CN114920703B - 一种喹唑啉衍生物及其制备方法和应用 - Google Patents
一种喹唑啉衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN114920703B CN114920703B CN202210587104.1A CN202210587104A CN114920703B CN 114920703 B CN114920703 B CN 114920703B CN 202210587104 A CN202210587104 A CN 202210587104A CN 114920703 B CN114920703 B CN 114920703B
- Authority
- CN
- China
- Prior art keywords
- compound
- dmso
- nmr
- 100mhz
- hrms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract 8
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 108091008605 VEGF receptors Proteins 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 9
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 230000036210 malignancy Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 7
- 102000020233 phosphotransferase Human genes 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 abstract description 5
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 abstract description 5
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 abstract description 4
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 3
- 231100000673 dose–response relationship Toxicity 0.000 abstract description 2
- 230000009036 growth inhibition Effects 0.000 abstract description 2
- 230000005917 in vivo anti-tumor Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 595
- 238000005481 NMR spectroscopy Methods 0.000 description 290
- 150000001875 compounds Chemical class 0.000 description 185
- 239000007787 solid Substances 0.000 description 119
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000003960 organic solvent Substances 0.000 description 30
- 150000003246 quinazolines Chemical class 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000002156 mixing Methods 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 15
- 238000006482 condensation reaction Methods 0.000 description 14
- -1 nucleoside triphosphate Chemical class 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 230000033115 angiogenesis Effects 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000007112 amidation reaction Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 4
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 4
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000011535 reaction buffer Substances 0.000 description 4
- PPSMYAUEJRADFE-HXUWFJFHSA-N 2-[(5r)-4-[2-[3-(6-methylpyridin-3-yl)oxyphenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound C1=NC(C)=CC=C1OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 PPSMYAUEJRADFE-HXUWFJFHSA-N 0.000 description 3
- MSSQOQPKGAMUSY-LEAFIULHSA-N 2-[1-[2-[(4r,6s)-8-chloro-6-(2,3-dimethoxyphenyl)-4,6-dihydropyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N3C=CC=C3[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC MSSQOQPKGAMUSY-LEAFIULHSA-N 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229940125876 compound 15a Drugs 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 3
- 229960004836 regorafenib Drugs 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 2
- MZCZXPHMOGJQBJ-OAQYLSRUSA-L (3r)-4-[[4-(4-fluorophenyl)-2-propan-2-yl-6,7-dihydro-5h-benzo[2,3]cyclohepta[2,4-c]pyridin-3-yl]methoxy-oxidophosphoryl]-3-hydroxybutanoate Chemical compound [O-]C(=O)C[C@@H](O)CP([O-])(=O)OCC=1C(C(C)C)=NC(C2=CC=CC=C2CCC2)=C2C=1C1=CC=C(F)C=C1 MZCZXPHMOGJQBJ-OAQYLSRUSA-L 0.000 description 2
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 2
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 2
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 2
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 2
- AXQACEQYCPKDMV-RZAWKFBISA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-n-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3C(O)=C(C[C@]2(O)[C@]34CC1)C(=O)NC(C)(C)C=1ON=C(N=1)C=1C=CC=CC=1)CC1CC1 AXQACEQYCPKDMV-RZAWKFBISA-N 0.000 description 2
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 2
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 2
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- FJZNNKJZHQFMCK-LRDDRELGSA-N 1-[(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea Chemical compound C1(=CC(=CC(=C1[C@H]1[C@@H](C(=O)NC1)NC(=O)NC1=CC=CC=C1)F)OC)F FJZNNKJZHQFMCK-LRDDRELGSA-N 0.000 description 2
- MOQCFMZWVKQBAP-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)benzoyl]-n-(4-chlorophenyl)piperidine-3-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2CC(CCC2)C(=O)NC=2C=CC(Cl)=CC=2)=C1 MOQCFMZWVKQBAP-UHFFFAOYSA-N 0.000 description 2
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JENUMEXEVAAAJX-SNVBAGLBSA-N 2-(3,5-dimethyl-1,2,4-triazol-1-yl)-1-[(2r)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone Chemical compound C([C@H]1C)N(C2=C(N=C(S2)C(F)(F)F)C=2C=NC(=NC=2)C(F)(F)F)CCN1C(=O)CN1N=C(C)N=C1C JENUMEXEVAAAJX-SNVBAGLBSA-N 0.000 description 2
- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 2
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 2
- KKKJYDOHVKIIQP-UHFFFAOYSA-N 2-[4-(3-chlorobenzoyl)phenoxy]-N-pyridin-3-ylacetamide Chemical compound ClC=1C=C(C(=O)C2=CC=C(OCC(=O)NC=3C=NC=CC=3)C=C2)C=CC=1 KKKJYDOHVKIIQP-UHFFFAOYSA-N 0.000 description 2
- CODBZFJPKJDNDT-UHFFFAOYSA-N 2-[[5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl]amino]-9-(trifluoromethyl)-5,7-dihydropyrimido[5,4-d][1]benzazepine-6-thione Chemical compound CN(C)CCCC1=CN=C(C)C(NC=2N=C3C4=CC=C(C=C4NC(=S)CC3=CN=2)C(F)(F)F)=C1 CODBZFJPKJDNDT-UHFFFAOYSA-N 0.000 description 2
- LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 2
- DNTVJEMGHBIUMW-IBGZPJMESA-N 3-[[4-[(1s)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid Chemical compound C1([C@H](C)N2N=C(C=C2C2=CC3=CC=C(C=C3C=C2)OC)C=2C=C(Cl)C=C(Cl)C=2)=CC=C(C(=O)NCCC(O)=O)C=C1 DNTVJEMGHBIUMW-IBGZPJMESA-N 0.000 description 2
- GOAKYBVMJUXOFY-LBPRGKRZSA-N 3-amino-4-[(3S)-3-(2-ethoxyethoxymethyl)piperidin-1-yl]thieno[2,3-b]pyridine-2-carboxamide Chemical compound CCOCCOC[C@@H](CCC1)CN1C1=C(C(N)=C(C(N)=O)S2)C2=NC=C1 GOAKYBVMJUXOFY-LBPRGKRZSA-N 0.000 description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 2
- ANMVTYAYYHHSTF-UHFFFAOYSA-N 4-(4-ethylpiperazin-1-yl)-N-[6-(2-fluoro-3-methoxyphenyl)-1H-indazol-3-yl]benzamide Chemical compound CCN1CCN(CC1)c1ccc(cc1)C(=O)Nc1n[nH]c2cc(ccc12)-c1cccc(OC)c1F ANMVTYAYYHHSTF-UHFFFAOYSA-N 0.000 description 2
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 2
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 2
- LIDUGWDLSDKCLM-CSKARUKUSA-N 4-[[3-[[[(e)-6,6-dimethylhept-2-en-4-ynyl]-ethylamino]methyl]phenoxy]methyl-dimethylsilyl]benzonitrile Chemical compound CC(C)(C)C#C/C=C/CN(CC)CC1=CC=CC(OC[Si](C)(C)C=2C=CC(=CC=2)C#N)=C1 LIDUGWDLSDKCLM-CSKARUKUSA-N 0.000 description 2
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 2
- OJKONCJPCULNOW-DYVFJYSZSA-N 5-chloro-2-fluoro-4-[(1s,2r)-2-(2-methylpyrazol-3-yl)cyclohexyl]oxy-n-pyrimidin-4-ylbenzenesulfonamide Chemical compound CN1N=CC=C1[C@@H]1[C@@H](OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2N=CN=CC=2)Cl)CCCC1 OJKONCJPCULNOW-DYVFJYSZSA-N 0.000 description 2
- HCFZUTSDEMKXQB-UHFFFAOYSA-N 6-[2-[2-(4-bromophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid Chemical compound O1CC(CC=CCCC(O)=O)C(C=2C=NC=CC=2)OC1C(C)(C)OC1=CC=C(Br)C=C1 HCFZUTSDEMKXQB-UHFFFAOYSA-N 0.000 description 2
- DJSWNINDPRRCLC-GOSISDBHSA-N 7-methyl-n-[(2r)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Chemical compound C([C@@H](C)NC(=O)C1=C(N2N=CC(=C2N=C1)C=1C=CC(=CC=1)C(C)C)C)OC1=CC=CC=C1 DJSWNINDPRRCLC-GOSISDBHSA-N 0.000 description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 2
- VADOZMZXXRBXNY-UHFFFAOYSA-N 8-cyclopentyl-2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=C(C#N)C(=O)N2C3CCCC3)C2=N1 VADOZMZXXRBXNY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126559 Compound 4e Drugs 0.000 description 2
- 229940125761 Compound 6g Drugs 0.000 description 2
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 2
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 2
- 229940125907 SJ995973 Drugs 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 2
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- BZVXYJWEOARYIS-UNMCSNQZSA-N [4-(3-ethoxyphenyl)phenyl]methyl (2s)-2-[[(1s)-3-amino-1-cyano-3-oxopropyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CCOC1=CC=CC(C=2C=CC(COC(=O)N3[C@@H](CCC3)C(=O)N[C@@H](CC(N)=O)C#N)=CC=2)=C1 BZVXYJWEOARYIS-UNMCSNQZSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125872 compound 4d Drugs 0.000 description 2
- 229940126115 compound 4f Drugs 0.000 description 2
- 229940125880 compound 4j Drugs 0.000 description 2
- 229940125801 compound 7f Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- PSBGROLQRNSAMY-UHFFFAOYSA-N n-(3-chlorophenyl)-4-methyl-3-(2-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)benzamide Chemical compound C1=C(C#CC2=CN3N=CC=C3N=C2)C(C)=CC=C1C(=O)NC1=CC=CC(Cl)=C1 PSBGROLQRNSAMY-UHFFFAOYSA-N 0.000 description 2
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 2
- VQVCFYIDCWPSNE-UHFFFAOYSA-N n-methyl-3-[(2-naphthalen-2-ylacetyl)amino]benzamide Chemical compound CNC(=O)C1=CC=CC(NC(=O)CC=2C=C3C=CC=CC3=CC=2)=C1 VQVCFYIDCWPSNE-UHFFFAOYSA-N 0.000 description 2
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- BHLXTPHDSZUFHR-UHFFFAOYSA-N varespladib Chemical compound CCC1=C(C(=O)C(N)=O)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 BHLXTPHDSZUFHR-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- OYRFISHCTITULC-UHFFFAOYSA-N 1-(2-chloro-4-hydroxyphenyl)-3-(4-fluorophenyl)urea Chemical compound ClC1=CC(O)=CC=C1NC(=O)NC1=CC=C(F)C=C1 OYRFISHCTITULC-UHFFFAOYSA-N 0.000 description 1
- JQIBCXMDAAJNOR-UHFFFAOYSA-N 1-(2-chloro-4-hydroxyphenyl)-3-phenylurea Chemical compound ClC1=CC(O)=CC=C1NC(=O)NC1=CC=CC=C1 JQIBCXMDAAJNOR-UHFFFAOYSA-N 0.000 description 1
- KPTATGCTNSXOGR-UHFFFAOYSA-N 1-(2-fluoro-4-hydroxyphenyl)-3-phenylurea Chemical compound FC1=CC(O)=CC=C1NC(=O)NC1=CC=CC=C1 KPTATGCTNSXOGR-UHFFFAOYSA-N 0.000 description 1
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 238000003043 HTRF KinEASE-TK Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine group Chemical group [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12 OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000003674 kinase activity assay Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及化药技术领域，尤其涉及一种喹唑啉衍生物及其制备方法和应用。本发明提供的喹唑啉衍生物，具有式Ⅰ所示结构，本发明所述喹唑啉衍生物对VEGFR1、VEGFR2和VEGFR3的激酶抑制活性均能够达到低纳摩尔浓度，可以以剂量依赖性抑制VEGFR的活性，并通过体内抗肿瘤实验进行验证，表现出了有效的抑制结指肠癌的生长作用。
Description
技术领域
本发明涉及化药技术领域，尤其涉及一种喹唑啉衍生物及其制备方法和应用。
背景技术
血管生成是指在血管生成相关因子的作用下，通过降解血管基质和基底膜，促进内皮细胞增殖和迁移，并引起新的内皮细胞重新排列，进而形成血管网络的过程。在肿瘤中常发现血管生成异常，而缺氧是引发肿瘤血管生成异常的主要因素。在缺氧条件下，脯氨酸羟化酶(PHD)的羟基化活性下降，进而导致其底物缺氧诱导因子(HIF)-1α降解受阻，HIF-1α易位进入细胞核，并与其异二聚体对应物HIF-1β结合，生成活性的HIF-1，并与缺氧反应元件(HRE)一起促进促血管生成因子如血管内皮生长因子A(VEGFA)等基因的表达，引发内皮细胞增殖，促进肿瘤内部血管生成。因此，VEGF是调节血管生成的关键的信号分子。
血管内皮生长因子受体(VEGFR)属于典型的酪氨酸激酶受体(RTK)，主要有三种亚型，包括VEGFR1、VEGFR2和VEGFR3。当VEGF和VEGFR结合后，便会诱导VEGFR形成二聚体，使其胞内域的构像改变，暴露出内腺嘌呤核苷三磷酸的结合位点，进而使VEGFR的酪氨酸残基发生自身磷酸化，并将信号传递到下游，造成肿瘤血管新生，促进肿瘤的发展和迁移。而VEGFR抑制剂会与腺嘌呤核苷三磷酸(ATP)竞争而占据催化域中ATP的结合口袋，从而抑制VEGF和VEGFR结合之后的信号传递，抑制肿瘤血管新生，起到抑制肿瘤增殖的作用。
此外，研究发现VEGFR在健康的组织或细胞中弱表达，而在结肠癌、乳腺癌、宫颈癌、卵巢癌、食道癌、肾透明细胞癌、非小细胞肺癌和胰腺癌等中高表达。因此，开发VEGFR抑制剂可以有效抑制肿瘤血管的生成进而起到抗肿瘤的作用，并且对肿瘤具有靶向性，对健康组织影响较小。
发明内容
本发明的目的在于提供一种喹唑啉衍生物及其制备方法和应用，所述喹唑啉衍生物能够通过抑制VEGFR高表达。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
优选的，所述取代的苯基中的取代基团为卤素、取代或未取代的烷基、取代或未取代的烷氧基、或芳香基；所述所述取代的苯基中的取代基团的个数为1或2；
所述取代的杂环基或未取代的杂环基中杂环基中的杂原子为N、O和S中的一种或几种；
所述取代的杂环基中的取代基团为烷基；
X为F或Cl。
优选的，所述喹唑啉衍生物为：
本发明还提供了上述技术方案所述喹唑啉衍生物的制备方法，包括以下步骤：
将具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物；
式Ⅷ～式Ⅸ中，X为卤素；n为1～10的正整数；
式Ⅱ～式Ⅶ和R-NH2中，R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
优选的，所述具有式Ⅷ所示结构的化合物的制备方法，包括以下步骤：
将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物；
将具有式Ⅳ所示结构的化合物、R-NH2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物；
