CN116891460A - 一种吲唑类衍生物或其药用盐及应用 - Google Patents
一种吲唑类衍生物或其药用盐及应用 Download PDFInfo
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- CN116891460A CN116891460A CN202310856587.5A CN202310856587A CN116891460A CN 116891460 A CN116891460 A CN 116891460A CN 202310856587 A CN202310856587 A CN 202310856587A CN 116891460 A CN116891460 A CN 116891460A
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- indazole derivative
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Abstract
本发明公开了一种吲唑类衍生物或其药用盐及应用。本发明发现了一类新的吲唑类衍生物,对ROCK激酶具有抑制功能,能够作为ROCK激酶抑制剂,且其结构类型较为新颖,能够作为多种疾病的潜在治疗药物,如炎性疾病、自身免疫性疾病、纤维化疾病、移植排斥、与IL‑17、IL‑21和/或IL‑23过度分泌相关的疾病、眼部疾病、心脑血管疾病、肿瘤转移、中枢神经系统疾病、糖尿病肾病和皮肤病等。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种吲唑类衍生物或其药用盐及应用。
背景技术
Rho蛋白相关的含螺旋激酶(ROCK)为AGC激酶家族的丝胺酸/苏胺酸蛋白激酶,是Rho的下游效应分子。ROCK激酶蛋白包含N端激酶结构域、Rho蛋白结合结构域(RBD)以及C端被锌指样基序域(CRD)一分为二的PH结构域。在经典的ROCK信号通路中,Rho GTPase激活下游ROCK激酶,并进一步磷酸化ROCK下游底物(MLC、LIMK、ERM、MARCKS、CRMP-2等),重塑细胞骨架、诱导肌动蛋白-肌球蛋白收缩以及调节微管动力。ROCK激酶由ROCK1和ROCK2两种亚型组成,ROCK1和ROCK2在氨基酸序列上有65%的同源性,在激酶结构域处的氨基酸序列具有92%的相似性。ROCK分布于全身组织,相比较而言,ROCK1在非神经性组织如血液、小肠、胸腺等中有更高表达,ROCK2在脑、心脏和结肠等中有更高表达。
ROCK激酶参与了多种疾病的发生发展,如眼部疾病、心脑血管疾病、肿瘤转移、中枢神经系统疾病、糖尿病肾病等,是治疗多种疾病的重要靶标。Rho GTPase介导的信号通路在平衡和协调T细胞介导的免疫过程包括T细胞的发展、激活以及分化中发挥重要作用。近期多项研究表明ROCK激酶的过度激活在炎性疾病及自身免疫性疾病中也扮演着不可或缺的重要角色,如银屑病、炎症性肠炎、类风湿性关节炎、系统性红斑狼疮等。尽管失调的ROCK激酶主要是通过调节动态细胞骨架影响自身免疫过程,其中ROCK2可以通过控制促炎和抑炎T细胞群的平衡来调节自身免疫。最近的报道显示,ROCK2在小鼠中通过磷酸化干扰素调节因子4(IRF4)调节IL-21和IL-17的生成,在自身免疫的发展中发挥重要作用。在人外周血CD4+T细胞极化产生的Th17细胞中,ROCK2与磷酸化的STAT3结合调控Th17细胞特异性的基因转录。一项临床研究显示,口服选择性的ROCK2抑制剂(KD025)能够在健康志愿者中降低外界刺激诱导的IL-17和IL-21的分泌(Natl.Acad.Sci.2014,111,16814-16819)。另两项研究显示,靶向ROCK2通过抑制STAT3磷酸化,提高STAT5的磷酸化,从而下调过度活化的Th17细胞,并增强调节性T细胞(Treg)功能,进而重建免疫平衡(Blood.2016,127,2144-2154)。Tenggesdal等人的研究表明KD025下调IL-17的分泌不依赖于IL-1和IL-6(Eur.J.Immunol.2018,48,1679-1686)。在非血液细胞中,ROCK蛋白也参与了控制Th17细胞核Treg细胞平衡的TGF-β信号通路(Nat.Commun.2020,11,2608)。基于ROCK2在抑制Th17细胞过度活化中的作用,其有望成为治疗银屑病的新的靶点。
迄今为止,仅有4种小分子ROCK激酶抑制剂获批上市。法舒地尔是第一个被批准的ROCK抑制剂,其抑制ROCK2的Ki值为0.33μM,主要用于治疗青光眼、脑血管痉挛和脑缺血等,同时在治疗肌萎缩侧索硬化(ALS)、诱导肿瘤细胞凋亡、抑制肿瘤转移、减轻神经系统疾病症状(如帕金森)等方面具有良好的作用效果。Ripasudil于2014年在日本批准上市,主要用于治疗青光眼和高眼压症,其抑制ROCK2和ROCK1的IC50分别为19和51nM。Netarsudil于2017年被FDA批准用于治疗青光眼或高眼压症,其抑制ROCK2的Ki值为2nM。KD025是ROCK2亚型激酶选择性最好的抑制剂,其抑制ROCK1的IC50值为24μM,抑制ROCK2的IC50值为105nM。2021年该化合物被FDA批准用于治疗抗移植物宿主病。除此之外,还有7个化合物处于临床研究阶段,主要用于治疗青光眼、脊髓损伤和肺纤维化等疾病。
发明内容
本发明的目的在于提供一种吲唑类衍生物或其药用盐及应用,对ROCK激酶具有抑制功能,能够作为ROCK激酶抑制剂。
本发明首先提供了一种吲唑类衍生物或其药用盐,所述吲唑类衍生物的结构式如通式(I)所示,
其中:
G为CH或N原子;
环A选自芳基、杂芳基、环烷基和杂环基;
各个R1相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、硝基、羧基、羟烷基、环烷基、杂环基、芳基和杂芳基;
各个R2相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、羟基、硝基、羧基、羟烷基、-NR4C(O)R5、-C(O)NR4 R5、环烷基、杂环基、芳基和杂芳基;
各个R3相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、羟基、硝基、羧基、羟烷基、环烷基、杂环基、芳基和杂芳基;
a为0、1、2、3或4;
q为0、1、2、3或4;
s为0、1或2。
优选的,所述吲唑类衍生物的结构式如通式(I-1)、(I-2)、(I-3)或(I-4)所示,
优选的,环A为5至10元环烷基。
更优选的,环A为环己烷,所述吲唑类衍生物的结构式如通式(II)所示,
进一步优选的,所述吲唑类衍生物的结构式如通式(II-1)、(II-2)、(II-3)或(II-4)所示,
进一步优选的,所述吲唑类衍生物为以下任意一个化合物:
其中(S)、(R)分别表示手性的顺式和反式。
本发明又提供了所述吲唑类衍生物或其药用盐在制备ROCK激酶抑制剂中的应用。
本发明又提供了所述吲唑类衍生物或其药用盐在制备用于治疗和/或预防疾病或病症的药物中的应用,所述的疾病或病症选自炎性疾病、自身免疫性疾病、纤维化疾病、移植排斥、与IL-17、IL-21和/或IL-23过度分泌相关的疾病、眼部疾病、心脑血管疾病、肿瘤转移、中枢神经系统疾病、糖尿病肾病和皮肤病学疾病相关疾病。
优选的,所述的疾病或病症选自类风湿性关节炎、骨关节炎、幼年特发性关节炎、银屑病、银屑病性关节炎、强直性脊柱炎、过敏性气道疾病、慢性阻塞性肺病、哮喘、支气管炎、炎性肠病、系统性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、自身免疫性肝疾病、舍格伦综合征、多发性硬化症、干眼病、I型糖尿病和与之相关的并发症、特应性湿疹、甲状腺炎、接触性皮炎、干燥综合征和肌萎缩性侧索硬化。
