吡啶联异噁唑类化合物的设计、 合成及抗肿瘤活性

doi:10.7503/cjcu20140333

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (12): 2584.doi: 10.7503/cjcu20140333

吡啶联异噁唑类化合物的设计、合成及抗肿瘤活性

杨洪亮¹, 徐国兴¹, 宝梅英², 张大鹏¹, 李志伟¹(), 裴亚中¹()

1. 吉林大学药学院, 组合化学与创新药物研究中心, 长春 130021
2. 长春吉大天元化学技术股份有限公司, 长春 130012

收稿日期:2014-04-09 出版日期:2014-12-10 发布日期:2014-11-06
作者简介:联系人简介: 裴亚中, 男, 博士, 教授, 博士生导师, 主要从事多样化合成与创新药物研究. E-mail:peiyz@jlu.edu.cn;李志伟, 男, 博士, 教授, 博士生导师, 主要从事生物和药物筛选研究. E-mail:zwl.jida@gmail.com
基金资助:
国家自然科学基金(批准号: 81172914, 81071743)、吉林大学唐敖庆教授启动资金和吉林省人才开发基金(批准号: 802110000432)资助

Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities^†

YANG Hongliang¹, XU Guoxing¹, BAO Meiying², ZHANG Dapeng¹, LI Zhiwei^1,^*(), PEI Yazhong^1,^*()

1. The Center for Combinatorial Chemistry and Drug Discovery, School of Pharmaceutical Sciences,Jilin University, Changchun 130021, China
2. Changchun Discovery Sciences Co. Ltd., Changchun 130012, China

Received:2014-04-09 Online:2014-12-10 Published:2014-11-06
Contact: LI Zhiwei,PEI Yazhong E-mail:zwl.jida@gmail.com;peiyz@jlu.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.81172914, 81071743), the Tang Aoqing Professorship Research Grant from Jilin University, China and Jilin Province Talent Development Program, China(No.802110000432)

摘要/Abstract

摘要：

根据已知的激酶变构抑制剂与其靶点激酶的X射线共晶结构, 设计了一系列以吡啶联异噁唑为中心结构的潜在激酶变构抑制剂. 以2-甲基-5-硝基-3-吡啶甲酸甲酯为原料, 通过形成酰胺、磺酰胺和连接嘧啶片段等衍生化手段合成了21个新的吡啶联异噁唑类化合物, 其结构经¹H NMR, ¹³C NMR和MS确证. 采用噻唑蓝(MTT)法测试了所合成化合物的体外抗肿瘤活性, 初步测试结果表明该类化合物对肿瘤细胞的增长具有显著的抑制作用.

关键词: 吡啶联异噁唑, 蛋白激酶, 变构抑制剂, 抗肿瘤活性

Abstract:

Based on the X-ray co-crystal structures of reported allosteric kinase inhibitors bound to their corresponding protein kinases, a pharmacophore model was proposed. To examine the validity of this hypothesis, 21 new pyridinylisoxazole derivatives were designed and synthesized. Their structures were confirmed using ¹H NMR, ¹³C NMR and MS data. Their inhibitory effects against human breast cancer cell(MCF-7) proliferation were evaluated. Preliminary results indicated that some of these pyridinylisoxazole derivatives possess potent anti-proliferative activities, with IC₅₀ data in the micromolar range. The mechanism-of-action of these compounds is under investigation.

Key words: Pyridinylisoxazole, Protein kinase, Allosteric kinase inhibitor, Antitumor activity

中图分类号:

O621

TrendMD:

杨洪亮, 徐国兴, 宝梅英, 张大鹏, 李志伟, 裴亚中. 吡啶联异噁唑类化合物的设计、合成及抗肿瘤活性. 高等学校化学学报, 2014, 35(12): 2584.

YANG Hongliang, XU Guoxing, BAO Meiying, ZHANG Dapeng, LI Zhiwei, PEI Yazhong. Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities^†. Chem. J. Chinese Universities, 2014, 35(12): 2584.

图/表 9

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Compd.	R₁	m.p./℃	MS, m/z [M+H⁺]	Compd.	R₂/NR₃R₄	m.p./℃	MS, m/z [M+H⁺]
2	—	116—118	167.2	10b		184—185	598.7
3	—	56—58	406.9	10c		176—178	614.7
4	—	191—193	378.8	10d		199—201	602.7
5	—	227—229		10e		153—155	652.7
6	—	213—215	391.8	10f		159—161	614.7
7	—	107—109	544.8	10g		199—201	602.6
8	—	125—127	444.8	10h		91—93	602.7
9a		195—197	528.9	10i		98—100	598.7
9b		163—165	542.8	10j		202—204	550.7
9c		161—163	528.8	11	—	91—93	556.8
9d		130—132	554.8	12a		121—123	620.7
9e		75—77	590.8	12b		185—186	627.7
9f		96—98	578.7	12c		106—108	551.7
9g		121—123	598.8	12d		154—156	659.7
10a		201—203	584.7

Compd.	R₁	m.p./℃	MS, m/z [M+H⁺]	Compd.	R₂/NR₃R₄	m.p./℃	MS, m/z [M+H⁺]
2	—	116—118	167.2	10b		184—185	598.7
3	—	56—58	406.9	10c		176—178	614.7
4	—	191—193	378.8	10d		199—201	602.7
5	—	227—229		10e		153—155	652.7
6	—	213—215	391.8	10f		159—161	614.7
7	—	107—109	544.8	10g		199—201	602.6
8	—	125—127	444.8	10h		91—93	602.7
9a		195—197	528.9	10i		98—100	598.7
9b		163—165	542.8	10j		202—204	550.7
9c		161—163	528.8	11	—	91—93	556.8
9d		130—132	554.8	12a		121—123	620.7
9e		75—77	590.8	12b		185—186	627.7
9f		96—98	578.7	12c		106—108	551.7
9g		121—123	598.8	12d		154—156	659.7
10a		201—203	584.7

