CN105473568B - 1,7‑萘啶衍生物 - Google Patents
1,7‑萘啶衍生物 Download PDFInfo
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- CN105473568B CN105473568B CN201480042466.6A CN201480042466A CN105473568B CN 105473568 B CN105473568 B CN 105473568B CN 201480042466 A CN201480042466 A CN 201480042466A CN 105473568 B CN105473568 B CN 105473568B
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- Prior art keywords
- naphthyridines
- formamides
- compound
- formulas
- phenyl
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Abstract
本发明涉及通式(I)的化合物,其中R1是苯基或吡啶基,所述苯基或吡啶基任选地被一个、两个或三个选白卤素、卤素取代的低级烷基、低级烷氧基、卤素取代的低级烷氧基、氰基或S(O)2‑低级烷基的取代基取代,或是吗啉基、二氢吡喃基或哌啶基,其中哌啶基任选地被卤素取代,或是C(O)O‑低级烷基;R2是氢;R3是氢、卤素取代的低级烷基、‑(CH2)n‑S(O)2‑低级烷基、‑(CH2)n‑环烷基或‑(CH2)n‑低级烷氧基;R4是氢或低级烷基;n是0、1或2;或涉及其药用酸加成盐、外消旋混合物或其相应的对映异构体和/或光学异构体。所述化合物可以用于治疗精神分裂症、强迫型人格障碍、重度抑郁症、双相型精神障碍、焦虑症、正常衰老、癫痫、视网膜变性、创伤性脑损伤、脊髓损伤、创伤后精神紧张性障碍、惊恐性障碍、帕金森病、痴呆、阿尔茨海默病、认知损害、化疗引起的认知功能障碍(“化疗后大脑”)、唐氏综合征、白闭症谱系障碍、听力损失、耳鸣、脊髓小脑性共济失调、肌萎缩侧索硬化、多发性硬化、亨廷顿病、中风和由放射治疗、慢性应激、视神经病变或黄斑变性或选白酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的神经活性药物的滥用导致的失调。
Description
本发明涉及通式I的化合物
其中
R1是苯基或吡啶基,所述苯基或吡啶基任选地被一个、两个或三个选自卤素、卤素取代的低级烷基、低级烷氧基、卤素取代的低级烷氧基、氰基或S(O)2-低级烷基的取代基取代,或是
吗啉基、二氢吡喃基或哌啶基,其中哌啶基任选地被卤素取代,或是
C(O)O-低级烷基;
R2是氢;
R3是氢、卤素取代的低级烷基、-(CH2)n-S(O)2-低级烷基、-(CH2)n-环烷基或-(CH2)n-低级烷氧基;
R4是氢或低级烷基;
n是0、1或2;
或涉及其药用酸加成盐、外消旋混合物或其相应的对映异构体和/或光学异构体。
现在已经显示,本发明的化合物刺激从神经干细胞(NSC)的神经发生。神经发生在发育过程中和成人脑中发生。概念上,该神经发生过程可以分为四个步骤:(i)NSC的增殖;(ii)NSC的神经元命运决定;(iii)新的神经元的存活和成熟;和(iv)新神经元功能性整合入神经元网络。
成人神经发生是整个生命中成人脑中发生的发育过程,借此,新的功能神经元从成人神经干细胞产生。在生理条件下组成型成人神经发生主要发生在两个“神经源性的”脑区域,1)海马齿状回中的亚颗粒区(SGZ),在那里产生新的齿状颗粒细胞,2)侧脑室的亚脑室区(SVZ),在那里新的神经元产生并且随后通过嘴侧迁移流(RMS)迁移至嗅球,从而成为中间神经 元。
广泛的证据提示,海马的成人神经发生在认知和情绪状态中发挥重要作用,尽管精确的功能仍然难以描述。已经主张,相对小量的新生颗粒神经元可以影响整个脑功能,因为它们使齿状回内的很多中间神经元受神经支配,其每个抑制数百个成熟颗粒细胞,导致神经发生依赖性的反馈抑制。与低激发阈值联合,所述新生神经元针对环境中非常细微的变化引发响应。该过程中的失调可以在行为上表明与精神疾病相关的模式分离上的短缺。例如,成人海马的神经发生与认知和情感能力相关,例如,体育锻炼,暴露于丰富的外界环境和典型的抗抑郁药并发地促进成人海马神经发生和认知和/或情绪状态,同时慢性应激(chronic stress),抑郁症,睡眠剥夺和衰老减少成人神经发生并且与负面的认知和/或情绪状态相关(Neuron 70,2011年5月26日,pp 582-588和pp 687-702;WO 2008/046072)。令人关注的是,抗抑郁药促进海马成人神经发生并且其对某些行为的影响需要刺激神经发生。通常相信,在其它成人CNS区域中的神经发生在正常生理条件下是非常有限的,但在损伤诸如中风(stroke),和中枢和外周脑损伤之后可以被诱导。
因此,据信,成人神经发生的刺激代表了用于正常衰老、尤其是用于多种神经变性疾病和神经精神疾病的神经再生治疗靶点,所述神经变性疾病和神经精神疾病包括精神分裂症(schizophrenia),强迫型人格障碍(obsessive-compulsive personalitydisorder),重度抑郁症(major depression),双相型精神障碍(bipolar disorders),焦虑症(anxiety disorders),癫痫(epilepsy),视网膜变性(retinal degeneration),创伤性脑损伤(traumatic brain injury),脊髓损伤(spinal cord injury),创伤后精神紧张性障碍(post-traumatic stress disorder),惊恐性障碍(panic disorder),帕金森病(Parkinson’s disease),痴呆(dementia),阿尔茨海默病(Alzheimer’s disease),轻度认知损害(mild cognitive impairment),化疗引起的认知功能障碍(chemotherapy-inducedcognitive