5mL)中。添加三乙胺(84μL,0.60mmol),随后添加4-(苯甲酰基)苯甲酸(34mg,0.150mmol)和HATU(57mg,0.150mmol)。将所得溶液在室温下搅拌15min且接着用水淬灭。用EtOAc萃取(两次),随后浓缩得到残余物,其在硅胶(12g己烷/EtOAc梯度15%-100%)上纯化以得到N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环己基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.72(d,J=6.1Hz,2H),7.81(s,4H),7.79-7.73(m,2H),7.67(d,J=5.2Hz,2H),7.61(t,J=7.5Hz,1H),7.48(t,J=7.7Hz,2H),7.19(d,J=7.4Hz,1H),6.60(d,J=8.0Hz,1H),4.11-3.92(m,2H),2.38-2.18(m,2H),1.89(m,2H),1.47(m,4H)。针对C26H25N3O3[M+H]的LCMS(ESI+)预测值=428.19,实验值=428.43。
实例47:N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺。
将HATU(114mg,0.300mmol)添加到((1R,2R)-2-氨基环戊基)氨基甲酸叔丁酯(60mg,0.300mmol)、异烟酸(37mg,0.300mmol)和三乙胺(84μL,0.600mmol)于乙腈(1.5mL)中的室温溶液中。30min之后,溶液用水淬灭且用EtOAc萃取。有机萃取物用水洗涤三次且在真空中浓缩。接着将残余物溶解于含4N HCl的二恶烷(2mL)中并搅拌18h。真空浓缩得到不经进一步纯化即使用的固体。将由此形成的N-((1R,2R)-2-氨基环戊基)异烟酰胺(0.200mmol)溶解于DMF(1.5mL)中。添加三乙胺(111μL,0.80mmol),随后添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(70mg,0.200mmol)和HATU(76mg,0.200mmol)。将所得溶液在室温下搅拌3h且接着用水淬灭。溶液用EtOAc萃取两次且接着在真空中浓缩。随后使THF(1mL)和1N HCl(2mL)中的溶解液升温到60℃持续2h。接着将溶液冷却到室温且分配于水性NaHCO3与EtOAc之间。将有机部分浓缩且在硅胶(12g,己烷/EtOAc梯度25%-100%)上纯化以得到N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ10.26(s,1H),8.74(d,J=6.2Hz,2H),7.87(d,J=8.5Hz,2H),7.76(dd,J=8.4,2.4Hz,2H),7.73-7.68(m,2H),7.62(d,J=5.6Hz,1H),7.21(t,J=9.2Hz,1H),6.93(d,J=6.5Hz,1H),6.83(dd,J=9.2,1.9Hz,1H),4.41-4.29(m,1H),4.18(m,1H),3.83(s,3H),2.42(ddq,J=58.7,13.5,6.8Hz,2H),1.92(m,2H),1.72-1.59(m,2H)。针对C26H24FN3O5[M+H]的LCMS(ESI+)预测值=478.17,实验值=478.44。
实例48:N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺。
在室温下,向小瓶中装入N-((1R,2R)-2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺(6.2mg)和DMF(1.0mL)。溶液用碘甲烷(以DMF溶液形式添加1当量)和过量碳酸钾处理。将溶液搅拌23h,用水淬灭且在HPLC上直接纯化以得到N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.74(d,J=6.1Hz,2H),7.91(d,J=8.4Hz,2H),7.85(d,J=8.4Hz,2H),7.65(d,J=6.1Hz,2H),7.51(d,J=5.7Hz,1H),7.03(t,J=9.2Hz,1H),6.93(d,J=6.4Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),4.32(ddd,J=17.5,10.4,7.3Hz,1H),4.23-4.12(m,1H),3.88(s,3H),3.67(s,3H),2.46(dq,J=13.3,6.8Hz,1H),2.35(dq,J=13.4,6.8Hz,1H),1.97-1.86(m,2H),1.74-1.55(m,4H)。针对C27H26FN3O5[M+H]的LCMS(ESI+)预测值=492.19,实验值=492.45。
实例49:N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环戊基)异烟酰胺。
将N-((1R,2R)-2-氨基环戊基)异烟酰胺(0.100mmol)溶解于DMF(1.5mL)中。添加三乙胺(84μL,0.60mmol),随后添加4-(苯甲酰基)苯甲酸(23mg,0.100mmol)和HATU(38mg,0.100mmol)。将所得溶液在室温下搅拌70min且接着用水淬灭。用EtOAc萃取(两次),随后浓缩得到残余物,其在硅胶(12g己烷/EtOAc梯度25%-80%)上纯化以得到N-((1R,2R)-2-(4-苯甲酰基苯甲酰胺基)环戊基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.75(d,J=5.1Hz,2H),7.89(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H),7.81-7.75(m,2H),7.75-7.67(m,2H),7.65-7.57(m,2H),7.49(t,J=7.7Hz,2H),6.96(d,J=6.5Hz,1H),4.36(m,1H),4.25-4.12(m,1H),2.47(dq,J=13.3,6.8Hz,1H),2.37(dq,J=13.4,6.8Hz,1H),1.91(m,2H),1.67(m,2H)。针对C25H23N3O3[M+H]的LCMS(ESI+)预测值=414.18,实验值=414.40。
实例50:N-((1R,2R)-1-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺。
将HATU(114mg,0.300mmol)添加到((1R,2R)-2-氨基-2,3-二氢-1H-茚-1-基)氨基甲酸叔丁酯(75mg,0.300mmol)、异烟酸(37mg,0.300mmol)和三乙胺(84μL,0.600mmol)于乙腈(1.5mL)中的室温溶液中。30min之后,溶液用水淬灭且用EtOAc萃取。有机萃取物用水洗涤三次且在真空中浓缩。接着将残余物溶解于含4N HCl的二恶烷(2mL)中并搅拌18h。真空浓缩得到不经进一步纯化即使用的固体。将由此形成的N-((1R,2R)-1-氨基-2,3-二氢-1H-茚-2-基)异烟酰胺(0.200mmol)溶解于MeCN(2.0mL)和DMF(1.5mL)中。添加三乙胺(111μL,0.80mmol),随后添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(70mg,0.200mmol)和HATU(76mg,0.200mmol)。将所得溶液在室温下搅拌3h且接着用水淬灭。溶液用EtOAc萃取两次且接着在真空中浓缩。随后使THF(1mL)和1N HCl(2mL)中的溶解液升温到60℃持续2h。接着将溶液冷却到室温且分配于水性NaHCO3与EtOAc之间。将有机部分浓缩且在硅胶(5g,己烷/EtOAc梯度20%-100%)上纯化以得到N-((1R,2R)-1-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ10.30(s,1H),8.85-8.74(m,2H),8.13(s,1H),7.94(d,J=8.3Hz,2H),7.88-7.75(m,4H),7.34(m,4H),7.22(t,J=9.1Hz,1H),6.90-6.82(m,2H),5.76(t,J=8.5Hz,1H),4.48(q,J=9.5,6.7Hz,1H),3.84(s,3H),3.79(dd,J=15.3,7.7Hz,1H),2.99-2.86(m,1H)。针对C30H24FN3O5[M+H]的LCMS(ESI+)预测值=526.17,实验值=526.45。
实例51:N-((1R,2R)-1-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺。
在室温下,向小瓶中装入N-((1R,2R)-1-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺(5.0mg)和DMF(1.0mL)。溶液用碘甲烷(以DMF溶液形式添加1当量)和过量碳酸钾处理。将溶液搅拌2h,用水淬灭且在HPLC上直接纯化以得到N-((1R,2R)-2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)环戊基)异烟酰胺。1HNMR(500MHz,氯仿-d)δ8.78(d,J=5.6Hz,2H),8.09(s,1H),7.95(d,J=8.3Hz,2H),7.92(d,J=8.4Hz,2H),7.80(d,J=5.1Hz,2H),7.39-7.29(m,4H),7.04(t,J=9.2Hz,1H),6.85(d,J=7.7Hz,1H),6.69(dd,J=9.1,1.6Hz,1H),5.74(t,J=8.5Hz,1H),4.53-4.43(m,1H),3.89(s,3H),3.78(dd,J=15.5,7.6Hz,1H),3.68(s,3H),2.91(dd,J=15.5,9.9Hz,1H)。针对C31H26FN3O5[M+H]的LCMS(ESI+)预测值=540.19,实验值=540.48。
实例52:N-((1R,2R)-1-(4-苯甲酰基苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺。
将N-((1R,2R)-1-氨基-2,3-二氢-1H-茚-2-基)异烟酰胺(0.100mmol)溶解于DMF(1.5mL)中。添加三乙胺(84μL,0.60mmol),随后添加4-(苯甲酰基)苯甲酸(23mg,0.100mmol)和HATU(38mg,0.100mmol)。将所得溶液在室温下搅拌60min且接着用水淬灭。用EtOAc萃取(两次),随后浓缩得到残余物,其在硅胶(5g己烷/EtOAc梯度25%-100%)上纯化以得到N-((1R,2R)-1-(4-苯甲酰基苯甲酰胺基)-2,3-二氢-1H-茚-2-基)异烟酰胺。1H NMR(500MHz,氯仿-d)δ8.71(d,J=6.1Hz,2H),8.12(d,J=5.3Hz,1H),7.96(d,J=8.3Hz,2H),7.81(d,J=8.3Hz,2H),7.79-7.75(m,2H),7.71-7.67(m,2H),7.65-7.59(m,1H),7.49(t,J=7.8Hz,2H),7.36(d,J=7.9Hz,1H),7.31(t,J=6.6Hz,1H),7.29-7.27(m,1H),7.24(d,J=7.2Hz,1H),5.75(t,J=8.6Hz,1H),4.48(tdd,J=9.6,7.6,5.3Hz,1H),3.62(dd,J=15.4,7.6Hz,1H),2.88(dd,J=15.4,9.9Hz,1H)。针对C29H23N3O3[M+H]的LCMS(ESI+)预测值=462.18,实验值=462.43。