本发明还提供了一种药物,活性成分为所述吲唑类衍生物或其药用盐。
本发明还提供了所述吲唑类衍生物或其药用盐的制备方法,反应式为:
其中,通式(IA)和通式(III)所示的化合物或其盐发生还原胺化反应得到通式(I)所示的化合物或其可药用的盐。
制备方法中还包括所述的通式(IA)的制备方法:
其中,通式(IA-1)和通式(IA-2)所示的化合物或其盐发生偶联反应得到通式(IA)所示的化合物或其盐。
制备方法中还包括所述的通式(III)的制备方法:
其中,通式(III-1)所示的化合物或其盐发生脱保护反应得到通式(III)所示的化合物或其盐。
制备方法中还包括所述的通式(III-1)的制备方法:
其中,通式(III-2)和通式(III-3)所示的化合物或其盐发生还原胺化反应得到通式(III-1)所示的化合物或盐。
本发明发现了一类新的吲唑类衍生物,对ROCK激酶具有抑制功能,能够作为ROCK激酶抑制剂,且其结构类型较为新颖,能够作为多种疾病的潜在治疗药物,如炎性疾病、自身免疫性疾病、纤维化疾病、移植排斥、与IL-17、IL-21和/或IL-23过度分泌相关的疾病、眼部疾病、心脑血管疾病、肿瘤转移、中枢神经系统疾病、糖尿病肾病和皮肤病等。
具体实施方式
以下结合实施例用于进一步描述本公开,但这些实施例并非限制着本公开的范围。本发明吲唑类衍生物为以下任意一个化合物:
实施例1
实施例1中的化合物均由以下反应通式获得:
第一步,合成1b:
冰浴环境下,将氢化钠(567mg,23.6mmol)加入无水四氢呋喃(80mL)中,并在氮气氛围中加入苄醇(1.5mL,14.16mmol),搅拌1小时。加入无水四氢呋喃(10mL)溶解的有不同取代基的化合物1a,50℃下反应18小时。冷却到室温,饱和氯化铵淬灭后,减压浓缩除去溶剂,二氯甲烷萃取残余液体,重复三次并合并有机相,无水硫酸钠干燥,过滤后滤液减压浓缩,残余物用硅胶柱色谱法以石油醚/L酸乙酯(40∶1,v/v,500mL)纯化,得到标题化合物1b,产率60-82%。
第二步,合成1c:
将有不同取代基的1b(6.45mmol),10%Pd/C(68mg,10mol%)加入到圆底烧瓶中,加入甲醇(60mL)与乙酸乙酯(30mL),在氢气氛围下,室温搅拌2小时,硅藻土过滤后,减压浓缩,残余物用硅胶柱色谱法以二氯甲烷/甲醇(20∶1,v/v,500mL)纯化,得到标题化合物1c,产率90-95%。
第三步,合成((1S)-3-((1H-吲唑-5-基)氨基)环己基)氨基甲酸叔丁酯1f:
将(S)-(3-羰基环己基)氨基甲酸叔丁酯1d(毕得医药,CAS号:1803033-61-5)(1.00g,4.69mmol),5-氨基吲唑1e(毕得医药,CAS号:19335-11-6)(750mg,5.63mmol),氰基硼氢化钠(500mg,7.96mmol)加入无水甲醇(50mL),醋酸调节pH至6.0-7.0,室温反应12小时。加入水(2mL),减压浓缩除去溶剂,残余物用硅胶柱色谱法以含体积百分比为1%三乙胺的二氯甲烷/甲醇(40∶1,v/v,500mL)纯化,得到标题化合物1f(1.42g),产率:92%。
所得产物1f质谱分析后,m/z(ESI):331.2[M+1]。
第四步,合成(3S)-N1-(1H-吲唑-5-基)环己基-1,3-二胺1g:
将化合物1f(1.42g,4.30mmol),三氟乙酸(10ml)溶于二氯甲烷(10ml),室温反应1小时。反应液减压浓缩,残余物用硅胶柱色谱以含体积百分比为1%三乙胺的二氯甲烷/甲醇(5:1,v/v,500mL)纯化得到标题化合物1g(815.7mg),产率82%。
所得产物1g质谱分析后,m/z(ESI):231.2[M+I]。
第五步,合成1i:
将有不同取代基的化合物1c(2.36mmol),3-甲酰基苯硼酸1h(毕得医药,CAS号:87199-16-4)(708mg,4.72mmol),醋酸铜(944mg,4.72mmol),吡啶(4.5mL),加入二氯甲烷(120mL)中,室温下反应12小时。反应液减压浓缩,残余物用硅胶柱色谱法以含体积百分比为1%三乙胺的二氯甲烷(500mL)纯化,得到相应的化合物1i,产率54-91%。
第六步,合成II-1和II-2:
将相应的化合物1i(0.43mmol),化合物1g(100mg,0.43mmol),氰基硼氢化钠(48mg,0.76mmol)加入无水甲醇(20mL),醋酸调节pH至6.0-7.0,室温反应12小时。加入水(1mL),减压浓缩除去溶剂,残余物经高效液相色谱法(分离条件:制备柱WelchXB-C18,21.2×250mm,5μm;洗脱体系:甲醇/水(体积比)=10%-100%,含体积百分比为0.5‰三氟乙酸,流速:10ml/min,洗脱时间:40min)纯化,得到相应的化合物II-1与II-2,产率分别为30-32%和61-63%。
单一构型化合物12-1与12-2由2-氯-5-氟-4-甲基吡啶1a(毕得医药,CAS号:881891-83-4)制备而来。
单一构型化合物12-1:1H NMR(600MHz,d4-Methanol)δ7.92(s,1H),7.65(d,J=5.0Hz,1H),7.60(t,J=7.8Hz,1H),7.57-7.54(m,2H),7.49-7.45(m,2H),7.12(d,J=8.7Hz,1H),6.53(d,J=6.9Hz,1H),4.32(d,J=13.3Hz,1H),4.27(d,J=13.3Hz,1H),3.54-3.49(m,1H),3.35-3.32(m,1H),2.55-2.53(m,1H),2.30(s,3H),2.27-2.25(m,1H),2.14-2.12(m,1H),2.04-2.01(m,1H),1.56-1.49(m,1H),1.47-1.41(m,2H),1.39-1.32(m,1H)。13CNMR(300MHz,d4-Methanol)δ162.4,149.8(d,J=232.6Hz),146.8(d,J=20.2Hz),141.9,138.5,137.5,134.0,133.9,131.6,131.4,129.6,128.8,124.7,124.2(d,J=39.0Hz),121.6,121.0(d,J=2.9Hz),112.5,106.9,57.0,55.4,49.6,35.2,31.6,29.5,23.1,15.3。MS m/z(ESI):446.2[M+1]。
单一构型化合物12-2:1H NMR(600MHz,d4-Methanol)δ7.82(s,1H),7.60(d,J=4.6Hz,1H),7.54((t,J=7.8Hz,1H),7.51-7.49(m,2H),7.46-7.44(m,1H),7.35(d,J=9.6Hz,1H),6.98(d,J=8.7Hz),6.51(dd,J=7.3,0.9Hz),4.29(d,J=13.3Hz,1H),4.24(d,J=13.3Hz,1H),3.92-3.91(m,1H),3.54-3.49(m,1H),2.48-2.45(m,1H),2.29(s,3H),2.20-2.18(m,1H),1.89-1.77(m,3H),1.76-1.69(m,2H),1.60-1.54(m,1H)。13C NMR(300MHz,d4-Methan01)δ162.4,149.8(d,J=234.1Hz),146.8(d,J=20.2Hz),142.2,141.9,137.1,133.8,133.3,131.6,131.6,129.6,128.7,125.0,124.2(d,J=39.0Hz),121.1,121.0(d,J=4.3Hz),112.1,101.5,54.5,49.6,48.6,32.9,30.3,29.7,20.2,15.3。MS m/z(ESI):446.2[M+1]。
单一构型化合物15-1与15-2由4-(叔丁基)-2-氯吡啶1a(毕得医药,CAS号:81167-60-4)制备而来。
