CN116283920B - 2, 4-disubstituted pyridine compound and application thereof - Google Patents
2, 4-disubstituted pyridine compound and application thereof Download PDFInfo
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- CN116283920B CN116283920B CN202310338831.9A CN202310338831A CN116283920B CN 116283920 B CN116283920 B CN 116283920B CN 202310338831 A CN202310338831 A CN 202310338831A CN 116283920 B CN116283920 B CN 116283920B
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- Prior art keywords
- carboxamide
- pyridin
- fluoro
- phenyl
- oxy
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- -1 2, 4-disubstituted pyridine compound Chemical class 0.000 title claims abstract description 213
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 208000032839 leukemia Diseases 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 130
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 116
- GUXPHGONOMGJLV-UHFFFAOYSA-N 3-hydroxyazetidine-1-carboxamide Chemical compound NC(=O)N1CC(O)C1 GUXPHGONOMGJLV-UHFFFAOYSA-N 0.000 claims description 88
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 23
- 238000006467 substitution reaction Methods 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- CLMGCKCDSPUQEE-UHFFFAOYSA-N cyclopropylurea Chemical compound NC(=O)NC1CC1 CLMGCKCDSPUQEE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- XTVYLDJATAIOKY-UHFFFAOYSA-N (1-methylpiperidin-4-yl)urea Chemical compound CN1CCC(NC(N)=O)CC1 XTVYLDJATAIOKY-UHFFFAOYSA-N 0.000 claims description 3
- IHCDQQHNHQCALV-UHFFFAOYSA-N 2-methoxyethylurea Chemical compound COCCNC(N)=O IHCDQQHNHQCALV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- LQBACDXBAQQNPL-UHFFFAOYSA-N 3-fluoropyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCC(F)C1 LQBACDXBAQQNPL-UHFFFAOYSA-N 0.000 claims description 3
- IBWVUBLVGBAZSN-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide Chemical compound C1CN(C)CCN1C1CCN(C(N)=O)CC1 IBWVUBLVGBAZSN-UHFFFAOYSA-N 0.000 claims description 3
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229940043355 kinase inhibitor Drugs 0.000 claims description 3
- FWTILHAJACCNCQ-UHFFFAOYSA-N oxan-4-ylurea Chemical compound NC(=O)NC1CCOCC1 FWTILHAJACCNCQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- BSGGFPXACSOGBQ-UHFFFAOYSA-N 3-hydroxy-3-methylpyrrolidine-1-carboxamide Chemical compound C(N)(=O)N1CCC(C1)(C)O BSGGFPXACSOGBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- CFLQPPVBAQNLTQ-UHFFFAOYSA-N 1-pyridin-3-yltriazole-4-carboxylic acid Chemical compound N1=NC(C(=O)O)=CN1C1=CC=CN=C1 CFLQPPVBAQNLTQ-UHFFFAOYSA-N 0.000 claims 1
- JNRMAJMETCYFOV-UHFFFAOYSA-N 3-[(dimethylamino)methyl]azetidine-1-carboxylic acid Chemical compound CN(C)CC1CN(C(O)=O)C1 JNRMAJMETCYFOV-UHFFFAOYSA-N 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 88
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 36
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
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- 210000004027 cell Anatomy 0.000 description 20
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
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- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
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- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 7
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
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- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
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- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 241000282414 Homo sapiens Species 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
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- 102000038030 PI3Ks Human genes 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 description 1
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 1
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
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- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
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- 210000004369 blood Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
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- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 2, 4-disubstituted pyridine compound and application thereof, and the general formula I is as follows. The compound and pharmaceutically acceptable salts and stereoisomers thereof have good FLT3-ITD inhibition activity, can inhibit proliferation of various leukemia cells, and simultaneously have good selectivity to c-Kit kinase and wild FLT3, and have better safety.
Description
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a 2, 4-disubstituted pyridine compound and also relates to application of the 2, 4-disubstituted pyridine compound in treating cancers such as leukemia.
Background
Acute myeloid leukemia (Acute myeloid leukemia, AML), the most common hematological malignancy with genetic diversity and invasiveness, is mainly characterized by a hindered differentiation and disordered proliferation of immature myeloid progenitor cells, further leading to severe infection, blood loss, hemorrhage, etc. Epidemiologically, AML patients have a 5-year survival rate of no more than 30%, and mortality rates are higher in patients over 60 years of age. Therefore, development of novel effective and highly safe small molecule drugs is still necessary.
FMS-related tyrosine kinase 3 (FLT 3) is a tyrosine kinase receptor expressed on hematopoietic cells. Clinical data indicate that activating mutations in FLT3 are found in about 30% of cases of Acute Myeloid Leukemia (AML). There are two main activating mutations of FLT 3: internal tandem replication (ITD) of the tyrosine kinase membrane proximal domain and point mutation of the tyrosine kinase domain (typically at residue D835). FLT3-ITD is one of the most common forms of FLT3 mutation, with an incidence of about 25% in AML patients. The point mutations in the tyrosine kinase domain account for approximately 5% to 7%. The FLT3-ITD mutation can activate various intracellular signal molecules, such as JAK/STAT, RAS/MAPK, PI3K/AKT and the like, so as to promote leukemia cell proliferation and inhibit apoptosis. Therefore, FLT3-ITD has become an effective target for FLT3-ITD positive AML. The drugs Midostaurin (Midostaurin), quezatinib (quezartinib), sorafenib in clinical stage III (CN 1341098A) and the like, which have been marketed at present, have a number of drawbacks, although they exhibit a better activity towards FLT-ITD: on one hand, the multi-target inhibition, especially the stronger inhibition effect on c-Kit kinase, is easy to cause synthesis lethal bone marrow inhibitioneLife2014, 3, No. e03445;Stem Cell Invest2017, 4, 48.), whereas midostaurin, quinacrine and sorafenib have better activity on c-Kit, IC 50 The method comprises the following steps: 1-100 nM; on the other hand, wild-type FLT3 (FLT 3 wt) is necessary for proliferation of primitive hematopoietic cells, however, neither wild-type FLT3 nor mutant FLT3 (FLT 3-ITD) selectivity is achieved by currently under investigation. In view of the above, there is a need in the art to develop novel FLT3 kinase inhibitors with good selectivity.
Disclosure of Invention
The invention aims to overcome the defects and provide the 2, 4-disubstituted pyridine compound which has better FLT3-ITD inhibition activity, can inhibit proliferation of various leukemia cells, has better selectivity to c-Kit kinase and wild FLT3 and further has better safety.
Another object of the invention is the use of a medicament for the preparation of an inhibitor of FLT3-ITD kinase, for the treatment and/or prevention of leukemia.
The specific technical scheme is as follows:
the invention provides a 2, 4-bipyridine compound, which has a structure shown in the following general formula I:
wherein:
R 1 is a 6-10 membered aryl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from O, N and S, and R 1 Optionally 1-3R 4 Substitution;
R 2 is hydrogen, C 1 -C 6 An alkyl group;
R 3 is substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-7 membered saturated heterocycle containing 1-3 members selected from N, O or S, - (CH) 2 )nNR 5 R 6 The substitution means substitution by one or more substituents selected from the following: hydroxy, C 1 -C 4 Straight-chain or branched alkyl, C 1 -C 4 Linear or branched alkoxy groups;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally being substituted with one or more R 7 Substitution;
R 4 is hydroxy, halogen, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkynyl, (C) 1 -C 6 ) Alkoxy, ring B, - (CH) 2 ) m ring B;
R 5 and R is 6 Independently selected from C substituted or unsubstituted with hydroxy 1 -C 6 An alkyl group;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached form a group containing 1-3N and 0-3 4-8 membered heterocycles selected from O, S, said heterocycles optionally being further substituted with one or more hydroxy groups, (C) 1 -C 6 ) Alkyl substituted;
n and m are integers from 1 to 4;
ring B is a substituted or unsubstituted 5-7 membered saturated heterocyclic group containing 1-3 heteroatoms selected from N, 0 and S, said substitution being hydroxy, (C) 1 -C 6 ) Straight or branched alkyl and alkoxy groups;
R 7 selected from hydroxy, amino, mono-or di (C) 1 -C 6 Alkyl) substituted amino, C 1 -C 6 Straight-chain or branched alkyl, C 1 -C 6 Straight-chain or branched alkoxy, C substituted by hydroxy or amino 1 -C 6 Linear or branched alkyl, 0-3 4-8 membered saturated heterocyclic rings selected from N, O, S, said heterocyclic rings being substituted with 1-3 groups selected from hydroxy, amino, mono-or di (C) 1 -C 6 Alkyl) substituted amino, C 1 -C 6 Straight-chain or branched alkyl, C substituted by hydroxy or amino 1 -C 6 Straight-chain or branched alkyl, C 1 -C 6 Substituted with straight or branched alkoxy groups;
a is selected from:
R 8 selected from hydrogen, methyl, trifluoromethyl;
preferred R 1 Is a six-membered aryl or heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, and R 1 Optionally 1-3R 4 Substitution;
R 2 is hydrogen or methyl;
R 3 is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-7 membered saturated heterocycle containing 1-3 members selected from N, O or S, - (CH) 2 )nNR 5 R 6 The substitution means substitution by one or more substituents selected from the following: hydroxy, C 1 -C 4 Straight-chain or branched alkyl, C 1 -C 4 Linear or branched alkoxy groups;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally being substituted with one or more R 7 Substitution;
R 4 is halogen, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, - (CH) 2 ) m ring B;
R 5 and R is 6 Independently selected from C 1 -C 6 An alkyl group;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, which heterocyclic ring may optionally also be substituted with one or more (C 1 -C 6 ) Alkyl substituted;
ring B is a substituted or unsubstituted 5-7 membered saturated heterocyclic group containing 1-3 heteroatoms selected from N, 0 and S, said substitution being (C 1 -C 6 ) Alkyl or alkoxy;
R 7 selected from hydroxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino, C 1 -C 6 Straight-chain or branched alkyl, C 1 -C 6 Linear or branched alkoxy groups, 0 to 3 4-8 membered saturated heterocycles selected from N, O, S, which may be substituted with 1 to 3 groups selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino;
more preferably R 1 Is phenyl or pyridyl, and R 1 Optionally 1-3R 4 Substitution;
R 2 is hydrogen or methyl;
R 3 is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-7 membered saturated heterocycle containing 1-3 members selected from N, O or S, - (CH) 2 )nNR 5 R 6 The substitution means substitution by one or more substituents selected from the following: hydroxy, C 1 -C 4 An alkyl group;
or R is 2 And R is 3 And to which they are attachedTogether the nitrogen atoms form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally being substituted with one or more R 7 Substitution;
R 4 is halogen;
R 7 selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino, 0-3 4-8 membered saturated heterocycles selected from N, O, S, said heterocycles being substituted with 1-3 groups selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino;
more preferably R 2 And R is 3 And the nitrogen atom to which they are attached are selected from the following structures:
R 4 F or Cl;
preferred specific compounds are as follows:
1- (4-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (2-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-chloro-3-fluorophenyl) materialN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2-3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1-phenyl-1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1 H-1,2, 3-triazole-4-carboxamide;
1- (4-fluoro-3-methylphenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide;
1- (3-chloro-4-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (3, 4-dimethoxyphenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4 ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-hydroxyphenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-Acetylylphenyl) propanoic acidN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (2, 4-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1 H-1,2, 3-triazole-4-carboxamide;
1- (4-cyanophenyl) propanesN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2,3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (4- (4- (1- (3-chloro-4-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) -2-fluorophenoxy) pyridin-2-yl) morpholine-4-carboxamide;
N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide;
N- (4- (2-fluoro-4- (1- (3-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-morpholinophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-iodophenyl) radicalsN- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-bromophenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4- (morpholinomethyl) phenyl) -1 H-1,2, 3-triazole-4-carboxamide;
1- (2, 3-dichloro-4-fluorophenyl) room temperatureN- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-2-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxy)Pyridin-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (6-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3- (tetrahydro-2))H-pyran-4-yl-urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (4- ((2- (3- (dimethylamino) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (4- (2-fluoro-4- (1- (pyridin-3-yl) -1)H-1,2, 3-triazole-4-carboxylic) phenoxy) pyridin-2-yl) -4-methoxypiperidine-1-carboxamide;
N- (3-fluoro-4- ((2- (3- (1-methylpiperidin-4-yl) urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4-trifluoromethylphenyl) -1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxy azetidine)Alk-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
1- (4-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-3-methylphenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-cyanophenyl) propanesN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-2-methoxyphenyl) materialN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-2-methylphenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-iodophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2, 4-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2-chloro-5-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acidAn amine;
1- (4-bromophenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-chloro-3-fluorophenyl) materialN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 4-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-1- (4- (methylsulfonyl) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 5-dichloro-4-fluorophenyl) room temperatureN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxypyrazine)Pyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-methoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (2-hydroxy-prop-2-yl) piperidin-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 5-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-5-fluorophenyl) materialN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3- (tetrahydro-2))H-pyran-4-yl) urea) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (4- (4-methylpiperazin-1-yl) piperidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) radicalN- (3-fluoro-4- ((2- (4-methylpiperidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-trifluoromethyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1- (p-tolyl) -2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (4-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1-phenyl-2, 3-dihydro-1 H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (3-chloro-4-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (2, 4-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (4- ((2- (3- (dimethylamino) propyl) urea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (4- ((2- (3- ((diethylamino) methyl) -3-methylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1 H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxycyclopentyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1)H-imidazole-4-carboxamide) phenoxy) -pyridin-2-yl) -4-hydroxypiperidine-1-carboxamide;
N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1)H-imidazole-4-carboxy) phenoxy) pyridin-2-yl) -4-methylpiperazine-1-carboxamide;
N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1)H-imidazole-4-carboxamide) phenoxy) pyridin-2-yl) -4- (2-hydroxyethyl) piperazine-1-carboxamide;
N- (3-fluoro-4- ((2- (3- (2-methoxyethyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (4- ((2- (3-ethoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (4- ((2- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
(R) -3-amino-)N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1) H-imidazole-4-carboxamido) phenoxy) pyridin-2-yl) piperidine-1-carboxamide;
4- (3- (dimethylamino) azetidin-1-yl) propanoic acidN- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1)H-imidazole-4-formyl) phenoxy) pyridin-2-yl) piperidine-1-carboxamide;
N- (3-fluoro-4- ((2- (3-fluoropyrrolidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
the application of the 2, 4-bipyridine compound and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof in preparing FLT3-ITD kinase inhibitors.
