CN114671861A - 一种汉黄芩素衍生物及其制备方法与应用 - Google Patents
一种汉黄芩素衍生物及其制备方法与应用 Download PDFInfo
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- CN114671861A CN114671861A CN202210379930.7A CN202210379930A CN114671861A CN 114671861 A CN114671861 A CN 114671861A CN 202210379930 A CN202210379930 A CN 202210379930A CN 114671861 A CN114671861 A CN 114671861A
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Abstract
本发明公开了一种汉黄芩素衍生物及其制备方法与应用，涉及药物化学技术领域，本发明汉黄芩素衍生物可用于生物学或药理学现象，CDK8参与的信号通路传导研究，以及对于新型CDK8抑制剂的评价；经体外抗CDK8活性筛选，结果显示其对CDK8表现出较强的抑制活性，同时毒性较低；经体内抗CDK8活性筛选，结果显示其对CDK8表现出较强的抑制活性，同时毒性较低；经体内IL‑10提升作用筛选，结果显示其对IL‑10水平表现出较强的提高作用，同时毒性较低；经体内抗炎症活性筛选，结果显示其对炎症性肠炎模型有效的治疗作用，同时毒性较低。
Description
技术领域：
本发明涉及药物化学技术领域，具体涉及一种汉黄芩素衍生物及其制备方法与应用。
背景技术：
炎症性肠病(IBD)是一种由慢性免疫系统介导的非传染性疾病，IBD包括克罗恩病和溃疡性结肠炎两种临床表现，其特征是胃肠道内不受控制的慢性炎症、上皮屏障破坏和微生物种群失调。IBD的确切病因和发病机制非常复杂，普遍接受的观点是疾病进展与免疫系统的过度激活和慢性促炎细胞因子的过度产生有关。提高抗炎细胞因子白细胞介素-10(IL-10)的水平是抑制炎症进展的有效策略。IL-10是一种多功能细胞因子，可调节细胞生长和分化，并通过多种机制促进免疫稳态。遗传学研究已将IL10基因的单核苷酸多态性与成人IBD发病联系起来，并发现IL10或IL10受体基因的功能丧失突变会导致严重的小儿结肠炎的发病。因此，提高IL-10的产生是治疗IBD的一种有前景的策略。
细胞周期蛋白依赖性激酶8(CDK8)是CDK家族的成员，属于丝氨酸/苏氨酸蛋白激酶。它可以与细胞周期蛋白C(CCNC)结合形成CDK8激酶模块，作为介体复合物的组分参与转录调控过程。CDK8作为抗炎靶点的可能性正在逐渐受到关注。已经证明，CDK8的抑制通过增强活化的骨髓衍生树突细胞(BMDCs)中的激活蛋白-1(AP-1)的转录活性上调IL-10的产生。尽管几种CDK8抑制剂(BRD6989,cortistatinA和CCT251921)可以有效上调IL-10的产生，但缺乏评估这些CDK8抑制剂体内抗炎活性的证据。先前报道的高效CDK8抑制剂的潜在毒性可能会限制这些CDK8抑制剂作为抗炎药物的使用。
汉黄芩素具有经典激酶抑制剂的化学型和广泛的生物活性，尤其是在高浓度时具有抗炎和抗肿瘤作用。虽然广谱靶标亲和力、泛分析干扰化合物(PAINS)的结构特征和较差的理化性质等各种缺点限制了其作为药物的直接使用，但已证实汉黄芩在体外可以抑制CDK8活性。本发明以汉黄芩素为起点，开发了多种结构骨架特征的汉黄芩素衍生物作为新型抗IBD小分子CDK8抑制剂，以期发现具有更佳治疗收益的CDK8抑制剂并扩展靶向CDK8的小分子库。
发明内容：
本发明所要解决的技术问题在于提供一种汉黄芩素衍生物及其制备方法，该类化合物作为一类CDK8抑制剂，可以应用于制备预防或治疗炎症性疾病和自身免疫性疾病的药物中。
本发明所要解决的技术问题采用以下的技术方案来实现：
本发明提供了一种汉黄芩素衍生物，如以下式I、式II、式III、式IV所示：
其中，R1选自噻吩基、呋喃基、异噁唑基、甲基吡唑基、吡啶基、嘧啶基、苯基、取代苯基；R2选自苯基和取代苯基；R3选自苯基、取代苯基、苄基、苯乙基、环己基或呋喃-2-基甲基；R4选自苯基、取代苯基、苄基、取代苄基、苯乙基、取代苯乙基、环己基或呋喃-2-基甲基；R5选自苯基、取代苯基、哌啶基、N-甲基哌啶基、吡啶基、嘧啶基、N-甲基吡唑基、吲哚基、苯并吡唑基或(哌啶-4-基)-1H-吡唑-4-基中的任一种基团。
所述汉黄芩素衍生物包括以下所示结构的化合物1-148：
表1以式I为通式的化合物1-33
表2以式I为通式的化合物34-55
表3以式III为通式的化合物56-87
表4以式IV为通式的化合物88-148
本发明还提供了一种所述汉黄芩素衍生物的制备方法，包括以下步骤：
(1)将5-羟基-4-氧代-2-苯基-4H-色烯-7-基三氟甲磺酸盐和不同的硼酸化合物经Suzuki交叉偶联反应，得到式I所示的化合物；
(2)将3-溴-5-羟基苯甲酸和(4-(哌嗪-1-羰基)苯基)硼酸经Suzuki交叉偶联反应，得到中间体I；
(3)中间体I和不同的伯胺经酰胺缩合反应，得到式II所示的化合物；
(4)将5-溴烟酸和(4-(哌嗪-1-羰基)苯基)硼酸经Suzuki交叉偶联反应，得到中间体II；
(5)中间体II和不同的伯胺经酰胺缩合反应，得到式III所示的化合物；
(6)将2-氨基-5-溴烟酸和硼酸经Suzuki交叉偶联反应，得到中间体III；
(7)中间体III和不同的伯胺经酰胺缩合反应，得到式IV所示的化合物。
反应方程式如下：
本发明还提供了一种药物组合物，包含所述汉黄芩素衍生物或其药学上可接受的盐。
本发明还提供了一种药物制剂，包含活性成分和药学上可以接受的赋形剂和/或载体，所述活性成分为所述汉黄芩素衍生物。
本发明还提供了所述汉黄芩素衍生物在制备CDK8抑制剂中的应用。
本发明还提供了所述汉黄芩素衍生物在制备治疗炎症性疾病药物中的应用。进一步地，所述炎症性疾病包括关节炎、类风湿性关节炎、炎症性肠炎、败血症、胰腺炎、呼吸系统的炎症性疾病、慢性阻塞性肺疾病、非囊性纤维化支气管扩张、急性肺损伤、病毒或细菌感染引起的肺炎或支气管肺炎、肾小球肾炎。
本发明还提供了所述汉黄芩素衍生物在制备抗肿瘤药物中的应用。进一步地，所述肿瘤包括乳腺癌、急性髓系白血病、结肠癌和直肠癌。
本发明的有益效果是：
(1)本发明的汉黄芩素衍生物可用于生物学或药理学现象，CDK8参与的信号通路传导研究，以及对于新型CDK8抑制剂的评价。
(2)本发明的汉黄芩素衍生物经体外抗CDK8活性筛选，结果显示其对CDK8表现出较强的抑制活性，同时毒性较低。
(3)本发明的汉黄芩素衍生物经体内抗CDK8活性筛选，结果显示其对CDK8表现出较强的抑制活性，同时毒性较低。
(4)本发明的汉黄芩素衍生物经体内IL-10提升作用筛选，结果显示其对IL-10水平表现出较强的提高作用，同时毒性较低。
(5)本发明的汉黄芩素衍生物经体内抗炎症活性筛选，结果显示其对炎症性肠炎模型有效的治疗作用，同时毒性较低。
(6)本发明所述的汉黄芩素衍生物结构新颖、合成工艺简单、产品纯度高，具有良好的应用前景。
附图说明：
图1为本发明的化合物68在模型组对IBD模型小鼠结肠组织的影响；
图2为本发明的化合物68对IBD模型小鼠体内炎症因子的影响。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例和图示，进一步阐述本发明。
实施例1：N-(2-乙基苯基)-5-(4-(哌嗪-1-羰基)苯基)烟酰胺(化合物68)的合成
1.1中间体II的制备：5-(4-(哌嗪-1-羰基)苯基)烟酸
取25mL封管以氩气进行气体置换。取5-溴烟酸(0.1g，0.5mmol)、(4-(哌嗪-1-羰基)苯基)硼酸(0.11g，0.5mmol)、Pd(PPh3)4(57mg，0.05mmol)和K3PO4(315mg，1.5mmol)加入到封管中，以10mL超干二氧六环搅拌溶解。密封封管并在90℃下反应12h。反应毕，冷却至室温，将反应液过滤，减压下除去溶剂，并用水/乙酸乙酯体系分配萃取。乙酸乙酯层用无水硫酸钠上干燥24h后过滤并浓缩乙酸乙酯层，得到的橙红色残留物。即为中间体II，无需纯化即可用于下一步。
1.2化合物68的合成
在中间体II(0.18g，0.60mmol)的DMF(5mL)溶液中加入HATU(0.28g，0.72mmol)。在室温下搅拌混合物1h，然后加入邻乙基苯胺(0.073g，0.60mmol)和DIPEA(0.2mL，1.21mmol)，继续反应18h。反应完成后，将反应混合物倒入水中，搅拌10min。混合物被过滤得到灰色的固体残留；残留产物使用自动色谱系统进行纯化，获得白色粉末。mp 176-177℃；1H NMR(400MHz,Methanol-d4)δ9.15(d,J＝2.0Hz,1H),9.08(d,J＝2.2Hz,1H),8.66(t,J＝2.2Hz,1H),7.91(d,J＝7.9Hz,2H),7.68–7.61(m,2H),7.38(dd,J＝7.0,2.3Hz,2H),7.34–7.23(m,2H),3.78(s,2H),3.54(m,6H),2.74(q,J＝7.6Hz,2H),1.50(s,9H),1.26(t,J＝7.6Hz,3H).13C NMR(101MHz,Methanol-d4)δ170.71,165.61,154.84,149.86,147.22,140.38,138.26,135.95,135.47,134.56,134.03,130.76,128.70,127.87(2C),127.32,127.29(2C),126.18,80.33,27.20(3C),26.58,24.11,13.45.HRMS(ESI):m/z[M+H]+calcdfor C30H34N4O4:515.2653；found:515.2672.
实施例2：5-羟基-2-苯基-7-(噻吩-3-基)-4H-色烯-4-酮(化合物1)的合成
合成方法参照实施例1。mp 190-191℃；1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),7.96–7.90(m,2H),7.64(s,1H),7.55(m,3H),7.44(s,2H),7.23(s,1H),7.06(s,1H),6.74(s,1H).HRMS(ESI):m/z[M+H]+calcd for C19H12O3S:321.0580；found:321.0583.
实施例3：5-羟基-2-苯基-7-(呋喃-3-基)-4H-色烯-4-酮(化合物2)的合成
合成方法参照实施例1。mp 155-156℃；1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),7.95(d,J＝6.3Hz,2H),7.89(s,1H),7.62–7.53(m,4H),7.14(s,1H),6.97(s,1H),6.78(s,1H),6.76(s,1H).HRMS(ESI):m/z[M+H]+calcd for C19H12O4:305.0808；found:305.0812.
实施例4：5-羟基-2-苯基-7-(3,5-二甲基异恶唑-4-基)-4H-色烯-4-酮(化合物3)的合成
合成方法参照实施例1。mp 126-127℃；1H NMR(400MHz,Chloroform-d)δ12.68(s,1H),7.96(d,J＝6.3Hz,2H),7.65–7.52(m,3H),6.93(s,1H),6.80(s,1H),6.75(s,1H),2.52(s,3H),2.38(s,3H).HRMS(ESI):m/z[M+H]+calcd for C20H15NO4:334.1074；found:334.1079.
实施例5：5-羟基-2-苯基-7-(1-甲基-1H-吡唑-4-基)-4H-色烯-4-酮(化合物4)的合成
合成方法参照实施例1。mp 226-227℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.95(d,J＝7.2Hz,2H),7.88(s,1H),7.75(s,1H),7.57(d,J＝8.0Hz,3H),7.14(s,1H),6.94(s,1H),6.75(s,1H),4.01(s,3H).HRMS(ESI):m/z[M+H]+calcd for C19H14N2O3:319.1077；found:319.1078.
实施例6：5-羟基-2-苯基-7-(吡啶-4-基)-4H-色烯-4-酮(化合物5)的合成
合成方法参照实施例1。mp 214-215℃；1H NMR(400MHz,Chloroform-d)δ12.66(s,1H),8.94(d,J＝2.3Hz,1H),8.71(d,J＝3.3Hz,1H),8.00–7.94(m,3H),7.59(q,J＝7.4,6.5Hz,3H),7.45(dd,J＝8.0,4.8Hz,1H),7.27(s,1H),7.07(s,1H),6.80(s,1H).HRMS(ESI):m/z[M+H]+calcd for C20H13NO3:316.0968；found:316.0970.
实施例7：5-羟基-2-苯基-7-(嘧啶-4-基)-4H-色烯-4-酮(化合物6)的合成
合成方法参照实施例1。mp 251-252℃；1H NMR(400MHz,Chloroform-d)δ12.74(s,1H),9.33(s,1H),9.06(s,2H),7.98(d,J＝8.2Hz,2H),7.59(p,J＝8.6,8.2Hz,3H),7.27(s,1H),7.07(s,1H),6.84(s,1H).HRMS(ESI):m/z[M+H]+calcd for C19H12N2O3:317.0921；found:317.0918.
实施例8：5-羟基-2,7-二苯基-4H-色烯-4-酮(化合物7)的合成
合成方法参照实施例1。mp 155-156℃；1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),7.94(d,J＝8.2Hz,2H),7.66(d,J＝7.2Hz,2H),7.56(m,4H),7.48(m,J＝7.2Hz,2H),7.25(s,1H),7.07(s,1H),6.76(s,1H).HRMS(ESI):m/z[M+H]+calcd for C21H14O3:315.1016；found:315.1018.