Compd.	¹H NMR(300 MHz, CDCl₃), δ	¹³C NMR(75 MHz, DMSO-d₆), δ
2^a	8.13(d, J=3.0 Hz, 1H), 7.52(d, J=2.7 Hz, 1H), 3.90(s, 3H), 3.65(s, 2H), 2.70(s, 3H)	167.9, 148.9, 140.3, 139.2, 124.8, 123.6, 52.0, 23.4
3^a	8.90(d, J=2.4 Hz, 1H), 8.74(d, J=2.1 Hz, 1H), 8.39(s, 2H), 8.30(s, 1H), 8.10(s, 1H), 3.95(s, 3H), 2.86(s, 3H)	166.3, 163.6, 156.1, 143.6, 135.8, 132.4(q, J=34.1 Hz), 132.2 , 130.6, 127.7, 125.7, 125.3, 122.7(q, J=271.4 Hz), 52.5, 23.9
4^b	10.75(s, 1H), 8.76(s, 1H), 8.63(s, 2H), 8.39(s, 1H), 8.12(s, 1H), 5.40(t, J=5.1 Hz, 1H), 4.53(d, J=5.1 Hz, 2H), 2.37(s, 3H)	162.5, 150.6, 139.0, 136.6, 135.4, 133.2, 130.5(q, J=33.2 Hz), 128.5, 125.9, 125.1, 123.1(q, J=271.4 Hz), 59.8, 20.8
5^b	9.15(s, 1H), 8.92(s, 1H), 8.70(s, 2H), 8.45(s, 1H), 8.42(s, 1H), 2.74(s, 3H)	163.2, 147.3, 143.2, 135.6, 133.3, 130.6(q, J=33.3 Hz), 130.5, 129.7, 128.8, 125.8, 122.9(q, J=271.3 Hz), 17.7
6^b	11.63(s, 1H), 10.83(s, 1H), 8.85(s, 1H), 8.64(s, 2H), 8.48(d, J=2.1 Hz, 1H), 8.41(s, 1H), 8.35(s, 1H), 2.56(s, 3H)	162.9, 150.9, 145.2, 141.5, 136.4, 132.9, 131.0, 130.4(q, J=33.2 Hz), 128.1, 124.6, 124.5(q, J=278.1 Hz), 21.3
7	9.00(s, 1H), 8.80(d, J=2.7 Hz, 1H), 8.43(s, 2H), 8.24(d, J=2.4 Hz, 1H), 8.04(s, 1H), 6.39(s, 1H), 5.23(t, J=5.4 Hz, 1H), 4.47(d, J=6.0 Hz, 2H), 2.61(s, 3H), 1.45(s, 9H)	162.8, 160.9, 155.6, 151.2, 145.4, 141.9, 136.3, 133.2, 130.5(q, J=33.2 Hz), 128.5, 125.3, 124.9, 124.3(q, J=270.5 Hz), 123.5, 102.0, 78.5, 36.1, 28.1, 23.3
8	8.73(s, 1H), 8.65(s, 1H), 8.39(s, 2H), 8.29(d, J=1.8 Hz, 1H), 8.07(s, 1H), 6.41(s, 1H), 4.07(s, 3H), 2.65(s, 3H)	175.7, 162.8, 160.8, 151.1, 142.0, 136.4, 133.4, 130.5(q, J=32.9 Hz), 128.7, 128.2, 125.3, 123.7, 123.1(q, J=271.6 Hz), 101.2, 37.8, 23.4
9a	9.78(s, 1H), 8.83(s, 1H), 8.50(s, 2H), 8.27(s, 1H), 8.03(s, 1H), 6.61(s, 1H), 6.35(s, 1H), 4.57(d, J=5.4 Hz, 2H), 2.57(s, 3H), 1.24(s, 9H)	177.8, 171.7, 162.8, 160.9, 151.3, 141.8, 136.4, 133.3, 130.6(q, J=33.2 Hz), 128.6, 128.4, 125.4, 123.7, 123.1(q, J=268.9 Hz), 101.8, 35.1, 27.3, 23.3
9b^a	9.13(s, 1H), 8.83(s, 1H), 8.48(s, 2H), 8.19(s, 1H), 8.07(s, 1H), 7.37(d, J=6.0 Hz, 1H), 6.37(s, 1H), 4.62(t, J=5.4 Hz, 2H), 4.40(dd, J=6.0 Hz, 1H), 4.06—3.84(m, 2H), 2.29(m, 1H), 2.11—1.82(m, 3H)	169.3, 164.1, 158.5, 156.2, 147.8, 137.2, 131.1, 127.7, 127.2(q, J=33.7 Hz), 124.0, 123.2, 120.6, 119.1, 118.0(q, J=266.0 Hz), 97.7, 64.7, 29.8, 25.3, 20.6, 18.5
9c^a	9.49(s, 1H), 8.79(d, J=2.4 Hz, 1H), 8.48(s, 2H), 8.09(d, J=2.4 Hz, 1H), 8.05(s, 1H), 6.53(t, J=6.0 Hz, 1H), 6.32(s, 1H), 4.58(d, J=5.7 Hz, 2H), 2.52(s, 3H), 2.11(s, 2H), 1.14(dd, J=6.9 Hz, 1H), 1.03—0.87(m, 6H)	173.8, 169.8, 163.9, 161.2, 152.7, 142.3, 136.1, 133.0, 132.3(q, J=33.7 Hz), 129.2, 128.3, 125.9, 124.3, 123.1(q, J=271.4 Hz), 102.8, 45.8, 35.5, 26.4, 23.4, 22.5
9d^b	8.79(d, J=2.4 Hz, 1H), 8.66(s, 2H), 8.44(t, J=6.0 Hz, 1H), 8.35(d, J=2.4 Hz, 1H), 8.26(s, 1H), 6.64(s, 1H), 4.47(d, J=5.7 Hz, 2H), 2.56(s, 3H), 2.18(m, 1H), 1.72(s, 4H), 1.63(s, 1H), 1.33(m, 3H), 1.20(m, 2H)	175.4, 171.1, 163.0, 161.1, 150.4, 142.6, 137.7, 135.0, 130.3(q, J=32.9 Hz), 128.5, 124.7, 123.4, 123.1(q, J=271.4 Hz), 102.0, 43.7, 34.5, 29.0, 25.4, 25.1, 23.2
9e	9.04(s, 1H), 8.81(d, J=2.4 Hz, 1H), 8.47(s, 1H), 8.12(d, J=2.1 Hz, 1H), 8.07(s, 1H), 7.24—7.23(m, 1H), 7.22(s, 1H), 7.19—7.11(m, 2H), 6.25(t, J=5.7 Hz, 1H), 6.21(s, 1H), 4.55(d, J=6.0 Hz, 2H), 2.96(t, J=7.5 Hz, 2H), 2.59(s, 3H), 2.56(d, J=7.5 Hz, 2H)	171.7, 171.1, 162.8, 160.9, 151.3, 142.0, 141.1, 136.4, 133.2, 130.6(q, J=33.3 Hz), 128.6, 128.2, 125.8, 125.4, 123.5, 123.1(q, J=271.1 Hz), 102.2, 36.7, 34.5, 30.9, 23.3