实例53:(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。
将HATU(114mg,0.300mmol)添加到哌嗪-1-甲酸叔丁酯(56mg,0.300mmol)、异烟酸(37mg,0.300mmol)和三乙胺(84μL,0.600mmol)于乙腈(1.5mL)中的室温溶液中。30min之后,溶液用水淬灭且用EtOAc萃取。有机萃取物用水洗涤三次且在真空中浓缩。接着将残余物溶解于含4N HCl的二恶烷(1mL)中并搅拌30min。真空浓缩得到不经进一步纯化即使用的固体。将由此形成的哌嗪-1-基(吡啶-4-基)甲酮(0.200mmol)溶解于MeCN(2.0mL)和DMF(1.0mL)中。添加三乙胺(111μL,0.80mmol),随后添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(70mg,0.200mmol)和HATU(76mg,0.200mmol)。将所得溶液在室温下搅拌18h且接着用水淬灭。溶液用EtOAc萃取两次且接着在真空中浓缩。随后使THF(1mL)和1NHCl(2mL)中的溶解液升温到60℃持续0.5h。接着将溶液冷却到室温且分配于水性NaHCO3与EtOAc之间。将有机部分浓缩且在硅胶(5g,己烷/EtOAc梯度0%-20%)上纯化以得到(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。1HNMR(500MHz,氯仿-d)δ10.23(s,1H),8.73(s,2H),7.77(s,2H),7.50(d,J=7.8Hz,2H),7.30(d,J=5.0Hz,2H),7.22(t,J=9.2Hz,1H),6.84(dd,J=9.2,1.8Hz,1H),3.85(s,3H),3.84(br,4H),3.48(br,4H)。针对C25H22FN3O5[M+H]的LCMS(ESI+)预测值=464.16,实验值=464.39。
实例54:(4-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。
在室温下,向小瓶中装入(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮(5.0mg)和DMF(1.0mL)。溶液用碘甲烷(以DMF溶液形式添加1当量)和过量碳酸钾处理。将溶液搅拌2h,用水淬灭且在HPLC上直接纯化以得到(4-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。1H NMR(500MHz,氯仿-d)δ8.73(s,2H),7.91(s,2H),7.48(d,J=7.6Hz,2H),7.30(s,2H),7.03(t,J=9.2Hz,1H),6.69(d,J=8.8Hz,1H),3.88(s,3H),3.75(br,4H),3.70(s,3H),3.49(br,4H)。针对C26H24FN3O5[M+H]的LCMS(ESI+)预测值=478.17,实验值=478.41。
实例55:(4-(4-苯甲酰基苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。
将哌嗪-1-基(吡啶-4-基)甲酮(0.100mmol)溶解于DMF(1.5mL)中。添加三乙胺(84μL,0.60mmol),随后添加4-(苯甲酰基)苯甲酸(23mg,0.100mmol)和HATU(38mg,0.100mmol)。将所得溶液在室温下搅拌85min且接着用水淬灭。用EtOAc萃取(两次),随后浓缩得到残余物,其在反相上纯化以得到(4-(4-苯甲酰基苯甲酰基)哌嗪-1-基)(吡啶-4-基)甲酮。1H NMR(500MHz,氯仿-d)δ8.74(s,2H),7.85(s,2H),7.80(d,J=7.6Hz,2H),7.62(t,J=7.4Hz,1H),7.51(m,4H),7.34(d,J=4.8Hz,2H),3.79(br,4H),3.49(br,4H)。针对C24H21N3O3[M+H]的LCMS(ESI+)预测值=400.16,实验值=400.38。
实例56:N-((3R,4R)-4-(4-苯甲酰基苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
将4-苯甲酰苯甲酸和HATU称量于20mL小瓶中且添加2ml无水MeCN,随后添加三乙胺并且将混合物在23℃下搅拌10min。添加(3R,4R)-3,4-二氨基吡咯烷-1-甲酸叔丁酯于2ml无水MeCN中的溶液且使混合物在23℃下搅拌1h。等分试样的LCMS分析显示起始酸以及单酰化和双酰化产物的完全转化。反应混合物用乙酸乙酯稀释且用饱和碳酸氢钠溶液和盐水萃取。浓缩有机层且残余物通过制备型TLC纯化并用甲醇/乙酸乙酯(0-20%)洗脱以获得胺,(3R,4R)-3-氨基-4-(4-苯甲酰基苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(25mg,28%)。1HNMR(400MHz,甲醇-d4)δ8.68(d,J=6.1Hz,2H),8.27(s,1H),7.94(d,J=8.4Hz,2H),7.82(d,J=8.4Hz,2H),7.79-7.75(m,4H),7.69-7.62(m,1H),7.53(t,J=7.7Hz,2H),4.80-4.68(m,2H),3.98-3.86(m,2H),3.42-3.33(m,2H)。向含(3R,4R)-3-氨基-4-(4-苯甲酰基苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(25mg,61.06μmol)的2ml无水二氯甲烷中添加三乙胺、DMAP和异烟酰氯盐酸盐(16.3mg,91.6μmol)且将混合物在23℃下搅拌2h。反应混合物用2ml二氯甲烷稀释且用饱和碳酸氢钠洗涤三次。合并且蒸发有机层且残余物通过RP-HPLC纯化以获得呈无色油状的产物(3R,4R)-3-(4-苯甲酰基苯甲酰胺基)-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯(7mg,22%)。向(3R,4R)-3-(4-苯甲酰基苯甲酰胺基)-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯中添加1ml 0.5M HCl且将混合物在70℃下加热1h。蒸发溶剂且添加0.5mL甲醇并蒸发(2×),并且在真空下干燥后获得呈白色固体状的产物N-((3R,4R)-4-(4-苯甲酰基苯甲酰胺基)吡咯烷-3-基)异烟酰胺的盐酸盐(6mg,98%);1H NMR(500MHz,甲醇-d4)δ8.92(d,J=6.6Hz,2H),8.62(d,J=6.7Hz,2H),8.06(d,J=8.3Hz,2H),7.81(d,J=8.4Hz,2H),7.74(d,J=6.9Hz,2H),7.62-7.58(m,2H),7.47(t,J=7.8Hz,2H),4.91-4.81(m,2H),3.94(ddd,J=12.6,7.2,1.8Hz,2H),3.65(dt,J=12.4,4.3Hz,2H);针对C24H22N4O3[M+H]的LCMS(ESI+)计算值=415.17,实验值=415.44。
实例57:N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)苯基)异烟酰胺。
向异烟酸(48mg,0.39mmol)中装入2mL乙腈、0.11mL(0.78mmol)三乙胺、177mg(0.47mmol)HATU,且接着装入81mg(0.39mmol)2-BOC-氨基苯胺(CAS号146551-75-4)。1.5h之后,LCMS显示良好的转化率且浓缩混合物。残余物用1mL二氯甲烷和1mL三氟乙酸处理。15分钟之后,LCMS显示良好的转化率且将混合物浓缩为橙色液体。将这个样品划分成两半,其中的一半用于合成下文所描述的N-(2-(4-苯甲酰基苯甲酰胺基)苯基)异烟酰胺。将剩余部分(大约0.2mmol)与1mL乙腈、0.27mL(2mmol)三乙胺、91mg(0.24mmol)HATU和70mg(0.2mmol)4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸合并。在搅拌18h之后,混合物用5mL水稀释且用三份2mL的乙酸乙酯萃取。使有机物通过硫酸镁的栓塞且浓缩为棕色油状物(332mg),其通过快速色谱法(25mL硅胶,50%乙酸乙酯/己烷,乙酸乙酯,5%甲醇/乙酸乙酯)部分纯化以返回128mg的黄色薄膜。将这个样品溶解于2mL四氢呋喃中且用1mL1N HCl处理。在搅拌17h之后,LCMS显示50%转化率,因此将温度增加到60℃。6.5h之后,混合物用8mL水稀释且pH用3.75N NaOH调节到约8。将所得含白色固体的黄色溶液浓缩且用三份2mL的20%甲醇/氯仿萃取。过滤有机物且将黄色滤液浓缩为黄色固体,127mg。这个样品通过反相制备型HPLC纯化以得到所需化合物,20.8mg。1H NMR(500MHz,甲醇-d4)δ8.79-8.65(m,2H),8.04(d,J=8.1Hz,2H),7.92(d,J=8.3Hz,2H),7.89-7.79(m,2H),7.67(ddd,J=22.5,6.2,3.7Hz,2H),7.38(dd,J=6.1,3.5Hz,2H),7.13(t,J=9.3Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),3.84(s,3H)。针对C27H20FN3O5[M+H]的LCMS(ESI+)预测值=486.14,实验值=486.39。
实例58:N-(2-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)苯基)异烟酰胺。
由0.20mL碘甲烷和20mL的N,N-二甲基甲酰胺制备储备溶液。向N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)苯基)异烟酰胺(11.9mg,0.025mmol,上文所描述的合成)的一部分中装入碳酸钾(10.4mg,0.075mmol)、0.8mL DMF和0.2mL递送2μL碘甲烷(0.032mmol)的储备溶液。在3天之后,混合物用8mL水稀释且用2份、1份和1mL份的20%甲醇/氯仿萃取。通过硫酸镁的栓塞过滤有机物且将其浓缩为70mg的橙色油状物。这个样品通过反相制备型HPLC纯化以得到呈甲酸盐形式的所需化合物,白色薄膜,2.3mg。1H NMR(500MHz,甲醇-d4)δ8.77-8.65(m,2H),8.49(s,1H),8.10-7.98(m,2H),7.96-7.79(m,4H),7.68(dd,J=6.1,3.5Hz,1H),7.64(dt,J=7.4,3.7Hz,1H),7.38(dd,J=6.0,3.6Hz,2H),7.22(t,J=9.4Hz,1H),6.88(dd,J=9.1,1.6Hz,1H),3.88(s,3H),3.67(s,3H)。针对C28H22FN3O5[M+H]的LCMS(ESI+)预测值=500.15,实验值=500.43。
实例59:N-(2-(4-苯甲酰基苯甲酰胺基)苯基)异烟酰胺。