将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物；
将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物；
式Ⅱ～式Ⅶ中，X为卤素；n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
优选的，所述第二缩合反应的温度为60～80℃，时间为4～6h。
本发明还提供了上述技术方案所述喹唑啉衍生物或上述技术方案所述的制备方法制备得到的喹唑啉衍生物的溶剂合物及其可溶性盐。
本发明还提供了上述技术方案所述喹唑啉衍生物或上述技术方案所述的喹唑啉衍生物的溶剂合物及其可溶性盐在制备治疗和/或预防癌症的药物中的应用。
优选的，所述癌症为VEGFR高表达的恶性肿瘤。
优选的，所述癌症为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
本发明所述喹唑啉衍生物具有与ATP的腺苷结构类似的喹唑啉母核，母核两端引入经过结构优化的杂环取代基以及脂肪链取代基可以进一步提升了其对VEGFR靶点的选择性和抑制作用。本发明所述喹唑啉衍生物对VEGFR1、VEGFR2和VEGFR3的激酶抑制活性均能够达到低纳摩尔浓度，可以以剂量依赖性抑制VEGFR的活性，并通过体内抗肿瘤实验进行验证，表现出了有效的抑制结指肠癌的生长作用。
具体实施方式
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
在本发明中，所述取代的苯基中的取代基团优选为卤素、取代或未取代的烷基、取代或未取代的烷氧基、或芳香基；所述所述取代的苯基中的取代基团的个数为1或2；
所述取代的杂环基或未取代的杂环基中杂环基中的杂原子优选为N、O和S中的一种或几种；
所述取代的杂环基中的取代基团优选为烷基；
X优选为F或Cl。
在本发明中，所述喹唑啉衍生物优选为：
本发明还提供了上述技术方案所述喹唑啉衍生物的制备方法，包括以下步骤：
将具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物；
式Ⅷ～式Ⅸ中，X为卤素；n为1～10的正整数；
式Ⅱ～式Ⅶ和R-NH2中，R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
在本发明中，若无特殊说明，所有制备原料均为本领域技术人员熟知的市售产品。
在本发明中，所述具有式Ⅷ所示结构的化合物的制备方法，优选包括以下步骤：
将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物；
将具有式Ⅳ所示结构的化合物、R-NH2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物；
将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物；
将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物；
式Ⅱ～式Ⅶ中，X为卤素；n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
在本发明中，由式Ⅱ制备喹唑啉衍生物的制备流程优选为：
本发明将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物。
在本发明中，所述具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物和吡啶的摩尔比优选为1：(1.1～1.2)：3，更优选为，最优选为1:1.2:3。
在本发明中，所述吡啶的作用是催化剂，促进反应的进行且保证不会有其他副反应的发生。
本发明对所述第一有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物和吡啶充分溶解并发生酰胺化反应即可。在本发明的实施例中，所述第一有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述混合优选为先将具有式Ⅱ所示结构的化合物与第一有机溶剂混合后，在冰浴和搅拌的条件下滴加吡啶后，再滴加具有式Ⅲ所示结构的化合物。本发明对所述搅拌和滴加的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
在本发明中，所述酰胺化反应优选在冰浴的条件下进行，所述酰胺化反应的时间优选为0.8～1.5h，更优选为0.9～1.2h，最优选为1h。
所述酰胺化反应完成后，本发明还优选包括对得到的产物体系进行后处理；所述后处理优选为在得到的产物体系中加入1M的盐酸水溶液搅拌1h，用饱和氯化钠溶液洗，乙酸乙酯萃取，将有机相浓缩，将残余物通过硅胶柱色谱层析法纯化(石油醚：乙酸乙酯＝6：1～1：1)。
所述具有式Ⅳ所示结构的化合物后，本发明将具有式Ⅳ所示结构的化合物、R-NH2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物。
在本发明中，所述具有式Ⅳ所示结构的化合物、R-NH2和N,N-二异丙基乙胺的摩尔比优选为1：(2～2.5)：(3～4)，更优选为1：2：3。
在本发明中，所述N,N-二异丙基乙胺为有机碱，促进取代反应的发生。
本发明对所述第二有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使具有式Ⅳ所示结构的化合物、R-NH2、N,N-二异丙基乙胺充分溶解并发生回流反应即可。在本发明的实施例中，所述第二有机溶剂为乙腈。
在本发明中，所述混合优选为将具有式Ⅳ所示结构的化合物、R-NH2和第二有机溶剂混合后，在得到的溶液中滴加N,N-二异丙基乙胺。
在本发明中，所述回流反应的温度优选为55～75℃，更优选为60～70℃，最优选为60℃；时间优选为1.8～3h，更优选为1.9～2.5h，最优选为2h。
所述回流反应完成后，本发明还优选包括将得到的产物体系进行后处理；所述后处理优选包括：将得到的产物体系进行浓缩后，通过硅胶柱色谱法层析法纯化(二氯甲烷：甲醇＝60:1～40:1)。
得到具有式Ⅴ所示结构的化合物后，本发明将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物。
在本发明中，所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物的摩尔比优选为(1.2～1.5)：1，更优选为1.2：1。
在本发明中，所述碱性条件优选通过添加碳酸钾实现；所述具有式Ⅴ所示结构的化合物和碳酸钾的摩尔比优选为1：(2.45～2.5)，更优选为2.21:5.52。
本发明对所述第三有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物充分溶解并能够保证在碱性条件下发生缩合反应即可。在本发明的实施例中，所述第三有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述第二缩合反应的温度优选为60～80℃，更优选为60～70℃，最优选为60℃；时间优选为5～7h，更优选为6～7h，最优选为6h。
所述第二缩合反应完成后，本发明还优选包括将得到的产物体系进行后处理，所述后处理优选包括将得到的产物体系用饱和氯化钠溶液洗涤后，用乙酸乙酯进行萃取，然后将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝80:1～60:1)纯化。
得到具有式Ⅶ所示结构的化合物后，本发明将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物。
在本发明中，所述钯碳催化剂占具有式Ⅶ所示结构的化合物的质量百分含量优选为10％。
本发明对所述第四有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使所述具有式Ⅶ所示结构的化合物和钯碳催化剂充分溶解并能够保证发生脱保护反应即可。在本发明的实施例中，所述第四有机溶剂为N,N-二甲基乙酰胺。
本发明对所述混合的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
通入氢气之前，本发明优选依次采用氩气和氢气对反应环境气进行置换，所述氩气的置换的次数优选为3次；所述氢气的置换的次数优选为3次。
本发明对所述通入氢气的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
在本发明中，所述脱保护反应的温度优选为室温；时间优选为2～3h，更优选为2～2.5h，最优选为2h。
所述脱保护反应完成后，本发明还优选包括将得到的产物体系进行后处理，所述后处理优选包括在抽滤漏斗中加入硅藻土，滤掉所述产物体系中的钯碳催化剂后，将滤液用饱和氯化钠溶液进行洗涤，用乙酸乙酯进行萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝45:1～20:1)纯化。
得到具有式Ⅷ所示结构的化合物后，本发明将所述具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物。
在本发明中，所述具有式Ⅷ所示结构的化合物、碳酸钾和具有式Ⅸ所示结构的化合物的摩尔比优选为(0.72～0.75):1.45:(0.798～0.89)，更优选为0.725:1.45:(0.798～0.89)，最优选为0.725:1.45:0.798。
本发明对所述第五有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使所述具有式Ⅷ所示结构的化合物、碳酸钾和具有式Ⅸ所示结构的化合物充分溶解并能够保证发生脱保护反应即可。在本发明的实施例中，所述第五有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述混合优选为将具有式Ⅷ所示结构的化合物和碳酸钾溶于第五有机溶剂中后，在得到的混合液中注射所述具有式Ⅸ所示结构的化合物。
在本发明中，所述第一缩合反应的温度优选为60～80℃，更优选为60～70℃，最优选为70℃；时间优选为6～8h，更优选为6～7h，最优选为6h。
所述第一缩合反应完成后，本发明还优选包括将得到的产物体系进行后处理；所述后处理优选包括：将得到的产物体系采用饱和氯化钠溶液进行洗涤，用乙酸乙酯进行萃取后，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝15：1-8:1)进行纯化。
本发明还提供了上述技术方案所述喹唑啉衍生物及其溶剂合物、可药用盐在制备治疗和/或预防癌症的药物中的应用。
在本发明中，所述癌症优选为VEGFR高表达的恶性肿瘤。
在本发明中，所述癌症优选为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
下面结合实施例对本发明提供的喹唑啉衍生物及其制备方法和应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
注：实施例1～30中各个化合物的结构均通过核磁共振(1H-NMR)和/或质谱(MS)来确定；NMR测定是用BrukerAdvance(400MHz)核磁共振仪，测定溶剂为氘代氯仿(CDCl3)、氘代二甲基亚砜(DMSO-d6)，TMS为内标；MS测定用Waters UPLC-Mass Spectrometer。柱层析采用青岛海洋化工厂的200-300目硅胶；
实施例1
化合物3：(2-氯-4-羟基苯基)氨基甲酸苯酯的制备路线为：
将化合物1(10.0g，69.6mmol)溶于N,N-二甲基甲酰胺(140mL)中，冰浴下搅拌滴加吡啶(16.4g，208mmol)，接着缓慢滴加化合物2(13.1g，83.5mmol)，冰浴下反应1h。反应完成后，加入1M的盐酸水溶液(300mL)搅拌1h，用饱和氯化钠溶液(150mL)洗，乙酸乙酯(300mL)萃取，将有机相浓缩，将残余物通过硅胶柱色谱层析法纯化(石油醚：乙酸乙酯的体积比＝6：1～1：1)，得到化合物3(淡黄色固体，16.1g，88％)；
对化合物3进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.47(s,1H),7.40(t,J＝7.7Hz,2H),7.32(d,J＝8.7Hz,1H),7.27-7.09(m,3H),6.77(dd,J＝8.7,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ156.8,153.5,151.3,129.8,126.2,125.7,122.3,116.3,115.1.HRMS(ESI)m/z calculated for C13H11ClNO3 +[M+H]+:264.0422,found:264.0423；
化合物4a：1-(2-氯-4-羟基苯基)-3-苯基脲的制备路线为：
制备过程：将化合物3(0.800g，3.04mmol)，苯胺(0.565g，6.08mmol)溶于乙腈(15mL)中，缓慢向溶液中滴加N,N-二异丙基乙胺(1.18g，9.12mmol)，反应回流2h。反应完成后，将混合物浓缩，并通过硅胶柱色谱法层析法纯化(二氯甲烷：甲醇＝60：1～40：1)，得到化合物4a(白色固体，0.653g，82％)。
对化合物4a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.11(s,1H),7.99(s,1H),7.74(d,J＝8.9Hz,1H),7.44(d,J＝8.0Hz,2H),7.27(t,J＝7.7Hz,2H),6.96(t,J＝7.3Hz,1H),6.85(d,J＝3.0Hz,1H),6.73(dd,J＝9.0,2.8Hz,1H).13CNMR(100MHz,DMSO-d6)δ154.1,153.1,140.3,129.3,127.8,124.9,124.8,122.2,118.5,115.8,114.9.HRMS(ESI)m/z calculated for C13H12ClN2O2 +[M+H]+:263.0581,found:263.0582；
化合物6a：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-苯基脲的制备路线为：
制备过程为：将化合物5(0.554g，1.84mmol)，化合物4a(0.578g，2.21mmol)，和K2CO3(0.761g，5.52mmol)溶于N,N-二甲基甲酰胺(10mL)中，于60℃下搅拌6h。待反应完毕后，用饱和氯化钠溶液(10mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝80：1～60：1)纯化，得到化合物6a(粉白色固体，0.726g，75％)。
对化合物6a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.57(d,J＝1.8Hz,1H),8.40(s,1H),8.23(dd,J＝9.1,1.8Hz,1H),7.59-7.27(m,13H),7.00(td,J＝7.4,1.7Hz,1H),5.35(s,2H),3.98(d,J＝1.8Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,152.7,150.7,149.3,147.5,139.9,136.5,134.2,129.4,129.0,128.7,128.6,123.6,122.8,122.6,122.5,122.0,118.7,110.2,108.5,101.4,70.7,56.5.HRMS(ESI)m/z calculated for C29H24ClN4O4 +[M+H]+:527.1480,found:527.1482；
化合物7a：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-苯基脲的制备路线为：
向三颈瓶中加入化合物6a(0.641g，1.22mmol)，10％钯碳(加约55％水湿润)(64mg)，然后加入N,N-二甲基乙酰胺(12mL)中，将反应装置用氩气置换三次，再用氢气置换三次，通入氢气室温反应2h。待反应完毕后，在抽滤漏斗中加入硅藻土，滤掉反应液中的钯碳，将反应液用饱和氯化钠溶液(15mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝45：1～20：1)纯化，得到化合物7a(白色固体，0.345g，65％)；
对化合物7a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.44(s,1H),8.50(s,1H),8.40(s,1H),8.21(d,J＝9.0Hz,1H),7.54(d,J＝3.5Hz,2H),7.49(d,J＝8.0Hz,2H),7.37-7.26(m,3H),7.24(s,1H),7.00(t,J＝7.3Hz,1H),3.98(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.0,152.7,152.5,150.4,149.4,147.56,139.9,134.1,129.4,123.5,122.8,122.6,122.6,122.0,118.7,110.1,109.4,101.6,56.5.HRMS(ESI)m/zcalculated for C22H18ClN4O4 +[M+H]+:437.1011,found:437.1013；
化合物9a 1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-苯基脲的制备路线：
制备过程：化合物7a(0.316g，0.725mmol)和K2CO3(0.202g，1.45mmol)溶于N,N-二甲基甲酰胺(7mL)中，接着向溶液中缓慢注射8(0.118g，0.798mmol)，于70℃下搅拌6h。待反应完毕后，用饱和氯化钠溶液(15mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝15：1-8：1)纯化，得到化合物9a(白色固体，0.265g，67％)。
对化合物9a进行检测，其检测结果如下：M.p.209.8-210.3℃；IR(KBr):3306,3062,2954,2853,1649,1501,1233,1069,845,745,648cm-1.1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.60(dd,J＝15.4,2.1Hz,2H),8.22(dd,J＝9.0,2.1Hz,1H),7.54(ddd,J＝9.9,7.6,2.1Hz,4H),7.46-7.24(m,4H),7.14-6.89(m,1H),4.43-4.24(m,2H),3.99(d,J＝2.1Hz,3H),3.20(s,6H),2.25(p,J＝6.8Hz,2H),1.92(q,J＝8.0,4.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.9,152.8,150.5,149.3,147.4,140.1,134.3,129.3,123.5,123.1,122.7,122.5,121.9,118.6,110.2,107.9,101.3,66.9,56.6,53.5,51.8,25.9,23.3.HRMS(ESI)m/z calculated for C29H31ClN5O4 +[M+H]+:548.2059,found:548.2060。
实施例2～30
参考实施例1的制备过程，区别仅在于调整R、X的种类，依次经过回流反应制备得到的4b～4z、12a～12c；经过第一缩合反应制备得到6b～6z、13a～13c；经过脱保护反应制备得到7b～7z、14a～14c；经过第二缩合反应制备得到9b～9z、15a～15c和17。
对应关系如表1所示：
表1实施例2～30中间产物和目标产物的对应关系
/>
/>
/>
4b～4z、12a～12c、6b～6z、13a～13c、7b～7z、14a～14c、9b～9z、15a～15c和17的收率和结构表征：
化合物4b：1-(2-氯-4-羟基苯基)-3-(4-氟苯基)脲(白色固体，84％)；
对化合物4b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.13(s,1H),7.97(s,1H),7.71(d,J＝8.9Hz,1H),7.52-7.32(m,2H),7.11(t,J＝8.9Hz,2H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.2,153.2,136.6,127.8,125.1,124.9,120.2,120.1,115.9,115.7,114.9.19F NMR(376MHz,DMSO-d6)δ-121.59.HRMS(ESI)m/z calculated for C13H11ClFN2O2 +[M+H]+:281.0487,found:281.0488；
化合物6b：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-氟苯基)脲(粉白色固体，80％)；
对化合物6b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.57(s,1H),8.38(s,1H),8.20(d,J＝9.0Hz,1H),7.60-7.48(m,7H),7.47-7.35(m,3H),7.30(dd,J＝9.0,2.7Hz,1H),7.20-7.08(m,2H),5.36(s,2H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.6,150.7,149.2,147.5,136.5,134.1,129.0,128.7,128.6,123.5,122.9,122.6,121.9,120.4,120.3,116.0,115.8,110.2,108.5,101.4,70.7,56.5.19F NMR(376MHz,DMSO-d6)δ-121.10.HRMS(ESI)m/z calculated for C29H23ClFN4O4 +[M+H]+:545.1386,found:545.1387；
化合物7b：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，58％)；
对化合物7b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.49(s,1H),8.39(s,1H),8.19(d,J＝9.0Hz,1H),7.63-7.47(m,4H),7.29(dd,J＝9.0,2.7Hz,1H),7.24(s,1H),7.15(t,J＝8.7Hz,2H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.8,152.5,150.4,149.4,147.6,123.6,122.9,122.6,122.1,120.4,120.3,116.0,115.8,110.1,109.4,101.6,56.5.19F NMR(376MHz,DMSO-d6)δ-121.07.HRMS(ESI)m/z calculated for C22H17ClFN4O4 +[M+H]+:455.0916,found:455.0918；
化合物9b：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，68％)；
对化合物9b进行检测，其检测结果如下：M.p.224.1-225.6℃；IR(KBr):3296,3055,2954,2803,1651,1374,1232,1045,815,785cm-1.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.60(d,J＝15.1Hz,2H),8.19(d,J＝9.0Hz,1H),7.60-7.49(m,4H),7.41(s,1H),7.30(dd,J＝9.0,2.7Hz,1H),7.21-7.07(m,2H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.20(s,6H),2.24(q,J＝7.1,6.4Hz,2H),1.93(d,J＝6.8Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.9,152.7,150.6,149.3,147.5,136.5,134.2,123.5,123.2,122.8,121.9,120.25,120.2,115.9,115.7,110.2,108.0,101.3,66.9,56.6,53.5,51.8,25.9,23.3.19FNMR(376MHz,DMSO-d6)δ-121.07.HRMS(ESI)m/z calculated for C29H30ClFN5O4 +[M+H]+:566.1964,found:566.1965；
化合物4c：1-(2-氯-4-羟基苯基)-3-(吡啶-4-基)脲(白色固体，83％)；
对化合物4c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.69(d,J＝27.1Hz,2H),8.36(d,J＝5.6Hz,2H),8.26(s,1H),7.68(d,J＝8.9Hz,1H),7.57-7.36(m,2H),6.87(d,J＝2.7Hz,1H),6.74(dd,J＝8.8,2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.8,152.8,150.2,147.4,127.1,125.8,125.7,115.9,115.0,112.6.HRMS(ESI)m/zcalculated for C12H11ClN3O2 +[M+H]+:264.0534,found:264.0535；
化合物6c：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(吡啶-4-基)脲(粉白色固体，72％)；
对化合物6c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.57(d,J＝2.2Hz,2H),8.44-8.35(m,2H),8.19(d,J＝9.0Hz,1H),7.61-7.56(m,2H),7.55-7.49(m,3H),7.49-7.36(m,5H),7.33(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),3.99(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.2,152.6,152.5,150.8,150.7,149.2,148.0,146.7,136.5,133.5,129.0,128.7,128.6,123.7,123.6,123.0,122.1,112.7,110.2,108.5,101.3,70.7,56.5.HRMS(ESI)m/z calculated for C28H23ClN5O4 +[M+H]+:528.1433,found:528.1435；
