CN117800898A - 一种咔唑类化合物及其应用 - Google Patents
一种咔唑类化合物及其应用 Download PDFInfo
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- CN117800898A CN117800898A CN202311794699.9A CN202311794699A CN117800898A CN 117800898 A CN117800898 A CN 117800898A CN 202311794699 A CN202311794699 A CN 202311794699A CN 117800898 A CN117800898 A CN 117800898A
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Abstract
本发明公开了一种如通式I所示的咔唑类化合物或其对映异构体、非对映异构体、外消旋体、药学上可接受的盐、含有其的药物组合物,此类化合物作为cGAS‑STING通路靶向抑制剂,能够靶向抑制cGAMP激动cGAS‑STING通路,具有制备治疗和/或预防炎症性疾病和自身免疫性疾病的药物的用途。
Description
技术领域
本发明属于医药技术领域,具体涉及一种咔唑类化合物的合成及其应用。该类化合物在稳转THP1细胞中具有较强的STING抑制活性。
背景技术
由干扰素基因刺激因子(Stimulator of interferon gene,STING)介导的cGAS-STING信号通路在宿主抵抗病毒感染和细菌入侵的固有免疫应答过程中发挥着重要作用。首先,环鸟苷酸-腺苷酸合成酶合酶(Cyclic GMP-AMP synthase,cGAS)作为细胞内DNA感受器识别外源性物质或自身的胞浆双链DNA(dsDNA),形成二聚体,稳定的DNA-cGAS复合物可组装成低聚体,随后以ATP和GTP为原料,快速合成重要信使分子2′,3′-cGAMP。2′,3′-cGAMP使STING激活并从内质网转移到高尔基体中,随后招募细胞质中的TANK结合激酶1(TANKbinding kinase-1,TBK1),形成STING-TBK1复合物并介导干扰素调节因子-3(interferonregulatory factor-3,IRF-3)的磷酸化。随后,磷酸化的IRF3形成同源二聚体并转位于细胞核内,诱导IFNs、细胞因子、T细胞募集因子等基因的转录和表达,发挥生物学效应。
STING信号通路的快速激活对于启动宿主的固有免疫应答至关重要,然而由于胞内dsDNA异常积累导致的STING过度激活会使宿主对自身抗原发生免疫反应,诱发一系列自身炎症性疾病,如Aicardi-Goutieres综合征(AGS)、STING相关的婴儿期血管病(STINGassociated vasculopathy of infancy,SAVI)、系统性红斑狼疮(Systemic lupuserythematosus,SLE)等。生物学研究表明通过抑制STING活性或敲除STING基因,均能防止由于Ⅰ型干扰素水平升高而引起的自身免疫性疾病。
综上所述,由于Ⅰ型干扰素和自身核酸都被认为是一些自身免疫性疾病发病机制的标志驱动因子,而STING过度激活导致的干扰素水平升高是多种自身免疫性疾病发生的重要原因,因此STING可作为“关键节点”展开抑制剂研究,为cGAS-STING异常导致的自身免疫性疾病提供新调控策略。
发明内容
发明目的:本发明目的之一在于提供一种如通式I的咔唑类化合物或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
R1选自氢、卤素或C1-C6烷基;
R2选自氢、卤素、C1-C6烷基或卤代C1-C6烷基;
R3选自氢、卤素、C1-C6烷基、卤代C1-C6烷基、硝基、氰基、烷氧基、-(CH2)m NRaRb、酰胺基、杂环基、芳基或杂芳基;所述烷基、杂环基、芳基或杂芳基未被取代或任选地被1-3个Rc取代;
Rc选自氢、卤素、C1-C6烷基或含有0-3个杂原子的3-10元环烷基;所述烷基、环烷基未被取代或任选地被1-3个Rd取代;
Rd选自氢、C1-C6烷基;
Ra、Rb分别独立地选自氢、C1-C6烷基或C3-C6环烷基;
m=0或1;
n=1或2。
在某些优选的实施方式中,
R1选自氢、氟、氯、溴或甲基。
在某些优选的实施方式中,
R2选自氢、三氟甲基或氟。
在某些优选的实施方式中,
R3选自氢、氟、氯、溴、甲基、异丙基、叔丁基、三氟甲基、硝基、氰基、酰胺基、甲氧基、环丙胺甲基、异丙基-2-胺甲基、N,N-二甲胺基、N,N-二甲基胺甲基、N,N-二乙基胺甲基、N-哌啶基甲基、N-吡咯烷基甲基、N-哌嗪基、N-哌嗪基甲基、1-甲基哌嗪基-4-甲基或1-乙基哌嗪基-4-甲基。
在一些优选的实施方式中,所述药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸、琥珀酸、甲磺酸、对甲苯磺酸、萘磺酸、富马酸、水杨酸或苯基乙酸;还包括通式I化合物与无机碱形成的酸式盐或由碱性胺制成的有机盐。
本发明通式I的化合物优选以下化合物:
本发明涉及的上述通式I化合物还可以以其盐的形式存在,它们在体内转化为通式I化合物。例如,在本发明的范围内,按照本领域已知的工艺,将本发明化合物转化为药学上可接受的盐的形式,并且以盐形式使用它们。
本发明通式I化合物的所有的互变异构形式均包括在本发明的范围之内。本发明的化合物可以存在特定的几何或立体异构体形式。烷基等取代基中可存在另外的不对称碳原子,所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
本发明还提供了具有通式I的化合物的合成路线。
合成路线一:
试剂与条件:(a)碳酸钾,丙酮,56℃,8h。
合成路线二:
试剂与条件:(b)四(三苯基膦)钯,甲苯,乙醇,2M碳酸钠溶液,100℃,2h;(c)三苯基膦,邻二氯苯,180℃,10h;(d)1M三溴化硼的二氯甲烷溶液,干燥二氯甲烷,常温,12h;(e)4-(溴甲基)-苯甲酸甲酯,碳酸钾,丙酮,56℃,12h;(f)氢氧化锂,四氢呋喃-甲醇-水,常温,5h;(g)R3-NH2,O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐,N,N-二异丙基乙胺,N,N-二甲基甲酰胺,常温,8h;(h)四氢锂铝,四氢呋喃,50℃,6h。
合成路线三:
试剂与条件:(i)二碳酸二叔丁酯,4-二甲氨基吡啶,乙腈,常温,8h;(j)R3-NH2,碳酸铯,1,1'-联萘-2,2'-双二苯膦,醋酸钯,100℃,10h;(k)三氟乙酸,二氯甲烷,常温,2h。
上述合成路线中R1、R2、R3如通式I中的定义。
本发明通式I化合物都可以用上述或类似上述的制备方法制备得到,根据取代基的不同和取代基位置的不同选用相应的起始原料即可。本领域技术人员应当认识到,上述路线有助于理解本发明,但并不限制本发明的内容,除非另有规定,变量如同通式I中提及的一样定义。
本发明另一目的在于提供一种药物组合物,所述药物组合物包括通式I的化合物或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体以及药学上可接受的载体。
本发明的药物组合物可以采用各种已知的方式施用,例如口服、胃肠外施用、通过吸入喷雾施用或经由植入的贮库施用。本发明的药物组合物可单独给药也可与其他药物联合用药。口服组合物可以是任何口服可接受的剂型,包含但不限于片剂、胶囊剂、乳剂以及混悬剂、分散物和溶液。常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
无菌可注射组合物可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
局部组合物可被配制成油、洗剂、乳膏剂等。用于组合物的载体包括植物油或矿物油、动物脂肪和高分子量醇等。药学上可接受的载体是活性成分在其中可溶的载体。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的的剂量水平取决于多种因素,包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体组合物的排泄速率、治疗的持续时间、与所用的具体组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
本发明另一目的在于提供通式I的化合物或其药学上可接受的盐、其对映异构体、非对映异构体、外消旋体在制备预防和/或治疗与STING蛋白功能相关的疾病的药物中的用途。
所述与STING蛋白功能相关的疾病是STING通路过度激活导致的疾病。
本发明另一目的在于提供通式I的化合物在制备用于预防和/或治疗炎症性疾病和自身免疫性疾病的药物中的用途。
所述与STING蛋白功能相关的疾病、炎症性疾病和自身免疫性疾病包括STING相关的婴儿期发病血管病变SAVI、Aicardi-Goutières综合征AGS、共溶体蛋白复合物α亚单位基因变异导致的COPA综合征、系统性红斑狼疮SLE、家族性冻疮性红斑狼疮FCL、帕金森症PD、肌萎缩侧索硬化症ALS、亨廷顿舞蹈症、非酒精性脂肪肝炎NASH、酒精肝、神经损伤、类风湿性关节炎、肾纤维化、系统性硬化症、椎间盘退变、肺纤维化、衰老、硬皮病,银屑病、炎症性肠病、自身免疫性结肠炎、肠易激综合征、溃疡性结肠炎、克罗恩病、葡萄膜炎、粘膜炎、糖尿病、心血管疾病或神经退行性疾病。
有益效果:
本发明基于细胞表型筛选发现并合成了一系列咔唑类化合物,该类化合物具有良好的cGAS-STING通路抑制活性,在稳转THP1细胞中表现出较强的IRF3基因转录抑制活性,能够制备治疗与STING蛋白功能相关疾病的药物,具有制备治疗和/或预防炎症性疾病和自身免疫性疾病的药物的前景,为临床应用提供了可靠途径。
具体实施方式
下面结合具体实施例描述本发明通式I化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明具体实施例中使用的起始原料、反应试剂等均为市售。本发明可以采用本领域常用的成盐方法制备成盐的形式,例如:室温下,将化合物溶于盐酸乙醇中进行反应,生成盐酸盐;或者向其中加入苯磺酸进行反应生成苯磺酸盐。
本发明实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。化合物的结构通过核磁共振氢谱(1HNMR)经由Bruker Avance300MHz光谱仪测定,使用TMS作为内标,记录温度为300 K。
实施例中无特殊说明,反应均在空气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20~30℃。
实施例1 4-苄氧基-9H-咔唑(1)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入苄溴(118μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体233mg,收率86.17%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.31(d,J=7.8Hz,1H,Ar-H),8.01(brs,1H,NH),7.58(d,J=7.3Hz,2H,Ar-H),7.48-7.27(m,6H,Ar-H),7.25-7.13(m,1H,Ar-H),7.04(d,J=7.9Hz,1H,Ar-H),6.74(d,J=7.9Hz,1H,Ar-H),5.33(s,2H,CH2)。
实施例2 4-(4-甲基苄氧基)-9H-咔唑(2)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对甲基苄溴(137μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体236mg,收率83.02%。1HNMR(300MHz,Chloroform-d)δ(ppm)8.30(d,J=7.8Hz,1H,Ar-H),8.01(brs,1H,NH),7.47(d,J=7.8Hz,2H,Ar-H),7.40-7.35(m,2H,Ar-H),7.31(t,J=8.0Hz,1H,Ar-H),7.27-7.21(m,3H,Ar-H),7.03(d,J=8.1Hz,1H,Ar-H),6.74(d,J=8.0Hz,1H,Ar-H),5.29(s,2H,CH2),2.39(s,3H,CH3)。
实施例3 4-(4-异丙基苄氧基)-9H-咔唑(3)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对异丙基苄溴(164μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体231mg,收率74.04%。1HNMR(300MHz,Chloroform-d)δ(ppm)8.33(d,J=7.8Hz,1H,Ar-H),8.00(brs,1H,NH),7.51(d,J=8.1Hz,2H,Ar-H),7.37(d,J=3.5Hz,2H,Ar-H),7.30(dd,J=8.1,2.2Hz,3H,Ar-H),7.23-7.16(m,1H,Ar-H),7.02(d,J=8.1Hz,1H,Ar-H),6.75(d,J=8.0Hz,1H,Ar-H),5.30(s,2H,CH2),3.03-2.87(m,1H,CH),1.29(d,J=6.9Hz,6H,CH3)。
实施例4 4-(4-叔丁基苄氧基)-9H-咔唑(4)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对叔丁基苄溴(181μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体241mg,收率73.95%。1HNMR(300MHz,Chloroform-d)δ(ppm)8.34(d,J=7.8Hz,1H,Ar-H),8.03(brs,1H,NH),7.57-7.42(m,4H,Ar-H),7.42-7.36(m,2H,Ar-H),7.32(t,J=8.0Hz,1H,Ar-H),7.24(s,1H,Ar-H),7.04(d,J=8.1Hz,1H,Ar-H),6.76(d,J=8.0Hz,1H,Ar-H),5.31(s,2H,CH2),1.36(s,9H,C(CH3)3)。
