CN116768886A - N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物及制备与用途 - Google Patents
N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物及制备与用途 Download PDFInfo
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- CN116768886A CN116768886A CN202310447718.4A CN202310447718A CN116768886A CN 116768886 A CN116768886 A CN 116768886A CN 202310447718 A CN202310447718 A CN 202310447718A CN 116768886 A CN116768886 A CN 116768886A
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- phenyl
- pyridin
- pyrrolo
- substituted
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- -1 N- (4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) amide derivatives Chemical class 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 claims description 26
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 239000000543 intermediate Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000005494 pyridonyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 43
- 238000003786 synthesis reaction Methods 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- 229940125878 compound 36 Drugs 0.000 description 18
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 14
- 239000012346 acetyl chloride Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical group OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
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- MDVRXWAAVDTLFJ-UHFFFAOYSA-N 5-methylfuran-3-carboxylic acid Chemical group CC1=CC(C(O)=O)=CO1 MDVRXWAAVDTLFJ-UHFFFAOYSA-N 0.000 description 2
- GQXLWUCQESKBSC-UHFFFAOYSA-N 6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene hydrochloride Chemical compound Cl.N=1C(=C23)C(C)=C(Br)C(Br)=C2CCCN3C=1N1CCNCC1 GQXLWUCQESKBSC-UHFFFAOYSA-N 0.000 description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 241001529936 Murinae Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 229960002751 imiquimod Drugs 0.000 description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical group OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
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- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical group OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/06—Antipsoriatics
Abstract
本发明公开了一种N‑(4‑(1H‑吡咯并[2,3‑b]吡啶‑5‑基)苯基)酰胺衍生物及其制备与用途，涉及药物化学技术领域，本发明设计并合成得到一种新型结构的N‑(4‑(1H‑吡咯并[2,3‑b]吡啶‑5‑基)苯基)酰胺衍生物，经体外CDK8激酶活性以及体外细胞活性筛选，发现其中部分化合物对CDK8激酶表现出较强的抑制活性，对银屑病具有良好的治疗效果，同时毒性较低，可应用于CDK8抑制剂和银屑病药物的研发。
Description
技术领域：
本发明涉及药物化学技术领域，具体涉及一种N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物及制备与用途。
背景技术：
周期蛋白依赖性激酶8(CDK8)是CDK家族的一员，属于丝氨酸/苏氨酸蛋白激酶。已经证实，CDK8通过形成激酶模块或转录因子磷酸化在转录调节中发挥重要作用，包括HIF-1α、TGF-β、β-catenin/TCF和STAT1。近年来，许多CDK8抑制剂被报道为抗肿瘤小分子，如CCT-251545、CCT-251921、BRD6989、Senexin B(BCD-115)和SEL120-34A。其中，BCD-115和SEL120-34A已分别进入治疗乳腺癌和急性髓系白血病的临床试验。
CDK8也被认为是NF-κB的共同调节因子。CDK8在NF-κB途径中的一个关键功能是调节RNA Pol II的C末端结构域(CTD)的磷酸化，完成NF-κB启动的转录。据报道，CDK8抑制剂能抑制NF-κB诱导的基因表达，如IL-8、CXCL1和CXCL2，但通常不影响基础表达。不同CDK在抑制NF-κB活化方面存在明显差异。本发明旨在以N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺为核心结构骨架进行“CDK8抑制剂”研发，以期发现高活性的CDK8抑制剂。
发明内容：
本发明所要解决的技术问题在于借助计算机辅助药物设计技术，基于药物化学结构修饰，设计合成了以N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺为核心结构骨架进行“CDK8抑制剂”研发，通过药理学评价，以期发现高活性的CDK8抑制剂，从而丰富靶向CDK8的小分子库。
本发明所要解决的技术问题采用以下的技术方案来实现：
本发明的第一个目的在于提供一种N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物，结构如式I所示：
其中，R1选自氢、卤素、烷基、烷氧基、苯基、苯氧基等取代基中的任一种；
R2选自烷基、烷基醇、环烷基、取代环烷基、苯基、取代苯基、呋喃基、取代呋喃基、四氢呋喃基、取代四氢呋喃基、噻唑基、取代噻唑基、苯并呋喃基、取代苯并呋喃基、吡啶基、取代吡啶基、嘧啶基、取代嘧啶基、吡啶酮基、取代吡啶酮基、吗啉基、取代吗啉基、四氢-2H-吡喃基、取代四氢-2H-吡喃基、哌啶基、取代哌啶基、哌嗪基、取代哌嗪基等取代基中的任一种。
本发明所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物具体包括以下结构式的化合物1-42，见表1。
表1
本发明的第二个目的在于提供一种所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物的制备方法，包括以下步骤：
(1)与5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯并[2,3-b]吡啶发生Suzuki-Miyaura反应，得到中间体M1；
(2)中间体M1与R2COOH或R2COCl发生酰胺缩合反应，得到化合物1-42。
反应方程式如下：
本发明的第三个目的在于提供一种药物组合物，含有所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐。
本发明的第四个目的在于提供一种药物制剂，包括有效成分和药学上可接受的辅料和/或载体，所述有效成分含有所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐。
本发明的第五个目的在于提供所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐在制备CDK8抑制剂中的应用。
本发明的第六个目的在于提供所述N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐在制备治疗银屑病药物中的应用。
本发明的有益效果是：本发明设计并合成得到一种新型结构的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物，经体外CDK8激酶活性以及体外细胞活性筛选，发现其中部分化合物对CDK8激酶表现出较强的抑制活性，对银屑病具有良好的治疗效果，同时毒性较低，可应用于CDK8抑制剂和银屑病药物的研发；并且本发明提供的制备方法简便易行，重复性好，能够得到高纯度的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物以用于进一步研究。
附图说明：
图1为化合物36的靶标验证；
图2为化合物36的体外机制研究；
图3为化合物36在鼠银屑病模型上的治疗效果研究。
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
1.1 3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯胺(中间体M1)的合成：
向反应瓶中加入4-溴-3-甲氧基苯胺(10g，49.77mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(13.4g，54.75mmol)、碳酸钾(17.2g，124.43mmol)、二氯[1,1'-二(二苯基膦)二茂铁]钯(0.73g，1.00mmol)、1,4-二氧六环/水(100mL/35mL)，氮气置换，升温至80℃反应14h。反应结束，加水和乙酸乙酯搅拌，硅藻土助滤，乙酸乙酯洗涤滤饼；滤液静置分液，取水相用乙酸乙酯再萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，旋干，得到黑色油状物；柱层析，得到黄色固体，收率45.6％。
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.21(d,J＝2.0Hz,1H),7.89(d,J＝1.9Hz,1H),7.48-7.37(m,1H),6.99(d,J＝8.1Hz,1H),6.42(dd,J＝3.3,1.8Hz,1H),6.35(d,J＝1.9Hz,1H),6.26(dd,J＝8.1,1.9Hz,1H),5.23(s,2H),3.69(s,3H).13C NMR(101MHz,DMSO-d6)δ157.49,149.98,147.34,143.92,131.53,128.40,127.11,126.42,119.57,116.20,106.94,100.18,98.09,55.49.