化合物7c：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(吡啶-4-基)脲(白色固体，54％)；
对化合物7c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.78(s,1H),8.56(s,1H),8.50(s,1H),8.43-8.34(m,2H),8.17(d,J＝9.0Hz,1H),7.57(d,J＝2.7Hz,1H),7.54(s,1H),7.51-7.43(m,2H),7.32(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.1,155.1,152.5,150.8,150.4,149.4,148.2,146.7,133.5,123.7,123.2,122.1,112.7,110.1,109.4,101.6,56.4.HRMS(ESI)m/zcalculated for C21H18ClN5O4 +[M+H]+:438.0963,found:438.0965；
化合物9c：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(吡啶-4-基)脲(白色固体，69％)；
对化合物9c进行检测，其检测结果如下：M.p.210.3-211.2℃；IR(KBr):3302,3056,2954,5,1654,1507,1243,1066,845,787cm-1.1H NMR(400MHz,DMSO-d6)δ10.58(d,J＝6.4Hz,1H),8.91(s,1H),8.58(s,1H),8.38(d,J＝5.5Hz,2H),8.15(d,J＝9.0Hz,1H),7.57(d,J＝4.5Hz,2H),7.49(d,J＝5.6Hz,2H),7.42(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.32(t,J＝6.3Hz,2H),3.99(s,3H),3.33-2.94(m,6H),2.26(d,J＝8.2Hz,2H),1.93(s,4H).13CNMR(100MHz,DMSO-d6)δ155.2,152.7,150.8,150.6,149.3,148.0,146.9,133.6,123.9,123.7,123.4,121.9,112.7,110.1,108.0,101.4,66.8,56.6,53.5,51.7,23.26.HRMS(ESI)m/z calculated for C28H30ClN6O4 +[M+H]+:549.2011,found:549.2013；
化合物4d：1-(2-氯-4-羟基苯基)-3-(对甲苯基)脲(白色固体，77％)；
对化合物4d进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.00(s,1H),7.94(s,1H),7.74(d,J＝8.8Hz,1H),7.39-7.27(m,2H),7.12-6.98(m,2H),6.84(d,J＝2.8Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ154.1,153.2,137.7,131.0,129.7,128.0,124.9,124.7,118.6,115.9,115.0,20.8.HRMS(ESI)m/z calculated for C14H14ClN2O2 +[M+H]+:277.0743,found:277.0745；
化合物6d：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(对甲苯基)脲(粉白色固体，70％)；
对化合物6d进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.56(d,J＝2.4Hz,1H),8.33(s,1H),8.23(d,J＝8.7Hz,1H),7.62-7.48(m,5H),7.48-7.34(m,5H),7.33-7.26(m,1H),7.11(d,J＝7.9Hz,2H),5.35(s,2H),3.98(s,3H),2.26(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,152.7,150.8,149.2,147.4,137.3,136.6,134.3,131.5,129.8,129.0,128.7,128.5,123.5,122.7,122.4,122.0,118.8,110.2,108.5,101.4,70.8,56.6,20.8.HRMS(ESI)m/zcalculated for C30H26ClN4O4 +[M+H]+:541.1637,found:541.1639；
化合物7d：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(对甲苯基)脲(白色固体，57％)；
对化合物7d进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.30(s,1H),8.49(s,1H),8.32(s,1H),8.25-8.15(m,1H),7.57-7.51(m,2H),7.37(d,J＝8.3Hz,2H),7.28(dd,J＝9.1,2.7Hz,1H),7.23(s,1H),7.11(d,J＝8.2Hz,2H),3.98(s,3H),2.26(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,152.7,152.5,150.4,149.4,137.4,134.2,131.5,129.8,128.6,123.6,122.7,122.4,122.0,118.8,110.1,109.4,101.6,56.5,20.8.HRMS(ESI)m/z calculated for C23H20ClN4O4 +[M+H]+:451.1167,found:451.1169；
化合物9d：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(对甲苯基)脲(白色固体，66％)；
对化合物9d进行检测，其检测结果如下：M.p.202.8-204.4℃；IR(KBr):3289,2950,2853,1710,1587,1270,1208,1145,840,667cm-1.1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.55(d,J＝26.4Hz,2H),8.21(d,J＝9.0Hz,1H),7.64-7.53(m,2H),7.49-7.37(m,3H),7.29(dd,J＝9.0,2.7Hz,1H),7.11(d,J＝8.1Hz,2H),4.32(t,J＝6.2Hz,2H),4.00(s,3H),3.30-2.89(m,6H),2.26(s,5H),1.94(d,J＝6.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.24,155.24,152.87,152.72,150.58,149.29,147.37,137.51,134.36,131.33,129.73,123.50,122.94,122.61,121.91,118.70,110.22,108.03,101.37,66.87,56.60,53.54,51.82,25.83,23.24,20.83.HRMS(ESI)m/z calculated for C30H33ClN5O4 +[M+H]+:562.2216,found:562.2217；
化合物4e：1-(2-氯-4-羟基苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，80％)；
对化合物4e进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),9.30(s,1H),8.03(s,1H),7.71(d,J＝8.9Hz,1H),7.58-7.44(m,2H),7.35-7.25(m,2H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.4,153.0,143.0,139.6,127.6,125.2,122.2,119.6,115.9,115.0.19F NMR(376MHz,DMSO-d6)δ-57.10.HRMS(ESI)m/z calculated for C14H11ClF3N2O3 +[M+H]+:347.0404,found:347.0406；
化合物6e：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-(三氟甲氧基)苯基)脲(粉白色固体，73％)；
对化合物6e进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.57(s,1H),8.43(s,1H),8.21(d,J＝9.0Hz,1H),7.60(d,J＝2.2Hz,1H),7.60-7.55(m,3H),7.55-7.49(m,3H),7.47-7.41(m,2H),7.41-7.23(m,4H),5.35(s,2H),3.99(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.1,152.7,152.6,150.7,149.3,147.7,143.3,139.2,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.3,122.0,119.8,110.2,108.5,101.3,70.7,56.5.19F NMR(376MHz,DMSO-d6)δ-57.09.HRMS(ESI)m/z calculatedfor C30H23ClF3N4O5 +[M+H]+:611.1303,found:611.1305；
化合物7e：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，58％)；
对化合物7e进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.60(s,1H),8.45(d,J＝30.9Hz,2H),8.20(d,J＝9.0Hz,1H),7.78-7.50(m,4H),7.31(dd,J＝9.2,7.1Hz,3H),7.23(s,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.1,155.1,152.7,152.5,150.4,149.4,147.7,143.3,139.2,133.8,123.6,123.1,122.7,122.3,122.1,119.8,110.1,109.4,101.6,56.4.19F NMR(376MHz,DMSO-d6)δ-57.08.HRMS(ESI)m/zcalculated for C23H17ClF3N4O5 +[M+H]+:521.0834,found:521.0835；
化合物9e：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，72％)；
对化合物9e进行检测，其检测结果如下：M.p.239.5-241.5℃；IR(KBr):3291,2957,2854,1722,1537,1257,1207,1186,846,683cm-1.1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.62(d,J＝30.9Hz,2H),8.18(d,J＝9.0Hz,1H),7.70-7.50(m,4H),7.42(s,1H),7.37-7.23(m,3H),4.33(t,J＝6.2Hz,2H),3.99(s,3H),3.30(s,6H),2.27(p,J＝6.5Hz,2H),1.93(d,J＝15.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.7,150.6,149.3,147.6,143.2,139.4,134.0,123.6,123.4,122.9,122.3,121.9,119.7,110.2,108.0,101.3,66.8,56.6,53.4,51.7,25.6,23.2.19F NMR(376MHz,DMSO-d6)δ-57.07.HRMS(ESI)m/zcalculated for C30H30ClF3N5O5 +[M+H]+:632.1882,found:632.1884；
化合物4f：1-(2-氯-4-羟基苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，81％)；
对化合物4f进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.51(s,1H),8.13(s,1H),7.71(d,J＝8.9Hz,1H),7.68-7.61(m,4H),6.86(d,J＝2.8Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.6,152.9,144.0,127.4,126.6,126.6,125.5,125.4,118.1,115.9,115.0,55.4.19FNMR(376MHz,DMSO-d6)δ-60.03.HRMS(ESI):m/z calculated for C14H11ClF3N2O2 +[M+H]+:331.0456,found:331.0457；
化合物6f：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-(三氟甲基)苯基)脲(粉白色固体，78％)；
对化合物6f进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.57(s,1H),8.51(s,1H),8.21(d,J＝9.0Hz,1H),7.75-7.63(m,4H),7.62-7.56(m,2H),7.57-7.48(m,3H),7.48-7.42(m,2H),7.41-7.35(m,1H),7.33(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.6,152.6,150.7,149.2,147.8,143.6,136.5,133.7,129.0,128.7,128.6,126.7,126.7,123.6,123.3,122.9,122.1,118.4,110.2,108.5,101.4,70.7,56.5.19F NMR(376MHz,DMSO-d6)δ-60.09.HRMS(ESI)m/z calculated for C30H23ClF3N4O4 +[M+H]+:595.1355,found:595.1356；
化合物7f：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，52％)；
对化合物7f进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.80(s,1H),8.50(s,2H),8.20(d,J＝9.0Hz,1H),7.76-7.62(m,4H),7.61-7.52(m,2H),7.31(dd,J＝9.0,2.7Hz,1H),7.24(s,1H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.5,152.4,150.3,149.4,147.9,143.7,133.6,126.7,126.3,123.7,123.4,122.9,122.1,118.4,110.1,109.4,101.6,56.4.19F NMR(376MHz,DMSO-d6)δ-60.09.HRMS(ESI)m/z calculated for C23H17ClF3N4O4 +[M+H]+:505.0885,found:505.0886；
化合物9f：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，63％)；
对化合物9f进行检测，其检测结果如下：M.p.232.8-234.7℃；IR(KBr):3299,2950,2850,1722,1545,1276,1203,1167,845,687cm-1.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.78(s,1H),8.59(s,1H),8.18(d,J＝9.0Hz,1H),7.72(d,J＝8.6Hz,2H),7.66(d,J＝8.7Hz,2H),7.61-7.56(m,2H),7.42(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.32(t,J＝6.2Hz,2H),4.00(s,3H),3.28(t,J＝7.7Hz,6H),2.27(p,J＝6.5Hz,2H),2.01-1.90(m,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.7,150.6,149.3,147.9,143.9,133.9,126.7,126.6,123.7,123.6,123.2,122.0,118.2,110.2,108.0,101.4,66.8,56.6,53.5,51.7,25.6,23.2.19F NMR(376MHz,DMSO-d6)δ-60.03.HRMS(ESI)m/z calculated forC30H30ClF3N5O4 +[M+H]+:616.1933,found:616.1934；
化合物4g：1-(2-氯-4-羟基苯基)-3-(2-氟-5-甲基苯基)脲(白色固体，77％)；
对化合物4g进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.97(d,J＝2.5Hz,1H),8.48(s,1H),7.98(dd,J＝7.9,2.2Hz,1H),7.72(d,J＝8.9Hz,1H),7.10(dd,J＝11.4,8.3Hz,1H),6.84(d,J＝2.7Hz,1H),6.78(ddd,J＝7.8,4.8,2.2Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),2.26(s,3H).13C NMR(100MHz,DMSO-d6)δ154.3,152.9,151.8,149.5,133.9,127.6,125.2,123.0,121.4,115.9,115.0,114.9,114.8,21.2.19F NMR(376MHz,DMSO-d6)δ-134.40.HRMS(ESI)m/z calculated for C14H13ClFN2O2 +[M+H]+:295.0644,found:295.0646；
化合物6g：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2-氟-5-甲基苯基)脲(粉白色固体，82％)；
对化合物6g进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.29(d,J＝2.4Hz,1H),8.86(s,1H),8.57(s,1H),8.21(d,J＝9.0Hz,1H),8.02(dd,J＝7.8,2.2Hz,1H),7.59-7.50(m,5H),7.44(dd,J＝8.4,6.4Hz,2H),7.38(t,J＝7.2Hz,1H),7.31(dd,J＝9.0,2.7Hz,1H),7.13(dd,J＝11.4,8.3Hz,1H),6.83(dq,J＝7.1,3.6,2.8Hz,1H),5.36(s,2H),3.99(s,3H),2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.7,152.6,150.7,149.2,147.6,136.5,134.0,129.0,128.6,128.5,123.6,123.1,122.8,121.9,121.6,115.2,115.0,110.2,108.5,101.4,70.7,56.6,21.3.19F NMR(376MHz,DMSO-d6)δ-133.92.HRMS(ESI)m/z calculated for C30H25ClFN4O4 +[M+H]+:559.1542,found:559.1544；
化合物7g：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-氟-5-甲基苯基)脲(白色固体，49％)；
对化合物7g进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.28(d,J＝2.4Hz,1H),8.86(s,1H),8.49(s,1H),8.20(d,J＝9.0Hz,1H),8.01(dd,J＝8.0,2.2Hz,1H),7.55(d,J＝3.1Hz,2H),7.29(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),7.13(dd,J＝11.4,8.3Hz,1H),6.83(ddd,J＝7.9,4.8,2.1Hz,1H),3.98(s,3H),2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.6,152.5,150.4,149.4,147.7,134.0,127.4,127.3,123.6,123.1,122.8,122.0,121.6,115.2,115.0,110.1,109.4,101.6,56.5,21.2.19F NMR(376MHz,DMSO-d6)δ-133.93.HRMS(ESI)m/z calculated for C23H19ClFN4O4 +[M+H]+:469.1073,found:469.1075；
化合物9g：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-氟-5-甲基苯基))脲(白色固体，68％)；
对化合物9g进行检测，其检测结果如下：M.p.210.5-211.9℃；IR(KBr):3342,3056,2977,2654,1651,1374,1221,1087,845,756cm-1.1H NMR(400MHz,DMSO-d6)δ9.39(d,J＝2.5Hz,1H),8.98(d,J＝3.0Hz,1H),8.58(s,1H),8.19(d,J＝9.0Hz,1H),7.99(dd,J＝7.8,2.2Hz,1H),7.73-7.51(m,2H),7.41(s,1H),7.31(dd,J＝9.0,2.7Hz,1H),7.13(dd,J＝11.3,8.3Hz,1H),6.83(ddd,J＝7.8,4.7,2.2Hz,1H),4.33(t,J＝6.3Hz,2H),3.99(s,3H),3.22(dt,J＝44.3,7.9Hz,6H),2.28(s,5H),1.95(s,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,150.5,149.2,147.7,134.0,133.9,127.3,127.2,123.6,123.3,123.1,121.9,121.8,115.2,115.0,110.2,108.0,101.3,66.8,56.6,53.4,51.6,25.5,23.2,21.2.19F NMR(376MHz,DMSO-d6)δ-133.49.HRMS(ESI)m/z calculated for C30H32ClFN5O4 +[M+H]+:580.2121,found:580.2122；
化合物4h：1-(2-氯-4-羟基苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，76％)；
对化合物4h进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.77(s,1H),7.89(s,1H),7.78-7.62(m,2H),7.37(d,J＝0.8Hz,1H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),4.42(hept,J＝6.7Hz,1H),1.38(d,J＝6.7Hz,6H).13CNMR(100MHz,DMSO-d6)δ153.9,153.1,129.6,128.2,124.7,124.6,122.1,117.8,115.8,114.9,53.4,23.1.HRMS(ESI)m/z calculated for C13H16ClN4O2 +[M+H]+:295.0956,found:295.0957；
化合物6h：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(粉白色固体，81％)。
对化合物6h进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.56(s,1H),8.35-8.18(m,2H),7.81(d,J＝0.7Hz,1H),7.57(s,1H),7.53(h,J＝2.5,2.1Hz,3H),7.50(s,1H),7.48-7.41(m,3H),7.40-7.33(m,1H),7.28(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.7,152.5,150.7,149.2,147.2,136.6,134.5,129.6,129.0,128.6,128.5,123.5,122.5,122.0,121.9,121.7,117.9,110.2,108.5,101.4,70.7,56.6,53.4,23.1.HRMS(ESI)m/z calculated for C29H28ClN6O4 +[M+H]+:559.1855,found:559.1856；
化合物7h：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，59％)；
对化合物7h进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.49(s,1H),8.31-8.18(m,2H),7.81(d,J＝0.8Hz,1H),7.58-7.49(m,2H),7.42(d,J＝0.8Hz,1H),7.30-7.16(m,2H),4.44(p,J＝6.6Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.6,152.5,150.4,149.4,147.3,134.4,129.7,123.5,122.5,122.0,121.9,121.7,118.0,110.1,109.4,101.6,56.5,53.4,23.1.HRMS(ESI)m/z calculated for C22H22ClN6O4 +[M+H]+:469.1385found:469.1386；