实施例5 4-(4-氟苄氧基)-9H-咔唑(5)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对氟苄溴(122μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体225mg,收率78.07%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.29(s,1H,NH),8.09(d,J=7.7Hz,1H,Ar-H),7.65(dd,J=8.5,5.7Hz,2H,Ar-H),7.46(d,J=8.1Hz,1H,Ar-H),7.36-7.22(m,4H,Ar-H),7.17-7.05(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.34(s,2H,CH2)。
实施例6 4-(4-硝基苄氧基)-9H-咔唑(6)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对硝基苄溴(212mg,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体251mg,收率79.7%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.35(s,1H,NH),8.33(d,J=8.4Hz,2H,Ar-H),8.17(d,J=7.7Hz,1H,Ar-H),7.87(d,J=7.8Hz,2H,Ar-H),7.48(d,J=8.0Hz,1H,Ar-H),7.41-7.25(m,2H,Ar-H),7.21-7.07(m,2H,Ar-H),6.78(d,J=7.7Hz,1H,Ar-H),5.54(s,2H,CH2)。
实施例7 4-(4-三氟甲基苄氧基)-9H-咔唑(7)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对三氟甲基苄溴(152μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体263mg,收率77.29%。1HNMR(300MHz,Chloroform-d)δ(ppm)8.30(d,J=7.8Hz,1H,Ar-H),8.08(brs,1H,NH),7.69(s,4H,Ar-H),7.43-7.38(m,2H,Ar-H),7.32(t,J=8.0Hz,1H,Ar-H),7.24-7.22(m,1H,Ar-H),7.08(d,J=8.4Hz,1H,Ar-H),6.70(d,J=8.0Hz,1H,Ar-H),5.40(s,2H,CH2)。
实施例8 4-(4-氰基苄氧基)-9H-咔唑(8)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对氰基苄溴(124μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体245mg,收率83.01%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),8.15(d,J=7.7Hz,1H,Ar-H),7.93(d,J=8.1Hz,2H,Ar-H),7.78(d,J=8.0Hz,2H,Ar-H),7.47(d,J=8.0Hz,1H,Ar-H),7.41-7.23(m,2H,Ar-H),7.22 -7.04(m,2H,Ar-H),6.77(d,J=7.9Hz,1H,Ar-H),5.49(s,2H,CH2)。
实施例9 4-(4-溴苄氧基)-9H-咔唑(9)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对溴苄溴(134μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体215mg,收率61.87%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.27(d,J=7.8Hz,1H,Ar-H),8.06(brs,1H,NH),7.56(d,J=8.4Hz,2H,Ar-H),7.45(d,J=8.2Hz,2H,Ar-H),7.42-7.35(m,2H,Ar-H),7.31(t,J=8.0Hz,1H,Ar-H),7.24-7.17(m,1H,Ar-H),7.06(d,J=8.1Hz,1H,Ar-H),6.70(d,J=8.0Hz,1H,Ar-H),5.28(s,2H,CH2)。
实施例10 4-(4-甲氧基苄氧基)-9H-咔唑(10)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入对甲氧基苄溴(134μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体251mg,收率83.64%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.27(s,1H,NH),8.07(d,J=7.8Hz,1H,Ar-H),7.52(d,J=8.6Hz,2H,Ar-H),7.45(d,J=8.1Hz,1H,Ar-H),7.30(t,J=8.0Hz,2H,Ar-H),7.08(d,J=8.1Hz,2H,Ar-H),7.01(d,J=8.7Hz,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.26(s,2H,CH2),3.78(s,2H,CH3)。
实施例11 4-(2-溴苄氧基)-9H-咔唑(11)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入2-溴苄溴(134μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体223mg,收率64.17%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),8.10(d,J=7.6Hz,1H,Ar-H),7.74(d,J=7.7Hz,2H,Ar-H),7.47(d,J=8.2Hz,2H,Ar-H),7.34(d,J=8.5Hz,3H,Ar-H),7.12(d,J=5.6Hz,2H,Ar-H),6.80(d,J=7.6Hz,1H,Ar-H),5.39(s,2H,CH2)。
实施例12 4-(3-溴苄氧基)-9H-咔唑(12)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入3-溴苄溴(134μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体217mg,收率62.44%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.33(s,1H,NH),8.12(d,J=7.7Hz,1H,Ar-H),7.83-7.77(m,1H,Ar-H),7.59(dd,J=11.6,7.4Hz,2H,Ar-H),7.51-7.39(m,2H,Ar-H),7.39-7.26(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.78(d,J=7.9Hz,1H,Ar-H),5.39(s,2H,CH2)。
实施例13 4-(4-氯苄氧基)-9H-咔唑(13)
将化合物4-羟基咔唑(200mg,1.09mmol)溶于丙酮(6mL)中,加入碳酸钾(206mg,1.49mmol),于室温搅拌10min后,加入4-氯苄溴(128μL,0.99mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体228mg,收率74.8%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.30(s,1H,NH),8.10(d,J=7.8Hz,1H,Ar-H),7.62(d,J=8.2Hz,2H,Ar-H),7.52(d,J=8.5Hz,2H,Ar-H),7.46(d,J=8.1Hz,1H,Ar-H),7.40-7.24(m,2H,Ar-H),7.18-7.05(m,2H,Ar-H),6.79(d,J=7.9Hz,1H,Ar-H),5.36(s,2H,CH2)。
实施例14 4-(4-氨甲酰基苄氧基)-9H-咔唑(14)
将化合物8(200mg,0.68mmol)溶于二甲基亚砜(5mL)中,0℃下依次加入碳酸钾(48mg,0.34mmol)和30%过氧化氢(74μL,0.74mmol),室温反应8h。将反应液倾倒入冰水中,混合液用乙酸乙酯(3×30mL)萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1,v/v),得白色固体176mg,收率81.88%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.33(s,1H,NH),8.14(d,J=7.8Hz,1H,Ar-H),8.03(brs,1H,NH2-1),7.95(d,J=8.3Hz,2H,Ar-H),7.67(d,J=8.2Hz,2H,Ar-H),7.47(d,J=8.1Hz,1H,Ar-H),7.43(brs,1H,NH2-2),7.39-7.33(m,1H,Ar-H),7.33-7.26(m,1H,Ar-H),7.19-7.06(m,2H,Ar-H),6.80(d,J=7.9Hz,1H,Ar-H),5.42(s,2H,CH2)。
实施例15 4-(4-(N,N-二甲胺基苄氧基))-9H-咔唑(15)
步骤1:化合物15-1的制备
将化合物9(500mg,1.42mmol)溶于乙腈(15mL)中,0℃下加入二碳酸二叔丁酯(489μL,2.13mmol)和4-二甲氨基吡啶(17mg,0.14mmol),室温反应过夜。加入甲醇淬灭反应,蒸干溶剂,乙酸乙酯稀释,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=60:1,v/v),得白色固体476mg,收率74.31%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.28(dd,J=11.2,7.3Hz,2H,Ar-H),7.96(d,J=8.4Hz,1H,Ar-H),7.56(d,J=8.4Hz,2H,Ar-H),7.47-7.40(m,3H,Ar-H),7.39-7.28(m,2H,Ar-H),6.85(d,J=8.1Hz,1H,Ar-H),5.27(s,2H,CH2),1.76(s,9H,C(CH3)3)。
步骤2:化合物15-2的制备
将中间体15-1(450mg,1.00mmol)溶于甲苯(10mL)中,加入二甲胺盐酸盐(98mg,1.20mmol)、碳酸铯(553mg,1.70mmol)、1,1'-联萘-2,2'-双二苯膦(74mg,0.12mmol)和醋酸钯(22mg,0.10mmol),氮气置换3次,100℃反应10h。蒸干溶剂,乙酸乙酯稀释,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=80:1,v/v),得白色固体219mg,收率52.62%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.28(d,J=8.0Hz,2H,Ar-H),7.94(d,J=10.1Hz,1H,Ar-H),7.50-7.27(m,6H,Ar-H),6.91(d,J=10.2Hz,2H,Ar-H),5.23(s,2H,CH2),3.02(s,6H,2×CH3),1.76(s,9H,C(CH3)3)。
步骤3:化合物15的制备
将中间体15-2(200mg,0.48mmol)溶于二氯甲烷-三氟乙酸(体积比4:1)混合溶剂(5mL)中,室温反应2h。加入饱和碳酸氢钠溶液淬灭反应,二氯甲烷稀释,分液,有机相用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=100:1,v/v),得黄色固体93mg,收率61.28%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.00(s,1H),8.97(s,1H),8.24(d,J=7.7Hz,1H),7.39(d,J=8.0Hz,1H),7.29(t,J=7.6Hz,1H),7.15-6.96(m,4H),6.89(d,J=8.2Hz,1H),6.64(d,J=8.7Hz,2H),3.98(s,2H),2.81(s,6H)。
实施例16 4-((4-(哌嗪-1-基)苄氧基)-9H-咔唑(16)
步骤1:化合物16-2的制备
将中间体15-1(450mg,1.00mmol)溶于甲苯(10mL)中,加入1-叔丁氧羰基哌嗪(223mg,1.20mmol)、碳酸铯(553mg,1.70mmol)、1,1'-联萘-2,2'-双二苯膦(74mg,0.12mmol)和醋酸钯(22mg,0.10mmol),氮气置换3次,100℃反应10h。蒸干溶剂,乙酸乙酯稀释,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=80:1,v/v),得白色固体209mg,收率37.5%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.28(dd,J=8.8,3.1Hz,2H,Ar-H),7.94(d,J=8.4Hz,1H,Ar-H),7.51-7.27(m,5H,Ar-H),7.07-6.95(m,2H,Ar-H),6.90(d,J=8.1Hz,1H,Ar-H),5.23(s,2H,CH2),3.72-3.50(m,4H,2×CH2),3.29-3.09(m,4H,2×CH2),1.76(s,9H,C(CH3)3),1.49(s,9H,C(CH3)3)。
步骤2:化合物16的制备