将合成N-(2-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)苯基)异烟酰胺中衍生自异烟酸的中间物的剩余部分(大约0.2mmol)与1mL乙腈、0.27mL(2mmol)三甲胺、91mg(0.24mmol)HATU和45mg(0.2mmol)的4-(苯甲酰基)苯甲酸合并。LCMS显示在1h之后完成;因此,在1.3h之后向混合物中装入4mL水。在搅拌隔夜之后,将黄色固体(81mg)收集且通过反相制备型HPLC纯化以得到13.4mg所需化合物。1H NMR(500MHz,甲醇-d4)δ8.16(d,J=8.1Hz,4H),7.81(dd,J=19.6,7.9Hz,8H),7.70(t,J=7.4Hz,2H),7.57(t,J=7.7Hz,4H)。针对C26H19N3O3[M+H]的LCMS(ESI+)预测值=422.14,实验值=422.38。
实例60:N-(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡啶-3-基)异烟酰胺。
向异烟酸(49mg,0.40mmol)中装入2mL乙腈、0.11mL(0.80mmol)三乙胺、183mg(0.48mmol)HATU且接着装入84.1mg(0.40mmol)3-氨基-4-BOC-氨基吡啶(CAS号183311-28-6)。在30分钟之后,LCMS显示大约75%转化率且在1h之后浓缩混合物。残余物用1mL二氯甲烷和1mL三氟乙酸处理。17h之后,LCMS显示良好转化率且将混合物浓缩为橙色悬浮液1克。将这个样品划分成两半,其中的一半用于合成下文所描述的N-(2-(4-N-(4-(4-苯甲酰基苯甲酰胺基)吡啶-3-基)异烟酰胺。将剩余部分(大约0.2mmol)与1mL乙腈、0.28mL(2mmol)三乙胺、91mg(0.24mmol)HATU和70mg(0.2mmol)4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸合并。LCMS在4和24h之后显示反应在约50%转化率停止,因此添加另一0.28mL三甲胺和91mg HATU。在额外4小时之后,LCMS指示良好转化率,且混合物用10mL水稀释并用三份2mL的乙酸乙酯萃取。使有机物通过硫酸镁的栓塞且浓缩为橙色油状物(294mg),其通过快速色谱法(25mL硅胶,2%到5%甲醇/氯仿)部分纯化以返回73mg的黄色油状物。将这个样品溶解于1mL四氢呋喃中且用1mL 1N HCl处理。在60℃下搅拌1.25h之后,混合物用8mL水稀释且pH用大约0.3mL的3.75N NaOH调节到约7。收集所得黄色固体122mg,且通过反相制备型HPLC纯化以得到呈二甲酸盐形式的所需化合物(49.2mg黄色薄膜)。1H NMR(400MHz,甲醇-d4)δ8.82-8.65(m,3H),8.46(d,J=5.6Hz,1H),8.21(s,2H),8.14-7.99(m,3H),7.99-7.84(m,4H),7.13(t,J=9.3Hz,1H),6.68(dd,J=8.9,1.7Hz,1H),3.84(s,3H)。针对C26H19FN4O5[M+H]的LCMS(ESI+)预测值=487.13,实验值=487.36。
实例61:N-(4-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)吡啶-3-基)异烟酰胺。
由0.20mL碘甲烷和20mL的N,N-二甲基甲酰胺制备储备溶液。向N-(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡啶-3-基)异烟酰胺(21.1mg,0.0434mmol,上文所描述的合成)的一部分中装入碳酸钾(18mg,0.13mmol)、0.8mL DMF和0.27mL递送2.7μL碘甲烷(0.043mmol)的储备溶液。在3天之后,混合物用8mL水稀释且用2份、1份和1mL份的20%甲醇/氯仿萃取。通过硫酸镁的栓塞过滤有机物且将其浓缩为110mg的黄色油状物。这个样品通过反相制备型HPLC纯化以得到呈甲酸盐形式的所需化合物,黄色固体,10.2mg。1H NMR(500MHz,甲醇-d4)δ9.24(d,J=1.8Hz,1H),8.81-8.63(m,3H),8.40(dd,J=7.0,1.8Hz,1H),8.24(s,2H),8.12(d,J=8.5Hz,2H),8.02-7.83(m,4H),7.13(t,J=9.3Hz,1H),6.69(dd,J=9.0,1.6Hz,1H),4.24(s,3H),3.84(s,3H)。针对C27H21FN4O5[M+H]的LCMS(ESI+)预测值=501.15,实验值=501.40。
实例62:N-(4-(4-苯甲酰基苯甲酰胺基)吡啶-3-基)异烟酰胺。
将合成上文所描述的N-(4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡啶-3-基)异烟酰胺中衍生自异烟酸的中间物的剩余部分(大约0.2mmol)与1mL乙腈、0.28mL(2mmol)三甲胺、91mg(0.24mmol)HATU和45mg(0.2mmol)的4-(苯甲酰基)苯甲酸合并。LCMS显示在3.5h之后完成。向混合物中装入8mL水且用2份、1份和1mL份的乙酸乙酯萃取。通过硫酸镁的栓塞过滤有机物且将其浓缩为黄色油状物254mg,所述黄色油状物通过反相制备型HPLC纯化以递送呈甲酸盐形式的所需化合物,26.8mg的白色固体。1H NMR(500MHz,甲醇-d4)δ8.84-8.67(m,3H),8.48(d,J=5.6Hz,1H),8.13(d,J=5.6Hz,1H),8.08(d,J=8.7Hz,3H),8.02-7.92(m,2H),7.92-7.84(m,2H),7.86-7.74(m,2H),7.73-7.62(m,1H),7.55(t,J=7.8Hz,2H)。针对C25H18N4O3[M+H]的LCMS(ESI+)预测值=423.14,实验值=423.34。
实例63:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯 烷-3-基)-1H-吡唑-4-甲酰胺。
在室温下,向小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(138mg,0.397mmol)、Et3N(55μL,0.397mmol)和DMF(2.0mL)。接着向这种溶液中添加HATU(151mg,0.397mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4R)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(80mg,0.397mmol)和HCl(4.0M二恶烷溶液,200μL)于DMF(2.0mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h,以得到可分离或直接就地使用的(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(30mg,0.056mmol)、1H-吡唑-4-甲酸(6.3mg,0.056mmol)、Et3N(16μL,0.112mmol)和DMF(500μL)。添加HATU(22mg,0.056mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1mL)和HCl水溶液(1.0M,1mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吡唑-4-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.53(s,1H),8.09(s,2H),7.97(d,J=8.4Hz,2H),7.92(d,J=8.2Hz,2H),7.15(t,J=9.3Hz,1H),6.70(dd,J=9.0,1.7Hz,1H),4.66(h,J=6.4Hz,2H),3.86(s,3H),3.76(td,J=11.8,7.4Hz,2H)甲酸盐。针对C23H22FN5O5[M+H]的LCMS(ESI+)预测值=468.16,实验值=468.45。
实例64:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-5-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(30mg,0.056mmol)、1H-吲唑-6-甲酸(9.0mg,0.056mmol)、Et3N(32μL,0.22mmol)和DMF(500μL)。添加HATU(22mg,0.056mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.5mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.37(s,1H),8.18(s,1H),7.97(d,J=8.2Hz,2H),7.94-7.88(m,3H),7.60(d,J=8.9Hz,1H),7.13(t,J=9.2Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),4.71(m,2H),3.84(s,3H),3.79(m,2H),3.35(m,2H)。针对C27H24FN5O5[M+H]的LCMS(ESI+)预测值=518.18,实验值=518.46。
实例65:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(30mg,0.056mmol)、嘧啶-4-甲酸(7.0mg,0.056mmol)、Et3N(32μL,0.22mmol)和DMF(500μL)。添加HATU(22mg,0.056mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。1H NMR(500MHz,甲醇-d4)δ9.29(s,1H),9.03(d,J=5.1Hz,1H),8.09(d,J=5.0Hz,1H),7.95(d,J=8.2Hz,2H),7.89(d,J=8.3Hz,2H),7.13(t,J=9.3Hz,1H),6.69(d,J=8.9Hz,1H),4.77(m,2H),3.84(m,5H),3.47(ddd,J=16.6,12.1,6.7Hz,2H)。针对C24H22FN5O5[M+H]的LCMS(ESI+)预测值=480.16,实验值=480.42。
实例66:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-2-羟基异烟酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(30mg,0.056mmol)、2-羟基异烟酸(7.8mg,0.056mmol)、Et3N(32μL,0.22mmol)和DMF(500μL)。添加HATU(22mg,0.056mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-2-羟基异烟酰胺。1H NMR(500MHz,甲醇-d4)δ7.95(d,J=8.3Hz,2H),7.90(d,J=8.1Hz,2H),7.53(d,J=6.8Hz,1H),7.14(t,J=9.3Hz,1H),6.90(s,1H),6.73-6.65(m,2H),4.67-4.63(m,2H),3.84(s,3H),3.75(m,2H),3.38-3.33(m,2H)。针对C25H23FN4O6[M+H]的LCMS(ESI+)预测值=495.16,实验值=495.42。