dysfunction)(″化疗后大脑(chemobrain)″),唐氏综合征(Down syndrome),自闭症谱系障碍(autism spectrum disorders),听力损失(hearing loss)(Neuroscience,167(2010)1216-1226;Nature Medicine,第11卷,第3期,(2005),271-276)耳鸣(tinnitus),脊髓小脑性共济失调(spinocerebellar ataxia),肌萎缩侧索硬化(amyotrophic lateral sclerosis),多发性硬化(multiple sclerosis),亨廷顿病(Huntington’s disease),中风(stroke),和由放射治疗(radiation therapy),慢性应激(chronic stress),或神经活性药物如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用导致的失调(US 2012/0022096)。
成人神经发生的刺激还代表视神经病变(S.Isenmann,A.Kretz,A.Cellerino,Progress in Retinal and Eye Research,22,(2003)483)和黄斑变性(G.Landa,O.Butovsky,J.Shoshani,M.Schwartz,A.Pollack,Current Eye Research 33,(2008)1011)的治疗靶点。
因此,化学刺激成人神经发生提供新的再生手段和机会,以开发用于治疗神经系统疾病和神经精神障碍的新药。
因此,本发明的目的是鉴定调节神经发生的化合物。已经发现,式I的化合物在该区域有活性并且它们可以因此用于治疗精神分裂症(schizophrenia)、强迫型人格障碍(obsessive-compulsive personality disorder)、重度抑郁症(major depression)、双相型精神障碍(bipolar disorders)、焦虑症(anxiety disorders)、正常衰老、癫痫(epilepsy)、视网膜变性(retinal degeneration)、创伤性脑损伤(traumatic braininjury)、脊髓损伤(spinal cord injury)、创伤后精神紧张性障碍(post-traumaticstress disorder)、惊恐性障碍(panic disorder)、帕金森病(Parkinson’s disease)、痴呆(dementia)、阿尔茨海默病(Alzheimer’s disease)、认知损害(cognitiveimpairment)、化疗引起的认知功能障碍(chemotherapy-induced cognitivedysfunction)(″chemobrain(化疗后大脑)″)、唐氏综合征(Down syndrome)、自闭症谱系障碍(autism spectrum disorders)、听力损失(hearing loss)、耳鸣(tinnitus)、脊髓小脑性共济失调(spinocerebellar ataxia)、肌萎缩侧索硬化(amyotrophic lateralsclerosis)、多发性硬化(multiple sclerosis)、亨廷顿病(Huntington’s disease)、中风(stroke)和由放射治疗(radiation therapy)、慢性应激(chronic stress)、视神经病变或黄斑变性或神经活性药物如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用导致的失调。
式I的化合物的最优选的适应症是阿尔茨海默病(Alzheimer’s disease),抑郁症(depression),焦虑症(anxiety disorders)和中风(stroke)。
本发明的一个目标是式I的化合物用于制备药物的用途,所述药物用于治疗性和/或预防性治疗上述疾病,
本发明的另一个目标是用于治疗精神分裂症、强迫型人格障碍、重度抑郁症、双相型精神障碍、焦虑症、正常衰老、癫痫、视网膜变性、创伤性脑损伤、脊髓损伤、创伤后精神紧张性障碍、惊恐性障碍、帕金森病、痴呆、阿尔茨海默病、认知损害、化疗引起的认知功能障碍、唐氏综合征、自闭症谱系障碍、听力损失、耳鸣、脊髓小脑性共济失调、肌萎缩侧索硬化、多发性硬化、亨廷顿病、中风、放射治疗、慢性应激、视神经病变或黄斑变性、神经活性药物如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用的方法,所述方法包括施用有效量的式I的化合物。
本发明的一个实施方案是式I的化合物,其中R1是苯基或吡啶基,所述苯基或吡啶基任选地被一个、两个或三个选自卤素、卤素取代的低级烷基、低级烷氧基、卤素取代的低级烷氧基、氰基或S(O)2-低级烷基的取代基取代,例如以下化合物:
5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4,5-三氟苯基)-l,7-萘啶-3-甲酰胺
5-(4-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氰基苯基)-1,7-萘啶-3-甲酰胺
5-(4-(甲基磺酰基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(4-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(4-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(3-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(环丙基甲基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(2-甲氧基乙基)-1,7-萘啶-3-甲酰胺
5-(3-甲氧基苯基)-1,7-萘啶-3-甲酰胺
5-(3-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(6-氯吡啶-3-基)-1,7-萘啶-3-甲酰胺,或