实施例9：5-羟基-2-苯基-7-(对甲苯基)-色烯-4-酮(化合物8)的合成
合成方法参照实施例1。mp 164-165℃；1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),7.96(d,J＝8.2Hz,2H),7.64–7.53(m,5H),7.32(d,J＝7.9Hz,2H),7.25(s,1H),7.08(s,1H),6.77(s,1H),2.45(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H16O3:329.1172；found:329.1170.
实施例10：5-羟基-2-苯基-7-(对甲氧苯基)-色烯-4-酮(化合物9)的合成
合成方法参照实施例1。mp 165-166℃；1H NMR(400MHz,Chloroform-d)δ12.56(s,1H),7.94(d,J＝8.2Hz,2H),7.62(d,J＝8.5Hz,2H),7.56(m,3H),7.21(s,1H),7.03(d,J＝6.0Hz,2H),7.01(s,1H),6.75(s,1H),3.88(s,3H).HRMS(ESI):m/z[M+H]+calcdforC22H16O4:345.1121；found:345.1123.
实施例11：5-羟基-2-苯基-7-(对乙苯基)-色烯-4-酮(化合物10)的合成
合成方法参照实施例1。mp 168-169℃；1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),7.96(d,J＝8.2Hz,2H),7.65–7.52(m,5H),7.35(d,J＝6.0Hz,2H),7.25(s,1H),7.08(s,1H),6.77(s,1H),2.75(q,J＝7.6Hz,2H),1.32(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C23H18O3:343.1329；found:343.1330.
实施例12：5-羟基-2-苯基-7-(3,4,5-三甲氧基苯基)-色烯-4-酮(化合物11)的合成
合成方法参照实施例1。mp 226-227℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.95(d,J＝7.9Hz,2H),7.56(m,3H),7.20(s,1H),7.04(s,1H),6.85(s,2H),6.76(s,1H),3.96(s,6H),3.92(s,3H).HRMS(ESI):m/z[M+H]+calcd for C24H20O6:405.1333；found:405.1325.
实施例13：5-羟基-2-苯基-7-(2,4,6-三甲氧基苯基)-色烯-4-酮(化合物12)的合成
合成方法参照实施例1。mp 115-116℃；1H NMR(400MHz,Chloroform-d)δ12.53(s,1H),7.97–7.90(m,2H),7.56(m,4H),7.25(s,1H),7.11(s,1H),6.99(s,1H),6.77(s,1H),3.95(s,3H),3.93(s,3H),3.75(s,3H).HRMS(ESI):m/z[M+H]+calcd for C24H20O6:405.1333；found:405.1330.
实施例14：5-羟基-2-苯基-7-(对氯苯基)-色烯-4-酮(化合物13)的合成
合成方法参照实施例1。mp 215-216℃；1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),7.94(d,J＝6.2Hz,2H),7.62–7.50(m,5H),7.46(d,J＝8.5Hz,2H),7.21(s,1H),7.02(s,1H),6.76(s,1H).HRMS(ESI):m/z[M+H]+calcd for C21H13O3Cl:349.0626；found:349.0626.
实施例15：5-羟基-2-苯基-7-(对三氟甲基苯基)-色烯-4-酮(化合物14)的合成
合成方法参照实施例1。mp 129-130℃；1H NMR(400MHz,Chloroform-d)δ12.64(s,1H),7.96(d,J＝6.2Hz,2H),7.77(s,4H),7.59(q,J＝7.6,6.6Hz,3H),7.26(s,1H),7.07(s,1H),6.80(s,1H).HRMS(ESI):m/z[M+H]+calcd for C22H13F3O3:383.0890；found:383.0890.
实施例16：5-羟基-2-苯基-7-(对三氟甲氧基苯基)-色烯-4-酮(化合物15)的合成
合成方法参照实施例1。mp 175-176℃；1H NMR(400MHz,Chloroform-d)δ12.61(s,1H),7.94(d,J＝6.4Hz,2H),7.71–7.64(m,2H),7.63–7.52(m,3H),7.35(d,J＝8.3Hz,2H),7.21(s,1H),7.02(s,1H),6.77(s,1H).HRMS(ESI):m/z[M+H]+calcd for C22H13F3O4:399.0839；found:399.0838.
实施例17：5-羟基-2-苯基-7-(对氨基苯基)-色烯-4-酮(化合物16)的合成
合成方法参照实施例1。mp 230-231℃；1H NMR(400MHz,Chloroform-d)δ12.53(s,1H),7.96–7.90(m,2H),7.61–7.47(m,5H),7.19(s,1H),7.03(s,1H),6.78(d,J＝8.5Hz,2H),6.73(s,1H),1.25(s,2H).HRMS(ESI):m/z[M+H]+calcd for C26H23NO5:430.1649；found:430.1651.
实施例18：5-羟基-2-苯基-7-(对二甲氨基苯基)-色烯-4-酮(化合物17)的合成
合成方法参照实施例1。mp 216-217℃；1H NMR(400MHz,Chloroform-d)δ12.53(s,1H),7.96–7.91(m,2H),7.62–7.53(m,5H),7.21(s,1H),7.05(s,1H),6.80(d,J＝8.9Hz,2H),6.72(s,1H),3.04(s,6H).HRMS(ESI):m/z[M+H]+calcd for C23H19NO3:358.1438；found:358.1438.
实施例19：5-羟基-2-苯基-7-((二甲氨基)甲基)苯基)-色烯-4-酮(化合物18)的合成
合成方法参照实施例1。mp 194-195℃；1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),7.97–7.91(m,2H),7.65(d,J＝8.0Hz,2H),7.56(m,3H),7.47(d,J＝7.9Hz,2H),7.24(s,1H),7.06(s,1H),6.76(s,1H),3.68(s,2H),2.40(s,6H).HRMS(ESI):m/z[M+H]+calcdfor C24H21NO3:372.1592；found:372.1593.
实施例20：5-羟基-2-苯基-7-(对乙酰氨基苯基)-色烯-4-酮(化合物19)的合成
合成方法参照实施例1。mp 272-273℃；1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),7.97(d,J＝7.9Hz,2H),7.64(s,4H),7.56(m,4H),7.23(s,1H),7.05(s,1H),6.76(s,1H),2.23(s,3H).HRMS(ESI):m/z[M+H]+calcd for C23H17NO4:372.1230；found:372.1234.
实施例21：4-(5-羟基-4-氧代-2-苯基-4H-色烯-7-基)-N,N-二甲基苯甲酰胺(化合物20)的合成
合成方法参照实施例1。mp 153-154℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.95(d,J＝7.9Hz,2H),7.69(d,J＝7.9Hz,2H),7.63–7.50(m,5H),7.26(s,1H),7.07(s,1H),6.78(s,1H),3.15(s,3H),3.05(s,3H).HRMS(ESI):m/z[M+H]+calcdfor C24H19NO4:386.1387；found:386.1386.
实施例22：叔丁基-4-(4-(5-羟基-4-氧代-2-苯基-4H-色烯-7-基)苯基)哌嗪-1-羧酸酯(化合物21)的合成
合成方法参照实施例1。mp 231-232℃；1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),7.95(d,J＝6.2Hz,2H),7.64(d,J＝5.2Hz,2H),7.57(d,J＝7.4Hz,3H),7.22(s,1H),7.07(d,J＝11.8Hz,3H),6.76(d,J＝2.8Hz,1H),3.68(s,4H),3.32–3.27(m,4H),1.52(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H30N2O5:499.2227；found:499.2215.
实施例23：5-羟基-7-(4-(4-甲基哌嗪-1-基)苯基)-2-苯基-4H-色烯-4-酮(化合物22)的合成
合成方法参照实施例1。mp 239-240℃；1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),7.96(d,J＝7.9Hz,2H),7.66–7.54(m,5H),7.23(s,1H),7.09–7.00(m,3H),6.76(s,1H),3.35(t,J＝5.1Hz,4H),2.64(t,J＝5.0Hz,4H),2.41(s,3H).HRMS(ESI):m/z[M+H]+calcd for C26H24N2O3:413.1860；found:416.1859.
实施例24：7-(4-(4-乙基哌嗪-1-基)苯基)-5-羟基-2-苯基-4H-色烯-4-酮(化合物23)的合成
合成方法参照实施例1。mp 244-245℃；1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),7.96(d,J＝6.7Hz,2H),7.65–7.56(m,5H),7.23(s,3H),7.09–7.02(m,1H),6.75(s,1H),3.36(s,4H),2.69(s,4H),2.55(t,J＝7.6Hz,2H),1.19(d,J＝7.1Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C27H26N2O3:427.2016；found:427.2045.
实施例25：5-羟基-7-(4-吗啉代苯基)-2-苯基-4H-色烯-4-酮(化合物24)的合成
合成方法参照实施例1。mp 256-257℃；1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),7.96(d,J＝6.4Hz,2H),7.64(d,J＝8.4Hz,2H),7.57(d,J＝7.4Hz,3H),7.23(s,1H),7.07(s,1H),7.04(d,J＝8.3Hz,2H),6.76(s,1H),3.93(d,J＝4.6Hz,4H),3.29(d,J＝4.8Hz,4H).HRMS(ESI):m/z[M+H]+calcd for C25H21NO4:400.1543；found:400.1546.
实施例26：叔丁基-4-(4-(5-羟基-4-氧代-2-苯基-4H-色烯-7-基)苄基)哌嗪-1-羧酸酯(化合物25)的合成
合成方法参照实施例1。mp 183-184℃；1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),7.94(d,J＝7.2Hz,2H),7.64(d,J＝7.8Hz,2H),7.56(d,J＝8.0Hz,3H),7.48(d,J＝7.8Hz,2H),7.25(s,1H),7.07(s,1H),6.76(s,1H),3.64(s,2H),3.51(s,4H),2.50(s,4H),1.48(s,9H).HRMS(ESI):m/z[M+H]+calcd for C31H32N2O5:513.2384；found:513.2386.
实施例27：5-羟基-7-(4-((4-甲基哌嗪-1-基)甲基)苯基)-2-苯基-4H-色烯-4-酮(化合物26)的合成
合成方法参照实施例1。mp 179-180℃；1H NMR(400MHz,Chloroform-d)δ12.55(s,1H),7.92(d,J＝7.2Hz,2H),7.60(d,J＝7.9Hz,2H),7.54(d,J＝7.6Hz,3H),7.43(d,J＝7.9Hz,2H),7.22(s,1H),7.05(s,1H),6.74(s,1H),3.58(s,2H),2.57(s,8H),2.36(s,3H).HRMS(ESI):m/z[M+H]+calcd for C27H26N2O3:427.2016；found:427.2014.
实施例28：5-羟基-7-(4-(吗啉甲基)苯基)-2-苯基-4H-色烯-4-酮(化合物27)的合成
合成方法参照实施例1。mp 194-195℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.96(d,J＝7.1Hz,2H),7.65(d,J＝7.9Hz,2H),7.57(d,J＝7.6Hz,3H),7.51(d,J＝6.6Hz,2H),7.26(s,1H),7.08(s,1H),6.78(s,1H),3.80(s,4H),3.65(s,2H),2.58(s,4H).HRMS(ESI):m/z[M+H]+calcd for C26H23NO4:414.1700；found:414.1694.
实施例29：4-[4-(5-羟基-4-氧代-2-苯基-4H-色烯-7-基)苯甲酰基]哌嗪-1-羧酸叔丁酯(化合物28)的合成
合成方法参照实施例1。mp 130-131℃；1H NMR(400MHz,Chloroform-d)δ12.65(s,1H),7.97(d,J＝7.1Hz,2H),7.76–7.70(m,2H),7.57(m,5H),7.29(s,1H),7.09(s,1H),6.81(s,1H),3.57(m,4H),2.56(m,4H).HRMS(ESI):m/z[M+H]+calcd for C26H22N2O4:427.1652；found:427.1653.
实施例30：羟基-7-(4-(吗啉-4-羰基)苯基)-2-苯基-4H-色烯-4-酮(化合物29)的合成
合成方法参照实施例1。mp 262-263℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.94(d,J＝7.4Hz,2H),7.70(d,J＝7.8Hz,2H),7.59–7.51(m,5H),7.24(s,1H),7.05(s,1H),6.77(s,1H),3.66(m,8H).HRMS(ESI):m/z[M+H]+calcd for C26H21NO5:428.1492；found:428.1491.
实施例31：5-羟基-2-苯基-7-(4-(硫代吗啉-4-羰基)苯基)-4H-色烯-4-酮(化合物30)的合成
合成方法参照实施例1。mp 253-254℃；1H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.94(d,J＝6.8Hz,2H),7.70(d,J＝7.8Hz,2H),7.60–7.46(m,5H),7.24(s,1H),7.05(s,1H),6.77(s,1H),3.91(m,4H),2.70(m,4H).HRMS(ESI):m/z[M+H]+calcd forC26H21NO4S:444.1264；found:444.1242.
实施例32：5-羟基-7-(4-(4-甲基哌嗪-1-羰基)苯基)-2-苯基-4H-色烯-4-酮(化合物31)的合成
合成方法参照实施例1。mp 200-202℃；1H NMR(400MHz,Chloroform-d)δ12.62(s,1H),7.99–7.93(m,2H),7.72(d,J＝8.0Hz,2H),7.65–7.50(m,5H),7.26(s,1H),7.08(s,1H),6.79(s,1H),3.73(m,4H),2.51(m,4H),2.40(s,3H).HRMS(ESI):m/z[M+H]+calcd forC27H24N2O4:441.1809；found:441.1792.
实施例33：7-(4-(4-乙基哌嗪-1-羰基)苯基)-5-羟基-2-苯基-4H-色烯-4-酮(化合物32)的合成
合成方法参照实施例1。mp 190-191℃；1H NMR(400MHz,Chloroform-d)δ12.62(s,1H),7.95(d,J＝7.4Hz,2H),7.71(d,J＝7.8Hz,2H),7.57(q,J＝7.7Hz,5H),7.26(s,1H),7.07(s,1H),6.78(s,1H),3.76(m,4H),2.65(m,4H),2.57(q,J＝7.2Hz,2H),1.18(t,J＝7.1Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C28H26N2O4:455.1965；found:455.1927.
