CN117986184A - N-取代吡啶酮类化合物及其制法和药物用途 - Google Patents
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，公开了式(I)所示的N‑取代吡啶酮类化合物或其生理上可接受的盐，所述化合物的制备方法，含有所述化合物的药物制剂，以及所述化合物在制备治疗与CDK8相关疾病药物中的临床应用。
Description
技术领域
本发明属于药物化学领域，涉及通式(I)的N-取代吡啶酮类化合物或其生理上可接受的盐。这些化合物在制备细胞周期蛋白依赖性激酶8(cyclin-dependent kinase 8,CDK8)抑制剂中的用途，在制备预防或治疗CDK8相关疾病的药物中的应用，还涉及其用于治疗的方法，以及含有所述化合物的药物组合物。
背景技术
CDK8作为细胞周期蛋白依赖性激酶(CDK)家族中的一员，可双向调节基因转录，同时还能通过形成激酶复合物来调节基因转录，参与与恶性肿瘤等疾病相关的多种信号通路。CDK8不仅在多种癌症细胞(例如结直肠癌、乳腺癌、胃癌、卵巢癌以及黑色素瘤等等)中存在高表达，而且参与了p53、wnt-β-catenin、TGF-β、NOTCH以及STAT1等与肿瘤相关的信号通路。因此，近年来CDK8因其有潜力成为抗肿瘤药物的治疗靶标而受到广泛关注。
CDK8与伴侣蛋白结合后，其结构中的αC螺旋、特征性的DMG片段的构象发生改变，因此，CDK8可呈现DMG-in和DMG-out两种不同构象状态。根据CDK8抑制剂的结合方式，可分为Type I型(与DMG-in构象结合)与Type II型(与DMG-out构象结合)抑制剂。CDK8小分子抑制剂与DMG-out状态下蛋白的复合物结构解析为基于蛋白结构合理设计CDK8 Type II抑制剂的研究奠定稳固的基础。
与其他激酶抑制剂一样，CDK8抑制剂的研究同样需要注重高活性与高选择性的平衡，实现CDK8抑制剂的选择性一直是开发此类抗肿瘤药物的重要难点。寻找CDK8抑制剂与CDK8酶结合作用的关键氨基酸和特有氨基酸，利用关键氨基酸保持高活性，利用特有氨基酸保持高选择性，是同步实现高活性和高选择性的合理途径。
目前，文献已报道的CDK8 Type II型小分子抑制剂多数由三个部分组成：疏水片段，与酶活性腔的疏水口袋结合，以多取代苯环居多；脲基或酰胺，与关键氨基酸Glu66与Asp173作用；氢键受体，与铰链区的Ala100产生关键作用。有研究表明，在CDK8 Type II型小分子抑制剂结构中引入与Arg365形成阳离子-π作用的芳香性片段，有可能提高CDK8的选择性。本申请拟引入与Arg365作用的第四个药效团特征，提供新结构类型的选择性CDK8小分子抑制剂，为新型抗肿瘤候选药物的研究提供化学模板。
发明内容
本发明的目的在于提供一种通式(I)所示新的N-取代吡啶酮类化合物。
本发明的另一目的在于提供一种制备通式(I)所示新的N-取代吡啶酮类化合物的方法。
本发明的又一目的在于提供通式(I)所示新的N-取代吡啶酮类化合物在抑制CDK8中的用途，以及治疗与CDK8有关的疾病中的用途。
为了完成本发明的目的，本发明采用的技术方案在于提供通式(I)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基；
R3选自卤素﹑C1-C3烷基﹑三氟甲基、C1-C3烷氧甲酰基。
本发明的又一技术方案在于提供通式(IA)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基。
本发明的又一技术方案在于提供通式(IAa)所示的化合物或其生理上可接受的盐：
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基。
本发明的又一技术方案在于提供通式(IAb)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R4选自卤素﹑C1-C4烷基﹑C1-C4烷氧基、三氟甲基。
本发明的又一技术方案在于提供通式(IAc)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R4选自卤素﹑C1-C4烷基﹑C1-C4烷氧基、三氟甲基；
R5选自氢﹑C1-C3烷基。
本发明的又一技术方案在于提供所示的化合物或其生理上可接受的盐，其特征在于，所述的化合物选自：
本发明的又一技术方案在于提供通式(I)所示的化合物制备方法，其特征在于，包括以下步骤：
式II化合物与式III化合物经亲核取代反应生成式IV化合物，式IV化合物与对硝基苯硼酸经Suzuki偶联反应生成式V化合物；式V化合物经还原本发明的又一技术方案在于提供通式(I)所示的化合物制备方法，其特征在于，包括以下步骤：反应生成式VI化合物；式VI化合物与式VII化合物反应生成式I目标化合物；
其中，R1、R2和R3的定义同权利要求1～6。
为了制成药剂，可将通式(I)化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合，并被制成片剂或包衣的片剂，或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明还涉及一种含有药物有效剂量的如通式(I)所述的化合物和药学上可接受的载体的药物组合物。
药理学研究表明，本发明的通式(I)化合物具有抑制CDK8的活性，可用于治疗与CDK8活性相关的疾病，如肿瘤、炎症、免疫性疾病等。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂，非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，***胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。
有益技术效果：