9f	9.25(s, 1H), 8.85(d, J=2.4 Hz, 1H), 8.46(s, 2H), 8.03(s, 1H), 8.00(d, J=2.4 Hz, 1H), 7.32(t, J=6.0 Hz, 2H), 7.04(d, J=6.6 Hz, 1H), 6.34(s, 1H), 4.77(d, J=6.0 Hz, 2H), 3.78(s, 3H), 2.57(s, 3H)	176.2, 171.8, 168.0, 164.4, 156.6, 147.2, 140.2, 138.4, 137.4, 135.8(q, J=33.8 Hz), 134.8, 134.7, 133.8, 133.5, 128.7, 125.4(q, J=251.4 Hz), 124.8, 122.6, 119.1, 117.7, 107.6, 60.4, 41.5, 28.6
9g	9.33(s, 1H), 8.87(d, J=2.4 Hz, 1H), 8.47(s, 2H), 8.32(s, 1H), 8.02(d, J=2.4 Hz, 1H), 8.00(s, 1H), 7.91—7.77(m, 4H), 7.61—7.50(m, 2H), 7.47(t, J=5.7 Hz, 2H), 6.35(s, 1H), 4.82(d, J=5.7 Hz, 2H), 2.54(s, 3H)	171.0, 166.5, 162.7, 161.1, 151.4, 142.0, 136.3, 134.3, 133.2, 132.1, 131.0, 130.6(q, J=33.2 Hz), 128.9, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6, 126.7, 125.3, 124.1, 123.5, 123.1(q, J=271.3 Hz), 102.5, 35.4, 23.4
10a^b	10.93(s, 1H), 8.92(d, J=1.8 Hz, 1H), 8.65(s, 2H), 8.57(t, J=6.0 Hz, 1H), 8.43(s, 1H), 8.30(d, J=2.1 Hz, 1H), 7.99—7.83(m, 2H), 7.63—7.55(m, 3H), 6.63(s, 1H), 4.33(d, J=6.0 Hz, 2H), 2.53(s, 3H)	169.2, 162.8, 160.7, 151.2, 141.9, 140.3, 136.3, 133.2, 132.5, 130.5(q, J=33.3 Hz), 129.1, 128.5, 128.1, 126.4, 125.3, 123.3, 123.0(q, J=271.4 Hz), 103.2, 23.2
10b	8.92(s, 1H), 8.63(s, 1H), 8.43(s, 2H), 8.17(s, 1H), 8.07(s, 1H), 7.76(d, J=8.1 Hz, 2H), 7.32(d, J=8.1 Hz, 2H), 6.37(s, 1H), 4.37(d, J=6.3 Hz, 2H), 2.61(s, 3H), 2.40(s, 3H)	169.3, 162.8, 160.8, 151.3, 142.8, 142.1, 137.6, 136.4, 133.2, 130.8(q, J=33.2 Hz), 129.6, 128.6, 128.2, 126.5, 125.3, 124.9(q, J=271.4 Hz), 123.3, 103.2, 38.0, 23.2, 20.8
10c	8.93(d, J=2.1 Hz, 1H), 8.69(s, 1H), 8.41(s, 2H), 8.06(d, J=2.1 Hz, 1H), 8.04(s, 1H), 7.78(d, J=9.0 Hz, 2H), 6.95(d, J=9.0 Hz, 2H), 6.32(s, 1H), 4.32(d, J=6.3 Hz, 2H), 3.80(s, 3H), 2.57(s, 3H)	162.8, 162.2, 160.7, 151.2, 142.0, 136.4, 133.1, 132.0, 131.4, 130.6(q, J=33.3 Hz), 128.7, 128.6, 128.2, 125.3, 123.3, 123.1(q, J=271.4 Hz), 114.2, 103.1, 55.5, 38.0, 23.2
10d^b	10.93(s, 1H), 8.92(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.30(d, J=2.7 Hz, 1H), 7.96—7.78(m, 2H), 7.41(t, J=9.0 Hz, 2H), 6.65(s, 1H), 4.35(d, J= 3.3 Hz, 2H), 2.54(s, 3H)	169.2, 165.8, 162.9, 162.5, 160.8, 151.3, 142.0, 136.9, 134.8(d, J=235.1 Hz), 130.6(q, J=33.2 Hz), 129.6(d, J=7.4 Hz), 128.6, 128.2, 125.5, 123.3, 123.1(q, J=271.1 Hz), 116.3(d, J=22.6 Hz), 103.3, 37.9, 23.3
10e^b	10.93(s, 1H), 8.91(d, J=2.4 Hz, 1H), 8.85(s, 1H), 8.65(s, 2H), 8.44(s, 1H), 8.28(d, J=2.4 Hz, 1H), 8.18—8.04(m, 2H), 8.01(d, J=8.1 Hz, 1H), 7.83(t, J=7.8 Hz, 1H), 6.66(s, 1H), 4.43(s, 2H), 2.51(s, 3H)	168.8, 162.9, 160.8, 151.2, 142.1, 141.7, 136.4, 133.2, 130.6(q, J=30.3 Hz), 130.6(q, J=33.8 Hz), 129.3, 128.6, 128.1, 125.6, 125.5(q, J=181.2 Hz), 123.6(q, J=271.6 Hz), 123.2, 103.4, 37.8, 23.3
10f^b	10.92(s, 1H), 8.92(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.55(t, J=6.0 Hz, 1H), 8.42(s, 1H), 8.31(d, J=2.4 Hz, 1H), 7.49(t, J=7.8 Hz, 1H), 7.41—7.35(m, 1H), 7.33—7.28(m, 1H), 7.17(m, 1H), 6.64(s, 1H), 4.33(d, J=6.0 Hz, 2H), 3.79(s, 3H), 2.53(s, 3H)	174.4, 168.0, 165.9, 164.5, 156.4, 147.2, 146.7, 141.5, 138.3, 135.9(q, J=33.0 Hz), 135.5, 133.7, 133.3, 130.5, 128.4, 128.2(q, J=271.6 Hz), 123.7, 123.6, 116.6, 108.4, 60.6, 43.1, 28.4
10g^b	10.93(s, 1H), 8.92(d, J=2.7 Hz, 1H), 8.73(t, J=6.3 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.30(d, J=2.4 Hz, 1H), 7.67—7.57(m, 3H), 7.55—7.45(m, 1H), 6.68(s, 1H), 4.38(d, J=6.0 Hz, 2H), 2.53(s, 3H)	174.2, 168.0, 166.8(d, J=247.1 Hz), 166.0, 156.4, 147.7(d, J=6.45 Hz), 147.2, 141.6, 138.4, 136.8(d, J=7.95 Hz), 135.7(q, J=33.1 Hz), 133.8, 133.3, 130.6, 128.5, 128.2(q, J=268.9 Hz), 127.9(d, J=2.9 Hz), 125.1(d, J=20.9 Hz), 118.7(d, J=24.3 Hz), 108.6, 43.1, 28.4