实例67:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-6-羟基烟酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(30mg,0.056mmol)、6-羟基烟酸(7.8mg,0.056mmol)、Et3N(32μL,0.22mmol)和DMF(500μL)。添加HATU(22mg,0.056mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-6-羟基烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.10(d,J=2.6Hz,1H),7.99(dd,J=9.6,2.7Hz,1H),7.96(d,J=8.3Hz,2H),7.90(d,J=8.2Hz,2H),7.13(t,J=9.3Hz,1H),6.69(d,J=9.0Hz,1H),6.54(d,J=9.6Hz,1H),4.70-4.66(m,2H),3.84(s,3H),3.82(m,2H),3.42(td,J=11.8,6.3Hz,2H)。针对C25H23FN4O6[M+H]的LCMS(ESI+)预测值=495.16,实验值=495.45。
实例68:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)烟酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.038mmol)、烟酸(4.6mg,0.038mmol)、Et3N(21μL,0.15mmol)和DMF(500μL)。添加HATU(15mg,0.038mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)烟酰胺。1H NMR(500MHz,甲醇-d4)δ9.00(s,1H),8.71(d,J=4.9Hz,1H),8.28(d,J=8.0Hz,1H),7.96(d,J=8.2Hz,2H),7.90(d,J=8.3Hz,2H),7.57(dd,J=8.0,4.9Hz,1H),7.14(t,J=9.3Hz,1H),6.69(d,J=9.0Hz,1H),4.76-4.72(m,2H),3.93-3.81(m,5H),3.46(dd,J=13.3,5.9Hz,2H)。针对C25H23FN4O5[M+H]的LCMS(ESI+)预测值=479.17,实验值=479.41。
实例69:4-(2-氟-6-羟基-3-甲氧基苯甲酰基)-N-((3R,4R)-4-(4-羟基苯甲酰胺基)吡咯烷-3-基)苯甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.038mmol)、4-羟基苯甲酸(5.2mg,0.038mmol)、Et3N(21μL,0.15mmol)和DMF(500μL)。添加HATU(15mg,0.038mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的4-(2-氟-6-羟基-3-甲氧基苯甲酰基)-N-((3R,4R)-4-(4-羟基苯甲酰胺基)吡咯烷-3-基)苯甲酰胺。1H NMR(500MHz,甲醇-d4)δ7.95(d,J=8.3Hz,2H),7.90(d,J=8.4Hz,2H),7.73(d,J=8.7Hz,2H),7.13(t,J=9.3Hz,1H),6.83(d,J=8.7Hz,2H),6.68(dd,J=8.9,1.7Hz,1H),4.59(d,J=6.2Hz,2H),3.84(s,3H),3.63(m,2H),3.22-3.16(m,2H)。针对C26H24FN3O6[M+H]的LCMS(ESI+)预测值=494.17,实验值=494.44。
实例70:2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.038mmol)、2-氨基嘧啶-4-甲酸(5.3mg,0.038mmol)、Et3N(21μL,0.15mmol)和DMF(500μL)。添加HATU(15mg,0.038mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到50℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.45(d,J=5.0Hz,1H),7.94(d,J=8.5Hz,2H),7.90(d,J=8.2Hz,2H),7.20(d,J=5.0Hz,1H),7.13(t,J=9.3Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),4.63(dq,J=24.7,6.9Hz,2H),3.84(s,3H),3.70(dd,J=12.0,7.8Hz,2H),3.27(m,2H)。针对C24H23FN6O5[M+H]的LCMS(ESI+)预测值=495.17,实验值=495.42。
实例71:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-2-氧代吲哚啉-5-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.038mmol)、2-氧代吲哚啉-5-甲酸(6.7mg,0.038mmol)、Et3N(21μL,0.15mmol)和DMF(500μL)。添加HATU(15mg,0.038mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(0.75mL)和HCl水溶液(1.0M,0.75mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-2-氧代吲哚啉-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ7.95(d,J=8.5Hz,2H),7.90(d,J=8.4Hz,2H),7.78-7.73(m,2H),7.13(t,J=9.3Hz,1H),6.95(d,J=8.1Hz,1H),6.68(dd,J=9.0,1.7Hz,1H),4.69-4.60(m,2H),3.84(s,3H),3.74(dt,J=11.8,7.0Hz,2H),3.57(d,J=10.7Hz,1H)。针对C28H25FN4O6[M+H]的LCMS(ESI+)预测值=533.18,实验值=533.45。
实例72:N-((3S,4S)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(86mg,0.248mmol)、Et3N(35μL,0.248mmol)和DMF(2.0mL)。接着向这种溶液中添加HATU(94mg,0.248mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3S,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(50mg,0.248mmol)和HCl(4.0M二恶烷溶液,124μL)于DMF(2.0mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h,接着分配于EtOAc与NaHCO3之间。有机部分用水洗涤且浓缩。在硅胶(5g,CH2Cl2/MeOH梯度)上纯化得到(3S,4S)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(81mg)。接着将这种材料溶解于DMF(2.0mL)中且在室温下依序用Et3N(84μL,0.60mmol)和异烟酸(18mg,0.15mmol)处理。20min之后,溶液用EtOAc稀释且用水洗涤两次。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,1.0mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3S,4S)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.71(d,J=5.8Hz,2H),7.96(d,J=8.2Hz,2H),7.90(d,J=8.3Hz,2H),7.81(d,J=5.8Hz,2H),7.14(t,J=9.3Hz,1H),6.69(d,J=8.9Hz,1H),4.73-4.70(m,2H),3.84(s,3H),3.80(dd,J=12.8,6.9Hz,2H),3.39(dd,J=12.2,6.6Hz,2H)。针对C25H23FN4O5[M+H]的LCMS(ESI+)预测值=479.17,实验值=479.41。
实例73:N-((3R,4R)-4-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)-1-甲基吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺(16.0mg,0.033mmol)和DMF(1mL)。溶液用碘甲烷(10μL,0.16mmol)和过量碳酸钾处理。将溶液搅拌18h,用水淬灭且在HPLC上直接纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酰胺基)-1-甲基吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.72(s,2H),7.96(s,2H),7.91(d,J=8.2Hz,2H),7.81(s,2H),7.13(t,J=9.3Hz,1H),6.68(d,J=9.1Hz,1H),5.10(m,2H),4.22(m,2H),3.84(m,5H),3.45(br,3H)。峰缺失,可能由MeOD遮挡了。针对C27H27FN4O5[M+H]的LCMS(ESI+)预测值=507.20,实验值=507.50。
实例74:N-((顺式)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(86mg,0.248mmol)、Et3N(35μL,0.248mmol)和DMF(2.0mL)。接着向这种溶液中添加HATU(94mg,0.248mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯叔丁酯(50mg,0.248mmol)和HCl(4.0M二恶烷溶液,124μL)于DMF(2.0mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h以得到可直接就地使用的(3R,4S)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯。向这种溶液中添加异烟酸(31mg,0.248mmol)、Et3N(139μL,0.992mmol)和HATU(94mg,0.248mmol)。将混合物在室温下搅拌1h,用水稀释且接着在HPLC上纯化以得到(3S,4R)-3-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯(50mg)。接着将这种材料溶解于THF(1mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4S)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.62(d,J=6.2Hz,2H),7.91-7.80(m,4H),7.71-7.62(m,2H),7.13(t,J=9.3Hz,1H),6.67(dd,J=8.9,1.7Hz,1H),4.83(s,2H),3.84(s,3H),3.66(m,2H),3.59(m,2H)。针对C25H23FN4O5[M+H]的LCMS(ESI+)预测值=479.17,实验值=479.46。
实例75:4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-3-(异烟酰胺基)哌啶-4-基酯。