实施例34：7-(4-(4-丙基哌嗪-1-羰基)苯基)-5-羟基-2-苯基-4H-色烯-4-酮(化合物33)的合成
合成方法参照实施例1。mp 206-207℃；1H NMR(400MHz,Chloroform-d)δ12.62(s,1H),7.95(d,J＝6.1Hz,2H),7.71(d,J＝8.1Hz,2H),7.62–7.52(m,5H),7.26(s,1H),7.07(s,1H),6.79(s,1H),4.04–3.50(m,4H),2.60(m,4H),2.50–2.30(m,2H),1.61(q,J＝7.6Hz,2H),0.96(td,J＝7.4,2.4Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C29H28N2O4:469.2122；found:469.2092.
实施例35：叔丁基-4-(3'-羟基-5'-(苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物34)的合成
合成方法参照实施例1。mp 206-207℃；1H NMR(400MHz,Chloroform-d)δ12.62(s,1H),7.95(d,J＝6.1Hz,2H),7.71(d,J＝8.1Hz,2H),7.62–7.52(m,5H),7.26(s,1H),7.07(s,1H),6.79(s,1H),4.04–3.50(m,4H),2.60(m,4H),2.50–2.30(m,2H),1.61(q,J＝7.6Hz,2H),0.96(td,J＝7.4,2.4Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C29H28N2O4:469.2122；found:469.2092.
实施例36：叔丁基-4-(3'-羟基-5'-(对甲苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物35)的合成
合成方法参照实施例1。mp 137-138℃；1H NMR(400MHz,Methanol-d4)δ7.78(d,J＝7.9Hz,2H),7.68(s,1H),7.58(d,J＝7.9Hz,2H),7.54(d,J＝8.0Hz,2H),7.37(s,1H),7.28(s,1H),7.19(d,J＝8.0Hz,2H),3.63(m,8H),2.34(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H33N3O5:516.2493；found:516.2505.
实施例37：叔丁基-4-(3'-羟基-5'-(间甲苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物36)的合成
合成方法参照实施例1。mp 126-127℃；1H NMR(400MHz,Methanol-d4)δ7.77(d,J＝7.8Hz,2H),7.68(s,1H),7.53(d,J＝8.0Hz,4H),7.37(s,1H),7.26(m,2H),6.99(d,J＝7.5Hz,1H),3.86–3.42(m,8H),2.36(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd forC30H33N3O5:538.2312；found:538.2318.
实施例38：叔丁基-4-(3'-羟基-5'-(对甲氧苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物37)的合成
合成方法参照实施例1。mp 123-124℃；1H NMR(400MHz,Methanol-d4)δ7.77(q,J＝7.9,7.3Hz,2H),7.68(d,J＝5.6Hz,1H),7.60(dd,J＝9.0,2.2Hz,2H),7.56–7.50(m,2H),7.37(s,1H),7.27(d,J＝7.1Hz,1H),6.94(t,J＝8.2Hz,2H),3.80(s,3H),3.50(m,8H),1.47(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C30H33N3O6:554.2262；found:554.2247.
实施例39：叔丁基-4-(3'-羟基-5'-(间甲氧苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物38)的合成
合成方法参照实施例1。mp 131-132℃；1H NMR(400MHz,Methanol-d4)δ7.76(d,J＝7.8Hz,2H),7.67(s,1H),7.52(d,J＝7.8Hz,2H),7.44(s,1H),7.36(s,1H),7.27(s,3H),6.73(d,J＝7.2Hz,1H),3.81(s,3H),3.77–3.42(m,8H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H33N3O6:532.2442；found:532.2444.
实施例40：叔丁基-4-(3'-羟基-5'-(对乙苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物39)的合成
合成方法参照实施例1。mp 146-147℃；1H NMR(400MHz,Methanol-d4)δ7.79(d,J＝7.9Hz,2H),7.69(s,1H),7.61(d,J＝8.2Hz,2H),7.55(d,J＝8.0Hz,2H),7.37(s,1H),7.28(s,1H),7.22(d,J＝8.3Hz,2H),3.63(m,8H),2.66(q,J＝7.6Hz,2H),1.49(s,9H),1.25(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C31H35N3O5:530.2649；found:530.2683.
实施例41：叔丁基-4-(3'-羟基-5'-(对异丙基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物40)的合成
合成方法参照实施例1。mp 117-118℃；1H NMR(400MHz,Methanol-d4)δ7.79(m,2H),7.69(s,1H),7.62(d,J＝8.5Hz,2H),7.55(m,2H),7.37(s,1H),7.26(m,3H),3.64(m,8H),2.97–2.87(m,1H),1.49(s,9H),1.27(dt,J＝6.9,2.1Hz,6H).HRMS(ESI):m/z[M+Na]+calcd for C32H37N3O5:566.2625；found:566.2670.
实施例42：叔丁基-4-(3'-羟基-5'-(间异丙苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物41)的合成
合成方法参照实施例1。mp 124-125℃；1H NMR(400MHz,Methanol-d4)δ7.79(dt,J＝7.5,4.3Hz,2H),7.70(s,1H),7.61(s,1H),7.55(dd,J＝7.8,3.2Hz,3H),7.38(s,1H),7.34–7.27(m,2H),7.06(d,J＝7.7Hz,1H),3.76(s,8H),2.93(t,J＝6.9Hz,1H),1.49(s,9H),1.29(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd for C32H37N3O5:544.2806；found:544.2835.
实施例43：叔丁基-4-(3'-羟基-5'-(邻异丙苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物42)的合成
合成方法参照实施例1。mp 129-130℃；1H NMR(400MHz,Methanol-d4)δ7.78(d,J＝7.9Hz,2H),7.72(s,1H),7.54(dd,J＝8.3,2.1Hz,2H),7.41(dd,J＝7.8,1.6Hz,2H),7.28(m,4H),3.50(m,8H),3.23(p,J＝6.9Hz,1H),1.47(s,9H),1.25(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd for C32H37N3O5:566.2625；found:566.2619.
实施例44：叔丁基-4-(3'-羟基-5'-(对叔丁苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物43)的合成
合成方法参照实施例1。mp 147-148℃；1H NMR(400MHz,Methanol-d4)δ7.80(d,J＝7.9Hz,2H),7.69(s,1H),7.63(d,J＝8.6Hz,2H),7.56(d,J＝8.2Hz,2H),7.42(d,J＝8.7Hz,2H),7.38(s,1H),7.28(s,1H),3.64(m,8H),1.49(s,9H),1.35(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C33H39N3O5:580.2782；found:580.2791.
实施例45：叔丁基-4-(3'-羟基-5'-(2,4,6-三甲基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物44)的合成
合成方法参照实施例1。mp 160-161℃；1H NMR(400MHz,Methanol-d4)δ7.81(d,J＝8.0Hz,2H),7.75(s,1H),7.57(d,J＝8.1Hz,2H),7.43(s,1H),7.31(s,1H),6.97(s,2H),3.64(m,8H),2.31(s,3H),2.26(s,6H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd forC32H37N3O5:544.2806；found:544.2805.
实施例46：叔丁基-4-(3'-羟基-5'-(对三氟甲基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物45)的合成
合成方法参照实施例1。mp 122-123℃；1H NMR(400MHz,Methanol-d4)δ7.96(d,J＝8.5Hz,2H),7.80(d,J＝8.0Hz,2H),7.72(s,1H),7.68(d,J＝8.5Hz,2H),7.56(d,J＝8.1Hz,2H),7.40(s,1H),7.31(s,1H),3.64(m,8H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd forC30H30F3N3O5:570.2210；found:570.2235.
实施例47：叔丁基-4-(3'-羟基-5'-(间三氟甲基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物46)的合成
合成方法参照实施例1。mp 127-128℃；1H NMR(400MHz,Methanol-d4)δ8.20(s,1H),7.98(d,J＝8.2Hz,1H),7.81(d,J＝7.9Hz,2H),7.73(s,1H),7.57(d,J＝8.1Hz,3H),7.46(d,J＝7.8Hz,1H),7.40(s,1H),7.31(s,1H),3.86–3.44(m,8H),1.49(s,9H).
实施例48：叔丁基-4-(3'-羟基-5'-(对三氟甲氧基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物47)的合成
合成方法参照实施例1。mp 130-131℃；1H NMR(400MHz,Methanol-d4)δ7.84(d,J＝9.0Hz,2H),7.79(t,J＝5.3Hz,2H),7.70(d,J＝1.8Hz,1H),7.59–7.53(m,2H),7.39(s,1H),7.29(s,3H),3.64(m,8H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C30H30F3N3O6:608.1979；found:608.1990.
实施例49：叔丁基-4-(3'-羟基-5'-(间三氟甲氧基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物48)的合成
合成方法参照实施例1。mp 122-123℃；1H NMR(400MHz,Methanol-d4)δ7.87(s,1H),7.78(d,J＝7.9Hz,2H),7.67(d,J＝9.6Hz,2H),7.54(d,J＝7.9Hz,2H),7.44(t,J＝8.3Hz,1H),7.37(s,1H),7.28(s,1H),7.05(d,J＝8.3Hz,1H),3.86–3.40(m,8H),1.47(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C30H30F3N3O6:608.1979；found:608.2019.
实施例50：叔丁基-4-(3'-羟基-5'-(对氟苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物49)的合成
合成方法参照实施例1。mp 149-150℃；1H NMR(400MHz,Methanol-d4)δ7.80(d,J＝8.3Hz,2H),7.76–7.67(m,3H),7.56(d,J＝8.3Hz,2H),7.38(s,1H),7.29(s,1H),7.12(t,J＝8.8Hz,2H),3.52(s,8H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C29H30FN3O5:542.2062；found:542.2061.
实施例51：叔丁基-4-(3'-羟基-5'-(间氟苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物50)的合成
合成方法参照实施例1。mp 122-123℃；1H NMR(400MHz,Methanol-d4)δ7.80(d,J＝8.3Hz,2H),7.75–7.62(m,2H),7.56(d,J＝8.3Hz,2H),7.48(d,J＝8.0Hz,1H),7.42–7.32(m,2H),7.30(t,J＝1.9Hz,1H),6.89(td,J＝8.4,2.6Hz,1H),3.64(m,8H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C29H30FN3O5:542.2062；found:542.2050.
实施例52：叔丁基-4-(3'-羟基-5'-(邻氟苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物51)的合成
合成方法参照实施例1。mp 142-143℃；1H NMR(400MHz,Methanol-d4)δ7.80(m,3H),7.73(s,1H),7.57(d,J＝7.9Hz,2H),7.41(s,1H),7.31(s,1H),7.30–7.18(m,3H),3.53(m,9H),1.49(s,8H).HRMS(ESI):m/z[M+Na]+calcdfor C29H30FN3O5:542.2062；found:542.2062.
实施例53：叔丁基-4-(3'-羟基-5'-(对氨基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物52)的合成
合成方法参照实施例1。mp 121-122℃；1H NMR(400MHz,Methanol-d4)δ7.78(m,2H),7.68(d,J＝6.6Hz,1H),7.62(d,J＝8.7Hz,2H),7.54(m,2H),7.42(d,J＝8.5Hz,2H),7.36(s,1H),7.27(m,1H),3.63(m,8H),1.54(s,9H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C34H40N4O7:639.2789；found:639.2778.
实施例54：叔丁基-4-(3'-羟基-5'-(间氨基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物53)的合成
合成方法参照实施例1。mp 118-119℃；1H NMR(400MHz,Methanol-d4)δ7.88(s,1H),7.78(d,J＝7.1Hz,2H),7.68(s,1H),7.54(d,J＝8.0Hz,2H),7.36(d,J＝6.1Hz,2H),7.32–7.22(m,2H),7.20(d,J＝8.4Hz,1H),3.64(m,8H),1.54(s,9H),1.49(s,9H).HRMS(ESI):m/z[M+Na]+calcd for C34H40N4O7:639.2789；found:639.2781.
实施例55：叔丁基-4-(3'-羟基-5'-(对乙酰氨基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物54)的合成
合成方法参照实施例1。mp 193-194℃；1H NMR(400MHz,Methanol-d4)δ7.79(d,J＝8.0Hz,2H),7.69(m,2H),7.66(s,1H),7.65–7.52(m,4H),7.37(s,1H),7.28(s,1H),3.64(m,8H),2.14(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C31H34N4O6:559.2551；found:559.2561.
实施例56：叔丁基-4-(3'-羟基-5'-(间乙酰氨基苯基氨基甲酰基)-[1,1'-联苯]-4-羰基)哌嗪-1-羧酸酯(化合物55)的合成
合成方法参照实施例1。mp 215-216℃；1H NMR(400MHz,Methanol-d4)δ8.04(t,J＝2.0Hz,1H),7.78(d,J＝8.2Hz,1H),7.68(t,J＝1.6Hz,2H),7.54(d,J＝8.2Hz,1H),7.44(dt,J＝7.9,1.6Hz,2H),7.37(dt,J＝7.5,1.7Hz,1H),7.31(d,J＝8.0Hz,2H),7.28(d,J＝2.2Hz,1H),3.63(m,8H),2.14(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd forC31H34N4O6:559.2551；found:559.2561.
实施例57：5-(4-(哌嗪-1-羰基)苯基)-N-(环己基)烟酰胺)(化合物56)的合成
合成方法参照实施例1。mp 125-126℃；1H NMR(400MHz,Methanol-d4)δ9.00(d,J＝2.2Hz,1H),8.98(d,J＝2.2Hz,1H),8.51(t,J＝2.1Hz,1H),7.88(d,J＝8.2Hz,2H),7.63(d,J＝8.3Hz,2H),3.92(m,1H),3.78(s,2H),3.51(m,6H),3.00(d,J＝2.7Hz,3H),2.09–1.97(m,2H),1.88–1.82(m,1H),1.49(s,9H),1.47(d,J＝2.9Hz,4H),1.43(d,J＝8.4Hz,2H).HRMS(ESI):m/z[M+H]+calcd for C28H36N4O4:493.2809；found:493.2815.
实施例58：5-(4-(哌嗪-1-羰基)苯基)-N-(苄基)烟酰胺(化合物57)的合成
合成方法参照实施例1。mp 134-135℃；1H NMR(400MHz,Methanol-d4)δ9.03(d,J＝2.1Hz,1H),9.01(d,J＝2.2Hz,1H),8.54(t,J＝2.1Hz,1H),7.86(d,J＝8.3Hz,2H),7.61(d,J＝8.2Hz,2H),7.44–7.33(m,4H),7.32–7.25(m,1H),4.64(s,2H),3.77(s,2H),3.53(d,J＝32.4Hz,6H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H32N4O4:501.2496；found:501.2545.