10h^b	10.91(s, 1H), 8.91(d, J=2.4 Hz, 1H), 8.86(t, J=6.0 Hz, 1H), 8.65(s, 2H), 8.41(s, 1H), 8.28(d, J=2.4 Hz, 1H), 7.78(td, J=7.5, 1.8 Hz, 1H), 7.72—7.60(m, 1H), 7.46—7.28(m, 2H), 6.63(s, 1H), 4.43(d, J=6.3 Hz, 2H), 2.52(s, 3H)	169.3, 163.2, 160.9, 158.4(d, J=252.2 Hz), 151.5, 142.2, 136.5, 135.8, 135.7(d, J=8.5 Hz), 133.4, 130.8(q, J=33.4 Hz), 129.8, 128.7(d, J=19.5 Hz), 128.4(d, J=9.9 Hz), 125.6, 125.2(q, J=271.0 Hz), 123.5, 123.0(d, J=3.7 Hz), 117.3(d, J=20.7 Hz), 103.5, 37.9, 23.4
10i^b	10.93(s, 1H), 8.92(d, J=2.1 Hz, 1H), 8.66(s, 2H), 8.42(s, 1H), 8.29(d, J=2.1 Hz, 1H), 7.83(d, J=7.2 Hz, 1H), 7.51—7.46(m, 1H), 7.41—7.27(m, 2H), 6.54(s, 1H), 4.34(d, J=6.3 Hz, 2H), 3.36(s, 3H), 2.59(s, 3H)	169.3, 162.8, 160.7, 151.2, 142.0, 138.4, 136.6, 136.4, 134.8, 133.2, 132.9, 132.6, 132.4, 130.1(q, J=33.4 Hz), 128.5, 128.1, 126.1, 123.3, 123.1(q, J=271.3 Hz), 103.1, 37.6, 23.2, 19.7
10j^b	10.94(s, 1H), 8.96(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.38(d, J=2.7 Hz, 1H), 7.93(t, J=5.7 Hz, 1H), 6.85(s, 1H), 4.45(d, J=4.8 Hz, 2H), 3.22(m, 1H), 2.62(s, 3H), 1.25(s, 3H), 1.23(s, 3H)	170.7, 162.8, 161.0, 151.3, 142.0, 136.3, 133.2, 130.6(q, J=33.3 Hz), 128.5, 128.2, 125.6, 123.4, 123.0(q, J=274.7 Hz), 103.0, 52.1, 38.0, 23.3, 16.2
11^b	10.90(s, 1H), 8.94(d, J=2.4 Hz, 1H), 8.64(s, 2H), 8.41(s, 1H), 8.39—8.33(m, 3H), 6.81(d, J=5.4 Hz, 1H), 6.76(s, 1H), 4.73(d, J=5.7 Hz, 2H), 2.60(s, 3H)	162.8, 161.9, 161.0, 160.9, 154.8, 151.3, 142.0, 136.3, 133.1, 130.5(q, J=33.2 Hz), 128.5, 128.2, 125.4, 123.5, 123.0(q, J=275.6 Hz), 110.4, 102.7, 102.6, 23.3, 13.2
12a^b	10.94(s, 1H), 8.93(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.41(s, 1H), 8.36(d, J=2.4 Hz, 1H), 7.78(d, J=5.7 Hz, 1H), 7.72(s, 1H), 6.73(s, 1H), 5.88(d, J=5.7 Hz, 1H), 4.69(d, J=5.4 Hz, 2H), 3.62(t, J=4.5 Hz, 4H), 2.60(s, 3H), 2.32(t, J=4.8 Hz, 4H), 2.15(s, 3H)	171.8, 162.8, 162.0, 161.0, 160.9, 155.4, 151.3, 141.9, 136.3, 133.2, 130.6(q, J=33.3 Hz), 128.6, 128.2, 125.5, 123.5, 123.1(q, J=271.8 Hz), 102.1, 54.4, 45.6, 43.1, 35.9, 23.4
12b^b	10.91(s, 1H), 8.95(s, 1H), 8.65(s, 2H), 8.42(s, 1H), 8.32(s, 1H), 7.71(d, J=5.7 Hz, 1H), 7.64(s, 1H), 7.28—7.20(m, 4H), 7.11(s, 1H), 6.62(s, 1H), 5.85(d, J=5.7 Hz, 1H), 4.68(d, J=4.8 Hz, 2H), 4.42(d, J=5.4 Hz, 2H), 2.58(s, 3H)	162.7, 162.3, 161.4, 157.3, 156.0, 154.5, 151.7, 141.2, 136.3, 133.0, 130.6(q, J=32.9 Hz), 128.5, 128.0, 125.4, 123.9, 123.0(q, J=271.2 Hz), 113.1, 98.0, 43.4, 25.0, 13.0
12c^b	10.91(s, 1H), 8.95(d, J=2.7 Hz, 1H), 8.64(s, 2H), 8.41(s, 1H), 8.34(d, J=2.4 Hz, 1H), 7.72(d, J=5.7 Hz, 1H), 7.58(s, 1H), 6.73(s, 1H), 6.45(d, J=4.5 Hz, 1H), 5.83(d, J=5.7 Hz, 1H), 4.70(d, J=6.0 Hz, 2H), 2.72(d, J=4.8 Hz, 3H), 2.61(s, 3H)	171.9, 162.8, 162.4, 162.2, 160.9, 155.3, 151.3, 141.9, 136.4, 133.2, 130.6(q, J=33.2 Hz), 128.6, 128.2, 125.4, 124.9(q, J=271.4 Hz), 123.6, 102.2, 35.1, 27.7, 23.4
12d^b	11.77(s, 1H), 10.89(s, 1H), 8.94(d, J=2.7 Hz, 1H), 8.63(s, 2H), 8.40(s, 1H), 8.31(d, J=2.4 Hz, 1H), 7.86(d, J=5.4 Hz, 2H), 6.74(s, 1H), 6.19(s, 1H), 6.02(d, J=5.7 Hz, 1H), 4.77(d, J=5.4 Hz, 2H), 2.57(s, 3H), 1.21(s, 9H)	171.7, 162.8, 162.2, 160.9, 159.0, 151.3, 142.0, 136.4, 133.2, 130.6(q, J=33.1 Hz), 128.6, 128.2, 125.4, 123.5, 123.1(q, J=267.8 Hz), 102.3, 36.0, 30.8, 30.0, 23.4