将中间体16-2(200mg,0.48mmol)溶于二氯甲烷-三氟乙酸(体积比4:1)混合溶剂(5mL)中,室温反应2h。加入饱和碳酸氢钠溶液淬灭反应,二氯甲烷稀释,分液,有机相用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=100:1,v/v),得棕色固体103mg,收率60.08%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.03(s,1H,NH),8.99(brs,1H,NH),8.23(d,J=7.7Hz,1H,Ar-H),7.39(d,J=8.1Hz,1H,Ar-H),7.34-7.24(m,1H,Ar-H),7.15-6.97(m,5H,Ar-H),6.89(d,J=8.1Hz,1H,Ar-H),6.81(d,J=8.7Hz,2H,Ar-H),4.00(s,2H,CH2),3.00-2.93(m,4H,CH2),2.88-2.80(m,4H,CH2)。
实施例17 4-(4-(N,N-二甲基)胺甲基苄氧基)-9H-咔唑(17)
步骤1:化合物17-2的制备
将4-羟基咔唑(1g,5.46mmol)溶于丙酮(20mL)中,加入碳酸钾(1.02g,7.44mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(1.13g,4.96mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体967mg,收率59.24%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.31(s,1H,NH),8.15(d,J=7.8Hz,1H,Ar-H),8.05(d,J=8.3Hz,2H,Ar-H),7.74(d,J=8.2Hz,2H,Ar-H),7.47(d,J=8.0Hz,1H,Ar-H),7.40-7.24(m,2H,Ar-H),7.20-7.06(m,2H,Ar-H),6.78(d,J=7.9Hz,1H,Ar-H),5.47(s,2H,CH2),3.87(s,3H,CH3)。
步骤2:化合物17-3的制备
将中间体17-2(500mg,1.51mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,20mL)混合溶剂中,加入氢氧化锂(317mg,7.55mmol),室温反应5h。加入1M盐酸调pH至4,蒸干溶剂,乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1,v/v),得白色固体312mg,收率65.16%。1H NMR(300MHz,DMSO-d6)δ(ppm)12.94(brs,1H,COOH),11.26(s,1H,NH),8.09(d,J=7.8Hz,1H,Ar-H),7.97(d,J=8.3Hz,2H,Ar-H),7.65(d,J=8.0Hz,2H,Ar-H),7.41(d,J=8.1Hz,1H,Ar-H),7.34-7.18(m,2H,Ar-H),7.14-7.00(m,2H,Ar-H),6.73(d,J=8.0Hz,1H,Ar-H),5.40(s,2H,CH2)。
步骤3:化合物17-4的制备
将中间体17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,冰浴下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入二甲胺盐酸盐(53mg,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体173mg,收率93.09%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.34(s,1H,NH),8.16(d,J=7.7Hz,1H,Ar-H),7.67(d,J=8.0Hz,2H,Ar-H),7.55-7.44(m,3H,Ar-H),7.42-7.27(m,2H,Ar-H),7.21-7.08(m,2H,Ar-H),6.83(d,J=7.9Hz,1H,Ar-H),5.43(s,2H,CH2),3.01(s,3H,CH3),2.95(s,3H,CH3)。
步骤4:化合物17的制备
将中间体17-4(145mg,0.42mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(24mg,0.63mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体83mg,收率59.85%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),8.13(d,J=7.8Hz,1H,Ar-H),7.70(d,J=7.9Hz,2H,Ar-H),7.56(d,J=7.9Hz,2H,Ar-H),7.47(d,J=8.0Hz,1H,Ar-H),7.40-7.25(m,2H,Ar-H),7.18-7.06(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.41(s,2H,CH2),4.26(s,2H,CH2),2.73(s,6H,2×CH3)。
实施例18 4-(4-(N-异丙基)胺甲基苄氧基)-9H-咔唑(18)
步骤1:化合物18-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入异丙胺(55.8mg,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体160mg,收率82.73%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),8.28(d,J=7.7Hz,1H,Ar-H),8.13(d,J=7.8Hz,1H,Ar-H),7.92(d,J=8.2Hz,2H,Ar-H),7.67(d,J=8.0Hz,2H,Ar-H),7.47(d,J=8.0Hz,1H,Ar-H),7.40-7.25(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.80(d,J=7.9Hz,1H,Ar-H),5.41(s,2H,CH2),4.20-4.03(m,1H,CH),1.17(d,J=6.6Hz,6H,2×CH3)。
步骤2:化合物18的制备
将中间体18-1(150mg,0.42mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(24mg,0.63mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体75mg,收率51.88%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.28(s,1H,NH),8.11(d,J=7.8Hz,1H,Ar-H),7.52(d,J=7.8Hz,2H,Ar-H),7.48-7.37(m,3H,Ar-H),7.37-7.25(m,2H,Ar-H),7.17-7.04(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.32(s,2H,CH2),3.72(s,2H,CH2),2.72(p,J=6.2Hz,1H,CH),1.01(d,J=6.2Hz,6H,2×CH3)。
实施例19 4-(4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(19)
步骤1:化合物19-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入四氢吡咯(54μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体152mg,收率76.04%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.30(s,1H,NH),8.15(d,J=7.7Hz,1H,Ar-H),7.69-7.55(m,4H,Ar-H),7.46(d,J=8.0Hz,1H,Ar-H),7.40-7.25(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.81(d,J=8.0Hz,1H,Ar-H),5.42(s,2H,CH2),3.48(t,J=6.7Hz,2H,CH2),3.44-3.38(m,2H,CH2),1.92-1.76(m,4H,2×CH2)。
步骤2:化合物19的制备
将中间体19-1(146mg,0.39mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(23mg,0.59mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得黄色固体67mg,收率48.23%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.31(s,1H,NH),8.13(d,J=7.7Hz,1H,Ar-H),7.56(d,J=7.8Hz,2H,Ar-H),7.50-7.38(m,3H,Ar-H),7.38-7.25(m,2H,Ar-H),7.18-7.05(m,2H,Ar-H),6.81(d,J=8.0Hz,1H,Ar-H),5.34(s,2H,CH2),3.72(s,2H,CH2),2.64-2.45(m,8H,4×CH2)。
实施例20 4-(4-(N,N-二乙基)胺甲基苄氧基)-9H-咔唑(20)
步骤1:化合物20-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入N,N-二乙基胺(68μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体165mg,收率76.04%。HNMR(300MHz,DMSO-d6)δ(ppm)11.30(s,1H,NH),8.14(d,J=7.7Hz,1H,Ar-H),7.65(d,J=7.9Hz,2H,Ar-H),7.50-7.39(m,3H,Ar-H),7.39-7.25(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.41(s,2H,CH2),3.50-3.38(m,2H,CH2),3.28-3.14(m,2H,CH2),1.17(t,J=7.1Hz,6H,2×CH3)。
步骤2:化合物20的制备
将中间体20-1(155mg,0.42mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(24mg,0.63mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体73mg,收率48.52%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.29(s,1H,NH),8.14(d,J=7.6Hz,1H,Ar-H),7.63-7.49(m,4H,Ar-H),7.46(d,J=8.1Hz,1H,Ar-H),7.38-7.25(m,2H,Ar-H),7.18-7.05(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.38(s,2H,CH2),3.91(s,2H,CH2),2.69(q,J=7.7Hz,2H,2×CH2),1.21(t,J=7.2Hz,3H,2×CH3)。
实施例21 4-(4-(环丙基胺甲基)苄氧基)-9H-咔唑(21)
步骤1:化合物21-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入环丙胺(45μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体159mg,收率82.67%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.30(s,1H,NH),8.47(d,J=4.3Hz,1H,Ar-H),8.12(d,J=7.7Hz,1H,Ar-H),7.89(d,J=8.1Hz,2H,Ar-H),7.66(d,J=8.1Hz,2H,Ar-H),7.46(d,J=8.1Hz,1H,Ar-H),7.39-7.24(m,2H,Ar-H),7.18-7.05(m,2H,Ar-H),6.79(d,J=8.0Hz,1H,Ar-H),5.41(s,2H,CH2),2.88-2.82(m,1H,CH),0.74-0.66(m,2H,CH2),0.61-0.53(m,2H,CH2)。
步骤2:化合物21的制备
将中间体21-1(151mg,0.42mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(24mg,0.63mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得棕色油状液体71mg,收率49.4%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.27(s,1H,NH),8.10(d,J=7.7Hz,1H,Ar-H),7.52(d,J=7.8Hz,2H,Ar-H),7.48-7.25(m,5H,Ar-H),7.17-7.04(m,2H,Ar-H),6.80(d,J=7.9Hz,1H,Ar-H),5.32(s,2H,CH2),3.75(s,2H,CH2),3.17(d,J=4.5Hz,1H,NH),2.12-1.99(m,1H,CH),0.41-0.31(m,2H,CH2),0.29-0.21(m,2H,CH2)。
实施例22 4-(4-(哌啶基胺甲基)苄氧基)-9H-咔唑(22)