单一构型化合物15-1:1H NMR(600MHz,d4-Metyhanol)δ7.91(s,1H),7.61(t,J=7.8Hz,1H),7.57-7.55(m,1H),7.54-7.52(m,2H),7.48(d,J=9.2Hz,1H),7.45-7.43(m,1H),7.12(d,J=8.7Hz,1H),6.63(dd,J=7.3,2.3Hz,1H),6.58(d,J=1.8Hz,1H),4.33(d,J=13.3Hz,1H),4.27(d,J=13.3Hz,1H),3.54-3.50(m,1H),3.35-3.31(m,1H),2.56-2.53(m,1H),2.27-2.25(m,1H),2.14-2.11(m,1H),2.04-2.01(m,1H),1.53-1.50(m,1H),1.47-1.41(m,2H),1.38-1.33(m,1H),1.31(s,9H)。13C NMR(300MHz,d4-Methanol)δ167.7,164.8,142.3,138.5,138.5,137.4,134.0,133.9,131.6,131.3,129.7,128.8,124.8,121.7,116.1,112.5,108.3,107.0,57.0,55.4,49.6,36.1,35.3,31.7,29.9,29.5,23.1。MS m/z(ESI):470.3[M+1]。
单一构型化合物15-2:1H NMR(600MHz,d4-Methanol)δ7.85(s,1H),7.55(t,J=7.8Hz,1H),7.52-7.49(m,2H),7.47(d,J=8.2Hz,1H),7.45-7.43(m,1H),7.39(d,J=8.7Hz,1H),7.03(d,J=9.2Hz,1H),6.58-6.56(m,2H),4.30(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.94-3.93(m,1H),3.57-3.53(m,1H),2.44-2.42(m,1H),2.20-2.18(m,1H),1.89-1.74(m,5H),1.63-1.58(m,1H),1.30(s,9H)。13C NMR(300MHz,d4-Methanol)δ167.7,164.8,142.3,141.1,138.4,137.4,133.8,133.5,131.6,131.4,129.6,128.8,125.0,121.2,116.1,112.2,108.2,101.9,54.4,50.6,48.8,36.1,32.8,30.0,29.9,29.5,20.1。MSm/z(ESI):470.3[M+1]。
实施例2
实施例2中的化合物均由以下反应通式获得:
第一步,合成1k:
将有5-氟胞嘧啶1j(毕得医药,CAS号:2022-85-7)(5.0mmol),3-甲酰基苯硼酸1h(毕得医药,CAS号:87199-16-4)(1499mg,10.0mmol),一水合醋酸铜(998mg,5.0mmol),四甲基乙二胺(1.5mL),加入二氯甲烷(120mL)中,室温下反应12小时。反应液减压浓缩,残余物用硅胶柱色谱法以含体积百分比为1%三乙胺的二氯甲烷(500mL)纯化,得到标题化合物1k(297.7mg),产率63%。
第二步,合成1-1和2-2:
将相应的化合物1k(100mg,0.43mmol),化合物1g(100mg,0.43mmol),氰基硼氢化钠(48mg,0.76mmol)加入无水甲醇(20mL),醋酸调节pH至6.0-7.0,室温反应12小时。加入水(1mL),减压浓缩除去溶剂,残余物经高效液相色谱法(分离条件:制备柱WelchXB-C18,21.2×250mm,5μm;洗脱体系:甲醇/水(体积比)=10%-100%,含体积百分比为0.5‰三氟乙酸,流速:10ml/min,洗脱时间:40min)纯化,得到相应的化合物II-1与II-2,产率分别为28%和56%。
单一构型化合物1-1:1H NMR(600MHz,d4-Methanol)δ8.06(s,1H),7.90(d,J=6.0Hz,1H),7.65-7.61(m,2H),7.56-7.52(m,2H),7.48(d,J=7.8Hz,1H),7.40(dq,J=7.8,0.9Hz,1H),7.30(dd,J=9.2,2.3Hz,1H),4.31(d,J=12.8Hz,1H),4.24d,J=12.8Hz,1H),3.65-3.59(m,1H),3.32-3.28(m,1H),2.45-2.40(m,1H),2.39-2.24(m,1H),2.15-2.11(m,1H),2.08-2.03(m,1H),1.60-1.40(m,4H).13C NMR(300MHz,d4-Methanol)δ160.1(d,J=15.9Hz),156.4,142.0,139.8,138.8(d,J=244.2Hz),134.7,133.6,131.6,131.3(d,J=33.2Hz),130.9,130.8,129.7,128.4,124.5,122.0,113.0,101.7,57.7,56.6,49.6,30.6,30.3,29.2,22.8。MS m/z(ESI):448.2[M+1]。
单一构型化合物1-2:1H NMR(600MHz,d4-Methanol)δ8.06(s,1H),7.95(d,J=6.0Hz,1H),7.61(d,J=8.7Hz,1H),7.58-7.51(m,3H),7.47-7.45(m,1H),7.29(dd,J=8.7,1.8Hz,1H),4.34(d,J=13.3Hz,1H),4.27(d,J=13.3Hz,1H),4.02-3.98(m,1H),3.69-3.64(m,1H),2.32-2.27(m,1H),2.15-2.10(m,1H),2.03-1.96(m,1H),1.90-1.74(m,5H).13C NMR(300MHz,d4-Methanol)δ159.9(d,J=15.9Hz),156.1,141.0,138.8,138.7(d,J=244.2Hz),137.9,134.2,133.5,131.5,131.4(d,J=31.8Hz),131.2,129.7,128.5,124.7,121.7,112.8,107.9,54.1,53.7,49.6,31.8,29.2,28.8,19.8。MS m/z(ESI):448.2[M+1]。
实施例3
实施例3中的化合物均由以下反应通式获得:
第一步,合成1i:
将有不同取代基的化合物1c(2.36mmol),3-甲酰基苯硼酸1h(毕得医药,CAS号:87199-16-4)(708mg,4.72mmol),醋酸铜(944mg,4.72mmol),吡啶(4.5mL),加入二氯甲烷(120mL)中,室温下反应12小时。反应液减压浓缩,残余物用硅胶柱色谱法以含体积百分比为1%三乙胺的二氯甲烷(500mL)纯化,得到相应的化合物1i,产率73-92%。
第六步,合成II-1和II-2:
将相应的化合物1i(0.43mmol),化合物1g(100mg,0.43mmol),氰基硼氢化钠(48mg,0.76mmol)加入无水甲醇(20mL),醋酸调节pH至6.0-7.0,室温反应12小时。加入水(1mL),减压浓缩除去溶剂,残余物经高效液相色谱法(分离条件:制备柱WelchXB-C18,21.2×250mm,5μm;洗脱体系:甲醇/水(体积比)=10%-100%,含体积百分比为0.5%‰三氟乙酸,流速:10ml/min,洗脱时间:40min)纯化,得到相应的化合物II-1与II-2,产率分别为23-32%和54-63%。
单一构型化合物2-1与2-2由4-氨基吡啶-2-酮1c(毕得医药,CAS号:38767-72-5)制备而来。