Compd.	¹H NMR(300 MHz, CDCl₃), δ	¹³C NMR(75 MHz, DMSO-d₆), δ
2^a	8.13(d, J=3.0 Hz, 1H), 7.52(d, J=2.7 Hz, 1H), 3.90(s, 3H), 3.65(s, 2H), 2.70(s, 3H)	167.9, 148.9, 140.3, 139.2, 124.8, 123.6, 52.0, 23.4
3^a	8.90(d, J=2.4 Hz, 1H), 8.74(d, J=2.1 Hz, 1H), 8.39(s, 2H), 8.30(s, 1H), 8.10(s, 1H), 3.95(s, 3H), 2.86(s, 3H)	166.3, 163.6, 156.1, 143.6, 135.8, 132.4(q, J=34.1 Hz), 132.2 , 130.6, 127.7, 125.7, 125.3, 122.7(q, J=271.4 Hz), 52.5, 23.9
4^b	10.75(s, 1H), 8.76(s, 1H), 8.63(s, 2H), 8.39(s, 1H), 8.12(s, 1H), 5.40(t, J=5.1 Hz, 1H), 4.53(d, J=5.1 Hz, 2H), 2.37(s, 3H)	162.5, 150.6, 139.0, 136.6, 135.4, 133.2, 130.5(q, J=33.2 Hz), 128.5, 125.9, 125.1, 123.1(q, J=271.4 Hz), 59.8, 20.8
5^b	9.15(s, 1H), 8.92(s, 1H), 8.70(s, 2H), 8.45(s, 1H), 8.42(s, 1H), 2.74(s, 3H)	163.2, 147.3, 143.2, 135.6, 133.3, 130.6(q, J=33.3 Hz), 130.5, 129.7, 128.8, 125.8, 122.9(q, J=271.3 Hz), 17.7
6^b	11.63(s, 1H), 10.83(s, 1H), 8.85(s, 1H), 8.64(s, 2H), 8.48(d, J=2.1 Hz, 1H), 8.41(s, 1H), 8.35(s, 1H), 2.56(s, 3H)	162.9, 150.9, 145.2, 141.5, 136.4, 132.9, 131.0, 130.4(q, J=33.2 Hz), 128.1, 124.6, 124.5(q, J=278.1 Hz), 21.3
7	9.00(s, 1H), 8.80(d, J=2.7 Hz, 1H), 8.43(s, 2H), 8.24(d, J=2.4 Hz, 1H), 8.04(s, 1H), 6.39(s, 1H), 5.23(t, J=5.4 Hz, 1H), 4.47(d, J=6.0 Hz, 2H), 2.61(s, 3H), 1.45(s, 9H)	162.8, 160.9, 155.6, 151.2, 145.4, 141.9, 136.3, 133.2, 130.5(q, J=33.2 Hz), 128.5, 125.3, 124.9, 124.3(q, J=270.5 Hz), 123.5, 102.0, 78.5, 36.1, 28.1, 23.3
8	8.73(s, 1H), 8.65(s, 1H), 8.39(s, 2H), 8.29(d, J=1.8 Hz, 1H), 8.07(s, 1H), 6.41(s, 1H), 4.07(s, 3H), 2.65(s, 3H)	175.7, 162.8, 160.8, 151.1, 142.0, 136.4, 133.4, 130.5(q, J=32.9 Hz), 128.7, 128.2, 125.3, 123.7, 123.1(q, J=271.6 Hz), 101.2, 37.8, 23.4
9a	9.78(s, 1H), 8.83(s, 1H), 8.50(s, 2H), 8.27(s, 1H), 8.03(s, 1H), 6.61(s, 1H), 6.35(s, 1H), 4.57(d, J=5.4 Hz, 2H), 2.57(s, 3H), 1.24(s, 9H)	177.8, 171.7, 162.8, 160.9, 151.3, 141.8, 136.4, 133.3, 130.6(q, J=33.2 Hz), 128.6, 128.4, 125.4, 123.7, 123.1(q, J=268.9 Hz), 101.8, 35.1, 27.3, 23.3
9b^a	9.13(s, 1H), 8.83(s, 1H), 8.48(s, 2H), 8.19(s, 1H), 8.07(s, 1H), 7.37(d, J=6.0 Hz, 1H), 6.37(s, 1H), 4.62(t, J=5.4 Hz, 2H), 4.40(dd, J=6.0 Hz, 1H), 4.06—3.84(m, 2H), 2.29(m, 1H), 2.11—1.82(m, 3H)	169.3, 164.1, 158.5, 156.2, 147.8, 137.2, 131.1, 127.7, 127.2(q, J=33.7 Hz), 124.0, 123.2, 120.6, 119.1, 118.0(q, J=266.0 Hz), 97.7, 64.7, 29.8, 25.3, 20.6, 18.5
9c^a	9.49(s, 1H), 8.79(d, J=2.4 Hz, 1H), 8.48(s, 2H), 8.09(d, J=2.4 Hz, 1H), 8.05(s, 1H), 6.53(t, J=6.0 Hz, 1H), 6.32(s, 1H), 4.58(d, J=5.7 Hz, 2H), 2.52(s, 3H), 2.11(s, 2H), 1.14(dd, J=6.9 Hz, 1H), 1.03—0.87(m, 6H)	173.8, 169.8, 163.9, 161.2, 152.7, 142.3, 136.1, 133.0, 132.3(q, J=33.7 Hz), 129.2, 128.3, 125.9, 124.3, 123.1(q, J=271.4 Hz), 102.8, 45.8, 35.5, 26.4, 23.4, 22.5