向小瓶中装入(3R,4R)-3-氨基-4-羟基哌啶-1-甲酸叔丁酯(50mg,0.23mmol)、异烟酸(28mg,0.23mmol)、Et3N(64μL,0.46mmol)和DMF(1.5mL)。接着添加HATU(87mg,0.23mmol)且在室温下搅拌45min以得到(3R,4R)-4-羟基-3-(异烟酰胺基)哌啶-1-甲酸叔丁酯。接着向这种溶液中添加Et3N(64μL,0.46mmol)、4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(80mg,0.23mmol)且最后添加HATU(87mg,0.23mmol)。将溶液在室温下搅拌18h,接着用EtOAc稀释且用水洗涤两次。将有机部分浓缩且接着再溶解于THF(1.0mL)和HCl(1.0N,1.0mL)中并升温到65℃持续1h。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-3-(异烟酰胺基)哌啶-4-基酯。1HNMR(500MHz,甲醇-d4)δ8.67-8.60(m,2H),8.09(d,J=8.4Hz,2H),7.87(d,J=8.3Hz,2H),7.71-7.60(m,2H),7.13(t,J=9.3Hz,1H),6.67(dd,J=9.0,1.7Hz,1H),5.30(td,J=10.3,4.6Hz,1H),4.56(td,J=10.8,4.7Hz,1H),3.84(s,3H),3.56(dd,J=12.9,4.6Hz,1H),3.50-3.41(m,1H),3.20-3.01(m,2H),2.47(m,1H),2.00(m,1H)。针对C26H24FN3O6[M+H]的LCMS(ESI+)预测值=494.17,实验值=494.47。
实例76:4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酸(3R,4R)-3-(异烟酰胺基)-1-甲基哌啶-4-基酯。
在室温下,向小瓶中装入4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-3-(异烟酰胺基)哌啶-4-基酯(23mg,0.047mmol)和DMF(1mL)。溶液用碘甲烷(20μL,0.33mmol)和过量碳酸钾处理。将溶液搅拌1h,用水淬灭且在HPLC上直接纯化以得到呈甲酸盐形式的4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酸(3R,4R)-3-(异烟酰胺基)-1-甲基哌啶-4-基酯。1H NMR(500MHz,甲醇-d4)δ8.67-8.60(m,2H),8.12(d,J=8.5Hz,2H),7.88(d,J=8.3Hz,2H),7.68-7.59(m,2H),7.14(t,J=9.3Hz,1H),6.67(dd,J=9.0,1.7Hz,1H),5.37(td,J=10.8,5.2Hz,1H),5.01-4.92(m,1H),3.83(m,4H),3.73(d,J=8.5Hz,2H),3.50(t,J=12.5Hz,1H),3.44(s,3H),3.33(s,3H),2.61-2.45(m,2H)。针对C28H28FN3O6[M+H]的LCMS(ESI+)预测值=522.20,实验值=522.51。
实例77:4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-4-(异烟酰胺基)吡咯烷-3-基酯。
向小瓶中装入(3R,4R)-3-氨基-4-羟基吡咯烷-1-甲酸叔丁酯(50mg,0.247mmol)、异烟酸(30mg,0.247mmol)、Et3N(138μL,0.988mmol)和MeCN(1.5mL)。接着添加HATU(94mg,0.247mmol)且在室温下搅拌20min以得到(3R,4R)-3-羟基-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯。接着,向这种溶液中添加4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸(86mg,0.247mmol)和HATU(94mg,0.247mmol)。将溶液在室温下搅拌18h,接着用EtOAc稀释且用水洗涤两次。将有机部分浓缩且接着再溶解于THF(1.0mL)和HCl(1.0N,1.0mL)中并升温到65℃持续4h。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-4-(异烟酰胺基)吡咯烷-3-酯。1H NMR(500MHz,甲醇-d4)δ8.73-8.68(m,2H),8.18(d,J=8.4Hz,2H),7.92(d,J=8.2Hz,2H),7.84-7.77(m,2H),7.14(t,J=9.2Hz,1H),6.68(d,J=9.0Hz,1H),5.49(m,1H),4.60(m,1H),3.84(s,3H),3.52(m,1H),3.48-3.40(m,1H),3.35(s,3H),3.17(m,1H),2.96(m,1H)。针对C25H22FN3O6[M+H]的LCMS(ESI+)预测值=480.15,实验值=480.43。
实例78:4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酸(3R,4R)-4-(异烟酰胺基)-1-甲基吡咯烷-3-基酯。
在室温下,向小瓶中装入4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酸(3R,4R)-4-(异烟酰胺基)吡咯烷-3-基酯(13mg)和DMF(1mL)。溶液用碘甲烷(20μL)和过量碳酸钾处理。将溶液搅拌1h,用水淬灭且在HPLC上直接纯化以得到呈甲酸盐形式的4-(2-氟-3,6-二甲氧基苯甲酰基)苯甲酸(3R,4R)-4-(异烟酰胺基)-1-甲基吡咯烷-3-基酯。1H NMR(500MHz,甲醇-d4)δ8.74(d,J=5.0Hz,2H),8.21(d,J=8.2Hz,2H),7.94(d,J=8.1Hz,2H),7.84(d,J=5.0Hz,2H),7.15(t,J=9.3Hz,1H),6.69(dd,J=9.0,1.7Hz,1H),5.95(s,1H),5.01(m,1H),4.38(m,1H),4.28(m,1H),4.16(m,1H),3.90(s,1H),3.84(s,3H),3.45(s,3H),3.43(s,3H)。针对C27H26FN3O6[M+H]的LCMS(ESI+)预测值=508.18,实验值=508.47。
实例79:N-((3R,4R)-4-(4-((2-氟-6-羟基-3-甲氧基苯基)(羟基)甲基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入(3R,4R)-3-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.031mmol)和CH2Cl2(1.0mL)。接着,向这种溶液中添加NaBH4(4mg,0.11mmol),随后添加三氟乙酸(0.5mL),从而使无色溶液变为红色,其历经10min而淡化。在4h之后,将溶液浓缩且在HPLC上纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-((2-氟-6-羟基-3-甲氧基苯基)(羟基)甲基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.70(d,J=6.2Hz,2H),8.32(s,1H),7.84-7.77(m,4H),7.52(d,J=8.2Hz,2H),6.88(t,J=9.2Hz,1H),6.55(dd,J=9.0,1.7Hz,1H),6.29(s,1H),4.69(q,J=6.9Hz,2H),3.84(dt,J=14.3,7.5Hz,2H),3.76(s,3H),3.49-3.40(m,2H)。针对C25H25FN4O5[M+H]的LCMS(ESI+)预测值=481.18,实验值=481.27。
实例80:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-苯并[d][1,2,3]三唑-5-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、1H-苯并[d][1,2,3]三唑-5-甲酸(16mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,1.0mL)中。使溶液升温到60℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-苯并[d][1,2,3]三唑-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.56-8.47(m,3H),7.99(d,J=8.3Hz,3H),7.93(dd,J=8.5,3.3Hz,3H),7.15(t,J=9.3Hz,1H),6.70(d,J=8.9Hz,1H),4.74(s,2H),3.86(s,3H),3.84-3.76(m,2H),3.40(d,J=7.7Hz,2H)。针对C26H23FN6O5[M+H]的LCMS(ESI+)预测值=519.17,实验值=519.28。
实例81:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-6-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、1H-吲唑-6-甲酸(16mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,1.0mL)中。使溶液升温到60℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-6-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.15-8.10(m,3H),7.99(d,J=8.0Hz,2H),7.92(d,J=8.1Hz,2H),7.91-7.78(m,2H),7.63(d,J=8.5Hz,1H),7.15(t,J=9.2Hz,1H),6.70(d,J=9.0Hz,1H),3.91(m,2H),3.86(s,3H),3.52(s,1H),2.75-2.70(m,1H)。针对C27H24FN5O5[M+H]的LCMS(ESI+)预测值=518.18,实验值=518.30。
实例82:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吡咯并[2,3-b]吡啶-4-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、1H-吡咯并[2,3-b]吡啶-4-甲酸(16mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,1.0mL)中。使溶液升温到60℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吡咯并[2,3-b]吡啶-4-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.32(s,1H),7.99(s,2H),7.93(d,J=8.0Hz,2H),7.55(s,1H),7.43(s,1H),7.15(t,J=9.3Hz,1H),6.88(d,J=16.4Hz,1H),6.70(d,J=9.0Hz,1H),3.93(m,2H),3.86(s,3H),3.55(m,2H),3.22(d,J=7.8Hz,2H)。针对C27H24FN5O5[M+H]的LCMS(ESI+)预测值=518.18,实验值=518.25。