实现选择性抑制是目前CDK8抑制剂研究面临的主要挑战之一。本发明化合物具有选择性抑制CDK8的特点和优势，有望提供新的安全有效的CDK8抑制剂用于***、炎症及免疫性疾病等与CDK8相关的疾病。
具体实施方式
以下结合实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或质谱(MS)或高分辨质谱(HRMS)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。m.p.是以℃给出的熔点，温度未加校正。柱层析一般使用200～300目硅胶为载体。NMR测定是用JEOL ECZ-400S和INOVA-500MHz，测定溶剂为DMSO-d6，内标为TMS，化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSDTOF液质联用仪。
实施例1：TM-1的制备:
1)5-溴-1-(4-氟苄基)吡啶-2(1H)-酮
将5-溴吡啶-2(1H)-酮(218mg，1.25mmol)和碳酸钾(345mg,2.5mmol)溶于10mL丙酮中，加入4-氟溴苄(189mg，1.0mmol)，回流反应8h。反应完毕，将固体滤掉，收集滤液，真空旋干，经柱层析得到产物(254mg，产率90％)。
2)1-(4-氟苄基)-5-(4-硝基苯基)吡啶-2(1H)-酮
称取5-溴-1-(4-氟苄基)吡啶-2(1H)-酮(324mg，1.0mmol)，(4-硝基苯基)硼酸(200mg，1.2mmol)，Pd(PPh3)4(23mg，2％mmol)及Na2CO3(222mg，2.1mmol)，溶于5mL DME与水的混合溶液中(DME:H2O＝2:1)，氩气保护，在100℃油浴下搅拌反应12h。反应完毕，将固体滤掉，收集滤液，EA与卤水萃取三遍，收集有机相，无水硫酸钠干燥，后经柱层析得到产物(125mg，产率38％)。
3)5-(4-氨基苯基)-1-(4-氟苄基)吡啶-2(1H)-酮
称取1-(4-氟苄基)-5-(4-硝基苯基)吡啶-2(1H)-酮(324mg，1.0mmol)，还原Fe粉100目(168mg，3mmol)及NH4Cl(160mg，3mmol)，5mL水与乙醇的悬浮液(H2O:EtOH＝1:1)，在85℃油浴下搅拌反应4h。反应完毕，趁热将Fe粉滤掉，收集滤液，真空旋干，经柱层析得到产物(241mg，产率82％)。
4)1-(4-氯-3-(三氟甲基)苯基)-3-(4-(1-(4-氟苄基)-6-氧代-1,6-二氢吡啶-3-基)苯基)脲
将5-(4-氨基苯基)-1-(4-氟苄基)吡啶-2(1H)-酮(147mg，0.5mmol)溶于5mL二氯甲烷中，加入4-氯-3-三氟甲基异氰酸苯酯(111mg，0.5mmol)，室温搅拌反应2h。反应完毕，有大量白色固体产生，将固体抽滤，二氯甲烷洗涤滤饼数次，得到固体产物(227mg，产率88％)。mp:212-214℃；1H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.94(s,1H),8.22(d,J＝2.7Hz,1H),8.11(d,J＝2.5Hz,1H),7.82(dd,J＝9.6,2.7Hz,1H),7.67-7.60(m,2H),7.51(s,4H),7.45(dd,J＝8.5,5.6Hz,2H),7.17(t,J＝8.7Hz,2H),6.51(d,J＝9.5Hz,1H),5.15(s,2H)ppm.HR-ESI-MS:m/z＝516.10964[M+H]+,calcd for C26 H19 O2 N3 Cl F4:516.11218.
实施例2：TM-2的制备
其合成方法及操作与化合物TM-1相同，产率42％。mp:209-211℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.93(s,1H),8.22(d,J＝2.7Hz,1H),8.11(d,J＝2.3Hz,1H),7.83(dd,J＝9.5,2.7Hz,1H),7.67–7.60(m,2H),7.51(s,4H),7.40(d,J＝2.2Hz,4H),6.52(d,J＝9.5Hz,1H),5.16(s,2H).HR-ESI-MS:m/z＝532.08258[M+H]+,calcd for C26H19O2N3Cl2F3:532.08009.
实施例3：TM-3的制备
其合成方法及操作与化合物TM-1相同，产率49％。mp:215-217℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.93(s,1H),8.19(d,J＝2.7Hz,1H),8.11(d,J＝2.4Hz,1H),7.81(dd,J＝9.5,2.7Hz,1H),7.70–7.59(m,2H),7.51(s,4H),7.38–7.34(m,2H),7.32–7.28(m,2H),6.51(d,J＝9.5Hz,1H),5.13(s,2H),1.25(s,9H).HR-ESI-MS:m/z＝554.18433[M+H]+,calcd for C30H28O2N3ClF3:554.18167.
实施例4：TM-4的制备
其合成方法及操作与化合物TM-1相同，产率54％。mp:246-248℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.93(s,1H),8.13(dd,J＝23.1,2.5Hz,2H),7.82(dd,J＝9.6,2.6Hz,1H),7.67–7.60(m,2H),7.51(s,4H),7.23(t,J＝7.5Hz,1H),7.20–7.06(m,3H),6.51(d,J＝9.4Hz,1H),5.13(s,2H),2.28(s,3H).HR-ESI-MS:m/z＝512.13605[M+H]+,calcdfor C27H22O2N3ClF3:512.13472.