9d^b	8.79(d, J=2.4 Hz, 1H), 8.66(s, 2H), 8.44(t, J=6.0 Hz, 1H), 8.35(d, J=2.4 Hz, 1H), 8.26(s, 1H), 6.64(s, 1H), 4.47(d, J=5.7 Hz, 2H), 2.56(s, 3H), 2.18(m, 1H), 1.72(s, 4H), 1.63(s, 1H), 1.33(m, 3H), 1.20(m, 2H)	175.4, 171.1, 163.0, 161.1, 150.4, 142.6, 137.7, 135.0, 130.3(q, J=32.9 Hz), 128.5, 124.7, 123.4, 123.1(q, J=271.4 Hz), 102.0, 43.7, 34.5, 29.0, 25.4, 25.1, 23.2
9e	9.04(s, 1H), 8.81(d, J=2.4 Hz, 1H), 8.47(s, 1H), 8.12(d, J=2.1 Hz, 1H), 8.07(s, 1H), 7.24—7.23(m, 1H), 7.22(s, 1H), 7.19—7.11(m, 2H), 6.25(t, J=5.7 Hz, 1H), 6.21(s, 1H), 4.55(d, J=6.0 Hz, 2H), 2.96(t, J=7.5 Hz, 2H), 2.59(s, 3H), 2.56(d, J=7.5 Hz, 2H)	171.7, 171.1, 162.8, 160.9, 151.3, 142.0, 141.1, 136.4, 133.2, 130.6(q, J=33.3 Hz), 128.6, 128.2, 125.8, 125.4, 123.5, 123.1(q, J=271.1 Hz), 102.2, 36.7, 34.5, 30.9, 23.3
9f	9.25(s, 1H), 8.85(d, J=2.4 Hz, 1H), 8.46(s, 2H), 8.03(s, 1H), 8.00(d, J=2.4 Hz, 1H), 7.32(t, J=6.0 Hz, 2H), 7.04(d, J=6.6 Hz, 1H), 6.34(s, 1H), 4.77(d, J=6.0 Hz, 2H), 3.78(s, 3H), 2.57(s, 3H)	176.2, 171.8, 168.0, 164.4, 156.6, 147.2, 140.2, 138.4, 137.4, 135.8(q, J=33.8 Hz), 134.8, 134.7, 133.8, 133.5, 128.7, 125.4(q, J=251.4 Hz), 124.8, 122.6, 119.1, 117.7, 107.6, 60.4, 41.5, 28.6
9g	9.33(s, 1H), 8.87(d, J=2.4 Hz, 1H), 8.47(s, 2H), 8.32(s, 1H), 8.02(d, J=2.4 Hz, 1H), 8.00(s, 1H), 7.91—7.77(m, 4H), 7.61—7.50(m, 2H), 7.47(t, J=5.7 Hz, 2H), 6.35(s, 1H), 4.82(d, J=5.7 Hz, 2H), 2.54(s, 3H)	171.0, 166.5, 162.7, 161.1, 151.4, 142.0, 136.3, 134.3, 133.2, 132.1, 131.0, 130.6(q, J=33.2 Hz), 128.9, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6, 126.7, 125.3, 124.1, 123.5, 123.1(q, J=271.3 Hz), 102.5, 35.4, 23.4
10a^b	10.93(s, 1H), 8.92(d, J=1.8 Hz, 1H), 8.65(s, 2H), 8.57(t, J=6.0 Hz, 1H), 8.43(s, 1H), 8.30(d, J=2.1 Hz, 1H), 7.99—7.83(m, 2H), 7.63—7.55(m, 3H), 6.63(s, 1H), 4.33(d, J=6.0 Hz, 2H), 2.53(s, 3H)	169.2, 162.8, 160.7, 151.2, 141.9, 140.3, 136.3, 133.2, 132.5, 130.5(q, J=33.3 Hz), 129.1, 128.5, 128.1, 126.4, 125.3, 123.3, 123.0(q, J=271.4 Hz), 103.2, 23.2
10b	8.92(s, 1H), 8.63(s, 1H), 8.43(s, 2H), 8.17(s, 1H), 8.07(s, 1H), 7.76(d, J=8.1 Hz, 2H), 7.32(d, J=8.1 Hz, 2H), 6.37(s, 1H), 4.37(d, J=6.3 Hz, 2H), 2.61(s, 3H), 2.40(s, 3H)	169.3, 162.8, 160.8, 151.3, 142.8, 142.1, 137.6, 136.4, 133.2, 130.8(q, J=33.2 Hz), 129.6, 128.6, 128.2, 126.5, 125.3, 124.9(q, J=271.4 Hz), 123.3, 103.2, 38.0, 23.2, 20.8
10c	8.93(d, J=2.1 Hz, 1H), 8.69(s, 1H), 8.41(s, 2H), 8.06(d, J=2.1 Hz, 1H), 8.04(s, 1H), 7.78(d, J=9.0 Hz, 2H), 6.95(d, J=9.0 Hz, 2H), 6.32(s, 1H), 4.32(d, J=6.3 Hz, 2H), 3.80(s, 3H), 2.57(s, 3H)	162.8, 162.2, 160.7, 151.2, 142.0, 136.4, 133.1, 132.0, 131.4, 130.6(q, J=33.3 Hz), 128.7, 128.6, 128.2, 125.3, 123.3, 123.1(q, J=271.4 Hz), 114.2, 103.1, 55.5, 38.0, 23.2