化合物9h：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物9h进行检测，其检测结果如下：M.p.162.8-163.5℃；IR(KBr):3302,2957,2853,2701,1701,1652,1418,1297,1136,1040,850,784cm-1.1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.57(s,1H),8.41(s,1H),8.23(d,J＝9.1Hz,1H),7.80(s,1H),7.57(s,1H),7.52(d,J＝2.7Hz,1H),7.41(d,J＝1.9Hz,2H),7.27(dd,J＝9.0,2.7Hz,1H),4.44(p,J＝6.7Hz,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.23(t,J＝7.0Hz,6H),2.25(t,J＝7.4Hz,2H),1.93(d,J＝6.1Hz,4H),1.40(d,J＝6.6Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,152.7,150.6,149.3,147.2,134.6,129.6,123.5,122.6,122.1,121.9,121.7,117.9,110.2,108.0,101.4,101.3,66.8,56.6,53.5,53.4,51.8,25.7,23.2,23.1.HRMS(ESI)m/z calculated for C29H35ClN7O4 +[M+H]+:580.2433,found:580.2435；
化合物4i：1-(2-氯-4-羟基苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，84％)；
对化合物4i进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.69(s,1H),8.38(s,1H),7.72(dd,J＝8.9,1.0Hz,1H),6.85(dd,J＝2.8,1.0Hz,1H),6.73(ddd,J＝8.9,2.8,1.0Hz,1H),6.45(s,1H),2.35(s,3H).13C NMR(100MHz,DMSO-d6)δ169.7,159.2,154.6,151.9,127.1,125.2,125.1,115.9,115.0,95.9,12.5.HRMS(ESI)m/zcalculated for C11H11ClN3O3 +[M+H]+:268.0483,found:268.0485；
化合物6i：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(5-甲基异恶唑-3-基)脲(粉白色固体，76％)；
对化合物6i进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.16(d,J＝2.0Hz,1H),8.76(s,1H),8.57(q,J＝2.3,1.9Hz,1H),8.21(dd,J＝9.0,2.1Hz,1H),7.61-7.56(m,2H),7.56-7.49(m,3H),7.49-7.42(m,2H),7.41-7.36(m,1H),7.33(dt,J＝9.0,2.4Hz,1H),6.52(s,1H),5.36(d,J＝1.9Hz,2H),3.99(d,J＝2.0Hz,3H),2.38(s,3H).13CNMR(100MHz,DMSO-d6)δ169.9,165.2,159.0,155.2,152.6,151.7,150.8,149.2,148.0,136.5,133.5,129.0,128.7,128.5,123.6,123.3,122.8,122.1,110.2,108.5,101.4,95.9,70.7,56.6,12.5.HRMS(ESI)m/zcalculated for C27H23ClN5O5 +[M+H]+:532.1382,found:532.1384；
化合物7i：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，59％)。
对化合物7i进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.76(s,1H),8.49(s,1H),8.19(d,J＝9.0Hz,1H),7.67-7.45(m,2H),7.31(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),6.51(d,J＝1.0Hz,1H),3.98(s,3H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ169.9,165.1,159.0,155.1,152.5,151.7,150.4,149.4,148.1,133.5,123.7,123.3,122.8,122.1,110.1,109.4,101.6,95.9,56.5,12.6.HRMS(ESI)m/z calculatedfor C20H17ClN5O5 +[M+H]+:442.0912,found:442.0913；
化合物9i：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，67％)；
对化合物9i进行检测，其检测结果如下：M.p.162.7-163.9℃；IR(KBr):3304,2957,2853,2701,1732,1652,1418,1299,1136,1040,850,774cm-1.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.96(s,1H),8.58(s,1H),8.17(d,J＝9.0Hz,1H),7.57(d,J＝2.9Hz,2H),7.41(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),6.52(s,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.28-3.02(m,6H),2.38(s,3H),2.27(t,J＝7.4Hz,2H),1.95(s,4H).13C NMR(100MHz,DMSO-d6)δ169.8,165.2,159.0,155.2,152.7,151.9,150.6,149.3,148.0,133.6,123.6,123.1,122.0,110.2,108.0,101.3,96.0,66.8,56.6,53.4,51.7,25.623.2,12.6.HRMS(ESI)m/z calculated for C27H30ClN6O5 +[M+H]+:553.1960,found:553.1962；
化合物4j：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，85％)；
对化合物4j进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.92(s,1H),7.91(s,1H),7.79(d,J＝8.9Hz,1H),7.70(d,J＝2.0Hz,1H),7.33(d,J＝8.7Hz,1H),7.26(d,J＝3.0Hz,1H),7.13(dd,J＝8.7,2.1Hz,1H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),6.34(dd,J＝3.0,0.8Hz,1H),3.75(s,3H).13C NMR(100MHz,DMSO-d6)δ153.7,153.5,133.3,132.2,130.5,128.6,128.3,124.6,124.3,115.8,114.9,114.8,110.3,110.1,100.4,32.9.HRMS(ESI)m/zcalculated for C16H15ClN3O2 +[M+H]+:316.0847,found:316.0849；
化合物6j：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吲哚-5-基)脲(粉白色固体，84％)；
对化合物6j进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.57(s,1H),8.38-8.24(m,2H),7.75(s,1H),7.58-7.36(m,9H),7.30(dd,J＝8.1,2.9Hz,2H),7.18(d,J＝8.6Hz,1H),6.37(d,J＝3.0Hz,1H),5.35(s,2H),3.98(s,3H),3.77(s,3H).13C NMR(100MHz,DMSO-d6)δ165.3,155.2,153.0,152.7,150.7,149.2,147.1,136.5,134.6,133.5,131.8,130.6,129.0,128.7,128.6,128.6,123.5,122.4,122.2,121.9,114.9,110.6,110.2,110.2,108.5,101.4,100.5,70.7,56.6,32.9.HRMS(ESI)m/zcalculated for C32H27ClN5O4 +[M+H]+:580.1746,found:580.1748；
化合物7j：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，61％)；
对化合物7j进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.22(s,1H),8.50(s,1H),8.39-8.17(m,2H),7.75(d,J＝2.1Hz,1H),7.60-7.47(m,2H),7.37(d,J＝8.7Hz,1H),7.33-7.26(m,2H),7.24(s,1H),7.17(dd,J＝8.7,2.1Hz,1H),6.37(d,J＝3.0Hz,1H),3.99(s,3H),3.77(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,153.0,152.5,150.3,149.4,147.2,134.5,133.5,131.8,130.6,128.6,123.5,122.4,122.1,121.9,114.9,110.6,110.2110.1,109.4,101.6,100.5,56.6,32.9.HRMS(ESI)m/zcalculated for C25H21ClN5O4 +[M+H]+:490.1276,found:490.1277；
化合物9j：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，63％)；
对化合物9j进行检测，其检测结果如下：M.p.158.7-159.0℃；IR(KBr):3298,2955,2879,1742,1609,1539,1250,1232,1180,846,683cm-1.1H NMR(400MHz,DMSO-d6)δ9.66(d,J＝13.4Hz,1H),8.58(s,1H),8.53(d,J＝5.5Hz,1H),8.26(d,J＝9.0Hz,1H),7.78(d,J＝1.7Hz,1H),7.60-7.50(m,2H),7.46-7.35(m,2H),7.29(dt,J＝5.2,2.5Hz,2H),7.22(dt,J＝8.8,1.7Hz,1H),6.36(d,J＝3.0Hz,1H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.77(s,3H),3.28-3.08(m,6H),2.28(p,J＝6.2Hz,2H),1.99-1.91(m,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,153.2,152.7,150.5,149.2,147.1,134.7,133.4,132.1,130.5,128.6,123.5,122.6,122.4,121.8,114.8,110.4,110.2,110.1,107.9,101.3,100.5,66.8,56.6,53.4,51.7,32.9,23.2.HRMS(ESI):m/z calculated forC32H34ClN6O4 +[M+H]+:601.2324,found:601.2326.
化合物4k：1-(2-氯-4-羟基苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，78％)；
对化合物4k进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.49(s,1H),8.12(s,1H),8.03(s,1H),7.71(d,J＝8.9Hz,1H),7.65-7.42(m,2H),7.30(d,J＝7.2Hz,1H),6.86(d,J＝2.7Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.8,153.1,139.9,132.5,127.2,125.9,125.8,123.2,122.6,116.9,116.9,115.9,115.0.19F NMR(376MHz,DMSO-d6)δ-61.33.HRMS(ESI)m/z calculated for C14H11ClF3N2O2 +[M+H]+:331.0456,found:331.0457.
化合物6k：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-(三氟甲基)苯基)脲(粉白色固体，76％)。
对化合物6k进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.57(s,1H),8.48(s,1H),8.21(d,J＝9.0Hz,1H),8.07(d,J＝2.4Hz,1H),7.61-7.50(m,7H),7.44(t,J＝7.1Hz,2H),7.41-7.30(m,3H),5.36(s,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,152.6,150.7,149.2,147.8,140.8,136.5,133.8,130.6,130.3,129.0,128.7,128.6,123.6,123.4,122.9,122.2,122.1,110.2,108.5,101.4,70.7,56.6.19F NMR(376MHz,DMSO-d6)δ-61.33.HRMS(ESI)m/z calculated for C30H23ClF3N4O4 +[M+H]+:595.1355,found:595.1356；
化合物7k：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，60％)；
对化合物7k进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.76(s,1H),8.48(d,J＝10.1Hz,2H),8.19(d,J＝9.0Hz,1H),8.06(d,J＝2.4Hz,1H),7.74-7.52(m,4H),7.45-7.28(m,2H),7.23(s,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.8,152.5,150.4,149.4,147.9,140.8,133.7,130.6,123.6,123.5,123.0,122.3,122.1,118.9,110.1,109.4,101.6,56.5.19FNMR(376MHz,DMSO-d6)δ-61.33.HRMS(ESI)m/z calculated for C23H17ClF3N4O4 +[M+H]+:505.0885,found:505.0886；
化合物9k：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，61％)；
对化合物9k进行检测，其检测结果如下：M.p.230.5-231.2℃；IR(KBr):3298,2955,2879,1742,1539,1250,1232,1180,846,683cm-1.1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.75(s,1H),8.58(s,1H),8.18(d,J＝9.0Hz,1H),8.07(d,J＝2.2Hz,1H),7.67-7.61(m,1H),7.60-7.50(m,3H),7.40(s,1H),7.37-7.29(m,2H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.29(t,J＝7.7Hz,6H),2.27(p,J＝6.4Hz,2H),1.96(d,J＝6.0Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.9,152.7,150.5,149.2,147.8,141.0,133.9,130.5,123.6,123.6,123.2,122.1,121.9,114.4,114.3,110.2,108.0,101.3,66.8,56.6,53.5,40.6,40.4,40.2,39.7,39.5,39.3,25.6,23.2.19F NMR(376MHz,DMSO-d6)δ-61.31.HRMS(ESI)m/z calculated for C30H30ClF3N5O4 +[M+H]+:616.1933,found:616.1934；
化合物4l：1-(苯并呋喃-5-基)-3-(2-氯-4-羟基苯基)脲(白色固体，75％)；
对化合物4l进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),9.11(s,1H),8.05-7.92(m,2H),7.83(d,J＝2.2Hz,1H),7.76(d,J＝8.9Hz,1H),7.49(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.2Hz,1H),6.91(dd,J＝2.2,1.0Hz,1H),6.85(d,J＝2.7Hz,1H),6.72(d,J＝2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.0,153.4,150.6,146.9,135.6,128.0,128.0,124.9,124.7,116.6,115.9,115.0,111.6,110.7,107.3.HRMS(ESI)m/zcalculated for C15H12ClN2O3 +[M+H]+:303.0537,found:303.0538；
化合物6l：1-(苯并呋喃-5-基)-3-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)脲(粉白色固体，74％)；
对化合物6l进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.57(s,1H),8.37(s,1H),8.26(d,J＝9.0Hz,1H),7.92(dd,J＝28.9,2.2Hz,2H),7.62-7.49(m,6H),7.48-7.37(m,3H),7.31(dt,J＝8.9,3.0Hz,2H),6.94(d,J＝2.1Hz,1H),5.36(s,2H),3.99(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.2,153.0,152.7,150.8,149.2,147.4,147.0,136.6,135.2,134.3,129.0,128.7,128.5,128.0,123.5,122.7,122.4,122.0,116.8,111.8,111.0,110.2,108.5,107.4,101.4,70.8,56.6.HRMS(ESI)m/zcalculated for C31H24ClN4O5 +[M+H]+:567.1430,found:567.1430；
化合物7l：1-(苯并呋喃-5-基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，62％)；
对化合物7l进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.50(s,1H),8.36(s,1H),8.24(d,J＝9.1Hz,1H),7.96(d,J＝2.2Hz,1H),7.88(d,J＝2.2Hz,1H),7.58-7.51(m,3H),7.36-7.26(m,2H),7.23(s,1H),6.94(d,J＝2.1Hz,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,153.0,152.5,150.8,150.4,149.4,147.5,147.0,135.3,134.2,128.0,123.6,122.7,122.4,122.0,116.8,111.8,111.0,110.1,109.3,107.4,101.6,56.5.HRMS m/z m/z calculated for C24H18ClN4O5 +[M+H]+:477.0921,found:477.0922；
化合物9l：1-(苯并呋喃-5-基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(白色固体，73％)。
对化合物9l进行检测，其检测结果如下：M.p.196.8-198.4℃；IR(KBr):3278,295,42838,1721,1587,1270,1208,1176,841,697cm-1.1H NMR(400MHz,DMSO-d6)δ9.79(d,J＝11.8Hz,1H),8.65-8.48(m,2H),8.24(d,J＝9.0Hz,1H),7.93(dd,J＝24.3,2.2Hz,2H),7.55(dd,J＝12.5,9.6Hz,3H),7.41(s,1H),7.32(ddd,J＝11.9,9.0,2.4Hz,2H),6.94(d,J＝2.1Hz,1H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.17(s,6H),2.23(dq,J＝13.8,6.6,6.1Hz,2H),1.92(d,J＝6.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.3,155.3,153.1,152.7,150.7,150.6,149.3,147.3,147.0,135.4,134.4,128.0,123.5,122.9,122.6,121.9,116.7,111.7,110.8,110.2,108.0,107.4,101.3,66.9,56.6,53.6,51.9,23.3.HRMS(ESI)m/z calculated for C31H31ClN5O5 +[M+H]+:588.2009,found:588.2009；
化合物4m：1-(4-溴-2-氟苯基)-3-(2-氯-4-羟基苯基)脲(白色固体，81％)；
对化合物4m进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.14(d,J＝2.4Hz,1H),8.52(s,1H),8.14(t,J＝8.8Hz,1H),7.71(d,J＝8.9Hz,1H),7.57(dd,J＝11.0,2.3Hz,1H),7.34(dt,J＝8.9,1.6Hz,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.5,152.8,128.0,128.0,127.4,125.3,125.1,122.1,118.9,115.9,115.0,112.9,112.8.19FNMR(376MHz,DMSO-d6)δ-126.54.HRMS(ESI)m/z calculated for C13H10BrClFN2O2 +[M+H]+:358.9588,found:358.9590；
化合物6m：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-溴-2-氟苯基)脲(粉白色固体，79％)；
对化合物6m进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.47(d,J＝2.5Hz,1H),8.92(s,1H),8.57(s,1H),8.23-8.13(m,2H),7.62-7.56(m,3H),7.52(s,2H),7.44(td,J＝7.8,7.4,1.9Hz,3H),7.39(dq,J＝5.8,1.8Hz,2H),7.32(dd,J＝9.0,2.7Hz,1H),5.36(s,2H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.7,150.8,149.2,147.9,142.6,136.6,136.6,133.8,129.0,128.7,128.5,123.7,123.3,123.0,122.2,122.0,119.0,115.8,113.3,110.2,108.5,101.4,70.8,56.6.19F NMR(376MHz,DMSO-d6)δ-126.02.HRMS(ESI)m/z calculated for C29H22BrClFN4O4 +[M+H]+:623.0492,found:623.0494；
化合物7m：1-(4-溴-2-氟苯基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，56％)；
对化合物7m进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.35(d,J＝2.5Hz,1H),8.87(s,1H),8.50(s,1H),8.20(dd,J＝8.7,2.9Hz,2H),7.55(d,J＝3.1Hz,2H),7.35-7.26(m,2H),7.25-7.18(m,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.7,152.7,152.5,150.3,149.4,147.8,133.9,127.7,125.0,123.7,123.3,123.1,122.9,122.0,121.3,115.5,110.1,109.4,101.6,56.5.19F NMR(376MHz,DMSO-d6)δ-126.02.HRMS(ESI)m/zcalculated for C22H16BrClFN4O4 +[M+H]+:533.0022,found:533.0022；