步骤1:化合物22-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入哌啶(56μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体161mg,收率77.6%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.31(s,1H,NH),8.14(d,J=7.7Hz,1H,Ar-H),7.65(d,J=7.9Hz,2H,Ar-H),7.51-7.40(m,3H,Ar-H),7.40-7.25(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.41(s,2H,CH2),3.67-3.52(m,2H,CH2),3.33-3.20(m,2H,CH2),1.68-1.39(m,6H,3×CH2)。
步骤2:化合物22的制备
将中间体22-1(150mg,0.39mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(23mg,0.59mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体66mg,收率45.71%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.19(d,J=7.8Hz,1H,Ar-H),7.65(d,J=7.9Hz,2H,Ar-H),7.47(d,J=8.1Hz,2H,Ar-H),7.42(d,J=8.2Hz,1H,Ar-H),7.37-7.21(m,2H,Ar-H),7.14-7.02(m,2H,Ar-H),6.73(d,J=7.9Hz,1H,Ar-H),5.35(s,2H,CH2),4.03(s,2H,CH2),3.05-2.85(m,4H,2×CH2),1.78-1.68(m,4H,2×CH2),1.66-1.52(m,2H,CH2)。
实施例23 4-(4-(哌嗪基胺甲基)苄氧基)-9H-咔唑(23)
步骤1:化合物23-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入哌啶(56μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体161mg,收率77.6%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.33(s,1H,NH),8.86(brs,1H,NH),8.15(d,J=7.8Hz,1H,Ar-H),7.69(d,J=7.9Hz,2H,Ar-H),7.56(d,J=8.1Hz,2H,Ar-H),7.47(d,J=8.0Hz,1H,Ar-H),7.40-7.25(m,2H,Ar-H),7.19-7.06(m,2H,Ar-H),6.82(d,J=7.9Hz,1H,Ar-H),5.43(s,2H,CH2),3.87-3.52(m,4H,2×CH2),3.23-3.08(m,4H,2×CH2)。
步骤2:化合物23的制备
将中间体23-1(150mg,0.39mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(23mg,0.59mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体66mg,收率45.71%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.29(s,1H,NH),8.55(brs,1H,NH),8.12(d,J=7.7Hz,1H,Ar-H),7.57(d,J=7.8Hz,2H,Ar-H),7.51-7.24(m,5H,Ar-H),7.18-7.05(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.35(s,2H,CH2),3.57(s,2H,CH2),3.07-3.02(m,4H,2×CH2),2.62-2.54(m,4H,2×CH2)。
实施例24 4-(4-((4-甲基哌嗪-1-基)甲基)苄氧基)-9H-咔唑(24)
步骤1:化合物24-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入N-甲基哌嗪(72μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体157mg,收率72.83%。1HNMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),8.15(d,J=7.7Hz,1H,Ar-H),7.66(d,J=7.9Hz,2H,Ar-H),7.47(d,J=8.0Hz,3H,Ar-H),7.40-7.25(m,2H,Ar-H),7.20-7.06(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.41(s,2H,CH2),3.75-3.45(m,4H,2×CH2),2.46-2.25(m,4H,2×CH2),2.21(s,3H,CH3)。
步骤2:化合物24的制备
将中间体24-1(148mg,0.37mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(22mg,0.56mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得淡黄色固体63mg,收率44.2%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.30(s,1H,NH),8.12(d,J=7.7Hz,1H,Ar-H),7.55(d,J=7.8Hz,2H,Ar-H),7.46(d,J=8.1Hz,1H,Ar-H),7.41-7.25(m,4H,Ar-H),7.18-7.05(m,2H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.34(s,2H,CH2),3.49(s,2H,CH2),3.45-3.29(m,2H,CH2),2.47-2.31(m,6H,3×CH2),2.20(s,3H,CH3)。
实施例25 4-(4-(4-乙基哌嗪-1-基)甲基)苄氧基)-9H-咔唑(25)
步骤1:化合物25-1的制备
制备方法同实施例17中步骤1和步骤2,得到化合物17-3,将17-3(170mg,0.54mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(308mg,0.81mmol)和N,N-二异丙基乙胺(142μL,0.81mmol),0℃下反应30min,加入N-乙基哌嗪(82μL,0.65mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体169mg,收率75.74%。1HNMR(300MHz,Methanol-d4)δ(ppm)8.20(d,J=7.9Hz,1H,Ar-H),7.70(d,J=7.9Hz,2H,Ar-H),7.49(d,J=8.2Hz,2H,Ar-H),7.41(d,J=8.1Hz,1H,Ar-H),7.34-7.28(m,1H,Ar-H),7.29-7.23(m,1H,Ar-H),7.15-7.02(m,2H,Ar-H),6.74(d,J=8.0Hz,1H,Ar-H),5.39(s,2H,CH2),3.89-3.69(m,2H,CH2),3.63-3.39(m,2H,CH2),2.70-2.36(m,6H,3×CH2),1.12(t,J=7.2Hz,3H,CH3)。
步骤2:化合物25的制备
将中间体25-1(160mg,0.39mmol)溶于四氢呋喃(10mL)中,0℃下分批加入四氢锂铝(23mg,0.59mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得黄色固体65mg,收率41.75%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.24(d,J=7.8Hz,1H,Ar-H),7.63(d,J=7.8Hz,2H,Ar-H),7.46(d,J=5.3Hz,3H,Ar-H),7.41-7.26(m,2H,Ar-H),7.20-7.07(m,2H,Ar-H),6.80(d,J=7.9Hz,1H,Ar-H),5.38(s,2H,CH2),3.66(s,2H,CH2),2.95-2.55(m,10H,5×CH2),1.22(t,J=7.3Hz,3H,CH3)。
实施例26 3-氟-5-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(26)
步骤1:化合物26-1的制备
将2-溴-4-氟-1-硝基苯(1g,4.57mmol)和2-甲氧基苯硼酸(764mg,5.03mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(266mg,0.23mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得淡黄色固体891mg,收率78.91%。1H NMR(300MHz,DMSO-d6)δ(ppm)8.08(dd,J=9.0,5.2Hz,1H,Ar-H),7.52-7.34(m,4H,Ar-H),7.15-7.02(m,2H,Ar-H),3.63(s,3H,CH3)。
步骤2:化合物26-2的制备
将中间体26-1(850mg,3.44mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(2.25g,8.60mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体673mg,收率90.97%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.34(s,1H,NH),7.81(dd,J=9.5,2.7Hz,1H,Ar-H),7.45(dd,J=8.8,4.5Hz,1H,Ar-H),7.34(t,J=8.0Hz,1H,Ar-H),7.20(td,J=9.2,2.7Hz,1H,Ar-H),7.09(d,J=8.1Hz,1H,Ar-H),6.69(d,J=7.9Hz,1H,Ar-H),4.02(s,3H,CH3)。
步骤3:化合物26-3的制备
将中间体26-2(660mg,2.86mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(7.15mL,7.15mmol),0℃下反应30min后,室温反应12h。冰浴下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体437mg,收率76%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.18(s,1H,NH),10.15(s,1H,OH),7.80(dd,J=9.4,2.7Hz,1H,Ar-H),7.40(dd,J=8.8,4.5Hz,1H,Ar-H),7.24-7.10(m,2H,Ar-H),6.92(d,J=8.2Hz,1H,Ar-H),6.55(d,J=8.5Hz,1H,Ar-H)。
步骤4:化合物26-4的制备
将中间体26-3(400mg,1.98mmol)溶于丙酮(10mL)中,加入碳酸钾(410mg,2.97mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(451mg,1.98mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体371mg,收率53.67%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.38(s,1H,NH),8.05(d,J=8.3Hz,2H,Ar-H),7.79(dd,J=9.4,2.6Hz,1H,Ar-H),7.73(d,J=8.0Hz,2H,Ar-H),7.47(dd,J=8.8,4.5Hz,1H,Ar-H),7.33(t,J=8.0Hz,1H,Ar-H),7.21(td,J=9.2,2.7Hz,1H,Ar-H),7.11(d,J=8.1Hz,1H,Ar-H),6.77(d,J=7.9Hz,1H,Ar-H),5.47(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物26-5的制备
将中间体26-4(349mg,1.00mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(210mg,5.00mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体311mg,收率92.81%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.52(s,1H,NH),8.03(d,J=8.0Hz,2H,Ar-H),7.79(dd,J=9.4,2.6Hz,1H,Ar-H),7.71(d,J=8.0Hz,2H,Ar-H),7.49(dd,J=8.9,4.5Hz,1H,Ar-H),7.33(t,J=8.1Hz,1H,Ar-H),7.23(dd,J=9.2,2.7Hz,1H,Ar-H),7.12(d,J=8.1Hz,1H,Ar-H),6.78(d,J=7.9Hz,1H,Ar-H),5.46(s,2H,CH2)。
步骤6:化合物26-6的制备
将中间体26-5(290mg,0.86mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(490mg,1.30mmol)和N,N-二异丙基乙胺(477μL,2.60mmol),0℃下反应30min,加入四氢吡咯(86μL,1.03mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体243mg,收率72.79%。1H NMR(300MHz,Methanol-d4)δ(ppm)7.80(dd,J=9.5,2.6Hz,1H,Ar-H),7.68(d,J=8.2Hz,2H,Ar-H),7.59(d,J=8.3Hz,2H,Ar-H),7.37(dd,J=8.8,4.4Hz,1H,Ar-H),7.29(t,J=8.0Hz,1H,Ar-H),7.13-7.02(m,2H,Ar-H),6.73(d,J=8.0Hz,1H,Ar-H),5.39(s,2H,CH2),3.78-3.64(m,2H,CH2),3.60(t,J=6.9Hz,2H,CH2),3.48(t,J=6.6Hz,2H,CH2),3.45-3.40(m,2H,CH2)。