1.2N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)乙酰胺(化合物1)的合成：
向反应瓶中加入中间体M1(240mg，1mmol)、N,N-二乙基异丙胺(194mg，1.5mmol)、乙酰氯(85mg，1.1mmol)和二氯甲烷(10mL)，升温至30℃反应2h。反应结束，浓缩，加水和乙酸乙酯搅拌，静置分液，取水相用乙酸乙酯再萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，柱层析，得到白色固体，收率52.5％。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.06(s,1H),8.28(d,J＝1.9Hz,1H),7.98(d,J＝1.6Hz,1H),7.48(d,J＝3.4Hz,2H),7.27(s,2H),6.46(dd,J＝3.1,1.7Hz,1H),3.75(s,3H),2.08(s,3H).13C NMR(101MHz,DMSO-d6)δ168.85,156.75,147.76,143.81,140.28,131.15,128.80,126.79,126.03,123.36,119.57,111.75,103.10,100.36,55.81,24.59.
实施例2
2-羟基-N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)乙酰胺(化合物2)的合成：
向反应瓶中加入中间体M1(240mg，1mmol)、N,N-二乙基异丙胺(194mg，1.5mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU，420mg，1.1mmol)、羟基乙酸(73mg，1.1mmol)和二氯甲烷(10mL)，升温至50℃反应10h。反应结束，浓缩，加水和乙酸乙酯搅拌，静置分液，取水相用乙酸乙酯再萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，柱层析，得到白色固体，收率38.55％。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.76(s,1H),8.28(d,J＝2.0Hz,1H),7.99(d,J＝1.9Hz,1H),7.59(d,J＝1.8Hz,1H),7.55-7.39(m,2H),7.29(d,J＝8.2Hz,1H),6.46(dd,J＝3.4,1.8Hz,1H),5.76(t,J＝6.0Hz,1H),4.03(d,J＝5.9Hz,2H),3.75(s,3H).13CNMR(101MHz,DMSO-d6)δ171.44,156.73,147.77,143.81,139.45,131.09,128.83,126.80,125.99,123.75,119.57,112.28,103.82,100.38,62.40,55.89.
实施例3
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)丙酰胺(化合物3)的合成：
参照实施例1，乙酰氯被替换成丙酰氯。
1H NMR(500MHz,DMSO-d6)δ11.61(s,1H),9.95(s,1H),8.28(d,J＝2.1Hz,1H),7.98(d,J＝1.9Hz,1H),7.52(s,1H),7.49-7.44(m,1H),7.27(d,J＝0.6Hz,2H),6.46(dd,J＝3.4,1.9Hz,1H),3.75(s,3H),2.36(q,J＝7.5Hz,2H),1.12(t,J＝7.6Hz,3H).13C NMR(126MHz,DMSO-d6)δ172.55,156.79,147.78,143.82,140.36,131.11,128.79,126.76,126.07,123.30,119.58,111.79,103.22,100.37,55.83,30.08,10.11.
实施例4
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)丁酰胺(化合物4)的合成：
参照实施例1，乙酰氯被替换成丁酰氯。
1H NMR(500MHz,DMSO-d6)δ11.54(s,1H),9.89(s,1H),8.20(d,J＝2.0Hz,1H),7.90(d,J＝1.8Hz,1H),7.45(s,1H),7.41-7.36(m,1H),7.20(s,2H),6.38(dd,J＝3.3,1.8Hz,1H),3.68(s,3H),2.25(t,J＝7.3Hz,2H),1.57(h,J＝7.4Hz,2H),0.87(t,J＝7.4Hz,3H).13CNMR(126MHz,DMSO-d6)δ171.72,156.79,147.78,143.83,140.32,131.11,128.79,126.76,126.08,123.36,119.59,111.82,103.23,100.37,55.83,38.91,19.03,14.11.
实施例5
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)异丁胺(化合物5)的合成：
参照实施例1，乙酰氯被替换成异丁酰氯。
1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.84(s,1H),8.20(d,J＝2.0Hz,1H),7.91(d,J＝1.9Hz,1H),7.48(d,J＝1.1Hz,1H),7.42-7.37(m,1H),7.23-7.18(m,2H),6.39(dd,J＝3.3,1.8Hz,1H),3.68(s,3H),2.61-2.50(m,1H),1.06(d,J＝6.8Hz,6H).13C NMR(126MHz,DMSO-d6)δ175.81,156.78,147.78,143.82,140.45,131.08,128.79,126.76,126.08,123.33,119.58,111.87,103.30,100.37,55.83,35.51,19.98(2C).
实施例6
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)新戊酰胺(化合物6)的合成：
参照实施例1，乙酰氯被替换成叔丁基酰氯。
1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.19(s,1H),8.21(d,J＝1.9Hz,1H),7.91(d,J＝1.8Hz,1H),7.49(d,J＝1.7Hz,1H),7.42-7.30(m,2H),7.19(d,J＝8.2Hz,1H),6.39(dd,J＝3.2,1.8Hz,1H),3.69(s,3H),1.19(s,9H).13C NMR(126MHz,DMSO-d6)δ177.03,156.63,147.78,143.82,140.44,130.85,128.79,126.75,126.10,123.45,119.59,112.75,104.22,100.37,55.88,39.75,27.68(3C).