实例83:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入(3R,4R)-3-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)-4-(异烟酰胺基)吡咯烷-1-甲酸叔丁酯(20mg,0.031mmol)和CH2Cl2(1.0mL)。接着,向这种溶液中添加三氟乙酸(0.5mL),随后添加Et3SiH(148μL,10当量)。在20h之后,将溶液浓缩且在HPLC上纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.72(d,J=4.5Hz,2H),8.44(s,2H),7.85-7.78(m,2H),7.75(d,J=7.7Hz,2H),7.37(d,J=7.9Hz,2H),6.85-6.79(m,1H),6.57(d,J=8.8Hz,1H),4.70(q,J=6.7Hz,2H),4.04(s,2H),3.84(d,J=9.8Hz,2H),3.79(d,J=2.1Hz,3H),3.46(d,J=14.8Hz,2H)。针对C25H25FN4O4[M+H]的LCMS(ESI+)预测值=465.19,实验值=465.27。
实例84:2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、2-((叔丁氧基羰基)氨基)异烟酸(24mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.05-7.89(m,5H),7.20-7.13(m,1H),7.01-6.91(m,2H),6.71(d,J=9.0Hz,1H),4.72(t,J=5.4Hz,2H),3.94-3.79(m,5H),3.53-3.39(m,2H)。针对C25H24FN5O5[M+H]的LCMS(ESI+)预测值=494.18,实验值=494.26。
实例85:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1-甲基-1H-吲唑-5-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、1-甲基-1H-吲唑-5-甲酸(18mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1-甲基-1H-吲唑-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.45(s,3H),8.37(s,1H),8.15(s,1H),8.03-7.89(m,5H),7.70-7.61(m,1H),7.15(t,J=9.3Hz,1H),6.70(d,J=9.1Hz,1H),4.75(d,J=5.0Hz,2H),4.12(d,J=3.4Hz,3H),3.86(d,J=3.1Hz,5H),3.47(s,2H)。针对C28H26FN5O5[M+H]的LCMS(ESI+)预测值=532.20,实验值=532.34。
实例86:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-苯并[d]咪唑-5-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(52mg,0.099mmol)、1H-苯并[d]咪唑-5-甲酸(16mg,0.099mmol)、HATU(38mg,0.099mmol)和DMF(1mL)。添加Et3N(40μL,0.29mmol)且将混合物在室温下搅拌1h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-苯并[d]咪唑-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.52(s,1H),8.33(d,J=3.5Hz,1H),8.21(s,1H),7.99(d,J=7.3Hz,2H),7.93(d,J=7.5Hz,2H),7.83(d,J=8.3Hz,1H),7.70(t,J=5.7Hz,1H),7.15(t,J=9.4Hz,1H),6.70(d,J=9.1Hz,1H),4.77-4.69(m,2H),3.86(d,J=3.3Hz,3H),3.84-3.75(m,2H),3.39(dd,J=11.6,5.7Hz,2H)。针对C27H24FN5O5[M+H]的LCMS(ESI+)预测值=518.18,实验值=518.29。
实例87:4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸。
在室温下,向圆底烧瓶中装入3-氟苯酚(1.0g,8.92mmol)和CH2Cl2(10mL)。接着向这种溶液中添加二异丙基乙胺(3.10mL,17.8mmol),随后添加(氯甲氧基)乙烷(1.65mL,17.8mmol)。将所得溶液在室温下搅拌直到通过LC-MS完成为止(18h)。溶液用水洗涤两次,且将有机部分浓缩并在硅胶(20g,己烷/EtOAc梯度2%-25%)上纯化以得到1-(乙氧基甲氧基)-3-氟苯。1H NMR(500MHz,氯仿-d)δ7.26-7.18(m,1H),6.82(dd,J=8.3,2.2Hz,1H),6.79(dd,J=10.8,2.3Hz,1H),6.74-6.65(m,1H),5.21(d,J=1.8Hz,2H),3.73(qd,J=7.1,1.8Hz,2H),1.23(t,J=7.1Hz,3H)。
在N2气氛下,向火焰干燥的圆底烧瓶中装入1-(乙氧基甲氧基)-3-氟苯(1.08g,6.35mmol)和无水THF(20mL)。将溶液在干冰/丙酮浴中冷却且接着用nBuLi(3.80mL的2.5M己烷溶液,9.51mmol)缓慢处理。在低温搅拌两小时之后,溶液用4-甲酰基苯甲酸甲酯(1.56mL,9.51mmol)于无水THF(4mL)中的溶液缓慢处理。使所得混合物缓慢升温到室温且通过LC-MS监测。完成后,溶液用乙酸乙酯稀释且依序用水和盐水洗涤。浓缩得到油状物,其接着在硅胶(20g,己烷/EtOAc梯度10%-100%)上纯化以得到4-((2-(乙氧基甲氧基)-6-氟苯基)(羟基)甲基)苯甲酸甲酯。1H NMR(500MHz,氯仿-d)δ8.01-7.94(m,2H),7.43(d,J=7.9Hz,2H),7.25-7.19(m,1H),6.93(d,J=8.5Hz,1H),6.81(t,J=9.1Hz,1H),6.26(d,J=11.0Hz,1H),5.21-5.14(m,1H),5.14-5.04(m,1H),3.90(s,3H),3.72(dd,J=11.1,2.3Hz,1H),3.46(m,1H),3.41-3.29(m,1H),1.08(td,J=7.1,2.0Hz,3H)。
在室温下,向圆底烧瓶中装入4-((2-(乙氧基甲氧基)-6-氟苯基)(羟基)甲基)苯甲酸甲酯(1.93g,5.77mmol)和CH2Cl2(40mL)。接着添加戴斯-马丁高碘烷(3.67g,8.66mmol)且将所得浅黄色悬浮液搅拌30min。溶液用二氯甲烷稀释且用NaHCO3洗涤。浓缩和硅胶(20g,己烷/EtOAc梯度5%-40%)上的纯化得到4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸甲酯。1H NMR(500MHz,氯仿-d)δ8.11(d,J=6.8Hz,2H),7.91(d,J=7.49Hz,2H),7.40(q,J=8.8,8.2Hz,1H),7.06(d,J=8.6,1H),6.88-6.80(m,1H),5.12(s,2H),3.95(s,3H),3.57-3.47(m,2H),1.16-1.07(t,J=7.3,3H)。
向小瓶中装入4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酸甲酯(300mg,0.903mmol)、THF(3mL)和水(1mL)。添加LiOH(86mg,3.6mmol)且将所得混合物在室温下搅拌2h。溶液接着用乙酸乙酯稀释且用10%柠檬酸溶液洗涤。浓缩有机部分得到4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸。1H NMR(500MHz,氯仿-d)δ8.23-8.14(d,J=7.7Hz,2H),7.95(d,J=7.5Hz,2H),7.44-7.37(m,1H),7.06(dd,J=8.7,2.9Hz,1H),6.85(t,J=8.6Hz,1H),5.13(s,1H),3.52(q,J=6.9,5.1Hz,2H),1.16-1.08(m,3H)。
实例88:N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。
在室温下,向小瓶中装入4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸(32mg,0.099mmol)、Et3N(14μL,0.099mmol)和DMF(1.0mL)。接着向这种溶液中添加HATU(38mg,0.099mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(20mg,0.099mmol)和HCl(4.0M二恶烷溶液,50μL)于DMF(0.5mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h以得到可直接就地使用的(3R,4R)-3-氨基-4-(4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯。向这种溶液中添加异烟酸(12mg,0.099mmol)、Et3N(42μL,0.298mmol)和HATU(38mg,0.099mmol)。将混合物在室温下搅拌1h,接着用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)异烟酰胺。1H NMR(500MHz,甲醇-d4)δ8.78-8.69(m,2H),8.50(s,1H),7.97(d,J=7.3Hz,2H),7.91(d,J=7.8Hz,2H),7.82(d,J=4.5Hz,2H),7.39(d,J=8.0Hz,1H),6.82-6.76(m,1H),6.72(t,J=9.0Hz,1H),4.73-4.65(m,2H),3.75(d,J=11.1Hz,2H),3.32(s,2H)。针对C24H21FN4O4[M+H]的LCMS(ESI+)预测值=449.16,实验值=449.26。
实例89:2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。
在室温下,向小瓶中装入4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸(32mg,0.099mmol)、Et3N(14μL,0.099mmol)和DMF(1.0mL)。接着向这种溶液中添加HATU(38mg,0.099mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(20mg,0.099mmol)和HCl(4.0M二恶烷溶液,50μL)于DMF(0.5mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h以得到可直接就地使用的(3R,4R)-3-氨基-4-(4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯。向这种溶液中添加2-氨基嘧啶-4-甲酸(14mg,0.099mmol)、Et3N(42μL,0.298mmol)和HATU(38mg,0.099mmol)。将混合物在室温下搅拌1h,接着用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.51(s,1H),8.47(d,J=5.2Hz,1H),7.96(s,2H),7.91(d,J=8.9Hz,2H),7.39(d,J=8.1Hz,1H),7.22(d,J=5.3Hz,1H),6.78(d,J=8.6Hz,1H),6.73(d,J=9.4Hz,1H),4.66(d,J=24.8Hz,3H),3.73(t,J=10.0Hz,2H)。针对C23H21FN6O4[M+H]的LCMS(ESI+)预测值=465.16,实验值=465.25。