5-(2,4-二氯苯基)-1,7-萘啶-3-甲酰胺。
本发明的一个实施方案还是式I的化合物,其中R1是吗啉基、二氢吡喃基或哌啶基,其中哌啶基任选地被卤素取代,例如:
5-吗啉代-1,7-萘啶-3-甲酰胺
3-氨基甲酰基-1,7-萘啶-5-甲酸甲酯
5-(3,6-二氢-2H-吡喃-4-基)-1,7-萘啶-3-甲酰胺,或
5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺。
本发明的一个实施方案还是式I的化合物,其中R2和R3都是氢,例如以下化合物:
5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4,5-三氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氰基苯基)-1,7-萘啶-3-甲酰胺
5-(4-(甲基磺酰基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-1,7-萘啶-3-甲酰胺
5-吗啉代-1,7-萘啶-3-甲酰胺
5-(3-甲氧基苯基)-1,7-萘啶-3-甲酰胺
5-(3-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
3-氨基甲酰基-1,7-萘啶-5-甲酸甲酯
5-(3,6-二氢-2H-吡喃-4-基)-1,7-萘啶-3-甲酰胺
5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺
5-(6-氯吡啶-3-基)-1,7-萘啶-3-甲酰胺,或
5-(2,4-二氯苯基)-1,7-萘啶-3-甲酰胺。
不论讨论的术语单独或组合出现,以下用于本说明书的通用术语的定义都适用。
如本文中使用的,术语“低级烷基”表示包括具有1-4个碳原子的直链或支链碳链的饱和的,即脂族的烃基团。“烷基”的实例是甲基,乙基,正丙基,和异丙基。
术语“烷氧基”表示基团-O-R’,其中R’是如上所定义的低级烷基。
术语“被卤素取代的低级烷基”表示如上所定义的低级烷基基团,其中至少一个氢原子被卤素原子替代。优选的基团是CF3。
术语“卤素取代的低级烷氧基”表示如上所定义的低级烷氧基,其中至少一个氢原子被卤素原子替代。优选的基团是OCF3。
术语“卤素”表示氯、溴、氟或碘。
术语″药用盐″或“药用酸加成盐”包括与无机和有机酸,如盐酸,硝酸,硫酸,磷酸,柠檬酸,甲酸,富马酸,马来酸,乙酸,琥珀酸,酒石酸,甲磺酸,对苯甲磺酸等的盐。
本发明的新的式I化合物及其药用盐可以通过本领域已知的方法制备,例如,通过下述方法制备,所述方法包括
a)将式1的化合物
与式2的化合物反应
NHR2R3 2
形成式I的化合物
并且,如果需要,将获得的化合物转化为药用酸加成盐,或
b)将式3的化合物
与式4的化合物反应
形成式I的化合物
并且,如果需要,将获得的化合物转化为药用酸加成盐。
本发明式I的化合物的制备可以以顺序或会聚的合成途径进行。本发明化合物的合成显示在以下方案1中。进行所述反应和纯化产生的产物的技术对于本领域技术人员已知。除非有相反说明,以下方法描述中使用的取代基和标记具有上文中给出的意义。
更详细地,可以通过下文给出的方法,通过实施例中给出的方法或通过类似方法制造式I的化合物。各个反应步骤的适当反应条件是本领域技术人员已知的。反应顺序不限于方案1中显示的顺序,而是依赖于起始材料和其相应反应性,反应步骤的顺序可以随意改变。起始材料是可商购的或可以通过与下文给出的方法类似的方法,通过说明书引用的参考文献中或实施例中描述的方法,或通过本领域已知的方法制备。
方案1
将式5的5-溴-1,7-萘啶-3-甲酸,N,N-二异丙基乙胺和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HATU)在二甲基甲酰胺中的混合物在室温搅拌10分钟。加入式2的相应胺并继续搅拌超过两天,获得式3的化合物。
此外,向式3的5-溴-1,7-萘啶3-甲酰胺和式4的硼酸和碳酸铯在二烷和水中的悬浮液中,加入双(二苯基膦基)二茂铁-二氯化钯(II)。将混合物在80℃搅拌3小时。通过蒸馏去除溶剂并色谱分离,获得式I的化合物。
化合物的分离和纯化
如果需要,本文中描述的化合物和中间体的分离和纯化可以通过任意合适的分离或纯化方法进行,所述方法诸如,例如,过滤,萃取,结晶,柱层析,薄层层析,厚层层析,制备型低或高压液相色谱或这些方法的组合。可以通过参考下文的制备和实施例获得适当的分离和离析方法的具体说明。然而,当然可以使用其它相当的分离或离析方法。可以使用手性HPLC分离式I的手性化合物的外消旋混合物。
式I的化合物的盐
式I的化合物是碱性的并且可以被转变为相应的酸加成盐。通过用至少化学计量的量的适当酸诸如盐酸,氢溴酸,硫酸,硝酸,磷酸等,和有机酸诸如乙酸,丙酸,乙醇酸,丙酮酸,草酸,苹果酸,丙二酸,琥珀酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸, 乙磺酸,对甲苯磺酸,水杨酸等处理实现转变。典型地,将游离碱溶解在惰性有机溶剂诸如二乙醚,乙酸乙酯,氯仿,乙醇或甲醇等中,并且将酸加入类似的溶剂中。将温度维持在0℃和50℃之间。产生的盐自发沉淀或可以用较小极性的溶剂带出溶液。
式I的碱性化合物的酸加成盐可以通过用至少化学计量当量的适当碱诸如氢氧化钠或氢氧化钾,碳酸钾,碳酸氢钠,氨水等处理转变为相应的游离碱。
式I的化合物和其药用加成盐具有有益的药学性质。具体地,已经发现本发明的化合物具有作为神经源性剂的活性。
根据下文给出的测试研究所述化合物。
神经发生测定
神经干细胞增殖测定
小分子的神经源性性质基于通过之前描述的双重smad抑制衍生的人胚胎干细胞衍生的神经干细胞(NSC)的增殖而确定(Chambers,S.M.,等人,Highly efficient neuralconversion ofhuman ES and iPS cells by dual inhibition of SMAD signaling,Nature biotechnology,2009.27(3):p.275-80.)