实施例7
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)环丙烷甲酰胺(化合物7)的合成：
参照实施例1，乙酰氯被替换成环丙基甲酰氯。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.32(s,1H),8.27(d,J＝2.0Hz,1H),7.98(d,J＝1.8Hz,1H),7.54(d,J＝1.3Hz,1H),7.49-7.44(m,1H),7.32-7.20(m,2H),6.46(dd,J＝3.4,1.8Hz,1H),3.75(s,3H),1.81(dq,J＝7.5,4.9Hz,1H),0.89-0.71(m,4H).13CNMR(101MHz,DMSO-d6)δ172.19,156.77,147.75,143.81,140.33,131.15,128.80,126.78,126.04,123.25,119.56,111.66,103.08,100.36,55.79,15.11,7.70(2C).
实施例8
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-1-甲基环丙烷-1-甲酰胺(化合物8)的合成：
参照实施例1，乙酰氯被替换成1-甲基环丙基甲酰氯。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.26(s,1H),8.29(s,1H),7.99(s,1H),7.55(s,1H),7.47(s,1H),7.34(dd,J＝58.1,8.2Hz,2H),6.46(s,1H),3.75(s,3H),1.44(s,3H),1.13(d,J＝1.6Hz,2H),0.66(d,J＝1.9Hz,2H).
实施例9
2-环丙基-N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)乙酰胺(化合物9)的合成：
参照实施例1，乙酰氯被替换成2-环丙基乙酰氯。
1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),9.89(s,1H),8.27(d,J＝2.0Hz,1H),7.97(d,J＝1.9Hz,1H),7.53(s,1H),7.49-7.43(m,1H),7.27(s,2H),6.45(dd,J＝3.3,1.8Hz,1H),3.75(s,3H),2.23(d,J＝7.0Hz,2H),1.13-1.02(m,1H),0.54-0.46(m,2H),0.26-0.16(m,2H).13C NMR(126MHz,DMSO-d6)δ171.35,156.80,147.78,143.82,140.32,131.12,128.79,126.76,126.07,123.40,119.59,111.82,103.23,100.38,55.84,42.00,8.23(2C),4.59(2C).
实施例10
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)环丁烷酰胺(化合物10)的合成：
参照实施例1，乙酰氯被替换成环丁基甲酰氯。
1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.74(s,1H),8.20(d,J＝2.0Hz,1H),7.90(d,J＝1.9Hz,1H),7.47(d,J＝1.2Hz,1H),7.42-7.36(m,1H),7.21(dt,J＝13.7,4.8Hz,2H),6.38(dd,J＝3.3,1.8Hz,1H),3.68(s,3H),3.18(p,J＝8.3Hz,1H),2.26 -2.12(m,2H),2.06(tdd,J＝11.8,8.8,3.4Hz,2H),1.93-1.81(m,1H),1.81-1.68(m,1H).13C NMR(126MHz,DMSO-d6)δ173.49,156.78,147.78,143.83,140.36,131.09,128.79,126.75,126.08,123.33,119.58,111.89,103.31,100.37,55.83,25.09(2C),18.21.
实施例11
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)环戊烷酰胺(化合物11)的合成：
参照实施例1，乙酰氯被替换成环戊基甲酰氯。
1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.88(s,1H),8.20(d,J＝2.0Hz,1H),7.90(d,J＝1.9Hz,1H),7.48(s,1H),7.42-7.36(m,1H),7.19(s,2H),6.39(dd,J＝3.4,1.8Hz,1H),3.68(s,3H),2.73(dd,J＝15.9,7.9Hz,1H),1.79(ddd,J＝6.7,5.5,2.8Hz,2H),1.73-1.58(m,4H),1.50(dt,J＝7.9,3.2Hz,2H).13C NMR(126MHz,DMSO-d6)δ174.98,156.78,147.77,143.82,140.47,131.08,128.78,126.76,126.09,123.28,119.58,111.84,103.26,100.37,55.83,45.84,30.57(2C),26.18(2C).
实施例12
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)环己烷酰胺(化合物12)的合成：
参照实施例1，乙酰氯被替换成环己基甲酰氯。
1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.81(s,1H),8.19(d,J＝2.0Hz,1H),7.90(d,J＝1.8Hz,1H),7.48(s,1H),7.42-7.36(m,1H),7.19(d,J＝2.7Hz,2H),6.38(dd,J＝3.3,1.8Hz,1H),3.67(s,3H),2.28(tt,J＝11.5,3.3Hz,1H),1.73(dd,J＝26.9,12.3Hz,4H),1.59(d,J＝12.1Hz,1H),1.37(ddd,J＝25.1,12.7,2.9Hz,2H),1.29-1.17(m,2H),1.17-1.10(m,1H).13C NMR(126MHz,DMSO-d6)δ174.88,156.76,147.77,143.81,140.50,131.06,128.77,126.76,126.09,123.25,119.57,111.81,103.23,100.36,55.82,45.46,29.64(2C),25.72(2C).
实施例13
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)苯甲酰胺(化合物13)的合成：
参照实施例1，乙酰氯被替换成苯甲酰氯。
1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.26(s,1H),8.24(d,J＝2.0Hz,1H),7.97-7.93(m,2H),7.92(d,J＝1.5Hz,1H),7.63(d,J＝1.8Hz,1H),7.59-7.51(m,1H),7.48(dd,J＝10.3,4.6Hz,3H),7.43-7.38(m,1H),7.27(d,J＝8.2Hz,1H),6.40(dd,J＝3.4,1.8Hz,1H),3.72(s,3H).13C NMR(126MHz,DMSO-d6)δ166.04,156.75,147.84,143.85,140.17,135.42,132.09,131.07,128.89(2C),128.85,128.12(2C),126.81,126.04,124.06,119.60,113.04,104.47,100.41,55.93.
实施例14
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)四氢呋喃-2-甲酰胺(化合物14)的合成：
参照实施例2，羟基乙酸被替换成四氢呋喃-2-甲酸。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.77(s,1H),8.27(d,J＝1.6Hz,1H),7.99(s,1H),7.59(s,1H),7.46(d,J＝7.6Hz,2H),7.28(d,J＝8.2Hz,1H),6.46(s,1H),4.42(dd,J＝8.0,5.7Hz,1H),4.06-3.97(m,1H),3.86(dd,J＝14.4,6.9Hz,1H),3.75(s,3H),2.20(dd,J＝13.6,6.2Hz,1H),2.01(td,J＝12.6,6.7Hz,1H),1.96-1.82(m,2H).13C NMR(101MHz,DMSO-d6)δ172.05,156.70,147.78,143.80,139.40,131.02,128.81,126.81,125.98,123.92,119.57,112.52,104.07,100.37,78.44,69.33,55.91,30.46,25.56.