化合物9m：1-(4-溴-2-氟苯基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(白色固体，66％)；
对化合物9m进行检测，其检测结果如下：M.p.167.3-168.7℃；IR(KBr):3320,3077,2965,2732,1657,1421,1287,1246,1016,955,786cm-1.1H NMR(400MHz,DMSO-d6)δ9.40(d,J＝2.5Hz,1H),8.93(s,1H),8.58(s,1H),8.19(t,J＝7.9Hz,2H),7.58-7.56(m,2H),7.41(s,1H),7.29(ddd,J＝19.7,10.3,5.4Hz,2H),7.16(t,J＝7.8Hz,1H),4.30(d,J＝6.2Hz,2H),3.99(s,3H),3.19-3.09(m,6H),2.23(t,J＝7.3Hz,2H),1.91(s,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.3,152.7,150.6,149.3,147.7,134.0,127.8,127.7,125.0,123.6,123.3,123.0,122.0,121.4,110.2,108.0,101.3,66.9,56.6,55.4,53.6,51.9,49.1,23.3.19F NMR(376MHz,DMSO-d6)δ-126.02.HRMS(ESI)m/z calculated forC29H29BrClFN5O4 +[M+H]+:644.1080,found:644.1081；
化合物4n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-羟苯基)脲(白色固体，80％)；
对化合物4n进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.62(s,1H),8.16(s,1H),8.11(s,1H),7.66(d,J＝8.9Hz,1H),7.61(d,J＝1.5Hz,2H),6.86(d,J＝2.7Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.8,153.1,139.9,132.5,127.2,125.9,125.8,123.2,122.6,117.0,116.9,116.0,115.0.19F NMR(376MHz,DMSO-d6)δ-61.51.HRMS(ESI)m/z calculated for C14H10Cl2F3N2O2 +[M+H]+:365.0072,found:365.0073；
化合物6n：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-氯-3-(三氟甲基)苯基)脲(粉白色固体，74％)；
对化合物6n进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.57(s,1H),8.50(s,1H),8.22-8.06(m,2H),7.65(d,J＝1.7Hz,2H),7.61-7.56(m,2H),7.53(dd,J＝9.8,2.8Hz,3H),7.49-7.41(m,2H),7.41-7.28(m,2H),5.36(s,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,150.8,149.2,148.0,139.5,136.5,133.6,132.7,129.0,128.7,128.6,123.7,123.4,123.2,122.1,117.1,110.2,108.5,101.3,70.7,56.6.19F NMR(376MHz,DMSO-d6)δ-61.52.HRMS(ESI)m/z calculated forC30H22Cl2F3N4O4 +[M+H]+:629.0965,found:629.0966；
化合物7n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，60％)；
对化合物7n进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.86(d,J＝6.1Hz,1H),8.50(d,J＝4.6Hz,2H),8.25-7.97(m,2H),7.75-7.48(m,4H),7.48-7.15(m,2H),3.99(d,J＝6.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.1,155.1,152.7,152.5,150.4,149.4,148.1,139.6,133.5,132.7,123.7,123.4,123.2,122.1,117.3,117.2,110.1,109.4,101.6,56.5.19F NMR(376MHz,DMSO-d6)δ-61.51.HRMS(ESI)m/zcalculated for C23H16Cl2F3N4O4 +[M+H]+:539.0496,found:539.0496；
化合物9n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧)苯基)脲(白色固体，75％)；
对化合物9n进行检测，其检测结果如下：M.p.197.3-198.4℃；IR(KBr):3312,3087,2968,2758,1670,1417,1269,1248,1014,967,792cm-1.1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.81(d,J＝7.0Hz,1H),8.58(s,1H),8.21-8.11(m,2H),7.70(dd,J＝8.8,2.5Hz,1H),7.65(s,1H),7.57(d,J＝2.4Hz,2H),7.40(d,J＝2.3Hz,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.31(d,J＝5.8Hz,2H),4.00(s,3H),3.26(s,6H),2.28(t,J＝7.5Hz,2H),1.96(d,J＝6.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.15,155.17,152.88,152.66,150.52,149.25,147.92,143.15,139.80,133.72,132.58,124.63,123.82,123.60,123.29,123.08,121.95,115.82,110.18,107.98,101.30,66.80,56.58,56.52,53.46,51.73,25.63,23.21.19F NMR(376MHz,DMSO-d6)δ-61.49.HRMS(ESI)m/z calculated for C30H29Cl2F3N5O4 +[M+H]+:650.1544,found:650.1545；
化合物4o：1-(2-氯-4-羟基苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，80％)；
对化合物4o进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.47(d,J＝10.3Hz,2H),7.88(d,J＝8.8Hz,1H),7.67(d,J＝8.9Hz,1H),6.83(d,J＝2.6Hz,1H),6.70(dd,J＝8.9,2.8Hz,1H),6.61(d,J＝2.6Hz,1H),6.46(dd,J＝8.9,2.7Hz,1H),3.85(s,3H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ155.4,154.1,153.4,149.9,128.1,125.5,125.1,122.4,120.6,115.8,114.9,104.5,99.2,56.2,55.7.HRMS(ESI)m/zcalculated for C15H16ClN2O4 +[M+H]+:323.0799,found:323.0799；
化合物6o：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2,4-二甲氧基苯基)脲(粉白色固体，82％)；
对化合物6o进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ8.83(d,J＝24.5Hz,2H),8.57(s,1H),8.17(d,J＝9.1Hz,1H),7.90(d,J＝8.8Hz,1H),7.64-7.49(m,5H),7.48-7.37(m,3H),7.28(dd,J＝9.0,2.7Hz,1H),6.64(d,J＝2.7Hz,1H),6.50(dd,J＝8.9,2.7Hz,1H),5.35(s,2H),3.98(s,3H),3.88(s,3H),3.75(s,3H).13C NMR(100MHz,DMSO-d6)δ165.3,155.8,155.1,153.1,152.7,150.7,149.2,147.3,136.5,134.5,129.1,128.7,128.6,123.5,123.1,121.9,121.1,110.2,108.5,104.6,101.3,99.3,70.7,56.6,56.3,55.7.HRMS(ESI)m/z m/z calculated for C31H28ClN4O6 +[M+H]+:587.1692,found:587.1693；
化合物7o：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，57％)；
对化合物7o进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.81(d,J＝24.7Hz,2H),8.50(d,J＝1.0Hz,1H),8.26-8.09(m,1H),8.00-7.79(m,1H),7.68-7.45(m,2H),7.34-7.11(m,2H),6.73-6.42(m,2H),3.98(s,3H),3.88(s,3H),3.75(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.8,155.0,153.1,152.5,150.3,150.3,149.4,147.4,134.4,123.5,123.1,123.0,121.9,121.9,121.1,110.1,109.4,104.6,101.6,99.3,56.5,56.3,55.8.HRMS(ESI)m/z m/z calculated for C24H22ClN4O6 +[M+H]+:497.1223,found:497.1224；
化合物9o：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，64％)；
对化合物9o进行检测，其检测结果如下：M.p.215.2-216.3℃；IR(KBr):3333,3076,2964,2701,1652,1417,1283,1238,1004,984,787cm-1.1H NMR(400MHz,DMSO-d6)δ8.85(d,J＝29.6Hz,2H),8.58(d,J＝1.5Hz,1H),8.32-8.10(m,1H),7.89(dd,J＝8.8,1.5Hz,1H),7.63-7.50(m,2H),7.42(s,1H),7.38-7.21(m,1H),6.63(t,J＝2.0Hz,1H),6.49(dd,J＝9.0,2.4Hz,1H),4.32(t,J＝6.3Hz,2H),3.99(s,3H),3.88(s,3H),3.75(s,3H),3.17(dd,J＝5.2,1.5Hz,6H),2.32-2.21(m,2H),1.94(s,4H).13C NMR(100MHz,DMSO-d6)δ165.3,155.2,153.1,152.7,150.6,150.3,149.3,147.3,134.5,123.5,123.1,123.1,121.9,121.9,121.2,110.2,108.0,104.6,101.3,99.3,66.8,56.6,56.3,55.8,55.4,53.4,51.7,23.2.HRMS(ESI)m/z calculated for C31H35ClN5O6 +[M+H]+:608.2271,found:608.2272；
化合物4p：1-(2-氯-4-羟基苯基)-3-(2-苯氧基苯基)脲(白色固体，81％)；
对化合物4p进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.89(s,1H),8.67(s,1H),8.25(dd,J＝8.2,2.1Hz,1H),7.67(dd,J＝9.0,2.0Hz,1H),7.48-7.37(m,2H),7.16(t,J＝7.3Hz,1H),7.07(dd,J＝11.3,8.0Hz,3H),6.94(t,J＝7.7Hz,1H),6.87-6.79(m,2H),6.73(dd,J＝9.0,2.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ157.3,154.4,153.3,145.7,131.9,130.5,127.6,125.9,125.5,124.3,124.0,122.7,120.5,119.0,118.8,115.9,114.9.HRMS(ESI)m/z calculated for C19H16ClN2O3 +[M+H]+:355.0850,found:355.0851；
化合物6p：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2-苯氧基苯基)脲(粉白色固体，77％)；
对化合物6p进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.00(s,1H),8.57(s,1H),8.38-8.09(m,2H),7.62-7.49(m,5H),7.49-7.34(m,5H),7.30(dd,J＝9.0,2.7Hz,1H),7.25-7.07(m,4H),6.98(td,J＝7.7,1.6Hz,1H),6.84(dd,J＝8.1,1.5Hz,1H),5.35(s,2H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,157.2,155.2,153.0,152.7,150.8,149.2,147.7,146.2,136.6,134.1,131.5,130.6,129.0,128.7,128.5,124.3,124.1,123.6,123.5,123.2,121.9,121.0,119.2,118.7,110.2,108.5,101.4,70.8,56.6.HRMS(ESI)m/z calculated for C35H27ClN4O5 +[M+H]+:618.1665,found:618.1666；
化合物7p：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-苯氧基苯基)脲(白色固体，62％)；
对化合物7p进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.99(s,1H),8.49(s,1H),8.25(dd,J＝8.2,1.6Hz,1H),8.14(d,J＝9.0Hz,1H),7.54(s,1H),7.53-7.50(m,1H),7.48-7.41(m,2H),7.28(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),7.21-7.15(m,2H),7.14-7.05(m,3H),6.99(ddd,J＝8.8,3.7,2.2Hz,1H),6.84(dd,J＝8.1,1.3Hz,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,157.2,155.1,153.0,152.6,152.5,150.4,149.4,147.8,143.1,134.0,130.6,124.3,124.1,123.6,123.5,123.1,122.2,121.9,121.0,119.2,118.8,115.8,110.1,109.4,101.6,56.5.HRMS(ESI)m/zcalculated for C28H22ClN4O5 +[M+H]+:529.1274,found:529.1275；
化合物9p：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-苯氧基苯基)脲(白色固体，69％)；
对化合物9p进行检测，其检测结果如下：M.p.221.1-222.3℃；IR(KBr):3267,2959,2809,1715,1588,1270,1208,1166,740,667cm-1.1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),9.00(s,1H),8.56(s,1H),8.25(dd,J＝8.2,1.6Hz,1H),8.15(d,J＝9.0Hz,1H),7.61-7.51(m,2H),7.49-7.41(m,2H),7.38(s,1H),7.30(dd,J＝9.0,2.7Hz,1H),7.21-7.15(m,1H),7.14-7.06(m,3H),6.98(td,J＝7.7,1.6Hz,1H),6.84(dd,J＝8.1,1.5Hz,1H),4.25(t,J＝6.4Hz,2H),3.98(s,3H),2.63(t,J＝7.2Hz,2H),2.52(s,4H),2.03-1.98(m,2H),1.72(p,J＝3.1Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,157.2,155.6,153.0,152.7,150.7,149.4,147.8,146.2,134.1,131.4,130.6,124.3,124.1,123.6,123.5,123.2,121.9,121.0,119.2,118.7,110.0,107.8,101.3,67.6,56.6,54.1,52.6,23.6.HRMS(ESI)m/zcalculated for C35H35ClN5O5 +[M+H]+:640.2322,found:640.2323；
化合物4q：1-(2-氯-4-羟基苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，77％)；
对化合物4q进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.52-9.45(m,1H),8.14(s,1H),7.76(dp,J＝4.5,2.4Hz,2H),7.45(td,J＝8.2,2.2Hz,1H),7.32(d,J＝8.2Hz,1H),6.99(d,J＝8.2Hz,1H),6.91(t,J＝2.4Hz,1H),6.79(dt,J＝8.9,2.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ153.0,149.2,142.0,131.0,127.4,125.5,125.3,117.1,117.0,115.9,115.0,114.1,110.4,110.3.19FNMR(376MHz,DMSO-d6)δ-56.60.HRMS(ESI)m/z calculated for C14H11ClF3N2O3 +[M+H]+:347.0404,found:347.0406；
化合物6q：1-([1,1'-联苯]-4-基)-3-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)脲(粉白色固体，69％)；
对化合物6q进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.57(s,1H),8.43(s,1H),8.21(d,J＝9.0Hz,1H),7.60(d,J＝2.2Hz,1H),7.60-7.55(m,3H),7.55-7.49(m,3H),7.47-7.41(m,2H),7.41-7.23(m,4H),5.35(s,2H),3.99(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.1,152.7,152.6,150.7,149.3,147.7,143.3,139.2,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.3,122.0,119.8,110.2,108.5,101.3,70.7,56.5.19F NMR(376MHz,DMSO-d6)δ-56.59.HRMS(ESI)m/z calculatedfor C30H23ClF3N4O5 +[M+H]+:611.1303,found:611.1305；
化合物7q：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-氟苯基)脲(白色固体，59％)；
对化合物7q进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.70(s,1H),8.47(d,J＝21.7Hz,2H),8.19(d,J＝9.0Hz,1H),7.74(s,1H),7.65-7.51(m,2H),7.44(t,J＝8.2Hz,1H),7.30(dd,J＝8.8,2.4Hz,2H),7.24(s,1H),7.05-6.93(m,1H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.7,152.5,150.4,149.4,149.3,147.9,141.7,133.7,131.0,123.7,123.3,122.9,122.1,117.3,114.5,110.6,110.1,109.4,101.6,56.5.19F NMR(376MHz,DMSO-d6)δ-56.59.HRMS(ESI)m/z calculated forC23H17ClF3N4O5 +[M+H]+:521.0834,found:521.0835；
化合物9q：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，74％)；
对化合物9q进行检测，其检测结果如下：M.p.239.5-241.5℃；IR(KBr):3291,2957,2854,1722,1537,1257,1207,1186,846,683cm-1.1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.67(s,1H),8.58(s,1H),8.18(d,J＝9.0Hz,1H),7.74(s,1H),7.61-7.53(m,2H),7.47-7.40(m,2H),7.33(ddd,J＝14.7,8.6,2.4Hz,2H),7.04-6.89(m,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.20(q,J＝7.6Hz,6H),2.24(t,J＝7.3Hz,2H),2.01-1.90(m,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.3,152.8,152.7,150.6,149.3,149.2,147.8,141.9,133.9,131.0,123.6,123.5,123.1,122.0,117.2,114.3,110.5,110.2,108.0,101.4,66.9,56.6,53.6,51.9,25.9,23.2.19F NMR(376MHz,DMSO-d6)δ-56.59.HRMS(ESI)m/z calculated for C30H30ClF3N5O5 +[M+H]+:632.1882,found:632.1884；
化合物4r：1-(2-氯-4-羟基苯基)-3-(2-氟苯基)脲(白色固体，83％)；
对化合物4r进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.03(d,J＝2.5Hz,1H),8.49(s,1H),8.15(td,J＝8.3,1.7Hz,1H),7.72(d,J＝8.9Hz,1H),7.23(ddd,J＝11.7,8.2,1.5Hz,1H),7.12(td,J＝7.8,1.5Hz,1H),6.99(tdd,J＝7.5,5.0,1.7Hz,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.3,153.6,152.9,151.2,128.1,127.6,125.3,125.1,124.9,122.8,121.0,115.9,115.4,114.9.19F NMR(376MHz,DMSO-d6)δ-129.69.HRMS(ESI)m/z calculated forC13H10ClFN2NaO2 +[M+Na]+:303.0307,found:303.0309；
化合物6r：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-(三氟甲氧基)苯基)脲(粉白色固体，80％)；
对化合物6r进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.35(d,J＝2.4Hz,1H),8.87(s,1H),8.57(s,1H),8.19(td,J＝8.6,6.1Hz,2H),7.59-7.56(m,2H),7.53(dd,J＝10.3,3.2Hz,3H),7.47-7.42(m,2H),7.41-7.36(m,1H),7.33-7.23(m,2H),7.19-7.13(m,1H),7.04(tdd,J＝7.6,5.1,1.7Hz,1H),5.36(s,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,153.8,152.6,150.7,149.2,147.7,136.5,133.9,129.0,128.6,128.5,127.7,125.0,123.6,123.3,123.2,122.9,122.0,121.3,115.7,115.5,110.2,108.5,101.4,70.8,56.6.19F NMR(376MHz,DMSO-d6)δ-129.19.HRMS(ESI)m/z calculatedfor C29H23ClFN4O4 +[M+H]+:545.1386,found:545.1388；
化合物7r：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，55％)；