实施例59：N-(呋喃-2-基甲基)-5-(4-(哌嗪-1-羰基)苯基)烟酰胺(化合物58)的合成
合成方法参照实施例1。mp 125-126℃；1H NMR(400MHz,Methanol-d4)δ9.02(t,J＝2.1Hz,2H),8.54(t,J＝2.1Hz,1H),7.87(d,J＝8.3Hz,2H),7.62(d,J＝8.2Hz,2H),7.48(dd,J＝1.9,0.9Hz,1H),6.40(dd,J＝3.2,1.9Hz,1H),6.37(dd,J＝3.3,0.9Hz,1H),4.63(s,2H),3.85–3.46(m,8H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C27H30N4O5:491.2289；found:491.2296.
实施例60：5-(4-(哌嗪-1-羰基)苯基)-N-(苯乙基)烟酰胺(化合物59)的合成
合成方法参照实施例1。mp 184-185℃；1H NMR(400MHz,Methanol-d4)δ9.00(d,J＝2.4Hz,1H),8.94(d,J＝1.8Hz,1H),8.45(d,J＝2.2Hz,1H),7.85(d,J＝8.2Hz,2H),7.63(d,J＝8.1Hz,2H),7.33–7.28(m,4H),7.27–7.18(m,1H),3.78(s,2H),3.67(m,2H),3.54(m,6H),2.98(t,J＝7.5Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H34N4O4:515.2653；found:515.2671
实施例61：5-(4-(哌嗪-1-羰基)苯基)-N-(对甲基苯基)烟酰胺(化合物60)的合成
合成方法参照实施例1。mp 170-171℃；1H NMR(400MHz,Methanol-d4)δ9.10(d,J＝2.1Hz,1H),9.05(d,J＝2.2Hz,1H),8.63(t,J＝2.2Hz,1H),7.91(d,J＝8.0Hz,2H),7.67–7.59(m,4H),7.22(d,J＝8.2Hz,2H),3.78(s,2H),3.62–3.44(m,6H),2.36(s,3H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H32N4O4:501.2496；found:501.2539.
实施例62：5-(4-(哌嗪-1-羰基)苯基)-N-(间甲基苯基)烟酰胺(化合物61)的合成
合成方法参照实施例1。mp 155-156℃；1H NMR(400MHz,Methanol-d4)δ9.15(s,1H),9.07(s,1H),8.67(s,1H),7.90(d,J＝6.1Hz,2H),7.64(d,J＝8.5Hz,2H),7.40(d,J＝7.0Hz,1H),7.33(d,J＝6.7Hz,1H),7.29–7.20(m,2H),3.78(s,2H),3.62–3.43(m,6H),2.35(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H32N4O4:501.2496；found:501.2543.
实施例63：5-(4-(哌嗪-1-羰基)苯基)-N-(邻甲基苯基)烟酰胺(化合物62)的合成
合成方法参照实施例1。mp 126-127℃；1H NMR(400MHz,Methanol-d4)δ9.09(d,J＝1.9Hz,1H),9.04(d,J＝2.2Hz,1H),8.62(t,J＝2.1Hz,1H),7.90(d,J＝7.9Hz,2H),7.66–7.51(m,4H),7.27(t,J＝7.8Hz,1H),7.02(d,J＝7.6Hz,1H),3.80–3.76(s,2H),3.54(m,6H),2.38(s,3H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H32N4O4:501.2496；found:501.2541.
实施例64：5-(4-(哌嗪-1-羰基)苯基)-N-(4-甲氧基苯基)烟酰胺(化合物63)的合成
合成方法参照实施例1。mp 145-146℃；1H NMR(400MHz,Methanol-d4)δ9.10(d,J＝2.1Hz,1H),9.05(d,J＝2.2Hz,1H),8.64(t,J＝2.1Hz,1H),7.91(d,J＝8.1Hz,2H),7.66(d,J＝2.7Hz,2H),7.64(d,J＝1.9Hz,2H),6.97(d,J＝9.0Hz,2H),3.83(s,3H),3.79(s,2H),3.54(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H32N4O5:517.2445；found:517.2481.
实施例65：5-(4-(哌嗪-1-羰基)苯基)-N-(3-甲氧基苯基)烟酰胺(化合物64)的合成
合成方法参照实施例1。mp 134-135℃；1H NMR(400MHz,Methanol-d4)δ9.10(s,1H),9.05(s,1H),8.65–8.61(m,1H),7.90(d,J＝7.9Hz,2H),7.64(d,J＝7.9Hz,2H),7.47(s,1H),7.30(d,J＝3.4Hz,2H),6.78(dd,J＝6.2,2.9Hz,1H),3.84(s,3H),3.78(s,2H),3.57(s,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H32N4O5:517.2445；found:517.2468.
实施例66：5-(4-(哌嗪-1-羰基)苯基)-N-(2-甲氧基苯基)烟酰胺(化合物65)的合成
合成方法参照实施例1。mp 126-127℃；1H NMR(400MHz,Methanol-d4)δ9.10(d,J＝2.1Hz,1H),9.05(d,J＝2.2Hz,1H),8.61(t,J＝2.1Hz,1H),7.95(d,J＝7.9Hz,1H),7.90(d,J＝7.9Hz,2H),7.64(d,J＝8.0Hz,2H),7.24(td,J＝7.9,1.6Hz,1H),7.11(dd,J＝8.3,1.3Hz,1H),7.01(td,J＝7.7,1.3Hz,1H),3.94(s,3H),3.78(s,2H),3.51(s,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H32N4O5:517.2445；found:517.2469.
实施例67：5-(4-(哌嗪-1-羰基)苯基)-N-(4-乙基苯基)烟酰胺(化合物66)的合成
合成方法参照实施例1。mp 156-157℃；1H NMR(400MHz,Methanol-d4)δ9.10(d,J＝2.0Hz,1H),9.04(d,J＝2.1Hz,1H),8.63(s,1H),7.90(d,J＝8.0Hz,2H),7.64(t,J＝7.6Hz,4H),7.24(d,J＝8.2Hz,2H),3.78(s,2H),3.54(d,J＝29.6Hz,6H),2.67(q,J＝7.6Hz,2H),1.50(s,9H),1.26(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd forC30H34N4O4:515.2653；found:515.2690.
实施例68：5-(4-(哌嗪-1-羰基)苯基)-N-(3-乙苯基苯基)烟酰胺(化合物67)的合成
合成方法参照实施例1。mp 140-141℃；1H NMR(400MHz,Methanol-d4)δ9.11(s,1H),9.05(s,1H),8.64(d,J＝2.1Hz,1H),7.91(d,J＝6.3Hz,2H),7.67–7.60(m,3H),7.58(d,J＝6.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.06(d,J＝7.0Hz,1H),3.78(s,2H),3.64–3.43(m,6H),2.69(q,J＝7.6Hz,2H),1.50(s,9H),1.28(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C30H34N4O4:515.2653；found:515.2694.
实施例69：5-(4-(哌嗪-1-羰基)苯基)-N-(4-异丙基苯基)烟酰胺(化合物69)的合成
合成方法参照实施例1。mp 146-145℃；1H NMR(400MHz,Methanol-d4)δ9.09(d,J＝2.0Hz,1H),9.03(d,J＝2.2Hz,1H),8.62(t,J＝2.1Hz,1H),7.88(d,J＝8.2Hz,2H),7.64(dd,J＝13.2,8.4Hz,4H),7.27(d,J＝8.5Hz,2H),3.77(s,2H),3.53(m,6H),2.93(p,J＝6.9Hz,1H),1.49(s,9H),1.27(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd forC31H36N4O4:529.2809；found:529.2835.
实施例70：5-(4-(哌嗪-1-羰基)苯基)-N-(3-异丙基苯基)烟酰胺(化合物70)的合成
合成方法参照实施例1。mp 125-126℃；1H NMR(400MHz,Methanol-d4)δ9.13–9.09(m,1H),9.05(d,J＝2.1Hz,1H),8.64(t,J＝2.1Hz,1H),7.91(d,J＝8.3Hz,2H),7.67–7.62(m,3H),7.59(d,J＝8.0Hz,1H),7.32(t,J＝7.9Hz,1H),7.09(dt,J＝7.7,1.4Hz,1H),3.78(s,2H),3.53(m,6H),2.95(p,J＝6.9Hz,1H),1.49(s,9H),1.29(s,6H).HRMS(ESI):m/z[M+H]+calcd for C31H36N4O4:529.2809；found:529.2814.
实施例71：5-(4-(哌嗪-1-羰基)苯基)-N-(2-异丙基苯基)烟酰胺(化合物71)的合成
合成方法参照实施例1。mp 127-128℃；1H NMR(400MHz,Methanol-d4)δ9.15(d,J＝2.0Hz,1H),9.09(d,J＝2.2Hz,1H),8.67(t,J＝2.2Hz,1H),7.92(d,J＝8.0Hz,2H),7.65(d,J＝8.1Hz,2H),7.46(dd,J＝7.8,1.6Hz,1H),7.36(ddd,J＝15.2,7.3,1.7Hz,2H),7.31–7.25(m,1H),3.79(s,2H),3.54(m,6H),3.31–3.18(m,1H),1.50(s,9H),1.28(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd for C31H36N4O4:529.2809；found:529.2804.
实施例72：5-(4-(哌嗪-1-羰基)苯基)-N-(4-叔丁基苯基)烟酰胺(化合物72)的合成
合成方法参照实施例1。mp 147-146℃；1H NMR(400MHz,Methanol-d4)δ9.11(d,J＝2.3Hz,1H),9.05(d,J＝2.4Hz,1H),8.65(t,J＝2.3Hz,1H),7.91(d,J＝7.6Hz,2H),7.71–7.61(m,4H),7.45(d,J＝8.8Hz,2H),3.81–3.76(m,2H),3.62–3.47(m,6H),1.50(d,J＝2.7Hz,9H),1.36(d,J＝2.7Hz,9H).HRMS(ESI):m/z[M+H]+calcdfor C32H38N4O4:543.2966；found:543.2999.
实施例73：5-(4-(哌嗪-1-羰基)苯基)-N-(4-氟苯基)烟酰胺(化合物73)的合成
合成方法参照实施例1。mp 141-142℃；1H NMR(400MHz,Methanol-d4)δ9.11(s,1H),9.05(s,1H),8.64(d,J＝2.1Hz,1H),7.90(d,J＝6.5Hz,2H),7.76(dd,J＝7.4,5.0Hz,2H),7.64(d,J＝6.5Hz,2H),7.14(t,J＝7.8Hz,2H),3.78(s,2H),3.53(s,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C28H29FN4O4:505.2246；found:505.2246.
实施例74：5-(4-(哌嗪-1-羰基)苯基)-N-(3-氟苯基)烟酰胺(化合物74)的合成
合成方法参照实施例1。mp 160-161℃；1H NMR(400MHz,Methanol-d4)δ9.11(d,J＝2.1Hz,1H),9.06(d,J＝2.2Hz,1H),8.64(t,J＝2.2Hz,1H),7.91(d,J＝8.1Hz,2H),7.73(dt,J＝11.3,2.3Hz,1H),7.64(d,J＝8.2Hz,2H),7.51(dd,J＝8.1,2.0Hz,1H),7.40(td,J＝8.2,6.5Hz,1H),6.93(td,J＝8.4,2.6Hz,1H),3.78(s,2H),3.63–3.46(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C28H29FN4O4:505.2246；found:505.2246.
实施例75：5-(4-(哌嗪-1-羰基)苯基)-N-(2-氟苯基)烟酰胺(化合物75)的合成
合成方法参照实施例1。mp 127-128℃；1H NMR(400MHz,Methanol-d4)δ9.13(s,1H),9.07(d,J＝2.7Hz,1H),8.65(t,J＝2.3Hz,1H),7.94–7.87(m,2H),7.83(t,J＝7.8Hz,1H),7.64(dd,J＝8.2,3.8Hz,2H),7.34–7.21(m,3H),3.78(s,2H),3.52(s,6H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C28H29FN4O4:505.2246；found:505.2249.
实施例76：5-(4-(哌嗪-1-羰基)苯基)-N-(4-三氟甲基苯基)烟酰胺(化合物76)的合成
合成方法参照实施例1。mp 158-159℃；1H NMR(400MHz,Chloroform-d)δ10.31(s,1H),9.60(s,1H),8.99(s,1H),8.78(s,1H),8.06(d,J＝8.4Hz,2H),7.69(d,J＝7.5Hz,2H),7.63(d,J＝8.4Hz,2H),7.51(d,J＝7.2Hz,2H),3.80(s,2H),3.51(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H29F3N4O4:555.2214；found:555.2214.
实施例77：5-(4-(哌嗪-1-羰基)苯基)-N-(3-三氟甲基苯基)烟酰胺(化合物77)的合成
合成方法参照实施例1。mp 141-142℃；1H NMR(400MHz,Chloroform-d)δ10.28(s,1H),9.37(s,1H),8.92(s,1H),8.60(s,1H),8.19(s,1H),8.16(d,J＝8.7Hz,1H),7.61(d,J＝7.7Hz,2H),7.51(t,J＝7.9Hz,1H),7.43(dd,J＝7.9,4.7Hz,3H),4.68(s,2H),3.85–3.53(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H29F3N4O4:555.2214；found:555.2242.
实施例78：5-(4-(哌嗪-1-羰基)苯基)-N-(4-三氟甲氧基苯基)烟酰胺(化合物78)的合成
合成方法参照实施例1。mp 174-175℃；1H NMR(400MHz,Chloroform-d)δ10.00(s,1H),9.36(s,1H),8.92(s,1H),8.60(s,1H),7.92(d,J＝8.7Hz,2H),7.62(d,J＝7.8Hz,2H),7.45(d,J＝7.7Hz,2H),7.24(d,J＝8.5Hz,2H),5.28(s,2H),3.68(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H29F3N4O5:571.2163；found:571.2168.