单一构型化合物2-1:1H NMR(600MHz,d4-Methanol)δ8.14(s,1H),7.71(dd,J=8.9,1.4Hz,1H),7.54(t,J=7.8Hz,1H),7.50(d,J=8.2Hz,1H),7.47(t,1.4Hz,1H),7.41(d,J=8.7Hz,1H),7.38-7.36(m,1H),7.36(d,J=7.8Hz,1H),6.13(d,J=7.3Hz,1H),4.31(d,J=13.3Hz,1H),4.24(d,J=13.3Hz,1H),3.70-3.65(m,1H),3.32-3.27(m,1H),2.44-2.41(m,1H),2.29-2.25(m,1H),2.13-2.10(m,1H),2.08-2.05(m,1H),1.65(q,J=11.9Hz,1H),1.54-1.42(m,3H).13C NMR(300MHz,d4-Methanol)δ164.8,161.1,142.4,141.9,140.9,139.5,135.2,133.4,131.4,130.9,130.0,128.9,124.2,122.4,118.7,113.4,107.1,103.0,59.7,56.3,49.6,33.2,29.6,29.0,22.5。MS m/z(ESI):429.2[M+1]。
单一构型化合物2-2:1H NMR(600MHz,d4-Methanol)δ7.84(s,1H),7.49(t,J=7.8Hz,1H),7.44-7.42(m,2H),7.38-7.65(m,2H),7.26(d,J=7.3Hz,1H),7.00(d,J=8.7Hz,1H),6.02(d,J=7.3Hz,1H),4.26(d,J=13.3Hz,1H),4.21(d,J=13.3Hz,1H),3.93-3.91(m,1H),3.66-3.50(m,1H),2.45-2.42(m,1H),2.20-2.16(m,1H),1.90-1.70(m,5H),1.61-1.54(m,1H)。13C NMR(300MHz,d4-Methanol)δ165.5,160.7,142.7,142.1,141.9,139.2,133.6,133.4,131.4,130.8,130.0,128.9,124.9,121.4,121.2,112.2,108.2,102.5,54.5,50.1,49.6,32.9,30.1,29.6,20.1。MS m/z(ESI):429.2[M+1]。
单一构型化合物3-1与3-2由4-甲基-5-硝基吡啶-2-酮1c(毕得医药,CAS号:21901-41-7)制备而来。
单一构型化合物3-1:1H NMR(600MHz,d4-Methanol)δ7.95(s,1H),7.46(d,J=8.7Hz,1H),7.26(t,J=7.6Hz,2H),7.05(d,J=8.7Hz,1H),6.90-6.81(m,5H),4.48-4.02(m,2H),3.38-3.33(m,1H),3.34(s,3H),3.30-3.26(m,1H),2.55-2.50(m,1H),2.20-2.15(m,1H),2.11-2.03(m,2H),1.61(q,J=11.5Hz,1H),1.45-1.27(m,3H)。13C NMR(300MHz,d4-Methanol)δ159.5,159.4,144.2,138.2,133.9,133.9,131.6,130.4,124.9,122.7,121.4,119.1,118.8,117.9,115.1,114.8,112.5,109.9,65.1,55.5,55.4,49.6,33.0,32.2,26.9,23.6。MS m/z(ESI):443.6[M+1]。
单一构型化合物3-2:1H NMR(600MHz,d4-Methanol)δ7.81(s,1H),7.34(d,J=9.2Hz,1H),7.27-7.22(m,1H),6.91-6.76(m,5H),6.65(s,1H),6.52(d,J=5.5Hz,H),4.42(d,J=12.8Hz,1H),4.24(d,J=12.8Hz,1H),4.09-4.02(m,1H),3.71-3.64(m,1H),3.33(s,3H),2.62-2.56(m,1H),2.18-2.14(m,1H),1.91-1.71(m,6H)。13C NMR(300MHz,d4-Methanol)δ159.4,159.2,142.9,142.9,136.9,133.2,132.3,131.6,131.4,125.1,123.4,123.0,121.1,119.0,118.6,118.0,117.8,112.1,59.4,55.3,55.2,49.6,30.8,29.1,27.6,21.1。MS m/z(ESI):443.6[M+1]。
单一构型化合物4-1与4-2由2-羟基-4-甲基吡啶1c(毕得医药,CAS号:13466-41-6)制备而来。
单一构型化合物4-1:1H NMR(600MHz,d4-Methanol)δ8.00(s,1H),7.60(t,J=7.3Hz,1H),7.57-7.54(m,2H),7.51(s,1H),7.49-7.47(m,2H),7.42(d,J=8.2Hz,1H),7.23(d,J=8.2Hz,1H),6.48(s,1H),6.40(d,J=7.3Hz,1H),4.32(d,J=12.8Hz,1H),4.26(d,J=12.8Hz,1H),3.60-3.55(m,1H),3.34-3.29(m,1H),2.52-2.48(m,1H),2.30(s,3H),2.28-2.24(m,1H),2.14-2.10(m,1H),2.06-2.02(m,1H),1.55-1.39(m,4H)。13C NMR(300MHz,d4-Methanol)δ164.4,155.8,142.4,139.4,139.4,138.5,134.4,133.8,131.6,131.3,129.6,128.8,124.6,121.9,119.8,112.8,111.4,110.2,56.9,56.8,49.6,34.5,30.9,29.3,22.9,21.4。MS mm/z(ESI):428.2[M+1]。
单一构型化合物4-2:1H NMR(600MHz,d4-Methanol)δ7.93(s,1H),7.56(t,J=7.3Hz,1H),7.54-7.51(m,2H),7.48-7.42(m,3H),7.23-7.20(m,1H),7.14-7.11(m,1H),6.46(s,1H),6.37(dd,J=6.4,1.8Hz,1H),4.32(d,J=12.8Hz,1H),4.26(d,J=12.8Hz,1H),3.98-3.94(m,1H),3.61-3.57(m,1H),2.41-2.36(m,1H),2.29(s,3H),2.19-2.14(m,1H),1.88-1.78(m,5H),1.69-1.61(m,1H)。13C NMR(300MHz,d4-Methanol)δ164.4,155.8,142.4,138.5,138.5,138.3,133.9,133.7,131.6,131.4,129.7,128.8,124.8,121.5,119.8,112.6,111.4,110.0,54.3,52.6,49.6,32.2,29.5,29.1,21.4,19.9。MS m/z(ESI):428.2[M+1]。
单一构型化合物5-1与5-2由2-吡啶酮1c(毕得医药,CAS号:142-08-5)制备而来。