实施例15
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)呋喃-2-甲酰胺(化合物15)的合成：
参照实施例2，羟基乙酸被替换成呋喃-2-甲酸。
1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.61(s,1H),9.32(s,1H),9.24(s,2H),8.25(d,J＝2.0Hz,1H),7.96(d,J＝1.9Hz,1H),7.57(d,J＝1.7Hz,1H),7.45-7.40(m,2H),7.31(d,J＝8.2Hz,1H),6.40(dd,J＝3.3,1.8Hz,1H),3.73(s,3H).13C NMR(126MHz,DMSO-d6)δ162.66,160.63,156.81,156.70(2C),147.87,143.82,139.46,131.24,129.05,128.88,126.86,125.87,124.71,119.60,113.05,104.42,100.43,55.97.
实施例16
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)呋喃-3-甲酰胺(化合物16)的合成：
参照实施例2，羟基乙酸被替换成呋喃-3-甲酸。
1H NMR(500MHz,DMSO-d6)δ11.55(s,1H),9.94(s,1H),8.35(s,1H),8.24(d,J＝1.9Hz,1H),7.94(d,J＝1.7Hz,1H),7.74(d,J＝1.5Hz,1H),7.53(d,J＝1.6Hz,1H),7.40(dd,J＝5.9,2.4Hz,2H),7.26(d,J＝8.2Hz,1H),6.97(d,J＝1.0Hz,1H),6.40(dd,J＝3.2,1.7Hz,1H),3.72(s,3H).13C NMR(126MHz,DMSO-d6)δ160.92,156.76,147.83,146.35,144.72,143.84,139.84,131.11,128.84,126.80,126.01,124.00,123.54,119.60,112.89,109.72,104.29,100.40,55.92.
实施例17
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)5-甲基呋喃-3-甲酰胺(化合物17)的合成：
参照实施例2，羟基乙酸被替换成5-甲基-呋喃-3-甲酸。
1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.09(s,1H),8.31(d,J＝2.1Hz,1H),8.01(d,J＝1.9Hz,1H),7.61(d,J＝1.9Hz,1H),7.55(dd,J＝8.3,1.9Hz,1H),7.50-7.45(m,1H),7.32(d,J＝8.2Hz,1H),7.26(d,J＝3.3Hz,1H),6.47(dd,J＝3.4,1.8Hz,1H),6.35(dd,J＝3.3,0.9Hz,1H),3.79(s,3H),2.41(s,3H).13C NMR(126MHz,DMSO-d6)δ156.72,156.70,155.68,147.82,146.50,143.84,139.66,131.07,128.83,126.80,126.01,123.96,119.60,116.49,112.96,109.09,104.42,100.40,55.93,14.06.
实施例18
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)噻唑-4-甲酰胺(化合物18)的合成：
参照实施例2，羟基乙酸被替换成噻唑-4-甲酸。
1H NMR(500MHz,DMSO-d6)δ11.55(s,1H),10.33(s,1H),9.22(d,J＝2.0Hz,1H),8.46(d,J＝2.0Hz,1H),8.24(d,J＝2.0Hz,1H),7.95(d,J＝1.8Hz,1H),7.69(d,J＝1.9Hz,1H),7.58(dd,J＝8.3,1.9Hz,1H),7.40(m,1H),7.26(d,J＝8.2Hz,1H),6.40(dd,J＝3.4,1.8Hz,1H),3.72(s,3H).13C NMR(126MHz,DMSO-d6)δ159.61,156.76,155.56,151.18,147.84,143.85,139.45,131.07,128.86,126.81,126.07,126.00,124.26,119.60,113.04,104.68,100.41,55.98.
实施例19
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)苯并呋喃-2-甲酰胺(化合物19)的合成：
参照实施例1，乙酰氯被替换成苯并呋喃-2-甲酰氯。
1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.54(s,1H),8.25(d,J＝2.0Hz,1H),7.96(d,J＝1.8Hz,1H),7.81-7.71(m,2H),7.65(dd,J＝19.8,5.0Hz,2H),7.55(dd,J＝8.3,1.9Hz,1H),7.44(ddd,J＝16.4,7.0,2.0Hz,2H),7.31(dd,J＝14.3,7.9Hz,2H),6.41(dd,J＝3.3,1.8Hz,1H),3.74(s,3H).13C NMR(126MHz,DMSO-d6)δ157.13,156.77,154.96,149.28,147.86,143.84,139.31,131.16,128.87,127.69,127.65,126.84,125.94,124.51,124.36,123.43,119.61,113.21,112.41,111.24,104.68,100.42,55.97.
实施例20
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)吡啶酰胺(化合物20)的合成：
参照实施例2，羟基乙酸被替换成2-吡啶甲酸。
1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.74(d,J＝19.3Hz,1H),8.76(dd,J＝10.4,4.6Hz,1H),8.32(d,J＝2.0Hz,1H),8.25-8.17(m,1H),8.09(td,J＝7.7,1.6Hz,1H),8.03(d,J＝1.9Hz,1H),7.82(d,J＝1.9Hz,1H),7.74-7.67(m,2H),7.48(dd,J＝8.5,5.7Hz,1H),7.36(d,J＝8.2Hz,1H),6.48(dd,J＝3.3,1.8Hz,1H),3.81(s,3H).13C NMR(126MHz,DMSO-d6)δ162.94,156.84,150.31,148.90,147.84,143.85,139.27,138.66,131.13,128.87,127.45,126.81,125.99,124.35,122.84,119.61,112.88,104.56,100.42,56.02.
实施例21
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)烟酰胺(化合物21)的合成：
参照实施例2，羟基乙酸被替换成3-吡啶甲酸。
1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.46(s,1H),9.09(d,J＝1.9Hz,1H),8.71(dd,J＝4.8,1.6Hz,1H),8.30-8.22(m,2H),7.95(d,J＝1.9Hz,1H),7.60(d,J＝1.8Hz,1H),7.52(dd,J＝7.9,4.9Hz,1H),7.49-7.38(m,2H),7.29(d,J＝8.2Hz,1H),6.41(dd,J＝3.4,1.8Hz,1H),3.73(s,3H).13C NMR(126MHz,DMSO-d6)δ164.54,156.77,152.63,149.15,147.85,143.83,139.79,135.92,131.15,131.04,128.87,126.84,125.95,124.40,123.99,119.60,113.07,104.48,100.42,55.95.