步骤7:化合物26的制备
将中间体26-6(200mg,0.51mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(30mg,0.77mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得黄色固体121mg,收率63.41%。1H NMR(300MHz,DMSO-d6)δ(ppm)7.79(dd,J=9.5,2.6Hz,1H,Ar-H),7.71(d,J=7.8Hz,2H,Ar-H),7.58(d,J=8.1Hz,2H,Ar-H),7.37(dd,J=8.8,4.4Hz,1H,Ar-H),7.30(t,J=8.0Hz,1H,Ar-H),7.15-7.02(m,2H,Ar-H),6.74(d,J=8.0Hz,1H,Ar-H),5.38(s,2H,CH2),4.38(s,2H,CH2),3.37-3.31(m,4H,2×CH2),2.15-2.02(m,4H,2×CH2)。
实施例27 3-氯-5-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(27)
步骤1:化合物27-1的制备
将2-溴-4-氯-1-硝基苯(1g,4.25mmol)和2-甲氧基苯硼酸(712mg,4.68mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(242mg,0.21mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得淡黄色固体931mg,收率83.28%。1H NMR(300MHz,Chloroform-d)δ(ppm)7.89(d,J=8.6Hz,1H,Ar-H),7.48-7.34(m,3H,Ar-H),7.30(dd,J=7.5,1.8Hz,1H,Ar-H),7.08(td,J=7.4,1.1Hz,1H,Ar-H),6.95-6.86(m,1H,Ar-H),3.70(s,3H,CH3)。
步骤2:化合物27-2的制备
将中间体27-1(900mg,3.42mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(2.25g,8.55mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体692mg,收率87.57%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.45(s,1H,NH),8.08(d,J=2.2Hz,1H,Ar-H),7.47(d,J=8.6Hz,1H,Ar-H),7.41-7.30(m,2H,Ar-H),7.10(d,J=8.1Hz,1H,Ar-H),6.72(d,J=7.9Hz,1H,Ar-H),4.02(s,3H,CH3)。
步骤3:化合物27-3的制备
将中间体27-2(670mg,2.90mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(7.25mL,7.25mmol),0℃下反应30min后,室温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体467mg,收率74.2%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.29(s,1H,NH),10.19(s,1H,OH),8.08(d,J=2.2Hz,1H,Ar-H),7.43(d,J=8.6Hz,1H,Ar-H),7.32(dd,J=8.6,2.2Hz,1H,Ar-H),7.20(t,J=7.9Hz,1H,Ar-H),6.93(d,J=8.0Hz,1H,Ar-H),6.58(d,J=7.7Hz,1H,Ar-H)。
步骤4:化合物27-4的制备
将中间体27-3(450mg,2.07mmol)溶于丙酮(10mL)中,加入碳酸钾(428mg,3.10mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(472mg,2.07mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体354mg,收率46.84%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.51(s,1H,NH),8.08(d,J=2.1Hz,1H,Ar-H),8.04(d,J=8.2Hz,2H,Ar-H),7.72(d,J=8.0Hz,2H,Ar-H),7.50(d,J=8.6Hz,1H,Ar-H),7.37(dd,J=6.8,1.8Hz,1H,Ar-H),7.35-7.30(m,1H,Ar-H),7.12(d,J=8.1Hz,1H,Ar-H),6.78(d,J=7.9Hz,1H,Ar-H),5.49(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物27-5的制备
将中间体27-4(324mg,0.89mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(187mg,4.45mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体256mg,收率81.93%。1H NMR(300MHz,DMSO-d6)δ(ppm)12.99(brs,1H,COOH),11.50(s,1H,NH),8.09(s,1H,Ar-H),8.02(d,J=7.8Hz,2H,Ar-H),7.70(d,J=7.8Hz,2H,Ar-H),7.50(d,J=8.5Hz,1H,Ar-H),7.42-7.27(m,2H,Ar-H),7.12(d,J=8.1Hz,1H,Ar-H),6.79(d,J=7.9Hz,1H,Ar-H),5.48(s,2H,CH2)。
步骤6:化合物27-6的制备
将中间体27-5(222mg,0.63mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(361mg,0.95mmol)和N,N-二异丙基乙胺(166μL,0.95mmol),0℃下反应30min,加入四氢吡咯(63μL,0.76mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体183mg,收率71.88%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.49(s,1H,NH),8.07(d,J=2.2Hz,1H,Ar-H),7.67-7.54(m,4H,Ar-H),7.49(d,J=8.6Hz,1H,Ar-H),7.41-7.29(m,2H,Ar-H),7.11(d,J=8.1Hz,1H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.44(s,2H,CH2),3.47(t,J=6.7Hz,2H,CH2),3.43-3.36(m,2H,CH2),1.92-1.76(m,4H,2×CH2)。
步骤7:化合物27的制备
将中间体27-6(152mg,0.38mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(22mg,0.57mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得黄色固体97mg,收率65.43%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.09(d,J=2.1Hz,1H,Ar-H),7.60(d,J=7.9Hz,2H,Ar-H),7.46(d,J=8.0Hz,2H,Ar-H),7.37(d,J=8.6Hz,1H,Ar-H),7.32-7.29(m,1H,Ar-H),7.29-7.25(m,1H,Ar-H),7.06(d,J=8.0Hz,1H,Ar-H),6.76(d,J=7.9Hz,1H,Ar-H),5.35(s,2H,CH2),3.86(s,2H,CH2),2.85-2.69(m,4H,2×CH2),1.91-1.85(m,4H,2×CH2)。
实施例28 3-溴-5-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(28)
步骤1:化合物28-1的制备
将4-溴-2-碘-1-硝基苯(1g,3.04mmol)和2-甲氧基苯硼酸(488mg,3.20mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(186mg,0.16mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体783mg,收率83.9%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.49(s,1H,NH),8.07(d,J=2.2Hz,1H,Ar-H),7.67-7.54(m,4H,Ar-H),7.49(d,J=8.6Hz,1H,Ar-H),7.41-7.29(m,2H,Ar-H),7.11(d,J=8.1Hz,1H,Ar-H),6.81(d,J=7.9Hz,1H,Ar-H),5.44(s,2H,CH2),3.47(t,J=6.7Hz,2H,CH2),3.43-3.36(m,2H,CH2),1.92-1.76(m,4H,2×CH2)。
步骤2:化合物28-2的制备
将中间体28-1(752mg,2.44mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(1.6g,6.10mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体670mg,收率99.85%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.48(s,1H,NH),8.23(d,J=1.9Hz,1H,Ar-H),7.51-7.30(m,3H,Ar-H),7.10(d,J=8.1Hz,1H,Ar-H),6.73(d,J=7.9Hz,1H,Ar-H),4.03(s,3H,CH3)。
步骤3:化合物28-3的制备
将中间体28-2(580mg,2.11mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(5.27mL,5.27mmol),0℃下反应30min后,室温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得淡黄色固体312mg,收率56.66%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H,NH),10.21(s,1H,OH),8.22(d,J=1.9Hz,1H,Ar-H),7.48-7.34(m,2H,Ar-H),7.20(t,J=7.9Hz,1H,Ar-H),6.93(d,J=8.0Hz,1H,Ar-H),6.59(d,J=7.7Hz,1H,Ar-H)。
步骤4:化合物28-4的制备
将中间体28-3(270mg,1.03mmol)溶于丙酮(10mL)中,加入碳酸钾(215mg,1.55mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(258mg,1.13mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体351mg,收率83.31%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.52(s,1H,NH),8.24(d,J=1.8Hz,1H,Ar-H),8.04(d,J=8.2Hz,2H,Ar-H),7.72(d,J=8.1Hz,2H,Ar-H),7.50-7.44(m,2H,Ar-H),7.34(t,J=8.1Hz,1H,Ar-H),7.12(d,J=8.1Hz,1H,Ar-H),6.78(d,J=8.0Hz,1H,Ar-H),5.50(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物28-5的制备
将中间体28-4(335mg,0.82mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(173mg,4.10mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体312mg,收率96.32%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.53(s,1H,NH),8.24(d,J=1.8Hz,1H,Ar-H),8.02(d,J=8.3Hz,2H,Ar-H),7.69(d,J=8.0Hz,2H,Ar-H),7.49-7.45(m,2H,Ar-H),7.34(t,J=8.0Hz,1H,Ar-H),7.12(d,J=8.1Hz,1H,Ar-H),6.79(d,J=8.0Hz,1H,Ar-H),5.49(s,2H,CH2)。
步骤6:化合物28-6的制备