The application of the 2, 4-bipyridine compound and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof in preparing medicaments for treating and/or preventing leukemia.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can be adopted as follows: experiments prove that the 2, 4-bipyridine compound or pharmaceutically acceptable salt, stereoisomer or prodrug molecules thereof can effectively inhibit the action of FLT3-ITD and can inhibit proliferation of various leukemia cells containing FLT3-ITD mutation. Meanwhile, compared with the existing medicines, the compounds have better selectivity on c-Kit and wild FLT3, so that the compounds have better safety and can be used for preparing medicines for preventing and treating excessive value-added diseases such as leukemia of human beings and other mammals.
Detailed Description
The present invention will be described in further detail with reference to the following examples, with the understanding that the scope of the following examples and preparations is not to be construed as limiting the scope of the invention in any way.
In the invention, the 2, 4-bipyridine compound in the structural formula I or pharmaceutically acceptable salt thereof. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acid addition salts being particularly preferred: salts of conventional inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and the like also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, trifluoroacetic acid and the like.
In addition, prodrugs of the derivatives of the invention are also encompassed by the invention. Prodrugs of the derivatives of the invention are derivatives of formula i which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
In the present invention, "halogen" means fluorine, chlorine, bromine or iodine; "C 1 -C 6 "means a group having 1,2,3, 4, 5 or 6 carbon atoms; "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a number of carbon atoms of 3 to 6; "aryl" refers to phenyl groups that are unsubstituted or substituted; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
Unless otherwise indicated, the formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers), such as R, S configuration containing an asymmetric center, the (Z), (E) isomers of double bonds and the conformational isomers of (Z), (E).
Synthetic scheme
The following schemes (scheme 1) describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the means described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these schematic drawings are as defined below or as defined in the claims.
Route 1
The derivatives of the formula I according to the invention are obtained directly (or after removal of the protecting groups) by condensation of the corresponding intermediate e with the corresponding carboxylic acid, in the manner described in scheme 1.
According to the invention, compounds of formula I, intermediate e are prepared as in scheme 2, and the other substituents are as defined in the claims.
Route 2: reagents (i) PhCl, 140 o C; (ii) CH 2 Cl 2 , pyridine, rt; (iii) CH 2 Cl 2 , Et 3 N, rt; (iv)H 2 , Pd/C, CH 3 CH 2 OH, rt.
Substituents R of all intermediates in the above two routes 1 R 2 And R is 3 As defined in the claims.
The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by ARX-600, and the mass spectrum is measured by Waters G2-XS Qtof; the reagents used are analytically pure or chemically pure.
Example 1: a process for the preparation of 1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide comprising the steps of:
step 1: preparation of intermediate b
15.0 g (95 mmol) of 2-fluoro-4-nitrophenol 1,8.18 g (63.33 mmol) of 2-amino-4-chloro-pyridine were placed in a 250 mL round bottom flask, and 150 mL of chlorobenzene was added for dissolution, and the reaction was stopped at 140for 72 h. Concentrating under reduced pressure to obtain brown residue, adding 100 mL ethyl acetate to dissolve the residue, adding saturated sodium carbonate solution 30 mL, extracting, layering, adding 3 mol/L hydrochloric acid to the water layer to adjust pH to 3, precipitating pale yellow solid, vacuum filtering to obtain pale yellow solid powder (2-fluoro-4-nitrophenol), and concentrating several layers under reduced pressure to obtain brown solid. Column chromatography V (petroleum ether): v (ethyl acetate) =3: 1 gave 15.37. 15.37 g as pale yellow solid b in 65% yield. 1 H NMR (600 MHz, DMSO-d6) 8.40 (dd,J= 10.5, 2.7 Hz, 1H), 8.19 8.14 (m, 1H), 7.90 (d,J= 5.8 Hz, 1H), 7.52 (t,J= 8.6 Hz, 1H), 6.25 (dt,J= 22.0, 11.0 Hz, 1H), 6.11 (s, 2H), 6.00 (d,J= 2.2 Hz, 1H). HRMS (ESI, m/z) calcd for C 11 H 9 FN 3 O 3 (M+H) + 250.0628, found 250.0627.
Step 2: preparation of intermediate c
The light yellow solid b of 15.37 g (61.72 mmol) is taken out in a 250 mL round bottom flask, 150 mL methylene dichloride is added for dissolution, 7.45 mL (92.59 mmol) pyridine and 10.08 mL (80.24 mmol) phenyl chloroformate are sequentially added, white solid is precipitated after the addition, the reaction is stirred at room temperature for 3 h, the reaction is stopped, 50 mL water is added, an organic layer is separated, saturated sodium carbonate solution (2X 40 mL) is washed, 50 mL saturated salt water is washed, anhydrous sodium sulfate is dried, the crude product is pulped by methyl tertiary butyl ether, 40 is dried, and 18.91 g white solid C is obtained, and the yield is 83%. 1 H NMR (600 MHz, DMSO-d6) 10.99 (s, 1H), 8.41 (dd,J= 10.4, 2.7 Hz, 1H), 8.32 (d,J= 5.7 Hz, 1H), 8.18 (dd,J= 9.0, 1.6 Hz, 1H), 7.63 (t,J= 8.5 Hz, 1H), 7.47 (d,J= 2.2 Hz, 1H), 7.42 (dd,J= 11.1, 4.7 Hz, 2H), 7.26 (t,J= 7.4 Hz, 1H), 7.19 (dd,J= 8.4, 0.9 Hz, 2H), 6.89 (dd,J= 5.7, 2.3 Hz, 1H). HRMS (ESI, m/z) calcd for C 18 H 12 FN 3 O 5 (M+H) + 370.0839found 370.0834.
Step 3: preparation of intermediate d
3-hydroxy azetidine hydrochloride 10 g (91.2 mmol) was taken in a 500 mL round bottom flask, 300 mL methylene chloride was added to dissolve, imidazole 24.84 g (364 mmol) was added, stirring was carried out at room temperature for 10min, then tert-butyl diphenylchlorosilane 50.16 g (182.4 mmol) was added, stirring was carried out at room temperature for 12 h, 80 mL water, 6M aqueous sodium hydroxide solution 32 mL were added in sequence, extraction was carried out, the organic layer was separated, the aqueous layer was extracted with 30 mL methylene chloride, the organic layer was combined, the organic layer was extracted with 120 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness to obtain crude colorless oil, column chromatography V (petroleum ether): v (ethyl acetate) =2: 1. 22.44. 22.44 g white solid 3- ((tert-butyldiphenylsilyl) oxy) azetidine was obtained in 79% yield.
Phenyl (4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamate 10 g (27 mmol) was taken in a 250 mL round bottom flask and dissolved in 80 mL dichloromethane, triethylamine 7.5 mL (54.15 mmol) was added in sequence, the white solid prepared above 12.62 g (40.5 mmol) was reacted at 50 under reflux for 2 h, cooled to room temperature, 30 mL water was added, the organic layer was separated, 30 mL saturated sodium chloride water washed, dried over anhydrous sodium sulfate, the filtrate concentrated under reduced pressure, column chromatography V (petroleum ether): v (ethyl acetate) =5:1, giving 10.88. 10.88 g as an off-white solid d in 68.7% yield. 1 H NMR (600 MHz, DMSO-d6) 9.39 (s, 1H), 8.43 (dd,J= 10.4, 2.7 Hz,1H), 8.22 (d,J= 5.8 Hz, 1H), 8.21-8.18 (m,1H), 7.63-7.57 (m, 6H), 7.54-7.44 (m, 6H), 6.76 (dd,J= 5.7, 2.4 Hz,1H), 4.64-4.58 (m, 1H), 4.14-4.06 (m, 2H), 3.85 (dd,J= 8.5, 3.8 Hz,2H), 1.02 (s, 9H). HRMS (ESI,m/z) calcd for C 31 H 31 FN 4 O 5 Si (M+H) + 587.2126, found 587.2124
Step 4: preparation of intermediate e
Taking the above-mentioned class 10.88 g (18.52 mmol) white solid d, placing in a 100 mL round bottom flask, adding 60 mL absolute ethyl alcohol, 10% palladium on carbon 3.94 g (mmol), catalytic hydrogenation reaction 5. 5 h at room temperature, filtering the catalyst, concentrating the filtrate under reduced pressure to obtain 10.01 g shallowYellow solid e, 97% yield. 1 H NMR (600 MHz, DMSO-d6) 9.15 (s, 1H), 8.07 (d,J= 5.7 Hz, 1H), 7.63-7.58 (m, 4H), 7.53-7.42 (m, 7H), 6.96 (t,J= 9.0 Hz, 1H), 6.54 (dd,J= 5.7, 2.4 Hz, 1H), 6.51 (dd,J= 13.1, 2.5 Hz, 1H), 6.42 (dd,J= 8.7, 2.3 Hz, 1H), 5.41 (d,J= 42.6 Hz, 2H), 4.65-4.56 (m, 1H), 4.16-4.02 (m,2H), 3.84 (dd,J= 8.9, 4.2 Hz, 2H), 1.02 (s,9H)
Step 5:1- (4-chlorophenyl) -1HPreparation of 1,2, 3-triazole-4-carboxylic acid
Taking p-chloroaniline (18 mmol) in a 100 mL round bottom flask, placing the flask in an environment of 0 , dropwise adding 15% hydrochloric acid 22 mL (9 mmol), 16.7mL of aqueous solution of sodium nitrite (21.6 mmol), controlling the temperature within 0-5 , stirring at room temperature to react 0.5 h, adding 7.2 mL sodium azide (29.25 mmol) aqueous solution, reacting at 0 after the addition is finished, reacting at 1 h, extracting with ethyl acetate, washing with water to be neutral, drying an organic layer with anhydrous sodium sulfate, concentrating under reduced pressure, and continuing to input the next reaction without purification.
To a 50 mL round bottom flask were added, in order, 0.1 g (0.679 mmol) of anhydrous copper sulfate, 0.269g (1.358 mmol) of sodium ascorbate, 9.5 mL water, the above-prepared compound (13.58 mmol), 9.5 mL t-butanol, 0.99mL (16.296 mmol) of propiolic acid, and after reacting at room temperature for 12. 12 h, an aqueous solution of sodium bicarbonate was added to quench, suction filtration was performed, the aqueous layer was made acidic with 2N hydrochloric acid, a solid was precipitated, suction filtration was performed, and a white solid was obtained after drying, 2.48 g, yield: 82%, HRMS (ESI, M/z) (M-H) - 222.0072
Step 6: preparation of 1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
Intermediate e (1.12 mmol), 1- (4-chlorophenyl) -1 was takenH1,2, 3-triazole-4-carboxylic acid (1.56 mmol) in a 25 mL round bottom flask was added 5 mL in sequenceN,NDissolving dimethylformamide, 2- (7-oxo-benzotriazol) oN,N,N', N' -tetramethylurea hexafluorophosphate (1.68 mmol),NNdiisopropylethylamine (1.68 mmol), reacting at room temperature for 6 h, adding ethyl acetate and water into the reaction solution in order after the reaction, extractingThe organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography V (dichloromethane): V (methanol) =50:1 to give the product, which was further subjected to the next reaction.
The above product was added to a 25 mL round bottom flask, 4 mL tetrahydrofuran was added to dissolve, the flask was placed in an environment of 0deg.C, 1.16 mL tetrabutylammonium fluoride (1.16 mmol) was added, the reaction was completed at room temperature of 1.1 h, 6 mL water was added, solids were precipitated, suction filtration, spin-drying of the cake, column chromatography V (dichloromethane): V (methanol) =35:1, a white solid was obtained, 0.51 g, yield 87%, mp: 225-228 . 1 H NMR (600 MHz, DMSO-d 6 ) 11.01 (s,1H), 9.55 (s,1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.09-8.04 (m, 3H), 7.82 (d,J= 8.8 Hz,1H), 7.75-7.70 (m, 2H), 7.50 (d,J= 1.7 Hz,1H), 7.38 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.2 Hz,1H), 5.62 (d,J= 6.3 Hz, 1H), 4.38 (dt,J= 11.1, 5.4 Hz, 1H), 4.13 (t,J= 7.2 Hz, 2H), 3.75-3.63 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) 165.64, 158.64, 156.39, 155.66, 154.65, 152.96, 149.65, 144.09, 139.50, 136.27 (d,J= 12.3 Hz, 1C), 130.25, 127.73 (d,J= 229.52 Hz, 1C), 126.84 , 124.31, 121.62, 117.61, 109.50 (d,J= 23.2 Hz,1C), 106.42, 98.62, 60.13, 59.72. HRMS (ESI, m/z) 524.1247
According to the method of example 1, intermediates e of different substituents are reacted with differently substituted carboxylic acids (A 1 -A 26 ) The compounds of examples 2-36 were prepared by the reaction.
Example 2:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 558.1513, 1 H NMR (400 MHz,DMSO-d6) 12.06 (s, 1H), 10.68 (s, 1H), 10.12 (s, 1H), 9.23 (d,J= 8.5 Hz, 2H), 9.05 (d,J= 5.7 Hz, 1H), 9.01 (d,J= 2.3 Hz,1H), 8.97 (d,J= 8.8 Hz, 3H), 8.76 (d,J= 8.9 Hz,1H), 8.43 (d,J= 2.2 Hz, 1H), 8.32 (t,J= 9.1 Hz, 1H), 7.55 (dt,J= 12.7, 6.3 Hz, 1H), 5.29 (d,J= 18.6 Hz,1H), 5.05 (t,J= 7.9 Hz,2H), 4.62 (dd,J= 9.0, 4.4 Hz, 2H).
Example 3:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 574.1367. 1 H NMR (600 MHz, DMSO-d6) 11.02 (s, 1H), 9.58 (d,J= 2.8 Hz, 1H), 9.19 (s, 1H), 8.19 (d,J= 9.0 Hz, 2H), 8.14 (d,J= 5.7 Hz, 1H), 8.07 (dd,J= 13.0, 2.1 Hz, 1H), 7.84 (d,J= 8.9 Hz, 1H), 7.69 (d,J= 8.5 Hz, 2H), 7.52 (d,J= 2.2 Hz, 1H), 7.40 (t,J= 9.0 Hz, 1H), 6.65 (dd,J= 5.6, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.44-4.35 (m, 1H), 4.15 (d,J= 7.0 Hz,2H), 3.76-3.66 (m, 2H).
Example 4:1- (2-chlorophenyl) room-endN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 524.1201. 1 H NMR (600 MHz, DMSO-d6) 11.00 (s, 1H), 9.27 (s, 1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.08-8.01 (m, 1H), 7.82 (dd,J= 15.1, 7.3 Hz, 3H), 7.70 (dd,J= 11.0, 4.4 Hz, 1H), 7.64 (t,J= 7.2 Hz, 1H), 7.50 (d,J= 1.9 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.6, 2.2 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.38 (m,J= 10.8, 4.5 Hz, 1H), 4.13 (m, 2H), 3.70 (m,J= 3.7 Hz, 2H).