实施例5：TM-5的制备
其合成方法及操作与化合物TM-1相同，产率47％。mp:217-219℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.92(s,1H),8.14(dd,J＝25.5,2.5Hz,2H),7.79(dd,J＝9.4,2.7Hz,1H),7.68–7.60(m,2H),7.50(d,J＝2.6Hz,4H),7.38–7.34(m,2H),6.92–6.88(m,2H),6.49(d,J＝9.4Hz,1H),5.09(s,2H),3.72(s,3H).HR-ESI-MS:m/z＝528.13055[M+H]+,calcd for C27H22O3N3ClF3:528.12963.
实施例6：TM-6的制备
其合成方法及操作与化合物TM-1相同，产率41％。mp:213-215℃；1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.89(s,1H),8.18(d,J＝2.7Hz,1H),8.07(d,J＝2.4Hz,1H),7.78(dd,J＝9.5,2.7Hz,1H),7.64–7.55(m,2H),7.47(s,4H),7.43–7.39(m,2H),7.17–7.08(m,3H),6.47(d,J＝9.5Hz,1H),5.12(s,2H).HR-ESI-MS:m/z＝564.11066[M+H]+,calcd forC27H20O3N3ClF5:564.11079.
实施例7：TM-7的制备
其合成方法及操作与化合物TM-1相同，产率51％。mp:213-215℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.94(s,1H),8.23(d,J＝2.7Hz,1H),8.11(d,J＝2.4Hz,1H),7.98–7.91(m,2H),7.86(dd,J＝9.5,2.7Hz,1H),7.67–7.59(m,2H),7.52(s,4H),7.48–7.43(m,2H),6.54(d,J＝9.4Hz,1H),5.25(s,2H),3.84(s,3H).HR-ESI-MS:m/z＝556.12555[M+H]+,calcd for C28H22O4N3ClF3:556.12454.
实施例8：TM-8的制备
其合成方法及操作与化合物TM-1相同，产率43％。mp:228-230℃；1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.90(s,1H),8.22(d,J＝2.7Hz,1H),8.07(d,J＝2.4Hz,1H),7.82(dd,J＝9.5,2.7Hz,1H),7.68(d,J＝8.1Hz,2H),7.63–7.56(m,2H),7.51(d,J＝8.1Hz,2H),7.48(s,4H),6.50(d,J＝9.5Hz,1H),5.22(s,2H).HR-ESI-MS:m/z＝566.10645[M+H]+,calcd for C27H19O2N3ClF6:566.10791.
实施例9：TM-9的制备
其合成方法及操作与化合物TM-1相同，产率55％。mp:226-228℃；1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.89(s,1H),8.18(d,J＝2.7Hz,1H),8.07(d,J＝2.4Hz,1H),7.80(dd,J＝9.4,2.7Hz,1H),7.64–7.54(m,2H),7.48(s,4H),7.36(td,J＝7.9,6.0Hz,1H),7.19–7.13(m,2H),7.09(td,J＝8.2,7.3,2.1Hz,1H),6.49(d,J＝9.4Hz,1H),5.14(s,2H).HR-ESI-MS:m/z＝516.11078[M+H]+,calcd forC26H19O2N3ClF4:516.10964.
实施例10：TM-10的制备
其合成方法及操作与化合物TM-1相同，产率53％。mp:251-253℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.93(s,1H),8.13(dd,J＝23.1,2.5Hz,2H),7.82(dd,J＝9.6,2.6Hz,1H),7.67–7.63(m,1H),7.61(d,J＝8.7Hz,1H),7.51(s,4H),7.23(t,J＝7.5Hz,1H),7.19–7.12(m,2H),7.09(d,J＝7.5Hz,1H),6.51(d,J＝9.4Hz,1H),5.13(s,2H),2.28(s,3H).HR-ESI-MS:m/z＝512.13330[M+H]+,calcd for C27H22O2N3ClF3:512.13472.
实施例11：TM-11的制备
其合成方法及操作与化合物TM-1相同，产率42％。mp:233-235℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.93(s,1H),8.17(d,J＝2.7Hz,1H),8.11(d,J＝2.4Hz,1H),7.82(dd,J＝9.5,2.7Hz,1H),7.61–7.57(m,2H),7.51(d,J＝1.1Hz,4H),7.26(t,J＝7.9Hz,1H),6.94(t,J＝2.1Hz,1H),6.91(d,J＝7.6Hz,1H),6.86(dd,J＝8.3,2.7Hz,1H),6.52(d,J＝9.4Hz,1H),5.14(s,2H),3.73(s,3H).HR-ESI-MS:m/z＝528.12823[M+H]+,calcd forC27H22O3N3ClF3:528.12963.
实施例12：TM-12的制备
其合成方法及操作与化合物TM-1相同，产率44％。mp:238-240℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.93(s,1H),8.13(dd,J＝11.6,2.6Hz,2H),7.86(dd,J＝9.5,2.7Hz,1H),7.67–7.60(m,2H),7.55–7.49(m,4H),7.40–7.32(m,1H),7.26–7.13(m,3H),6.52(d,J＝9.5Hz,1H),5.23(s,2H).HR-ESI-MS:m/z＝516.10803[M+H]+,calcd forC26H19O2N3ClF4:516.10964.