4天的孵育期之后,通过基于ATP水平的细胞增加(Promega: )测量化合物响应。
将NSC解冻并扩充3代。在第14天,将NSC以38μl培养基体积中21’000个细胞/cm2的细胞密度接种入Polyornithin/Laminin包被的384孔板中。
细胞接种后4小时,以2μl的体积添加化合物溶液。将化合物的储液(水,5%DMSO)稀释以获得剂量响应(11个点,稀释因子是2),范围从8μM至8nM。运行对照以不断确定细胞的神经源性性质:
阴性(中性)对照是细胞培养基(最终DMSO浓度:0.25%)。
阳性对照是:
1.细胞培养基+100ng/ml FGF2(最终DMSO浓度:0.1%)
2.细胞培养基+20ng/ml EGF(最终DMSO浓度:0.1%)
3.细胞培养基+100ng/ml Wnt3a(最终DMSO浓度:0.1%)
在37℃,5%CO2孵育4天之后,定量每孔的ATP量。ATP浓度与细胞数量成比例。通过使用Promega试剂盒定量ATP。 试剂含有细胞溶解缓冲液,热稳定荧光素酶(UltraGloTM重组荧光素酶),镁和荧光素。荧光素与ATP反应产生氧化荧光素,AMP和光。发光信号与ATP含量成比例。
对于各个测定板,通过采用16个阴性对照孔的平均确定阴性(中性)对照值。对于各个化合物,将神经源性化合物响应计算为(化合物/阴性对照)*100。
对于各个测试化合物,确定来自剂量响应曲线的EC150值。EC150是达到对照(100%)的150%活性的化合物浓度。
优选的化合物显示在<2.5μM的范围内的EC150(μM),如以下表1所示。
表1
新化合物的实例和EC1
50
数据的列表
式I的化合物和式I的化合物的药用盐可以用作药物,例如药物制剂形式的药物。所述药物制剂可以口服施用,例如以片剂、包衣片剂、糖衣丸(dragées)、硬和软明胶胶囊、溶液、乳液或混悬剂的形式施用。然而,施用还可以经直肠(例如以栓剂的形式)或经肠胃外(例如以注射液的形式)实现。
式I的化合物可以用药学上惰性的、无机或有机载体处理以用于生产药物制剂。例如,可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等作为此种载体用于片剂、包衣片剂、糖衣丸和硬明胶胶囊。用于软明胶胶囊的合适的载体是例如,植物油、蜡、脂肪、半固体和液体多元醇等。然而,根据活性物质的性质,在软明胶胶囊的情形下,通常不需要载体。用于生产溶液和糖浆的适当载体是,例如,水、多元醇、甘油、植物油等。用于栓剂的适当载体是例如,天然或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,药物制剂可以含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、甜味剂、着色剂、香料、改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它治疗上有价值的物质。
含有式I的化合物或其药用盐和治疗上惰性的载体的药物也是本发明的目的,其制备方法也是本发明的目的,所述方法包括将一种或多种式I的化合物和/或药用酸加成盐和(如果需要)一种或多种其它治疗上有价值的物质与一种或多种治疗惰性载体一起制成盖伦制剂施用形式。
根据本发明的最优选的适应证是包括中枢神经系统的病症的那些,例如治疗或预防抑郁、精神病、帕金森病、焦虑、注意力缺陷多动症(ADHD)和糖尿病。
剂量可以在宽范围内改变并且当然将适于各个特定案例中的个体需求。在口服给药的情况下,成人的剂量可以在约0.01mg至约1000mg/天的通式I的化合物或相应量的其药用盐的范围内变化。每日剂量可以作为单剂或以分开的多剂施用并且,此外,当发现必要时,也可以超过所述上限。
制造过程
1.混合项目1、2、3和4并用纯化的水制粒。
2.在50℃干燥颗粒。
3.将颗粒通过合适的研磨装置。
4.添加项目5并混合三分钟;在合适的压力机上压制。
制造过程
1.在适当的混合器中混合1、2和3项达30分钟。
2.添加4和5项并混合3分钟。
3.装入适当的胶囊中。
实施例1
5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
a)5-溴-1,7-萘啶-3-甲酸乙酯
将在乙酸(3ml)中的1,7-萘啶-3-甲酸乙酯(CAS949922-44-5,50.0mg,247μmol)和N-溴琥珀酰亚胺(52.8mg,297μmol)在80℃搅拌1小时。将粗反应混合物在真空中浓缩并通过色谱法(硅胶,乙酸乙酯/庚烷=30∶70至 100∶0)纯化从而产生标题化合物,为浅褐色固体(62mg,89%)。MS:m/e=281.2,283.3[M+H]+。
b)5-(4-氯苯基)-1,7-萘啶-3-甲酸乙酯
向5-溴-1,7-萘啶-3-甲酸乙酯(55mg,196μmol)和4-氯苯基硼酸(30.6mg,196μmol)和碳酸铯(70.1mg,215μmol)在二烷(5ml)和水(0.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(7.16mg,9.78μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=20∶80至100∶0)和与二乙醚/戊烷一起研磨产生标题化合物,为浅褐色固体(54mg,88%)。MS:m/e=313.4[M+H]+。
c)5-(4-氯苯基)-1,7-萘啶-3-甲酸
将5-(4-氯苯基)-1,7-萘啶-3-甲酸乙酯(50mg,160μmol)与二烷(6ml)合并从而提供浅褐色溶液。加入在水(1ml)中的氢氧化锂(4.59mg,192μmol)并将混合物在室温搅拌3小时。将粗反应混合物在真空中浓缩,倒入水(10ml)中,用2N盐酸水溶液酸化并用乙酸乙酯萃取从而产生标题化合物,为浅褐色固体(24mg,53%)。MS:m/e=285.4[M+H]+。
d)5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
将5-(4-氯苯基)-1,7-萘啶-3-甲酸(240mg,843μmol)、1,1’-羰基二咪唑(137mg,843μmol)在二氯甲烷(40ml)中的混合物在室温搅拌1小时。加入氢氧化铵水溶液(25%,40ml,1.03mol)并继续搅拌1小时。用水/二氯甲烷萃取和色谱法(乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为浅黄色固体(55mg,23%)。MS:m/e=284.5[M+H]+。
实施例2
5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
a)5-溴-1,7-萘啶-3-甲酸
将5-溴-1,7-萘啶-3-甲酸乙酯(1.893g,6.73mmol)与二烷(100ml)合并从而提供浅褐色溶液。加入在水(16.7ml)中的氢氧化锂(194mg,8.08mmol)并将混合物在室温搅拌过夜。将粗反应混合物在真空中浓缩并倒入水中。将混合物用2N盐酸水溶液酸化。将沉淀过滤并干燥从而产生标题化合物,为浅褐色固体(1.55g,91%)。MS:m/e=253.4,255.3[M+H]+。
b)5-溴-1,7-萘啶-3-甲酰胺
将5-溴-1,7-萘啶-3-甲酸(1.00g,3.95mmol)、1,1’-羰基二咪唑(641mg,3.95mmol)在二氯甲烷(188ml)中的混合物在室温搅拌1小时。加入氢氧化 铵水溶液(25%,143ml,3.7mol)并继续搅拌2小时。用水/二氯甲烷萃取并与甲醇(0.5ml)一起研磨产生标题化合物,为灰白色固体(435mg,44%)。MS:m/e=252.4,254.4[M+H]+。
c)5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和4-(三氟甲氧基)苯基硼酸(32.7mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(25mg,47%)。MS:m/e=334.4[M+H]+。
实施例3
5-(2-氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和2-氟苯基硼酸(22.2mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为浅褐色固体(40mg,94%)。MS:m/e=268.4[M+H]+。
实施例4