Example 5:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 508.1554. 1 H NMR (600 MHz, DMSO-d6) 10.99 (s, 1H), 9.50 (s, 1H), 9.18 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.08 (ddd,J= 15.3, 9.7, 3.5 Hz, 3H), 7.83 (dd,J= 8.9, 1.0 Hz, 1H), 7.55-7.49 (m,3H), 7.39 (t,J= 9.0 Hz, 1H), 6.64 (dd,J= 5.7, 2.3 Hz, 1H), 5.61 (d,J= 6.4 Hz, 1H), 4.42-4.35 (m, 1H), 4.14 (m,J= 7.5 Hz, 2H), 3.70 (m,J= 8.4, 3.9 Hz, 2H).
Example 6:1- (4-chloro-3-fluorophenyl) materialN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 542.1047. 1 H NMR (600 MHz, DMSO-d6) 11.02 (s, 1H), 9.59 (s, 1H), 9.18 (s, 1H), 8.23 (dd,J= 10.0, 2.4 Hz, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.06 (dd,J= 13.0, 2.3 Hz, 1H), 7.98 (dd,J= 8.7, 1.7 Hz, 1H), 7.90 (t,J= 8.3 Hz, 1H), 7.83 (d,J= 8.8 Hz, 1H), 7.51 (d,J= 2.2 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.64 (dd,J= 5.7, 2.4 Hz, 1H), 5.61 (d,J= 6.4 Hz, 1H), 4.39 (m,J= 11.3, 6.6, 4.7 Hz, 1H), 4.18-4.10 (m, 2H), 3.70 (m,J= 8.7, 4.2 Hz, 2H).
Example 7:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1-phenyl-1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 490.1634. 1 H NMR (400 MHz, DMSO-d6) 10.99 (s, 1H), 9.51 (s, 1H), 9.17 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 8.08-8.01 (m, 2H), 8.00 (s, 1H), 7.81 (d,J= 8.9 Hz, 1H), 7.63 (t,J= 7.8 Hz, 2H), 7.54 (t,J= 7.4 Hz, 1H), 7.49 (d,J= 2.3 Hz, 1H), 7.37 (t,J= 9.1 Hz, 1H), 6.61 (dd,J= 5.7, 2.4 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.42-4.31 (m, 1H), 4.11 (t,J= 7.9 Hz, 2H), 3.67 (dd,J= 9.1, 4.4 Hz, 2H).
Example 8:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 504.1794. 1 H NMR (400 MHz, DMSO-d6) 10.92 (s, 1H), 9.40 (s, 1H), 9.12 (s, 1H), 8.06 (d,J= 5.7 Hz, 1H), 7.99 (dd,J= 13.1, 2.4 Hz, 1H), 7.84 (d,J= 8.5 Hz, 2H), 7.76 (d,J= 8.9 Hz, 1H), 7.44 (d,J= 2.4 Hz, 1H), 7.38 (d,J= 8.5 Hz, 2H), 7.32 (t,J= 9.1 Hz, 1H), 6.56 (dd,J= 5.8, 2.4 Hz, 1H), 5.55 (d,J= 6.4 Hz, 1H), 4.35-4.26 (m, 1H), 4.06 (t,J= 7.9 Hz, 2H), 3.62 (dd,J= 9.0, 4.4 Hz, 2H), 2.34 (s, 3H).
Example 9:1- (4-fluoro-3-methylphenyl) schemeN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 522.1707. 1 H NMR (400 MHz, DMSO-d6) 10.96 (s, 1H), 9.42 (s, 1H), 9.16 (s,1H), 8.09 (d,J= 5.7 Hz, 1H), 8.02 (dd,J= 13.1, 2.3 Hz, 1H), 7.98 (dd,J= 6.5, 2.5 Hz, 1H), 7.88-7.81 (m, 1H), 7.79 (d,J= 9.0 Hz, 1H), 7.47 (d,J= 2.2 Hz, 1H), 7.37 (dt,J= 17.8, 9.1 Hz, 2H), 6.60 (dd,J= 5.7, 2.4 Hz, 1H), 5.58 (d,J= 6.4 Hz, 1H), 4.39-4.29 (m, 1H), 4.09 (t,J= 7.8 Hz, 2H), 3.66 (dd,J= 9.1, 4.4 Hz, 2H), 2.32 (d,J= 1.3 Hz, 3H).
Example 10:1- (3-chloro-4-fluorophenyl) radicalN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 542.1154. 1 H NMR (400 MHz, DMSO-d6) 11.01 (s, 1H), 9.54 (s, 1H), 9.17 (s, 1H), 8.34 (dd,J= 6.4, 2.7 Hz, 1H), 8.11 (d,J= 5.7 Hz, 1H), 8.09-8.01 (m, 2H), 7.80 (d,J= 9.0 Hz, 1H), 7.71 (t,J= 9.0 Hz, 1H), 7.48 (d,J= 2.3 Hz, 1H), 7.37 (t,J= 9.1 Hz, 1H), 6.61 (dd,J= 5.7, 2.4 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.41-4.32 (m, 1H), 4.11 (t,J= 7.9 Hz, 2H), 3.67 (dd,J= 9.0, 4.4 Hz, 2H).
Example 11:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 508.1489. 1 H NMR (600 MHz, DMSO-d6) 11.01 (s, 1H), 9.57 (s, 1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.05 (dd,J= 13.0, 2.2 Hz, 1H), 7.98 (d,J= 9.7 Hz, 1H), 7.95-7.89 (m, 1H), 7.82 (d,J= 8.8 Hz, 1H), 7.70 (dd,J= 14.5, 8.0 Hz, 1H), 7.50 (d,J= 1.8 Hz, 1H), 7.46-7.35 (m, 2H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.42-4.34 (m, 1H), 4.13 (t,J= 7.3 Hz, 2H), 3.73-3.65 (m, 2H).
Example 12:1- (3, 4-dimethoxyphenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 550.1849. 1 H NMR (400 MHz, DMSO-d6) 10.92 (s, 1H), 9.42 (s, 1H), 9.12 (s, 1H), 8.06 (d,J= 5.7 Hz, 1H), 8.00 (dd,J= 13.1, 2.4 Hz, 1H), 7.76 (d,J= 9.0 Hz, 1H), 7.52 (d,J= 2.5 Hz, 1H), 7.48 (dd,J= 8.6, 2.5 Hz, 1H), 7.43 (d,J= 2.3 Hz, 1H), 7.32 (t,J= 9.1 Hz, 1H), 7.11 (d,J= 8.8 Hz, 1H), 6.57 (dd,J= 5.7, 2.4 Hz, 1H), 5.56 (d,J= 6.4 Hz, 1H), 4.31 (dt,J= 11.0, 5.5 Hz, 1H), 4.06 (t,J= 7.9 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.62 (dd,J= 9.1, 4.4 Hz, 2H).
Example 13:N- (3-fluoro-4 ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 508.1516. 1 H NMR (600 MHz, DMSO-d6) 11.03 (s, 1H), 9.30 (d,J= 1.3 Hz, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.05 (dd,J= 13.0, 2.3 Hz, 1H), 7.93 (td,J= 7.8, 1.3 Hz, 1H), 7.81 (dd,J= 8.8, 1.1 Hz, 1H), 7.72-7.66 (m, 1H), 7.65-7.60 (m, 1H), 7.50 (dd,J= 10.2, 4.9 Hz, 2H), 7.39 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 5.7 Hz, 1H), 4.38 (d,J= 5.0 Hz, 1H), 4.13 (t,J= 7.5 Hz, 2H), 3.69 (dd,J= 8.6, 4.1 Hz, 2H).
Example 14:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-hydroxyphenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 506.1570. 1 H NMR (600 MHz, DMSO-d6) 10.94 (s, 1H), 10.07 (s, 1H), 9.32 (s, 1H), 9.17 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.06 (dd,J= 13.1, 1.9 Hz, 1H), 7.81 (dd,J= 15.0, 9.1 Hz, 3H), 7.51 (d,J= 1.8 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.98 (d,J= 8.7 Hz, 2H), 6.64 (dd,J= 5.6, 2.2 Hz, 1H), 5.61 (s, 1H), 4.39 (s, 1H), 4.14 (t,J= 7.3 Hz, 2H), 3.70 (dd,J= 8.3, 3.8 Hz, 2H).
Example 15:1- (4-Acetylylphenyl) propanoic acidN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 514.1649. 1 H NMR (600 MHz, DMSO-d6) 11.17 (s, 1H), 10.80 (s, 1H), 9.69 (s, 1H), 8.31 (d,J= 6.9 Hz, 1H), 8.16 (dd,J= 13.0, 1.9 Hz, 1H), 8.06 (d,J= 8.6 Hz, 2H), 7.92 (d,J= 8.7 Hz, 1H), 7.75 (d,J= 8.5 Hz, 2H), 7.56-7.45 (m, 1H), 7.21 (s, 1H), 7.12 (d,J= 5.1 Hz, 1H), 4.51 4.44 (m, 1H), 4.42 (s, 1H), 4.26 (s, 2H), 3.88-3.70 (m, 2H).
Example 16:1- (2, 4-difluorophenyl) room-heating N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 526.1432. 1 H NMR (400 MHz, DMSO-d6) 10.85 (s, 1H), 9.17 (s,1H), 8.98 (s, 1H), 8.06 (t,J= 4.8 Hz, 1H), 8.01-7.90 (m, 2H), 7.74 (ddd,J= 8.9, 2.3, 1.1 Hz, 1H), 7.69-7.61 (m, 1H), 7.46 (d,J= 2.4 Hz, 1H), 7.38-7.27 (m, 2H), 6.56 (dd,J= 5.7, 2.4 Hz, 1H), 5.48 (d,J= 6.3 Hz, 1H), 4.38-4.30 (m, 1H), 4.08 (dd,J= 9.1, 6.9 Hz,2H), 3.65 (dd,J= 9.4, 4.6 Hz, 2H).
Example 17:1- (4-cyanophenyl) propanesN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 515.1571. 1 H NMR (600 MHz, DMSO-d6) 11.03 (s, 1H), 9.67 (s, 1H), 9.18 (s, 1H), 8.28 (d,J= 7.7 Hz, 2H), 8.14 (dd,J= 14.8, 6.6 Hz, 3H), 8.06 (d,J= 12.6 Hz, 1H), 7.82 (d,J= 8.0 Hz, 1H), 7.51 (s, 1H), 7.39 (t,J= 8.6 Hz, 1H), 6.63 (d,J= 2.8 Hz, 1H), 5.61 (d,J= 5.7 Hz, 1H), 4.38 (s, 1H), 4.13 (s, 2H), 3.70 (s, 2H).
Example 18:N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 520.1718. 1 H NMR (600 MHz, DMSO-d6) 10.94 (s,1H), 9.39 (s, 1H), 9.17 (s,1H), 8.12 (d,J= 4.5 Hz, 1H), 8.06 (d,J= 12.7 Hz, 1H), 7.92 (d,J= 8.2 Hz, 2H), 7.81 (d,J= 8.2 Hz, 1H), 7.51 (s, 1H), 7.38 (t,J= 8.7 Hz, 1H), 7.17 (d,J= 8.2 Hz,2H), 6.63 (d,J= 3.0 Hz, 1H), 5.60 (d,J= 5.9 Hz, 1H), 4.38 (d,J= 4.1 Hz, 1H), 4.13 (s, 2H), 3.85 (s,3H), 3.70 (s, 2H).
Example 19:N- (4- (4- (1- (3-chloro-4-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) -2-fluorophenoxy) pyridin-2-yl) morpholine-4-carboxamide
ESI-MS[M+H] (m/z): 556.1348. 1 H NMR (600 MHz, DMSO-d6) 11.01 (s, 1H), 9.55 (s, 1H), 9.31 (s, 1H), 8.36 (dd, J = 6.3, 2.5 Hz, 1H), 8.16 (d, J = 5.7 Hz, 1H), 8.08 (m, J = 17.8, 10.9, 2.8 Hz,2H), 7.83 (d, J = 8.7 Hz, 1H), 7.73 (t, J = 8.9 Hz, 1H), 7.44-7.37 (m, 2H), 6.66 (dd, J = 5.6, 2.1 Hz, 1H), 3.60-3.54 (m, 4H), 3.45-3.40 (m, 4H).
Example 20:N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide
ESI-MS[M+H] (m/z): 522.1684. 1 H NMR (600 MHz, DMSO-d6) 11.01 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.14 (d,J= 5.7 Hz, 1H), 8.11-8.03 (m, 3H), 7.86-7.77 (m, 1H), 7.50 (dd,J= 12.1, 5.4 Hz, 2H), 7.44-7.34 (m, 2H), 6.65 (dd,J= 5.7, 2.4 Hz, 1H), 3.59-3.52 (m, 4H), 3.45-3.38 (m, 4H).
Example 21:N- (4- (2-fluoro-4- (1- (3-fluorophenyl) -1)H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide
ESI-MS[M+H] (m/z): 522.1632. 1 H NMR (400 MHz, DMSO-d6) 10.84 (s, 1H), 9.49-9.42 (m, 1H), 9.12 (s,1H), 8.09 (d,J= 5.7 Hz, 1H), 7.99 (dd,J= 13.1, 2.4 Hz, 1H), 7.93-7.84 (m, 2H), 7.78-7.73 (m, 1H), 7.64 (td,J= 8.3, 6.3 Hz, 1H), 7.39-7.28 (m, 3H), 6.57 (dt,J= 8.2, 4.1 Hz,1H), 3.53-3.48 (m,4H), 3.38-3.34 (m, 4H).
Example 22:N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-morpholinophenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 575.2164. 1 H NMR (600 MHz, DMSO) 10.95 (s, 1H), 9.37 (s, 1H), 9.19 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.06 (dd,J= 13.1, 2.4 Hz, 1H), 7.87 7.80 (m, 3H), 7.51 (d,J= 2.3 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.14 (d,J= 9.2 Hz, 2H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.42 4.37 (m, 1H), 4.13 (t,J= 7.4 Hz, 2H), 3.80 3.75 (m, 4H), 3.70 (dd,J= 8.6, 4.0 Hz, 2H), 3.24 3.19 (m, 4H).
Example 23:1- (4-iodophenyl) radicalsN- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 616.0604. 1 H NMR (600 MHz, DMSO) 11.01 (s, 1H), 9.54 (s, 1H), 9.19 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.06 (dd,J= 13.1, 2.2 Hz, 1H), 8.03 7.99 (m, 2H), 7.87 7.80 (m, 3H), 7.51 (s, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.1 Hz, 1H), 4.41 4.36 (m, 1H), 4.14 (t,J= 6.7 Hz, 2H), 3.72 3.67 (m, 2H).
Example 24:1- (4-bromophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl)-1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 568.0748. 1 H NMR (600 MHz, DMSO) 11.01 (s, 1H), 9.55 (s, 1H), 9.19 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.06(dd,J= 13.1, 2.3 Hz, 1H), 8.02 7.99 (m, 2H), 7.88 7.84 (m, 2H), 7.82 (d,J= 8.9 Hz, 1H), 7.50 (d,J= 2.1 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.41 4.36 (m, 1H),4.13 (t,J= 7.3 Hz, 2H), 3.69 (dd,J= 8.4, 3.9 Hz, 2H).
Example 25:N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4- (morpholinomethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 603.2128. 1 H NMR (600 MHz, DMSO) 11.00 (s, 1H), 9.50 (s, 1H), 9.20 (s, 1H), 8.12 (d,J= 4.6 Hz, 1H), 8.06 (d,J= 13.1 Hz, 1H), 7.98 (d,J= 8.3 Hz, 2H), 7.82 (d,J= 8.8 Hz, 1H), 7.57 (d,J= 8.4 Hz, 2H), 7.50 (s, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.5, 2.0 Hz, 1H), 5.62 (dd,J= 6.4, 2.1 Hz, 1H), 4.42 4.34 (m, 1H), 4.18 4.08 (m, 2H), 3.69 (d,J= 3.7 Hz, 2H), 3.65 3.51 (m, 6H), 2.39 (s, 4H).
Example 26:1- (2, 3-dichloro-4-fluorophenyl) room temperatureN- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 576.0762. 1 H NMR (600 MHz, DMSO) 11.05 (s, 1H), 9.28 (s, 1H), 9.19 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.05 (d,J= 13.0 Hz, 1H), 7.96 (dd,J= 8.9, 5.2 Hz, 1H), 7.83 7.75 (m, 2H), 7.51 (s, 1H), 7.39 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 5.66 5.57 (m, 1H), 4.43 4.35 (m, 1H), 4.17 4.09 (m, 2H), 3.70 (d,J= 3.0 Hz, 2H).
Example 27:N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-2-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 491.1585. 1 H NMR (600 MHz, DMSO) 11.18 (s, 1H), 9.61 (s, 1H), 9.28 (s, 1H), 8.68 (d,J= 4.7 Hz, 1H), 8.24 8.17 (m, 2H),8.16 8.05 (m, 2H), 7.84 (d,J= 8.8 Hz, 1H), 7.67 7.61 (m, 1H), 7.49 (s, 1H), 7.40 (t,J= 9.0 Hz, 1H), 6.66 (s, 1H), 5.76 (s, 1H), 4.38 (s,J= 6.6 Hz, 1H), 4.13 (t, 2H), 3.70 (d,J= 4.0 Hz, 2H).
Example 28:N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 491.1609. 1 H NMR (600 MHz, DMSO) 11.05 (s, 1H), 9.62 (s, 1H), 9.26 (s, 1H), 9.21 (s, 1H), 8.77 (d,J= 4.0 Hz, 1H), 8.46 (d,J= 8.3 Hz, 1H), 8.13 (d,J= 5.4 Hz, 1H), 8.06 (dd,J= 13.0, 2.0 Hz, 1H), 7.83 (d,J= 8.7 Hz, 1H), 7.71 (dd,J= 8.2, 4.8 Hz, 1H), 7.50 (s, 1H), 7.40 (t,J= 9.0 Hz, 1H), 6.64 (d,J= 3.7 Hz, 1H), 5.62 (d,J= 6.1 Hz, 1H), 4.42 4.35 (m, 1H), 4.13 (t,J= 8.4 Hz, 2H), 3.73 3.67 (m, 2H).
Example 29:N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (6-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 509.2553. Purity:>95% (HPLC). 1 H NMR (600 MHz, DMSO) 10.98 (s, 1H),9.29 (s, 1H), 9.19 (s, 1H), 8.18 (d,J= 2.7 Hz, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.03 (ddd,J= 12.8, 11.4, 2.7 Hz, 2H), 7.81 (dd,J= 8.9, 1.2 Hz, 1H), 7.49 (d,J= 2.2 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 6.63 (dd,J= 5.7, 2.2 Hz, 1H), 6.57 (d,J= 9.7 Hz, 1H), 5.63 (d,J= 6.3 Hz, 1H), 4.42 4.34 (m, 1H), 4.12 (t,J= 7.2 Hz, 2H), 3.72 3.63 (m, 2H).
Example 30:N- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 519.1995. 1 H NMR (600 MHz, DMSO) 11.18 (s, 1H), 9.79 (s, 1H), 9.25 (d,J= 2.4 Hz, 1H), 8.77 (dd,J= 4.7, 0.8 Hz, 1H), 8.73 (s, 1H), 8.47 8.43 (m, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.10 (dd,J= 13.1, 2.0 Hz, 1H), 7.87 (d,J= 8.8 Hz, 1H), 7.72 (dd,J= 8.2, 4.8 Hz, 1H), 7.49 (s, 1H), 7.40 (t,J= 9.0 Hz, 1H), 6.64 (dd,J= 5.5, 1.9 Hz, 1H), 4.87 (s, 1H), 3.41 (s, 4H), 1.78 (d,J= 27.8 Hz, 2H), 1.27 (s, 3H).
Example 31:N- (3-fluoro-4- ((2- (3-hydroxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1 H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 505.1756. 1 H NMR (600 MHz, DMSO) 11.06 (s, 1H), 9.62 (s, 1H), 9.26 (d,J= 2.1 Hz, 1H), 8.80 (s, 1H), 8.77 (d,J= 4.5 Hz, 1H), 8.46 (d,J= 8.2 Hz, 1H), 8.14 (d,J= 5.7 Hz, 1H), 8.07 (dd,J= 13.0, 1.7 Hz, 1H), 7.84 (d,J= 8.8 Hz, 1H), 7.71 (dd,J= 8.1, 4.8 Hz, 1H), 7.50 (s, 1H), 7.40 (t,J= 9.0 Hz, 1H), 6.65 (dd,J= 5.5, 1.9 Hz, 1H), 4.96 (s, 1H), 4.26 (s, 1H), 3.44 (s, 3H), 3.28 (d,J= 9.9 Hz, 1H), 1.88 (s, 1H), 1.78 (s, 1H).
Example 32:N- (3-fluoro-4- ((2- (3- (tetrahydro-2))H-pyran-4-yl-urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 519.1896. 1 H NMR (600 MHz, DMSO) 11.06 (s, 1H), 9.62 (s, 1H), 9.26 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.46 (d,J= 6.5 Hz, 1H), 8.14 8.04 (m, 2H), 7.99 7.80 (m, 2H), 7.71 (s, 1H), 7.41 (t,J= 8.1 Hz, 1H), 7.03 (s, 1H), 6.62 (s, 1H), 3.80 (d,J= 9.5 Hz, 2H), 3.71 (s, 1H), 3.44 3.38 (m, 2H), 1.80 (d,J= 10.3 Hz, 2H), 1.38 (d,J= 9.3 Hz, 2H).
Example 33:N- (4- ((2- (3- (dimethylamino) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 519.1896. 1 H NMR (600 MHz, DMSO) 11.06 (s, 1H), 9.62 (s, 1H), 9.26 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.46 (d,J= 6.5 Hz, 1H), 8.14 8.04 (m, 2H), 7.99 7.80 (m, 2H), 7.71 (s, 1H), 7.41 (t,J= 8.1 Hz, 1H), 7.03 (s, 1H), 6.62 (s, 1H), 3.80 (d,J= 9.5 Hz, 2H), 3.71 (s, 1H), 3.44 3.38 (m, 2H), 1.80 (d,J= 10.3 Hz, 2H), 1.38 (d,J= 9.3 Hz, 2H).
Example 34:N- (4- (2-fluoro-4- (1- (pyridin-3-yl) -1)H-1,2, 3-triazole-4-carboxylic) phenoxy) pyridin-2-yl) -4-methoxypiperidine-1-carboxamide
ESI-MS[M+H] (m/z): 533.2039. 1 H NMR (600 MHz, DMSO) 11.05 (s, 1H), 9.62 (s, 1H), 9.27 (s, 1H), 9.25 (d,J= 2.4 Hz, 1H), 8.77 (dd,J= 4.7, 1.0 Hz, 1H), 8.46 (dd,J= 8.3, 1.0 Hz, 1H), 8.13 (d,J= 5.7 Hz, 1H), 8.07 (dd,J= 13.0, 2.2 Hz, 1H), 7.83 (d,J= 8.7 Hz, 1H), 7.71 (dd,J= 8.2, 4.8 Hz, 1H), 7.42 7.37 (m, 2H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 3.76 3.70 (m, 2H),3.36 (s, 4H), 3.14 3.08 (m, 2H), 1.88 1.74 (m, 2H), 1.42 1.31 (m, 2H).
Example 35:N- (3-fluoro-4- ((2- (3- (1-methylpiperidin-4-yl) urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 532.2219. 1 H NMR (600 MHz, DMSO) 11.12 (s, 1H), 9.70 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H), 8.77 (d,J= 3.9 Hz, 1H), 8.46 (d,J= 7.6 Hz, 1H), 8.14 8.05 (m, 2H), 7.94 (s, 1H), 7.85 (d,J= 8.4 Hz, 1H), 7.72 (dd,J= 7.7, 4.7 Hz, 1H), 7.40 (t,J= 8.9 Hz, 1H),7.05 (s, 1H), 6.60 (d,J= 3.9 Hz, 1H), 2.60 (s, 2H), 2.14 (s, 3H), 2.01 (s, 2H), 1.85 1.72 (m, 3H), 1.45 1.34 (m, 2H).
Example 36:N- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide
ESI-MS[M+H] (m/z): 475.1620. 1 H NMR (600 MHz, DMSO) 11.06 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 9.05 (s, 1H), 8.78 (s, 1H), 8.46 (d,J= 7.7 Hz, 1H), 8.13 8.06 (m, 2H), 7.98 7.90 (m, 1H), 7.85 (d,J= 8.5 Hz, 1H), 7.76 7.68 (m, 1H), 7.41 (t,J= 8.9 Hz, 1H), 7.11 7.00 (m, 1H), 6.62 (d,J= 3.9 Hz, 1H), 2.58 2.54 (m, 1H), 0.64 (d,J= 5.6 Hz, 2H), 0.42 (s, 2H).
Example 37:Na process for the preparation of- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide comprising the steps of:
step 1: (E) Synthesis of ethyl-2- (2- (4-fluorophenyl) hydrazine) -3-oxobutyrate
Anhydrous sodium acetate (2.36 g, 54.03 mmol) was added to a mixture of water (20 mL) and absolute ethanol (65 mL), and ethyl acetoacetate (3.58 mL, 18.01 mmol) was added thereto, and reacted at room temperature for 2 h to prepare a solution a. 4-fluoroaniline (2.00 g, 18.01 mmol) was added to 10% hydrochloric acid (1.78 mL, 54.03 mmol), and 10% aqueous sodium nitrite solution (1.50 g, 21.61 mmol) was slowly added dropwise at-5and the temperature was kept below 0and the reaction was continued at 0.5 h after the addition. And (3) placing the solution A in an environment of-5 , slowly adding the prepared diazonium salt solution, dropwise adding the diazonium salt solution, continuing to react for 2 h after the addition, adding ethyl acetate for extraction after the reaction is finished, extracting an organic layer with saturated sodium chloride, and concentrating the organic layer under reduced pressure to obtain a yellow solid 2.60 g with the yield of 57.78%.
Step 2: synthesis of ethyl 1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylate
Ethyl (E) -2- (2- (4-fluorophenyl) hydrazine) -3-oxobutyrate (2.60 g, 10.41 mmol) and ethoxyformylmethylene triphenylphosphine (3.59 g, 20.82 mmol) were added to toluene (40 mL), reacted at 120 for 5 h, the reaction mixture was evaporated to dryness to give a brown solid, 15 mL diethyl ether was added, stirred at room temperature for 1 h, suction filtered, and the filter cake was washed with diethyl ether to give a yellow solid, 1.5 g, with a yield of 58.59%.
Step 3: synthesis of 1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid
The above ethyl 1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylate (1.50 g, 5.43 mmol) was added to a mixture of ethanol (16 mL) and tetrahydrofuran (8 mL), 10% sodium hydroxide solution was added dropwise to a pH of 12, reflux reaction was conducted at 50for 5 h, the solvent was evaporated to dryness, 20 mL water was added, suction filtration was conducted, the aqueous layer was adjusted to pH 2 with 3N hydrochloric acid, solid was precipitated, suction filtration was conducted, the cake was washed with water, and the cake was dried by spinning to give a yellow solid 1.14 g in a yield of 85.08%.
Step 4: synthesis of N- (4- ((2- (3- ((tert-butyldiphenylsilicon) oxy) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid (0.14 g, 0.54 mmol), 2- (7-oxybenzotriazole) and method of preparing the sameN,N,N',N' -tetramethylurea hexafluorophosphate (0.21 g, 0.54 mmol),NNDiisopropylethylamine (0.96 mL, 0.54 mmol), N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) -3- ((tert-butyldiphenylsilyl) oxy) azetidine-1-carboxamide (0.2 g, 0.36 mmol) was added to N, N-dimethylformamide (5 mL) and reacted at room temperature for 6 h. After the reaction, slowly pouring the mixture into ice water, stirring the mixture while inverting the mixture, precipitating solids, carrying out suction filtration, and spin-drying the solids to obtain yellow solid 0.26-g with the yield of 91.88%. .
Step 5: synthesis of N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-yl) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
N- (4- ((2- (3- ((tert-butyldiphenylsilicon) oxy) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide (0.26 g,0.33 mmol) was added to tetrahydrofuran and tetrabutylammonium fluoride (0.091 mL, 0.35 mmol) was added dropwise at 0deg.C and the addition was completed, reacting at room temperature for 1 h. After the reaction, adding saturated ammonium chloride to quench the reaction, extracting, collecting an organic layer, evaporating the solvent under reduced pressure, and performing column chromatography V (dichloromethane): v (methanol) =99%: 1%, a white solid was obtained in an yield of 0.23. 0.23 g, 82.45%. HRMS ESI-MS [ M+H ] ] + (m/z): 549.1653. 1 H NMR (600 MHz, DMSO-d 6 ) 10.80 (s, 1H), 9.16 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.90 (dd,J= 12.8, 2.0 Hz, 1H), 7.79 (dd,J= 8.9, 5.0 Hz, 2H), 7.58 (d,J= 8.7 Hz, 1H), 7.48 (d,J= 2.0 Hz, 1H), 7.37 (t,J= 8.8 Hz, 3H), 7.07 (s, 1H), 6.62 (dd,J= 5.7, 2.3 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.41 4.34 (m, 1H), 4.12 (t,J= 7.3 Hz, 2H), 3.68 (dd,J= 8.3, 3.8 Hz, 2H), 2.42 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.59, 162.32, 161.78 (d,J= 246.1 Hz), 159.08, 156.38, 155.67, 153.85 (d,J= 245.6 Hz), 149.64, 143.39, 141.72, 137.54, 137.46 (d,J= 3.0 Hz), 136.48 (d,J= 12.3 Hz), 130.20, 128.38, 128.36 (d,J= 8.8 Hz, 2C), 117.33, 115.92 (d,J= 22.9 Hz, 2C), 109.23 (d,J= 22.7 Hz), 106.47, 98.54, 60.14, 59.74(2C), 18.70.
According to the method of example 37, intermediate e of different substituents is reacted with a different substituted carboxylic acid (B 1 -B 25 ) The compounds of examples 38-71 were prepared.
Example 38: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 545.1937. 1 H NMR (600 MHz, DMSO-d 6 ) 10.78 (t, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.6 Hz, 1H), 7.91 (d,J= 12.5 Hz, 1H), 7.62 7.57 (m, 3H), 7.49 (s, 1H), 7.37 (t,J= 9.0 Hz, 1H), 7.33 (d,J= 8.0 Hz, 2H), 7.05 (s, 1H), 6.62 (d,J= 3.5 Hz, 1H), 5.62 (d,J= 6.2 Hz, 1H), 4.41 4.36 (m, 1H), 4.13 (t,J= 7.8 Hz, 2H), 3.78 3.65 (m, 2H), 2.41 (s, 3H), 2.38 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.61, 162.43, 159.13, 156.40, 155.69,153.87 (d,J= 245.6 Hz), 149.65, 143.17, 141.60, 138.79, 138.29, 137.57 (d,J= 9.7 Hz), 136.46 (d,J= 12.6 Hz), 130.13, 129.49(2C), 125.87(2C), 124.48, 117.33, 109.22 (d,J= 23.0 Hz), 106.46, 98.57, 60.15, 59.76(2C), 21.17, 18.68.
Example 39: n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4-trifluoromethylphenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 599.1653. 1 H NMR (400 MHz, DMSO-d 6 ) 10.80 (s, 1H), 9.16 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.93 7.86 (m, 3H),7.62 7.51 (m, 3H), 7.48 (d,J= 2.2 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.10 (d,J= 1.1 Hz, 1H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 5.60 (d,J= 6.4 Hz, 1H), 4.42 4.33 (m, 1H), 4.12 (t,J= 7.9 Hz, 2H), 3.68 (dd,J= 9.0, 4.4 Hz, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.18, 159.00, 156.39, 155.68,153.86 (d,J= 246.0 Hz), 149.64, 144.27, 143.67, 142.13, 137.49 (d,J= 9.7 Hz), 136.47 (d,J= 12.2 Hz), 130.43, 128.84 (d,J= 32.2 Hz), 126.78(2C), 126.31 (d,J= 3.8 Hz, 2C), 124.53, 124.45 (d,J= 270.0 Hz), 117.34, 109.22 (d,J= 23.1 Hz), 106.49, 98.46, 60.13, 59.76(2C), 18.75.
Example 40: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 599.1595. 1 H NMR (600 MHz, DMSO-d 6 ) 10.80 (s, 1H), 9.16 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.93 7.88 (m,J= 9.2 Hz, 3H), 7.59 (d,J= 8.7 Hz, 1H), 7.55 (d,J= 8.6 Hz, 2H), 7.50 7.47 (m, 1H), 7.37 (t,J= 9.0 Hz, 1H), 7.10 7.08 (m,J= 1.2 Hz, 1H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 5.59 (m,J= 6.2, 3.3 Hz, 1H), 4.40 4.35 (m, 1H), 4.12 (t,J= 7.8 Hz, 2H), 3.72 3.66 (m, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.59, 162.23, 159.03, 156.38, 155.68, 153.86 (d,J= 246.1 Hz), 149.63, 148.01, 143.57, 141.85, 140.00, 137.50 (d,J= 9.8 Hz), 136.50 (d,J= 12.6 Hz), 130.31, 128.11(2C), 124.47, 121.80(2C), 120.52 (d,J= 257.1 Hz), 117.37, 109.26 (d,J= 23.0 Hz), 106.47, 98.54, 60.15, 59.74(2C), 18.75.
Example 41:1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 565.1399. 1 H NMR (600 MHz, DMSO-d 6 ) 10.83 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.91 (d,J= 12.8 Hz, 1H), 7.80 (m, 2H), 7.60 (m, 3H), 7.49 (m, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.08 (s, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (m, 1H), 4.38 (m, 1H), 4.12 (t,J= 7.8 Hz, 2H), 3.69 (m, 2H), 2.42 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.59, 162.26, 158.99, 156.38, 155.68,153.86 (d,J= 246.2 Hz), 149.64, 143.45, 141.88, 139.91, 137.51 (d,J= 9.7 Hz), 136.48 (d,J= 12.2 Hz), 133.09, 130.26, 129.09(2C), 127.83(2C), 124.49, 117.34, 109.23 (d,J= 23.3 Hz), 106.47, 98.52, 60.14, 59.75(2C), 18.71.
Example 42:N- (3-fluoro-4- ((2- (3-hydroxyazetidine)-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 563.1863. 1 H NMR (600 MHz, DMSO-d 6 ) 10.79 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.91 (d,J= 12.8 Hz, 1H), 7.65 (dd,J= 6.6, 1.8 Hz, 1H), 7.58 (t,J= 8.2 Hz, 2H), 7.49 (s, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.30 (t,J= 9.1 Hz, 1H), 7.06 (d,J= 1.2 Hz, 1H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 5.61 (d,J= 6.3 Hz, 1H), 4.41 4.35 (m, 1H), 4.12 (t,J= 6.7 Hz, 2H), 3.69 (dd,J= 8.4, 3.6 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.61, 162.34, 160.38 (d,J= 245.0 Hz), 159.10, 156.39, 155.69, 153.87 (d,J= 245.5 Hz), 149.65, 143.38, 141.66, 137.54 (d,J= 9.7 Hz), 137.09 (d, J = 4.5 Hz), 136.47 (d, J = 12.3 Hz), 130.16, 129.35 (d, J =5.5 Hz), 125.72 (d, J = 8.7 Hz), 125.22 (d,J= 18.5 Hz), 124.50, 117.35, 115.49 (d,J= 23.4 Hz), 109.24 (d,J= 23.1 Hz), 106.48, 98.54, 60.15, 59.76(2C), 18.71, 14.61.
Example 43:1- (4-cyanophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 556.1746. 1 H NMR (600 MHz, DMSO-d 6 ) 10.85 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.03 (s, 4H), 7.90 (dd,J= 12.8, 2.2 Hz, 1H), 7.59 (d,J= 8.8 Hz, 1H), 7.48 (d,J= 2.2 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 7.12 (d,J= 1.2 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.61 (d,J= 6.4 Hz, 1H), 4.42 4.35 (m, 1H), 4.12 (t,J= 7.9 Hz, 2H), 3.68 (dd,J= 8.5, 4.0 Hz, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.12, 158.93, 156.38, 155.68,153.86 (d,J= 245.8 Hz), 149.65, 144.61, 143.68, 142.30, 137.46 (d,J= 9.7 Hz), 136.52 (d,J= 12.3 Hz), 133.35(2C), 130.49, 126.75(2C), 124.52, 118.83, 117.36, 111.13, 109.25 (d,J= 23.1 Hz), 106.49, 98.50, 60.14, 59.75(2C), 18.72.
Example 44:1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 565.1405. 1 H NMR (600 MHz, DMSO-d 6 ) 10.76 (s, 1H), 9.18 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.89 (d,J= 12.8 Hz, 1H), 7.71 7.66 (m, 2H), 7.60 7.53 (m, 3H), 7.49 (s, 1H), 7.36 (t,J= 9.0 Hz, 1H), 7.11 (d,J= 1.2 Hz, 1H), 6.61 (dd,J= 5.7, 2.3 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.41 4.35 (m, 1H), 4.12 (t,J= 6.2 Hz, 2H), 3.69 (dd,J= 8.3 Hz, 2H), 2.45 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.12, 158.70, 156.39, 155.69, 153.82 (d,J= 246.2 Hz), 149.65, 144.09, 141.95, 138.81, 137.39 (d,J= 9.8 Hz), 136.55 (d,J= 12.7 Hz), 131.42, 131.11, 130.39, 130.28, 129.94, 128.76, 124.40, 117.54,109.47 (d,J= 22.9 Hz), 106.44, 98.62, 60.16, 59.76(2C), 18.99.
Example 45:1- (4-fluoro-2-methoxyphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 579.1805. 1 H NMR (600 MHz, DMSO-d 6 ) 10.77 (s,J= 8.4 Hz, 1H), 9.20 (s, 1H), 8.11 (d,J= 5.0 Hz, 1H), 7.89 (d,J= 12.5 Hz, 1H), 7.59 (d,J= 8.0 Hz, 1H), 7.55 7.45 (m, 2H), 7.36 (t,J= 8.6 Hz, 1H), 7.16 (d,J= 10.1 Hz, 1H), 7.02 (s, 1H), 6.94 (t,J= 8.4 Hz, 1H), 6.62 (d,J= 2.5 Hz, 1H), 5.64 (d,J= 4.8 Hz, 1H), 4.42 4.35 (m, 1H), 4.12 (t,J= 7.7 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 2H), 2.41 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.61, 163.58 (d,J= 246.0 Hz), 162.34, 158.91, 156.09 (d,J= 10.9 Hz), 156.05, 155.67, 153.81 (d,J= 245.6 Hz), 149.62, 143.59, 141.69, 137.52 (d,J= 9.6 Hz), 136.42 (d,J= 12.1 Hz), 130.35 (d,J= 10.7 Hz), 129.62, 126.63, 124.42, 117.43, 109.33 (d,J= 22.8 Hz), 107.39 (d,J= 22.7 Hz), 106.45, 101.21 (d,J= 27.3 Hz), 98.55, 60.13, 59.76(2C), 56.84, 18.87.
Example 46:1- (4-fluoro-2-methylphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 563.1876. 1 H NMR (600 MHz, DMSO-d 6 ) 10.69 (s, 1H), 9.18 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.88 (dd,J= 12.8, 2.2 Hz, 1H), 7.57 (d,J= 8.8 Hz, 1H), 7.50 7.47 (m, 2H), 7.36 (t,J= 9.0 Hz, 1H), 7.29 (dd,J= 9.6, 2.8 Hz, 1H), 7.22 (td,J= 8.5, 2.8 Hz, 1H), 7.08 (d,J= 1.2 Hz, 1H), 6.61 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.41 4.35 (m, 1H), 4.12 (t,J= 7.4 Hz, 2H), 3.69 (dd,J= 8.5, 4.0 Hz, 2H), 2.44 (s, 3H), 2.14 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.29 (d,J= 246.0 Hz), 162.29, 159.11, 156.39, 155.68, 153.83 (d,J= 246.2 Hz), 149.65, 143.75, 141.74, 138.20 (d,J= 8.8 Hz), 137.39 (d,J= 9.8 Hz), 136.92 (d,J= 3.0 Hz), 136.53 (d,J= 12.1 Hz), 130.18 (d,J= 9.0 Hz), 129.93, 124.40, 117.54 (d,J= 4.3 Hz), 117.41, 114.00 (d,J= 22.8 Hz), 109.47 (d,J= 23.0 Hz), 106.45, 98.60, 60.15, 59.75(2C),18.93, 17.81.
Example 47: n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-iodophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 657.0762. 1 H NMR (400 MHz, DMSO-d 6 ) 10.80 (s, 1H), 9.16 (s, 1H), 8.12 (d,J= 5.3 Hz, 1H), 7.90 (d,J= 8.7 Hz, 3H), 7.64 7.56 (m, 3H), 7.49 (s, 1H), 7.38 (t,J= 8.8 Hz, 1H), 7.07 (s, 1H), 6.63 (d,J= 3.4 Hz, 1H), 5.61 (d,J= 6.1 Hz, 1H), 4.46 4.32 (m, 1H), 4.13 (t,J= 7.0 Hz, 2H), 3.76 3.65 (m, 2H), 2.41 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.60, 162.26, 158.93, 156.39, 155.69, 153.87 (d,J= 245.7 Hz), 149.65, 143.43, 141.89, 140.86, 137.92(2C), 137.52 (d,J= 9.7 Hz), 136.49 (d,J= 12.0 Hz), 130.27, 128.12(2C), 124.50, 117.35, 109.24 (d,J= 23.1 Hz), 106.48, 98.55, 94.68, 60.15, 59.76(2C), 18.73.
Example 48:1- (2, 4-difluorophenyl) room-heatingN- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 567.1617. 1 H NMR (600 MHz, DMSO-d 6 ) 10.86 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.90 (d,J= 12.9 Hz, 1H), 7.81 (td,J= 8.5, 5.8 Hz, 1H), 7.59 (d,J= 8.7 Hz, 1H), 7.57 7.50 (m, 1H), 7.49 (s, 1H), 7.37 (t,J= 9.0 Hz, 1H), 7.32 (td,J= 8.7, 2.7 Hz, 1H), 7.10 (d,J= 1.6 Hz, 1H), 6.62 (dd,J= 5.8, 2.4 Hz, 1H), 5.63 (d,J= 6.0 Hz, 1H), 4.41 4.34 (m, 1H), 4.12 (t,J= 8.0 Hz, 2H), 3.69 (dd,J= 9.3, 4.5 Hz, 2H), 2.43 (s, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.59, 162.74 (dd, J = 249.0, 11.6Hz), 162.08, 158.60, 157.17 (dd, J = 252.0, 12.0 Hz), 156.39, 155.69, 153.84 (d, J = 246.1 Hz), 149.65, 144.10, 142.50, 137.45 (d,J= 9.6 Hz), 136.53 (d,J= 12.1 Hz), 131.03 (d,J= 10.6 Hz), 129.61, 125.61 (dd,J= 12.6, 3.8 Hz), 124.46, 117.37 (d,J= 3.0 Hz), 112.78 (dd, J = 22.8, 3.1 Hz), 109.28 (d, J = 22.9 Hz), 106.45, 105.32 (dd, J = 25.5,24.0 Hz), 98.57, 60.14, 59.75(2C), 18.87.
Example 49:1- (2-chloro-5-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 1 H NMR (600 MHz, DMSO-d 6 ) 10.75 (s, 1H), 9.18 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.88 (dd,J= 12.9, 2.2 Hz, 1H), 7.74 (ddd,J= 11.4, 8.7, 4.2 Hz, 2H), 7.58 (d,J= 8.9 Hz, 1H), 7.51 7.44 (m, 2H), 7.36 (t,J= 9.0 Hz, 1H), 7.14 7.10 (m, 1H), 6.61 (dd,J= 5.7, 2.4 Hz, 1H), 5.61 (d,J= 6.4 Hz, 1H), 4.41 4.35 (m, 1H), 4.12 (t,J= 7.5 Hz, 2H), 3.68 (dd,J= 8.6, 4.1 Hz, 2H), 2.45 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.34 (d,J= 250.4 Hz), 162.05, 158.74, 156.39, 155.69, 153.82 (d,J= 246.2 Hz), 149.65, 144.21, 142.01, 137.36 (d,J= 9.7 Hz), 136.56 (d,J= 12.2 Hz), 135.48 (d,J= 4.1 Hz), 132.46 (d,J= 11.8 Hz), 131.87 (d,J= 9.8 Hz), 129.94, 124.40, 117.77 (d,J= 26.2 Hz), 117.53 (d,J= 3.0 Hz), 115.97 (d,J= 22.8 Hz), 109.46 (d,J= 22.9 Hz), 106.45, 98.60, 60.15, 55.38(2C), 19.01.
Example 50:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 583.1318. 1 H NMR (600 MHz, DMSO-d 6 ) 10.81 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 3.9 Hz, 1H), 7.97 (d,J= 9.3 Hz, 1H), 7.91 (d,J= 12.0 Hz, 1H), 7.81 7.75 (m, 1H), 7.74 7.68 (m, 1H), 7.59 (d,J= 7.2 Hz, 1H), 7.49 (s, 1H), 7.40 (t,J= 7.7 Hz, 1H), 7.10 (s, 1H), 6.63 (s, 1H), 5.61 (d,J= 4.5 Hz, 1H), 4.38 (s, 1H), 4.12 (s, 2H), 3.69 (s, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.60, 162.11, 158.88, 157.12 (d,J= 246.2 Hz), 156.40, 155.69, 153.87 (d,J= 245.3 Hz), 149.65, 143.68, 141.94, 140.97 (d,J= 9.2 Hz), 137.46 (d,J= 9.6 Hz), 136.54 (d,J= 12.9 Hz), 130.87, 130.43, 124.52, 123.29, 119.67 (d,J= 17.3 Hz), 117.43, 114.93 (d,J= 24.7 Hz), 109.32 (d,J= 23.4 Hz), 106.49, 98.54, 60.15, 59.76(2C), 18.76.
Example 51:1- (4-bromophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 609.0889. 1 H NMR (600 MHz, DMSO-d 6 ) 10.81 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.91 (d,J= 12.6 Hz, 1H), 7.74 (s, 4H), 7.59 (d,J= 8.7 Hz, 1H), 7.49 (s, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.08 (s, 1H), 6.63 (dd,J= 5.6, 2.3 Hz, 1H), 5.62 (d,J= 6.2 Hz, 1H), 4.43 4.34 (m, 1H), 4.13 (t,J= 7.2 Hz, 2H), 3.74 3.65 (m, 2H), 2.42 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.60, 162.26, 158.97, 156.40, 155.69, 153.87 (d,J= 245.5 Hz), 149.65, 143.48, 141.88, 140.35, 137.51 (d,J= 9.7 Hz), 136.50 (d,J= 12.0 Hz), 132.05(2C), 130.29, 128.12(2C), 124.50, 121.59, 117.35, 109.25 (d,J= 23.0 Hz), 106.49, 98.54, 60.15, 59.76(2C), 18.73.
Example 52:1- (4-chloro-3-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 583.1317. 1 H NMR (600 MHz, DMSO-d 6 ) 10.82 (s, 1H), 9.19 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.95 7.85 (m, 2H),7.70 7.65 (m, 1H), 7.59 (d,J= 8.9 Hz, 1H), 7.53 (t,J= 9.3 Hz, 1H), 7.49 (d,J= 1.8 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.14 7.10 (m, 1H), 6.62 (dd,J= 5.7, 2.3 Hz, 1H), 5.62 (d,J= 6.3 Hz, 1H), 4.43 4.35 (m, 1H), 4.13 (t,J= 7.4 Hz, 2H), 3.69 (dd,J= 8.4, 3.9 Hz, 2H), 2.44 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.61, 161.98, 158.41, 156.39, 155.67, 155.80 (d,J= 251.8 Hz), 153.85 (d,J= 246.2 Hz), 149.61, 144.31, 142.46, 137.42 (d,J= 9.7 Hz), 136.55 (d,J= 12.3 Hz), 131.50 (d,J= 8.4 Hz), 129.89 (d,J= 14.8 Hz), 129.69, 129.51, 129.02 (d,J= 3.0 Hz), 124.47, 118.52 (d,J= 21.2 Hz), 117.46 (d,J= 3.0 Hz), 109.36 (d,J= 23.3 Hz), 106.46, 98.59, 60.15, 59.75(2C), 18.96.
Example 53:1- (3, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 567.1606. 1 H NMR (600 MHz, DMSO-d 6 ) 10.81 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.01 7.94 (m, 1H),7.91 (d,J= 12.7 Hz, 1H), 7.70 7.66 (m, 1H), 7.65 7.61 (m, 1H), 7.59 (d,J= 9.4 Hz, 1H), 7.49 (s, 1H), 7.39 (t,J= 8.9 Hz, 1H), 7.10 (s, 1H), 6.71 6.60 (m, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.40 4.36 (m, 1H), 4.13 (T,J= 7.0 Hz, 2H), 3.72 3.67 (m, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.60, 162.16, 158.95, 156.40, 155.69, 153.87 (d,J= 246.2 Hz), 150.15 (dd,J=23.5, 12.7 Hz), 149.66, 148.51 (dd,J= 22.1, 12.6 Hz), 143.64, 141.81, 137.51 (t,J= 11.0 Hz), 136.53 (d,J= 12.0 Hz), 130.35, 124.51, 123.32 (dd,J= 6.0, 3.0 Hz), 117.86, 117.74, 117.42 (d,J= 3.0 Hz), 116.00 (d,J= 20.7 Hz), 109.31 (d,J= 22.9 Hz), 106.49, 98.53, 60.15, 59.76(2C), 18.75.
Example 54: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-1- (4- (methylsulfonyl) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 609.1553. 1 H NMR (400 MHz, DMSO-d 6 ) 10.89 (s, 1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.09 (s, 4H), 7.92 (dd,J= 12.9, 2.3 Hz, 1H), 7.61 (d,J= 8.9 Hz, 1H), 7.49 (d,J= 2.3 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 7.12 (d,J= 0.6 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.38 (dt,J= 11.2, 3.2 Hz, 1H), 4.13 (t,J= 7.9 Hz, 2H), 3.69 (dd,J= 9.1, 4.4 Hz, 2H), 3.30 (s, 3H), 2.44 (d,J= 1.0 Hz, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.61, 162.17, 159.01, 156.40, 155.69,153.87 (d,J= 246.3 Hz), 149.65, 144.97, 143.74, 142.25, 140.55, 137.52 (d,J= 9.9 Hz), 136.51 (d,J= 12.1 Hz), 130.45, 128.15(2C), 126.86(2C), 124.51, 117.37, 109.26 (d,J= 22.9 Hz), 106.50, 98.52, 60.15, 59.76(2C), 43.96, 18.77.
Example 55:1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 583.1303. 1 H NMR (600 MHz, DMSO-d 6 ) 10.84 (s, 1H), 9.21 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.09 (dd,J= 6.7, 2.5 Hz, 1H), 7.91 (dd,J= 12.8, 2.2 Hz, 1H), 7.82 (ddd,J= 8.8, 4.2, 2.7 Hz, 1H), 7.63 7.57 (m, 2H), 7.48 (d,J= 1.7 Hz, 1H), 7.39 (t,J= 9.0 Hz, 1H), 7.10 (s, 1H), 6.64 (dd,J= 5.6, 2.1 Hz, 1H), 5.62 (d,J= 5.2 Hz, 1H), 4.40 4.35 (m, 1H),4.13 (t,J= 6.7 Hz, 2H), 3.69 (dd,J= 9.0, 4.3 Hz, 2H), 2.42 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.66, 162.19, 158.99, 157.08 (d,J= 248.5 Hz), 156.38, 155.64, 153.86 (d,J= 246.3 Hz), 149.57, 143.69, 141.82, 137.92 (d,J= 3.1 Hz), 137.53 (d,J= 9.9 Hz), 136.46 (d,J= 12.2 Hz), 130.31, 128.44, 127.15 (d,J= 7.7 Hz), 124.54, 119.84 (d,J= 18.6 Hz), 117.40, 117.25, 109.27 (d,J= 23.0 Hz), 106.51, 98.50, 60.13, 59.77(2C), 18.77.
Example 56:1- (3-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 565.1401. 1 H NMR (600 MHz, DMSO-d 6 ) 10.85 (s, 1H), 9.20 (s, 1H), 8.12 (d,J= 5.6 Hz, 1H), 7.95 7.88 (m, 2H),7.75 (d,J= 7.7 Hz, 1H), 7.63 7.52 (m, 3H), 7.49 (s, 1H), 7.39 (t,J= 8.9 Hz, 1H), 7.09 (s, 1H), 6.67 6.60 (m, 1H), 5.63 (d,J= 6.2 Hz, 1H), 4.41 4.35 (m,J= 7.2 Hz, 1H), 4.12 (t,J= 7.2 Hz, 2H), 3.72 3.66 (m, 2H), 2.42 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.62, 162.24, 158.99, 156.40, 155.67, 153.86 (d,J= 246.2 Hz), 149.62, 143.57, 142.23, 141.90, 137.54 (d,J= 9.7 Hz), 136.47 (d,J= 12.3 Hz), 133.30, 130.77, 130.33, 128.73, 126.06, 124.91, 124.52, 117.40,109.27 (d,J= 22.9 Hz), 106.47, 98.53, 60.14, 59.76(2C), 18.75.
Example 57: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 561.1898. 1 H NMR (600 MHz, DMSO-d 6 ) 10.78 (s, 1H), 9.18 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.91 (d,J= 12.8 Hz, 1H), 7.67 7.62 (m, 2H), 7.59 (d,J= 8.8 Hz, 1H), 7.49 (s, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.08 7.07 (m, 1H), 7.07 7.06 (m, 1H), 7.04 (d,J= 1.2 Hz, 1H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 5.63 5.61 (m, 1H), 4.40 4.36 (m, 1H), 4.13 (t,J= 6.7 Hz, 2H), 3.82 (s, 3H), 3.71 3.67 (m, 2H), 2.41 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.62, 162.47, 159.34, 159.18, 156.40, 155.68, 153.87 (d,J= 245.6 Hz), 149.65, 143.10, 141.45, 137.59 (d,J= 9.8 Hz), 136.44 (d,J= 12.0 Hz), 134.19, 130.04, 127.37(2C), 124.48, 117.31, 114.18(2C), 109.20 (d,J= 22.9 Hz), 106.47, 98.56, 60.15, 59.76(2C), 55.94, 18.68.
Example 58: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 549.1696. 1 H NMR (600 MHz, DMSO-d 6 ) 10.83 (s, 1H), 9.20 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.89 (d,J= 12.7 Hz, 1H), 7.70 (t,J= 7.6 Hz, 1H), 7.62 7.57 (m, 2H), 7.49 (s, 1H), 7.45 (t,J= 6.0 Hz, 1H), 7.42 7.34 (m, 2H),7.11 (s, 1H), 6.66 6.60 (m, 1H), 5.63 (d,J= 6.3 Hz, 1H), 4.43 4.34 (m, 1H), 4.12 (t,J= 7.3 Hz, 2H), 3.73 3.66 (m, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.13, 158.58, 156.86 (d,J= 251.4 Hz, 1C), 156.39, 155.67, 153.83 (d,J= 246.1 Hz, 1C), 149.64, 143.99, 142.41, 137.45 (d,J= 9.7 Hz, 1C), 136.47 (d,J= 12.3 Hz, 1C), 131.68 (d,J= 8.0 Hz, 1C), 129.68, 129.63, 128.88 (d,J= 12.5 Hz, 1C), 125.63, 124.48, 117.37, 116.74 (d,J= 19.5 Hz, 1C), 109.27 (d,J= 22.9 Hz, 1C), 106.45, 98.52, 60.13, 59.76, 18.87.
Example 59:1- (3, 5-dichloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 617.0840.
Example 60: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 531.1714. 1H NMR (600 MHz, DMSO-d6) 10.81 (s, 1H), 9.19 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H),7.91 (d, J = 12.9 Hz, 1H), 7.73 (d, J = 9.3 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.517.47 (m, 1H),7.46 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 8.9 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 6.63 (dd, J = 5.6, 2.4 Hz, 1H), 5.62 (d, J = 6.4 Hz, 1H), 4.41 4.35 (m, 1H), 4.12 (t, J = 7.8 Hz, 2H), 3.69 (dd, J =9.3, 4.6 Hz, 2H), 2.42 (s, 3H). 13C NMR (151 MHz, DMSO-d6) 165.61, 162.41, 159.12, 156.40, 155.69, 153.87 (d, J = 245.6 Hz), 149.66, 143.30, 141.75, 141.19, 137.56 (d, J = 9.7 Hz), 136.46 (d, J= 12.4 Hz), 130.23, 129.12(2C), 128.76, 126.13(2C), 124.49, 117.35, 109.23 (d, J = 23.0 Hz), 106.47, 98.55, 60.15, 59.76(2C), 18.70.
Example 61:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 597.1387. 1 H NMR (600 MHz, DMSO-d6) 10.81 (s, 1H), 8.77 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.94 7.87 (m, 2H), 7.70 7.64 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 9.3Hz, 1H), 7.47 (s, 1H), 7.38 (t, J = 9.0 Hz, 1H), 7.11 (s, 1H), 6.63 (dd, J = 5.7, 2.4 Hz, 1H), 4.93 (s, 1H), 4.25 (s, 1H), 3.43 (s, 3H), 3.26 (d, J = 11.1Hz, 1H), 2.44 (d, J = 1.3 Hz, 3H), 1.87 (s, 1H), 1.77 (s, 1H). 13 C NMR (151 MHz, DMSO) 165.59, 161.98,158.41, 155.86, 155.80 (d, J = 251.8 Hz), 153.85 (d, J = 245.4 Hz), 153.74, 149.43, 144.30, 142.46, 137.39 (d, J = 9.7 Hz), 136.59 (d, J = 12.1 Hz), 131.50(d, J = 8.0 Hz), 129.90 (d, J = 14.1 Hz), 129.69, 129.51, 129.01 (d, J = 3.0 Hz), 124.45, 118.53 (d, J = 21.6 Hz), 117.49, 109.39 (d, J = 23.2 Hz), 106.46,98.93, 72.40, 55.38, 54.56, 44.25, 18.95.
Example 62:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-methoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid amide
ESI-MS[M+H] (m/z): 611.1543. 1 H NMR (600 MHz, DMSO-d6) 10.79 (s, 1H), 9.14 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.93 7.84 (m, 2H), 7.70 7.63 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.52 (t, J = 9.3Hz, 1H), 7.41 7.34 (m, 2H), 7.11 (d, J = 1.4 Hz, 1H), 6.60 (dd, J = 5.7, 2.4 Hz, 1H), 4.17 (d, J = 13.5 Hz, 2H), 4.11 (s, 1H), 2.62(t, J = 14.1 Hz, 2H), 2.48 2.40 (m, 3H), 1.66 (d, J = 10.8 Hz, 2H), 1.23 (s, 1H), 1.09 (dd, J = 12.6, 3.8 Hz, 2H), 1.02 (s, 6H). 13 C NMR (151 MHz, DMSO) 165.46, 161.98,158.40, 156.31, 155.81 (d, J = 251.8 Hz), 154.50, 153.85 (d, J = 245.6 Hz), 149.56, 144.30, 142.45, 137.36 (d, J = 9.8 Hz), 136.63 (d, J = 12.2 Hz), 131.51(d, J = 7.8 Hz), 129.90 (d, J = 14.2 Hz), 129.70, 129.51, 129.01 (d, J = 3.0 Hz), 124.46, 118.53 (d, J = 21.6 Hz), 117.48, 109.39 (d, J = 22.8 Hz), 106.34,99.29, 70.58, 47.35, 44.87(2C), 27.36(2C), 27.00(2C), 18.95.
Example 63:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (2-hydroxy-prop-2-yl) piperidin-1-yl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 653.2013. 1 H NMR (600 MHz, DMSO-d 6 ) 10.79 (s, 1H), 9.14 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.93 7.84 (m, 2H),7.70 7.63 (m, 1H), 7.58 (d,J= 8.9 Hz, 1H), 7.52 (t,J= 9.3 Hz, 1H), 7.41 7.34 (m, 2H), 7.11 (d,J= 1.4 Hz, 1H), 6.60 (dd,J= 5.7, 2.4 Hz, 1H), 4.17 (d,J= 13.5 Hz, 2H), 4.11 (s, 1H), 2.62 (t,J= 14.1 Hz, 2H), 2.48 2.40 (m, 3H), 1.66 (d,J= 10.8 Hz, 2H), 1.23 (s, 1H), 1.09 (dd,J= 12.6, 3.8 Hz, 2H), 1.02 (s, 6H). 13 C NMR (151 MHz, DMSO) 165.46, 161.98,158.40, 156.31, 155.81 (d,J= 251.8 Hz), 154.50, 153.85 (d,J= 245.6 Hz), 149.56, 144.30, 142.45, 137.36 (d,J= 9.8 Hz), 136.63 (d,J= 12.2 Hz), 131.51 (d,J= 7.8 Hz), 129.90 (d,J= 14.2 Hz), 129.70, 129.51, 129.01 (d,J= 3.0 Hz), 124.46, 118.53 (d,J= 21.6 Hz), 117.48, 109.39 (d,J= 22.8 Hz), 106.34, 99.29, 70.58, 47.35, 44.87(2C), 27.36(2C), 27.00(2C), 18.95.
Example 64:1- (3, 5-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 567.1629. 11 H NMR (600 MHz, DMSO-d 6 ) 10.82 (s, 1H), 9.20 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.92 (dd,J= 12.8, 2.2 Hz, 1H), 7.66 (dd,J= 8.0, 2.0 Hz, 2H), 7.60 (d,J= 8.8 Hz, 1H), 7.50 (d,J= 2.1 Hz, 1H), 7.45 7.36 (m, 2H), 7.11 (d,J= 1.1 Hz, 1H), 6.63 (dd,J= 5.7, 2.3 Hz, 1H), 5.63 (d,J= 6.4 Hz, 1H), 4.42 4.34 (m, 1H), 4.13 (t,J= 7.8 Hz, 2H), 3.71 3.67 (m, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 163.13 (d,J= 14.3 Hz), 162.04, 161.50 (d,J= 14.3 Hz), 158.81, 156.39, 155.68, 153.86 (d,J= 246.1 Hz), 149.64, 142.95 (t,J= 13.1 Hz), 142.83 (d,J= 270.3 Hz, 2C), 137.44 (d,J= 9.7 Hz), 136.52 (d,J= 12.1 Hz), 130.49, 124.51, 117.47, 109.94 (d,J= 16.8 Hz), 109.92 (d,J= 3.0 Hz, 2C), 109.35 (d,J= 22.8 Hz), 106.45, 104.35 (t,J= 25.9 Hz), 98.52, 60.13, 59.75(2C), 18.78.
Example 65:1- (3-chloro-5-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 583.1304. 1 H NMR (600 MHz, DMSO-d 6 ) 10.86 (s, 1H), 9.20 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.92 (dd,J= 12.8, 2.3 Hz, 1H), 7.84 (s, 1H), 7.78 (dt,J= 9.8, 2.0 Hz, 1H), 7.63 7.57 (m, 2H),7.50 (d,J= 2.2 Hz, 1H), 7.40 (t,J= 9.0 Hz, 1H), 7.11 (d,J= 1.2 Hz, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.63 (d,J= 6.4 Hz, 1H), 4.42 4.35 (m, 1H), 4.12 (t,J= 6.7 Hz, 2H), 3.69 (dd,J= 8.2, 3.8 Hz, 2H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.58, 162.09 (d,J= 247.0 Hz, 1C), 161.28, 158.84, 156.39, 155.68, 153.85 (d,J= 245.7 Hz, 1C), 149.65, 143.77, 142.97 (d,J= 11.9 Hz, 1C), 141.97, 137.46 (d,J= 9.8 Hz, 1C, 136.51 (d,J= 12.2 Hz, 1C), 134.16 (d,J= 12.1 Hz, 1C), 130.44, 124.52, 122.46 (d,J= 3.0 Hz, 1C), 117.45, 116.37 (d,J= 25.1 Hz, 1C), 112.73 (d,J= 25.6 Hz, 1C), 109.33 (d,J= 22.9 Hz, 1C), 106.44, 98.52, 60.13, 59.76, 18.79.
Example 66:1- (5-chloro-2-fluorophenyl) -N- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 567.1281. 1 H NMR (600 MHz, DMSO-d 6 ) 10.79 (s, 1H), 9.00 (s, 1H), 8.07 (d,J= 5.8 Hz, 1H), 7.93 7.86 (m, 2H),7.82 (s, 1H), 7.70 7.64 (m, 1H), 7.59 (d,J= 10.4 Hz, 1H), 7.53 (t,J= 9.3 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 6.59 (dd,J= 5.8, 2.4 Hz, 1H), 2.54 (dq,J= 7.0, 3.5 Hz, 1H), 2.44 (s, 3H), 0.63 (td,J= 7.0, 4.8 Hz, 2H), 0.40 (dt,J= 6.7, 4.5 Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.73, 161.98, 158.40, 155.80 (d,J= 251.8 Hz), 155.76, 155.68, 153.83 (d,J= 246.2 Hz), 149.36, 144.29, 142.45, 137.49 (d,J= 9.3 Hz), 136.45 (d,J= 12.1 Hz), 131.50 (d,J= 8.3 Hz), 129.90 (d,J= 14.2 Hz), 129.70, 129.50, 129.01 (d,J= 2.9 Hz), 124.47, 118.54 (d,J= 21.8 Hz), 117.49, 109.39 (d,J= 22.9 Hz), 106.05, 97.37, 22.62, 18.95, 6.76(2C).
Example 67:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 611.1543. 1 H NMR (600 MHz, DMSO-d 6 ) 10.79 (s, 1H), 8.69 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.95 7.86 (m, 2H),7.67 (ddd,J= 8.9, 4.2, 2.7 Hz, 1H), 7.58 (dd,J= 12.0, 1.2 Hz, 1H), 7.53 (t,J= 9.3 Hz, 1H), 7.47 (d,J= 2.4 Hz, 1H), 7.37 (t,J= 9.0 Hz, 1H), 7.11 (d,J= 1.4 Hz, 1H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 4.77 (s, 1H), 3.46 (s, 2H), 3.31 (s, 1H), 3.26 3.10 (m, 1H), 2.44 (d,J= 1.4 Hz, 3H), 1.76 (d,J= 19.8 Hz, 2H), 1.26 (s, 3H). 13 C NMR (151 MHz, DMSO) 165.53, 161.98, 158.41, 155.90, 155.81 (d,J= 252.5 Hz), 153.85 (d,J= 246.3 Hz), 153.69, 149.55, 144.31, 142.46, 137.37 (d,J= 9.6 Hz), 136.62 (d,J= 12.6 Hz), 131.51 (d,J= 7.7 Hz), 129.90 (d,J= 14.1 Hz), 129.70, 129.51, 129.01 (d,J= 3.0 Hz), 124.46, 118.53 (d,J= 21.6 Hz), 117.48, 109.39 (d,J= 22.9 Hz), 106.41, 98.92, 75.60, 58.99, 55.38, 45.28, 25.78, 18.96.
Example 68:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3- (tetrahydro-2H-pyran-4-yl) urea) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 611.1543. 1 H NMR (600 MHz, DMSO-d 6 ) 10.79 (s, 1H), 9.02 (s, 1H), 8.09 (d,J= 5.8 Hz, 1H), 7.93 7.87 (m, 2H),7.84 (s, 1H), 7.67 (ddd,J= 8.9, 4.2, 2.5 Hz, 1H), 7.62 7.56 (m, 1H), 7.53 (t,J= 9.3 Hz, 1H), 7.38 (t,J= 9.0 Hz, 1H), 7.12 7.09 (m, 1H),7.02 (s, 1H), 6.59 (dd,J= 5.8, 2.3 Hz, 1H), 3.80 (dt,J= 11.7, 3.9 Hz, 2H), 3.73 3.67 (m, 1H),3.38 (td,J= 11.3, 2.4 Hz, 2H), 2.44 (d,J= 1.2 Hz, 3H), 1.79 (dd,J= 12.6, 3.8 Hz, 2H), 1.44 1.34 (m, 2H). 13 C NMR (151 MHz, DMSO) 165.72, 161.99, 158.40, 155.81, 155.80 (d,J= 251.8 Hz), 154.20, 153.83 (d,J= 246.1 Hz), 149.37, 144.27, 142.45, 137.48 (d,J= 9.8 Hz), 136.45 (d,J= 12.1 Hz), 131.51 (d,J= 8.3 Hz), 129.90 (d,J= 14.2 Hz), 129.71, 129.49, 129.01 (d,J= 2.7 Hz), 124.47, 118.54 (d,J= 21.6 Hz), 117.48, 109.38 (d,J= 22.9 Hz), 106.02, 97.37, 66.14(2C), 45.58, 33.46(2C), 18.94.
Example 69:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (4- (4-methylpiperazin-1-yl) piperidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 693.2438. 1 H NMR (600 MHz, DMSO-d 6 ) 11.02 (s, 1H), 9.22 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 8.01 (dd,J= 6.2, 2.7 Hz, 1H), 7.92 (dd,J= 12.9, 2.5 Hz, 1H), 7.73 7.59 (m, 2H),7.52 (t,J= 9.2 Hz, 1H), 7.46 7.33 (m, 2H), 7.11 (d,J= 1.5 Hz, 1H), 6.60 (dd,J= 5.7, 2.4 Hz, 1H), 4.11 (d,J= 13.2 Hz, 2H), 3.50 3.24 (m, 4H), 2.80 2.68 (m, 2H), 2.63 2.52 (m, 4H), 2.43 (s, 4H), 2.24 (s, 3H), 1.81 1.66 (m, 2H), 1.62 1.41(m, 1H), 1.20 0.99 (m, 1H). 13 C NMR (151 MHz, DMSO) 165.48, 162.05, 158.40, 156.26, 155.78(d,J= 251.8 Hz), 154.51, 153.83 (d,J= 246.6 Hz), 149.57, 144.19, 142.57, 137.47 (d,J= 9.0 Hz), 136.58 (d,J= 12.1 Hz), 131.47 (d,J= 8.4 Hz), 129.92 (d,J= 13.5 Hz), 129.63, 129.61, 129.02 (d,J= 3.0 Hz), 124.43, 118.47 (d,J= 21.4 Hz), 117.45, 109.34 (d,J= 23.7 Hz), 106.36, 99.36, 61.20, 54.97(2C), 48.27(2C), 45.41, 43.62(2C), 28.32(2C), 18.87.
Example 70:1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (4-methylpiperidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
ESI-MS[M+H] (m/z): 609.1750. 1 H NMR (600 MHz, DMSO-d 6 ) 10.78 (s, 1H), 9.16 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.93 7.86 (m, 2H),7.67 (ddd,J= 9.0, 4.1, 2.7 Hz, 1H), 7.61 7.56 (m, 1H), 7.53 (t,J= 9.3 Hz, 1H), 7.40 7.34 (m, 2H), 7.11 (d,J= 1.5 Hz, 1H), 6.60 (dd,J= 5.7, 2.4 Hz, 1H), 4.06 (d,J= 13.3 Hz, 2H), 2.71 (td,J= 12.9, 2.5 Hz, 2H), 2.43 (d,J= 1.3 Hz, 3H), 1.59 1.54 (m, 2H), 0.99 (dd,J= 11.4, 3.6 Hz, 2H), 0.95 (d,J= 6.6 Hz, 1H), 0.89 (d,J= 6.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) 165.45, 161.98, 158.40, 156.33, 155.81 (d,J= 251.8 Hz), 154.53, 153.85 (d,J= 246.2 Hz), 149.55, 144.29, 142.45, 137.35 (d,J= 9.7 Hz), 136.64 (d,J= 12.1 Hz), 131.51 (d,J= 8.2 Hz), 129.90 (d,J= 14.2 Hz), 129.70, 129.51, 129.00 (d,J= 3.0 Hz), 124.45, 118.54 (d,J= 21.1 Hz), 117.47 (d,J= 2.8 Hz), 109.38 (d,J= 23.0 Hz), 106.33, 99.31, 44.52(2C), 34.18(2C), 30.81, 22.15, 18.95.
Example 71:1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-trifluoromethyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide
HRMS ESI-MS[M+H] + (m/z): 637.0952.
Example 72:1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-a process for the preparation of imidazole-4-carboxamide comprising the steps of:
step 1: synthesis of ethyl 2-diazonium-3-oxobutyrate
8 g (41 mmol) of p-toluenesulfonyl chloride is taken in a 250 mL round bottom flask, 96 mL acetone is added for dissolution, the flask is placed in an environment of 0 , 96 mL sodium azide 3.27 g (50.3 mmol) water solution is slowly added, after the addition, the temperature is raised to room temperature for reaction 1 h, acetone is dried in a spinning way at room temperature, dichloromethane extraction is carried out, anhydrous sodium sulfate is dried, 8.13 g colorless liquid is obtained, and the yield is 99%.