单一构型化合物5-1:1H NMR(600MHz,d4-Methanol)δ8.11(s,1H),7.69-7.63(m,2H),7.61-7.58(m,2H),7.57-7.53(m,2H),7.44-7.42(m,1H),7.37(d,J=8.7Hz,1H),6.66(d,J=9.2Hz,1H),6.51(td,J=6.9,1.4Hz,1H),4.34(d,J=12.8Hz,1H),4.26(d,J=12.8Hz,1H),3.69-3.63(m,1H),3.34-3.29(m,1H),2.47-2.42(m,1H),2.29-2.25(m,1H),2.14-2.11(m,1H),2.08-2.05(m,1H),1.63(q,J=11.9Hz,1H),1.52-1.44(m,3H)。13C NMR(300MHz,d4-Methanol)δ164.5,143.2,142.5,140.5,139.8,139.7,135.0,133.8,131.7,131.4,129.6,128.8,124.3,122.2,121.6,113.2,111.1,108.9,59.0,56.4,49.6,33.5,29.9,29.0,22.6。MS m/z(ESI):414.2[M+1]。
单一构型化合物5-2:1H NMR(600MHz,d4-Methanol)δ7.92(s,1H),7.66-7.62(m,1H),7.59-7.52(m,4H),7.48-7.44(m,2H),7.22-7.19(m,1H),7.14-7.10(m,1H),6.65(d,J=9.2Hz,1H),6.48(td,J=7.3,1.8Hz,1H),4.32(d,J=12.8Hz,1H),4.27(d,J=12.8Hz,1H),3.94-3.98(m,1H),3.57-3.62(m,1H),2.42-2.37(m,1H),2.20-2.14(m,1H),1.89-1.78(m,5H),1.70-1.63(m,1H)。13C NMR(300MHz,d4-Methanol)δ164.5,143.2,142.5,139.7,138.3,138.2,133.9,133.8,131.6,131.5,129.6,128.8,124.8,121.6,121.5,112.5,108.9,105.7,54.3,52.4,49.6,30.2,29.5,29.1,19.9。MS m/z(ESI):414.2[M+1]。、
单一构型化合物6-1与6-2由2-氧代-1,2-二氢吡啶-4-腈1c(毕得医药,CAS号:94805-51-3)制备而来。
单一构型化合物6-1:1H NMR(600MHz,d4-Methanol)δ8.14(s,1H),7.76(d,J=6.9Hz,1H),7.71(dd,J=9.2,0.9Hz,1H),7.61-7.55(m,3H),7.45(dt,J=6.9,1.8Hz,1H),7.42(d,J=9.2Hz,1H),7.06(d,J=1.8Hz,1H),6.62(dd,J=6.9,1.8Hz,1H),4.34(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.70-3.64(m,1H),3.33-3.29(m,1H),2.48-2.43(m,1H),2.29-2.25(m,1H),2.13-2.09(m,1H),2.08-2.04(m,1H),1.69(q,J=11.9Hz,1H),1.56-1.45(m,3H)。13C NMR(300MHz,d4-Methanol)δ162.4,141.8,141.7,141.0,140.8,135.2,134.0,131.8,131.7,129.3,128.6,127.7,126.5,124.2,122.4,116.6,115.9,113.3,107.6,59.7,56.4,49.6,33.2,29.5,28.9,22.5。MS m/z(ESI):414.2[M+1]。
单一构型化合物6-2:1H NMR(600MHz,d4-Methanol)δ7.84(s,1H),7.70(d,J=6.9Hz,1H),7.58-7.52(m,3H),7.46(dt,J=7.3,1.8Hz,1H),7.37(d,J=9.6Hz,1H),7.05(d,J=1.4Hz,1H),7.00(d,J=9.2Hz,1H),6.57(dd,J=6.9,1.8Hz,1H),4.30(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.93-3.90(m,1H),3.55-3.50(m,1H),2.47-2.42(m,1H),2.21-2.16(m,1H),1.89-1.71(m,5H),1.62-1.55(m,1H)。13C NMR(300MHz,d4-Methanol)δ162.5,141.8,141.8,138.3,138.1,133.9,133.4,132.0,131.7,129.4,128.6,127.8,126.5,124.8,121.5,116.6,112.6,107.6,101.8,54.4,52.5,49.6,32.2,29.6,29.1,19.9。MS m/z(ESI):414.2[M+1]。
单一构型化合物7-1与7-2由2-氧代-1,2-二氢吡啶-4-酰胺1c(毕得医药,CAS号:175277-69-7)制备而来。
单一构型化合物7-1:1H NMR(600MHz,d4-Methanol)δ7.92(s,1H),7.69(d,J=6.9Hz,1H),7.64(t,J=7.8Hz,1H),7.60-7.58(m,1H),7.56(t,J=1.4Hz,1H),7.49-7.47(m,2H),7.11(d,J=8.7Hz,1H),7.05(d,J=1.4Hz,1H),6.81(dd,J=7.3,1.8Hz,1H),4.34(d,J=13.3Hz,1H),4.28(d,J=13.3Hz,1H),3.55-3.50(m,1H),3.37-3.32(m,1H),2.56-2.52(m,1H),2.29-2.25(m,1H),2.16-2.11(m,1H),2.06-2.01(m,1H),1.57-1.49(m,1H),1.47-1.38(m,2H),1.38-1.31(m,1H)。13C NMR(300MHz,d4-Methanol)δ169.0,164.3,147.8,142.2,140.2,140.0,137.8,134.8,133.8,131.8,131.6,129.5,128.7,124.4,122.0,120.5,113.1,106.6,106.5,58.0,56.6,49.6,34.0,30.4,29.2,22.7。MS m/z(ESI):457.2[M+1]。
单一构型化合物7-2:1H NMR(600MHz,d4-Methanol)δ7.90(s,1H),7.65(d,J=6.9Hz,1H),7.58(t,J=8.2Hz,1H),7.56-7.53(m,2H),7.47(dt,J=7.8,1.4Hz,1H),7.4(d,J=8.7Hz,1H),7.09(d,J=9.2Hz,1H),7.04(d,J=1.4Hz,1H),6.78(dd,J=6.9,1.8Hz,1H),4.32(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.96-3.93(m,1H),3.60-3.55(m,1H),2.43-2.38(m,1H),2.22-2.15(m,1H),1.88-1.77(m,5H),1.67-1.61(m,1H)。13C NMR(300MHz,d4-Methanol)δ169.0,164.3,147.8,142.2,140.2,139.3,138.2,134.4,133.7,131.8,131.7,129.6,128.8,124.6,121.8,120.5,113.0,106.5,105.1,54.7,54.2,49.6,31.6,28.9,28.6,19.7。MS m/z(ESI):457.2[M+1]。
单一构型化合物8-1与8-2由2-羟基-3-甲基吡啶1c(毕得医药,CAS号:1003-56-1)制备而来。