5-(3,4,5-三氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和3,4,5-三氟苯基硼酸(27.9mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(25mg,52%)。MS:m/e=304.4[M+H]+。
实施例5
5-(4-氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和4-氟苯基硼酸(22.2mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(29mg,68%)。MS:m/e=268.4[M+H]+。
实施例6
5-(3,4-二氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和3,4-二氟苯基硼酸(25.1mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(35mg,77%)。MS:m/e=286.4[M+H]+。
实施例7
5-(2,4-二氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和2,4-二氟苯基硼酸(25.1mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶O)并与二乙醚一起研磨产生标题化合物,为灰白色固体(42mg,93%)。MS:m/e=286.4[M+H]+。
实施例8
5-(4-氰基苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和4-氰基苯基硼酸(23.3mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。 将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(25mg,57%)。MS:m/e=275.4[M+H]+。
实施例9
5-(4-(甲基磺酰基)苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和4-(甲基磺酰基)苯基硼酸(31.7mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(37mg,71%)。MS:m/e=328.4[M+H]+。
实施例10
5-(4-(三氟甲基)苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(20mg,79.3μmol)和4-(三氟甲基)苯基硼酸(15.1mg,79.3μmol)和碳酸铯(28.4mg,87.3μmol)在二烷(5ml)和水(0.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(2.9mg,3.97μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(18mg,72%)。MS:m/e=318.4[M+H]+。
实施例11
5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
a)5-溴-2-甲基-1,7-萘啶-3-甲酸乙酯
将在乙酸(50ml)中的2-甲基-1,7-萘啶-3-甲酸乙酯(CAS55234-62-3,760mg,3.51mmol)和N-溴琥珀酰亚胺(751mg,4.22mmol)在80℃加热2小时。将粗反应混合物在真空中浓缩并通过色谱法(硅胶,乙酸乙酯/庚烷=0∶100至50∶50)纯化从而产生标题化合物,为灰白色固体(266mg,26%)。MS:m/e=295.3,297.3[M+H]+。
b)5-溴-2-甲基-1,7-萘啶-3-甲酸
将5-溴-2-甲基-1,7-萘啶-3-甲酸乙酯(260mg,881μmol)与二烷(30ml)合并从而提供浅褐色溶液。加入在水(5ml)中的氢氧化锂(25.3mg,1.06mmol)并将混合物在室温搅拌4天。将粗反应混合物在真空中浓缩,倒入水(10ml)中,用2N盐酸水溶液酸化。将沉淀过滤并在真空中干燥从而产生标题化合物,为灰白色固体(215mg,91%)。MS:m/e=267.3,269.2[M+H]+。
c)5-溴-2-甲基-1,7-萘啶-3-甲酰胺
将5-溴-2-甲基-1,7-萘啶-3-甲酸(210mg,786μmol)、1,1’-羰基二咪唑(127mg,786μmol)在二氯甲烷(10ml)中的混合物在室温搅拌1小时。加入氢氧化铵水溶液(25%,3.0ml,77mo1)并继续搅拌1小时。用水/二氯甲烷萃取产生标题化合物,为灰白色固体(154mg,74%)。MS:m/e=266.3,268.3[M+H]+。
d)5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
向5-溴-2-甲基-1,7-萘啶-3-甲酰胺(100mg,376μmol)和4-氯苯基硼酸(58.8mg,376μmol)和碳酸铯(135mg,413μmol)在二烷(15ml)和水(1.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(13.7mg,18.8μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=20∶80至100∶0)并与二乙醚一起研磨产生标题化合物,为灰白色固体(69mg,62%)。MS:m/e=298.4[M+H]+。
实施例12
5-(4-氯-2-氟苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(40mg,159μmol)和4-氯-2-氟苯基硼酸(27.7mg,159μmol)和碳酸铯(56.9mg,175μmol)在二烷(5ml)和水(0.6ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(5.81mg,7.93μmol)。 将混合物在80℃搅拌2小时。通过蒸馏除去溶剂,并且通过色谱法(硅胶,乙酸乙酯/庚烷=20∶80至100∶0)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(41mg,86%)。MS:m/e=302.4[M+H]+。
实施例13
5-(4-氯-2-氟苯基)-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺
a)5-溴-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(30ml)中的5-溴-1,7-萘啶-3-甲酸(500mg,1.98mmol)与3滴二甲基甲酰胺合并。在冷却下缓慢加入草酰氯(2.51g,1.73ml,19.8mmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(30ml)中并在0℃加入至2-(甲基磺酰基)乙胺盐酸盐(315mg,1.98mmol)和三乙胺(420mg,578μl,4.15mmol)在二氯甲烷(30ml)中的混合物。将混合物在0℃搅拌30分钟然后在室温搅拌2小时。用二氯甲烷/水萃取并与乙酸乙酯(5ml)一起研磨产生标题化合物,为浅褐色固体(470mg,66%)。MS:m/e=358.4,360.4[M+H]+。
b)5-(4-氯-2-氟苯基)-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺
向5-溴-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺(100mg,279μmol) 和4-氯-2-氟苯基硼酸(48.7mg,279μmol)和碳酸铯(100mg,307μmol)在二烷(10ml)和水(1ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(10.2mg,14.0μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(60mg,53%)。MS:m/e=408.4[M+H]+。
实施例14
5-(2-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