实施例22
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)异烟酰胺(化合物22)的合成：
参照实施例2，羟基乙酸被替换成4-吡啶甲酸。
1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.51(s,1H),8.75(d,J＝5.8Hz,2H),8.25(d,J＝2.0Hz,1H),7.96(d,J＝1.9Hz,1H),7.87–7.79(m,2H),7.60(d,J＝1.7Hz,1H),7.47(dd,J＝8.3,1.8Hz,1H),7.44–7.39(m,1H),7.30(d,J＝8.2Hz,1H),6.41(dd,J＝3.3,1.8Hz,1H),3.73(s,3H).13C NMR(126MHz,DMSO-d6)δ164.46,156.78,150.77(2C),147.87,143.83,142.37,139.55,131.17,128.88,126.85,125.91,124.64,122.04(2C),119.61,113.19,104.59,100.42,55.96.
实施例23
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)嘧啶-5-甲酰胺(化合物23)的合成：
参照实施例2，羟基乙酸被替换成嘧啶-5-甲酸。
1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.44(s,1H),8.61(s,1H),8.24(d,J＝2.1Hz,1H),7.95(d,J＝3.5Hz,2H),7.52(d,J＝1.9Hz,1H),7.47-7.38(m,2H),7.28(d,J＝8.2Hz,1H),6.40(dd,J＝3.4,1.8Hz,1H),3.72(s,3H).13C NMR(126MHz,DMSO-d6)δ156.78,155.42,154.33,147.86,145.70,143.82,139.03,131.20,130.61,128.87,126.84,125.87,124.63,119.60,113.19,104.60,100.42,55.96.
实施例24
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-甲基烟酰胺(化合物24)的合成：
参照实施例2，羟基乙酸被替换成2-甲基烟酸。
1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.47(s,1H),8.51(dd,J＝4.9,1.7Hz,1H),8.23(d,J＝2.0Hz,1H),7.94(d,J＝1.9Hz,1H),7.83(dd,J＝7.7,1.6Hz,1H),7.57(d,J＝1.4Hz,1H),7.43–7.33(m,2H),7.32–7.24(m,2H),6.40(dd,J＝3.4,1.8Hz,1H),3.71(s,3H),2.54(s,3H).13C NMR(126MHz,DMSO-d6)δ167.15,156.85,155.55,150.27,147.85,143.83,139.98,135.64,132.73,131.24,128.85,126.84,125.98,124.28,121.41,119.60,112.45,103.83,100.41,55.92,23.1
实施例25
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺(化合物25)的合成：
参照实施例2，羟基乙酸被替换成1-甲基-2-氧代-1,2-二氢吡啶-3-甲酸。
1H NMR(500MHz,DMSO-d6)δ12.23(s,1H),11.55(s,1H),8.41(dd,J＝7.3,2.2Hz,1H),8.23(d,J＝2.1Hz,1H),8.10(dd,J＝6.5,2.1Hz,1H),7.94(d,J＝1.9Hz,1H),7.50(d,J＝1.8Hz,1H),7.43-7.38(m,1H),7.30(dt,J＝20.1,5.0Hz,2H),6.59-6.52(m,1H),6.40(dd,J＝3.4,1.9Hz,1H),3.74(s,3H),3.59(s,3H).13C NMR(126MHz,DMSO-d6)δ162.56,162.03,157.06,147.83,145.01,144.06,143.82,139.31,131.46,128.85,126.82,125.93,124.29,119.78,119.59,112.47,107.09,103.80,100.41,56.01,38.41.
实施例26
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-(吡啶-2-基)乙酰胺(化合物26)的合成：
参照实施例2，羟基乙酸被替换成2-(吡啶-2-基)乙酸。
1H NMR(500MHz,DMSO-d6)δ11.61(s,1H),10.34(s,1H),8.57(s,1H),8.49(s,1H),8.27(d,J＝1.5Hz,1H),7.98(d,J＝1.9Hz,1H),7.77(d,J＝7.8Hz,1H),7.51(d,J＝1.0Hz,1H),7.50–7.44(m,1H),7.39(d,J＝4.7Hz,1H),7.31–7.23(m,2H),6.46(dd,J＝3.3,1.8Hz,1H),3.75(s,5H).13C NMR(126MHz,DMSO-d6)δ169.10,156.83,150.68,148.29,147.80,143.80,140.02,137.26,132.09,131.20,128.80,126.79,125.98,123.91,123.76,119.58,111.91,103.33,100.38,55.85,40.74.
实施例27
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-(吡啶-3-基)乙酰胺(化合物27)的合成：
参照实施例2，羟基乙酸被替换成2-(吡啶-3-基)乙酸。
11H NMR(500MHz,DMSO-d6)δ11.61(s,1H),10.35(s,1H),8.55-8.50(m,1H),8.28(d,J＝2.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.55(s,1H),7.49-7.40(m,2H),7.33-7.25(m,3H),6.46(dd,J＝3.4,1.9Hz,1H),3.89(s,2H),3.75(s,3H).13CNMR(126MHz,DMSO-d6)δ168.76,156.82,156.47,149.47,147.80,143.82,140.14,137.03,131.18,128.81,126.78,126.01,124.49,123.65,122.40,119.58,111.86,103.28,100.38,55.85,46.45.
实施例28
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-(吡啶-4-基)乙酰胺化合物28的合成：
参照实施例2，羟基乙酸被替换成2-(吡啶-4-基)乙酸。
1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),10.35(s,1H),8.55-8.50(m,1H),8.28(d,J＝2.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.77(td,J＝7.6,2.0Hz,1H),7.53(s,1H),7.48-7.43(m,2H),7.36-7.30(m,3H),6.46(dd,J＝3.24,2.0Hz,1H),3.89(s,2H),3.75(s,3H).13CNMR(126MHz,DMSO-d6)δ168.76,156.82,156.47,149.47,147.80,143.82,140.14,137.03,131.18,128.81,126.78,126.01,124.51,123.65,122.44 119.58,111.84,103.28,100.37,55.85,46.44.