实施例13：TM-13的制备
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其合成方法及操作与化合物TM-1相同，产率52％。mp:250-252℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.93(s,1H),8.12(dd,J＝11.6,2.5Hz,2H),7.82(dd,J＝9.5,2.7Hz,1H),7.65(dd,J＝8.9,2.4Hz,1H),7.61(d,J＝8.8Hz,1H),7.51(s,4H),6.96(s,2H),6.91(s,1H),6.51(d,J＝9.4Hz,1H),5.09(s,2H),2.23(s,6H).HR-ESI-MS:m/z＝526.14935[M+H]+,calcd for C28H24O2N3ClF3:526.15037
实施例14：TM-14的制备
其合成方法及操作与化合物TM-1相同，产率44％。mp:227-229℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.94(s,1H),8.24(d,J＝2.7Hz,1H),8.11(d,J＝2.3Hz,1H),7.85(dd,J＝9.5,2.6Hz,1H),7.67–7.63(m,1H),7.61(d,J＝8.7Hz,1H),7.57(t,J＝8.1Hz,1H),7.52(s,4H),7.44(dd,J＝10.4,1.9Hz,1H),7.25–7.21(m,1H),6.53(d,J＝9.4Hz,1H),5.16(s,2H).HR-ESI-MS:m/z＝550.07080[M+H]+,calcd for C26H18O2N3Cl2F4:550.07067.
实施例15：TM-15的制备
其合成方法及操作与化合物TM-1相同，产率15％。mp:124-126℃；1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.95(s,1H),8.53(d,J＝5.2Hz,2H),8.23(s,1H),8.11(s,1H),7.89(d,J＝9.4Hz,1H),7.62(t,J＝7.0Hz,2H),7.52(s,4H),7.25(d,J＝5.0Hz,2H),6.55(d,J＝9.5Hz,1H),5.21(s,2H).HR-ESI-MS:m/z＝499.11383[M+H]+,calcd for C25H19O2N4ClF3:499.11431.
实施例16：TM-16的制备
其合成方法及操作与化合物TM-1相同，产率45％。mp:235-237℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.93(s,1H),8.18(d,J＝2.7Hz,1H),8.11(d,J＝2.4Hz,1H),7.80(dd,J＝9.5,2.7Hz,1H),7.68–7.59(m,2H),7.55–7.47(m,6H),7.17(dd,J＝4.9,1.4Hz,1H),6.51(d,J＝9.5Hz,1H),5.15(s,2H).HR-ESI-MS:m/z＝504.07553[M+H]+,calcd forC24H18O2N3ClF3S:504.07549.
实施例17：TM-17的制备
其合成方法及操作与化合物TM-1相同，产率46％。mp:237-239℃；1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),9.10(s,1H),8.12(d,J＝2.3Hz,1H),7.87(d,J＝7.2Hz,1H),7.73–7.68(m,2H),7.66–7.62(m,2H),7.61–7.56(m,2H),7.44–7.39(m,2H),7.19(dd,J＝10.1,7.7Hz,2H),6.69(d,J＝2.0Hz,1H),6.63(dd,J＝7.2,2.1Hz,1H),5.11(s,2H).HR-ESI-MS:m/z＝3 516.10950[M+H]+,calcd for C26H19O2N3ClF4:516.10964.
实施例18：TM-18的制备
其合成方法及操作与化合物TM-1相同，产率56％。mp:157-159℃；1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.92(s,1H),8.10(dd,J＝11.5,2.5Hz,2H),7.73(dd,J＝2.7,1.3Hz,1H),7.67–7.59(m,2H),7.51(s,4H),7.45(dd,J＝8.6,5.6Hz,2H),7.17(t,J＝8.9Hz,2H),5.16(s,2H),2.08(s,3H).HR-ESI-MS:m/z＝530.12524[M+H]+,calcd forC27H21O2N3ClF4:530.12529.
实施例19：TM-19的制备
其合成方法及操作与化合物TM-1相同，产率51％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.96(s,1H),8.19–8.06(m,2H),7.88(dd,J＝11.5,2.4Hz,1H),7.64(d,J＝2.4Hz,1H),7.62(d,J＝8.8Hz,1H),7.57–7.50(m,4H),7.49–7.44(m,2H),7.23–7.15(m,2H),5.22(s,2H).HR-ESI-MS:m/z＝534.10028[M+H]+,calcd for C26H18O2N3ClF5:534.10022.
实施例20：TM-20的制备
其合成方法及操作与化合物TM-1相同，产率42％。mp:229-231℃；1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.96(s,1H),8.32(d,J＝2.6Hz,1H),8.17(d,J＝2.6Hz,1H),8.11(t,J＝2.9Hz,1H),7.67–7.62(m,2H),7.61–7.56(m,1H),7.54(d,J＝5.4Hz,3H),7.51–7.44(m,2H),7.22–7.16(m,2H),5.22(s,2H).HR-ESI-MS:m/z＝550.07123[M+H]+,calcd forC26H18O2N3Cl2F4:550.07067.
实施例21：TM-21的制备
其合成方法及操作与化合物TM-1相同，产率36％。mp:243-245℃；1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.97(s,1H),8.59(d,J＝2.9Hz,1H),8.31(dd,J＝11.5,2.8Hz,1H),8.11(d,J＝2.4Hz,1H),7.65(dd,J＝8.8,2.4Hz,1H),7.62(d,J＝8.8Hz,1H),7.55(s,4H),7.46(dd,J＝6.1,2.6Hz,2H),7.20(d,J＝8.8Hz,2H),5.20(s,2H),3.77(s,3H).HR-ESI-MS:m/z＝574.11511[M+H]+,calcd for C28H21O4N3ClF4:574.11512.