实施例79：5-(4-(哌嗪-1-羰基)苯基)-N-(3-三氟甲氧基苯基)烟酰胺(化合物79)的合成
合成方法参照实施例1。mp 198-199℃；1H NMR(400MHz,Chloroform-d)δ10.29(s,1H),9.59(s,1H),8.97(s,1H),8.78(s,1H),7.95(s,1H),7.86(d,J＝8.2Hz,1H),7.68(d,J＝7.3Hz,2H),7.50(d,J＝6.0Hz,2H),7.40(t,J＝8.2Hz,1H),7.06(d,J＝8.8Hz,1H),3.68(m,8H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C29H29F3N4O5:571.2163；found:571.2157.
实施例80：5-(4-(哌嗪-1-羰基)苯基)-N-(4-氯苯基)烟酰胺(化合物80)的合成
合成方法参照实施例1。mp 152-153℃；1H NMR(400MHz,Methanol-d4)δ9.18(d,J＝1.9Hz,1H),9.15(d,J＝2.1Hz,1H),8.86(d,J＝2.1Hz,1H),7.95(d,J＝8.3Hz,2H),7.79(d,J＝8.9Hz,2H),7.66(d,J＝8.4Hz,2H),7.40(d,J＝8.9Hz,2H),3.78(s,2H),3.53(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C28H29ClN4O4:521.1950；found:521.1973.
实施例81：5-(4-(哌嗪-1-羰基)苯基)-N-(2-氯苯基)烟酰胺(化合物81)的合成
合成方法参照实施例1。mp 164-165℃；1H NMR(400MHz,Methanol-d4)δ9.19(d,J＝2.0Hz,1H),9.16(d,J＝2.2Hz,1H),8.87(t,J＝2.1Hz,1H),7.98–7.93(m,3H),7.70–7.64(m,3H),7.39(t,J＝8.1Hz,1H),7.20(ddd,J＝8.0,2.0,0.9Hz,1H),3.79(s,2H),3.64–3.44(m,6H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C28H29ClN4O4:521.1950；found:521.1967.
实施例82：5-(4-(哌嗪-1-羰基)苯基)-N-(4-氨基苯基)烟酰胺(化合物82)的合成
合成方法参照实施例1。mp 212-213℃；1H NMR(400MHz,Methanol-d4)δ9.12(d,J＝2.0Hz,1H),9.07(d,J＝2.1Hz,1H),8.69(s,1H),7.91(d,J＝8.0Hz,2H),7.69–7.61(m,4H),7.44(d,J＝8.6Hz,2H),3.78(s,2H),3.54(m,6H),1.55(s,9H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C33H39N5O6:602.2973；found:602.2997.
实施例83：5-(4-(哌嗪-1-羰基)苯基)-N-(3-氨基苯基)烟酰胺(化合物83)的合成
合成方法参照实施例1。mp 180-181℃；1H NMR(400MHz,Methanol-d4)δ9.11(s,1H),9.07(s,1H),8.67(s,1H),7.95(s,1H),7.91(d,J＝8.2Hz,2H),7.64(d,J＝8.0Hz,2H),7.41(d,J＝7.4Hz,1H),7.29(t,J＝8.1Hz,1H),7.20(d,J＝8.1Hz,1H),3.78(s,2H),3.50(m,6H),1.55(s,9H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C33H39N5O6:602.2973；found:602.2971.
实施例84：5-(4-(哌嗪-1-羰基)苯基)-N-(2-氨基苯基)烟酰胺(化合物84)的合成
合成方法参照实施例1。mp 167-168℃；1H NMR(400MHz,Methanol-d4)δ9.15(d,J＝2.1Hz,1H),9.07(d,J＝2.4Hz,1H),8.67(s,1H),7.90(d,J＝8.0Hz,2H),7.64(d,J＝8.3Hz,3H),7.53(dd,J＝7.9,1.7Hz,1H),7.27(m,2H),3.78(s,2H),3.54(m,6H),1.49(s,9H),1.48(s,9H).HRMS(ESI):m/z[M+H]+calcd for C33H39N5O6:602.2973；found:602.2981.
实施例85：5-(4-(哌嗪-1-羰基)苯基)-N-(4-乙酰氨基苯基)烟酰胺(化合物85)的合成
合成方法参照实施例1。mp 233-234℃；1H NMR(400MHz,Methanol-d4)δ9.11(d,J＝2.0Hz,1H),9.06(d,J＝2.2Hz,1H),8.65(s,1H),7.91(d,J＝7.9Hz,2H),7.71(d,J＝8.7Hz,2H),7.64(d,J＝8.0Hz,2H),7.59(d,J＝8.7Hz,2H),3.78(s,2H),3.51(s,6H),2.15(s,3H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H33N5O5:544.2554；found:544.2560.
实施例86：5-(4-(哌嗪-1-羰基)苯基)-N-(3-乙酰氨基苯基)烟酰胺(化合物86)的合成
合成方法参照实施例1。mp 248-249℃；1H NMR(400MHz,Methanol-d4)δ9.11(s,1H),9.07(s,1H),8.65(s,1H),8.10(s,1H),7.93(d,J＝8.1Hz,2H),7.65(d,J＝7.3Hz,2H),7.50(d,J＝7.8Hz,1H),7.34(m,2H),3.79(s,2H),3.55(m,6H),2.16(s,3H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H33N5O5:544.2554；found:544.2569.
实施例87：5-(4-(哌嗪-1-羰基)苯基)-N-(2-乙酰氨基苯基)烟酰胺(化合物87)的合成
合成方法参照实施例1。mp 131-132℃；1H NMR(400MHz,Chloroform-d)δ10.50(s,1H),9.42(s,1H),8.83(s,1H),7.78(d,J＝7.7Hz,2H),7.64(d,J＝7.7Hz,1H),7.58(d,J＝7.5Hz,2H),7.36(d,J＝7.5Hz,1H),7.10(p,J＝7.4Hz,2H),3.79(s,2H),3.51(m,6H),2.23(s,3H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C30H33N5O5:544.2554；found:544.2572.
实施例88：叔丁基-4-(4-(6-氨基-5-(苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物88)的合成
合成方法参照实施例1。mp:190-191℃；1H NMR(400MHz,Methanol-d4)δ8.34(d,J＝2.2Hz,1H),8.27(d,J＝2.1Hz,1H),8.09(s,1H),7.89(s,1H),7.68(d,J＝8.0Hz,2H),7.37(t,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),4.39(tt,J＝11.7,4.2Hz,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.16–2.09(m,2H),1.95(qd,J＝12.3,4.3Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C25H30N6O3:463.2452；found:463.2454.
实施例89：叔丁基-4-(4-(6-氨基-5-(4-甲基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物89)的合成
合成方法参照实施例1。mp:203-204℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.25(d,J＝2.3Hz,1H),8.09(s,1H),7.89(s,1H),7.54(d,J＝8.5Hz,2H),7.19(d,J＝8.3Hz,2H),4.39(tt,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),2.99(s,2H),2.35(s,3H),2.12(d,J＝9.6Hz,2H),1.95(qd,J＝12.4,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O3:477.2609；found:477.2638.
实施例90：叔丁基-4-(4-(6-氨基-5-(3-甲基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物90)的合成
合成方法参照实施例1。mp:178-179℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.24(d,J＝2.3Hz,1H),8.07(s,1H),7.88(s,1H),7.50(s,1H),7.47(d,J＝8.0Hz,1H),7.24(t,J＝7.8Hz,1H),6.98(d,J＝7.5Hz,1H),4.38(tt,J＝11.6,4.1Hz,1H),4.23(d,J＝13.5Hz,2H),2.98(s,2H),2.36(s,3H),2.10(s,2H),1.94(qd,J＝12.3,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O3:477.2609；found:477.2614.
实施例91：叔丁基-4-(4-(6-氨基-5-(2-甲基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物91)的合成
合成方法参照实施例1。mp:221-222℃；1H NMR(400MHz,Methanol-d4)δ8.37(d,J＝2.4Hz,1H),8.35(d,J＝2.2Hz,1H),8.10(s,1H),7.88(s,1H),7.37–7.29(m,2H),7.31–7.21(m,2H),4.47–4.36(m,1H),4.24(d,J＝13.5Hz,2H),3.02(s,2H),2.33(s,3H),2.13(d,J＝12.3Hz,2H),1.96(s,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O3:477.2609；found:477.2604.
实施例92：叔丁基-4-(4-(6-氨基-5-(4-乙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物92)的合成
合成方法参照实施例1。mp:165-166℃；1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),8.25(s,1H),8.08(s,1H),7.88(s,1H),7.57(d,J＝8.5Hz,2H),7.21(d,J＝8.0Hz,2H),4.39(dtd,J＝11.5,7.8,3.1Hz,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.65(q,J＝7.6Hz,2H),2.12(d,J＝10.3Hz,2H),1.95(qd,J＝12.3,4.4Hz,2H),1.50(s,9H),1.25(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C27H34N6O3:491.2765；found:491.2766.
实施例93：叔丁基-4-(4-(6-氨基-5-(3-乙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物93)的合成
合成方法参照实施例1。mp:135-136℃；1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),8.24(s,1H),8.07(s,1H),7.87(s,1H),7.54–7.47(m,2H),7.27(t,J＝7.7Hz,1H),7.01(d,J＝7.7Hz,1H),4.38(td,J＝11.6,4.6Hz,1H),4.23(d,J＝12.0Hz,2H),2.98(s,2H),2.66(q,J＝7.6Hz,2H),2.11(d,J＝11.8Hz,2H),1.94(d,J＝12.4Hz,2H),1.49(s,9H),1.26(td,J＝7.8,2.7Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C27H34N6O3:491.2765；found:491.2758.
实施例94：叔丁基-4-(4-(6-氨基-5-(2-乙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物94)的合成
合成方法参照实施例1。mp:192-193℃；1H NMR(400MHz,Methanol-d4)δ8.37(d,J＝2.2Hz,1H),8.33(d,J＝2.3Hz,1H),8.08(s,1H),7.87(s,1H),7.39–7.25(m,4H),4.40(tt,J＝11.6,4.0Hz,1H),4.24(d,J＝13.2Hz,2H),2.98(s,2H),2.71(q,J＝7.6Hz,2H),2.12(dd,J＝12.4,3.3Hz,2H),1.95(qd,J＝12.4,4.4Hz,2H),1.50(s,9H),1.24(t,J＝7.6Hz,3H).HRMS(ESI):m/z[M+H]+calcd for C27H34N6O3:491.2765；found:491.2755.
实施例95：叔丁基-4-(4-(6-氨基-5-(4-甲氧基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物95)的合成
合成方法参照实施例1。mp:160-161℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.4Hz,1H),8.24(d,J＝2.3Hz,1H),7.88(s,1H),8.08(s,1H),7.55(d,J＝9.1Hz,2H),6.94(d,J＝9.1Hz,2H),4.39(tt,J＝10.5,4.2Hz,1H),4.24(d,J＝13.5Hz,2H),3.81(s,3H),2.98(s,2H),2.12(d,J＝13.5Hz,2H),1.96(ddt,J＝21.2,13.2,6.2Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O4:493.2558；found:493.2555.
实施例96：叔丁基-4-(4-(6-氨基-5-(3-甲氧基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物96)的合成
合成方法参照实施例1。mp:115-116℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.25(d,J＝2.3Hz,1H),8.07(s,1H),7.88(s,1H),7.38(t,J＝2.1Hz,1H),7.32–7.19(m,2H),6.73(dt,J＝7.6,2.2Hz,1H),4.38(tt,J＝11.5,4.0Hz,1H),4.23(d,J＝13.5Hz,2H),3.82(s,3H),2.97(s,2H),2.11(d,J＝11.8Hz,2H),1.94(qd,J＝12.3,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O4:493.2558；found:493.2561.
实施例97：叔丁基-4-(4-(6-氨基-5-(2-甲氧基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物97)的合成
合成方法参照实施例1。mp:195-196℃；1H NMR(400MHz,Methanol-d4)δ8.34(s,1H),8.22(s,1H),8.07(s,1H),7.85(d,J＝12.0Hz,2H),7.21(t,J＝7.8Hz,1H),7.08(d,J＝8.3Hz,1H),4.39(td,J＝11.5,5.6Hz,1H),4.24(d,J＝13.5Hz,2H),3.91(s,3H),2.97(s,2H),2.12(d,J＝11.4Hz,2H),1.95(qd,J＝12.2,4.3Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C26H32N6O4:493.2558；found:493.2542.
实施例98：叔丁基-4-(4-(6-氨基-5-(4-异丙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌-1-羧酸盐(化合物98)的合成
合成方法参照实施例1。mp:200-201℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.25(d,J＝2.3Hz,1H),8.07(s,1H),7.87(s,1H),7.57(d,J＝8.5Hz,2H),7.24(d,J＝8.4Hz,2H),4.38(tt,J＝11.6,4.0Hz,1H),4.23(d,J＝13.5Hz,2H),2.92(m,3H),2.11(d,J＝9.7Hz,2H),1.94(qd,J＝12.3,4.4Hz,2H),1.50(s,9H),1.26(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd for C28H36N6O3:505.2922；found:505.2922.
实施例99：叔丁基-4-(4-(6-氨基-5-(3-异丙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物99)的合成
合成方法参照实施例1。mp:175-176℃；1H NMR(400MHz,Methanol-d4)δ8.34(d,J＝2.3Hz,1H),8.27(d,J＝2.3Hz,1H),8.09(t,J＝2.0Hz,1H),7.89(t,J＝1.3Hz,1H),7.56(t,J＝1.9Hz,1H),7.52(d,J＝8.0Hz,1H),7.29(t,J＝7.9Hz,1H),7.05(dt,J＝7.7,1.5Hz,1H),4.44–4.33(m,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.99–2.89(m,1H),2.16–2.08(m,2H),2.03–1.88(m,2H),1.50(s,9H),1.29(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd for C28H36N6O3:505.2922；found:505.2917.