对化合物7r进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.34(d,J＝2.4Hz,1H),8.87(s,1H),8.50(s,1H),8.18(td,J＝8.8,2.7Hz,2H),7.55(d,J＝2.4Hz,2H),7.32-7.26(m,2H),7.24(d,J＝2.7Hz,1H),7.16(td,J＝7.8,1.5Hz,1H),7.07-7.01(m,1H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.7,152.5,149.4,147.8,133.9,127.7,125.1,123.7,123.3,123.2,122.9,122.0,121.3,115.6,115.5,110.1,109.4,101.6,56.5,29.5.19F NMR(376MHz,DMSO-d6)δ-129.20.HRMS(ESI)m/zcalculated for C22H17ClFN4O4 +[M+H]+:455.0917,found:455.0917；
化合物9r：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-氟苯基)脲(白色固体，68％)；
对化合物9r进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.41(d,J＝2.4Hz,1H),8.94(s,1H),8.58(s,1H),8.23-8.13(m,2H),7.61-7.52(m,2H),7.42(s,1H),7.33-7.20(m,2H),7.16(td,J＝7.8,1.5Hz,1H),7.10-6.97(m,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.27-2.91(m,6H),2.23(t,J＝7.4Hz,2H),1.91(s,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.3,153.9,152.7,150.6,149.3,147.7,134.0,125.0,123.6,123.3,123.1,121.9,121.4,115.5,110.2,108.0,101.3,66.9,56.6,53.6,51.9,23.3.19F NMR(376MHz,DMSO-d6)δ-128.94.HRMS(ESI)m/zcalculated for C29H30ClFN5O4 +[M+H]+:566.1965,found:566.1969；
化合物4s：1-(2-氯-4-羟基苯基)-3-(3-氟苯基)脲(白色固体，82％)；
对化合物4s进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.66(d,J＝1.9Hz,1H),9.34(s,1H),8.07(s,1H),7.70(dd,J＝8.9,1.9Hz,1H),7.49(dq,J＝12.0,2.1Hz,1H),7.34-7.26(m,1H),7.08(d,J＝8.2Hz,1H),6.85(t,J＝2.2Hz,1H),6.81-6.70(m,2H).13C NMR(100MHz,DMSO-d6)δ154.4,153.0,142.2,130.8,127.5,125.3,115.9,115.0,114.2,105.3.19F NMR(376MHz,DMSO-d6)δ-112.12.HRMS(ESI)m/z calculated forC13H11ClFN2O2 +[M+H]+:281.0488,found:281.0489；
化合物6s：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(二苯并[b,d]呋喃-4-基)脲(粉白色固体，80％)；
对化合物6s进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.57(d,J＝1.4Hz,1H),8.45(s,1H),8.20(dd,J＝9.0,1.4Hz,1H),7.61-7.29(m,11H),7.13(d,J＝8.1Hz,1H),6.83(ddd,J＝11.1,5.7,2.1Hz,1H),5.36(s,2H),3.98(d,J＝1.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.2,164.1,161.7,155.1,152.6,150.7,149.1,147.7,136.4,133.8,130.9,129.0,128.7,128.5,123.6,123.3,122.9,122.0,114.4,110.2,108.4,105.5,105.2,101.3,70.7,56.5,55.3.19F NMR(376MHz,DMSO-d6)δ-111.96.HRMS(ESI)m/z calculated for C29H23ClFN4O4 +[M+H]+:545.1386,found:545.1388；
化合物7s：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-氟苯基)脲(白色固体，55％)；
对化合物7s进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.63(s,1H),8.58-8.33(m,2H),8.33-8.09(m,1H),7.54(d,J＝9.7Hz,3H),7.41-7.04(m,4H),6.83(t,J＝8.9Hz,1H),3.98(d,J＝5.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.6,150.3,149.4,147.8,133.8,131.0,130.9,123.6,123.2,122.8,122.0,114.4,110.1,109.4,109.0,108.8,105.5,105.2,101.5,56.4.19F NMR(376MHz,DMSO-d6)δ-111.98.HRMS(ESI)m/z calculated for C22H17ClFN4O4 +[M+H]+:455.0917,found:455.0915；
化合物9s：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-氟苯基)脲(白色固体，64％)；
对化合物9s进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.22(d,J＝3.4Hz,1H),8.70(s,1H),8.58(s,1H),8.17(d,J＝9.0Hz,1H),7.60-7.48(m,3H),7.41(s,1H),7.41-7.27(m,2H),7.17(dd,J＝8.0,2.0Hz,1H),6.81(td,J＝8.5,2.6Hz,1H),4.31(t,J＝6.3Hz,2H),3.99(s,3H),3.17(d,J＝4.5Hz,6H),2.22(d,J＝9.0Hz,2H),1.99-1.81(m,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.7,150.5,149.3,147.7,133.9,130.9,123.5,123.4,123.0,121.9,114.3,110.1,108.8,108.0,105.3,105.1,101.3,66.5,56.6,55.4,53.5,51.8,23.2.19F NMR(376MHz,DMSO-d6)δ-112.00.HRMS(ESI)m/zcalculated for C29H30ClFN5O4 +[M+H]+:566.1965,found:66.1966；
化合物4t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-羟基苯基)脲(白色固体，83％)；
对化合物4t进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.23(s,1H),8.05(s,1H),7.77(d,J＝8.8Hz,1H),7.69-7.51(m,6H),7.44(t,J＝7.7Hz,2H),7.35-7.28(m,1H),6.86(d,J＝2.7Hz,1H),6.75(dd,J＝8.9,2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ154.2,153.0,140.3,139.8,133.9,129.3,127.8,127.5,127.2,126.5,124.9,124.9,118.8,115.9,115.0,21.6.HRMS(ESI)m/zcalculated for C19H16ClN2O2 +[M+H]+:399.0895,found:399.0898；
化合物6t(粉白色固体，72％)。
对化合物6t进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.58(s,1H),8.43(s,1H),8.27(s,1H),7.80-7.27(m,21H),5.36(s,2H),3.99(s,3H).13CNMR(100MHz,DMSO-d6)δ165.2,155.1,152.6,149.2,147.5,140.2,139.4,136.5,134.3,134.1,129.3,129.0,128.6,128.5,127.6,127.3,126.6,123.5,122.5,122.0,119.0,110.2,108.4,101.3,70.7,56.5.HRMS(ESI)m/z calculated for C35H28ClN4O4 +[M+H]+:603.1794,found:603.1794；
化合物7t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，55％)；
对化合物7t进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.53(s,1H),8.50(s,1H),8.42(s,1H),8.24(d,J＝9.0Hz,1H),7.73-7.39(m,10H),7.37-7.19(m,3H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.6,152.4,150.3,147.6,140.3,139.4,134.3,134.0,129.3,127.6,127.3,126.6,123.6,122.9,122.5,122.0,119.0,110.1,109.4,101.6,56.4,29.8.HRMS(ESI)m/z calculated forC28H22ClN4O4 +[M+H]+:513.1324,found:513.1322；
化合物9t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(粉白色固体，64％)；
对化合物9t进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.11(d,J＝4.4Hz,1H),8.71(d,J＝4.4Hz,1H),8.67-8.51(m,1H),8.33-8.13(m,1H),7.77-7.12(m,13H),4.30(q,J＝5.8Hz,2H),4.03-3.90(m,3H),3.02(d,J＝18.2Hz,6H),2.19(q,J＝6.8Hz,2H),1.87(d,J＝6.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.3,152.8,152.6,150.5,149.3,147.5,134.2,134.1,129.3,127.5,127.3,126.6,123.5,123.2,122.8,121.9,118.9,110.1,107.9,101.3,67.1,56.5,53.6,52.0,26.5,23.4.HRMS(ESI)m/zcalculated for C35H35ClN5O4 +[M+H]+:625.1455,found:625.1453；
化合物4u：1-(2-氯-4-羟基苯基)-3-(3-氟-4-甲基苯基)脲(白色固体，74％)；
对化合物4u进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),9.20(s,1H),8.01(s,1H),7.71(d,J＝8.9Hz,1H),7.43(d,J＝12.4Hz,1H),7.16(d,J＝8.5Hz,1H),7.00(s,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝9.0,2.6Hz,1H),2.16(s,3H).13C NMR(100MHz,DMSO-d6)δ154.3,153.0,139.7,139.6,131.9,131.8,127.6,125.2,125.1,117.2,117.1,115.8,115.0,114.0,105.3,105.0,14.0.19F NMR(376MHz,DMSO-d6)δ-116.30.HRMS(ESI)m/z calculated for C14H13ClFN2O2 +[M+H]+:295.0644,found:295.0645；
化合物6u:1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-氟-4-甲基苯基)脲(粉白色固体，83％)；
对化合物6u进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.57(s,1H),8.41(s,1H),8.21(d,J＝9.0Hz,1H),7.60-7.29(m,10H),7.19(t,J＝8.6Hz,1H),7.04(dd,J＝8.2,2.1Hz,1H),5.35(s,2H),3.98(s,3H),2.18(d,J＝1.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.2,159.8,155.1,152.65,150.7,149.2,147.6,136.5,134.0,132.0,129.0,128.6,128.5,123.5,123.0,122.6,122.0,117.7,117.5,114.2,110.2,108.4,105.5,105.2,101.3,70.7,56.5,29.5,14.0.19F NMR(376MHz,DMSO-d6)δ-116.12.HRMS(ESI)m/z calculated for C30H25ClFN4O4 +[M+H]+:559.1543,found:559.1544；
化合物7u:1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-氟-4-甲基苯基)脲(白色固体，45％)；
对化合物7u进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.50(s,1H),8.44(d,J＝40.3Hz,2H),8.20(d,J＝9.1Hz,1H),7.57-7.42(m,3H),7.36-7.18(m,3H),7.04(dd,J＝8.2,2.1Hz,1H),3.98(s,3H),2.18(s,3H).13C NMR(100MHz,DMSO-d6)δ165.1,155.2,152.6,152.4,150.4,149.4,147.7,139.3,133.9,132.0,131.9,123.6,123.0,122.6,122.0,117.7,114.2,110.1,109.3,105.5,105.2,101.5,56.4,29.5,14.0.19FNMR(376MHz,DMSO-d6)δ-116.13.HRMS(ESI)m/z calculated for C23H19ClFN4O4 +[M+H]+:469.1073,found:469.1075；
化合物9u:1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-氟-4-甲基苯基))脲(白色固体，65％)；
对化合物9g进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.71-8.50(m,2H),8.18(d,J＝9.0Hz,1H),7.66-7.38(m,4H),7.37-7.02(m,3H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.03(d,J＝108.6Hz,6H),2.20(d,J＝19.2Hz,5H),1.90(s,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.7,150.5,147.6,134.0,131.9,123.5,123.3,122.8,121.9,117.5,114.2,110.2,108.0,105.4,105.1,101.3,66.9,56.6,53.5,51.8,23.3,14.04.19F NMR(376MHz,DMSO-d6)δ-116.13.HRMS(ESI)m/z calculatedfor C30H31ClFN5NaO4 +[M+Na]+:602.1941,found:602.1943；
化合物4v：1-(2-氯-4-羟基苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，77％)；
对化合物4v进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.54(s,1H),8.64(s,1H),8.18(ddd,J＝18.4,8.0,1.2Hz,2H),7.86-7.72(m,3H),7.62-7.54(m,1H),7.44(t,J＝7.5Hz,1H),7.33(t,J＝7.9Hz,1H),6.88(d,J＝2.7Hz,1H),6.76(dd,J＝8.9,2.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ155.5,154.3,153.1,145.5,128.0,127.7,125.6,125.1,124.9,124.5,124.2,124.0,123.8,121.8,117.3,115.9,115.0,114.5,112.1,55.4,29.5.HRMS(ESI)m/z calculated for C19H14ClN2O3 +[M+H]+:353.0687,found:353.0688；
化合物6v:1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(二苯并[b,d]呋喃-4-基)脲(粉白色固体，82％)；
对化合物6v进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.02(s,1H),8.57(d,J＝5.8Hz,1H),8.33-8.13(m,2H),7.78(t,J＝8.0Hz,2H),7.67-7.27(m,12H),5.36(d,J＝2.3Hz,2H),3.99(d,J＝3.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ156.5,152.9,152.0,145.0,134.0,131.9,124.5,124.3,123.7,123.5,117.5,116.9,116.5,114.2,111.5,106.4HRMS(ESI)m/z calculated for C35H26ClN4O5 +[M+H]+:617.1586,found:617.1586；
化合物7v：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，46％)；
对化合物7v进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.01(s,1H),8.53-8.42(m,1H),8.31-8.10(m,3H),7.77(q,J＝9.3,8.5Hz,2H),7.67-7.14(m,8H),3.98(d,J＝5.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.0,152.8,152.4,150.3,149.4,147.7,145.7,134.0,128.2,125.3,124.5,124.0,123.7,123.1,122.9,122.0,121.9,117.6,114.9,112.1,110.1,109.4,101.5,56.5.HRMS(ESI)m/z calculatedfor C28H20ClN4O5 +[M+H]+:527.1117,found:527.1118；
化合物9v：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，68％)；
对化合物9v进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.07(s,1H),8.59(s,1H),8.36-8.10(m,3H),7.78(t,J＝8.6Hz,2H),7.59(d,J＝4.1Hz,3H),7.53-7.28(m,4H),4.31(t,J＝6.4Hz,2H),4.00(s,3H),3.08(s,6H),2.30-2.13(m,2H),1.89(s,4H).13C NMR(100MHz,DMSO-d6)δ166.2,156.6,156.3,153.9,153.7,151.6,150.3,148.7,146.8,135.1,129.1,126.3,125.5,125.4,125.0,124.9,124.7,124.2,123.9,123.0,122.9,118.8,116.0,113.1,111.2,109.0,68.0,57.6,54.6,52.9,24.4.HRMS(ESI)m/z calculated for C35H33ClN5O5 +[M+H]+:638.2165,found:638.2166；
化合物4w：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，80％)；
对化合物4w进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.01(s,1H),8.25(s,1H),7.71(d,J＝8.9Hz,1H),7.29(dd,J＝9.4,1.9Hz,1H),6.86(d,J＝2.7Hz,1H),6.79-6.68(m,1H),6.17(d,J＝2.0Hz,1H),3.68(s,3H).13C NMR(100MHz,DMSO-d6)δ154.4,152.4,137.8,137.8,137.4,127.6,125.2,121.6,116.2,115.9,115.0,97.2,35.8,35.8.HRMS(ESI)m/z calculated for C11H12ClN4O2 +[M+H]+:267.0643,found:267.0644；
化合物6w：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吡唑-5-基)脲(粉白色固体，81％)；
对化合物6w进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.67(s,1H),8.57(s,1H),8.19(d,J＝9.0Hz,1H),7.62-7.49(m,5H),7.49-7.28(m,5H),6.23(d,J＝1.9Hz,1H),5.36(s,2H),3.98(s,3H),3.72(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.6,152.0,150.7,149.2,147.7,137.9,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.1,110.2,108.5,101.3,97.2,70.7,56.5,35.8.HRMS(ESI)m/z calculated for C27H24ClN6O4 +[M+H]+:531.1542,found:531.1545；
化合物7w：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，44％)；
对化合物7w进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.90(s,1H),8.55-8.47(m,2H),7.58(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.30(s,3H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ163.2,153.1,152.6,152.5,149.4,148.3,147,1,137.8,137.7,132.8,128.37,123.5,122.5,122.0,121.9,110.9,110.3,106.4,101.2,56.4,38.0.HRMS(ESI)m/z calculated forC20H18ClN6O4 +[M+H]+:441.8440,found:441.8445；
化合物9w：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，65％)；
对化合物9w进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.98(s,1H),8.57(s,1H),8.16(d,J＝9.0Hz,1H),7.55(d,J＝3.1Hz,2H),7.44-7.22(m,3H),6.22(d,J＝2.0Hz,1H),4.27(t,J＝6.4Hz,2H),3.98(s,3H),3.76(s,3H),2.80(d,J＝26.7Hz,6H),2.10(p,J＝7.0Hz,2H),1.78(d,J＝5.6Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.1,155.4,152.6,152.1,150.6,149.3,147.7,137.9,137.7,134.0,123.6,123.0,121.9,110.0,107.8,101.2,96.8,67.3,56.5,53.8,52.2,36.0,27.3,23.5.HRMS(ESI)m/zcalculated for C27H31ClN7O4 +[M+H]+:553.0395,found:553.0397；
化合物4x：1-(2-氯-4-羟基苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，78％)；