实施例22：TM-22的制备
其合成方法及操作与化合物TM-1相同，产率45％。mp:209-211℃；1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.96(s,1H),8.43(d,J＝1.2Hz,1H),8.15(d,J＝1.1Hz,1H),8.12(d,J＝2.3Hz,1H),7.81–7.77(m,2H),7.66–7.61(m,2H),7.56–7.52(m,2H),7.52–7.48(m,2H),7.23–7.17(m,2H),5.13(s,2H).HR-ESI-MS:m/z＝517.10516[M+H]+,calcd forC25H18O2N4ClF4:517.10489.
实施例23：TM-23的制备
其合成方法及操作与化合物TM-1相同，产率49％。mp:159-161℃；1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.01(s,1H),8.78(dd,J＝2.5,0.9Hz,1H),8.12(d,J＝2.4Hz,1H),7.93(dd,J＝8.4,2.5Hz,1H),7.68–7.63(m,4H),7.60–7.56(m,2H),7.50–7.44(m,2H),7.37(dd,J＝8.4,0.9Hz,1H),7.16–7.11(m,2H),4.46(s,2H).HR-ESI-MS:m/z＝532.08679[M+H]+,calcd for C26H19ON3ClF4S:532.08680.
实施例24：TM-24的制备
其合成方法及操作与化合物TM-1相同，产率53％。mp:244-246℃；1H NMR(400MHz,DMSO-D6)δ9.17(s,1H),8.99(s,1H),8.60(dd,J＝2.7,1.4Hz,1H),8.11(d,J＝2.4Hz,1H),7.78(d,J＝2.6Hz,1H),7.70–7.66(m,2H),7.66–7.63(m,1H),7.61(d,J＝8.8Hz,1H),7.53–7.49(m,2H),7.49–7.43(m,2H),7.23–7.16(m,2H),5.22(s,2H).HR-ESI-MS:m/z＝584.09894[M+H]+,calcd for C27H18O2N3ClF7:584.09703.
实施例25：TM-25的制备
其合成方法及操作与化合物TM-1相同，产率41％。mp:198-200℃；1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.09(s,1H),8.11(d,J＝2.3Hz,1H),8.04(d,J＝9.8Hz,1H),7.87–7.82(m,2H),7.68–7.62(m,2H),7.62–7.56(m,2H),7.43(dd,J＝8.6,5.6Hz,2H),7.18(t,J＝8.8Hz,2H),7.07(d,J＝9.7Hz,1H),5.30(s,2H).HR-ESI-MS:m/z＝517.10474[M+H]+,calcd for C25H18O2N4ClF4:517.10489.
实施例26：TM-26的制备
其合成方法及操作与化合物TM-1相同，产率46％。mp:256-258℃；1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),9.12(s,1H),8.22(d,J＝2.7Hz,1H),7.89(d,J＝2.5Hz,1H),7.83(dd,J＝9.5,2.7Hz,1H),7.51(s,5H),7.40(d,J＝1.5Hz,4H),7.34(dd,J＝8.8,2.5Hz,1H),6.51(d,J＝9.4Hz,1H),5.16(s,2H).HR-ESI-MS:m/z＝498.05557[M+H]+,calcd forC25H19O2N3Cl3:498.05374.
实施例27：TM-27的制备
其合成方法及操作与化合物TM-1相同，产率59％。mp:215-217℃；1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.94(s,1H),8.18(d,J＝2.7Hz,1H),7.89(d,J＝2.5Hz,1H),7.81(dd,J＝9.5,2.7Hz,1H),7.53–7.48(m,5H),7.38–7.32(m,3H),7.32–7.28(m,2H),6.50(d,J＝9.5Hz,1H),5.13(s,2H),1.25(s,9H).HR-ESI-MS:m/z＝520.15533[M+H]+,calcd forC29H28O2N3Cl2:520.15531.
实施例28：TM-28的制备
将3-氨基-5-叔丁基异唑(70mg，0.5mmol)和1,8-双二甲氨基萘(321mg，1.5mmol)溶于5mL无水二氯甲烷中，氩气保护，冰浴条件下，缓慢逐滴加入溶于5mL无水二氯甲烷中三光气(74mg，0.25mmol)，随后升至室温搅拌反应2h。反应结束后，旋干上述溶液，重新加入5mL无水二氯甲烷，冰浴条件下加入5-(4-氨基苯基)-1-(4-氟苄基)吡啶-2(1H)-酮(70mg，0.25mmol)和DIPEA(1mmol)，随后升至室温反应24h，反应完毕，过柱纯化得固体产物，产率10％。mp:209-211℃；1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.05(s,1H),8.19(d,J＝2.7Hz,1H),7.80(d,J＝8.5Hz,1H),7.50(s,6H),7.16(d,J＝4.7Hz,1H),6.54–6.47(m,2H),5.14(s,2H),1.30(s,9H).HR-ESI-MS:m/z＝449.16357[M+H]+,calcd for C24H25O3N4S:449.16419.
实施例29：TM-29的制备
其合成方法及操作与化合物TM-28相同，产率15％。mp:240-242℃；1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.07(d,J＝5.6Hz,1H),8.20(d,J＝2.6Hz,1H),7.86(s,1H),7.81(dd,J＝9.5,2.7Hz,1H),7.56–7.43(m,6H),7.16(dd,J＝4.9,1.4Hz,1H),6.50(d,J＝9.5Hz,1H),5.14(s,2H).HR-ESI-MS:m/z＝477.06570[M+H]+,calcd for C21H16O2N4F3S2:477.06613.