实施例100：叔丁基-4-(4-(6-氨基-5-(2-异丙基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物100)的合成
合成方法参照实施例1。mp:234-235℃；1H NMR(400MHz,Methanol-d4)δ8.37(d,J＝2.2Hz,1H),8.35(d,J＝2.3Hz,1H),8.09(s,1H),7.88(s,1H),7.44(d,J＝7.3Hz,1H),7.34(ddd,J＝8.0,5.4,3.4Hz,1H),7.27(d,J＝2.6Hz,2H),4.41(tt,J＝11.6,4.1Hz,1H),4.25(d,J＝13.5Hz,2H),3.22(p,J＝6.9Hz,1H),2.99(s,2H),2.13(d,J＝10.0Hz,2H),1.96(qd,J＝12.4,4.4Hz,2H),1.50(s,9H),1.26(d,J＝6.9Hz,6H).HRMS(ESI):m/z[M+H]+calcd forC28H36N6O3:505.2922；found:505.2925.
实施例101：叔丁基-4-(4-(6-氨基-5-(4-叔丁基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物101)的合成
合成方法参照实施例1。mp:212-213℃；1H NMR(400MHz,Methanol-d4)δ8.31(s,1H),8.24(s,1H),8.07(s,1H),7.87(s,1H),7.56(d,J＝7.8Hz,2H),7.40(d,J＝8.7Hz,2H),4.38(tt,J＝11.7,3.9Hz,1H),4.22(d,J＝13.1Hz,2H),2.97(s,2H),2.10(d,J＝12.2Hz,2H),2.03–1.86(m,2H),1.48(s,9H),1.33(s,9H).HRMS(ESI):m/z[M+H]+calcd forC29H38N6O3:519.3078；found:519.3080.
实施例102：叔丁基-4-(4-(6-氨基-5-(3-叔丁基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物102)的合成
合成方法参照实施例1。mp:115-116℃；1H NMR(400MHz,Methanol-d4)δ8.34(d,J＝2.3Hz,1H),8.27(d,J＝2.2Hz,1H),8.08(s,1H),7.88(s,1H),7.71(s,1H),7.54(d,J＝6.9Hz,1H),7.30(t,J＝8.0Hz,1H),7.22(dt,J＝8.0,1.4Hz,1H),4.39(tt,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.11(d,J＝11.5Hz,2H),1.95(qd,J＝12.2,4.0Hz,2H),1.50(s,9H),1.26(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H38N6O3:519.3078；found:519.3079.
实施例103：叔丁基-4-(4-(6-氨基-5-(4-氟苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物103)的合成
合成方法参照实施例1。mp:156-157℃；1H NMR(400MHz,Methanol-d4)δ8.32(s,1H),8.24(s,1H),8.06(s,1H),7.86(s,1H),7.67(dd,J＝8.7,4.8Hz,2H),7.09(t,J＝8.6Hz,2H),4.39(d,J＝11.8Hz,1H),4.22(d,J＝12.5Hz,2H),3.00(s,2H),2.10(d,J＝11.7Hz,2H),1.94(m,2H),1.49(s,9H).HRMS(ESI):m/z[M+H]+calcd for C25H29FN6O3:481.2358；found:481.2387.
实施例104：叔丁基-4-(4-(6-氨基-5-(3-氟苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物104)的合成
合成方法参照实施例1。mp:198-199℃；1H NMR(400MHz,Methanol-d4)δ8.35(d,J＝2.3Hz,1H),8.26(d,J＝2.3Hz,1H),8.10(s,1H),7.88(s,1H),7.67(dt,J＝11.4,2.2Hz,1H),7.44(d,J＝8.7Hz,1H),7.37(td,J＝8.1,6.4Hz,1H),6.89(m,1H),4.42(tt,J＝11.6,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),3.01(s,2H),2.12(d,J＝10.3Hz,2H),2.04–1.89(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C25H29FN6O3:481.2358；found:481.2391.
实施例105：叔丁基-4-(4-(6-氨基-5-(2-氟苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物105)的合成
合成方法参照实施例1。mp:209-210℃；1H NMR(400MHz,Methanol-d4)δ8.37(s,1H),8.34(s,1H),8.10(s,1H),7.89(s,1H),7.72(t,J＝8.0Hz,1H),7.25(m,3H),4.41(td,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),3.01(s,2H),2.16–2.09(m,2H),2.03–1.88(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C25H29FN6O3:481.2358；found:481.2416.
实施例106：叔丁基-4-(4-(6-氨基-5-(4-氯苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物106)的合成
合成方法参照实施例1。mp:187-188℃；1H NMR(400MHz,Methanol-d4)δ8.34(d,J＝2.2Hz,1H),8.28(d,J＝2.2Hz,1H),8.10(s,1H),7.89(s,1H),7.70(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H),4.46–4.34(m,1H),4.24(d,J＝13.2Hz,2H),3.01(s,2H),2.13(d,J＝10.0Hz,2H),2.03–1.88(qd,J＝12.3,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C25H29ClN6O3:497.2062；found:497.22105.
实施例107：叔丁基-4-(4-(6-氨基-5-(3-氯苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物107)的合成
合成方法参照实施例1。mp:215-216℃；1H NMR(400MHz,Methanol-d4)δ8.35(d,J＝2.2Hz,1H),8.27(d,J＝2.3Hz,1H),8.09(s,1H),7.88(d,J＝2.2Hz,2H),7.59(ddd,J＝8.3,2.1,1.0Hz,1H),7.35(t,J＝8.1Hz,1H),7.15(ddd,J＝8.0,2.1,1.0Hz,1H),4.41(tt,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),2.99(s,2H),2.12(d,J＝12.4Hz,2H),1.96(dd,J＝12.2,4.3Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C25H29ClN6O3:497.2062；found:497.2118.
实施例108：叔丁基-4-(4-(6-氨基-5-(3-三氟甲基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物108)的合成
合成方法参照实施例1。white oil,1H NMR(400MHz,Methanol-d4)δ8.37(d,J＝2.3Hz,1H),8.30(d,J＝2.3Hz,1H),8.16(s,1H),8.10(s,1H),7.93(d,J＝9.1Hz,1H),7.89(s,1H),7.35(t,J＝8.1Hz,1H),7.44(d,J＝7.8Hz,1H),4.42(tt,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),3.01(s,2H),2.12(d,J＝14.3Hz,2H),2.02–1.91(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H29F3N6O3:531.2326；found:531.2376.
实施例109：叔丁基-4-(4-(6-氨基-5-(4-三氟甲氧基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物109)的合成
合成方法参照实施例1。mpP:135-136℃；1H NMR(400MHz,Methanol-d4)δ8.35(d,J＝2.1Hz,1H),8.27(d,J＝2.0Hz,1H),8.09(s,1H),7.88(s,1H),7.80(d,J＝9.2Hz,2H),7.28(d,J＝8.6Hz,2H),4.41(tt,J＝11.7,4.1Hz,1H),4.24(d,J＝13.5Hz,2H),3.04–2.97(m,2H),2.12(d,J＝9.4Hz,2H),2.06–1.88(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C26H29F3N6O4:547.2275；found:547.2332.
实施例110：叔丁基-4-(4-(6-氨基-5-(3-三氟甲氧基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物110)的合成
合成方法参照实施例1。mp:120-121℃；1H NMR(400MHz,Methanol-d4)δ8.37(q,J＝2.3Hz,2H),8.16(s,1H),8.13(d,J＝0.8Hz,1H),7.95(d,J＝8.7Hz,1H),7.91(d,J＝0.8Hz,1H),7.58(t,J＝8.0Hz,1H),7.45(d,J＝7.9Hz,1H),4.42(tt,J＝11.6,4.0Hz,1H),4.25(d,J＝13.5Hz,2H),3.00(s,2H),2.14(d,J＝11.0Hz,2H),1.96(dd,J＝12.2,4.3Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H29F3N6O4:547.2275；found:547.2326.
实施例111：叔丁基-4-(4-(6-氨基-5-(4-氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物111)的合成
合成方法参照实施例1。mp:145-146℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.1Hz,1H),8.26(d,J＝2.4Hz,1H),8.08(s,1H),7.88(s,1H),7.58(d,J＝8.9Hz,2H),7.41(d,J＝8.6Hz,2H),4.44–4.34(m,1H),4.24(d,J＝13.5Hz,2H),2.99(s,2H),2.16–2.08(m,2H),2.03–1.88(m,2H),1.54(s,9H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd forC30H39N7O5:578.3085；found:578.3127.
实施例112：叔丁基-4-(4-(6-氨基-5-(3-氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物112)的合成
合成方法参照实施例1。mp:144-145℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.25(d,J＝2.3Hz,1H),8.08(d,J＝0.8Hz,1H),7.88(dd,J＝2.5,1.4Hz,2H),7.32(ddd,J＝8.0,2.0,1.2Hz,1H),7.25(t,J＝8.0Hz,1H),7.16(ddd,J＝8.0,2.1,1.2Hz,1H),4.38(tt,J＝11.6,4.1Hz,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.11(d,J＝15.7Hz,2H),1.95(qd,J＝12.4,4.4Hz,2H),1.54(s,9H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H39N7O5:578.3085；found:578.3129.
实施例113：叔丁基-4-(4-(6-氨基-5-(2-氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物113)的合成
合成方法参照实施例1。mp:125-126℃；1H NMR(400MHz,Methanol-d4)δ8.46(d,J＝2.2Hz,1H),8.35(d,J＝2.2Hz,1H),8.12(s,1H),7.90(s,1H),7.54(ddd,J＝9.5,7.8,1.7Hz,2H),7.25(dtd,J＝21.6,7.5,1.6Hz,2H),4.41(tt,J＝11.5,4.0Hz,1H),4.24(d,J＝13.5Hz,2H),2.99(s,2H),2.13(d,J＝9.3Hz,2H),1.95(qd,J＝12.4,4.4Hz,2H),1.50(s,9H),1.45(s,9H).HRMS(ESI):m/z[M+H]+calcd for C30H39N7O5:578.3085；found:578.3127.
实施例114：叔丁基-4-(4-(6-氨基-5-(4-乙酰氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物114)的合成
合成方法参照实施例1。mp:213-214℃；1H NMR(400MHz,Methanol-d4)δ8.35(s,1H),8.27(s,1H),8.10(s,1H),7.90(s,1H),7.64(d,J＝8.6Hz,2H),7.57(d,J＝8.7Hz,2H),4.51–4.37(m,1H),4.25(d,J＝13.6Hz,2H),3.00(s,2H),2.15(s,5H),2.03–1.93(m,2H),1.51(s,9H).HRMS(ESI):m/z[M+H]+calcd for C27H33N7O4:520.2667；found:520.2703.
实施例115：叔丁基-4-(4-(6-氨基-5-(3-乙酰氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物115)的合成
合成方法参照实施例1。mp:147-148℃；1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),8.27(d,J＝2.2Hz,1H),8.09(s,1H),8.04(s,1H),7.88(s,1H),7.40(d,J＝6.2Hz,1H),7.30(d,J＝7.5Hz,2H),4.43–4.32(m,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.14(s,3H),2.10(s,2H),1.95(qd,J＝12.1,4.2Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C27H33N7O4:520.2667；found:520.2699.
实施例116：叔丁基-4-(4-(6-氨基-5-(2-乙酰氨基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物116)的合成
合成方法参照实施例1。mp:140-141℃；1H NMR(400MHz,Methanol-d4)δ8.36(d,J＝2.2Hz,1H),8.25(d,J＝2.2Hz,1H),8.08(s,1H),7.88(s,1H),7.68(d,J＝8.3Hz,1H),7.46(d,J＝7.3Hz,1H),7.28(pd,J＝7.4,1.8Hz,2H),4.40(tt,J＝11.6,4.2Hz,1H),4.24(d,J＝13.5Hz,2H),2.99(s,2H),2.18(s,3H),2.13(d,J＝9.7Hz,2H),1.96(qd,J＝12.3,4.6Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C27H33N7O4:520.2667；found:520.2703.
实施例117：叔丁基-4-(4-(6-氨基-5-(3-羟基苯基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物117)的合成
合成方法参照实施例1。mp:139-140℃；1H NMR(400MHz,Methanol-d4)δ8.32(d,J＝2.3Hz,1H),8.26(d,J＝1.6Hz,1H),8.09(s,1H),7.88(s,1H),7.29(t,J＝2.2Hz,1H),7.17(t,J＝8.1Hz,1H),7.08(ddd,J＝8.0,1.9,1.0Hz,1H),6.61(ddd,J＝8.1,2.4,1.0Hz,1H),4.40(td,J＝11.4,5.5Hz,1H),4.24(d,J＝13.5Hz,2H),2.98(s,2H),2.12(d,J＝10.2Hz,2H),1.95(qd,J＝12.3,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd forC25H30N6O4:479.2401；found:479.2428.
实施例118：叔丁基-4-(4-(6-氨基-5-(环己基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物118)的合成
合成方法参照实施例1。mp:215-216℃；1H NMR(400MHz,Methanol-d4)δ8.28(s,1H),8.09(d,J＝2.3Hz,1H),8.06(d,J＝3.7Hz,1H),7.85(s,1H),4.40(td,J＝11.4,5.5Hz,1H),4.24(d,J＝12.7Hz,2H),3.90–3.80(m,1H),2.99(s,2H),2.12(d,J＝12.3Hz,2H),2.03–1.88(m,4H),1.84(d,J＝10.9Hz,2H),1.71(d,J＝12.4Hz,1H),1.50(s,9H),1.39(m,4H).HRMS(ESI):m/z[M+H]+calcd for C25H36N6O3:469.2922；found:469.2948.
实施例119：叔丁基-4-(4-(6-氨基-5-(苄基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物119)的合成
合成方法参照实施例1。mp:105-106℃；1H NMR(400MHz,Methanol-d4)δ8.30(d,J＝2.3Hz,1H),8.15(d,J＝2.3Hz,1H),8.03(d,J＝1.8Hz,1H),7.82(s,1H),7.41–7.31(m,4H),7.27(t,J＝6.9Hz,1H),4.58(s,2H),4.38(t,J＝11.6Hz,1H),4.23(d,J＝13.4Hz,2H),2.98(s,2H),2.10(d,J＝12.2Hz,2H),1.93(qd,J＝12.1,4.1Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C26H32N6O3:477.2609；found:477.2631.