单一构型化合物8-1:1H NMR(600MHz,d4-Methanol)δ7.98(s,1H),7.60(t,J=7.8Hz,1H),7.57-7.54(m,2H),7.53-7.51(m,2H),7.46-7.42(m,2H),7.22(d,J=9.2Hz,1H),6.42(t,J=6.9Hz,1H),4.33(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.60-3.54(m,1H),3.35-3.30(m,1H),2.53-2.49(m,1H),2.28-2.24(m,1H),2.15(s,3H),2.15-2.10(m,1H),2.06-2.01(m,1H),1.54-1.39(m,4H)。13C NMR(300MHz,d4-Methanol)δ164.6,143.0,140.6,140.2,137.0,135.0,133.7,131.6,131.2,131.1,129.7,128.8,124.3,122.3,118.9,117.0,113.2,108.5,59.1,56.4,49.6,33.5,29.9,29.0,22.6,17.2。MS m/z(ESI):428.2[M+1]。
单一构型化合物8-2:1H NMR(600MHz,d4-Methanol)δ7.87(d,J=0.9Hz,1H),7.55(t,J=7.8Hz,1H),3.52-3.49(m,3H),7.44-7.42(m,1H),7.42-7.39(m,2H),7.05(d,J=8.7Hz,1H),6.38(t,J=6.9Hz,1H),4.30(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.95-3.92(m,1H),3.58-3.52(m,1H),2.45-2.40(m,1H),2.20-2.15(m,1H),2.14(s,3H),1.90-1.75(m,5H),1.65-1.58(m,1H)。13C NMR(300MHz,d4-Methanol)δ164.6,143.0,140.2,140.2,139.2,137.0,134.3,133.5,131.6,131.4,131.1,129.8,128.9,124.6,121.8,118.8,112.9,108.5,54.5,54.0,49.6,31.7,28.9,28.7,19.7,17.2。MS m/z(ESI):428.2[M+1]。
单一构型化合物9-1与9-2由5-甲基吡啶-2-酮1c(毕得医药,CAS号:1003-68-5)制备而来。
单一构型化合物9-1:1H NMR(600MHz,d4-Methanol)δ8.09(d,J=1.2Hz,1H),7.72(br,1H),7.66(d,J=8.7Hz,1H),7.59(t,J=7.78Hz,1H),7.56-7.54(m,2H),7.51(t,J=1.83,1H),7.43-7.41(m,1H),7.40(s,1H),7.35(d,J=8.7Hz,1H),6.60(d,J=9.6Hz,1H),4.33(d,J=12.8Hz,1H),4.26(d,J=13.3Hz,1H),3.66-3.62(m,1H),3.33-3.29(m,1H),2.47-2.45(m,1H),2.28-2.25(m,1H),2.15(d,J=0.9Hz,3H),2.15-2.10(m,1H),2.07-2.04(m,1H),1.65-1.59(m,1H),1.51-1.44(m,3H)。13C NMR(300MHz,d4-Methanol)δ163.7,145.8,142.6,140.3,137.0,134.9,133.8,131.6,131.3,130.8,129.6,128.8,124.3,122.2,121.1,118.7,113.9,113.2,58.7,56.5,49.6,33.6,30.1,29.0,22.6,16.8。MS m/z(ESI):428.2[M+1]。
单一构型化合物9-2:1H NMR(600MHz,d4-Methanol)δ8.04(s,1H),7.61-7.58(m,2H),7.57(br,1H),7.56-7.53(m,2H),7.47-7.45(m,1H),7.41(s,1H),7.29-7.27(m,1H),6.60(d,J=9.2Hz,1H),4.35(d,J=13.3Hz,1H),4.29(d,J=13.3Hz,1H),4.01-3.98(m,1H),3.68-3.65(m,1H),2.33-2.30(m,1H),2.16-2.12(m,1H),2.15(d,J=0.9Hz,3H),2.00-1.97(m,1H),1.88-1.74(m,5H)。13C NMR(300MHz,d4-Methanol)δ163.7,145.8,142.6,142.7,139.5,137.0,134.5,133.6,131.6,131.5,129.8,128.9,124.5,121.9,121.1,118.8,113.0,110.5,55.2,54.0,49.6,31.5,28.7,28.5,19.6,16.8。MS m/z(ESI):428.2[M+1]。
单一构型化合物10-1与10-2由4-氟吡啶-2-酮1c(毕得医药,CAS号:96530-75-5)制备而来。
单一构型化合物10-1:1H NMR(600MHz,d4-Methanol)δ7.97(s,1H),7.72(t,J=7.3Hz,1H),7.61(t,J=7.8Hz,1H),7.58(dt,J=7.8,1.4Hz,1H),7.54-7.52(m,2H),7.44(dt,J=7.3,1.4Hz,1H),7.19(d,J=8.7Hz,1H),7.47(m,1H),7.33(dd,J=10.6,2.8Hz,1H),4.33(d,J=13.3Hz,1H),4.27(d,J=13.3Hz,1H),3.58-3.52(m,1H),3.35-3.29(m,1H),2.54-2.50(m,1H),2.28-2.23(m,1H),2.14-2.10(m,1H),2.05-2.01(m,1H),1.53-1.43(m,3H),1.43-1.35(m,1H)。13C NMR(300MHz,d4-Methanol)δ172.8(d,J=267.3Hz),165.7(d,J=20.2Hz),142.2(d,J=14.4Hz),141.9,140.1,138.8,134.8,133.9,131.7,131.6,129.7,128.9,124.4,122.1,113.1,104.0(d,J=17.3Hz),100.9(d,J=28.9Hz),109.0,58.3.56.6,49.6,33.8,30.2,29.1,22.7。MS m/z(ESI):432.2[M+1]。
单一构型化合物10-2:1H NMR(600MHz,d4-Methanol)δ8.02(s,1H),7.71(t,J=7.8Hz,1H),7.60-7.54(m,4H),7.47-7.45(m,1H),7.24(d,J=8.7Hz,1H),6.47-6.44(m,1H),7.33(dd,J=7.8,2.8Hz,1H),4.35(d,J=13.3Hz,1H),4.28(d,J=13.3Hz,1H),4.01-3.97(m,1H),3.67-3.63(m,1H),2.35-2.30(m,1H),2.16-2.11(m,1H),1.98-1.93(m,1H),1.88-1.79(m,4H),1.77-1.72(m,1H)。13C NMR(300MHz,d4-Methanol)δ172.8(d,J=268.8Hz),165.8(d,J=18.8Hz),142.2(d,J=13.0Hz),141.8,141.6,139.2,134.4,133.7,131.7,131.7,129.8,129.0,124.6,121.8,112.9,109.4,104.0(d,J=17.3Hz),101.0(d,J=27.4Hz),54.4,54.2,49.6,31.6,29.0,28.6,19.7。MS m/z(ESI):432.2[M+1]。