a)5-溴-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(20ml)中的5-溴-l,7-萘啶-3-甲酸(300mg,1.19mmol)与3滴二甲基甲酰胺合并。在冷却下缓慢加入草酰氯(752mg,519μl,5.93mmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(30ml)中并在0℃加入至2,2,2-三氟乙胺(117mg,1.19mmol)和三乙胺(252mg,347μl,2.49mmol)在二氯甲烷(20ml)中的混合物。将混合物在0℃搅拌30分钟然后在室温搅拌1小时。用二氯甲烷/水的萃取和色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为浅褐色固体(230mg,58%)。MS:m/e=334.3,336.3[M+H]+。
b)5-(2-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
向5-溴-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺(100mg,299μmol)和2-氟苯基硼酸(41.9mg,299μmol)和碳酸铯(107mg,329μmol)在二烷(15ml)和水(1.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(11.0mg,15.0μmo1)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(101mg,97%)。MS:m/e=350.4[M+H]+。
实施例15
5-(2,4-二氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
向5-溴-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺(100mg,299μmol)和2,4-二氟苯基硼酸(47.3mg,299μmol)和碳酸铯(107mg,329μmol)在二烷(15ml)和水(1.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(11.0mg,15.0μmol)。将混合物在80℃搅拌3小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(86mg,78%)。MS:m/e=368.4[M+H]+。
实施例16
5-吗啉代-1,7-萘啶-3-甲酰胺
a)5-吗啉代-1,7-萘啶-3-甲酸乙酯
向5-溴-1,7-萘啶-3-甲酸酯(500mg,1.78mmol)和乙酸钯(II)(39.9mg,178μmol)和(1,1′-联萘-2,2′-二基)双(二苯基膦)(BINAP,222mg,356μmol)和碳酸铯(1.74g,5.34mmol)在甲苯(30ml)中的悬浮液加入吗啉(232mg,2.67mmol)。将混合物在80℃搅拌15小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=20∶80至100∶0)产生标题化合物,为黄色固体(496mg,97%)。MS:m/e=288.5[M+H]+。
b)5-吗啉代-1,7-萘啶-3-甲酸
将5-吗啉代-1,7-萘啶-3-甲酸乙酯(495mg,1.72mmol)与二烷(20ml)合并从而提供黄色溶液。加入在水(3ml)中的氢氧化锂(49.5mg,2.07mmol)并将混合物在室温搅拌过夜。将粗反应混合物在真空中浓缩,倒入水(20ml)中并用2N盐酸水溶液酸化。将沉淀在真空中干燥从而产生标题化合物,为黄色固体(415mg,93%)。MS:m/e=260.4[M+H]+。
c)5-吗啉代-1,7-萘啶-3-甲酰胺
将5-吗啉代-1,7-萘啶-3-甲酸(200mg,771μmol)、1,1’-羰基二咪唑(125mg,771μmol)在二氯甲烷(15ml)中的混合物在室温搅拌1小时。加入氢氧化铵水溶液(25%,3.0ml,77mo1)并继续搅拌过夜。用水/二氯甲烷的萃取和色谱法(硅胶,乙酸乙酯/庚烷=40∶60至100∶0,然后制备型HPLC,C18反相,水(0.1%甲酸)/乙腈=80∶20至98∶2)产生标题化合物,为灰白色固体(7mg,4%)。MS:m/e=259.4[M+H]+。
实施例17
5-(4-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
向5-溴-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺(115mg,293μmol)和4-氟苯基硼酸(40.9mg,293μmol)和碳酸铯(105mg,322μmol)在二烷(18ml)和水(1.8ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(10.7mg,14.6μmol)。将混合物在80℃搅拌3小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(45mg,44%)。MS:m/e=350.4[M+H]+。
实施例18
5-(4-氯苯基)-N-(4-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(10ml)中的5-(4-氯苯基)-1,7-萘啶-3-甲酸(34mg,119μmol)与2滴二甲基甲酰胺合并。在0℃缓慢加入草酰氯(75.8mg,52.3μl, 597μmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(10ml)中并在0℃加入至(4-(甲基磺酰基)苯基)甲胺盐酸盐(26.5mg,119μmol)和三乙胺(37.5mg,51.6μl,370μmol)在二氯甲烷(10ml)中的混合物。将混合物在0℃搅拌30分钟然后在室温搅拌1小时。用二氯甲烷/水的萃取和色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为灰白色固体(25mg,46%)。MS:m/e=452.4[M+H]+。
实施例19
5-(4-氯苯基)-N-(3-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(20ml)中的5-(4-氯苯基)-1,7-萘啶-3-甲酸(70mg,246μmol)与2滴二甲基甲酰胺合并。在0℃缓慢加入草酰氯(156mg,108μl,1.23mmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(20ml)中并在0℃加入至(3-(甲基磺酰基)苯基)甲胺(45.5mg,246μmol)和三乙胺(77.1mg,106μl,762μmol)在二氯甲烷(20ml)中的混合物。将混合物在0℃搅拌20分钟然后在室温搅拌1小时。用二氯甲烷/水的萃取和色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为灰白色固体(62mg,56%)。MS:m/e=452.3[M+H]+。
实施例20
5-(4-氯苯基)-N-(环丙基甲基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(30ml)中的5-(4-氯苯基)-1,7-萘啶-3-甲酸(100mg,351μmol)与3滴二甲基甲酰胺合并。在0℃缓慢加入草酰氯(223mg,154μl,1.76mmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(30ml)中并在0℃加入至环丙基甲胺(25.0mg,30.5μl,351μmol)和三乙胺(110mg,152μl,1.09mmol)在二氯甲烷(30ml)中的混合物。将混合物在0℃搅拌20分钟然后在室温搅拌1小时。用二氯甲烷/水的萃取和色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为灰白色固体(111mg,94%)。MS:m/e=338.4[M+H]+。
实施例21
5-(4-氯苯基)-N-(2-甲氧基乙基)-1,7-萘啶-3-甲酰胺
将在二氯甲烷(10ml)中的5-(4-氯苯基)-1,7-萘啶-3-甲酸(70mg,246μmol)与3滴二甲基甲酰胺合并。在0℃缓慢加入草酰氯(156mg,108μl,1.23mmol)。将混合物在0℃搅拌30分钟并在室温搅拌30分钟。将粗反应混合物在真空中浓缩。将其置于二氯甲烷(20ml)中并在0℃加入至2-甲氧基乙胺(22.2mg,25.4μl,295μmol)和三乙胺(74.6mg,103μl,738μmol)在二氯甲烷(10ml)中的混合物。将混合物在0℃搅拌20分钟然后在室温搅拌1小时。用二氯甲烷/水的萃取和色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为灰白色固体(71mg,85%)。MS:m/e=342.4[M+H]+。
实施例22
5-(3-甲氧基苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(60mg,238μmol)和3-甲氧基苯基硼酸(36.2mg,238μmol)和碳酸铯(85.3mg,262μmol)在二烷(5ml)和水(0.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(8.71mg,11.9μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(60mg,90%)。MS:m/e=280.4[M+H]+。
实施例23
5-(3-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(60mg,238μmol)和3-(三氟甲氧基)苯基硼酸(49.0mg,238μmol)和碳酸铯(85.3mg,262μmol)在二烷(5ml)和水(0.5ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(8.71mg,11.9μmol)。将混合物在80℃搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯)并且与二乙醚/戊烷一起研磨产生标题化合物,为灰白色固体(68mg,86%)。MS:m/e=334.4[M+H]+。
实施例24
3-氨基甲酰基-1,7-萘啶-5-甲酸甲酯
将5-溴-1,7-萘啶-3-甲酰胺(100mg,397μmol)和三乙胺(80.3mg,111μl,793μmol)在甲醇(5ml)和乙酸乙酯(5.00ml)中的溶液在钢反应器(35ml)中在氩气氛下与双(二苯基膦基)二茂铁-二氯化钯(II)(14.5mg,19.8μmol)合并。将反应器用一氧化碳(10bar)冲洗3次然后置于一氧化碳气氛(50bar)下并加热至110℃。2小时后,将混合物过滤并在真空中浓缩从而产生标题化合物,为灰白色固体(65mg,71%)。MS:m/e=232.4[M+H]+。
实施例25
5-(3,6-二氢-2H-吡喃-4-基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(100mg,397μmol)和2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(83.3mg,397μmol)和碳酸铯(142mg,436μmol)在二烷(3ml)和水(0.3ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(14.5mg,19.8μmol)。将混合物在80℃搅拌一小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/甲醇=100∶0至50∶50)产生标题化合物,为褐色固体(45mg,44%)。MS:m/e=256.3[M+H]+。
实施例26
5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺
a)5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酸乙酯
向5-溴-1,7-萘啶-3-甲酸乙酯(500mg,1.78mmol)和乙酸钯(II)(39.9mg,178μmol)和(1,1′-联萘-2,2′-二基)双(二苯基膦)(222mg,356μmol)和碳酸铯(1.74g,5.34mmol)在甲苯(30ml)中的悬浮液加入4,4-二氟哌啶(215mg,1.78mmol)。将混合物在80℃搅拌15小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=20∶80至100∶0)产生标题化合物,为黄色固体(452mg,79%)。MS:m/e=322.4[M+H]+。
b)5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酸
将5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酸乙酯(445mg,1.38mmol)与二烷(20ml)合并从而提供黄色悬浮液。加入在水(3ml)中的氢氧化锂(39.8mg,1.66mmol)并将混合物在室温搅拌3小时。将粗反应混合物在真空中浓缩,倒入水(15ml)中,并用1N盐酸水溶液酸化。将沉淀过滤并干燥从而产生标题化合物,为浅黄色固体(285mg,70%)。MS:m/e=292.5[M-H]-。
c)5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺
将5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酸(280mg,955μmol)和1,1’-羰基二咪唑(325mg,2.00mmol)在二氯甲烷(20ml)中的混合物在室温搅拌1小时。加入氯化铵(255mg,4.77mmol)和三乙胺(483mg,665μl,4.77mmol)并继续搅拌2小时。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯/庚烷=50∶50至100∶0)产生标题化合物,为黄色固体(144mg,52%)。MS:m/e=293.4[M+H]+。
实施例27
5-(6-氯吡啶-3-基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(70mg,278μmol)和6-氯吡啶-3-基硼酸(43.7mg,278μmol)和碳酸铯(99.5mg,305μmol)在二烷(10ml)和水(1.0ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(10.2mg,13.9μmol)。将混合物在80℃搅拌过夜。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯)产生标题化合物,为灰白色固体(65mg,82%)。MS:m/e=285.4[M+H]+。
实施例28
5-(2,4-二氯苯基)-1,7-萘啶-3-甲酰胺
向5-溴-1,7-萘啶-3-甲酰胺(70mg,278μmol)和2,4-二氯苯基硼酸(53.0mg,278μmol)和碳酸铯(99.5mg,305μmol)在二烷(10ml)和水(1.0ml)中的悬浮液加入双(二苯基膦基)二茂铁-二氯化钯(II)(10.2mg,13.9μmol)。 将混合物在80℃搅拌过夜。通过蒸馏除去溶剂并且通过色谱法(硅胶,乙酸乙酯)产生标题化合物,为白色固体(79mg,90%)。MS:m/e=318.3[M+H]+。
Claims (12)
1.式I的化合物
其中
R1是苯基或吡啶基,所述苯基或吡啶基任选地被一个、两个或三个选自卤素、卤素取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基、氰基或S(O)2-C1-4烷基的取代基取代,或是
吗啉基、二氢吡喃基或哌啶基,其中哌啶基任选地被卤素取代,或是C(O)O-C1-4烷基;
R2是氢;
R3是氢、卤素取代的C1-4烷基、-(CH2)n-S(O)2-C1-4烷基、-(CH2)n-环烷基或-(CH2)n-C1-4烷氧基;
R4是氢或C1-4烷基;
n是0、1或2;
或其药用酸加成盐、外消旋混合物或其光学异构体。
2.根据权利要求1所述的式I的化合物,其中R1是苯基或吡啶基,所述苯基或吡啶基任选地被一个、两个或三个选自卤素、卤素取代的C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷氧基、氰基或S(O)2-C1-4烷基的取代基取代。
3.根据权利要求1或2中任一项所述的式I的化合物,所述化合物是:
5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4,5-三氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氰基苯基)-1,7-萘啶-3-甲酰胺