实施例120：叔丁基-4-(4-(6-氨基-5-(糠胺基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物120)的合成
合成方法参照实施例1。mp:127-128℃；1H NMR(400MHz,Methanol-d4)δ8.29(d,J＝2.3Hz,1H),8.14(d,J＝2.3Hz,1H),8.04(s,1H),7.83(s,1H),7.46(dd,J＝1.9,0.9Hz,1H),6.38(dd,J＝3.2,1.8Hz,1H),6.33(dd,J＝3.2,0.9Hz,1H),4.56(s,2H),4.38(tt,J＝11.6,4.1Hz,1H),4.23(d,J＝13.4Hz,2H),2.98(s,2H),2.11(d,J＝9.8Hz,2H),1.94(qd,J＝12.4,4.4Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C24H30N6O4:467.2401；found:467.2421.
实施例121：叔丁基-4-(4-(6-氨基-5-(苯乙基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物121)的合成
合成方法参照实施例1。mp:109-110℃；1H NMR(400MHz,Methanol-d4)δ8.28(d,J＝2.2Hz,1H),8.01(d,J＝2.5Hz,1H),7.97(d,J＝2.3Hz,1H),7.79(s,1H),7.36–7.26(m,4H),7.26–7.19(m,1H),4.39(td,J＝11.3,5.4Hz,1H),4.24(d,J＝13.5Hz,2H),3.64–3.56(m,2H),2.95(q,J＝10.1,7.1Hz,4H),2.12(d,J＝12.6Hz,2H),2.01–1.87(m,2H),1.51(s,9H).HRMS(ESI):m/z[M+H]+calcd for C27H34N6O3:491.2765；found:491.2788.
实施例122：叔丁基-4-(4-(6-氨基-5-(3-甲氧基苄基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物122)的合成
合成方法参照实施例1。mp:153-154℃；1H NMR(400MHz,Methanol-d4)δ8.30(d,J＝2.3Hz,1H),8.14(d,J＝2.3Hz,1H),8.03(s,1H),7.83(s,1H),7.26(t,J＝7.9Hz,1H),7.06–6.92(m,3H),6.87–6.80(m,1H),4.55(s,2H),4.38(tt,J＝11.6,4.1Hz,1H),4.23(d,J＝13.5Hz,2H),3.80(s,3H),2.98(s,2H),2.14–2.07(m,2H),2.01–1.86(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C27H34N6O4:507.2714；found:507.2736.
实施例123：叔丁基-4-(4-(6-氨基-5-(4-氯苄基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物123)的合成
合成方法参照实施例1。mp:105-106℃；1H NMR(400MHz,Methanol-d4)δ8.31(d,J＝2.3Hz,1H),8.15(d,J＝2.2Hz,1H),8.04(s,1H),7.83(s,1H),7.47(s,2H),7.36(d,J＝2.4Hz,2H),4.56(s,2H),4.39(tt,J＝11.9,4.1Hz,1H),4.24(d,J＝13.6Hz,2H),2.98(s,2H),2.11(d,J＝12.5Hz,2H),1.94(qd,J＝12.4,4.5Hz,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdfor C26H31ClN6O3:511.2219；found:511.2239.
实施例124：叔丁基-4-(4-(6-氨基-5-(2-氯苄基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐)(化合物124)的合成
合成方法参照实施例1。mp:152-153℃；1H NMR(400MHz,Methanol-d4)δ8.32(d,J＝2.3Hz,1H),8.19(d,J＝2.3Hz,1H),8.05(s,1H),7.83(s,1H),7.55(dt,J＝7.4,2.2Hz,1H),7.44(m,0H),4.67(s,2H),4.39(tt,J＝11.9,4.1Hz,1H),4.23(d,J＝13.7Hz,2H),2.98(s,2H),2.15–2.07(m,2H),2.02–1.87(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcdforC26H31ClN6O3:511.2219；found:511.2241.
实施例125：叔丁基-4-(4-(6-氨基-5-(4-氯苯乙基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物125)的合成
合成方法参照实施例1。mp:145-146℃；1H NMR(400MHz,Methanol-d4)δ8.28(s,1H),8.00(s,1H),7.96(d,J＝2.3Hz,1H),7.80(s,1H),7.37(d,J＝6.4Hz,2H),7.29(d,J＝8.5Hz,2H),4.39(td,J＝11.6,5.4Hz,1H),4.28–4.21(m,2H),3.63–3.55(m,2H),3.19(dd,J＝8.7,6.8Hz,2H),2.12(d,J＝12.7Hz,1H),2.02–1.89(m,2H),1.50(s,9H).HRMS(ESI):m/z[M+H]+calcd for C27H33ClN6O3:525.2375；found:525.2398.
实施例126：叔丁基-4-(4-(6-氨基-5-(3-氯苯乙基氨基甲酰基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(化合物126)的合成
合成方法参照实施例1。mp:130-131℃；1H NMR(400MHz,Methanol-d4)δ8.29(s,1H),8.01(d,J＝2.6Hz,1H),7.98(d,J＝2.6Hz,1H),7.81(s,1H),7.40–7.19(m,5H),4.41(tt,J＝11.6,3.6Hz,1H),4.25(d,J＝13.6Hz,2H),3.60(td,J＝7.4,2.6Hz,2H),3.21(td,J＝8.4,7.8,2.6Hz,2H),2.13(d,J＝12.6Hz,2H),1.96(ddt,J＝16.1,12.6,6.6Hz,2H),1.51(d,J＝2.7Hz,9H).HRMS(ESI):m/z[M+H]+calcd for C27H33ClN6O3:525.2375；found:525.2401.
实施例127：N-(4-乙酰氨基苯基)-2-氨基-5-(1-甲基-1H-吡唑-4-基)烟酰胺(化合物127)的合成
合成方法参照实施例1。white oli.1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.3Hz,1H),8.26(d,J＝2.3Hz,1H),7.93(s,1H),7.63(d,J＝9.0Hz,2H),7.58(d,J＝6.1Hz,2H),6.86(s,1H),3.33(s,3H),2.15(s,3H).
实施例128：叔丁基-5-((4-乙酰氨基苯基)氨基甲酰基)-6-氨基-5',6'-二氢-[3,4'-联吡啶]-1'(2'H)-羧酸酯(化合物128)的合成
合成方法参照实施例1。mp:185-186℃；1H NMR(400MHz,Methanol-d4)δ8.18(d,J＝2.3Hz,1H),8.12(d,J＝2.4Hz,1H),7.62(d,J＝9.0Hz,2H),7.55(d,J＝9.0Hz,2H),6.11(s,1H),4.08(s,2H),3.67(m,2H),2.57–2.52(m,2H),2.14(s,3H),1.51(s,9H).HRMS(ESI):m/z[M+H]+calcd for C19H21N5O2:352.17680；found:352.17618.
实施例129：N-(4-乙酰氨基苯基)-6-氨基-1'-甲基-1',2',3',6'-四氢-[3,4'-联吡啶]-5-甲酰胺(化合物129)的合成
合成方法参照实施例1。mp:145-146℃；1H NMR(400MHz,Methanol-d4)δ8.19(s,1H),8.12(d,J＝2.4Hz,1H),7.61(d,J＝9.1Hz,2H),7.55(d,J＝9.0Hz,2H),6.13(t,J＝3.6Hz,1H),3.36–3.27(m,2H),2.95–2.85(m,2H),2.68(d,J＝2.3Hz,2H),2.54(s,3H),2.14(s,3H).HRMS(ESI):m/z[M+H]+calcd for C20H23N5O2:366.19254；found:366.19153.
实施例130：N-(4-乙酰氨基苯基)-6-氨基-[3,4'-联吡啶]-5-甲酰胺(化合物130)的合成
合成方法参照实施例1。mp:260-261℃；1H NMR(400MHz,Methanol-d4)δ8.32(d,J＝2.3Hz,1H),8.23(d,J＝2.3Hz,1H),7.95(d,J＝0.8Hz,1H),7.85(d,J＝0.9Hz,1H),7.63(d,J＝9.0Hz,2H),7.56(d,J＝9.0Hz,2H),2.14(s,3H).
实施例131：N-(4-乙酰氨基苯基)-2-氨基-5-(嘧啶-5-基)烟酰胺(化合物131)的合成
合成方法参照实施例1。mp:222-223℃；1H NMR(400MHz,Methanol-d4)δ8.60–8.57(m,2H),8.50(d,J＝2.4Hz,1H),7.81(d,J＝1.7Hz,1H),7.80(d,J＝1.7Hz,1H),7.66(d,J＝9.1Hz,2H),7.58(d,J＝9.0Hz,2H),2.15(s,3H).
实施例132：N-(4-乙酰氨基苯基)-2-氨基-5-苯基烟酰胺(化合物132)的合成
合成方法参照实施例1。mp:270-271℃；1H NMR(400MHz,Methanol-d4)δ8.39(d,J＝2.4Hz,1H),8.34(d,J＝2.3Hz,1H),7.69–7.63(m,4H),7.57(d,J＝9.0Hz,2H),7.49–7.44(m,2H),7.35(t,J＝7.4Hz,1H),2.15(s,3H).HRMS(ESI):m/z[M+H]+calcdfor C20H18N4O2:347.15025；found:347.14951.
实施例133：N-(4-乙酰氨基苯基)-2-氨基-5-(4-氨基苯基)烟酰胺(化合物133)的合成
合成方法参照实施例1。mp:260-261℃；1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.94(s,1H),8.35(d,J＝2.3Hz,1H),8.17(d,J＝2.4Hz,1H),7.61(d,J＝9.1Hz,2H),7.56(d,J＝9.1Hz,2H),7.39(d,J＝8.5Hz,2H),6.91(s,2H),6.65(d,J＝8.5Hz,2H),5.17(s,2H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C20H19N5O2:360.160518；found:360.160520.
实施例134：N-(4-乙酰氨基苯基)-2-氨基-5-(4-氨基苯基)烟酰胺(化合物134)的合成
合成方法参照实施例1。mp:268-269℃；1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.95(s,1H),8.37(d,J＝2.3Hz,1H),8.23(d,J＝2.4Hz,1H),7.61(d,J＝9.1Hz,2H),7.56(d,J＝9.1Hz,2H),7.10(t,J＝7.9Hz,1H),7.05(s,2H),6.85(dd,J＝7.2,1.4Hz,2H),6.54(dt,J＝7.0,1.5Hz,1H),5.14(s,2H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd forC20H19N5O2:360.160709；found:360.160710.
实施例135：N-(4-乙酰氨基苯基)-2-氨基-5-(4-(二甲基氨基)苯基)烟酰胺(化合物135)的合成
合成方法参照实施例1。mp:227-228℃；1H NMR(400MHz,Methanol-d4)δ8.31(d,J＝2.3Hz,1H),8.24(d,J＝2.3Hz,1H),7.63(d,J＝9.0Hz,2H),7.56(d,J＝9.0Hz,2H),7.50(d,J＝8.9Hz,2H),6.85(d,J＝8.9Hz,2H),2.14(s,3H).HRMS(ESI):m/z[M+H]+calcd forC22H23N5O2:390.19245；found:390.19174.
实施例136：N-(4-乙酰氨基苯基)-2-氨基-5-(4-((二甲基氨基)甲基)苯基)烟酰胺(化合物136)的合成
合成方法参照实施例1。mp:205-206℃；1H NMR(400MHz,Methanol-d4)δ8.38(d,J＝2.4Hz,1H),8.30(d,J＝2.3Hz,1H),7.67(d,J＝8.3Hz,2H),7.62(d,J＝9.0Hz,2H),7.55(d,J＝9.0Hz,2H),7.46(d,J＝8.2Hz,2H),2.13(s,2H),2.13(s,3H).HRMS(ESI):m/z[M+H]+calcd for C23H25N5O2:404.20810；found:404.20715.
实施例137：叔丁基-4-(4-(5-((4-乙酰氨基苯基)氨基甲酰基)-6-氨基吡啶-3-基)苯基)哌嗪-1-羧酸酯(化合物137)的合成
合成方法参照实施例1。mp:225-226℃；1H NMR(400MHz,Methanol-d4)δ8.34(d,J＝2.3Hz,1H),8.28(d,J＝2.3Hz,1H),7.64(d,J＝9.1Hz,2H),7.58(d,J＝8.3Hz,2H),7.56(d,J＝8.3Hz,2H),7.09(d,J＝8.9Hz,2H),3.61(s,4H),3.23–3.16(m,4H),2.15(s,3H),1.51(s,9H).HRMS(ESI):m/z[M+H]+calcd for C29H34N6O4:531.27143；found:531.27014.
实施例138：N-(4-乙酰氨基苯基)-2-氨基-5-(4-(4-甲基哌嗪-1-基)苯基)烟酰胺(化合物138)的合成
合成方法参照实施例1。mp:165-166℃；1H NMR(400MHz,Methanol-d4)δ8.31(d,J＝2.4Hz,1H),8.23(d,J＝2.4Hz,1H),7.63(d,J＝9.0Hz,2H),7.59–7.50(m,4H),7.04(d,J＝8.8Hz,2H),3.27(t,J＝5.1Hz,4H),2.78(t,J＝5.1Hz,4H),2.47(s,3H),2.13(s,3H).HRMS(ESI):m/z[M+H]+calcd for C25H28N6O2:445.23465；found:445.23404.
实施例139：N-(4-乙酰氨基苯基)-2-氨基-5-(4-(4-乙基哌嗪-1-基)苯基)烟酰胺(化合物139)的合成
合成方法参照实施例1。mp:162-163℃；1H NMR(400MHz,Methanol-d4)δ8.33(d,J＝2.4Hz,1H),8.25(d,J＝2.4Hz,1H),7.63(d,J＝9.0Hz,2H),7.56(dt,J＝8.5,1.9Hz,4H),7.07(d,J＝8.8Hz,2H),3.38–3.28(m,7H),2.94(t,J＝5.1Hz,4H),2.79(q,J＝7.3Hz,2H),2.14(s,3H).HRMS(ESI):m/z[M+H]+calcd for C26H30N6O2:459.25030；found:459.24957.
实施例140：叔丁基-4-(4-(5-((4-乙酰氨基苯基)氨基甲酰基)-6-氨基吡啶-3-基)苄基)哌嗪-1-羧酸盐(化合物140)的合成
合成方法参照实施例1。mp:227-228℃；1H NMR(400MHz,Methanol-d4)δ8.39(d,J＝2.3Hz,1H),8.31(d,J＝2.4Hz,1H),7.68–7.60(m,2H),7.56(m,4H),7.44(m,2H),3.45(s,4H),2.47(q,J＝5.1Hz,4H),2.14(s,3H),1.47(s,9H).HRMS(ESI):m/z[M+H]+calcdforC30H36N6O4:545.28708；found:545.28528.