单一构型化合物11-1与11-2由4-乙基吡啶-2(1H)-酮1c(毕得医药,CAS号:37529-91-2)制备而来。
单一构型化合物11-1:1H NMR(600MHz,d4-Methanol)δ7.98(s,1H),7.59(t,J=7.8Hz,1H),7.56-7.55(m,2H),7.52-7.50(m,2H),7.43-7.42(m,1H),7.22(d,J=8.7Hz,1H),6.48(d,J=1.8Hz,1H),6.44(dd,J=6.9,1.8Hz,1H),4.32(d,J=13.3Hz,1H),4.26(d,J=13.3Hz,1H),3.59-3.55(m,1H),3.34-3.30(m,1H),2.61(q,J=7.3Hz,2H),2.52-2.49(m,1H),2.27-2.24(m,1H),2.13-2.10(m,1H),2.05-2.02(m,1H),1.54-1.39(m,4H),1.26(t,J=7.8Hz,3H)。13C NMR(300MHz,d4-Methanol)δ164.7,161.3,142.4,139.3,139.2,138.8,134.4,133.8,131.6,131.3,129.6,128.8,124.6,121.9,118.3,112.8,110.4,109.8,56.8,56.8,49.1,34.6,31.0,29.4,29.3,22.9,13.8。MS m/z(ESI):442.3[M+1]。
单一构型化合物11-2:1H NMR(600MHz,d4-Methanol)δ7.87(s,1H),7.55(t,J=7.8Hz),7.52-7.50(m,2H),7.46(d,J=7.3Hz),7.43(dt,J=7.8,1.8Hz,1H),7.42(dd,J=8.7,0.9Hz),7.06(d,J=8.7Hz,1H),6.47(d,J=1.87Hz,1H),6.40(dd,J=7.3,1.8Hz,1H),4.30(d,J=13.3Hz,1H),4.25(d,J=13.3Hz,1H),3.95-3.93(m,1H),3.58-3.55(m,1H),2.60(q,J=7.8Hz,2H),2.43-2.40(m,1H),2.19-2.16(m,1H),1.88-1.75(m,5H),1.65-1.59(m,1H),1.25(t,J=7.8Hz,3H)。13C NMR(300MHz,d4-Methanol)δ164.7,161.4,142.4,140.3,139.2,138.7,134.4,133.6,131.6,131.4,129.8,128.9,124.6,121.8,118.3,112.9,110.4,104.3,54.5,54.1,49.6,31.7,29.4,28.9,28.7,19.7,13.8。MS m/z(ESI):442.3[M+1]。
单一构型化合物13-1与13-2由4-三氟甲基吡啶-2(1H)-酮1c(毕得医药,CAs号:50650-59-4)制备而来。
单一构型化合物13-1:1H NMR(600MHz,d4-Methanol)δ7.90(s,1H),7.81(d,J=7.3Hz,1H),7.64(t,J=7.8Hz,1H),7.61-7.59(m,1H),7.58(t,J=1.8Hz,1H),7.51-7.49(m,1H),7.46(d,J=8.7Hz,1H),7.10(d,J=8.7Hz,1H),6.94(s,1H),6.64(dd,J=6.9,1.8Hz,1H),4.34(d,J=13.3Hz),4.29(d,J=13.3Hz),3.53-3.49(m,1H),3.36-3.31(m,1H),2.57-2.54(m,1H),2.28-2.25(m,1H),2.14-2.12(m,1H),2.04-2.01(m,1H),1.56-1.49(m,1H),1.47-1.39(m,2H),1.37-1.29(m,1H)。13C NMR(300MHz,d4-Methanol)δ163.3,143.5(q,J=30.3Hz),142.0,141.8,138.3,138.0,134.1,133.9,131.8,131.8,129.4,128.7,124.8,123.4(q,J=283.2Hz),121.5,119.4(d,J=4.3Hz),112.4,106.3,103.2,57.1,54.9,48.9,35.5,31.9,29.5,23.1.MS m/z(ESI):482.2[M+1]。
单一构型化合物13-2:1H NMR(600MHz,d4-Methanol)δ7.86(s,1H),7.73(d,J=7.3Hz),7.55(t,J=7.8Hz),7.53-7.51(m,2H),7.47(dt,J=7.3,1.8Hz,1H),7.33(d,J=8.7Hz,1H),6.99(d,J=8.7Hz,1H),6.91(s,1H),6.57(dd,J=6.9,2.3Hz,1H),4.29(d,J=13.8Hz,1H),4.24(d,J=13.8Hz),3.92-3.89(m,1H),3.54-3.49(m,1H),2.45-2.42(m,1H),2.19-2.16(m,1H),1.88-1.82(m,2H),1.81-1.76(m,1H),1.74-1.68(m,2H),1.60-1.53(m,1H)。13C NMR(300MHz,d4-Methanol)δ163.3,143.7(q,J=33.2Hz),142.1,142.0,141.8,141.9,137.4,134.0,134.0,131.9,131.7,129.4,128.7,124.4,123.4(q,J=245.6Hz),121.1,119.4(d,J=2.9Hz),112.3,103.2,101.6,54.5,50.2,49.6,32.9,30.2,29.6,20.1。MS m/z(ESI):482.2[M+1]。
单一构型化合物14-1与14-2由2-羟基-4苯基吡啶1c(毕得医药,CAS号:19006-81-6)制备而来。
单一构型化合物14-1:1H NMR(600MHz,d4-Methanol)δ7.89(s,1H),7.74(dd,J=7.3,1.8Hz,2H),7.68(d,J=7.3Hz,1H),7.64(t,J=7.79,1H),7.60-7.58(m,2H),7.52-7.49(m,4H),7.45(d,J=8.7Hz,1H),7.10(d,J=8.7Hz,1H),6.89(d,J=1.8Hz,1H),6.85(dd,J=7.3,2.3Hz,1H),4.35(d,J=12.8Hz,1H),4.30(d,J=12.8Hz,1H),3.54-3.49(m,1H),3.38-3.33(m,1H),2.26-2.56(m,1H),2.28-2.26(m,1H),2.14-2.12(m,1H),2.05-2.01m,1H),1.57-1.51(m,1H),1.49-1.39(m,2H),1.37-1.30(m,1H)。13C NMR(300MHz,d4-Methanol)δ164.6,155.4,142.3,139.6,138.3,138.3,138.0,134.0,133.8,131.7,131.4,131.3,130.3,129.6,128.8,128.0,124.8,121.5,117.3,112.4,108.3,106.2,57.1,54.9,49.6,35.5,31.9,29.5,23.1。MS m/z(ESI):490.3[M+1]。