5-(4-(甲基磺酰基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-N-(2-(甲基磺酰基)乙基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(4-氟苯基)-N-(2,2,2-三氟乙基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(4-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(3-(甲基磺酰基)苄基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(环丙基甲基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-N-(2-甲氧基乙基)-1,7-萘啶-3-甲酰胺
5-(3-甲氧基苯基)-1,7-萘啶-3-甲酰胺
5-(3-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(6-氯吡啶-3-基)-1,7-萘啶-3-甲酰胺,或
5-(2,4-二氯苯基)-1,7-萘啶-3-甲酰胺。
4.根据权利要求1所述的式I的化合物,其中R1是吗啉基、二氢吡喃基或哌啶基,其中哌啶基任选地被卤素取代。
5.根据权利要求1所述的式I的化合物,所述化合物是:
5-吗啉代-1,7-萘啶-3-甲酰胺
3-氨基甲酰基-1,7-萘啶-5-甲酸甲酯
5-(3,6-二氢-2H-吡喃-4-基)-1,7-萘啶-3-甲酰胺,或
5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺。
6.根据权利要求1所述的式I的化合物,其中R2和R3都是氢。
7.根据权利要求1或6中任一项所述的式I的化合物,所述化合物是
5-(4-氯苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
5-(2-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4,5-三氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氟苯基)-1,7-萘啶-3-甲酰胺
5-(3,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(2,4-二氟苯基)-1,7-萘啶-3-甲酰胺
5-(4-氰基苯基)-1,7-萘啶_3_甲酰胺
5-(4-(甲基磺酰基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-(三氟甲基)苯基)-1,7-萘啶-3-甲酰胺
5-(4-氯苯基)-2-甲基-1,7-萘啶-3-甲酰胺
5-(4-氯-2-氟苯基)-1,7-萘啶-3-甲酰胺
5-吗啉代-1,7-萘啶-3-甲酰胺
5-(3-甲氧基苯基)-1,7-萘啶-3-甲酰胺
5-(3-(三氟甲氧基)苯基)-1,7-萘啶-3-甲酰胺
3-氨基甲酰基-1,7-萘啶-5-甲酸甲酯
5-(3,6-二氢-2H-吡喃-4-基)-1,7-萘啶-3-甲酰胺
5-(4,4-二氟哌啶-1-基)-1,7-萘啶-3-甲酰胺
5-(6-氯吡啶-3-基)-1,7-萘啶-3-甲酰胺,或
5-(2,4-二氯苯基)-1,7-萘啶-3-甲酰胺。
8.用于制备如权利要求1至7中任一项所限定的式I的化合物的方法,所述方法包括:
a)将式1的化合物
与式2的化合物反应
NHR2R3 2
形成式I的化合物
并且,如果需要,将获得的化合物转化为药用酸加成盐,或
b)将式3的化合物
与式4的化合物反应
形成式I的化合物
并且,如果需要,将获得的化合物转化为药用酸加成盐。
9.根据权利要求1-7中任一项所述的式I的化合物,其用作治疗活性物质。
10.根据权利要求1-7中任一项所述的式I的化合物,其用于治疗精神分裂症、强迫型人格障碍、抑郁症、双相型精神障碍、焦虑症、正常衰老、癫痫、视网膜变性、创伤性脑损伤、脊髓损伤、创伤后精神紧张性障碍、惊恐性障碍、帕金森病、痴呆、阿尔茨海默病、认知损害、化疗引起的认知功能障碍、唐氏综合征、自闭症谱系障碍、听力损失、耳鸣、脊髓小脑性共济失调、肌萎缩侧索硬化、多发性硬化、亨廷顿病、中风、放射治疗、慢性应激、视神经病变或黄斑变性、选自酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的神经活性药物的滥用。
11.药物组合物,所述药物组合物包含权利要求1-7中任一项所要求保护的式I的化合物和药用赋形剂。
12.根据权利要求1-7中任一项所述的式I的化合物用于制备药物的用途,所述药物用于治疗精神分裂症、强迫型人格障碍、抑郁症、双相型精神障碍、焦虑症、正常衰老、癫痫、视网膜变性、创伤性脑损伤、脊髓损伤、创伤后精神紧张性障碍、惊恐性障碍、帕金森病、痴呆、阿尔茨海默病、认知损害、化疗引起的认知功能障碍、唐氏综合征、自闭症谱系障碍、听力损失、耳鸣、脊髓小脑性共济失调、肌萎缩侧索硬化、多发性硬化、亨廷顿病、中风、放射治疗、慢性应激、视神经病变或黄斑变性、选自酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的神经活性药物的滥用。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008036308A2 (en) * | 2006-09-18 | 2008-03-27 | Signal Pharmaceuticals, Llc | Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith |
WO2008046072A2 (en) * | 2006-10-13 | 2008-04-17 | The Board Of Regents Of The University Of Texas System | Chemical inducers of neurogenesis |
CN101277958A (zh) * | 2005-10-05 | 2008-10-01 | 弗·哈夫曼-拉罗切有限公司 | 萘啶衍生物 |
WO2009155121A2 (en) * | 2008-05-30 | 2009-12-23 | Amgen Inc. | Inhibitors of pi3 kinase |
CN102741249A (zh) * | 2010-02-05 | 2012-10-17 | 默克专利有限公司 | 杂芳基-[1,8]萘啶衍生物 |
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WO2014079787A1 (en) * | 2012-11-20 | 2014-05-30 | F. Hoffmann-La Roche Ag | Substituted 1,6-naphthyridines |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101277958A (zh) * | 2005-10-05 | 2008-10-01 | 弗·哈夫曼-拉罗切有限公司 | 萘啶衍生物 |
WO2008036308A2 (en) * | 2006-09-18 | 2008-03-27 | Signal Pharmaceuticals, Llc | Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith |
WO2008046072A2 (en) * | 2006-10-13 | 2008-04-17 | The Board Of Regents Of The University Of Texas System | Chemical inducers of neurogenesis |
WO2009155121A2 (en) * | 2008-05-30 | 2009-12-23 | Amgen Inc. | Inhibitors of pi3 kinase |
CN102741249A (zh) * | 2010-02-05 | 2012-10-17 | 默克专利有限公司 | 杂芳基-[1,8]萘啶衍生物 |
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