将中间体28-5(300mg,0.76mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(434mg,1.14mmol)和N,N-二异丙基乙胺(199μL,1.14mmol),0℃下反应30min,加入四氢吡咯(77μL,0.92mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体219mg,收率64.31%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.51(s,1H,NH),8.22(d,J=1.8Hz,1H,Ar-H),7.68-7.54(m,4H,Ar-H),7.51-7.41(m,2H,Ar-H),7.33(d,J=8.0Hz,1H,Ar-H),7.11(d,J=8.1Hz,1H,Ar-H),6.81(d,J=8.0Hz,1H,Ar-H),5.44(s,2H,CH2),3.52-3.44(m,2H,CH2),3.43-3.37(m,2H,CH2),1.92-1.76(m,4H,2×CH2)。
步骤7:化合物28的制备
将中间体28-6(200mg,0.44mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(34mg,0.88mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体132mg,收率69.11%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.18(d,J=7.8Hz,1H,Ar-H),7.67-7.58(m,2H,Ar-H),7.51-7.43(m,2H,Ar-H),7.41(d,J=8.5Hz,1H,Ar-H),7.36-7.23(m,2H,Ar-H),7.06(d,J=8.3Hz,1H,Ar-H),6.80-6.70(m,1H,Ar-H),5.35(s,2H,CH2),3.92(s,2H,CH2),2.96-2.77(m,4H,2×CH2),2.07-1.80(m,4H,2×CH2)。
实施例29 2,3-二氯-5-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(29)
步骤1:化合物29-1的制备
将1-溴-4,5-二氯-2-硝基苯(1g,3.69mmol)和2-甲氧基苯硼酸(617mg,4.06mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(208mg,0.18mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体1.05g,收率95.81%。1H NMR(300MHz,DMSO-d6)δ(ppm)8.34(s,1H,Ar-H),7.82(s,1H,Ar-H),7.42(s,2H,Ar-H),7.09(s,2H,Ar-H),3.63(s,3H,CH3)。
步骤2:化合物29-2的制备
将中间体29-1(1.03g,3.47mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(2.28g,8.68mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得灰色固体537mg,收率58.4%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.58(s,1H,NH),8.23(s,1H,Ar-H),7.71(s,1H,Ar-H),7.40(t,J=8.1Hz,1H,Ar-H),7.13(d,J=8.1Hz,1H,Ar-H),6.76(d,J=7.9Hz,1H,Ar-H),4.03(s,3H,CH3)。
步骤3:化合物29-3的制备
将中间体29-2(492mg,1.86mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(4.65mL,4.65mmol),0℃下反应30min后,室温反应12h。冰浴下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体423mg,收率90.61%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.41(s,1H,NH),10.33(s,1H,OH),8.21(s,1H,Ar-H),7.65(s,1H,Ar-H),7.24(t,J=8.0Hz,1H,Ar-H),7.00-6.91(m,1H,Ar-H),6.66-6.57(m,1H,Ar-H)。
步骤4:化合物29-4的制备
将中间体29-3(397mg,1.58mmol)溶于丙酮(10mL)中,加入碳酸钾(328mg,2.37mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(360mg,1.58mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体609mg,收率96.59%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.85(s,1H,NH),8.21(s,1H,Ar-H),8.04(d,J=8.0Hz,2H,Ar-H),7.78-7.66(m,3H,Ar-H),7.37(t,J=8.0Hz,1H,Ar-H),7.15(d,J=8.1Hz,1H,Ar-H),6.81(d,J=8.0Hz,1H,Ar-H),5.49(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物29-5的制备
将中间体29-4(594mg,1.48mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(311mg,7.40mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体392mg,收率68.79%。1H NMR(300MHz,DMSO-d6)δ(ppm)12.99(brs,1H,COOH),11.63(s,1H,NH),8.21(s,1H,Ar-H),8.05-7.90(m,2H,Ar-H),7.77-7.57(m,3H,Ar-H),7.43-7.25(m,1H,Ar-H),7.20-7.01(m,1H,Ar-H),6.87-6.69(m,1H,Ar-H),5.49(s,3H,CH3)。
步骤6:化合物29-6的制备
将中间体29-5(374mg,0.97mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(555mg,1.46mmol)和N,N-二异丙基乙胺(255μL,1.46mmol),0℃下反应30min,加入四氢吡咯(96μL,1.16mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体298mg,收率70.13%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.62(s,1H,NH),8.21(s,1H,Ar-H),7.73(s,1H,Ar-H),7.69-7.51(m,4H,Ar-H),7.47-7.28(m,1H,Ar-H),7.21-7.07(m,1H,Ar-H),6.93-6.74(m,1H,Ar-H),5.45(s,2H,CH2),3.55-3.45(m,2,CH2),3.45-3.37(m,2H,CH2),1.95-1.73(m,4H,2×CH2)。
步骤7:化合物29的制备
将中间体29-6(284mg,0.65mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(38mg,0.98mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体162mg,收率58.77%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.18(s,1H,Ar-H),7.69(d,J=8.1Hz,2H,Ar-H),7.57(d,J=8.2Hz,2H,Ar-H),7.55(s,1H,Ar-H),7.33(t,J=8.1Hz,1H,Ar-H),7.07(d,J=8.1Hz,1H,Ar-H),6.77(d,J=8.0Hz,1H,Ar-H),5.38(s,2H,CH2),4.38(s,2H,CH2),3.37-3.32(m,4H,2×CH2),2.14-2.03(m,4H,2×CH2)。
实施例30 3-甲基-5-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(30)
步骤1:化合物30-1的制备
将2-溴-4-甲基-1-硝基苯(1g,4.65mmol)和2-甲氧基苯硼酸(779mg,5.12mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(266mg,0.23mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体1.02g,收率90.24%。1H NMR(300MHz,DMSO-d6)δ(ppm)7.88(d,J=8.3Hz,1H,Ar-H),7.43-7.35(m,2H,Ar-H),7.33(dd,J=7.5,1.7Hz,1H,Ar-H),7.28(d,J=1.9Hz,1H,Ar-H),7.13-6.99(m,2H,Ar-H),3.61(s,3H,CH3),2.43(s,3H,CH3)。
步骤2:化合物30-2的制备
将中间体30-1(880mg,3.47mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(2.37g,9.05mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得淡黄色固体361mg,收率49.28%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.15(s,1H,NH),7.96(s,1H,Ar-H),7.35(d,J=8.2Hz,1H,Ar-H),7.30(t,J=8.0Hz,1H,Ar-H),7.17(dd,J=8.2,1.8Hz,1H,Ar-H),7.06(d,J=8.0Hz,1H,Ar-H),6.68(d,J=7.9Hz,1H,Ar-H),4.02(s,3H,CH3),2.47(s,3H,CH3)。
步骤3:化合物30-3的制备
将中间体30-2(337mg,1.60mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(4.0mL,4.00mmol),0℃下反应30min后,室温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得白色固体221mg,收率70.09%。1H NMR(300MHz,DMSO-d6)δ(ppm)10.95(s,1H,NH),9.93(s,1H,OH),7.95(s,1H,Ar-H),7.29(d,J=8.2Hz,1H,Ar-H),7.167.07(m,2H,Ar-H),6.87(d,J=8.0Hz,1H,Ar-H),6.53(d,J=7.3Hz,1H,Ar-H),2.45(s,3H,CH3)。
步骤4:化合物30-4的制备
将中间体30.3(208mg,1.06mmol)溶于丙酮(10mL)中,加入碳酸钾(220mg,1.59mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(242mg,1.06mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体281mg,收率76.81%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.38(s,1H,NH),8.05(d,J=8.2Hz,2H,Ar-H),7.98(s,1H,Ar-H),7.73(d,J=8.1Hz,2H,Ar-H),7.37(d,J=8.2Hz,1H,Ar-H),7.25(t,J=8.0Hz,1H,Ar-H),7.17(dd,J=8.3,1.8Hz,1H,Ar-H),7.07(d,J=8.1Hz,1H,Ar-H),6.71(d,J=7.9Hz,1H,Ar-H),5.48(s,2H,CH2),3.87(s,3H,CH3),2.44(s,3H,CH3)。
步骤5:化合物30-5的制备
将中间体30-4(260mg,0.75mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(158mg,3.76mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体231mg,收率93.07%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.17(s,1H,NH),8.03(d,J=8.2Hz,2H,Ar-H),7.99(s,1H,Ar-H),7.71(d,J=8.0Hz,2H,Ar-H),7.36(d,J=8.2Hz,1H,Ar-H),7.25(t,J=8.0Hz,1H,Ar-H),7.18(dd,J=8.2,1.8Hz,1H,Ar-H),7.06(d,J=8.1Hz,1H,Ar-H),6.73(d,J=7.9Hz,1H,Ar-H),5.47(s,2H,CH2),2.44(s,3H,CH3)。
步骤6:化合物30-6的制备
将中间体30-5(175mg,0.53mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(302mg,0.80mmol)和N,N-二异丙基乙胺(277μL,1.59mmol),0℃下反应30min,加入四氢吡咯(52μL,0.63mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体143mg,收率70.23%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.02(s,1H,Ar-H),7.69(d,J=7.9Hz,2H,Ar-H),7.58(d,J=8.2Hz,2H,Ar-H),7.29(d,J=8.2Hz,1H,Ar-H),7.23(t,J=8.0Hz,1H,Ar-H),7.16(d,J=1.8Hz,1H,Ar-H),7.03(d,J=8.1Hz,1H,Ar-H),6.69(d,J=7.9Hz,1H,Ar-H),5.40(s,2H,CH2),3.60(t,J=6.8Hz,2H,CH2),3.48(t,J=6.5Hz,2H,CH2),2.44(s,3H,CH3),1.98-1.85(m,4H,2×CH2)。