实例90:N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-5-甲酰胺。
在室温下,向小瓶中装入4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酸(32mg,0.099mmol)、Et3N(14μL,0.099mmol)和DMF(1.0mL)。接着向这种溶液中添加HATU(38mg,0.099mmol)且将混合物搅拌5min。接着,将这种溶液添加到含有(3R,4S)-3,4-二氨基吡咯烷-1-甲酸叔丁酯(20mg,0.099mmol)和HCl(4.0M二恶烷溶液,50μL)于DMF(0.5mL)中的新制备混合物的第二小瓶中。将所得溶液在室温下搅拌18h以得到可直接就地使用的(3R,4R)-3-氨基-4-(4-(2-(乙氧基甲氧基)-6-氟苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯。向这种溶液中添加1H-吲唑-5-甲酸(16mg,0.099mmol)、Et3N(42μL,0.298mmol)和HATU(38mg,0.099mmol)。将混合物在室温下搅拌1h,接着用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.5mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-1H-吲唑-5-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.54(s,1H),8.38(s,1H),8.20(s,1H),8.03-7.95(m,2H),7.91(d,J=8.7Hz,3H),7.62(d,J=8.5Hz,1H),7.39(s,1H),6.78(d,J=7.9Hz,1H),6.71(d,J=12.3Hz,1H),4.68(s,2H),3.69(d,J=9.0Hz,2H),3.25(s,2H)。针对C26H22FN5O4[M+H]的LCMS(ESI+)预测值=488.17,实验值=488.27。
实例91:N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-3H-咪唑并[4,5-b]吡啶-7-甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(66mg,0.124mmol)、3H-咪唑并[4,5-b]吡啶-7-甲酸(20mg,0.124mmol)、HATU(47mg,0.124mmol)和DMF(1mL)。添加Et3N(52μL,0.372mmol)且将混合物在室温下搅拌2h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.3mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)-3H-咪唑并[4,5-b]吡啶-7-甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.55(d,J=5.1Hz,1H),8.53(s,1H),8.50(s,2H),7.98(d,J=8.2Hz,2H),7.92(d,J=8.2Hz,2H),7.81(d,J=5.1Hz,1H),7.15(t,J=9.3Hz,1H),6.70(dd,J=9.0,1.6Hz,1H),4.84-4.71(m,2H),3.92-3.81(m,5H),3.48(dd,J=12.3,6.3Hz,1H),3.41(dd,J=12.1,6.6Hz,1H)。针对C26H23FN6O5[M+H]的LCMS(ESI+)预测值=519.17,实验值=519.32。
实例92:N-((3R,4R)-4-(2-(1H-吡唑-4-基)乙酰胺基)吡咯烷-3-基)-4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(66mg,0.124mmol)、2-(1H-吡唑-4-基)乙酸(16mg,0.124mmol)、HATU(47mg,0.124mmol)和DMF(1mL)。添加Et3N(52μL,0.372mmol)且将混合物在室温下搅拌2h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.3mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的N-((3R,4R)-4-(2-(1H-吡唑-4-基)乙酰胺基)吡咯烷-3-基)-4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺。1H NMR(400MHz,甲醇-d4)δ8.39(d,J=1.6Hz,2H),7.92(s,4H),7.55(s,1H),7.15(t,J=9.3Hz,1H),6.70(d,J=9.0Hz,1H),4.53(dq,J=27.9,7.2Hz,2H),3.86(d,J=1.6Hz,3H),3.82-3.69(m,2H),3.47(s,2H),3.30-3.21(m,2H)。针对C24H24FN5O5[M+H]的LCMS(ESI+)预测值=482.18,实验值=482.30。
实例93:4-(2-氟-6-羟基-3-甲氧基苯甲酰基)-N-((3R,4R)-4-(2-(吡啶-3-基)乙酰胺基)吡咯烷-3-基)苯甲酰胺。
向小瓶中装入(3R,4R)-3-氨基-4-(4-(6-(乙氧基甲氧基)-2-氟-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-1-甲酸叔丁酯(66mg,0.124mmol)、2-(吡啶-3-基)乙酸(17mg,0.124mmol)、HATU(47mg,0.124mmol)和DMF(1mL)。添加Et3N(52μL,0.372mmol)且将混合物在室温下搅拌2h。溶液用水淬灭且用EtOAc萃取。将有机部分在真空中浓缩且接着再溶解于THF(1.0mL)和HCl水溶液(1.0M,0.3mL)中。使溶液升温到65℃并搅拌直到通过LCMS完全去除氨基甲酸酯和缩醛保护基为止。接着,溶液经由HPLC纯化以得到呈甲酸盐形式的4-(2-氟-6-羟基-3-甲氧基苯甲酰基)-N-((3R,4R)-4-(2-(吡啶-3-基)乙酰胺基)吡咯烷-3-基)苯甲酰胺。1H NMR(500MHz,甲醇-d4)δ8.48(d,J=2.2Hz,1H),8.41(dd,J=5.0,1.5Hz,1H),8.38(s,2H),7.90(s,3H),7.80-7.76(m,1H),7.35(dd,J=7.9,4.9Hz,1H),7.16(t,J=9.3Hz,1H),6.71(dd,J=9.0,1.6Hz,1H),4.56(dq,J=37.2,7.3Hz,2H),3.87(s,3H),3.75(ddd,J=12.0,10.1,7.8Hz,2H),3.63(s,2H),3.28(dd,J=12.1,7.5Hz,1H)。针对C26H25FN4O5[M+H]的LCMS(ESI+)预测值=493.18,实验值=493.28。
实例94:2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺。
在室温下,向小瓶中装入2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲酰基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺(8mg,0.016mmol)和CH2Cl2(1.0mL)。接着,向这种溶液中添加三氟乙酸(0.5mL),随后添加Et3SiH(30μL)。在20h之后,将溶液浓缩且在HPLC上纯化以得到部分还原的甲醇和完全还原的亚甲基化合物两者。2-氨基-N-((3R,4R)-4-(4-(2-氟-6-羟基-3-甲氧基苯甲基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺:1H NMR(500MHz,甲醇-d4)δ8.50(s,2H),8.47(d,J=5.1Hz,1H),7.74(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.22(d,J=5.0Hz,1H),6.82(t,J=9.2Hz,1H),6.57(d,J=8.9Hz,1H),4.65(dq,J=31.2,7.2Hz,2H),4.04(s,2H),3.79(s,5H),3.38(s,2H)。针对C24H25FN6O4[M+H]的LCMS(ESI+)预测值=481.20,实验值=481.29。2-氨基-N-((3R,4R)-4-(4-((2-氟-6-羟基-3-甲氧基苯基)(羟基)甲基)苯甲酰胺基)吡咯烷-3-基)嘧啶-4-甲酰胺:1H NMR(500MHz,甲醇-d4)δ8.47(d,J=5.0Hz,1H),8.39(s,8H),7.81(d,J=8.1Hz,2H),7.53(d,J=8.0Hz,2H),7.22(d,J=4.9Hz,1H),6.90(t,J=9.2Hz,1H),6.57(d,J=8.7Hz,1H),6.30(s,1H),4.68(dd,J=24.2,7.0Hz,2H),3.85(q,J=8.9Hz,2H),3.78(s,3H),3.45(d,J=11.6Hz,2H)。针对C24H25FN6O5[M+H]的LCMS(ESI+)预测值=497.19,实验值=497.27。
合成并未明确显示的其它所公开的化合物可通过与以上实例中所示的那些类似的方法来制备。
实例95:细胞制备和培养
预涂培养板:在实验前的当天,通过将50μl聚-D-赖氨酸溶液(PDL,0.5mg/mL)接种于每个孔中来预涂96孔板。在下一早晨,板用HBSS或PBS(150μl/冲洗)洗涤四或五次,接着静置于缓冲液中直到细胞接种为止。
制备细胞:使用IACUC批准的方法使携带E18胚胎的定时怀孕大鼠安乐死。在层流净化罩中,将胚胎去除且放置于含有具有20mm HEPES的汉克氏平衡盐溶液(Hank'sBalanced Salt Solution;HBSS),pH 7.3的皮氏培养皿(petri dish)中。将幼鼠大脑解剖(参见Meberg等人,2003)且将海马(hippocampi)收集于15mL含有具有SM1的Hibernate E(2%v/v)的锥形管中。
解离介质通过将4.5mL具有0.5mL的胰蛋白酶(trypsin)的Hibernate E(不含SM1)和100μl DNA酶溶液合并来制备。将海马上方的介质小心地去除且用解离溶液替换,接着在37℃下培育15-20分钟,偶尔使管旋动。
使用火焰抛光的棉塞巴斯德移液管(Pasteur pipette),去除解离介质,且接着添加5mL含有SM1的Hibernate E。将管旋动以彻底地洗涤组织。使组织沉降到管的底部,且小心地去除冲洗溶液。将这个步骤重复5次以稀释出胰蛋白酶和DNA酶且从裂解细胞去除任何碎片。