10d^b	10.93(s, 1H), 8.92(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.30(d, J=2.7 Hz, 1H), 7.96—7.78(m, 2H), 7.41(t, J=9.0 Hz, 2H), 6.65(s, 1H), 4.35(d, J= 3.3 Hz, 2H), 2.54(s, 3H)	169.2, 165.8, 162.9, 162.5, 160.8, 151.3, 142.0, 136.9, 134.8(d, J=235.1 Hz), 130.6(q, J=33.2 Hz), 129.6(d, J=7.4 Hz), 128.6, 128.2, 125.5, 123.3, 123.1(q, J=271.1 Hz), 116.3(d, J=22.6 Hz), 103.3, 37.9, 23.3
10e^b	10.93(s, 1H), 8.91(d, J=2.4 Hz, 1H), 8.85(s, 1H), 8.65(s, 2H), 8.44(s, 1H), 8.28(d, J=2.4 Hz, 1H), 8.18—8.04(m, 2H), 8.01(d, J=8.1 Hz, 1H), 7.83(t, J=7.8 Hz, 1H), 6.66(s, 1H), 4.43(s, 2H), 2.51(s, 3H)	168.8, 162.9, 160.8, 151.2, 142.1, 141.7, 136.4, 133.2, 130.6(q, J=30.3 Hz), 130.6(q, J=33.8 Hz), 129.3, 128.6, 128.1, 125.6, 125.5(q, J=181.2 Hz), 123.6(q, J=271.6 Hz), 123.2, 103.4, 37.8, 23.3
10f^b	10.92(s, 1H), 8.92(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.55(t, J=6.0 Hz, 1H), 8.42(s, 1H), 8.31(d, J=2.4 Hz, 1H), 7.49(t, J=7.8 Hz, 1H), 7.41—7.35(m, 1H), 7.33—7.28(m, 1H), 7.17(m, 1H), 6.64(s, 1H), 4.33(d, J=6.0 Hz, 2H), 3.79(s, 3H), 2.53(s, 3H)	174.4, 168.0, 165.9, 164.5, 156.4, 147.2, 146.7, 141.5, 138.3, 135.9(q, J=33.0 Hz), 135.5, 133.7, 133.3, 130.5, 128.4, 128.2(q, J=271.6 Hz), 123.7, 123.6, 116.6, 108.4, 60.6, 43.1, 28.4
10g^b	10.93(s, 1H), 8.92(d, J=2.7 Hz, 1H), 8.73(t, J=6.3 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.30(d, J=2.4 Hz, 1H), 7.67—7.57(m, 3H), 7.55—7.45(m, 1H), 6.68(s, 1H), 4.38(d, J=6.0 Hz, 2H), 2.53(s, 3H)	174.2, 168.0, 166.8(d, J=247.1 Hz), 166.0, 156.4, 147.7(d, J=6.45 Hz), 147.2, 141.6, 138.4, 136.8(d, J=7.95 Hz), 135.7(q, J=33.1 Hz), 133.8, 133.3, 130.6, 128.5, 128.2(q, J=268.9 Hz), 127.9(d, J=2.9 Hz), 125.1(d, J=20.9 Hz), 118.7(d, J=24.3 Hz), 108.6, 43.1, 28.4
10h^b	10.91(s, 1H), 8.91(d, J=2.4 Hz, 1H), 8.86(t, J=6.0 Hz, 1H), 8.65(s, 2H), 8.41(s, 1H), 8.28(d, J=2.4 Hz, 1H), 7.78(td, J=7.5, 1.8 Hz, 1H), 7.72—7.60(m, 1H), 7.46—7.28(m, 2H), 6.63(s, 1H), 4.43(d, J=6.3 Hz, 2H), 2.52(s, 3H)	169.3, 163.2, 160.9, 158.4(d, J=252.2 Hz), 151.5, 142.2, 136.5, 135.8, 135.7(d, J=8.5 Hz), 133.4, 130.8(q, J=33.4 Hz), 129.8, 128.7(d, J=19.5 Hz), 128.4(d, J=9.9 Hz), 125.6, 125.2(q, J=271.0 Hz), 123.5, 123.0(d, J=3.7 Hz), 117.3(d, J=20.7 Hz), 103.5, 37.9, 23.4
10i^b	10.93(s, 1H), 8.92(d, J=2.1 Hz, 1H), 8.66(s, 2H), 8.42(s, 1H), 8.29(d, J=2.1 Hz, 1H), 7.83(d, J=7.2 Hz, 1H), 7.51—7.46(m, 1H), 7.41—7.27(m, 2H), 6.54(s, 1H), 4.34(d, J=6.3 Hz, 2H), 3.36(s, 3H), 2.59(s, 3H)	169.3, 162.8, 160.7, 151.2, 142.0, 138.4, 136.6, 136.4, 134.8, 133.2, 132.9, 132.6, 132.4, 130.1(q, J=33.4 Hz), 128.5, 128.1, 126.1, 123.3, 123.1(q, J=271.3 Hz), 103.1, 37.6, 23.2, 19.7
10j^b	10.94(s, 1H), 8.96(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.43(s, 1H), 8.38(d, J=2.7 Hz, 1H), 7.93(t, J=5.7 Hz, 1H), 6.85(s, 1H), 4.45(d, J=4.8 Hz, 2H), 3.22(m, 1H), 2.62(s, 3H), 1.25(s, 3H), 1.23(s, 3H)	170.7, 162.8, 161.0, 151.3, 142.0, 136.3, 133.2, 130.6(q, J=33.3 Hz), 128.5, 128.2, 125.6, 123.4, 123.0(q, J=274.7 Hz), 103.0, 52.1, 38.0, 23.3, 16.2
11^b	10.90(s, 1H), 8.94(d, J=2.4 Hz, 1H), 8.64(s, 2H), 8.41(s, 1H), 8.39—8.33(m, 3H), 6.81(d, J=5.4 Hz, 1H), 6.76(s, 1H), 4.73(d, J=5.7 Hz, 2H), 2.60(s, 3H)	162.8, 161.9, 161.0, 160.9, 154.8, 151.3, 142.0, 136.3, 133.1, 130.5(q, J=33.2 Hz), 128.5, 128.2, 125.4, 123.5, 123.0(q, J=275.6 Hz), 110.4, 102.7, 102.6, 23.3, 13.2
12a^b	10.94(s, 1H), 8.93(d, J=2.4 Hz, 1H), 8.65(s, 2H), 8.41(s, 1H), 8.36(d, J=2.4 Hz, 1H), 7.78(d, J=5.7 Hz, 1H), 7.72(s, 1H), 6.73(s, 1H), 5.88(d, J=5.7 Hz, 1H), 4.69(d, J=5.4 Hz, 2H), 3.62(t, J=4.5 Hz, 4H), 2.60(s, 3H), 2.32(t, J=4.8 Hz, 4H), 2.15(s, 3H)	171.8, 162.8, 162.0, 161.0, 160.9, 155.4, 151.3, 141.9, 136.3, 133.2, 130.6(q, J=33.3 Hz), 128.6, 128.2, 125.5, 123.5, 123.1(q, J=271.8 Hz), 102.1, 54.4, 45.6, 43.1, 35.9, 23.4
12b^b	10.91(s, 1H), 8.95(s, 1H), 8.65(s, 2H), 8.42(s, 1H), 8.32(s, 1H), 7.71(d, J=5.7 Hz, 1H), 7.64(s, 1H), 7.28—7.20(m, 4H), 7.11(s, 1H), 6.62(s, 1H), 5.85(d, J=5.7 Hz, 1H), 4.68(d, J=4.8 Hz, 2H), 4.42(d, J=5.4 Hz, 2H), 2.58(s, 3H)	162.7, 162.3, 161.4, 157.3, 156.0, 154.5, 151.7, 141.2, 136.3, 133.0, 130.6(q, J=32.9 Hz), 128.5, 128.0, 125.4, 123.9, 123.0(q, J=271.2 Hz), 113.1, 98.0, 43.4, 25.0, 13.0
12c^b	10.91(s, 1H), 8.95(d, J=2.7 Hz, 1H), 8.64(s, 2H), 8.41(s, 1H), 8.34(d, J=2.4 Hz, 1H), 7.72(d, J=5.7 Hz, 1H), 7.58(s, 1H), 6.73(s, 1H), 6.45(d, J=4.5 Hz, 1H), 5.83(d, J=5.7 Hz, 1H), 4.70(d, J=6.0 Hz, 2H), 2.72(d, J=4.8 Hz, 3H), 2.61(s, 3H)	171.9, 162.8, 162.4, 162.2, 160.9, 155.3, 151.3, 141.9, 136.4, 133.2, 130.6(q, J=33.2 Hz), 128.6, 128.2, 125.4, 124.9(q, J=271.4 Hz), 123.6, 102.2, 35.1, 27.7, 23.4
12d^b	11.77(s, 1H), 10.89(s, 1H), 8.94(d, J=2.7 Hz, 1H), 8.63(s, 2H), 8.40(s, 1H), 8.31(d, J=2.4 Hz, 1H), 7.86(d, J=5.4 Hz, 2H), 6.74(s, 1H), 6.19(s, 1H), 6.02(d, J=5.7 Hz, 1H), 4.77(d, J=5.4 Hz, 2H), 2.57(s, 3H), 1.21(s, 9H)	171.7, 162.8, 162.2, 160.9, 159.0, 151.3, 142.0, 136.4, 133.2, 130.6(q, J=33.1 Hz), 128.6, 128.2, 125.4, 123.5, 123.1(q, J=267.8 Hz), 102.3, 36.0, 30.8, 30.0, 23.4

Compd.	Inhibition^*(%)	IC₅₀/(μmol·L^-1)	Compd.	Inhibition^*(%)	IC₅₀/(μmol·L^-1)
9a	15.5		10e	17.3
9b	9.7		10f	10.0
9c	22.5		10g	51.8	8.5
9d	24.1		10h	56.7	13.4
9e	16.1		10i	72.2	6.7
9f	20.6		10j	12.8
9g	28.3		12a	65.0	15.6
10a	59.8	9.4	12b	100.0	7.3
10b	20.4		12c	63.0	15.2
10c	21.9		12d	82.0	11.3
10d	47.2		INK128		0.36

吡啶联异噁唑类化合物的设计、合成及抗肿瘤活性

Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities^†

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吡啶联异噁唑类化合物的设计、 合成及抗肿瘤活性

Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities†

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吡啶联异噁唑类化合物的设计、合成及抗肿瘤活性

Design and Synthesis of Pyridinylisoxazoles and Their Anticancer Activities^†