对化合物4x进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.54(dd,J＝51.6,2.9Hz,2H),7.92(d,J＝9.0Hz,1H),7.60(d,J＝3.1Hz,1H),7.03-6.64(m,2H),6.03(s,1H),5.76(d,J＝2.8Hz,1H),4.57(pd,J＝7.2,2.7Hz,1H),2.20-1.52(m,8H).13C NMR(100MHz,DMSO-d6)δ153.8,152.5,148.2,129.9,128.1,124.1,123.8,115.8,114.9,94.2,62.3,55.3,32.6,24.2.HRMS(ESI)m/zcalculated for C15H18ClN4O2 +[M+H]+:321.7845,found:321.7844；
化合物6x：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(粉白色固体，76％)；
对化合物6x进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.56(s,1H),8.33(d,J＝9.1Hz,1H),7.78-7.18(m,10H),5.35(s,2H),4.60(p,J＝7.2Hz,1H),3.98(s,3H),2.17-1.54(m,8H).13C NMR(100MHz,DMSO-d6)δ165.2,152.7,152.2,150.7,149.2,147.4,136.5,134.3,129.1,128.7,128.5,123.5,122.3,122.2,122.0,110.2,108.5,101.4,70.7,62.3,56.5,32.7,24.2.HRMS(ESI)m/z calculated forC31H30ClN6O4 +[M+H]+:585.2017,found:585.2018；
化合物7x：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，48％)；
对化合物7x进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.60(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.60(s,1H),2.40-1.62(m,8H).13C NMR(100MHz,DMSO-d6)δ165.2,153.1,152.6,152.5,151.4,149.4,146.6,138.4,136.7,123.5,122.5,122.0,121.9,121.7,112.0,109.1,106.4,101.6,98.8,61.2,56.4,32.1,24.0.HRMS(ESI)m/zcalculated for C24H24ClN6O4 +[M+H]+:495.1542,found:495.1544；
化合物9x：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，65％)；
对化合物9x进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.62(s,1H),8.36(d,J＝9.1Hz,1H),7.77-7.67(m,1H),7.60(s,2H),7.44(s,1H),7.35(dd,J＝9.0,2.8Hz,1H),6.12(s,1H),4.65(p,J＝7.2Hz,1H),4.34(t,J＝6.3Hz,2H),4.04(s,3H),3.00(dd,J＝27.8,15.4Hz,6H),2.26-1.77(m,12H),1.68(td,J＝7.3,3.7Hz,2H).13CNMR(100MHz,DMSO-d6)δ165.2,155.3,152.7,152.3,150.5,149.3,134.3,123.5,122.4,122.3,122.0,110.1,107.9,101.2,67.1,62.3,56.5,53.6,52.0,32.6,24.2,23.3.HRMS(ESI)m/z calculated for C31H36ClN7NaO4 +[M+Na]+:628.2517,found:628.2519；
化合物4y：1-(2-氯-4-羟基苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，82％)。
对化合物4y进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.70-9.48(m,1H),8.76(d,J＝2.6Hz,1H),7.98-7.70(m,3H),7.36(d,J＝2.5Hz,1H),6.83(d,J＝2.9Hz,1H),6.70(dt,J＝9.0,2.9Hz,1H),5.84-5.65(m,1H),4.60(pd,J＝7.2,2.3Hz,1H),2.12-1.50(m,8H).13C NMR(100MHz,DMSO-d6)δ153.9,153.0,129.8,128.1,124.7,122.2,118.8,115.8,114.9,62.5,55.3,32.9,24.2.HRMS(ESI)m/z calculated for C15H18ClN4O2 +[M+H]+:321.1118,found:321.1119；
化合物6y：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(粉白色固体，80％)；
对化合物6y进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.22(d,J＝9.0Hz,1H),7.80(s,1H),7.65-7.24(m,10H),5.35(s,2H),4.64(p,J＝7.0Hz,1H),3.98(s,3H),2.89(s,1H),2.73(s,1H),2.13-1.54(m,8H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.6,150.7,149.2,147.1,134.5,129.8,129.0,128.6,128.5,123.4,122.6,122.1,121.9,118.9,108.4,101.3,70.7,62.5,56.5,32.9,24.2.HRMS(ESI)m/zcalculated for C31H30ClN6O4 +[M+H]+:585.2017,found:585.2015；
化合物7y：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，48％)；
对化合物7y进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.60(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.60(s,1H),2.40-1.62(m,8H).13C NMR(100MHz,DMSO-d6)δ165.2,153.1,152.6,152.5,151.4,149.4,146.6,138.4,136.7,130,89,124.2,123.5,122.5,122.0,121.9,121.7,112.0,109.1,106.4,67.0,56.5,31.7,24.0.HRMS(ESI)m/zcalculated for C24H24ClN6O4 +[M+H]+:495.1542,found:495.1544；
化合物9y：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，66％)；
对化合物9y进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.57(s,1H),8.39(s,1H),8.23(d,J＝9.0Hz,1H),7.80(s,1H),7.73-7.38(m,4H),7.27(dd,J＝9.1,2.8Hz,1H),4.65(q,J＝7.0Hz,1H),4.30(t,J＝6.2Hz,2H),3.99(d,J＝4.9Hz,3H),3.14(d,J＝28.9Hz,6H),2.37-1.59(m,14H).13C NMR(100MHz,DMSO-d6)δ165.2,155.3,152.7,152.6,150.5,149.2,147.1,134.5,129.8,123.4,122.5,122.1,121.9,121.8,118.9,110.1,107.9,101.3,67.0,62.5,56.6,53.6,52.0,32.9,24.2,23.3.HRMS(ESI)m/zcalculated for C31H37ClN7O4 +[M+H]+:607.2596,found:607.2599；
化合物4z：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，82％)；
对化合物4z进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.78(s,1H),7.87(s,1H),7.79-7.69(m,2H),7.34(s,1H),6.82(d,J＝2.7Hz,1H),6.70(dd,J＝8.9,2.7Hz,1H),3.77(s,3H).13C NMR(100MHz,DMSO-d6)δ153.9,152.9,129.9,128.1,124.6,122.4,120.9,115.8,114.9,39.1.HRMS(ESI)m/z calculated for C11H12ClN4O2 +[M+H]+:267.0649,found:267.0650；
化合物6z：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吡唑-4-基)脲(粉白色固体，83％)；
对化合物6z进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.56(s,1H),8.31(d,J＝9.8Hz,1H),8.23(d,J＝9.0Hz,1H),7.77(s,1H),7.65-7.35(m,9H),7.28(dd,J＝9.1,2.7Hz,1H),5.35(s,2H),3.98(s,3H),3.79(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.7,152.5,150.7,149.2,136.5,129.9,129.0,128.6,128.7,123.5,122.2,121.9,110.2,108.49,101.38,70.7,56.5,39.1.HRMS(ESI)m/z calculatedfor C27H24ClN6O4 +[M+H]+:531.1548,found:531.1549；
化合物7z：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，47％)；
对化合物7z进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.90(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.30(s,3H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,153.1,152.6,152.5,151.4,149.4,148.3,137.4,136.7,131.1,127.72,123.5,122.5,122.0,121.9,121.7,118.0,109.1,106.7,56,5,39.0.HRMS(ESI)m/z calculated forC20H18ClN6O4 +[M+H]+:441.8440,found:441.8441；
化合物9z：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，68％)；
对化合物9z进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.56(s,1H),8.31(d,J＝11.2Hz,1H),8.23(d,J＝9.0Hz,1H),7.78(s,1H),7.54(q,J＝2.8Hz,2H),7.39(d,J＝15.3Hz,2H),7.28(dd,J＝9.0,2.7Hz,1H),4.24(t,J＝6.4Hz,2H),3.98(s,3H),2.56(t,J＝7.1Hz,2H),2.46(d,J＝5.6Hz,4H),2.03-1.95(m,2H),1.73-1.63(m,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.6,152.6,152.5,150.6,149.3,147.2,134.4,130.0,123.2,122.4,122.1,122.0,121.1,109.9,107.7,101.2,67.6,56.5,54.1,52.6,39.1,28.4,23.6.HRMS(ESI)m/zcalculated for C27H31ClN7O4 +[M+H]+:552.2126,found:552.2127；
化合物11：(2-氟-4-羟基苯基)氨基甲酸苯酯(淡黄固体，88％)；
对化合物11进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.53(s,1H),7.40(t,J＝7.9Hz,2H),7.35-7.27(m,1H),7.27-7.11(m,3H),6.71-6.57(m,2H).13C NMR(100MHz,DMSO-d6)δ153.3,151.3,129.8,125.7,122.3,116.8,116.7,111.6,111.6,103.5,103.3.19F NMR(376MHz,DMSO-d6)δ-121.42.HRMS(ESI)m/z calculated forC13H12FNO3 +[M+H]+:249.0801,found:249.0808；
化合物15a：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，75％)；
对化合物12a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.90(s,1H),8.10(d,J＝1.7Hz,1H),7.67(t,J＝9.2Hz,1H),7.59-7.29(m,2H),7.29-7.03(m,2H),6.81-6.46(m,2H).13C NMR(100MHz,DMSO-d6)δ158.9,156.5,155.5,154.3,153.2,136.6,124.2,120.1,118.8,115.8,111.4,103.2.19FNMR(376MHz,DMSO-d6)δ-121.66,-126.10.HRMS(ESI)m/z calculated for C13H11F2N2O2 +[M+H]+:265.0783,found:265.0784；
化合物13a：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-(4-氟苯基)脲(粉白色固体，74％)；
对化合物13a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.57(d,J＝3.9Hz,2H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.54-7.41(m,7H),7.41-7.33(m,2H),7.27-7.06(m,3H),5.35(s,2H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.8,152.6,151.3,150.7,149.2,136.5,136.2,129.0,128.7,128.5,121.6,120.4,120.3,118.6,115.9,115.7,110.7,110.5,110.2,108.5,101.3,70.7,56.5.19F NMR(376MHz,DMSO-d6)δ-121.15,-126.84.HRMS(ESI)m/z calculated for C29H23F2N4O4 +[M+H]+:529.1681,found:529.1683；
化合物14a：1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，62％)；
对化合物14a进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.10(s,1H),8.57(d,J＝2.4Hz,1H),8.49(s,1H),8.16(t,J＝9.1Hz,1H),7.54(s,1H),7.52-7.45(m,2H),7.37(dd,J＝11.8,2.7Hz,1H),7.23(s,1H),7.18-7.10(m,3H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.1,155.0,152.8,152.4,151.3,150.3,149.4,136.2,121.6,120.3,120.3,118.6,115.9,115.7,110.5,110.1,109.4,101.6,56.4,55.3.19F NMR(376MHz,DMSO-d6)δ-121.15,-126.86.HRMS(ESI)m/z calculated for C22H17F2N4O4 +[M+H]+:439.1212,found:439.1214；
化合物15a：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，73％)；
对化合物15a进行检测，其检测结果如下：M.p.200.2-201.7℃；IR(KBr):3302,3075,2997,2830,1751,1374,1272,1029,867,766cm-1.1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.84-8.74(m,1H),8.58(s,1H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.54-7.48(m,2H),7.41(s,1H),7.38(dd,J＝9.7,2.0Hz,1H),7.20-7.11(m,3H),4.31(d,J＝5.9Hz,2H),3.99(s,3H),3.26-3.14(m,6H),2.25(d,J＝7.5Hz,2H),1.93(d,J＝6.6Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.9,152.7,150.5,149.2,147.2,136.4,125.7,121.8,120.2,120.1,118.5,115.9,115.7,110.7,110.5,110.2,108.0,101.3,66.7,56.6,53.5,51.7,25.5,23.1.19F NMR(376MHz,DMSO-d6)δ-121.15,-126.86.HRMS(ESI)m/z calculatedfor C29H30F2N5O4 +[M+H]+:550.2260,found:550.2262；
化合物12b：1-(2-氟-4-羟基苯基)-3-苯基脲(白色固体，75％)；
对化合物12b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.86(s,1H),8.12(d,J＝1.8Hz,1H),7.71(t,J＝9.2Hz,1H),7.55-7.41(m,2H),7.41-7.20(m,2H),7.14-6.79(m,1H),6.75-6.52(m,2H).13C NMR(100MHz,DMSO-d6)δ155.5,154.3,153.2,140.2,129.2,124.1,124.0,122.1,118.4,111.4,103.1.19F NMR(376MHz,DMSO-d6)δ-126.30.HRMS(ESI)m/z calculated for C13H12FN2O2 +[M+H]+:247.0877,found:247.0879；
化合物13b：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-苯基脲(粉白色固体，74％)；
对化合物13b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.57(d,J＝8.1Hz,2H),8.20(t,J＝9.1Hz,1H),7.57(s,1H),7.55-7.41(m,7H),7.41-7.35(m,2H),7.31(t,J＝7.9Hz,2H),7.19-7.09(m,1H),7.00(t,J＝7.3Hz,1H),5.35(s,2H),3.98(s,3H).13C NMR(100MHz,DMSO-d6)δ165.24,155.2,152.7,152.7,150.8,149.2,147.2,147.1,139.9,136.6,129.4,129.0,128.6,128.5,125.7,125.6,122.6,121.6,118.6,110.7,110.5,110.3,108.5,101.3,70.7,56.7.19F NMR(376MHz,DMSO-d6)δ-126.95.HRMS(ESI)m/z calculated for C29H24FN4O4 +[M+H]+:511.1776,found:511.1778；
化合物14b：1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-苯基脲(白色固体，62％)；
对化合物14b进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.60(d,J＝2.4Hz,1H),8.49(s,1H),8.20(t,J＝9.1Hz,1H),7.54(s,1H),7.48(d,J＝7.8Hz,2H),7.37(dd,J＝11.8,2.6Hz,1H),7.31(t,J＝7.8Hz,2H),7.24(s,1H),7.13(dt,J＝8.9,1.8Hz,1H),7.02-6.97(m,1H),3.99(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.8,152.6,152.5,150.4,149.5,139.9,129.5,129.4,122.6,121.6,118.7,118.6,110.8,110.6,110.2,109.4,109.3,101.6,101.5,56.4,55.4.19F NMR(376MHz,DMSO-d6)δ-122.27.HRMS(ESI)m/z calculated for C22H18FN4O4 +[M+H]+:421.1306,found:421.1308；
化合物15b：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-苯基脲(白色固体，73％)；
对化合物15b进行检测，其检测结果如下：M.p.190.4-191.9℃；IR(KBr):3306,3062,2954,2853,1649,1501,1233,1069,845,785cm-1.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.93(t,J＝2.8Hz,1H),8.58(s,1H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.53-7.47(m,2H),7.41(s,1H),7.36(dd,J＝11.7,2.7Hz,1H),7.33-7.26(m,2H),7.13(dt,J＝9.1,1.9Hz,1H),6.98(td,J＝7.3,1.3Hz,1H),4.33(t,J＝6.2Hz,2H),3.99(s,3H),3.30-2.94(m,6H),2.29(dq,J＝12.7,6.5Hz,2H),1.94(d,J＝14.8Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.2,155.1,152.9,152.7,150.6,149.2,140.1,129.3,125.7,125.6,122.4,118.5,118.4,110.7,110.5,110.2,108.0,101.3,66.7,56.6,53.4,51.6,25.5,23.2.19F NMR(376MHz,DMSO-d6)δ-125.98.HRMS(ESI)m/z calculated for C29H31FN5O4 +[M+H]+:532.2354,found:532.2356；
化合物12c：1-(2-氟-4-羟基苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，68％)；
对化合物12c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.54(s,1H),8.07(d,J＝1.6Hz,1H),7.75(s,1H),7.67(t,J＝9.2Hz,1H),7.37(s,1H),6.70–6.49(m,2H),4.48–4.35(m,1H),1.38(dd,J＝6.9,2.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.44,154.16,154.05,153.18,153.04,129.58,124.09,124.05,122.15,119.19,119.07,117.73,111.33,111.30,103.13,102.91,53.36,23.09.19F NMR(376MHz,DMSO-d6)δ-126.30(t,J＝11.1Hz).HRMS(ESI)m/z calculated for C13H16FN4O2 +[M+H]+:278.2874,found:278.2876；
化合物13c：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物13c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.55(d,J＝11.2Hz,2H),8.18(t,J＝9.1Hz,1H),7.80(d,J＝0.8Hz,1H),7.63–7.31(m,9H),7.11(ddd,J＝8.9,2.7,1.3Hz,1H),5.35(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ165.26,155.15,152.71,152.65,150.75,149.21,136.55,129.70,129.05,128.68,128.56,121.73,121.28,118.56,117.97,110.67,110.44,110.23,108.48,101.33,70.75,56.55,53.42,23.12.19F NMR(376MHz,DMSO-d6)δ-127.17(t,J＝10.3Hz).HRMS(ESI)m/z calculated for C29H28FN6O4 +[M+H]+:542.5714,found:542.5715.