实施例141：N-(4-乙酰氨基苯基)-2-氨基-5-(1H-吲唑-5-基)烟酰胺(化合物141)的合成
合成方法参照实施例1。mp:238-239℃；1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),10.28(s,1H),9.95(s,1H),8.51(d,J＝2.4Hz,1H),8.36(d,J＝2.4Hz,1H),8.12(s,1H),8.10–8.06(m,1H),7.74(dd,J＝8.7,1.7Hz,1H),7.65–7.55(m,5H),7.07(s,2H),2.05(s,3H).HRMS(ESI):m/z[M+H]+calcd for C21H18N6O2:387.156099；found:387.156100.
实施例142：N-(4-乙酰氨基苯基)-2-氨基-5-(2-吲哚基-5-yl)烟酰胺(化合物142)的合成
合成方法参照实施例1。mp:270-271℃；1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.24(s,1H),9.95(s,1H),8.41(d,J＝2.4Hz,1H),8.25(d,J＝2.4Hz,1H),7.59(q,J＝9.1Hz,5H),7.53(d,J＝8.2Hz,1H),7.04(s,2H),6.89(d,J＝8.1Hz,1H),3.55(s,2H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H19N5O3:402.155759；found:402.155760.
实施例143：N,5-双(4-乙酰氨基苯基)-2-氨基烟酰胺(化合物143)的合成
合成方法参照实施例1。mp:178-179℃；1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),10.01(s,1H),9.94(s,1H),8.46(d,J＝2.3Hz,1H),8.29(d,J＝2.4Hz,1H),7.67(s,4H),7.62(d,J＝9.1Hz,2H),7.57(d,J＝9.2Hz,2H),7.07(s,2H),2.07(s,3H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H21N5O3:402.171048；found:402.171050.
实施例144：5-(3-乙酰氨基苯基)-N-(4-乙酰氨基苯基)-2-氨基烟酰胺(化合物144)的合成
合成方法参照实施例1。mp:263-264℃；1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),10.03(s,1H),9.94(s,1H),8.40(d,J＝2.3Hz,1H),8.26(d,J＝2.4Hz,1H),7.81(s,1H),7.59(q,J＝9.1Hz,5H),7.39(d,J＝5.5Hz,2H),7.12(s,2H),2.07(s,3H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H21N5O3:404.171449；found:404.171450.
实施例145：N-(4-乙酰氨基苯基)-2-氨基-5-(4-氨基甲酰基苯基)烟酰胺(化合物145)的合成
合成方法参照实施例1。mp:220-221℃；1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.96(s,1H),8.57(d,J＝2.4Hz,1H),8.40(d,J＝2.4Hz,1H),8.03(s,1H),7.97(d,J＝8.5Hz,2H),7.84(d,J＝8.5Hz,2H),7.62(d,J＝9.1Hz,2H),7.57(d,J＝9.1Hz,2H),7.39(s,1H),7.22(s,2H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C21H19N5O3:390.155609；found:390.155610.
实施例146：N-(4-乙酰氨基苯基)-2-氨基-5-(3-氨基甲酰基苯基)烟酰胺(化合物146)的合成
合成方法参照实施例1。mp:264-265℃；1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.98(s,1H),8.57(d,J＝2.3Hz,1H),8.52(d,J＝2.4Hz,1H),8.26(t,J＝1.9Hz,1H),8.13(s,1H),7.91(d,J＝8.0Hz,1H),7.85(d,J＝7.8Hz,1H),7.64(d,J＝9.1Hz,2H),7.61–7.53(m,4H),7.49(s,1H),7.41(s,1H),2.05(s,3H).HRMS(ESI):m/z[M+H]+calcd forC21H19N5O3:390.155759；found:390.155760.
实施例147：N-(4-乙酰氨基苯基)-5-(4-乙酰苯基)-2-氨基烟酰胺(化合物147)的合成
合成方法参照实施例1。mp:258-259℃；1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.96(s,1H),8.60(d,J＝2.4Hz,1H),8.42(d,J＝2.4Hz,1H),8.04(d,J＝8.5Hz,2H),7.91(d,J＝8.5Hz,2H),7.62(d,J＝9.1Hz,2H),7.58(d,J＝9.2Hz,2H),7.28(s,2H),2.61(s,3H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H20N4O3:389.160429；found:389.160430.
实施例148：N-(4-乙酰氨基苯基)-5-(3-乙酰苯基)-2-氨基烟酰胺(化合物148)的合成
合成方法参照实施例1。mp:269-270℃；1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.96(s,1H),8.56(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),8.26(t,J＝1.8Hz,1H),8.03–7.98(m,1H),7.91(dt,J＝7.9,1.4Hz,1H),7.65–7.54(m,5H),7.19(s,2H),2.67(s,3H),2.04(s,3H).HRMS(ESI):m/z[M+H]+calcd for C22H20N4O3:389.160249；found:389.160250.
实施例149
体外CDK8酶抑制作用评价：
化合物对CDK 8激酶活性的抑制能力用ADP-GloTM法进行测定。将待测化合物用去离子水配制成浓度为1μM的工作液备用。配制反应体系，使体系中各组分浓度分别为：CDK 8酶5ng，底物0.5μg，反应缓冲液1μL，DTT(50μM)1μL。保证每孔体积为3μL，若不足3μL，加去离子水补至3μL。在384孔板上分别设置空白孔、对照孔和实验孔，空白孔和对照孔加入1μL去离子水，实验孔每孔加入1μL待测化合物工作液(此时化合物的终浓度为200nM)。加入化合物后室温孵育20min，随后每孔加入1μL的ATP溶液，保证ATP的终浓度为50μM。室温孵育1h后，每孔加入5μLADP-GloTM试剂，继续室温孵育40min，再往每孔中加入10μL萤光素酶检测试剂，避光孵育10-30min即可上机检测。根据荧光强度值计算抑制率。
实施例150
体外细胞内CDK8提高IL-10水平作用评价：
将诱导分化成熟的BMDCs细胞用EDTA消化后计数，接种于96孔板中，每孔1×104/100μL。实验需设置空白组(只含细胞，不做任何处理)，模型组(细胞+R848)以及实验组(细胞+R848+化合物)。24h后，弃掉上清，加入100μL待测化合物的工作液，此时化合物的浓度为500nM。2h后每孔加入10μLTLR7/8激活剂R848，使其终浓度为2μg/mL。放置于37℃，含5％CO2的培养箱中继续培养。24h后，取细胞培养液，12000转离心5min后取上清。细胞上清中IL-10的含量用ELISA试剂盒检测。
以上检测结果用SPSS17.0计算IC50值，结果如下表：
a化合物在200nM浓度下对CDK 8酶活性的抑制率(％)。b由浓度为5μM的化合物引起的活化BMDCs中的IL-10增强率(％)，表示为与R848孔相比测试化合物孔中增加的百分比。c未测出.dNT＝未测试。
实施例151
体内急性毒性评价：
选择20只ICR小鼠(约20g，年龄6～8周，从安徽医科大学动物系购买)进行化合物68的体内急性毒性试验。将它们随机平均分为两组并适应性饲养一周。禁食12h后，一次分别口服1500mg/kg(0.5％CMC-Na作为溶剂)化合物68。每天观察并记录小鼠的体重，死亡率和行为，持续一周。随后，将小鼠麻醉并将组织用于HE染色。急性毒性测试结果为LD50>1500mg/kg，组织器官未见病理改变。
实施例152
体内抗炎活性评估：
DSS诱导的小鼠IBD模型与人溃疡性肠炎在症状表现和组织学表现上极度相似，本发明选用该模型对化合物68的体内抗炎活性进行评价。40只雄性Balb/c小鼠购自安徽医科大学动物实验中心，体重约20g。适应性饲养一周，自由饮水进食。一周后将小鼠随机分为4组，分别为正常组(N＝10)，模型组(3.5％DSS,N＝10)，化合物高剂量组(10mg/kg,N＝10)，化合物低剂量组(2mg/kg,N＝10)。实验开始时，除正常组，将其余三组饮用水更换为3.5％DSS水溶液。化合物高低剂量组按剂量灌胃给药，连续一周。一周内每日对小鼠称重，观察小鼠的活动度、毛色变化及粪便特征并记录评分。一周后，对小鼠进行摘眼球取血，脱颈处死。取小鼠的心、肝、脾、肺、肾组织，固定于甲醛中以备HE染色。取小鼠结肠，将结肠中粪便冲洗干净，拍照比较各组小鼠结肠长度。小鼠结肠部分固定于甲醛中，以备HE染色；部分加生理盐水进行匀浆备用，测炎症因子含量。小鼠血浆和结肠组织中炎症因子的含量利用ELISA试剂盒进行检测。小鼠眼球取血后，血样3000转离心15min，取上层血清，-20℃备保存用。小鼠结肠组织用生理盐水清洗干净后，按100mg/200μL的比例加入生理盐水，置于组织匀浆机中匀浆，至无明显组织块时，停止匀浆。12000转离心30min，取上清液，-20℃保存备用。血清和组织样品中炎症因子含量用ELISA试剂盒检测。小鼠结肠组织清洗干净后，称重按1mg/μL的比例加入含有PMSF和磷酸酶抑制剂的RIPA裂解液，冰上放置5min。随后，用眼科剪将组织剪碎。该步骤全程置于冰上操作。剪碎后置于匀浆机中，匀浆完成后，12000转离心30min，取上清液，按比例加入蛋白上样缓冲液，混匀后置于100℃加热10min。蛋白样品置于-20℃保存备用。
除对照组的动物外，疾病活动性指数(DAI)评分在6天内均有所增加。DSS组得分最高，化合物组的分数从7天减少浓度依赖的方式，这表明口服化合物68显著降低结肠炎的发展评估DAI评分。测定结肠组织中MPO的活性，作为中性粒细胞浸润的指标。3.5％DSS组MPO活性显著增加，化合物68处理后MPO活性增加，呈剂量依赖性。结果如图1显示，与对照组动物结肠长度减少有显著差异，但复合处理组动物结肠长度明显增加。
为了评价化合物68在DSS诱导的结肠炎中的抗炎作用，本发明测定了血清和结肠组织中一些典型的炎症细胞因子的水平。结果显示，与对照组相比，DSS处理组血清中IL-6和TNF-α水平显著升高。用化合物68治疗可显著降低这些炎症细胞因子的水平。促炎细胞因子分泌的增强似乎是肠道炎症发生和持续的一个重要因素。IL-10作为一种抗炎细胞因子，参与维持肠道正常的非炎症状态。IL-10的免疫调节活性是基于其抑制细胞因子合成和抗原呈递的能力。IL-10抑制TNF-α和IL-6的合成。如图2所示，DSS组血清中IL-10水平显著升高，化合物进一步提高了IL-10水平，且呈剂量依赖性。在结肠组织中也可以观察到类似的结果。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种汉黄芩素衍生物，其特征在于，所述汉黄芩素衍生物如以下式I、式II、式III、式IV所示：
其中，R1选自噻吩基、呋喃基、异噁唑基、甲基吡唑基、吡啶基、嘧啶基、苯基、取代苯基；R2选自苯基和取代苯基；R3选自苯基、取代苯基、苄基、苯乙基、环己基或呋喃-2-基甲基；R4选自苯基、取代苯基、苄基、取代苄基、苯乙基、取代苯乙基、环己基或呋喃-2-基甲基；R5选自苯基、取代苯基、哌啶基、N-甲基哌啶基、吡啶基、嘧啶基、N-甲基吡唑基、吲哚基、苯并吡唑基或(哌啶-4-基)-1H-吡唑-4-基中的任一种基团。
2.如权利要求1所述的汉黄芩素衍生物，其特征在于，所述汉黄芩素衍生物包括以下所示结构的化合物1-148：
以式I为通式的化合物1-33
以式I为通式的化合物34-55
以式III为通式的化合物56-87
以式IV为通式的化合物88-148
3.如权利要求1所述的汉黄芩素衍生物的制备方法，其特征在于，包括以下步骤：
(1)将5-羟基-4-氧代-2-苯基-4H-色烯-7-基三氟甲磺酸盐和不同的硼酸化合物经Suzuki交叉偶联反应，得到式I所示的化合物；
(2)将3-溴-5-羟基苯甲酸和(4-(哌嗪-1-羰基)苯基)硼酸经Suzuki交叉偶联反应，得到中间体I；
(3)中间体I和不同的伯胺经酰胺缩合反应，得到式II所示的化合物；
(4)将5-溴烟酸和(4-(哌嗪-1-羰基)苯基)硼酸经Suzuki交叉偶联反应，得到中间体II；
(5)中间体II和不同的伯胺经酰胺缩合反应，得到式III所示的化合物；
(6)将2-氨基-5-溴烟酸和硼酸经Suzuki交叉偶联反应，得到中间体III；
(7)中间体III和不同的伯胺经酰胺缩合反应，得到式IV所示的化合物；
反应方程式如下：
4.一种药物组合物，包含权利要求1所述的汉黄芩素衍生物或其药学上可接受的盐。
5.一种药物制剂，包含活性成分和药学上可以接受的赋形剂和/或载体，所述活性成分为权利要求1所述的汉黄芩素衍生物。
6.如权利要求1所述的汉黄芩素衍生物在制备CDK8抑制剂中的应用。
7.如权利要求1所述的汉黄芩素衍生物在制备治疗炎症性疾病药物中的应用。
8.如权利要求7所述的应用，其特征在于：所述炎症性疾病包括关节炎、类风湿性关节炎、炎症性肠炎、败血症、胰腺炎、呼吸系统的炎症性疾病、慢性阻塞性肺疾病、非囊性纤维化支气管扩张、急性肺损伤、病毒或细菌感染引起的肺炎或支气管肺炎、肾小球肾炎。
9.如权利要求1所述的汉黄芩素衍生物在制备抗肿瘤药物中的应用。
10.如权利要求9所述的应用，其特征在于：所述肿瘤包括乳腺癌、急性髓系白血病、结肠癌和直肠癌。
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