实施例30：TM-30的制备
其合成方法及操作与化合物TM-28相同，产率11％。mp:105-107℃；1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.49(s,1H),8.17(d,J＝2.7Hz,1H),7.79(dd,J＝9.5,2.7Hz,1H),7.50(dq,J＝5.2,2.8Hz,6H),7.16(dd,J＝4.8,1.3Hz,1H),6.50(d,J＝9.4Hz,1H),6.05(s,1H),5.14(s,2H),3.60(s,3H),1.21(s,9H).HR-ESI-MS:m/z＝462.19620[M+H]+,calcd for C25H28O2N5S:462.19582.
实施例31：TM-31的制备
其合成方法及操作与化合物TM-28相同，产率13％。mp:223-225℃；1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.90(s,1H),8.18(d,J＝2.7Hz,1H),7.80(dd,J＝9.4,2.7Hz,1H),7.54–7.46(m,6H),7.16(dd,J＝4.8,1.4Hz,1H),6.61(s,1H),6.50(d,J＝9.5Hz,1H),5.14(s,2H),3.77(s,3H).HR-ESI-MS:m/z＝474.12042[M+H]+,calcd forC22H19O2N5F3S:474.12061.
实施例32：TM-32的制备
其合成方法及操作与化合物TM-28相同，产率12％。mp:213-215℃；1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.90(s,1H),8.19(d,J＝2.7Hz,1H),7.81(dd,J＝9.5,2.7Hz,1H),7.53–7.49(m,5H),7.50–7.47(m,1H),7.16(dd,J＝4.9,1.4Hz,1H),6.50(d,J＝9.5Hz,1H),6.06(s,1H),5.14(s,2H),1.26(s,9H).HR-ESI-MS:m/z＝449.16412[M+H]+,calcd for C24H25O3N4S:449.16419.
实施例33：TM-33的制备
其合成方法及操作与化合物TM-28相同，产率14％。mp:108-110℃；1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.44(s,1H),8.12(d,J＝2.7Hz,1H),7.74(dd,J＝9.5,2.7Hz,1H),7.55(d,J＝1.9Hz,1H),7.54–7.48(m,4H),7.46(dd,J＝4.9,3.0Hz,1H),7.44(d,J＝1.6Hz,1H),7.43–7.38(m,5H),7.12(dd,J＝4.9,1.4Hz,1H),6.45(d,J＝9.5Hz,1H),6.43(d,J＝1.9Hz,1H),5.10(s,2H).HR-ESI-MS:m/z＝468.14917[M+H]+,calcd forC26H22O2N5S:468.14887.
实施例34：TM-34的制备
其合成方法及操作与化合物TM-28相同，产率16％。mp:200-202℃；1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.00(s,1H),8.20(d,J＝2.7Hz,1H),7.92–7.86(m,2H),7.81(dd,J＝9.5,2.7Hz,1H),7.55(s,1H),7.53(s,4H),7.51–7.49(m,1H),7.47(dd,J＝2.9,1.3Hz,1H),7.42(dd,J＝8.3,7.0Hz,2H),7.36–7.28(m,1H),7.16(dd,J＝4.9,1.4Hz,1H),6.50(d,J＝9.4Hz,1H),5.14(s,2H).HR-ESI-MS:m/z＝485.11029[M+H]+,calcd forC26H21O2N4S2:485.11004.
实施例35：TM-35的制备
其合成方法及操作与化合物TM-28相同，产率21％。mp:249-251℃；1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.64(s,1H),8.40(s,1H),8.16(d,J＝2.7Hz,1H),7.80(dd,J＝9.5,2.7Hz,1H),7.68(d,J＝2.0Hz,1H),7.54–7.51(m,1H),7.51–7.47(m,4H),7.46(d,J＝1.9Hz,1H),7.32–7.28(m,2H),7.19–7.15(m,1H),7.07(dd,J＝8.6,2.1Hz,1H),6.50(d,J＝9.4Hz,1H),6.35(t,J＝2.6Hz,1H),5.14(s,2H).HR-ESI-MS:m/z＝441.13785[M+H]+,calcd for C25H21O2N4S:441.13797.
实施例36：TM-36的制备
其合成方法及操作与化合物TM-28相同，产率46％。mp:237-239℃；1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.80(s,1H),8.18(d,J＝2.7Hz,1H),7.80(dd,J＝9.4,2.7Hz,1H),7.52–7.50(m,1H),7.50–7.47(m,6H),7.17(dd,J＝4.8,1.4Hz,1H),7.10(s,1H),6.86(s,1H),6.50(d,J＝9.4Hz,1H),5.14(s,2H),2.28(s,3H).HR-ESI-MS:m/z＝450.10403[M+H]+,calcd for C24H21O2N3ClS:450.10375.
实施例37：TM-37的制备
其合成方法及操作与化合物TM-28相同，产率49％。mp:249-251℃；1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.74(s,1H),8.17(d,J＝2.7Hz,1H),7.80(dd,J＝9.5,2.7Hz,1H),7.52–7.47(m,6H),7.44(s,1H),7.30(t,J＝1.8Hz,2H),7.16(dd,J＝4.8,1.4Hz,1H),6.50(d,J＝9.5Hz,1H),5.14(s,2H),2.30(s,3H).HR-ESI-MS:m/z＝450.10391[M+H]+,calcd for C24H21O2N3ClS:450.10375.