实施例29
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-3-(吡啶-4-基)丙烯酰胺(化合物29)的合成：
参照实施例2，羟基乙酸被替换成3-(吡啶-4-基)丙烯酸。
1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.47(s,1H),8.67(d,J＝5.8Hz,2H),8.30(d,J＝2.0Hz,1H),8.01(d,J＝1.9Hz,1H),7.64-7.57(m,4H),7.50-7.45(m,1H),7.41(dd,J＝8.2,1.7Hz,1H),7.34(d,J＝8.2Hz,1H),7.08(d,J＝15.8Hz,1H),6.47(dd,J＝3.3,1.8Hz,1H),3.79(s,3H).13C NMR(126MHz,DMSO-d6)δ163.33,156.88,150.93(2C),147.84,143.82,142.39,139.90,138.16,131.33,128.84,127.22,126.83,125.95,124.18,122.24(2C),119.59,112.23,103.53,100.41,55.91.
实施例30
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-3-(吡啶-4-基)丙酰胺(化合物30)的合成：
参照实施例2，羟基乙酸被替换成3-(吡啶-4-基)丙酸。
1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.06(s,1H),8.48(dd,J＝4.5,1.5Hz,2H),8.27(d,J＝2.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.47(t,J＝2.7Hz,2H),7.33-7.23(m,4H),6.46(dd,J＝3.4,1.8Hz,1H),3.75(s,3H),2.96(t,J＝7.5Hz,2H),2.72(t,J＝7.6Hz,2H).13C NMR(126MHz,DMSO-d6)δ169.45,155.74,149.50(2C),148.91,146.72,142.74,139.01,130.11,127.72,125.72,124.95,123.22(2C),122.48,118.51,110.80,102.18,99.31,54.78,35.88,29.25.
实施例31
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-4-(吡啶-2-基)苯甲酰胺(化合物31)的合成：
参照实施例2，羟基乙酸被替换成4-(吡啶-2-基)苯甲酸。
1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.35(s,1H),8.69-8.64(m,1H),8.23(dd,J＝23.1,5.3Hz,3H),8.05(dd,J＝23.0,8.2Hz,3H),7.96(d,J＝1.9Hz,1H),7.87(td,J＝7.7,1.8Hz,1H),7.65(d,J＝1.8Hz,1H),7.52(dd,J＝8.3,1.9Hz,1H),7.44-7.32(m,2H),7.29(d,J＝8.2Hz,1H),6.41(dd,J＝3.3,1.9Hz,1H),3.74(s,3H).13C NMR(126MHz,DMSO-d6)δ165.59,156.75,155.44,150.22,147.84,143.85,141.97,140.13,137.89,135.56,131.09,128.87,128.67(2C),126.91(2C),126.82,126.03,124.13,123.73,121.29,119.61,113.10,104.52,100.42,55.95.
实施例32
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-4-(吡啶-3-基)苯甲酰胺(化合物32)的合成：
参照实施例2，羟基乙酸被替换成4-(吡啶-3-基)苯甲酸。
1H NMR(500MHz,DMSO-d6)δ11.66(s,1H),10.48(s,1H),9.01(d,J＝2.1Hz,1H),8.64(dd,J＝4.7,1.4Hz,1H),8.32(d,J＝2.0Hz,1H),8.24-8.13(m,3H),8.03(d,J＝2.0Hz,1H),7.94(d,J＝8.3Hz,2H),7.75(d,J＝1.5Hz,1H),7.57(ddd,J＝12.7,8.1,3.3Hz,2H),7.48(d,J＝3.2Hz,1H),7.35(d,J＝8.2Hz,1H),6.48(d,J＝3.3Hz,1H),3.81(s,3H).13C NMR(126MHz,DMSO-d6)δ165.49,156.74,149.60,148.33,147.83,143.84,140.55,140.16,135.06,134.86,134.76,131.06,129.01(2C),128.84,127.31(2C),126.83,126.02,124.44,124.11,119.60,113.10,104.53,100.39,55.96.
实施例33
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-4-(吡啶-4-基)苯甲酰胺(化合物33)的合成：
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参照实施例2，羟基乙酸被替换成4-(吡啶-4-基)苯甲酸。
1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.54(s,1H),8.67-8.60(m,2H),8.25(d,J＝2.0Hz,1H),8.15(d,J＝8.3Hz,2H),7.94(dd,J＝16.7,5.1Hz,3H),7.79-7.69(m,3H),7.57(dd,J＝8.3,1.1Hz,1H),7.45-7.39(m,1H),7.28(d,J＝8.2Hz,1H),6.41(dd,J＝3.3,1.8Hz,1H),3.74(s,3H).13C NMR(126MHz,DMSO-d6)δ165.38,156.71,150.84(2C),147.81,146.45,143.83,140.51,140.15,135.71,131.02,129.14(2C),128.84,127.29(2C),126.84,126.02,124.12,121.86(2C),119.61,113.19,104.66,100.38,55.97.
实施例34
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-4-吗啉代苯甲酰胺(化合物34)的合成：
参照实施例2，羟基乙酸被替换成4-吗啉苯甲酸。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),11.62(s,1H),10.04(s,1H),8.54(d,J＝2.1Hz,1H),8.31(d,J＝2.0Hz,1H),8.23(d,J＝2.0Hz,1H),8.01(d,J＝1.8Hz,1H),7.94(d,J＝8.9Hz,2H),7.70(d,J＝1.8Hz,1H),7.57-7.45(m,3H),7.31(d,J＝8.2Hz,1H),7.05(d,J＝8.9Hz,2H),6.49(ddd,J＝20.2,3.3,1.8Hz,2H),3.79(s,3H),3.78-3.71(m,4H),3.29-3.23(m,4H).13C NMR(126MHz,DMSO-d6)δ164.40,155.62,152.63,147.22,146.72,142.78,141.11,129.90,128.46,127.74,126.48,126.24,125.70,125.05,122.48,119.16,112.74,111.82,103.24,99.43,65.32(2C).,54.83,46.66,46.59
实施例35
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-4-(吗啉甲基)苯甲酰胺(化合物35)的合成：
参照实施例2，羟基乙酸被替换成4-(吗啉甲基)苯甲酸。
1H NMR(500MHz,DMSO-d6)δ10.29(s,1H),8.31(d,J＝1.9Hz,1H),8.02(d,J＝1.8Hz,1H),7.96(d,J＝8.2Hz,2H),7.69(d,J＝1.8Hz,1H),7.48(t,J＝5.8Hz,3H),7.34(d,J＝8.2Hz,1H),6.47(d,J＝1.5Hz,1H),3.79(s,3H),3.66-3.57(m,4H),3.56(s,2H),2.39(s,4H).13C NMR(126MHz,DMSO-d6)δ165.87,156.73,147.83,143.84,142.25,140.20,134.17,131.06,129.28(2C),128.83,128.11(2C),126.80,126.04,124.00,119.60,112.99,104.41,100.40,66.65(2C),62.42,55.92,53.64(2C).