单一构型化合物14-2:1H NMR(600MHz,d4-Methanol)δ7.83(s,1H),7.73-7.71(m,2H),7.61(d,J=6.9Hz,1H),7.58-7.56(m,2H),7.53-7.49(m,5H),7.36(dd,J=8.7,0.9Hz,1H),7.00(d,J=8.7Hz,1H),6.88(d,J=1.8Hz,1H),6.79(d,J=7.3,1.8Hz,1H),4.31(d,J=13.3Hz,1H),4.27(d,J=13.3Hz,1H),3.94-3.92(m,1H),3.56-3.52(m,1H),2.47-2.45(m,1H),2.21-2.19(m,1H),1.90-1.85(m,2H),1.84-1.78(m,1H),1.77-1.72(m,2H),1.62-1.56(m,1H)。13C NMR(300MHz,d4-Methanol)δ164.6,155.3,142.3,142.1,139.6,138.0,137.2,133.8,133.4,131.6,131.5,131.2,130.3,129.6,128.8,127.9,125.0,121.1,117.2,112.2,108.2,101.7,54.5,50.2,49.6,32.9,30.2,29.6,20.2。MS m/z(ESI):490.3[M+1]。
检测例1
以下方法用来测定本公开化合物对ROCK2激酶活性的抑制作用。实验方法简述如下:ROCK2激酶抑制活性均采用基于时间分辨荧光技术的HTRF KinEASE kit(PerkinElmer,货号:62ST2PEB)测定。以KD025(MCE,CAS号:911417-87-3)作为阳性对照,平行设置3个复孔。于白色384孔板中每孔依次加入4μL待测化合物或缓冲液、2μL反应底物S2、2μL ROCK2激酶和2μL ATP。置于37℃孵育箱中孵育30min。依次加入5μL链激酶素标记的XL-665及5μLEuK标记的抗磷酸化的蛋白激酶抗体,室温反应60min,采用Tecan多功能酶标仪检测荧光信号。在λ=665nm处所测的样品孔的荧光强度值为F1,λ=620m处的荧光强度值为F2,信号比率计算公式为:信号比率=F1/F2×104。待测化合物对蛋白激酶的抑制率计算公式为:抑制率(%)=[1-(待测化合物信号比率最小信号比率)/(最大信号比率最小信号比率)]×100。其中最大信号比率为溶剂对照,最小信号比率为不加链激酶素标记的XL-665孔的信号比率。运用GraphPad Prism8软件计算化合物抑制活性的IC50值见表1。
表1本公开化合物对ROCK2激酶活性的抑制活性
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结论:本公开化合物具有很好的抑制ROCK2激酶的活性。
检测例2
测定本公开化合物对ROCK1激酶活性的抑制作用,实验方法同检测例1,但孵育时间改为20min,检测结果如表2所示。
表2本公开化合物对ROCK1激酶活性的抑制活性
化合物 | ICso(nM) | 化合物 | IC50(nM) |
4-1 | 812.25±21.43 | 10-1 | 272.75±9.12 |
4-2 | 170.85±21.99 | 10-2 | 206.65±5.16 |
5-1 | 643.80±9.76 | 11-1 | 312.60±24.18 |
5-2 | 161.65±16.33 | 11-2 | 209.40±8.91 |
6-1 | 272.10±0.42 | 12-1 | 215.70±14.42 |
6-2 | 285.20±16.69 | 12-2 | 71.20±11.26 |
7-1 | 464.00±3.39 | 13-1 | 966.55±18.17 |
7-2 | 237.80±1.98 | 13-2 | 279.50±6.79 |
8-1 | 811.05±3.61 | 14-1 | 99.38±0.17 |
8-2 | 277.15±4.45 | 14-2 | 96.13±2.75 |
9-1 | 102.43±12.97 | 15-1 | 335.05±3.61 |
9-2 | 152.40±15.41 | 15-2 | 209.90±3.39 |
KD025 | 3259.50±98.29 |
结论:本公开化合物具有很好的抑制ROCK1激酶的活性。
Claims (13)
1.一种吲唑类衍生物或其药用盐,其特征在于,所述吲唑类衍生物的结构式如通式(I)所示,
其中:
G为CH或N原子;
环A选自芳基、杂芳基、环烷基和杂环基;
各个R1相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、硝基、羧基、羟烷基、环烷基、杂环基、芳基和杂芳基;
各个R2相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、羟基、硝基、羧基、羟烷基、-NR4C(O)R5、-C(O)NR4R5、环烷基、杂环基、芳基和杂芳基;
各个R3相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、氰基、羟基、硝基、羧基、羟烷基、环烷基、杂环基、芳基和杂芳基;
a为0、1、2、3或4;
q为0、1、2、3或4;
s为0、1或2。
2.根据权利要求1所述吲唑类衍生物或其药用盐,其特征在于,所述吲唑类衍生物的结构式如通式(I-1)、(I-2)、(I-3)或(I-4)所示,
3.根据权利要求1所述吲唑类衍生物或其药用盐,其特征在于,环A为5至10元环烷基。
4.根据权利要求3所述吲唑类衍生物或其药用盐,其特征在于,环A为环己烷,所述吲唑类衍生物的结构式如通式(II)所示,
5.根据权利要求4所述吲唑类衍生物或其药用盐,其特征在于,所述吲唑类衍生物的结构式如通式(II-1)、(II-2)、(II-3)或(II-4)所示,
6.根据权利要求5所述吲唑类衍生物或其药用盐,其特征在于,所述吲唑类衍生物为以下任意一个化合物:
7.权利要求6所述吲唑类衍生物或其药用盐的应用,其特征在于,为以下任意一种:
(1)在制备ROCK激酶抑制剂中的应用;
(2)在制备用于治疗和/或预防疾病或病症的药物中的应用,所述的疾病或病症选自炎性疾病、自身免疫性疾病、纤维化疾病、移植排斥、与IL-17、IL-21和/或IL-23过度分泌相关的疾病、眼部疾病、心脑血管疾病、肿瘤转移、中枢神经系统疾病、糖尿病肾病和皮肤病学疾病相关疾病。
8.根据权利要求7所述的应用,其特征在于,所述的疾病或病症选自类风湿性关节炎、骨关节炎、幼年特发性关节炎、银屑病、银屑病性关节炎、强直性脊柱炎、过敏性气道疾病、慢性阻塞性肺病、哮喘、支气管炎、炎性肠病、系统性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、自身免疫性肝疾病、舍格伦综合征、多发性硬化症、干眼病、I型糖尿病和与之相关的并发症、特应性湿疹、甲状腺炎、接触性皮炎、干燥综合征和肌萎缩性侧索硬化。
9.一种药物,其特征在于,活性成分为权利要求6所述吲唑类衍生物或其药用盐。
10.权利要求1所述吲唑类衍生物或其药用盐的制备方法,其特征在于,反应式为:
其中,通式(IA)和通式(III)所示的化合物或其盐发生还原胺化反应得到通式(I)所示的化合物或其可药用的盐。
11.根据权利要求10所述的制备方法,其特征在于,通式(IA)的制备方法为:
其中,通式(IA-1)和通式(IA-2)所示的化合物或其盐发生偶联反应得到通式(IA)所示的化合物或其盐。
12.根据权利要求10所述的制备方法,其特征在于,通式(III)的制备方法为:
其中,通式(III-1)所示的化合物或其盐发生脱保护反应得到通式(III)所示的化合物或其盐。
13.根据权利要求12所述的制备方法,其特征在于,通式(III-1)的制备方法为:
其中,通式(III-2)和通式(III-3)所示的化合物或其盐发生还原胺化反应得到通式(III-1)所示的化合物或盐。
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