步骤7:化合物30的制备
将中间体30-6(130mg,0.34mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(20mg,0.51mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得黄色固体94mg,收率74.68%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.02(s,1H,Ar-H),7.70(d,J=8.0Hz,2H,Ar-H),7.55(d,J=8.1Hz,2H,Ar-H),7.30(d,J=8.2Hz,1H,Ar-H),7.23(t,J=8.0Hz,1H,Ar-H),7.16(dd,J=8.2,1.7Hz,1H,Ar-H),7.03(d,J=8.0Hz,1H,Ar-H),6.69(d,J=7.9Hz,1H,Ar-H),5.40(s,2H,CH2),4.31(s,2H,CH2),3.29-3.21(m,4H,2×CH2),2.44(s,3H,CH3),2.10-1.99(m,4H,2×CH2)。
实施例31 6-溴-2-氟-4-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(31)
步骤1:化合物31-1的制备
将4-溴-2-碘-1-硝基苯(1g,3.05mmol)和4-氟-2-甲氧基苯硼酸(675mg,3.97mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(173mg,0.15mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体693mg,收率69.91%。1H NMR(300MHz,Chloroform-d)δ(ppm)7.82(d,J=8.6Hz,1H,Ar-H),7.61(dd,J=8.6,2.1Hz,1H,Ar-H),7.53(d,J=2.2Hz,1H,Ar-H),7.25(dd,J=8.4,6.4Hz,1H,Ar-H),6.79(td,J=8.2,2.4Hz,1H,Ar-H),6.64(dd,J=10.6,2.4Hz,1H,Ar-H),3.69(s,3H,CH3)。
步骤2:化合物31-2的制备
将中间体31-1(672mg,2.07mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(1.36g,5.18mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体386mg,收率63.64%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.33(d,J=2.0Hz,1H,Ar-H),8.04(s,1H,Ar-H),7.43(dd,J=8.5,2.0Hz,1H,Ar-H),7.23(d,J=8.5Hz,1H,Ar-H),6.70(dd,J=9.1,2.0Hz,1H,Ar-H),6.44(dd,J=11.7,2.0Hz,1H,Ar-H),4.04(s,3H,CH3)。
步骤3:化合物31-3的制备
将中间体31-2(360mg,1.23mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(3.00mL,3.00mmol),0℃下反应30min后,室温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得棕色固体235mg,收率68.49%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.44(s,1H,NH),10.75(s,1H,OH),8.17(d,J=1.8Hz,1H,Ar-H),7.47-7.34(m,2H,Ar-H),6.72(dd,J=9.7,2.1Hz,1H,Ar-H),6.40(dd,J=11.6,2.1Hz,1H,Ar-H)。
步骤4:化合物31-4的制备
将中间体31-3(214mg,0.77mmol)溶于丙酮(10mL)中,加入碳酸钾(160mg,1.16mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(194mg,0.85mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体299mg,收率90.94%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.65(s,1H,NH),8.16(s,1H,Ar-H),8.05(d,J=8.1Hz,2H,Ar-H),7.72(d,J=8.2Hz,2H,Ar-H),7.49-7.43(m,2H,Ar-H),6.92(dd,J=9.5,1.9Hz,1H,Ar-H),6.75(dd,J=12.0,2.0Hz,1H,Ar-H),5.51(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物31-5的制备
将中间体31-4(290mg,0.68mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(143mg,3.40mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体271mg,收率96.49%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.71(s,1H,NH),8.16(s,1H,Ar-H),8.02(d,J=7.9Hz,2H,Ar-H),7.66(d,J=8.0Hz,2H,Ar-H),7.46(s,2H,Ar-H),6.92(dd,J=9.5,1.9Hz,1H,Ar-H),6.75(dd,J=12.0,2.0Hz,1H,Ar-H),5.48(s,2H,CH2)。
步骤6:化合物31-6的制备
将中间体31-5(264mg,0.64mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(365mg,0.96mmol)和N,N-二异丙基乙胺(168μL,0.96mmol),0℃下反应30min,加入四氢吡咯(64μL,0.77mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体231mg,收率77.44%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.63(s,1H,NH),8.14(s,1H,Ar-H),7.67-7.55(m,4H,Ar-H),7.45(s,2H,Ar-H),6.91(dd,J=9.6,1.9Hz,1H,Ar-H),6.77(dd,J=12.0,2.0Hz,1H,Ar-H),5.45(s,2H,CH2),3.52-3.38(m,4H,2×CH2),1.92-1.76(m,4H,2×CH2)。
步骤7:化合物31的制备
将中间体31-6(100mg,0.22mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(13mg,0.33mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体59mg,收率59.32%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.17(d,J=2.0Hz,1H,Ar-H),7.60(d,J=7.9Hz,2H,Ar-H),7.48(d,J=7.9Hz,2H,Ar-H),7.39(dd,J=8.6,1.9Hz,1H,Ar-H),7.31(d,J=8.5Hz,1H,Ar-H),6.77(dd,J=9.4,2.1Hz,1H,Ar-H),6.60(dd,J=11.8,1.9Hz,1H,Ar-H),5.34(s,2H,CH2),3.87(s,2H,CH2),2.82-2.76(m,4H,2×CH2),1.92-1.86(m,4H,2×CH2)。
实施例32 6-溴-1-氟-4-((4-(吡咯烷-1-基甲基)苄氧基)-9H-咔唑(32)
步骤1:化合物32-1的制备
将4-溴-2-碘-1-硝基苯(1g,3.05mmol)和5-氟-2-甲氧基苯硼酸(622mg,3.66mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(173mg,0.15mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体763mg,收率76.98%。1H NMR(300MHz,Chloroform-d)δ(ppm)7.84(d,J=8.6Hz,1H,Ar-H),7.63(dd,J=8.6,2.1Hz,1H,Ar-H),7.54(d,J=2.2Hz,1H,Ar-H),7.15-6.99(m,2H,Ar-H),6.83(dd,J=8.8,4.3Hz,1H,Ar-H),3.67(s,3H,CH3)。
步骤2:化合物32-2的制备
将中间体32-1(749mg,2.30mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(1.51g,5.75mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得棕色固体435mg,收率64.55%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.92(s,1H,NH),8.25(d,J=2.0Hz,1H,Ar-H),7.54(dd,J=8.6,2.0Hz,1H,Ar-H),7.47(d,J=8.6Hz,1H,Ar-H),7.23(dd,J=10.9,8.7Hz,1H,Ar-H),6.64(dd,J=8.7,3.0Hz,1H,Ar-H),4.02(s,3H,CH3)。
步骤3:化合物32-3的制备
将中间体32-2(417mg,1.42mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(3.55mL,3.55mmol),0℃下反应30min后,室温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得棕色固体157mg,收率39.63%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.74(s,1H,NH),10.20(s,1H,OH),8.25(d,J=2.0Hz,1H,Ar-H),7.51(dd,J=8.6,2.0Hz,1H,Ar-H),7.43(d,J=8.7Hz,1H,Ar-H),7.08(dd,J=10.9,8.5Hz,1H,Ar-H),6.48(dd,J=8.6,3.1Hz,1H,Ar-H)。
步骤4:化合物32-4的制备
将中间体32-3(130mg,0.47mmol)溶于丙酮(10mL)中,加入碳酸钾(98mg,0.71mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(194mg,0.85mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体193mg,收率96.16%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.97(s,1H,NH),8.25(d,J=2.0Hz,1H,Ar-H),8.03(d,J=8.2Hz,2H,Ar-H),7.71(d,J=8.1Hz,2H,Ar-H),7.55(dd,J=8.7,2.0Hz,1H,Ar-H),7.48(d,J=8.7Hz,1H,Ar-H),7.22(dd,J=10.8,8.7Hz,1H,Ar-H),6.70(dd,J=8.8,3.0Hz,1H,Ar-H),5.47(s,2H,CH2),3.87(s,3H,CH3)。
步骤5:化合物32-5的制备
将中间体32-4(185mg,0.43mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(90mg,2.15mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体163mg,收率91.78%。1H NMR(300MHz,DMSO-d6)δ(ppm)12.98(s,1H,brs),11.97(s,1H,NH),8.25(d,J=2.0Hz,1H,Ar-H),8.01(d,J=8.2Hz,2H,Ar-H),7.68(d,J=8.2Hz,2H,Ar-H),7.55(dd,J=8.6,2.0Hz,1H,Ar-H),7.48(d,J=8.6Hz,1H,Ar-H),7.18(dd,J=10.0,8.3Hz,1H,Ar-H),6.71(dd,J=8.7,2.9Hz,1H,Ar-H),5.47(s,2H,CH2)。
步骤6:化合物32-6的制备
将中间体32-5(140mg,0.34mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(194mg,0.51mmol)和N,N-二异丙基乙胺(90μL,0.51mmol),0℃下反应30min,加入四氢吡咯(34μL,0.41mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体91mg,收率57.43%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.96(s,1H,NH),8.23(d,J=2.0Hz,1H,Ar-H),7.65-7.57(m,4H,Ar-H),7.57-7.52(m,1H,Ar-H),7.48(d,J=8.7Hz,1H,Ar-H),7.22(dd,J=10.8,8.6Hz,1H,Ar-H),6.73(dd,J=8.7,3.0Hz,1H,Ar-H),5.42(s,2H,CH2),3.47(t,J=6.7Hz,2H),3.43-3.36(m,2H),1.92-1.76(m,2H)。