实施例38：TM-38的制备
其合成方法及操作与化合物TM-28相同，产率41％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.15–8.11(m,1H),7.97(s,1H),7.86(d,J＝8.8Hz,1H),7.76(dd,J＝9.5,2.7Hz,1H),7.50–7.41(m,6H)7.23(dd,J＝2.6,0.8Hz,1H),7.16(dd,J＝8.6,2.6Hz,1H),7.13(dd,J＝4.9,1.4Hz,1H),6.46(d,J＝9.3Hz,1H),5.10(s,2H),2.21(s,3H).HR-ESI-MS:m/z＝450.10382[M+H]+,calcd for C24H21O2N3ClS:450.10375.
实施例39：TM-39的制备
其合成方法及操作与化合物TM-28相同，产率41％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.42(s,1H),8.16(d,J＝2.7Hz,1H),7.79(dd,J＝9.4,2.7Hz,1H),7.53–7.42(m,6H),7.31(d,J＝8.9Hz,2H),7.16(dd,J＝4.8,1.4Hz,1H),6.93–6.86(m,2H),6.50(d,J＝9.4Hz,1H),5.14(s,2H),3.77–3.71(m,4H),3.05–3.00(m,4H).HR-ESI-MS:m/z＝487.17953[M+H]+,calcd for C27H27O3N4S:487.17984.
实施例40：TM-40的制备
其合成方法及操作与化合物TM-28相同，产率37％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.52(s,1H),8.12(d,J＝2.7Hz,1H),7.75(dd,J＝9.4,2.7Hz,1H),7.49–7.42(m,6H),7.31(d,J＝8.5Hz,2H),7.12(dd,J＝4.7,1.4Hz,1H),7.08(d,J＝8.5Hz,2H),6.46(d,J＝9.4Hz,1H),5.10(s,2H),1.73(d,J＝9.5Hz,4H),1.66(d,J＝12.9Hz,1H),1.31(d,J＝10.1Hz,4H),1.20(s,2H).HR-ESI-MS:m/z＝484.20618[M+H]+,calcd for C29H30O2N3S:484.20532.
实施例41：TM-41的制备
其合成方法及操作与化合物TM-28相同，产率32％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.66(s,1H),8.16(d,J＝2.8Hz,1H),7.79(dd,J＝9.5,2.7Hz,1H),7.51(t,J＝2.4Hz,1H),7.49(dd,J＝3.5,2.1Hz,4H),7.40(d,J＝8.1Hz,2H),7.20(d,J＝8.2Hz,2H),7.16(dd,J＝4.9,1.4Hz,1H),6.50(d,J＝9.5Hz,1H),5.14(s,2H),3.57(d,J＝4.8Hz,3H),3.39(s,2H),2.33(s,3H),1.28–1.24(m,3H).HR-ESI-MS:m/z＝501.19681[M+H]+,calcd for C28H29O3N4S:501.19549.
实施例42：TM-42的制备
其合成方法及操作与化合物TM-28相同，产率30％。mp:135-137℃；1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.66(d,J＝2.2Hz,1H),8.17(dd,J＝2.7,0.7Hz,1H),7.79(dd,J＝9.5,2.7Hz,1H),7.68(dd,J＝10.5,2.5Hz,1H),7.50(dd,J＝4.9,3.0Hz,1H),7.48(d,J＝1.7Hz,4H),7.46–7.42(m,1H),7.33–7.28(m,2H),7.29–7.21(m,2H),7.20–7.16(m,2H),7.16–7.12(m,1H),6.52–6.48(m,1H),5.19(d,J＝2.3Hz,2H),5.14(s,2H).HR-ESI-MS:m/z＝560.12134[M+H]+,calcd for C30H24O3N3ClFS:560.12054.
药理实验：
实验例1：体外激酶抑制活性测试
采用LanthaScreen Eu激酶结合实验来评价CDK8抑制剂的活性。化合物以DMSO溶液稀释100倍，与缓冲溶液(50mM HEPES pH 7.5，0.01％ BRIJ-35，10mM MgCl2，1mM EGTA)，激酶和抗体的混合物以及Tracer混合，振摇30s，然后在室温下孵育60min。随后在酶标仪上读取Emission Ratio(ER)，即AF647 Emission(665nm)与Europium Emission(615nm)的比值，并分析。IC50测试中，化合物以3倍梯度稀释，共测试10个浓度。测试中设置空白对照，阳性对照以sorafenib为参考。结果以“空白对照的ER与测试样品的ER之差”和“空白对照的ER与阳性对照的ER之差”的百分比给出，百分比越大说明化合物与激酶结合得越好。表1是本发明化合物的CDK8激酶的体外抑制活性结果。
表1目标化合物对CDK8/cyclin C的活性评价
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ND：not determined(未测试)；
a：单浓度抑制率的数值由两次测量值取平均值得到；
b：IC50值由10个浓度(双复孔)计算得到，最大值为10μM。
实验例2：本发明的化合物激酶选择性评价
为了考察抑制剂对CDK8的选择性，采用LanthaScreen Eu激酶结合实验，评价了部分化合物对35种激酶的选择性。选取的激酶种类包括CDKs家族的CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK9、CDK11、CDK13、CDK14、CDK16、CDK17和CDK18，以及其他激酶家族的CSNK1D、GSK3A、p38α、MAPK7、MAP2K5、MARK1、MKNK1、PKCα、CAMK4、PTK2、ROCK1、ROCK2、SRC、BRAF、DAPK1、LRRK2、CLK1、FGFR1、JAK1和PDK1。
表2化合物对35种激酶的抑制率
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*抑制率为10μM浓度下两次测量的平均值。
CDKs(cyclin dependent kinases)：细胞周期蛋白依赖性激酶；CSNK1D：酪氨酸激酶1D(casein kinase 1isoform delta)；DAPK1：死亡相关蛋白激酶1(death-associatedprotein kinase 1)；GSK3α:糖原合酶激酶3α(glycogen synthase kinase 3α)；MAPK14：丝裂原激活的蛋白激酶14(mitogen-activated protein kinase 14)；MAPK7：丝裂原激活的蛋白激酶7(mitogen-activated protein kinase 7)；MAP2K5：双重特异性促***原活化蛋白激酶激酶5(dual specificity mitogen-activated protein kinase kinase 5)；MARK1：微管亲和力调节激酶1(microtubule affinity regulating kinase 1)；MKNK1：MAP激酶相互作用丝/苏氨酸激酶1(MAP kinase-interacting serine/threonine-proteinkinase 1)；PRKCA：蛋白激酶Cα(protein kinase Cα)；CaMK4：钙/钙调素依赖蛋白激酶4(calcium/calmodulin-dependent protein kinase 4)；FAK：粘附斑激酶(focal adhesionkinase)；ROCK1：Rho关联，含卷曲螺旋蛋白激酶1(rho-associated,coiled-coilcontaining protein kinase 1)；ROCK2：Rho关联，含卷曲螺旋蛋白激酶2(rho-associated,coiled-coil containing protein kinase 2)；SRC：原癌基因酪氨酸蛋白激酶(proto-oncogene tyrosine-protein kinase)；BRAF：肉瘤滤过性病毒致癌基因同源体B1(v-raf murine sarcomaviral oncogene homolog B1)；DAPK1：死亡相关蛋白激酶1(death-associated protein kinase 1)；LRRK2：亮氨酸丰富重复激酶2(leucine-richrepeat serine/threonine-protein kinase 2)；CLK1：CDC样激酶1(CDC like kinase 1)；FGFR1：成纤维生长因子受体1(fibroblast growth factor receptor 1)；JAK1：两面神激酶1(Janus kinase 1)；PDK1：3-磷酸肌醇依赖性蛋白激酶1(3-phosphoinositide-dependent protein kinase)。
Claims (12)
1.一种由下述通式(I)表示的N-取代吡啶酮类化合物或其生理上可接受的盐，
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基；
R3选自氢、卤素﹑C1-C3烷基﹑三氟甲基、C1-C3烷氧甲酰基。
2.根据权利要求1所述的化合物或其生理上可接受的盐，其特征在于，所述的化合物是通式(IA)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基。
3.根据权利要求2所述的化合物或其生理上可接受的盐，其特征在于，所述的化合物是通式(IAa)所示的化合物或其生理上可接受的盐：
R2选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的异噁唑、取代或未取代的吡唑基、取代或未取代的吲哚基，所述取代基为单取代或多取代，独立地选自卤素﹑三氟甲基﹑C1-C6烷基﹑苯基、吗啉基、吗啉基甲基、卤素取代的苄氧基。
4.根据权利要求2所述的化合物或其生理上可接受的盐，其特征在于，所述的化合物是通式(IAb)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R4选自卤素﹑C1-C4烷基﹑C1-C4烷氧基、三氟甲基。
5.根据权利要求2所述的化合物或其生理上可接受的盐，其特征在于，所述的化合物是通式(IAc)所示的化合物或其生理上可接受的盐：
R1选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的噻吩基、取代或未取代的呋喃基，所述取代基为单取代或多取代，独立地选自卤素﹑C1-C4烷基﹑C1-C4烷氧基﹑三氟甲基﹑二氟甲氧基﹑C1-C3烷氧甲酰基；
R4选自卤素﹑C1-C4烷基﹑C1-C4烷氧基、三氟甲基；
R5选自氢﹑C1-C3烷基。
6.具有如下结构的化合物或其生理上可接受的盐，其特征在于，所述化合物选自：
7.权利要求1～6任一项所述化合物的制备方法，其特征在于，包括以下步骤：
式II化合物与式III化合物经亲核取代反应生成式IV化合物，式IV化合物与对硝基苯硼酸经Suzuki偶联反应生成式V化合物；式V化合物经还原反应生成式VI化合物；式VI化合物与式VII化合物反应生成式I目标化合物；
其中，R1、R2和R3的定义同权利要求1～6任一项。
8.一种药物组合物，其特征在于，药物组合物含有有效剂量的如权利要求1～6任一项所述的化合物或其生理上可接受的盐和在药学上可接受的载体。
9.根据权利要求8所述的药物组合物，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药***。
10.权利要求1～6任一项所述的化合物或其生理上可接受的盐在制备CDK8抑制剂中的用途。
11.权利要求1～6任一项所述的化合物或其生理上可接受的盐用于制备预防或治疗CDK8相关疾病的药物中的应用。
12.根据权利要求11所述的应用，所述的疾病选自肿瘤、炎症、和免疫性疾病。
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