实施例36
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)吗啉-4-甲酰胺(化合物36)的合成：
参照实施例1，乙酰氯被替换成吗啉甲酰氯。
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.65(s,1H),8.27(d,J＝2.0Hz,1H),7.97(d,J＝1.8Hz,1H),7.53-7.43(m,1H),7.37(d,J＝0.9Hz,1H),7.22(t,J＝5.3Hz,2H),6.45(dd,J＝3.3,1.8Hz,1H),3.74(s,3H),3.68-3.60(m,4H),3.55-3.41(m,4H).13C NMR(101MHz,DMSO-d6)δ156.61,155.54,147.69,143.83,141.45,130.82,128.74,126.72,126.23,122.11,119.57,112.14,103.63,100.33,66.47(2C),55.78,44.64(2C).
实施例37
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-吗啉代乙酰胺(化合物37)的合成：
参照实施例2，羟基乙酸被替换成2-吗啉乙酸。
1H NMR(500MHz,DMSO-d6)δ11.54(s,1H),9.74(s,1H),8.20(d,J＝2.0Hz,1H),7.91(d,J＝1.8Hz,1H),7.45(d,J＝1.7Hz,1H),7.42-7.37(m,1H),7.28(dd,J＝8.2,1.8Hz,1H),7.21(d,J＝8.2Hz,1H),6.39(dd,J＝3.3,1.8Hz,1H),3.69(s,3H),3.62-3.56(m,4H),3.09(s,2H),2.49-2.44(m,4H).13C NMR(126MHz,DMSO-d6)δ168.65,156.81,147.80,143.81,139.56,131.12,128.80,126.79,126.01,123.84,119.58,112.23,103.68,100.38,66.56(2C),62.64,55.94,53.66(2C).
实施例38
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-3-吗啉代丙酰胺(化合物38)的合成：
参照实施例2，羟基乙酸被替换成3-吗啉丙酸。
1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.17(s,1H),8.20(d,J＝1.9Hz,1H),7.91(d,J＝2.0Hz,1H),7.44(s,1H),7.40(s,1H),7.20(s,2H),6.39(d,J＝3.0Hz,1H),3.68(s,3H),3.56-3.51(m,4H),2.58(t,J＝7.0Hz,2H),2.46(d,J＝8.0Hz,2H),2.36(s,4H).13CNMR(126MHz,DMSO-d6)δ170.72,156.79,147.77,143.79,140.25,131.14,128.78,126.80,126.04,123.43,119.58,111.83,103.23,100.35,66.68(2C),55.85,54.67,53.53(2C),34.47.
实施例39
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)四氢-2H-吡喃-4-甲酰胺(化合物39)的合成：
参照实施例2，羟基乙酸被替换成四氢-2H-吡喃-4-甲酸。
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.00(s,1H),8.27(d,J＝2.0Hz,1H),7.98(d,J＝1.8Hz,1H),7.49(dd,J＝20.3,17.2Hz,2H),7.27(d,J＝0.7Hz,2H),6.46(dd,J＝3.4,1.8Hz,1H),3.93(dd,J＝8.0,2.9Hz,2H),3.75(s,3H),3.44-3.32(m,2H),2.62(ddd,J＝15.4,10.3,5.3Hz,1H),1.89-1.61(m,4H).13C NMR(101MHz,DMSO-d6)δ173.57,156.77,147.77,143.81,140.32,131.11,128.79,126.79,126.04,123.40,119.57,111.83,103.23,100.37,66.87(2C),55.82,42.35,29.35(2C).
实施例40
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-(四氢-2H-吡喃-4-基)乙酰胺(化合物40)的合成：
参照实施例2，羟基乙酸被替换成2-(四氢-2H-吡喃-4-基)乙酸。
1H NMR(500MHz,DMSO-d6)δ11.54(s,1H),9.93(s,1H),8.20(d,J＝2.0Hz,1H),7.90(d,J＝1.9Hz,1H),7.47-7.36(m,2H),7.23-7.18(m,2H),6.38(dd,J＝3.4,1.8Hz,1H),3.77(dd,J＝11.4,2.6Hz,2H),3.68(s,3H),3.24(td,J＝11.7,1.8Hz,2H),2.21(d,J＝7.1Hz,2H),2.07-1.91(m,1H),1.54(dd,J＝12.8,1.7Hz,2H),1.20(qd,J＝12.0,4.4Hz,2H).13CNMR(126MHz,DMSO-d6)δ170.59,156.79,147.78,143.82,140.18,131.13,128.79,126.77,126.06,123.47,119.58,111.84,103.23,100.37,67.36(2C),55.84,44.21,32.89(2C),32.61.
实施例41
N-(3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-2-(哌啶-1-基)乙酰胺(化合物41)的合成：
参照实施例2，羟基乙酸被替换成2-(哌啶-1-基)乙酸。
1H NMR(500MHz,DMSO-d6)δ11.62(s,2H),9.73(s,2H),8.28(d,J＝2.0Hz,2H),7.98(d,J＝1.8Hz,2H),7.53(d,J＝1.7Hz,2H),7.50-7.44(m,2H),7.36(dd,J＝8.2,1.7Hz,2H),7.28(d,J＝8.2Hz,2H),6.47(dd,J＝3.3,1.8Hz,2H),3.77(s,6H),3.10(s,4H),2.52-2.50(m,3H),1.67-1.54(m,8H),1.42(d,J＝4.8Hz,4H).13C NMR(126MHz,DMSO-d6)δ169.18,156.84,147.80,143.81,139.56,131.13,128.80,126.79,126.02,123.79,119.58,112.12,103.59,100.38,63.26,55.96,54.56,25.91,24.03.