化合物14c:1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，58％)；
对化合物14c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.55(d,J＝11.2Hz,2H),8.18(t,J＝9.1Hz,1H),7.80(d,J＝0.8Hz,1H),7.82-7.42(m,9H),7.33(ddd,J＝8.9,2.7,1.3Hz,1H),5.45(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.2,155.2,152.7,152.6,150.7,149.2,136.5,129.7,129.0,128.6,128.5,121.7,121.2,118.5,117.9,110.6,110.4,110.2,108.4,101.3,70.7,56.5,53.4,23.1.19F NMR(376MHz,DMSO-d6)δ-127.17.HRMS(ESI)m/z calculated for C22H22FN6O4 +[M+H]+:453.1687,found:453.1688；
化合物15c：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物15c进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.63(d,J＝2.4Hz,1H),8.56(s,1H),8.18(t,J＝9.1Hz,1H),7.80(s,1H),7.54(s,1H),7.37(dd,J＝15.7,9.7Hz,3H),7.11(ddd,J＝8.9,2.7,1.3Hz,1H),4.44(hept,J＝6.7Hz,1H),4.27(t,J＝6.4Hz,2H),3.98(s,3H),2.80(d,J＝28.0Hz,6H),2.09(p,J＝6.5Hz,2H),1.86-1.71(m,4H),1.40(d,J＝6.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.2,155.4,152.7,152.6,150.6,149.3,129.6,121.7,121.3,118.5,117.9,110.6,110.4,110.0,107.8,101.2,67.3,56.5,53.8,53.4,52.3,23.4,23.1.19F NMR(376MHz,DMSO-d6)δ-126.93.HRMS(ESI)m/z calculated for C29H35FN7O4 +[M+H]+:564.2735,found:564.2738；
化合物17：1-(2-氯-4-((6-甲氧基-7-(2-(吡咯烷-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，60％)；
对化合物17进行检测，其检测结果如下：M.p.247.2-248.7℃；IR(KBr):3300,3070,2998,2832,1752,1381,1282,1039,877,765cm-1.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.57(s,1H),8.32(s,1H),8.23(d,J＝9.1Hz,1H),7.81(s,1H),7.61-7.51(m,2H),7.42(d,J＝4.0Hz,2H),7.27(dd,J＝9.0,2.7Hz,1H),4.45(h,J＝6.7Hz,1H),4.34(t,J＝5.7Hz,2H),3.98(s,3H),2.97(d,J＝22.9Hz,2H),2.68(s,4H),1.77-1.70(m,4H),1.40(d,J＝6.6Hz,6H).13C NMR(100MHz,DMSO-d6)δ155.3,152.6,150.6,149.3,147.1,134.5,123.5,122.4,122.0,121.9,121.7,117.9,110.1,107.9,101.3,56.5,54.5,54.2,53.4,23.5,23.1.HRMS(ESI)m/z calculated for C28H33ClN7O4 +[M+H]+:566.2283,found:566.2284。
测试例
酶学测试实验步骤：
采用了HTRF KinEASE-TK kit方法进行VEGFR激酶活性测定：(1)首先制备1倍体积的5X激酶反应缓冲液和4倍体积的水；5mM MgCl2；1mM DTT；(2)1mM MnCl2在稀释板中用DMSO对化合物进行3倍梯度稀释，化合物最终起始浓度为1μM；(3)将化合物40倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟；(4)用1X的酶反应缓冲液配制准备2X激酶，向反应板中每孔加入2μL激酶；(5)向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟；(6)用1X的酶反应缓冲液配制2.5x TK-substrate-biotin和ATP混合液，向反应板中加入2μl TK-substrate-biotin/ATP混合液；(7)用封板膜封住板子1000g离心30秒，室温反应50分钟；(8)用HTRF检测缓冲液配制4X Sa-XL 665；(9)每孔加入5μlSa-XL 665和5μLTK-antibody-Cryptate，1000g离心30秒，室温反应1小时。(10)用BMG酶标仪读615nm(Cryptate)和665nm(XL665)的荧光信号。计算IC50并绘制化合物的抑制曲线：利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：用Graphpad7.0软件进行数据分析，测试结果如表2所示：
表2激酶活性测试结果(对VEGFR蛋白的IC50值)
/>
由表2可知，合成的化合物在VEGFR1、VEGFR2和VEGFR3上都显示出来强效的抑制效果；大多数化合物对于VEGFR1、VEGFR2和VEGFR3的抑制活性均超过了阳性药物瑞格菲尼。
测试例2
动物实验：
实验过程为：收集生长状态良好的肿瘤细胞，用1×PBS洗涤2次，细胞计数仪计算细胞总数，用1XPBS将细胞液稀释成1*107个/mL。每只小鼠接种细胞量为1×106个，取100μL细胞悬浮液接种至小鼠前肢腋窝处。待肿瘤平均体积超过100cm3时(个体间肿瘤体积差异不超过10％)，将小鼠随机分组，每组8只。药物每两天口服灌胃给药，100mg/kg。给药结束后，用安乐死的方法处死小鼠，测量肿瘤重量与体积，并计算肿瘤抑制率；测试结果如表3所示：
表3不同物质对不同肿瘤细胞的抑制率(％)
/>
由表3可知，相对于阳性对照药物瑞格菲尼来说，化合物9a，9h，9u和9y都表现出来强效的抑制多种肿瘤细胞增殖的活性。大多数化合物抑制肿瘤增殖的效果都强于或不弱于阳性对照药物瑞格菲尼。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.一种喹唑啉衍生物，其特征在于，所述喹唑啉衍生物为：
2.权利要求1所述喹唑啉衍生物的可溶性盐。
3.权利要求1所述喹唑啉衍生物或权利要求2所述的喹唑啉衍生物的可溶性盐在制备治疗和/或预防癌症的药物中的应用，所述癌症为VEGFR高表达的恶性肿瘤。
4.如权利要求3所述的应用，其特征在于，所述癌症为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210587104.1A CN114920703B (zh) | 2022-05-26 | 2022-05-26 | 一种喹唑啉衍生物及其制备方法和应用 |
| PCT/CN2022/131932 WO2023226323A1 (zh) | 2022-05-26 | 2022-11-15 | 一种喹唑啉衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210587104.1A CN114920703B (zh) | 2022-05-26 | 2022-05-26 | 一种喹唑啉衍生物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114920703A CN114920703A (zh) | 2022-08-19 |
| CN114920703B true CN114920703B (zh) | 2024-01-09 |
Family
ID=82811098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210587104.1A Active CN114920703B (zh) | 2022-05-26 | 2022-05-26 | 一种喹唑啉衍生物及其制备方法和应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114920703B (zh) |
| WO (1) | WO2023226323A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114920703B (zh) * | 2022-05-26 | 2024-01-09 | 天津济坤医药科技有限公司 | 一种喹唑啉衍生物及其制备方法和应用 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1925676A1 (en) * | 2005-08-02 | 2008-05-28 | Eisai R&D Management Co., Ltd. | Method for assay on the effect of vascularization inhibitor |
| CN103304572A (zh) * | 2012-03-09 | 2013-09-18 | 上海医药集团股份有限公司 | 一类3-氰基喹啉类化合物及其药用组合物和应用 |
| CN104292170A (zh) * | 2014-09-22 | 2015-01-21 | 广西师范大学 | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 |
| CN106632033A (zh) * | 2016-10-28 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | 乐伐替尼的一种制备方法 |
| US20180133225A1 (en) * | 2013-02-15 | 2018-05-17 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| CN108341813A (zh) * | 2017-01-24 | 2018-07-31 | 四川大学 | 取代的1-(异恶唑-3-基)-3-(3-氟-4-苯基)脲衍生物及其制备方法和用途 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478621B (zh) * | 2016-09-30 | 2018-12-25 | 遵义医学院 | 喹啉或喹唑啉类衍生物、制备方法及其应用 |
| CN114920703B (zh) * | 2022-05-26 | 2024-01-09 | 天津济坤医药科技有限公司 | 一种喹唑啉衍生物及其制备方法和应用 |
-
2022
- 2022-05-26 CN CN202210587104.1A patent/CN114920703B/zh active Active
- 2022-11-15 WO PCT/CN2022/131932 patent/WO2023226323A1/zh unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1925676A1 (en) * | 2005-08-02 | 2008-05-28 | Eisai R&D Management Co., Ltd. | Method for assay on the effect of vascularization inhibitor |
| CN103304572A (zh) * | 2012-03-09 | 2013-09-18 | 上海医药集团股份有限公司 | 一类3-氰基喹啉类化合物及其药用组合物和应用 |
| US20180133225A1 (en) * | 2013-02-15 | 2018-05-17 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| CN104292170A (zh) * | 2014-09-22 | 2015-01-21 | 广西师范大学 | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 |
| CN106632033A (zh) * | 2016-10-28 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | 乐伐替尼的一种制备方法 |
| CN108341813A (zh) * | 2017-01-24 | 2018-07-31 | 四川大学 | 取代的1-(异恶唑-3-基)-3-(3-氟-4-苯基)脲衍生物及其制备方法和用途 |
Non-Patent Citations (1)
| Title |
|---|
| Inhibition of tumor cell growth and angiogenesis by 7-Aminoalkoxy-4-aryloxy-quinazoline ureas, a novel series of multi-tyrosine kinase inhibitors;Séverine Ravez et al.;European Journal of Medicinal Chemistry;第79卷;369-381 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114920703A (zh) | 2022-08-19 |
| WO2023226323A1 (zh) | 2023-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101034351B1 (ko) | 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의약학적으로 허용가능한 염, 이의 제조방법 및 이를유효성분으로 함유하는 이상세포 성장 질환의 예방 및치료용 약학적 조성물 | |
| KR20100110344A (ko) | Ｃ―ｍｅｔ의 저해제로서 활성을 나타내는 융합 피리딘 | |
| CN105837575B (zh) | 3-乙炔基吡唑并嘧啶衍生物及其制备方法和用途 | |
| CN112724145A (zh) | 用于抑制shp2活性的吡嗪衍生物 | |
| TW201518278A (zh) | 吡啶酮類衍生物、其製備方法及其在醫藥上的應用 | |
| WO2014194667A1 (zh) | 一类炔基杂环类化合物及其应用 | |
| CN108069929B (zh) | 3-取代香豆素类衍生物及应用和gpr35受体的激动剂 | |
| US10689361B2 (en) | Quinoline derivative and use thereof | |
| CN114920703B (zh) | 一种喹唑啉衍生物及其制备方法和应用 | |
| CN107056755B (zh) | 五元杂环酰胺类wnt通路抑制剂 | |
| CN111542522B (zh) | 可用作激酶抑制剂的被取代的吡唑并嘧啶 | |
| EP4085055A1 (en) | Aminopyrimidine compounds | |
| JP7251841B2 (ja) | 芳香環結合ジオキシノ－キナゾリンまたはジオキシノ－キノリン系化合物、組成物およびその使用 | |
| CN110835332A (zh) | 芳杂环取代的吲唑类衍生物及其制备方法和其在医药上的用途 | |
| CN108699030B (zh) | 一类取代的氨基六元氮杂环类化合物及其制备和用途 | |
| CN111116585B (zh) | 具有c-MET激酶抑制活性化合物、制备方法、组合物及用途 | |
| CN112313207A (zh) | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 | |
| Wang et al. | Investigation on the 1, 6-naphthyridine motif: Discovery and SAR study of 1 H-imidazo [4, 5-h][1, 6] naphthyridin-2 (3 H)-one-based c-Met kinase inhibitors | |
| Chen et al. | Design, synthesis and anticancer evaluation of 6, 7-disubstituted-4-phenoxyquinoline derivatives bearing 1, 8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs | |
| KR101546743B1 (ko) | 인돌 유도체 화합물, 이를 포함하는 Ａｂｌ 키나제 저해제 조성물 및 이상세포 성장 질환의 예방 및 치료용 약학 조성물 | |
| KR20100032496A (ko) | 신규 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 Ｒａｆ 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물 | |
| CN111423379B (zh) | 取代3-吲唑类Mcl-1蛋白抑制剂及制备方法和应用 | |
| TW202246243A (zh) | 胺基嘧啶化合物及其使用方法 | |
| KR20140107153A (ko) | 인돌 유도체 화합물, 이를 포함하는 Ａｂｌ 키나제 저해제 조성물 및 이상세포 성장 질환의 예방 및 치료용 약학 조성물 | |
| JP2021512930A (ja) | ジオキシノキノリン系化合物、その調製方法および使用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |