CN116836121A - 一种喹唑啉类化合物及其制备方法和应用 - Google Patents
一种喹唑啉类化合物及其制备方法和应用 Download PDFInfo
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- CN116836121A CN116836121A CN202310686643.5A CN202310686643A CN116836121A CN 116836121 A CN116836121 A CN 116836121A CN 202310686643 A CN202310686643 A CN 202310686643A CN 116836121 A CN116836121 A CN 116836121A
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- quinazoline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- -1 Quinazoline compound Chemical class 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 150000003246 quinazolines Chemical class 0.000 claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 150000004982 aromatic amines Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 32
- BZORFPDSXLZWJF-UHFFFAOYSA-N N,N-dimethyl-1,4-phenylenediamine Chemical compound CN(C)C1=CC=C(N)C=C1 BZORFPDSXLZWJF-UHFFFAOYSA-N 0.000 claims description 21
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 5
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 claims description 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- DYOZNCVZPFIXLU-UHFFFAOYSA-N 1,1,2-trimethoxyethane Chemical compound COCC(OC)OC DYOZNCVZPFIXLU-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 abstract description 18
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical group OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 97
- VDUKDQTYMWUSAC-UHFFFAOYSA-N (4-methylsulfonylphenyl)boronic acid Chemical group CS(=O)(=O)C1=CC=C(B(O)O)C=C1 VDUKDQTYMWUSAC-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- QNGVNLMMEQUVQK-UHFFFAOYSA-N 4-n,4-n-diethylbenzene-1,4-diamine Chemical group CCN(CC)C1=CC=C(N)C=C1 QNGVNLMMEQUVQK-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108010033040 Histones Proteins 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical group CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 4
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- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明公开了一种喹唑啉类化合物，具有结构通式
Description
技术领域
本发明属于药物化学领域，涉及一种喹唑啉类化合物及其制备方法和应用。
背景技术
表观遗传学(Epigenetics)是指在DNA序列没有改变的情况下，发生的基因功能的可遗传的改变[6]。DNA修饰(DNA modification)、组蛋白修饰(Histone modification)、非编码RNA修饰(Noncoding RNA modification)和核小体的重塑等均属于表观遗传学的调控机制。表观遗传调控异常会使基因错误表达，引起各种疾病，甚至发生肿瘤。其中组蛋白修饰作为表观遗传的最重要修饰方式之一，包括甲基化、磷酸化、泛素化和乙酰化等，其中乙酰化和甲基化是最重要的内容。研究表明，它们对基因的转录具有调控作用。2004年，首个组蛋白赖氨酸去甲基化酶1(Lysine Specific Demethylase l，LSD1)被发现，证实了组蛋白去甲基化是一个可逆的过程。机体内组蛋白赖氨酸残基上的甲基化水平通过2种特异性酶-组蛋白甲基转移酶和组蛋白去甲基化酶进行调节，LSD1是一种黄素腺嘌呤二核苷酸依赖的去甲基化酶，主要作用是作为转录激活剂或转录抑制剂，催化去除H3K4单甲基化和双甲基化。当H3K4发生甲基化时，可引起基因转录的激活。
LSD1在多种肿瘤细胞中高表达，包括小细胞肺癌、膀胱癌、胃癌、前列腺癌乳腺癌和急性髓系白血病等，在肿瘤的分化、增殖、转移或侵袭方面起着重要作用。在一些癌细胞系中，通过RNAi敲除抑制LSD1可以激活肿瘤抑制基因(如p53)的表达，以及降低相关靶标基因的表达，因此，LSD1是一个很有潜力的抗肿瘤靶标。研究开发高效低毒的LSD1抑制剂用于肿瘤的预防和治疗是重要的研究方向，已成为当前肿瘤药物研究的热点。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种喹唑啉类化合物，该化合物对LSD1具有良好的抑制活性。
本发明的目的之二在于提供一种喹唑啉类化合物的制备方法。
本发明的目的之三在于提供喹唑啉类化合物在制备靶向LSD1的抗肿瘤药物中的应用。
本发明的目的之一采用如下技术方案实现：
一种喹唑啉类化合物，所述喹唑啉类化合物为具有结构通式Ⅰ的化合物，或结构通式I所示化合物在药学上可接受的盐：
其中，X选自O或NH；
基团R1选自H、C1-C10烷氧基、烷基取代烷氧基；R2选自H、烷基、C1-C10烷氧基、烷基取代烷氧基或卤素；
R3选自芳胺、脂肪胺、芳基或杂芳基；
R4选自Me、 中的一种。
在一些实施方式中，R1选自H、甲氧基、二甲氧基乙烷中的一种；R2选自H、甲基、甲氧基、氯、氟和三氟甲基中的一种；
R3选自
中的一种；
R4选自Me、 中的一种。
在一些实施方式中，R1、R2、R3、R4选自下列基团：
本发明的目的之二采用如下技术方案实现：
如本发明目的之一的喹唑啉类化合物的制备方法，包括以下步骤：
合成路线a：化合物1a-c和三氯氧磷在碱性物质作用下发生氯代反应得到化合物2a-c；
合成路线b：化合物2a-c或者5a-h和氨类化合物溶解于有机溶剂和水的混合溶液中，在碱性物质作用下发生取代反应得到化合物Ⅰ、6a-q；
合成路线c：化合物2b和N,N-二甲基对苯二胺溶解于醇溶剂中，在酸性物质作用下发生取代反应得到化合物Ⅰ。
合成路线d：不同取代的邻氨基苯甲酸化合物3a-h和尿素反应得到化合物4a-h；
合成路线e：化合物4a-h和三氯氧磷溶于有机溶剂中，在碱性物质作用下发生氯代反应得到化合物5a-h；
合成路线f：化合物5a和氨基苯酚溶解于有机溶剂中，在碱性物质作用下发生取代反应得到化合物6r。
合成路线g：化合物6a-r和硼酸类化合物溶解于有机溶剂和水的混合溶液中，在碱性物质及钯催化作用下，发生Suzuki偶联反应得到化合物Ⅰ，
所述X为NH或O。
在一些实施方式中，所述合成路线a中由化合物1a-c合成化合物2a-c的反应温度为50℃-150℃；合成路线b中由化合物2a-c或者5a-h合成化合物1-3、5、6a-q的反应温度为60℃-130℃；合成路线c中由化合物2b合成化合物4的反应温度为45℃-120℃；合成路线d中由化合物3a-h合成化合物4a-h的反应温度为90℃-180℃；合成路线e中由化合物4a-h合成化合物5a-h的反应温度为60℃-140℃；合成路线f中由化合物5a合成化合物6r的反应温度为45℃-120℃；合成路线g中由化合物6a-r合成化合物6-53的反应温度为45℃-125℃。
在一些实施方式中，合成路线b、e、f、g中所述有机溶剂选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氧六环中的一种。合成路线c中所述醇溶剂选自甲醇、乙醇、正丁醇、异丙醇中的一种。
在一些实施方式中，合成路线b、e、f、g中所述碱性物质选自碳酸钠、乙酸钠、碳酸钾、氢氧化钠、氢氧化钾、N,N-二甲基苯胺、N,N-二异丙基乙胺中的一种。
在一些实施方式中，合成路线c中所述酸性物质选自冰醋酸、浓盐酸、浓硫酸中的一种。
在一些实施方式中，合成路线g中所述钯催化剂为四(三苯基膦)钯、双(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯中的一种。
本发明的目的之三采用如下技术方案实现：
一种喹唑啉类化合物的应用，具体是喹唑啉类化合物在制备基于LSD1靶点的抗肿瘤药物中的应用。
本发明公开了一种喹唑啉类化合物，骨架新颖，对LSD1有较好的抑制活性。本发明还公开了上述化合物的制备方法，在喹唑啉的2-位引入芳环、芳杂环、环状烯烃和并环等基团修饰，喹唑啉的4-位引入脂肪胺、芳胺、苯酚等基团修饰，并在喹唑啉的6-位和7-位引入不同取代的柔性长链、给电子和吸电子基团，设计合成了一类喹唑啉类化合物，具有反应条件温和、操作简单、反应收率高的特点。经测试，上述喹唑啉类化合物表现出较好的LSD1抑制活性，为开发高效的基于LSD1靶点的抗肿瘤药物提供了新颖的结构骨架。
本发明提供的喹唑啉类化合物在制备基于LSD1靶点的抗肿瘤药物中的应用，所涉及的喹唑啉类化合物对LSD1表现出了良好的抑制活性，显示出良好的药物开发潜力，为基于LSD1靶点的药物研发提供了新方向。
具体实施方式
下面结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
化合物1-5的制备过程如下：
实施例1
化合物1的制备：X＝NH，R4＝H。
(1)以1a(1mmol)为起始原料，在三氯氧磷(3mmol)和N,N-二甲基苯胺(1.1mmol)的混合体系中回流5小时，用薄层色谱检测反应，待反应完成后冷却至室温，减压蒸馏出三氯氧磷，然后将浓缩过的反应体系倒入冰水中，加入饱和的碳酸氢钠水溶液，将pH调节至中性后，加入乙酸乙酯(25mL×3)萃取，有机相用无水硫酸镁干燥，浓缩后经柱层析纯化即得中间体2a，收率为78.7％。
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.47(s,1H),7.43(s,1H),4.39–4.33(m,4H),3.78–3.77(m,4H),3.36(d,J＝3.3Hz,6H).13C NMR(100MHz,DMSO-d6)δ158.62,154.50,148.73,146.25,137.40,114.65,107.03,104.49,70.05,69.87,68.50,68.36,58.33,58.30.
(2)将步骤(1)制备得到的化合物2a(1mmol)，4-(4-甲基哌嗪)苯胺(1.1mmol)，乙酸钠(1.1mmol)溶解于四氢呋喃和水的混合溶液(VTHF：V水＝3:1，8mL)中，在65℃条件下反应5小时。用薄层色谱检测反应，待反应完成后，向反应体系中加入乙酸乙酯稀释该反应体系，用饱和食盐水(25mL×3)洗涤有机相，并用无水硫酸镁进行干燥，通过柱层析分离纯化即得化合物1，收率为56.5％。
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.37(s,1H),7.88(s,1H),7.60(d,J＝8.9Hz,2H),7.18(s,1H),6.99(d,J＝9.0Hz,2H),4.30–4.26(m,4H),3.81–3.70(m,4H),3.36(d,J＝6.8Hz,6H),3.24(s,4H),2.80(s,4H),2.46(s,3H).13C NMR(100MHz,DMSO-d6)δ156.53,153.34,153.09,147.82,146.88,146.62,131.39,123.80,115.64,108.76,108.12,103.42,70.12,68.34,67.95,58.34,53.69,47.52.HRMS(ESI)calcd for C25H33N5O4[M+H]+,468.2606；found,468.2613.
实施例2
化合物2的制备：X＝NH，R4＝H。
实施例2与实施例1的区别在于将步骤(2)中的4-(4-甲基哌嗪)苯胺替换为4-氨基-N,N-二甲基苯胺，其余与实施例1相同。制备得到化合物2，收率为64.3％。
1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.34(s,1H),7.84(s,1H),7.50(d,J＝8.9Hz,2H),7.16(s,1H),6.77(d,J＝9.0Hz,2H),4.30–4.24(m,4H),3.79–3.73(m,4H),3.37(s,6H),2.90(s,6H).13C NMR(100MHz,DMSO-d6)δ156.71,153.25,153.18,147.74,147.47,146.42,128.54,124.32,112.37,108.71,108.04,103.37,70.11,68.27,67.93,58.32.HRMS(ESI)calcd for C22H28N4O4[M+H]+,413.2184；found,413.2191.
实施例3
化合物3的制备：R1＝H，R2＝H，X＝NH，R4＝H。
(1)将实施例1的步骤(1)中的的1a替换为4-羟基喹唑啉，其它条件与实施例1的步骤(1)相同。制备得到化合物2b，收率为70.2％。
1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.19(d,J＝8.0Hz,1H),7.97(t,J＝7.7Hz,1H),7.89(d,J＝8.0Hz,1H),7.69(t,J＝7.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.47,147.99,141.60,135.53,128.28,126.52,122.39,121.45.
(2)将实施例1的步骤(2)中的2a替换为以上合成的2b，其它条件与实施例1的步骤(2)相同。制备得到化合物3，收率为46.1％。
1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.55–8.48(m,2H),7.83(t,J＝7.5Hz,1H),7.75(d,J＝7.9Hz,1H),7.62(dd,J＝11.6,8.5Hz,3H),6.97(d,J＝9.0Hz,2H),3.22–3.03(m,4H),2.49–2.43(m,4H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ157.78,154.68,149.54,147.78,132.72,130.57,127.65,125.94,123.85,122.84,115.31,115.11,54.60,48.42,45.76.HRMS(ESI)calcd for C19H21N5[M+H]+,319.1797；found,319.1762.
实施例4
化合物4的制备：R1＝H，R2＝H，X＝NH，R4＝H。
(1)将2b(0.92mmol)，N,N-二甲基对苯二胺(1mmol)依次加入到5mL的异丙醇中，然后向反应体系中加入浓盐酸3滴，在80℃下反应5小时。用薄层色谱检测反应，待反应完成后，减压蒸馏除去多余的溶剂，浓缩后经柱层析分离纯化即得化合物4。收率为67.3％。
1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),9.11(d,J＝8.3Hz,1H),8.93(s,1H),8.12(t,J＝7.7Hz,1H),8.05(d,J＝8.1Hz,1H),7.86(t,J＝7.6Hz,1H),7.79(d,J＝8.4Hz,2H),7.50(s,2H),3.09(s,6H).13C NMR(100MHz,DMSO-d6)δ159.66,150.63,138.09,136.25,128.60,126.08,125.18,119.22,113.45,48.54,43.34.HRMS(ESI)calcd for C16H16N4[M+H]+,265.1448；found,265.1452.
实施例5
化合物5的制备：R1＝H，R2＝H，X＝NH，R4＝CH3。
(1)将实施例1的步骤(1)中的的1a替换为2-甲基-4(3H)-喹唑啉酮，其它条件与实施例1的步骤(1)相同。制备得到化合物2c，收率为74.3％。
1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.3Hz,1H),8.00–7.85(m,2H),7.65(t,J＝8.2Hz,1H),2.86(s,3H).13C NMR(100MHz,CDCl3)δ163.54,162.16,151.49,134.84,128.02,127.99,125.71,121.83,26.02.
(2)将实施例1的步骤(2)中的2a替换为以上合成的2c，4-(4-甲基哌嗪)苯胺替换为4-氨基-N,N-二甲基苯胺，其它条件与实施例1的步骤(2)相同。制备得到化合物5，收率为41.7％。
1H NMR(400MHz,CDCl3)δ7.79(d,J＝6.4Hz,2H),7.72(q,J＝7.1Hz,1H),7.60(t,J＝6.1Hz,2H),7.44(t,J＝7.1Hz,1H),7.29(s,1H),6.79(d,J＝9.0Hz,2H),2.96(s,6H),2.66(s,3H).13C NMR(100MHz,CDCl3)δ164.35,157.46,150.54,148.06,132.54,128.14,125.32,123.22,120.30,113.05,40.94,26.69.HRMS(ESI)calcd for C17H18N4[M+H]+,279.1604；found,279.1607.
化合物6-53的制备过程如下：
实施例6
化合物6的制备：R1＝H，R2＝H，X＝NH，/>
(1)将3a(7mmol)和尿素(35mmol)在160℃下反应3小时。反应完成后，将反应体系冷却至100℃，加入50mL的水淬灭反应体系。抽滤，滤渣用水洗涤，烘干。将烘干的滤渣中加入到0.5N的氢氧化钠溶液中，50℃下搅拌一小时后冷却至0℃，用浓盐酸调pH至中性后进行抽滤，所得烘干后的滤渣即为中间体4a。将烘干的4a(2mmol)溶解于三氯氧磷(5mL)中，加入N,N-二异丙基乙胺(500μL)，N,N-二甲基甲酰胺(5滴)，在90℃下反应8小时。待反应完全后，将多余的三氯氧磷旋出，冷却后将反应体系倒入冰水中，加入饱和的碳酸氢钠水溶液，将pH调节至中性后，加入乙酸乙酯(25mL×3)萃取，有机相用无水硫酸镁干燥，浓缩后经柱层析纯化即得中间体5a。收率为44.9％。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝8.4Hz,1H),8.19(t,J＝7.7Hz,1H),8.06(d,J＝8.4Hz,1H),7.92(t,J＝7.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ163.40,153.72,151.77,136.99,130.10,127.50,125.94,121.96.
(2)将中间体5a(1mmol)，N,N-二甲基对苯二胺(1.1mmol)，乙酸钠(1.1mmol)依次加入到四氢呋喃和水的混合溶液(VTHF：V水＝3:1，8mL)中，在65℃下反应5小时。使用薄层色谱监测反应进程，待反应完成后，向反应体系中加入乙酸乙酯(25mL)，用饱和食盐水(25mL×3)洗涤有机相，萃取后的有机相用无水硫酸镁干燥，浓缩，柱层析分离纯化即得中间体6a。收率为51.7％。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.51(d,J＝7.5Hz,1H),7.84(d,J＝6.7Hz,1H),7.74–7.57(m,2H),7.52(d,J＝7.4Hz,2H),6.80(d,J＝7.2Hz,2H),2.92(s,6H).13C NMR(100MHz,DMSO-d6)δ159.36,156.64,150.67,148.06,133.72,127.13,126.73,126.28,124.52,123.27,113.76,112.24.
(3)将中间体6a(1mmol)，苯硼酸(1.5mmol)，碳酸钾(1.75mmol)，双(三苯基膦)二氯化钯(0.025mmol)依次加入到1,4-二氧六环和水的混合溶液(V1,4-二氧六环：V水＝4:1，10mL)中，在氮气保护下85℃反应6小时。用薄层色谱检测反应，待反应完成后减压蒸馏除去多余的溶剂，通过柱层析分离纯化即得化合物6。收率为32.2％
1H NMR(400MHz,CDCl3)δ8.53(dd,J＝7.8,1.6Hz,2H),7.97(d,J＝8.3Hz,1H),7.84(d,J＝8.2Hz,1H),7.76(t,J＝7.6Hz,1H),7.70(d,J＝9.0Hz,2H),7.47(q,J＝6.1Hz,4H),7.36(s,1H),6.85(d,J＝9.0Hz,2H),3.00(s,6H).13C NMR(100MHz,CDCl3)δ160.57,157.53,150.93,147.99,138.82,132.61,130.09,129.12,128.51,128.29,125.74,123.23,120.29,113.85,113.03,40.99.HRMS(ESI)calcd for C22H20N4[M+H]+,341.1761；found,341.1764.
实施例7
化合物7的制备：R1＝H，R2＝H，X＝NH，/>
实施例7与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-联苯硼酸，其余与实施例6相同。制备得到化合物7，收率为74.4％。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.53(t,J＝8.1Hz,3H),7.85–7.83(m,3H),7.81(s,1H),7.78–7.76(m,4H),7.59–7.55(m,1H),7.50(t,J＝7.4Hz,2H),7.40(t,J＝7.0Hz,1H),6.86(d,J＝8.8Hz,2H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ158.90,157.81,150.33,147.42,141.60,139.57,137.59,132.87,128.97,128.59,128.46,127.95,127.74,126.67,126.56,125.59,123.73,122.89,114.03,112.30,40.44.HRMS(ESI)calcdfor C28H24N4[M+H]+,417.2014；found,417.2078.
实施例8
化合物8的制备：R1＝H，R2＝H，X＝NH，/>
实施例8与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-氟苯硼酸，其余与实施例6相同。制备得到化合物8，收率为82.0％。
1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.52(s,1H),8.46(dd,J＝8.7,5.8Hz,2H),7.82(d,J＝2.2Hz,2H),7.72(d,J＝9.0Hz,2H),7.58–7.54(m,1H),7.32(t,J＝8.9Hz,2H),6.84(d,J＝9.0Hz,2H),2.94(s,6H).13C NMR(100MHz,DMSO-d6)δ164.79,162.34,158.27,157.85,150.23,147.45,135.02,134.99,132.90,130.10,130.02,128.45,127.87,125.59,123.78,122.90,115.26,115.05,113.91,112.28,40.42.HRMS(ESI)calcd for C22H19FN4[M+H]+,359.1667；found,359.1667.
实施例9
化合物9的制备：R1＝H，R2＝H，X＝NH，/>
实施例9与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-三氟甲基苯硼酸，其余与实施例6相同。制备得到化合物9，收率为49.5％。
1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.60(d,J＝8.1Hz,2H),8.56(d,J＝8.3Hz,1H),7.88(s,1H),7.86(d,J＝3.4Hz,3H),7.73(d,J＝9.0Hz,2H),7.63–7.59(m,1H),6.85(d,J＝9.0Hz,2H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ157.95,150.08,147.50,142.40,133.07,130.15,129.83,128.42,128.08,126.18,125.66,125.31,125.27,124.50,123.81,122.95,114.19,112.28,40.40.HRMS(ESI)calcd for C23H19F3N4[M+H]+,409.1635；found,409.1639.
实施例10
化合物10的制备：R1＝H，R2＝H，X＝NH，/>
实施例10与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-甲氧基苯硼酸，其余与实施例6相同。制备得到化合物10，收率为65.4％。
1H NMR(400MHz,CDCl3)δ8.49(d,J＝8.8Hz,2H),7.91(s,1H),7.79(s,1H),7.72(t,J＝7.8Hz,1H),7.68(d,J＝8.9Hz,2H),7.42(t,J＝7.4Hz,1H),7.32(s,1H),6.99(d,J＝8.8Hz,2H),6.83(d,J＝9.0Hz,2H),3.87(s,3H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ161.45,160.31,157.43,151.01,147.95,132.54,131.54,130.12,128.86,128.37,125.30,123.25,120.32,113.63,113.02,40.99.HRMS(ESI)calcd for C23H22N4O[M+H]+,371.1867；found,371.1872.
实施例11
化合物11的制备：R1＝H，R2＝H，X＝NH，/>
实施例11与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-甲巯基苯硼酸，其余与实施例6相同。制备得到化合物11，收率为76.2％。
1H NMR(400MHz,CDCl3)δ8.45(d,J＝8.5Hz,2H),7.92(s,1H),7.80(s,1H),7.73(d,J＝7.2Hz,1H),7.67(d,J＝9.0Hz,2H),7.44(d,J＝7.2Hz,1H),7.33(d,J＝8.5Hz,3H),6.83(d,J＝9.0Hz,2H),3.00(s,6H),2.53(s,3H).13C NMR(100MHz,CDCl3)δ160.12,157.47,150.97,147.98,141.08,135.60,132.60,129.03,128.87,128.23,125.74,125.58,124.99,123.27,120.30,113.81,112.97,40.97,15.42.HRMS(ESI)calcd for C23H22N4S[M+H]+,387.1638；found,387.1639.
实施例12
化合物12的制备：R1＝H，R2＝H，X＝NH，/>
实施例12与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-氰基苯硼酸，其余与实施例6相同。制备得到化合物12，收率为91.8％。
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.59–8.54(m,3H),7.96(d,J＝8.4Hz,2H),7.86(d,J＝3.8Hz,2H),7.71(d,J＝9.0Hz,2H),7.62(dt,J＝8.2,5.0Hz,1H),6.85(d,J＝8.4Hz,2H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ157.92,157.49,149.91,147.46,142.70,134.12,133.06,132.32,128.29,128.02,126.28,123.86,122.95,118.79,116.32,114.11,112.19,40.35.HRMS(ESI)calcd for C23H19N5[M+H]+,366.1713；found,366.1716.
实施例13
化合物13的制备：R1＝H，R2＝H，X＝NH，/>
实施例13与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-羟基苯硼酸，其余与实施例6相同。制备得到化合物13，收率为74.1％。
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),9.62(s,1H),8.50(d,J＝8.3Hz,1H),8.28(d,J＝8.7Hz,2H),7.80–7.74(m,4H),7.50(t,J＝6.2Hz,1H),6.86(t,J＝8.6Hz,4H),2.94(s,6H).13CNMR(100MHz,DMSO-d6)δ159.54,159.15,157.49,147.25,132.67,129.57,128.65,124.85,123.47,122.81,114.98,113.58,112.24,40.40.HRMS(ESI)calcd forC22H20N4O[M+H]+,366.1713；found,366.1716.
实施例14
化合物14的制备：R1＝H，R2＝H，X＝NH，/>
实施例14与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-氨基苯硼酸，其余与实施例6相同。制备得到化合物14，收率为58.8％。
1H NMR(400MHz,CDCl3)δ8.36(d,J＝8.5Hz,2H),7.90(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,1H),7.72–7.64(m,3H),7.54–7.44(m,1H),7.40(t,J＝7.2Hz,1H),7.35(s,1H),3.87(s,2H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ160.64,157.30,151.16,148.48,147.88,132.45,130.11,129.27,128.78,128.57,124.95,123.16,120.28,114.60,113.58,113.07,41.03.HRMS(ESI)calcd for C22H21N5[M+H]+,356.187；found,356.1872.
实施例15
化合物15的制备：R1＝H，R2＝H，X＝NH，/>
实施例15与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-氨基甲酰苯硼酸，其余与实施例6相同。制备得到化合物15，收率为55.8％。
1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.57(d,J＝8.3,1H),8.48(d,J＝8.3Hz,2H),8.08(s,1H),8.01(d,J＝8.3Hz,2H),7.86(d,J＝3.5Hz,2H),7.75(d,J＝8.9Hz,2H),7.61–7.58(m,1H),7.45(s,1H),6.86(d,J＝8.9,2H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ167.60,158.45,157.84,147.45,140.90,135.54,133.02,128.45,127.85,127.58,127.55,125.95,124.49,123.80,122.98,114.06,112.27,40.45.HRMS(ESI)calcd forC23H21N5O[M+H]+,384.1819；found,384.1820.
实施例16
化合物16的制备：R1＝H，R2＝H，X＝NH，/>
实施例16与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-(N-甲基甲酰氨)苯基硼酸，其余与实施例6相同。制备得到化合物16，收率为60.1％。
1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.55–8.51(m,2H),8.47(d,J＝8.4Hz,2H),7.96(d,J＝8.4Hz,2H),7.85(d,J＝3.8Hz,2H),7.74(d,J＝9.0Hz,2H),7.61–7.57(m,1H),6.84(s,2H),2.95(s,6H),2.82(s,3H).13C NMR(100MHz,DMSO-d6)δ168.29,159.15,157.63,150.23,147.29,139.36,139.09,132.86,128.72,128.56,127.83,125.59,123.40,122.89,122.76,120.87,118.73,114.04,112.44,40.45,24.02.HRMS(ESI)calcd for C24H23N5O[M+H]+,398.1976；found,398.1976.
实施例17
化合物17的制备：R1＝H，R2＝H，X＝NH，/>
实施例17与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6相同。制备得到化合物17，收率为65.1％。
1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.64–8.59(m,3H),8.07(d,J＝8.4Hz,2H),7.88–7.87(m,1H),7.75(d,J＝8.8Hz,1H),7.65–7.61(m,1H),6.88(d,J＝6.5Hz,2H),3.27(s,3H),2.95(s,3H).13C NMR(100MHz,DMSO-d6)δ157.87,157.63,143.00,141.77,133.13,128.46,127.04,126.30,123.76,122.98,115.62,114.11,112.34,43.41,40.41.HRMS(ESI)calcd for C23H22N4O2S[M+H]+,419.1536；found,419.1535.
实施例18
化合物18的制备：R1＝H，R2＝H，X＝NH，/>
实施例18与实施例6的区别在于将步骤(3)中的苯硼酸替换为3-(甲磺酰基)苯硼酸，其余与实施例6相同。制备得到化合物18，收率为67.5％。
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.98(s,1H),8.71(d,J＝7.7Hz,1H),8.56(d,J＝8.3Hz,2H),8.05(d,J＝7.8Hz,1H),7.87(q,J＝8.5Hz,2H),7.80(t,J＝7.8Hz,1H),7.74(d,J＝8.8Hz,2H),7.62(t,J＝7.3Hz,1H),6.85(d,J＝8.9Hz,2H),3.29(s,3H),2.94(s,6H).13C NMR(100MHz,DMSO-d6)δ157.91,157.58,150.13,147.54,141.23,139.63,133.12,132.35,129.74,128.38,128.25,128.05,126.11,123.87,122.97,114.20,112.23,43.56,40.41.HRMS(ESI)calcd for C23H22N4O2S[M+H]+,447.1849；found,447.1848.
实施例19
化合物19的制备：R1＝H，R2＝H，X＝NH，/>
实施例19与实施例6的区别在于将步骤(3)中的苯硼酸替换为3-乙酰胺基苯硼酸，其余与实施例6相同。制备得到化合物19，收率为52.8％。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.68(s,1H),8.64(s,1H),8.55(d,J＝8.3Hz,1H),8.09(d,J＝7.8Hz,1H),7.86–7.77(m,5H),7.59–7.57(m,1H),7.41(t,J＝7.9Hz,1H),6.87(d,J＝9.1Hz,2H),2.94(s,6H),2.09(s,3H).13C NMR(100MHz,DMSO-d6)δ166.30,158.47,157.83,150.17,147.47,140.81,135.72,132.98,128.45,127.99,127.63,127.11,125.90,123.77,122.91,114.07,112.25,40.43,26.25.HRMS(ESI)calcd forC24H23N5O[M+H]+,398.1976；found,398.1979.
实施例20
化合物20的制备：R1＝H，R2＝H，X＝NH，/>
实施例20与实施例6的区别在于将步骤(3)中的苯硼酸替换为3-乙酰基苯硼酸，其余与实施例6相同。制备得到化合物20，收率为47.6％。
1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),9.04(s,1H),8.66(d,J＝7.8Hz,1H),8.55(d,J＝8.3Hz,1H),8.06(d,J＝7.7Hz,1H),7.88–7.83(m,2H),7.75(d,J＝9.0Hz,2H),7.66(t,J＝7.7Hz,1H),7.61–7.57(m,1H),6.85(d,J＝9.0Hz,2H),2.94(s,6H),2.66(s,3H).13CNMR(100MHz,DMSO-d6)δ197.66,158.26,157.89,150.26,147.53,138.89,136.93,133.00,132.08,129.57,128.83,128.39,128.02,127.82,125.87,123.96,122.92,114.11,112.22,40.44,26.71.HRMS(ESI)calcd for C24H22N4O[M+H]+,383.1867；found,383.1867.
实施例21
化合物21的制备：R1＝H，R2＝H，X＝NH，/>
实施例21与实施例6的区别在于将步骤(3)中的苯硼酸替换为4-氰基-3-氟苯硼酸，其余与实施例6相同。制备得到化合物21，收率为64.2％。
1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.55(d,J＝8.3Hz,1H),8.36(d,J＝8.1Hz,1H),8.27(d,J＝11.0Hz,1H),8.11–7.98(m,1H),7.86(s,2H),7.65(d,J＝8.8Hz,3H),6.84(d,J＝9.0Hz,2H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ161.30,158.05,156.48,149.84,147.69,146.13,146.05,134.09,133.25,128.20,127.93,126.69,124.25,124.10,123.00,114.83,114.62,114.28,114.10,112.19,101.07,100.92.HRMS(ESI)calcd forC23H18FN5[M+H]+,384.1637；found,384.1625.
实施例22
化合物22的制备：R1＝H，R2＝H，X＝NH，/>
实施例22与实施例6的区别在于将步骤(3)中的苯硼酸替换为3,4,5-三甲氧基苯基硼酸，其余与实施例6相同。制备得到化合物22，收率为51.1％。
1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.3Hz,1H),7.88(s,2H),7.84(d,J＝8.1Hz,1H),7.76(t,J＝7.7Hz,1H),7.68(d,J＝9.0Hz,2H),7.47(t,J＝8.0Hz,1H),7.37(s,1H),6.79(d,J＝9.0Hz,2H),3.98(s,6H),3.91(s,3H),2.97(s,6H).13C NMR(100MHz,CDCl3)δ159.78,157.50,152.99,151.02,148.13,139.91,134.22,132.66,129.02,128.19,125.66,123.77,120.39,113.69,112.67,105.51,60.94,55.99,40.96.HRMS(ESI)calcd forC25H26N4O3[M+H]+,431.2078；found,431.2083.
实施例23
化合物23的制备：R1＝H，R2＝H，X＝NH，/>
实施例23与实施例6的区别在于将步骤(3)中的苯硼酸替换为吡啶-3-硼酸，其余与实施例6相同。制备得到化合物23，收率为91.8％。
1H NMR(400MHz,CDCl3)δ9.71(d,J＝1.6Hz,1H),8.79(d,J＝8.0Hz,1H),8.67(dd,J＝4.7,1.3Hz,1H),7.96(d,J＝8.4Hz,1H),7.90(d,J＝8.2Hz,1H),7.77(d,J＝7.6Hz,1H),7.66(d,J＝9.0Hz,1H),7.52–7.44(m,2H),7.40(dd,J＝7.9,4.8Hz,1H),6.82(d,J＝8.9Hz,2H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ158.58,157.75,150.57,150.25,148.13,135.86,134.33,132.86,132.14,132.04,128.96,128.61,128.49,127.75,126.22,123.55,123.24,120.59,114.06,112.89,40.87.HRMS(ESI)calcd for C21H19N5[M+H]+,342.1713；found,342.1717.
实施例24
化合物24的制备：R1＝H，R2＝H，X＝NH，/>
实施例24与实施例6的区别在于将步骤(3)中的苯硼酸替换为6-甲氧基-3-吡啶硼酸，其余与实施例6相同。制备得到化合物24，收率为91.0％。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.54(d,J＝8.2Hz,1H),8.27–8.25(m,1H),8.08–8.06(m,1H),7.85–7.77(m,4H),7.62–7.58(m,1H),7.10(dd,J＝7.3,4.9Hz,1H),6.76(d,J＝9.1Hz,2H),3.97(s,3H),2.89(s,6H).13C NMR(100MHz,DMSO-d6)δ161.02,159.69,157.19,150.09,147.29,147.06,139.63,132.76,128.78,127.75,125.87,123.66,123.24,122.76,116.74,113.58,112.24,53.24,40.46.HRMS(ESI)calcd for C22H21N5O[M+H]+,372.1819；found,372.1826.
实施例25
化合物25的制备：R1＝H，R2＝H，X＝NH，/>
实施例25与实施例6的区别在于将步骤(3)中的苯硼酸替换为5-嘧啶硼酸，其余与实施例6相同。制备得到化合物25，收率为66.7％。
1H NMR(400MHz,CDCl3)δ9.75(s,2H),9.28(s,1H),7.96(d,J＝8.2Hz,1H),7.90(d,J＝8.2Hz,1H),7.81(t,J＝7.7Hz,1H),7.61(d,J＝9.0Hz,2H),7.54(t,J＝8.0Hz,2H),6.82(d,J＝9.0Hz,2H),3.00(s,6H).13C NMR(100MHz,CDCl3)δ159.22,157.91,156.95,156.56,150.55,148.35,133.08,132.16,132.06,131.95,129.23,128.58,128.46,127.25,126.68,123.78,120.49,114.22,112.81,40.80.HRMS(ESI)calcd for C20H18N6[M+H]+,343.1666；found,343.1670.
实施例26
化合物26的制备：R1＝H，R2＝H，X＝NH，/>
实施例26与实施例6的区别在于将步骤(3)中的苯硼酸替换为2-氨基嘧啶-5-硼酸，其余与实施例6相同。制备得到化合物26，收率为75.3％。
1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.11(s,2H),8.51(d,J＝8.2Hz,1H),7.81–7.68(m,4H),7.51(t,J＝6.9Hz,1H),7.10(s,2H),6.84(d,J＝9.0Hz,2H),2.93(s,6H).13CNMR(100MHz,DMSO-d6)δ164.05,158.05,157.61,157.02,147.49,132.92,128.32,127.38,125.10,123.87,122.96,113.89,112.18,40.43.HRMS(ESI)calcd for C20H19N7[M+H]+,358.1775；found,358.1777.
实施例27
化合物27的制备：R1＝H，R2＝H，X＝NH，/>
实施例27与实施例6的区别在于将步骤(3)中的苯硼酸替换为2-呋喃硼酸，其余与实施例6相同。制备得到化合物27，收率为63.6％。
1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.3Hz,1H),7.81(d,J＝8.2Hz,1H),7.73(t,J＝8.1Hz,1H),7.67(d,J＝9.0Hz,2H),7.62(s,1H),7.44(t,J＝7.2Hz,2H),7.28(d,J＝3.2Hz,1H),6.81(d,J＝9.0Hz,2H),6.54–6.53(m,1H),2.98(s,6H).13C NMR(100MHz,CDCl3)δ157.37,153.65,153.18,150.51,148.01,144.68,132.81,128.96,128.17,125.73,123.11,120.41,113.96,113.47,112.93,111.82,40.94.HRMS(ESI)calcd for C20H18N4O[M+H]+,331.1554；found,331.1561.
实施例28
化合物28的制备：R1＝H，R2＝H，X＝NH，/>
实施例28与实施例6的区别在于将步骤(3)中的苯硼酸替换为2-噻吩硼酸，其余与实施例6相同。制备得到化合物28，收率为72.2％。
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.87(s,1H),7.79(d,J＝8.2Hz,1H),7.72(d,J＝8.9Hz,3H),7.42(d,J＝5.9Hz,2H),7.33(s,1H),7.13(dd,J＝4.9,3.8Hz,1H),6.83(d,J＝9.0Hz,2H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ157.27,157.09,150.82,147.94,145.07,132.70,129.01,128.77,128.48,128.24,127.94,125.47,122.93,120.30,113.77,112.95,40.96.HRMS(ESI)calcd for C20H18N4S[M+H]+,347.1325；found,347.1329.
实施例29
化合物29的制备：R1＝H，R2＝H，X＝NH，/>
实施例29与实施例6的区别在于将步骤(3)中的苯硼酸替换为1-甲基-4-吡唑硼酸，其余与实施例6相同。制备得到化合物29，收率为98.0％。
1H NMR(400MHz,CDCl3)δ8.22(s,1H),8.08(s,1H),7.84–7.78(m,2H),7.70(t,J＝7.6Hz,1H),7.65(d,J＝9.0Hz,2H),7.42–7.37(m,2H),6.81(d,J＝9.0Hz,2H),3.95(s,3H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ157.45,157.14,150.90,147.98,140.20,132.61,131.34,128.29,128.25,125.06,124.30,123.25,120.39,113.61,112.91,40.95,39.15.HRMS(ESI)calcd for C20H20N6[M+H]+,345.1822；found,345.1830.
实施例30
化合物30的制备：R1＝H，R2＝H，X＝NH，/>
实施例30与实施例6的区别在于将步骤(3)中的苯硼酸替换为环戊烯-1-基硼酸，其余与实施例6相同。制备得到化合物30，收率为93.2％。
1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.3Hz,1H),7.78(d,J＝8.1Hz,1H),7.72–7.70(m,1H),7.67(d,J＝9.0Hz,2H),7.42(t,J＝8.2Hz,1H),6.99–6.97(m,1H),6.82–6.78(m,2H),2.97(s,6H),2.95–2.91(m,2H),2.62–2.57(m,2H),2.10–2.02(m,2H).13C NMR(100MHz,CDCl3)δ159.75,156.75,150.78,147.79,145.03,136.75,132.35,128.97,128.66,125.40,122.76,120.20,113.72,113.05,41.02,33.59,32.41,23.72.HRMS(ESI)calcd for C21H22N4[M+H]+,331.1917；found,331.1923.
实施例31
化合物31的制备：R1＝H，R2＝H，X＝NH，/>
实施例31与实施例6的区别在于将步骤(3)中的苯硼酸替换为环己烯-1-基硼酸，其余与实施例6相同。制备得到化合物31，收率为67.4％。
1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.2Hz,1H),7.77(d,J＝8.2Hz,1H),7.71–7.67(m,1H),7.66–7.62(m,2H),7.43–7.39(m,1H),7.28–7.26(m,1H),7.23(s,1H),6.82–6.78(m,2H),2.97(s,6H),2.69–2.67(m,2H),2.32–2.29(m,2H),1.82–1.76(m,2H),1.71–1.66(m,2H).13CNMR(100MHz,CDCl3)δ162.23,156.72,150.74,147.78,137.32,133.18,132.30,128.96,128.62,125.20,122.84,120.20,113.75,113.09,41.03,26.29,25.56,22.92,22.26.HRMS(ESI)calcd for C22H24N4[M+H]+,345.2074；found,345.2081.
实施例32
化合物32的制备：R1＝H，R2＝H，X＝NH，/>
实施例32与实施例6的区别在于将步骤(3)中的苯硼酸替换为5-吲哚硼酸，其余与实施例6相同。制备得到化合物32，收率为82.8％。
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),9.59(s,1H),8.70(s,1H),8.50(d,J＝8.3Hz,1H),8.27(d,J＝10.0Hz,1H),7.85–7.72(m,4H),7.54–7.44(m,2H),7.42–7.36(m,1H),6.88(d,J＝9.0Hz,2H),6.57(s,1H),2.95(s,6H).13C NMR(100MHz,DMSO-d6)δ160.54,157.52,147.33,137.34,132.70,129.45,128.88,127.56,126.10,124.81,123.54,122.83,121.55,120.69,113.72,112.36,110.95,102.26.HRMS(ESI)calcd for C24H21N5[M+H]+,380.1870；found,380.1875.
实施例33
化合物33的制备：R1＝H，R2＝H，X＝NH，/>
实施例33与实施例6的区别在于将步骤(3)中的苯硼酸替换为1-甲基-5-吲哚硼酸，其余与实施例6相同。制备得到化合物33，收率为69.4％。
1H NMR(400MHz,CDCl3)δ8.86(d,J＝1.1Hz,1H),8.48(dd,J＝8.7,1.5Hz,1H),7.95(d,J＝8.0Hz,1H),7.80(d,J＝8.1Hz,3H),7.75–7.72(m,2H),7.43–7.37(m,1H),7.33(s,1H),7.06(d,J＝3.1Hz,1H),6.86(d,J＝9.0Hz,2H),6.60(d,J＝3.0Hz,1H),3.81(s,3H),3.00(s,6H).13CNMR(100MHz,CDCl3)δ161.70,157.28,151.14,147.86,138.26,132.43,130.26,129.32,128.81,128.68,128.54,125.03,123.14,122.57,122.12,120.35,113.66,113.10,108.83,102.38,41.05,32.95.HRMS(ESI)calcd for C25H23N5[M+H]+,394.2026；found,394.2031.
实施例34
化合物34的制备：R1＝H，R2＝H，X＝NH，/>
实施例34与实施例6的区别在于将步骤(3)中的苯硼酸替换为苯并-1,4-二氧六环-6-硼酸，其余与实施例6相同。制备得到化合物34，收率为38.7％。
1H NMR(400MHz,CDCl3)δ8.08–8.04(m,1H),7.91(d,J＝8.3Hz,1H),7.79(d,J＝8.2Hz,1H),7.73(t,J＝7.7Hz,1H),7.67(d,J＝9.0Hz,2H),7.43(t,J＝7.6Hz,1H),7.30(s,1H),6.95(d,J＝8.4Hz,1H),6.83(d,J＝9.0Hz,2H),4.30(s,4H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ160.07,157.38,151.00,147.94,145.59,143.30,132.64,132.51,128.99,128.36,125.37,123.12,122.17,120.26,117.71,117.00,113.69,113.06,64.64,64.24,41.00.HRMS(ESI)calcd for C24H22N4O2[M+H]+,399.1816；found,399.1822.
实施例35
化合物35的制备：R1＝H，R2＝H，X＝NH，/>/>
实施例35与实施例6的区别在于将步骤(3)中的苯硼酸替换为喹啉-3-硼酸，其余与实施例6相同。制备得到化合物35，收率为31.2％。
1H NMR(400MHz,CDCl3)δ10.03(s,1H),9.30(s,1H),8.15(s,1H),8.00(dd,J＝15.1,8.3Hz,2H),7.90(d,J＝8.2Hz,1H),7.83–7.73(m,2H),7.71(d,J＝8.9Hz,2H),7.60–7.56(m,1H),7.55–7.51(m,2H),6.85(d,J＝8.9Hz,2H),3.01(s,6H).13C NMR(100MHz,CDCl3)δ158.65,157.70,151.04,148.74,148.22,136.09,132.98,130.23,129.13,129.02,127.77,126.72,126.27,123.55,120.52,114.01,112.92,40.89.HRMS(ESI)calcd forC25H21N5[M+H]+,392.1870；found,392.1873.
实施例36
化合物36的制备：R1＝H，R2＝H，X＝NH，/>
实施例36与实施例6的区别在于将步骤(3)中的苯硼酸替换为苯并噻吩-2-硼酸，其余与实施例6相同。制备得到化合物36，收率为80.7％。
1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.93(d,J＝8.2Hz,1H),7.89–7.84(m,2H),7.81–7.73(m,4H),7.46(t,J＝7.5Hz,1H),7.37–7.34(m,3H),6.87(d,J＝9.4Hz,2H),3.01(s,6H).13C NMR(100MHz,CDCl3)δ157.40,157.09,150.70,148.02,145.10,141.76,140.36,132.81,128.96,128.11,125.91,125.18,125.12,124.61,124.26,123.01,122.58,120.32,113.93,112.98,40.96.HRMS(ESI)calcd for C24H20N4S[M+H]+,397.1482；found,397.1487.
实施例37
化合物37的制备：R1＝H，R2＝H，X＝O，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为4-二甲氨基苯酚，将4-二甲氨基苯酚(1mmol)溶解于5mL的N,N-二甲基甲酰胺中(5mL)，然后向反应体系中加入碳酸钾(2.5mmol)，搅拌5分钟，最后加入中间体5a在80℃条件下反应5小时，用薄层色谱检测反应，待反应完成后，向反应体系中加入乙酸乙酯(25mL)，用饱和食盐水(25mL×3)洗涤有机相，萃取后的有机相用无水硫酸镁干燥，浓缩，柱层析分离纯化即得中间体6r。收率为45.0％。
1H NMR(400MHz,CDCl3)δ8.34(d,J＝8.2Hz,1H),7.90(d,J＝5.1Hz,2H),7.65–7.61(m,1H),7.15(d,J＝9.0Hz,2H),6.79(d,J＝9.0Hz,2H),2.99(s,6H).13C NMR(100MHz,CDCl3)δ168.37,156.22,152.74,148.86,142.79,134.88,127.49,127.07,124.07,121.77,115.05,113.12,40.91.
(2)将实施例6的步骤(3)中的中间体6a替换为6r，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6相同。制备得到化合物37，收率为61.8％。
1H NMR(400MHz,DMSO-d6)δ8.43(dd,J＝18.9,8.3Hz,3H),8.11–8.03(m,4H),(dd,J＝15.2,7.5Hz,4H),7.79(t,J＝7.9Hz,1H),7.28(d,J＝8.9Hz,2H),6.86(d,J＝9.0Hz,2H),3.24(s,3H),2.97(s,6H).13C NMR(100MHz,DMSO-d6)δ167.10,157.40,151.55,148.38,142.59,142.36,141.70,134.93,128.54,128.25,127.90,127.30,123.59,122.04,114.81,112.74,43.37,40.45.HRMS(ESI)calcd for C23H21N3O3S[M+H]+,420.1377；found,420.1379.
实施例38
化合物38的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为N5,N5-二甲基吡啶-2,5-二胺，其余与实施例6的步骤(2)相同。制备得到中间体6b，收率为28.6％。
1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.67(d,J＝8.3Hz,1H),7.98–7.92(m,2H),7.87(t,J＝7.6Hz,1H),7.70(d,J＝8.3Hz,1H),7.60(t,J＝7.6Hz,1H),7.32(dd,J＝9.1,3.0Hz,1H),2.96(s,6H).13C NMR(100MHz,DMSO-d6)δ158.93,156.18,150.81,144.16,140.88,133.99,131.85,126.75,126.58,123.66,121.03,118.02,113.61.
(2)将实施例6的步骤(3)中的中间体6a替换为6b，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物38，收率为50.8％。
1H NMR(400MHz,CDCl3)δ8.75(d,J＝8.1Hz,2H),8.60(d,J＝9.4Hz,1H),8.17(s,1H),8.09(d,J＝8.3Hz,2H),7.99(t,J＝7.8Hz,2H),7.91(d,J＝3.0Hz,1H),7.84(t,J＝8.0Hz,1H),7.59(t,J＝7.6Hz,1H),7.29(dd,J＝9.1,2.9Hz,1H),3.11(s,3H),3.03(s,6H).13C NMR(100MHz,CDCl3)δ158.45,156.61,150.63,144.19,143.81,142.70,142.28,141.40,133.19,132.30,129.33,129.28,127.47,127.03,121.86,120.74,115.52,44.61,40.64.HRMS(ESI)calcd for C22H21N5O2S[M+H]+,420.1489；found,420.1490.
实施例39
化合物39的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为4-二甲氨基苄胺，其余与实施例6的步骤(2)相同。制备得到中间体6c，收率为49.9％。
1H NMR(400MHz,DMSO-d6)δ9.18(t,J＝5.5Hz,1H),8.32(d,J＝8.2Hz,1H),7.79(t,J＝7.6Hz,1H),7.64(d,J＝8.3Hz,1H),7.53(t,J＝7.6Hz,1H),7.24(d,J＝8.5Hz,2H),6.69(d,J＝8.5Hz,2H),4.65(d,J＝5.7Hz,2H),2.85(s,6H).13C NMR(100MHz,DMSO-d6)δ160.87,157.00,150.36,149.71,133.52,128.57,126.59,126.00,125.80,123.08,113.54,112.31,43.57.
(2)将实施例6的步骤(3)中的中间体6a替换为6c，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物39，收率为67.2％。
1H NMR(400MHz,DMSO-d6)δ8.94(t,J＝5.7Hz,1H),8.72(d,J＝8.3Hz,2H),8.33(d,J＝8.3Hz,1H),8.06(d,J＝8.4Hz,2H),7.81(d,J＝3.1Hz,2H),7.61–7.49(m,1H),7.32(d,J＝8.5Hz,2H),6.69(d,J＝8.5Hz,2H),4.81(d,J＝5.6Hz,2H),3.27(s,3H),2.83(s,6H).13CNMR(100MHz,DMSO-d6)δ159.57,157.75,149.69,149.62,143.35,141.72,132.94,128.53,127.97,127.03,126.97,126.01,122.75,114.03,112.37,43.53.HRMS(ESI)calcd forC24H24N4O2S[M+H]+,433.1693；found,433.1696.
实施例40
化合物40的制备：R1＝H，R2＝H，X＝NH，/>/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为4-氨基-N,N-二甲基苯甲酰胺，其余与实施例6的步骤(2)相同。制备得到中间体6d，收率为44.8％。
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.61(d,J＝8.3Hz,1H),7.91(d,J＝8.3Hz,3H),7.80–7.62(m,2H),7.50(d,J＝8.4Hz,2H),3.00(s,6H).13C NMR(100MHz,DMSO-d6)δ169.71,159.21,155.99,150.88,139.23,134.21,132.19,127.69,126.95,126.73,123.50,121.89,113.79.
(2)将实施例6的步骤(3)中的中间体6a替换为6d，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物40，收率为43.5％。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.65(dd,J＝12.5,8.4Hz,3H),8.08(dd,J＝13.7,8.4Hz,4H),8.01–7.90(m,2H),7.70(t,J＝8.2Hz,1H),7.56(d,J＝8.5Hz,2H),3.28(s,3H),3.03(s,6H).13C NMR(100MHz,DMSO-d6)δ169.90,157.96,157.52,150.30,142.82,141.97,140.17,133.62,131.25,128.60,128.34,127.81,127.25,126.79,123.15,121.38,114.22,54.88,43.48.HRMS(ESI)calcd for C24H22N4O3S[M+H]+,447.1486；found,447.1499.
实施例41
化合物41的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为4-氨基-N-甲基乙酰苯胺，其余与实施例6的步骤(2)相同。制备得到中间体6e，收率为43.9％。
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.59(d,J＝8.2Hz,1H),7.91(t,J＝7.7Hz,3H),7.74(d,J＝8.3Hz,1H),7.68(t,J＝7.6Hz,1H),7.41(d,J＝8.2Hz,2H),3.18(s,3H),1.83(s,3H).13C NMR(100MHz,DMSO-d6)δ169.11,159.20,156.07,150.85,140.51,137.24,134.16,127.28,126.93,126.68,123.43,123.37,113.76,36.49,22.24.
(2)将实施例6的步骤(3)中的中间体6a替换为6e，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物41，收率为40.2％。
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.97(d,J＝7.9Hz,1H),8.56(d,J＝7.8Hz,2H),8.30(d,J＝7.7Hz,1H),8.09(d,J＝7.9Hz,2H),8.02(t,J＝7.2Hz,1H),7.93(s,2H),7.76(t,J＝7.1Hz,1H),7.42(d,J＝7.6Hz,2H),3.27(s,3H),3.16(s,3H),1.81(s,3H).13C NMR(100MHz,DMSO-d6)δ169.10,158.79,156.17,143.82,141.68,135.60,129.95,128.19,127.33,124.88,124.60,122.16,113.15,43.22,36.59,22.32.HRMS(ESI)calcdfor C24H22N4O3S[M+H]+,447.1486；found,447.1478.
实施例42
化合物42的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为苯胺，其余与实施例6的步骤(2)相同。制备得到中间体6f，收率为76.1％。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.58(d,J＝8.3Hz,1H),7.90(t,J＝7.7Hz,1H),7.79(d,J＝8.3Hz,2H),7.73(d,J＝8.3Hz,1H),7.66(t,J＝7.7Hz,1H),7.45(t,J＝8.0Hz,2H),7.22(t,J＝7.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.39,156.21,150.84,138.15,134.06,128.61,126.89,126.59,124.73,123.44,122.97,113.74.
(2)将实施例6的步骤(3)中的中间体6a替换为6f，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物42，收率为45.6％。
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.64(t,J＝8.3Hz,3H),8.08(d,J＝8.3Hz,2H),8.01–7.95(m,2H),7.94–7.88(m,2H),7.72–7.64(m,1H),7.49(t,J＝7.8Hz,2H),7.21(t,J＝7.4Hz,1H),3.28(s,3H).13C NMR(100MHz,DMSO-d6)δ158.07,157.57,150.24,142.96,141.93,139.03,133.47,128.55,128.28,127.18,126.64,123.89,123.12,122.38,122.27,114.18,43.47.HRMS(ESI)calcd for C21H17N3O2S[M+H]+,376.1114；found,376.1118.
实施例43
化合物43的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6g，收率为70.9％。
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.52(d,J＝8.2Hz,1H),7.84(t,J＝7.3Hz,1H),7.66(d,J＝8.2Hz,1H),7.59(t,J＝7.6Hz,1H),7.35(d,J＝8.4Hz,2H),6.67(d,J＝8.3Hz,2H),5.76(s,2H).13C NMR(100MHz,DMSO-d6)δ159.87,152.27,139.82,134.08,133.85,126.40,125.88,124.81,124.73,124.46,117.48,110.59.
(2)将实施例6的步骤(3)中的中间体6a替换为6g，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物43，收率为70.3％。
1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.60(d,J＝8.4Hz,2H),8.53(d,J＝8.2Hz,1H),8.05(d,J＝8.4Hz,2H),7.87(d,J＝3.8Hz,2H),7.61(dt,J＝8.2,3.9Hz,1H),7.53(d,J＝8.6Hz,2H),6.72(d,J＝8.6Hz,2H),3.26(s,3H).13C NMR(100MHz,DMSO-d6)δ158.60,158.23,150.50,145.22,143.69,142.29,133.62,128.96,128.54,127.54,126.80,124.83,123.43,114.65,43.97.HRMS(ESI)calcd for C21H18N4O2S[M+H]+,391.1223；found,391.1226.
实施例44
化合物44的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6h，收率为60.4％。
1H NMR(400MHz,CDCl3)δ7.81–7.77(m,2H),7.76–7.71(m,1H),7.52(s,1H),7.50–7.44(m,3H),6.68(d,J＝9.0Hz,2H),3.35(q,J＝7.1Hz,4H),1.16(t,J＝7.1Hz,6H).13C NMR(101MHz,CDCl3)δ158.80,157.69,151.31,145.89,133.43,128.02,126.31,125.56,123.94,120.80,113.55,112.06,44.53,12.60.
(2)将实施例6的步骤(3)中的中间体6a替换为6h，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物44，收率为43.4％。
1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.64(d,J＝8.4Hz,2H),8.56(d,J＝8.3Hz,1H),8.07(d,J＝8.4Hz,2H),7.87(d,J＝2.8Hz,2H),7.70(d,J＝8.9Hz,2H),7.64–7.60(m,1H),6.78(d,J＝9.0Hz,2H),3.38(q,J＝7.0Hz,4H),3.27(s,3H),1.14(t,J＝7.0Hz,6H).13CNMR(100MHz,CDCl3)δ158.70,150.74,144.24,141.19,132.90,129.34,127.30,126.54,123.80,120.43,114.10,112.12,44.61,12.65.HRMS(ESI)calcd for C25H26N4O2S[M+H]+,447.1849；found,447.1855.
实施例45
化合物45的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为N,N-二乙基-1,4-环己烷二胺，其余与实施例6的步骤(2)相同。制备得到中间体6i，收率为58.3％。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝8.3Hz,1H),8.24(d,J＝6.4Hz,1H),7.79(t,J＝7.6Hz,1H),7.60(d,J＝8.3Hz,1H),7.51(t,J＝7.6Hz,1H),4.24(s,1H),3.31(s,1H),2.60(s,4H),1.88(s,4H),1.56(d,J＝48.2Hz,4H),0.96(s,6H).13C NMR(100MHz,DMSO-d6)δ160.42,156.94,150.33,133.48,126.48,125.75,123.66,113.55,54.46,48.63,42.12,26.97,26.12,11.81.
(2)将实施例6的步骤(3)中的中间体6a替换为6i，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物45，收率为47.3％。
1H NMR(400MHz,DMSO-d6)δ8.69(d,J＝8.4Hz,2H),8.51(d,J＝8.3Hz,1H),8.06(d,J＝8.4Hz,2H),7.91(d,J＝6.5Hz,1H),7.81(d,J＝3.8Hz,2H),7.53(dt,J＝8.2,4.1Hz,1H),4.48(d,J＝6.6Hz,1H),3.27(s,3H),2.60(q,J＝6.9Hz,5H),2.12–1.96(m,2H),1.93–1.83(m,2H),1.81–1.66(m,2H),1.65–1.52(m,2H),0.97(t,J＝7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ159.22,157.69,149.72,143.44,141.69,132.83,128.45,127.87,127.03,125.72,123.33,114.06,55.36,48.26,43.54,42.28,27.39,25.88,12.32.HRMS(ESI)calcdfor C25H32N4O2S[M+H]+,453.2319；found,453.2320.
实施例46
化合物46的制备：R1＝H，R2＝H，X＝NH，/>
(1)将实施例6的步骤(2)中的N,N-二甲基对苯二胺替换为3-二乙胺基丙胺，其余与实施例6的步骤(2)相同。制备得到中间体6j，收率为58.3％。
H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.22(d,J＝8.2Hz,1H),7.79(t,J＝7.6Hz,1H),
7.61(d,J＝8.3Hz,1H),7.53(t,J＝7.6Hz,1H),3.53(t,J＝6.7Hz,2H),2.54(d,J＝3.9Hz,4H),1.91(s,2H),1.79(p,J＝7.0Hz,2H),0.97(t,J＝7.1Hz,6H).13C NMR(100MHz,DMSO-d6)δ160.98,157.05,150.18,133.48,126.62,125.98,122.94,113.54,50.01,46.18,25.35,21.15,11.35.
(2)将实施例6的步骤(3)中的中间体6a替换为6j，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物46，收率为50.3％。
1H NMR(400MHz,DMSO-d6)δ8.73(d,J＝8.4Hz,2H),8.67(s,1H),8.31(d,J＝7.8Hz,1H),8.06(d,J＝8.4Hz,2H),7.83(d,J＝3.6Hz,2H),7.56(dt,J＝8.1,3.7Hz,1H),3.77(d,J＝5.1Hz,2H),3.28(s,4H),2.93(s,5H),2.05(s,2H),1.12(s,6H).13C NMR(100MHz,DMSO-d6)δ160.36,158.28,150.11,143.84,142.28,138.80,133.48,129.38,129.05,128.51,127.48,126.52,123.28,114.54,46.68,44.06.HRMS(ESI)calcd for C22H28N4O2S[M+H]+,413.2006；found,413.2015.
实施例47
化合物47的制备：R1＝CH3O，R2＝CH3O，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3b，4a替换为4b，其余与实施例6的步骤(1)相同。制备得到化合物5b，收率为43.9％。
1H NMR(400MHz,DMSO-d6)δ7.40(s,1H),7.32(s,1H),3.99(s,6H).
(2)将实施例6的步骤(2)中的5a替换为5b，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6k，收率为84.4％。
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),7.83(s,1H),7.40(d,J＝8.7Hz,2H),7.12(s,1H),6.72(d,J＝8.7Hz,2H),3.92(d,J＝5.9Hz,6H),3.38(s,4H),1.11(t,J＝6.9Hz,6H).13CNMR(100MHz,DMSO-d6)δ158.26,154.81,154.55,148.70,147.73,144.97,126.27,124.96,111.42,107.09,106.59,102.32,56.21,55.90,43.71,12.45.
(3)将实施例6的步骤(3)中的中间体6a替换为6k，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物47，收率为84.7％。
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.60(d,J＝8.2Hz,2H),8.04(d,J＝8.4Hz,2H),7.89(s,1H),7.63(d,J＝8.7Hz,2H),7.29(s,1H),6.79(d,J＝8.8Hz,2H),3.97(d,J＝2.1Hz,6H),3.41–3.36(m,4H),3.26(s,3H),1.14(t,J＝6.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ156.68,156.16,154.18,149.03,147.05,144.37,143.57,141.30,128.08,127.54,127.05,124.11,111.54,107.82,102.14,56.24,55.76,43.76,43.52,12.48.HRMS(ESI)calcd for C27H30N4O4S[M+H]+,507.2061；found,507.2062.
实施例48
化合物48的制备：R1＝CH3O，R2＝H，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3c，4a替换为4c，其余与实施例6的步骤(1)相同。制备得到化合物5c，收率为40.8％。
1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝9.2Hz,1H),7.81(dd,J＝9.2,2.8Hz,1H),7.47(s,1H),4.00(s,3H).
(2)将实施例6的步骤(2)中的5a替换为5c，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6l，收率为60.8％。
1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),7.91(d,J＝2.2Hz,1H),7.61(d,J＝9.1Hz,1H),7.53–7.39(m,3H),6.73(d,J＝8.9Hz,2H),3.93(s,3H),3.38(d,J＝6.9Hz,4H),1.12(t,J＝6.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ158.73,157.40,154.47,145.82,145.12,128.25,126.02,124.96,124.44,114.32,111.38,102.88,55.99,43.71,12.45.
(3)将实施例6的步骤(3)中的中间体6a替换为6l，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物48，收率为80.4％。
1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.60(d,J＝8.4Hz,2H),8.04(d,J＝8.4Hz,2H),7.96(s,1H),7.81(d,J＝9.1Hz,1H),7.67(d,J＝8.9Hz,2H),7.50(d,J＝11.5Hz,1H),6.79(d,J＝8.9Hz,2H),3.97(s,3H),3.38(q,J＝6.9Hz,4H),3.26(s,3H),1.14(t,J＝6.9Hz,6H).13CNMR(100MHz,DMSO-d6)δ157.62,157.16,155.76,145.32,144.52,143.41,141.38,129.75,128.16,127.30,127.07,124.16,123.99,114.76,111.49,102.55,56.05,43.76,43.53,12.49.HRMS(ESI)calcd for C26H28N4O3S[M+H]+,477.1955；found,477.1954.
实施例49
化合物49的制备：R1＝H，R2＝CH3O，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3d，4a替换为4d，其余与实施例6的步骤(1)相同。制备得到化合物5d，收率为44.9％。
1H NMR(400MHz,CDCl3)δ8.04(d,J＝9.2Hz,1H),7.26–7.22(m,1H),7.20–7.19(m,1H),3.92(s,3H).13C NMR(100MHz,CDCl3)δ165.94,162.55,155.88,155.08,127.36,122.41,117.42,105.90,56.20.
(2)将实施例6的步骤(2)中的5a替换为5d，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6m，收率为37.2％。
1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.40(d,J＝9.2Hz,1H),7.44(d,J＝9.0Hz,2H),7.19(dd,J＝9.1,2.5Hz,1H),7.10(d,J＝2.5Hz,1H),6.70(d,J＝9.0Hz,2H),3.91(s,3H),3.40–3.33(m,4H),1.11(t,J＝7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ163.26,158.93,157.17,153.14,145.02,126.22,124.79,117.11,111.42,107.71,106.61,55.72,43.72,12.43.
(3)将实施例6的步骤(3)中的中间体6a替换为6m，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物49，收率为85.8％。
1H NMR(400MHz,CDCl3)δ8.68(d,J＝8.6Hz,2H),8.01(d,J＝8.6Hz,2H),7.74(d,J＝9.1Hz,1H),7.57(d,J＝9.0Hz,2H),7.30(d,J＝2.5Hz,1H),7.12(dd,J＝9.0,2.5Hz,1H),6.77(d,J＝9.0Hz,2H),3.97(s,3H),3.40(q,J＝7.1Hz,4H),3.07(s,3H),1.21(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ163.26,159.28,157.60,153.10,145.43,144.30,141.13,129.29,127.27,126.76,123.91,121.97,118.52,112.19,108.28,107.84,55.73,44.60,12.63.HRMS(ESI)calcd for C26H28N4O3S[M+H]+,477.1955；found,477.1960.
实施例50
化合物50的制备：R1＝H，R2＝CH3，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3e，4a替换为4e，其余与实施例6的步骤(1)相同。制备得到化合物5e，收率为40.7％。
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.5Hz,1H),7.83(s,1H),7.74(d,J＝8.6Hz,1H),2.60(s,3H).
(2)将实施例6的步骤(2)中的5a替换为5e，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6n，收率为39.3％。
1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.4Hz,1H),7.57(s,1H),7.48(d,J＝9.0Hz,2H),7.40(s,1H),7.30(d,J＝9.4Hz,1H),6.70(d,J＝9.0Hz,2H),3.36(q,J＝7.1Hz,4H),2.51(s,3H),1.17(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ158.66,157.68,151.57,145.80,144.39,128.18,127.34,125.75,123.87,120.51,112.12,111.33,44.54,21.87,12.58.
(3)将实施例6的步骤(3)中的中间体6a替换为6n，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物50，收率为71.9％。
1H NMR(400MHz,CDCl3)δ8.68(d,J＝8.4Hz,2H),8.01(d,J＝8.4Hz,2H),7.74(d,J＝9.1Hz,1H),7.57(d,J＝8.8Hz,2H),7.30(s,1H),7.15–7.10(m,1H),6.77(d,J＝8.5Hz,1H),3.97(s,3H),3.40(q,J＝7.0Hz,4H),3.07(s,3H),1.21(t,J＝7.0Hz,6H).13C NMR(100MHz,CDCl3)δ163.26,159.26,157.59,153.07,144.28,141.13,129.29,127.26,123.89,122.00,118.52,112.22,108.27,107.83,55.67,44.60,12.62.HRMS(ESI)calcdfor C26H28N4O2S[M+H]+,461.2006；found,461.2010.
实施例51
化合物51的制备：R1＝H，R2＝F，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3f，4a替换为4f，其余与实施例6的步骤(1)相同。制备得到化合物5f，收率为43.1％。
1H NMR(400MHz,DMSO-d6)δ8.42(dd,J＝9.2,5.8Hz,1H),7.94(d,J＝12.0Hz,1H),7.84(t,J＝10.1Hz,1H).
(2)将实施例6的步骤(2)中的5a替换为5f，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6o，收率为37.8％。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.59(dd,J＝9.2,6.0Hz,1H),7.55–7.49(m,1H),7.47–7.42(m,3H),6.72(d,J＝9.0Hz,2H),3.39–3.34(m,4H),1.11(t,J＝7.0Hz,6H).13CNMR(100MHz,DMSO-d6)δ166.19,163.69,158.91,157.90,152.78,152.65,145.23,126.50,126.39,125.75,124.87,115.55,115.31,111.33,110.90,43.71,12.41.