从管去除最终冲洗介质且添加1满管(1-2mL)具有SM1的Hibernate E。使用火焰抛光的巴斯德移液管(用冲洗介质预湿),将管研磨直到将所有细胞解离且没有可见组织块剩余为止。典型地执行少于十次研磨。使用含有SM1的Hibernate E将体积调节到8-12mL,将孔混合且测定细胞浓度。
接种:将细胞在培养基(NbActiv4细胞培养基)中稀释到10,000个细胞/毫升的最终浓度。从PDL涂布的板抽吸HBSS,且将150μL细胞溶液以1500个细胞/孔装载于中间48孔中。将水装载于外部孔中以从边缘孔减少蒸发。在处理之前,使细胞在组织培养培育箱中黏附2小时。
处理:将化合物稀释到各种浓度以提供20μM、10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM、0.15625μM和0.078125μM的9种剂量反应浓度。将板培养48小时,暴露于各种剂量反应浓度下的化合物。
固定培养基:将培养基从板中去除且立即用100-200μl热(37℃)的含4%多聚甲醛(paraformaldehyde;PFA)溶液的磷酸盐缓冲盐水(PBS)替换。将细胞在室温下固定15-20分钟,且接着用PBS(200微升/孔×3)冲洗。
染色和成像:将PBS去除且用100μl封闭/渗透缓冲液(PBS,0.2%鱼明胶,0.03%Triton X-100,0.02%NaN3)替换,接着在4℃下培育隔夜。向其中添加100μl初级抗体溶液(含小鼠抗βIII微管蛋白的封闭缓冲液)且在4℃下培育隔夜。孔用PBS(200μl×3)冲洗,接着将其去除且用100μl二级抗体溶液(含山羊抗小鼠Alexa 488、10μg/ml赫斯特(Hoechst)33342、0.2%鱼明胶、0.02%叠氮化物的PBS)替换。将板在旋转振荡器上轻轻地振荡2小时,接着用PBS(200μl×5)冲洗。
使用Cellomics ArrayScan VTI在2个不同通道中对板进行成像,以用于细胞核染色(赫斯特)和细胞体/神经突染色(βIII-微管蛋白)。典型地,每孔九个视区用5×物镜成像且通过神经元轮廓生物应用程序(Neuronal Profiling Bioapplication)自动追踪。为获得可再现性结果,每种情况测量至少200-300个有效神经元。
将如上文分析中所评估的每个化合物的数据呈现于下表1中,从而显示在暴露于每个浓度下的化合物后的神经突生长长度(%NTL)。
表1
实例96:活体内轴突生长测定
为评估本文中所描述的化合物在活体内轴突生长中的作用,采用单侧锥体束切断术模型,其中将腹侧脑干中的锥体单侧切断,延髓到皮质脊髓束(corticospinal tract;CST)轴突交叉。随后,动物接受本文中所描述的化合物(或DMSO)与AAV8-UbC-GFP或AAV8-UbC-TdTomato(5×1013个GC/mL)1:1混合的双侧皮质注射,最终浓度为2mM(每个情况2只动物(小鼠))。在每个半球上的感觉运动皮层中以0.5mm的深度且在以下坐标进行五次注射(每个500nl):2mm/±1.5mm、1.25mm/±1.5mm、0.5mm/±1.5mm、-0.25mm/±1mm和-1mm/±1mm(前后/中侧到前囟)。在5周之后,评估颈脊髓中的轴突生长。脊髓的颈截面用针对PKCγ(评估病变的完整性)和GFP(扩大来自病毒的信号)的抗体染色。为了分析,在中央管外侧0、500、1000μm处对萌发到失神经灰质中的GFP+轴突进行计数,且标准化为脑干水平下的GFP+纤维数量(萌发轴突指数)。在用RO48(A92)或其衍生物(SBI-0799926-化合物A16,和SBI-0814654-化合物A88)治疗的动物中,通过萌发轴突指数曲线图(图3)测量,萌发存在几乎两倍增加。这些结果证实RO48可在单次给予化合物之后促进CST轴突生长(AL-Ali等人,ACSChem Biol.2015;10(8):1939-512015),且指示衍生化合物在活体内场景中也能够促进轴突生长。
实例97:神经突生长测定
为评估化合物促进神经突生长的能力,HCS分析使用如Al-Ali等人,Sittampalam等人编的分析指导手册(Assay Guidance Manual)[因特网]中的“利用原代神经元的高含量筛选(High Content Screening with Primary Neurons)”,贝塞斯达(MD):礼来公司(Eli Lilly&Company)和国家转化科学推进中心(the National Center for AdvancingTranslational Sciences);2004.2013年10月15日[2014年10月1日更新]中所描述的方案来执行。这种分析的结果呈现于下表2中。
表2
“-”表示>20的活性
Claims (43)
1.一种化合物或其医药学上可接受的盐,其具有式(I)结构:
其中
环A包括具有1、2或3个氮环原子的5到6元单环杂芳基环或8到11元双杂芳基环;
L1不存在或为C1-2亚烷基;
X1为-NH-、-CH2NH-、-NHCH2-、-CH2CH2NH-或-NHCH2CH2-;
X2为NR2或O;
X3为NR2或O;
L2为C(O)、O、CH2或CHOH;
R1为H或卤基;
各R2独立地为H或C1-3烷基;
R3为H、C1-3烷基、C3-6环烷基、芳基、C(O)C1-3烷基、C(O)C3-6环烷基或C(O)芳基;
R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C1-4烷氧基-芳基、C(O)OC3-6环烷基或C(O)O芳基;以及
R5为H、卤基、C1-4烷基或C1-4烷氧基。
2.根据权利要求1所述的化合物或盐,其中环A包括吡咯基、吡唑基、咪唑基、三唑基、吡啶基、吡嗪基、嘧啶基、吲哚基、吲唑基、苯并三唑基、苯并咪唑基、吡咯并吡啶基或咪唑并吡啶基(imidazopyrindinyl)。
3.根据权利要求1所述的化合物或盐,其中环A包括吡啶基、嘧啶基、吡咯并吡啶基、吲唑基或咪唑并吡啶基。
5.根据权利要求1到4中任一项所述的化合物,其中环A经一个或两个选自NH2、OH和C1-3烷基的基团取代。
6.根据权利要求1到4中任一项所述的化合物,其中环A未经取代。
7.根据权利要求1到6中任一项所述的化合物或盐,其中L1不存在。
8.根据权利要求1到6中任一项所述的化合物或盐,其中L1为CH2。
9.根据权利要求1到8中任一项所述的化合物或盐,其中X1为NH-、-CH2NH-或-NHCH2。
10.根据权利要求9所述的化合物或盐,其中X1为NH。
11.根据权利要求9所述的化合物或盐,其中X1为CH2NH或NHCH2。
12.根据权利要求1到8中任一项所述的化合物或盐,其中X1为-CH2CH2NH-或-NHCH2CH2-。
13.根据权利要求1到12中任一项所述的化合物或盐,其中X2为NR2。
14.根据权利要求13所述的化合物或盐,其中R2为H或Me。
15.根据权利要求1到12中任一项所述的化合物或盐,其中X2为O。
16.根据权利要求1到15中任一项所述的化合物或盐,其中X3为NR2。
17.根据权利要求16所述的化合物或盐,其中R2为H或Me。
18.根据权利要求1到15中任一项所述的化合物或盐,其中X3为O。
19.根据权利要求1到18中任一项所述的化合物或盐,其中R1为H。
20.根据权利要求1到18中任一项所述的化合物或盐,其中R1为卤基。
21.根据权利要求20所述的化合物或盐,其中R1为氟。
22.根据权利要求1到21中任一项所述的化合物或盐,其中L2为C(O)。
23.根据权利要求1到21中任一项所述的化合物或盐,其中L2为O或CHOH。
24.根据权利要求1到23中任一项所述的化合物或盐,其中R3为H。
25.根据权利要求1到23中任一项所述的化合物或盐,其中R3为Me。
26.根据权利要求1到23中任一项所述的化合物或盐,其中R3为C(O)C1-3烷基。
27.根据权利要求26所述的化合物或盐,其中R4为OMe、OH、F、Cl或Me。
28.根据权利要求1到26中任一项所述的化合物或盐,其中R4为H、OH、卤基、C1-4烷基、C1-4烷氧基、C(O)C1-4烷氧基、C3-6环烷基、芳基、-OC3-6环烷基、-O芳基、C(O)OC3-6环烷基或C(O)O芳基。
29.根据权利要求1到28中任一项所述的化合物或盐,其中R5为H。
30.根据权利要求1到28中任一项所述的化合物或盐,其中R5为F、OMe、Cl或Me。
31.根据权利要求1到28和30中任一项所述的化合物,其中R5与R4相邻。
32.一种化合物或其医药学上可接受的盐,其具有如表A中所列的结构。
33.一种化合物或其医药学上可接受的盐,其具有如表B中所列的结构。
34.一种化合物或其医药学上可接受的盐,其具有如表C中所列的结构。
35.一种组合物,其包括根据权利要求1到34中任一项所述的化合物或盐和医药学上可接受的赋形剂。
36.一种抑制Rho激酶(ROCK)或核糖体蛋白S6激酶(S6K)或PKC的方法,其包括使ROCK或S6K或蛋白激酶C(PKC)与呈有效抑制ROCK或S6K或PKC的量的根据权利要求1到34中任一项所述的化合物或盐接触。
37.一种抑制Rho激酶(ROCK)和核糖体蛋白S6激酶(S6K)的方法,其包括使ROCK和S6K与呈有效抑制ROCK和S6K的量的根据权利要求1到34中任一项所述的化合物或盐接触。
38.一种诱导神经突生长的方法,其包括使神经元与呈有效增加神经突生长的量的根据权利要求1到34中任一项所述的化合物或盐接触。
39.一种治疗有需要的个体中与神经元和/或轴突损伤相关的中枢神经系统(centralnervous system;CNS)病症的方法,其包括以有效修复神经元和/或轴突损伤且治疗所述CNS病症的量向所述个体给予根据权利要求1到34中任一项所述的化合物或盐。
40.根据权利要求39所述的方法,其中所述CNS病症为麻痹、脊髓损伤、视神经损伤、青光眼、多发性硬化症、创伤性脑损伤、弥漫性轴突损伤、中风或退行性疾病(如帕金森病(Parkinson's disease))。
41.一种治疗有需要的个体中与神经元和/或轴突损伤相关的周边神经系统(peripheral nervous system;PNS)病症的方法,其包括以有效修复所述神经元和/或所述轴突损伤且治疗所述PNS病症的量向所述个体给予根据权利要求1到34中任一项所述的化合物或盐。
42.根据权利要求41所述的方法,其中所述PNS病症为周边神经创伤、重复性应激、肌肉萎缩性侧索硬化(amyotrophic lateral sclerosis;ALS)、勃起功能障碍、与器官移植相关的病症、神经纤维瘤、血管疾病、糖尿病、自体免疫病症、与化学毒性相关的病症或肾病。
43.一种治疗经受癌症治疗的个体的神经退化症的方法,其包括以有效治疗所述神经退化症的量向所述个体给予根据权利要求1到34中任一项所述的化合物或盐。
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KR20200080273A (ko) | 2020-07-06 |
AU2018359413B2 (en) | 2023-11-23 |
IL274067B2 (en) | 2023-03-01 |
US20210163444A1 (en) | 2021-06-03 |
IL274067B (en) | 2022-11-01 |
EP3704103A1 (en) | 2020-09-09 |
US11926613B2 (en) | 2024-03-12 |
AU2018359413A1 (en) | 2020-05-07 |
WO2019089729A1 (en) | 2019-05-09 |
CN111801322B (zh) | 2024-03-15 |
JP2021503442A (ja) | 2021-02-12 |
IL274067A (en) | 2020-06-30 |
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