实施例42
叔丁基-4-(2-((3-甲氧基-4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)氨基)-2-氧乙基)哌嗪-1-甲酸酯(化合物42)的合成：
参照实施例2，羟基乙酸被替换成4-叔丁氧羰基-1-哌嗪乙酸。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.84(s,1H),8.27(d,J＝2.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.52(d,J＝1.8Hz,1H),7.50-7.45(m,1H),7.36(dd,J＝8.3,1.8Hz,1H),7.29(d,J＝8.2Hz,1H),6.46(dd,J＝3.4,1.8Hz,1H),3.76(s,3H),3.41(s,4H),3.37(s,4H),3.19(s,2H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ166.67,156.78,154.33,147.78,143.79,139.55,131.13,128.81,126.82,125.98,123.79,119.57,112.16,103.57,100.37,79.29,55.92(2C),52.88(2C),28.52(3C).
实施例43
体外CDK8激酶酶抑制活性和体外细胞活性评价：
使用384孔板通过ADP-Glo Kinase Assay(Promega)测试本发明化合物1-42对CDK8激酶的抑制活性。将活性CDK8激酶稀释在混合物中(5ng CDK8激酶、0.5μg底物、50μMDTT、1μL buffer，每孔加入dd H2O至3μL)，然后每孔加入1uL浓度为1uM的化合物溶液(化合物终浓度为200nM)，随后加入1uL ATP(三磷酸腺苷)，使其最终浓度为50μM。在室温下孵育1h后加入ADP-Glo溶液和激酶检测试剂，数据由酶标仪收集。选取CCT251545为阳性对照物，结果见表2。
表2化合物1-42在浓度200nM下的CDK8抑制活性
从表2中筛选出抑制率高的化合物进一步测定其CDK8 IC50、IL-8抑制率和NF-KB抑制率，结果见表3。
表3部分高活性化合物的活性数据
从表3可以看出，化合物36表现出好的CDK8抑制活性，同时对IL-8和NF-κB具有很好抑制活性。
实施例44
化合物36的靶标验证：
采用pull-down试验验证化合物36的靶向性。将HCT-116细胞接种到60mm培养皿中，每皿1×106个细胞；用化合物36预处理(或用化合物36和CCT-251545共同处理)12h，再用含有PMSF的NP-40裂解细胞，并在4℃下以14000r/min离心30min，取上清；然后吸取40μL上清液并加入10μL 5×SDS上样缓冲液作为Input组，并将剩余上清液与链霉亲和素琼脂糖混合；在4℃孵育6h后使用裂解缓冲液洗涤珠子3次，并将其重悬于2×SDS上样缓冲液中。
将HEK293T细胞接种到60mm培养皿中并培养过夜，然后使用无血清培养基通过脂质体2000将10μg CDK8质粒转染到HEK293T细胞上，6h后无血清培养基被完全DMEM培养基取代。后续处理方法同上。
结果见图1。从图1可知，化合物36能以浓度依赖性的方式结合CDK8蛋白，并与CCT-251545竞争性地与CDK8结合。
实施例45
化合物36的体外机制研究：
将HEK293细胞以每孔3×104个细胞的密度接种在96孔板中，12h后使用脂质体2000转染pNF-κB-TA-Gluc质粒(每孔100ng)至细胞，6h后加入不同浓度的化合物36，随后用10ng/mL重组人TNF-α处理3h；收集的细胞上清液采用人IL-8ELISA试剂盒进行分析，NF-κB转录活性使用双荧光素酶检测试剂盒进行检测。
将HEK-293细胞接种到60mm培养皿中并孵育24h，用0.1％ DMSO、化合物36或50μMTPCK分别处理细胞2h，然后用20ng/mL TNF-α处理30min。用核提取物试剂盒提取核蛋白，并通过蛋白质印迹法分析核内P65和P50的表达。
结果见图2。从图2可知，化合物36可以显著抑制TNF-α诱导的IL-8的表达以及NF-κB的活性，但是对P65和P50的核易位没有影响，表明化合物36对NF-κB的影响作用于核内，符合CDK8抑制剂对NF-κB的特异性。
实施例46
化合物36在鼠银屑病模型上治疗效果研究：
将雄性Balb/C小鼠随机分为五组，剃除小鼠背部皮肤2cm×3cm的区域。第二天对照组小鼠给予凡士林乳膏，模型组小鼠给予5％咪喹莫特乳膏处理，化合物组小鼠(5，10，20mg/kg)给予5％咪喹莫特乳膏和不同剂量的化合物36。每天对小鼠进行评分，范围从0到4分，以描述银屑病的严重程度。0：无；1：轻微；2：中等；3：有标记；4：非常明显。每天拍摄照片以观察皮肤的变化。在试验结束时，所有小鼠脱颈处死。采集血液和皮肤样本。将部分背部病变皮肤样品收集在10％福尔马林中进行HE染色，其余皮肤样品用WB分析。血液样本采用IL-6和TNF-αELISA试剂盒进行分析。
结果见图3。从图3可知，化合物36对小鼠银屑病模型有明显的缓解作用。
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 (6)
1.一种N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物，其特征在于，结构如式I所示：
其中，R1选自氢、卤素、烷基、烷氧基、苯基、苯氧基中的任一种；
R2选自烷基、烷基醇、环烷基、取代环烷基、苯基、取代苯基、呋喃基、取代呋喃基、四氢呋喃基、取代四氢呋喃基、噻唑基、取代噻唑基、苯并呋喃基、取代苯并呋喃基、吡啶基、取代吡啶基、嘧啶基、取代嘧啶基、吡啶酮基、取代吡啶酮基、吗啉基、取代吗啉基、四氢-2H-吡喃基、取代四氢-2H-吡喃基、哌啶基、取代哌啶基、哌嗪基、取代哌嗪基中的任一种。
2.权利要求1所述的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物的制备方法，其特征在于，包括以下步骤：
(1)与5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯并[2,3-b]吡啶发生Suzuki-Miyaura反应，得到中间体M1；
(2)中间体M1与R2COOH或R2COCl发生酰胺缩合反应，得到化合物1-42；
反应方程式如下：
3.一种药物组合物，含有权利要求1所述的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐。
4.一种药物制剂，包括有效成分和药学上可接受的辅料和/或载体，所述有效成分含有权利要求1所述的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐。
5.权利要求1所述的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐在制备CDK8抑制剂中的应用。
6.权利要求1所述的N-(4-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)酰胺衍生物或其药学上可接受的盐在制备治疗银屑病药物中的应用。
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