(3)将实施例6的步骤(3)中的中间体6a替换为6o，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物51，收率为63.1％。
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.65(dd,J＝9.1,6.1Hz,1H),8.61(d,J＝8.5Hz,2H),8.06(d,J＝8.5Hz,2H),7.67(d,J＝9.0Hz,2H),7.59(d,J＝10.2Hz,1H),7.52(t,J＝10.1Hz,1H),6.78(d,J＝9.1Hz,2H),3.44–3.35(m,4H),3.27(s,3H),1.14(t,J＝7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ163.45,158.95,157.67,152.28,152.15,144.68,142.88,142.00,128.63,127.11,126.95,124.19,111.45,111.34,43.75,43.48,12.48.HRMS(ESI)calcd for C25H25FN4O2S[M+H]+,465.1760；found,465.1760.
实施例52
化合物52的制备：R1＝H，R2＝Cl，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3g，4a替换为4g，其余与实施例6的步骤(1)相同。制备得到化合物5g，收率为42.9％。
1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.9Hz,1H),7.93(d,J＝1.9Hz,1H),7.62(dd,J＝8.9,2.0Hz,1H).
(2)将实施例6的步骤(2)中的5a替换为5g，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6p。收率为36.0％。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.53(d,J＝8.9Hz,1H),7.72(d,J＝2.0Hz,1H),7.65(dd,J＝8.8,2.0Hz,1H),7.47(d,J＝8.9Hz,2H),6.71(d,J＝8.9Hz,2H),3.35(d,J＝10.1Hz,4H),1.11(t,J＝7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ158.93,157.87,151.63,145.24,138.29,126.55,125.72,125.58,125.43,124.77,112.60,111.30,43.70,12.43.
(3)将实施例6的步骤(3)中的中间体6a替换为6p，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物52，收率为57.1％。
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.59(t,J＝8.9Hz,3H),8.06(d,J＝8.4Hz,2H),7.88(d,J＝2.0Hz,1H),7.67(t,J＝7.7Hz,3H),6.78(d,J＝9.0Hz,2H),3.38(q,J＝7.0Hz,4H),3.27(s,3H),1.14(t,J＝7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ158.98,157.66,151.20,144.70,142.82,142.05,137.67,128.64,127.13,126.88,126.78,126.48,125.21,124.11,112.94,111.43,43.75,43.48,12.47.HRMS(ESI)calcd for C25H25ClN4O2S[M+H]+,481.1460；found,481.1464.
实施例53
化合物53的制备：R1＝H，R2＝CF3，X＝NH，/>
(1)将实施例6的步骤(1)中的3a替换为3h，4a替换为4h，其余与实施例6的步骤(1)相同。制备得到化合物5h，收率为45.4％。
1H NMR(400MHz,DMSO-d6)δ8.55–8.47(m,1H),8.22(dd,J＝41.4,8.5Hz,1H),7.98–7.80(m,1H).
(2)将实施例6的步骤(2)中的5a替换为5h，N,N-二甲基对苯二胺替换为N,N-二乙基对苯二胺，其余与实施例6的步骤(2)相同。制备得到中间体6q，收率为35.6％。
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.74(d,J＝8.6Hz,1H),7.99(s,1H),7.91(d,J＝8.6Hz,1H),7.50(d,J＝9.0Hz,2H),6.73(d,J＝9.1Hz,2H),3.36(q,J＝7.1Hz,5H),1.11(t,J＝7.0Hz,7H).13C NMR(100MHz,DMSO-d6)δ158.84,158.15,150.38,145.35,133.45,133.13,125.58,125.37,124.76,123.96,121.70,116.34,111.28,43.70,12.43.
(3)将实施例6的步骤(3)中的中间体6a替换为6q，苯硼酸替换为4-(甲磺酰基)苯硼酸，其余与实施例6的步骤(3)相同。制备得到化合物53，收率为81.8％。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.77(d,J＝8.6Hz,1H),8.62(d,J＝8.4Hz,2H),8.14(s,1H),8.08(d,J＝8.4Hz,2H),7.90(d,J＝8.7Hz,1H),7.70(d,J＝8.9Hz,2H),6.79(d,J＝9.0Hz,2H),3.39(q,J＝6.9Hz,5H),3.27(s,3H),1.14(t,J＝6.9Hz,7H).13CNMR(100MHz,DMSO-d6)δ159.23,157.58,149.84,144.82,142.63,142.18,128.70,127.17,126.70,125.25,125.07,124.15,116.55,111.38,43.75,43.46,12.48.HRMS(ESI)calcdfor C26H25F3N4O2S[M+H]+,515.1723；found,515.1728.
实验例1
LSD1抑制活性测定：
LSD1抑制活性的检测样品为实施例1至53所制备得到的化合物经纯化得到。样品储备液的配制过程为：称取1～2mg样品置于1.5mL EP管中，用DMSO配制成浓度为20mM的溶液，于4℃环境下保存备用，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白在室温孵育后，加入LSD1底物H3K4me2并孵育反应，最后加入荧光染料Amplex和辣根过氧化酶HRP室温孵育，在酶标仪上激发光530nm、发射光590nm检测荧光数值，抑制率的计算公式如下所示。实验结果采用SPSS软件计算IC50值，结果如表1所示。
表1
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由表1可知，本发明提供的一种喹唑啉类化合物对LSD1有一定的抑制活性。当化合物浓度为10μM时，如化合物2、4、6-11、13-17、19-20、22-34、37-38、43-44、49-51等抑制活性较好，对LSD1的抑制活性较高，均达80％以上。化合物4、6、10、12-17、19-20、22-37、43-44、49-51等发挥作用时，其IC50值较低，均低于1μM，具有较小的生物毒性。
综上，本发明提供的喹唑啉类化合物对LSD1具有良好的抑制活性，显示出良好的开发潜力，为开发新型抗肿瘤药物、药物的联合用药以及新型LSD1抑制剂药物的开发开辟了一条有效途径，具有良好的市场应用前景。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (10)
1.一种喹唑啉类化合物，其特征在于，其为具有结构通式Ⅰ的化合物，或结构通式I所示化合物在药学上可接受的盐：
其中，X选自O或NH；
R1选自H、C1-C10烷氧基、烷基取代烷氧基；R2选自H、烷基、C1-C10烷氧基、烷基取代烷氧基或卤素；
R3选自芳胺、脂肪胺、芳基或杂芳基；
R4选自Me、 中的一种。
2.如权利要求1所述的喹唑啉类化合物，其特征在于，R1选自H、甲氧基、二甲氧基乙烷中的一种；R2选自H、甲基、甲氧基、二甲氧基乙烷、氯、氟和三氟甲基中的一种；
R3选自 中的一种。
3.如权利要求2所述的喹唑啉类化合物，其特征在于，R1、R2、R3、R4选自下列基团：
4.如权利要求1至3任一项所述的喹唑啉类化合物的制备方法，其特征在于，包括以下步骤：
合成路线a：化合物1a-c和三氯氧磷在碱性物质作用下发生氯代反应得到化合物2a-c；
合成路线b：化合物2a-c或者5a-h和氨类化合物溶解于有机溶剂和水的混合溶液中，在碱性物质作用下发生取代反应得到化合物Ⅰ、6a-q；
合成路线c：化合物2b和N,N-二甲基对苯二胺溶解于醇溶剂中，在酸性物质作用下发生取代反应得到化合物Ⅰ；
合成路线d：不同取代的邻氨基苯甲酸化合物3a-h和尿素反应得到化合物4a-h；
合成路线e：化合物4a-h和三氯氧磷溶于有机溶剂中，在碱性物质作用下发生氯代反应得到化合物5a-h；
合成路线f：化合物5a和氨基苯酚溶解于有机溶剂中，在碱性物质作用下发生取代反应得到化合物6r；
合成路线g：化合物6a-r和硼酸类化合物溶解于有机溶剂和水的混合溶液中，在碱性物质及钯催化作用下，发生Suzuki偶联反应得到化合物Ⅰ；
所述X为NH或O。
5.如权利要求4所述的喹唑啉类化合物的制备方法，其特征在于，所述合成路线a中由化合物1a-c合成化合物2a-c的反应温度为50℃-150℃；
合成路线b中由化合物2a-c或者5a-h合成化合物Ⅰ、6a-q的反应温度为60℃-130℃；
合成路线c中由化合物2b合成化合物Ⅰ的反应温度为45℃-120℃；
合成路线d中由化合物3a-h合成化合物4a-h的反应温度为90℃-180℃；
合成路线e中由化合物4a-h合成化合物5a-h的反应温度为60℃-140℃；
合成路线f中由化合物5a合成化合物6r的反应温度为45℃-120℃；
合成路线g中由化合物6a-r合成化合物Ⅰ的反应温度为45℃-125℃。
6.如权利要求4所述的喹唑啉类化合物的制备方法，其特征在于，合成路线b、e、f、g中所述有机溶剂选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氧六环中的一种；
合成路线c中所述醇溶剂选自甲醇、乙醇、正丁醇、异丙醇中的一种。
7.如权利要求4所述的喹唑啉类化合物的制备方法，其特征在于，合成路线b、e、f、g中所述碱性物质选自碳酸钠、乙酸钠、碳酸钾、氢氧化钠、氢氧化钾、N,N-二甲基苯胺、N,N-二异丙基乙胺中的一种。
8.如权利要求4所述的喹唑啉类化合物的制备方法，其特征在于，合成路线c中所述酸性物质选自冰醋酸、浓盐酸、浓硫酸中的一种。
9.如权利要求4所述的喹唑啉类化合物的制备方法，其特征在于，合成路线g中所述钯催化剂为四(三苯基膦)钯、双(三苯基膦)二氯化钯、双(二亚苄基丙酮)钯中的一种。
10.如权利要求1至3任一项所述的喹唑啉类化合物、和/或权利要求4至9任一项所述的制备方法制备得到的喹唑啉类化合物在制备靶向LSD1的抗肿瘤药物中的应用。
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