步骤7:化合物32的制备
将中间体32-6(80mg,0.17mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(10mg,0.26mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体31mg,收率40.34%。1H NMR(300MHz,Methanol-d4)δ(ppm)8.26(d,J=1.9Hz,1H,Ar-H),7.65(d,J=8.0Hz,2H,Ar-H),7.52(d,J=8.0Hz,2H,Ar-H),7.47(dd,J=8.6,1.9Hz,1H,Ar-H),7.40(d,J=8.6Hz,1H,Ar-H),7.07(dd,J=10.7,8.6Hz,1H,Ar-H),6.67(dd,J=8.6,3.0Hz,1H,Ar-H),5.35(s,2H,CH2),4.12(s,2H,CH2),3.07-3.01(m,4H,2×CH2),2.01-1.95(m,4H,2×CH2)。
实施例33 6-溴-4-((4-(吡咯烷-1-基甲基)苄氧基)-2-(三氟甲基)-9H-咔(33)
步骤1:化合物33-1的制备
将4-溴-2-碘-1-硝基苯(1g,3.05mmol)和(4-三氟甲基-2-甲氧基苯基)硼酸(805mg,3.66mmol)溶于甲苯(20mL)中,加入2M碳酸钠水溶液(20mL)、乙醇(20mL)、四(三苯基膦)钯(173mg,0.15mmol),氮气保护下,100℃反应2h。蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得淡黄色固体1.07mg,收率93.56%。1H NMR(300MHz,Chloroform-d)δ(ppm)7.89(d,J=8.6Hz,1H,Ar-H),7.66(dd,J=8.6,2.2Hz,1H,Ar-H),7.54(d,J=2.2Hz,1H,Ar-H),7.41(d,J=7.9Hz,1H,Ar-H),7.37(s,1H,Ar-H),7.11(s,1H,Ar-H),3.75(s,3H,CH3)。
步骤2:化合物33-2的制备
将中间体33-1(1.05g,2.80mmol)溶于邻二氯苯(5mL)中,加入三苯基膦(1.83g,7.00mmol),氮气保护下,180℃反应10h。反应液经硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得棕色固体289mg,收率30.09%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.79(s,1H,NH),8.23(d,J=1.8Hz,1H,Ar-H),7.56-7.44(m,2H,Ar-H),7.40(s,1H,Ar-H),6.91(s,1H,Ar-H),4.04(s,3H,CH3)。
步骤3:化合物33-3的制备
将中间体33-2(260mg,0.76mmol)溶于干燥二氯甲烷(20mL)中,0℃下滴加1M三溴化硼的二氯甲烷溶液(1.90mL,1.90mmol),0℃下反应30min后,常温反应12h。0℃下滴加甲醇(10mL)淬灭反应,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=50:1,v/v),得黄色固体195mg,收率77.99%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.70(s,1H,NH),10.91(s,1H,OH),8.30(d,J=1.8Hz,1H,Ar-H),7.58-7.53(m,1H,Ar-H),7.53(s,1H,Ar-H),7.28(s,1H,Ar-H),6.84(d,J=1.4Hz,1H,Ar-H)。
步骤4:化合物33-4的制备
将中间体33-3(160mg,0.49mmol)溶于丙酮(10mL)中,加入碳酸钾(103mg,0.74mmol),于室温搅拌10min后,加入4-(溴甲基)-苯甲酸甲酯(123mg,0.54mmol)回流12h。蒸干溶剂,剩余物溶于二氯甲烷中,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=40:1,v/v),得白色固体193mg,收率82.57%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.88(s,1H,NH),8.28(s,1H,Ar-H),8.05(d,J=8.3Hz,2H,Ar-H),7.74(d,J=8.2Hz,2H,Ar-H),7.60-7.55(m,2H,Ar-H),7.49(s,1H,Ar-H),7.09(s,1H,Ar-H),5.59(s,2H,CH2),3.88(s,3H,CH3)。
步骤5:化合物33-5的制备
将中间体33-4(159mg,0.33mmol)溶于四氢呋喃-甲醇-水(体积比3:1:1,10mL)中,加入氢氧化锂(69mg,1.65mmol),室温反应5h。加入1M盐酸调pH至4,过滤,滤渣用水洗涤,烘干,得白色固体132mg,收率86.39%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.88(s,1H,NH),8.28(s,1H,Ar-H),8.03(d,J=8.2Hz,2H,Ar-H),7.72(d,J=8.1Hz,2H,Ar-H),7.60-7.55(m,2H,Ar-H),7.49(s,1H,Ar-H),7.09(s,1H,Ar-H),5.58(s,2H,CH2)。
步骤6:化合物33-6的制备
将中间体33-5(78mg,0.17mmol)溶于N,N-二甲基甲酰胺(5mL)中,0℃下加入O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(99mg,0.26mmol)和N,N-二异丙基乙胺(46μL,0.26mmol),0℃下反应30min,加入四氢吡咯(17μL,0.20mmol),室温反应8h。反应液倾倒至水中,加入乙酸乙酯(3×50mL)萃取,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(石油醚:乙酸乙酯=5:1,v/v),得白色固体80mg,收率91.19%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.87(s,1H,NH),8.26(s,1H,Ar-H),7.65(d,J=8.2Hz,2H,Ar-H),7.60(d,J=8.2Hz,2H,Ar-H),7.58-7.55(m,2H,Ar-H),7.49(s,1H,Ar-H),7.11(s,1H,Ar-H),5.53(s,2H,CH2),3.48(t,J=6.6Hz,2H,CH2),3.43-3.36(m,2H,CH2),1.93-1.76(m,4H,2×CH2)。
步骤7:化合物33的制备
将中间体33-6(72mg,0.14mmol)溶于四氢呋喃(5mL)中,0℃下分批加入四氢锂铝(9mg,0.21mmol),0℃下反应30min,恢复室温反应30min,升至50℃反应6h。加水终止反应,硅藻土助滤,蒸干溶剂,加入乙酸乙酯稀释,依次用水、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析纯化(二氯甲烷:甲醇=20:1,v/v),得白色固体25mg,收率35.57%。1H NMR(300MHz,DMSO-d6)δ(ppm)11.88(s,1H,NH),8.25(s,1H,Ar-H),7.60-7.52(m,4H,Ar-H),7.48(s,1H,Ar-H),7.43(d,J=7.8Hz,2H,Ar-H),7.10(s,1H,Ar-H),5.47(s,2H,CH2),3.74(s,2H,CH2),2.65-2.54(m,4H,2×CH2),1.80-1.67(m,4H,2×CH2)。
实施例34生物学活性
通过荧光素酶方法检测化合物对THP1-Dual细胞中cGAMP激动STING通路的抑制作用,方法如下:
(1)将处于对数生长期的THP1-Dual细胞(InvivoGen公司购买)4×104个/孔种于96孔板中,加入梯度稀释(20μM,10μM,5μM,2.5μM,1.25μM,0.625μM,0.3125μM,0.15625μM)的化合物,DMSO组作为空白对照,化合物H151作为阳性组(MCE公司购买)。
(2)细胞转染10μg/mL cGAMP与lipofectamine 2000(Invitrogen)复合物培养24h,cGAMP组细胞只加cGAMP不加化合物,作为阴性对照。
(3)采用QUANTI-LucTM试剂检测荧光素酶活性。取10μL细胞培养液上清加入96孔板中,再加入50μL QUANTI-LucTM试剂,用多功能酶标仪进行读值(Thermo)。
相对荧光素酶活性计算方法:RLU空白对照=RLU(DMSO组),RLU阴性对照=RLU(cGAMP组),RLU代表原始荧光素酶数值。
相对荧光素酶活性=[RLU-RLU(空白对照)]/[RLU(阴性对照)-RLU(空白对照)]。
测得化合物IC50如表1:
表1化合物IC50
编号 | IC50(μM) | 编号 | IC50(μM) | 编号 | IC50(μM) |
H151 | 2.55±0.66 | 12 | 7.7±0.39 | 24 | 3.41±0.37 |
1 | 10.65±0.26 | 13 | 9.46±0.29 | 25 | 4.13±0.36 |
2 | 8.80±0.35 | 14 | 9.46±0.29 | 26 | 4.13±0.36 |
3 | 8.03±0.22 | 15 | 4.36±0.53 | 27 | 2.97±0.16 |
4 | 9.30±0.21 | 16 | 4.36±0.53 | 28 | 1.76±0.11 |
5 | 7.28±0.31 | 17 | 4.36±0.53 | 29 | 3.80±0.50 |
6 | 7.70±0.65 | 18 | 4.41±0.42 | 30 | 7.53±0.25 |
7 | 9.10±0.27 | 19 | 3.06±0.32 | 31 | 7.53±0.25 |
8 | 10.96±0.50 | 20 | >50 | 32 | 7.53±0.25 |
9 | 5.80±0.50 | 21 | 4.17±0.22 | 33 | 2.56±0.25 |
10 | 11.45±0.72 | 22 | >10 | ||
11 | >50 | 23 | 9.17±0.52 |
从上表可知:本发明的上述化合物对cGAS-STING通路具有较好的抑制作用,可为制备治疗与STING蛋白功能相关疾病的药物提供依据,具有制备治疗和/或预防炎症性疾病和自身免疫性疾病的药物的前景,为临床应用提供了可靠途径。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (10)
1.一种通式I的咔唑类化合物或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
R1选自氢,卤素或C1-C6烷基;
R2选自氢、卤素、C1-C6烷基或卤代C1-C6烷基;
R3选自氢、卤素、C1-C6烷基、卤代C1-C6烷基、硝基、氰基、烷氧基、-(CH2)mNRaRb、酰胺基、杂环基、芳基或杂芳基;所述烷基、杂环基、芳基或杂芳基未被取代或任选地被1-3个Rc取代;
Rc选自氢、卤素、C1-C6烷基或含有0-3个杂原子的3-10元环烷基;所述烷基、环烷基未被取代或任选地被1-3个Rd取代;
Rd选自氢、C1-C6烷基;
Ra、Rb分别独立地选自氢、C1-C6烷基或C3-C6环烷基;
m=0或1;
n=1或2。
2.根据权利要求1所述的化合物,其特征在于,R1选自氢、氟、氯、溴或甲基。
3.根据权利要求1所述的化合物,其特征在于,R2选自氢、三氟甲基或氟。
4.根据权利要求1所述的化合物,其特征在于,R3选自氢、氟、氯、溴、甲基、异丙基、叔丁基、三氟甲基、硝基、氰基、酰胺基、甲氧基、环丙胺甲基、异丙基-2-胺甲基、N,N-二甲胺基、N,N-二甲基胺甲基、N,N-二乙基胺甲基、N-哌啶基甲基、N-吡咯烷基甲基、N-哌嗪基、N-哌嗪基甲基、1-甲基哌嗪基-4-甲基或1-乙基哌嗪基-4-甲基。
5.根据权利要求1所述的化合物,其特征在于,所述药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸、琥珀酸、甲磺酸、对甲苯磺酸、萘磺酸、富马酸、水杨酸或苯基乙酸;还包括通式I化合物与无机碱形成的酸式盐或由碱性胺制成的有机盐。
6.根据权利要求1所述的化合物,其特征在于选自:
7.一种药物组合物,其特征在于,包括权利要求1-6任一项所述的化合物或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体以及药学上可接受的载体。
8.根据权利要求1-6任一项所述的化合物在制备预防和/或治疗与STING蛋白功能相关的疾病的药物中的用途。
9.根据权利要求1-6任一项所述的化合物在制备用于预防和/或治疗炎症性疾病和自身免疫性疾病的药物中的用途。
10.根据权利要求8所述的用途,其特征在于,所述与STING蛋白功能相关疾病包括STING相关的婴儿期发病血管病变SAVI、Aicardi-Goutières综合征AGS、共溶体蛋白复合物α亚单位基因变异导致的COPA综合征、系统性红斑狼疮SLE、家族性冻疮性红斑狼疮FCL、帕金森症PD、肌萎缩侧索硬化症ALS、亨廷顿舞蹈症、非酒精性脂肪肝炎NASH、酒精肝、神经损伤、类风湿性关节炎、肾纤维化、系统性硬化症、椎间盘退变、肺纤维化、衰老、硬皮病、银屑病、炎症性肠病、自身免疫性结肠炎、肠易激综合征、溃疡性结肠炎、克罗恩病、葡萄膜炎、粘膜炎、糖尿病、心血管疾病或神经退行性疾病。
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