4.958 g (38.39 mmol) of ethyl acetoacetate was taken in a 100 mL double-necked flask, 50 mL of anhydrous tetrahydrofuran was added, the mixture was left at 0to slowly drop 0.701 g (46.07 mmol) of 1, 8-diazabicyclo undec-7-ene (DBU), 8.13 g (41.22 mmol) of the above-prepared product was dissolved in 15 mL of anhydrous tetrahydrofuran and slowly added to the reaction flask, and the mixture was reacted at room temperature of 2 h, concentrated under reduced pressure, column chromatography V (petroleum ether): v (ethyl acetate) =5: 1, 5.38. 5.38 g yellow liquid was obtained in 89.8% yield.
Step 2:1- (3-chloro-4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1 HSynthesis of ethyl-imidazole-4-carboxylate
1.5 g (7.95 mmol) of 3-chloro-4-fluorobenzourea and 1.86 g (11.925 mmol) of ethyl 2-diazonium-3-oxobutyrate are taken in a 100mL round-bottom flask, 20 mL toluene and 1.2-dichloroethane solution are added to dissolve each, the mixture is refluxed at 80 , then 0.124 g (0.159 mmol) of rhodium octoate dimer toluene solution (8 mL) is added dropwise, the reaction is carried out at 80 for 12 h, the mixture is cooled to room temperature after completion, 7.67 mL (103.35 mmol) of trifluoroacetic acid is added, the reaction is carried out at room temperature for 5 h, 5 mL diethyl ether is added to pulp the oily substance after decompression concentration, light yellow solid is separated out, and the product of 0.98 g is obtained by suction filtration.
Step 3:1- (3-chloro-4-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1HSynthesis of ethyl-imidazole-4-carboxylate
Taking the product of 0.98 g (3.28 mmol) in a 25 mL round bottom flask, adding 3 mL of DMF for dissolution, placing in a 0 environment, adding 0.98 g (3.28 mmol) of potassium carbonate, dropwise adding 0.3 mL (4.92 mmol) of methyl iodide, heating to room temperature after the addition to react with 4 h, pouring the reaction solution into 10 mL ice water after the reaction is finished, precipitating pale yellow solid, filtering and drying to obtain the product of 0.72 g.
Step 4:1- (3-chloro-4-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1HSynthesis of imidazole-4-carboxylic acid
Taking 1- (3-chloro-4-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1 HImidazole-4-carboxylic acid ethyl ester 0.72 g (2.3 mmol) was added to a 25 mL round bottom flask, 3 mL methanol and tetrahydrofuran were added to dissolve, 0.29 g (6.9 mmol) aqueous solution of lithium hydroxide monohydrate 3 mL was added dropwise, 3. 3 h was reacted at room temperature, solvent was dried by spinning, 5 mL was added, pH was adjusted to acidity with 3N hydrochloric acid, pale yellow solid was precipitated, suction filtration was performed, and filter cake was dried by spinning to obtain 0.51 g product.
Step 5:1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1HSynthesis of imidazole-4-carboxamide
0.51 g (1.79 mmol) of 1- (3-chloro-4-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxylic acid was taken in a 25 mL round bottom flask, 4 mL of dry dichloromethane was added to dissolve, 0.65 mL (8.95 mmol) of thionyl chloride was added dropwise, reflux reaction 8H was carried out, and the crude product after spinning was directly put into the next step without purification.
0.51 g (0.92 mmol) of intermediate e was taken in a 25 mL round bottom flask, 2 mL dry dichloromethane was added to dissolve, 0.146 g (1.38 mmol) of sodium carbonate was added, the above crude product was dissolved in 3 mL dry dichloromethane, this was added to the reaction flask, reaction was carried out at room temperature of 5 h, dichloromethane and water were added, extraction was carried out, the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography V (dichloromethane): V (methanol) =50:1, to give 0.5 g product.
The above 0.5. 0.5 g (0.61 mmol) product was placed in a 25 mL round bottom flask, 5 mL tetrahydrofuran was added to dissolve, the reaction flask was placed in a 0 environment, 0.73. 0.73 mL (0.73 mmol) tetrabutylammonium fluoride was added, reaction 1 h was completed at room temperature, 8 mL water was added, solids were precipitated, suction filtration, filter cake was spun-dried, column chromatography V (dichloromethane): v (methanol) =30:1, yielding 0.28 g pure. ESI-MS [ M+H ]](m/z): 585.1461. 1 H NMR (600 MHz, DMSO-d6) 10.50 (s, 1H), 9.18 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 7.87 (dd,J= 12.9, 2.3 Hz, 1H), 7.73 (dd,J= 6.6, 2.5 Hz, 1H), 7.63 (t,J= 8.9 Hz, 2H), 7.55-7.48 (m, 1H), 7.44 (ddd,J= 8.7, 4.1, 2.7 Hz, 1H), 7.38 (t,J= 9.0 Hz,1H), 6.64 (dd,J= 5.7, 2.4 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.43- 4.35 (m, 1H), 4.13 (dt,J= 10.6, 6.5 Hz, 2H), 3.71 (dd,J= 8.7, 4.1 Hz, 2H), 3.36 (s, 3H), 2.15 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.62, 158.82, 158.23156.52, 156.38, 155.66, 153.39, 152.23,149.63, 137.69, 136.40, 131.83, 130.72, 129.33, 124.24 (d,J= 65.1 Hz, 1C), 120.48, 118.03 (d,J= 22.2 Hz, 1C), 116.99, 116.60, 108.99, 106.47, 98.55, 60.14, 59.75, 56.49, 49.38.
Intermediate e of different substituents was reacted with a different substituted carboxylic acid (C) according to the procedure of example 72 1 -C 5 ) The compounds of examples 73-77 were prepared by reaction.
Example 73: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1- (p-tolyl) -2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 547.2109. 1 H NMR (600 MHz, DMSO-d 6 ) 10.45 (s,1H), 9.16 (s, 1H), 8.11 (d,J= 5.7 Hz, 1H), 7.85 (dd,J= 12.9, 2.3 Hz, 1H), 7.50 (dd,J= 12.8, 1.8 Hz, 2H), 7.36 (t,J= 9.0 Hz, 3H), 7.23 (d,J= 8.2 Hz,2H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 5.61 (d,J= 6.4 Hz, 1H), 4.39-4.34 (m, 1H), 4.11 (dt,J= 10.5, 6.6 Hz,2H), 3.69 (dd,J= 8.6, 4.1 Hz, 2H), 3.34 (s, 3H), 2.38 (s, 3H), 2.09 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.64, 159.00, 156.39, 155.66, 154.96,153.27,152.44,149.63,138.40,138.19,136.11,135.94,132.06, 130.31, 128.13, 124.43, 116.93, 116.21, 109.04, 106.45, 98.55, 60.14, 59.90, 56.49, 49.06.
Example 74:1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 567.1554. 1 H NMR (600 MHz, DMSO-d 6 ) 10.53 (s, 1H), 9.18 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 7.87 (dd,J= 12.9, 2.4 Hz, 1H), 7.66-7.61 (m, 2H), 7.55-7.49 (m, 2H), 7.45-7.34 (m,3H), 6.64 (dd,J= 5.7, 2.4 Hz, 1H), 5.64 (d,J= 6.4 Hz,1H), 4.42-4.36 (m, 1H), 4.17 4.10 (m, 2H), 3.70 (dd,J= 8.7, 4.2 Hz, 2H), 3.37 (s, 3H), 2.14 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.63, 158.88, 156.38, 155.66, 153.28, 152.21, 149.63, 138.10, 136.24, 133.54, 133.30, 129.97 (d,J= 29.7 Hz, 1C), 124.44, 123.97, 116.98, 116.62, 109.12, 106.46, 98.55, 60.13, 59.99, 56.49, 49.33.
Example 75: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 551.1861. 1 H NMR (600 MHz, DMSO-d 6 ) 10.51 (s, 1H), 9.18 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 7.86 (dd,J= 12.9, 2.1 Hz, 1H), 7.62 (dd,J= 14.8, 8.0 Hz, 1H), 7.51 (dd,J= 9.5, 6.2 Hz, 2H), 7.36 (ddd,J= 14.7, 14.1, 9.3 Hz, 3H), 7.25 (d,J= 7.9 Hz, 1H), 6.64 (dd,J= 5.7, 2.3 Hz, 1H), 5.62 (d,J= 6.4 Hz, 1H), 4.46-4.36 (m, 1H), 4.22-4.10 (m, 2H), 3.70 (dd,J= 8.4, 4.0 Hz, 2H), 3.36 (s, 3H), 2.16 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.63, 163.35, 161.73, 158.86, 156.39, 155.66, 154.89, 153.07, 152.15, 149.64, 137.93 (d,J= 275 Hz, 1C), 136.11 (d,J= 17.5 Hz, 1C), 131.44 (d,J= 9.5 Hz, 1C), 124.47, 123.91, 115.91, 115.77, 115.62, 108.96, 108.81, 106.47, 98.55,60.14, 59.74, 58.13, 55.41.
Example 76: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1-phenyl-2, 3-dihydro -1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): found 533.1951. 1 H NMR (600 MHz, DMSO-d 6 ) 10.58 (s, 1H), 9.19 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 7.88 (dd,J= 12.9, 2.2 Hz, 1H), 7.63-7.57 (m, 1H), 7.57-7.47 (m, 4H), 7.42 (d,J= 7.7 Hz, 1H), 7.40 (d,J= 3.1 Hz, 1H), 7.37 (d,J= 9.0 Hz, 1H), 6.64 (dd,J= 5.7, 2.3 Hz, 1H), 5.66 (s, 1H), 4.46-4.35 (m, 1H), 4.14 (t,J= 7.3 Hz, 2H), 3.70 (dt,J= 22.5, 11.3 Hz, 2H), 3.38 (s, 3H), 2.09 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.63, 158.81, 157.47, 156.39, 155.66, 151.98, 149.64, 137.99 (d,J= 262 Hz, 1C), 136.25 (d,J= 12.4 Hz, 1C), 131.74, 131.45, 125.80, 124.42, 122.11 (d,J= 12.9 Hz, 1C), 117.22, 117.09, 116.94, 116.72, 108.99, 108.83, 106.46, 98.54,60.12, 59.75.
Example 77: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 551.1857. 1 H NMR (600 MHz, DMSO-d 6 ) 10.57 (s, 1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz,1H), 7.87 (dd,J= 12.9, 2.3 Hz, 1H), 7.59 (ddd,J= 7.2, 5.2, 1.6 Hz,1H), 7.53 (dt,J= 6.7, 3.3 Hz,1H), 7.52-7.46 (m, 3H), 7.42-7.33 (m, 2H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 5.65 (s,1H), 4.38 (s, 1H), 4.19-4.04 (m,2H), 3.69 (dd,J= 8.6, 4.1 Hz, 2H), 3.35 (s, 3H), 2.08 (s,3H). 13 C NMR (151 MHz, DMSO-d6) 165.63, 159.25,158.82,157.66, 156.39, 155.66, 154.78, 153.16, 151.98,149.64,138.04, 136.10, 131.45, 125.81, 124.42, 122.17, 117.21,117.09, 116.95, 116.73, 108.99, 108.89, 106.45, 98.55, 60.13, 59.92, 57.99.
Example 78: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-a process for the preparation of imidazole-4-carboxamide comprising the steps of:
step 1: synthesis of 1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxylic acid
1g (6.48 mmol) of 2-fluorobenzourea and 1.79 (g) (9.72 mmol) of tert-butyl 2-diazo-3-oxobutyrate are taken in a 100 mL round bottom flask, 30 mL toluene and 1.2-dichloroethane solution are added to dissolve each, reflux is carried out at 80 , 0.101 g (0.129 mmol) of rhodium octoate dimer toluene solution (8 mL) is added dropwise, 12 h is reacted at 80 , cooling is carried out to room temperature, 6.25 mL (84.24 mmol) of trifluoroacetic acid is added, 5 h is reacted at room temperature, reduced pressure concentration and dichloromethane dissolution are carried out, 3N hydrochloric acid is used for acidity adjustment, solid precipitation is carried out, suction filtration and filter cake spinning is carried out, 1.19g of white solid product is obtained, yield: 78%.
Step 2: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro -1HSynthesis of imidazole-4-carboxamide
0.4. 0.4g (1.69 mmol) of 1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxylic acid was taken in a 25 mL round bottom flask, 4 mL methylene chloride, 0.61 mL (8.45 mmol) of sulfoxide chloride was added, the reaction was performed under reflux, 8. 8H was performed, and the crude acid chloride product was obtained by spin-drying and was directly put into the next reaction.
0.4g (0.72 mmol) of intermediate e was taken in a 25 mL round bottom flask, 2 mL dry dichloromethane was added to dissolve, 0.15 g (1.44 mmol) of sodium carbonate was added, the above obtained acid chloride was dissolved in 4 mL dry dichloromethane, this was added to the reaction flask, reaction 5 h was carried out at room temperature, dichloromethane and water were added to extract, the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography V (dichloromethane): V (methanol) =50:1 to obtain the product.
0.27 of g (0.35 mmol) of the obtained product is taken in a 25 mL round bottom flask, 4 mL tetrahydrofuran is added for dissolution, the reaction flask is placed in a 0 environment, 0.42 mL (0.42 mmol) of tetrabutylammonium fluoride is added, after the addition, 1h is reacted at room temperature, 10 mL of water is added, solid precipitation is carried out, suction filtration is carried out, a filter cake is dried by spinning, column chromatography V (methylene dichloride) V (methanol) =30:1 is carried out, white solid is obtained, and the yield is 0.33 g: 83.33%. ESI-MS [ M+H ]] + (m/z): 537.1697. 1 H NMR (600 MHz, DMSO-d6) 10.74 (s, 1H), 9.84 (s, 1H), 9.20 (s, 1H), 8.15 (d,J= 5.7 Hz, 1H), 7.90 (dd,J= 12.9, 2.4 Hz, 1H), 7.61 (ddd,J= 7.3, 5.2, 1.6 Hz, 1H), 7.56 (td,J= 7.8, 1.5 Hz, 1H), 7.53 (d,J= 2.3 Hz, 1H), 7.50 (dd,J= 10.0, 1.5 Hz, 2H), 7.44-7.36 (m, 2H), 6.66 (dd,J= 5.7, 2.4 Hz, 1H), 5.64 (d,J= 6.4 Hz, 1H), 4.47-4.38 (m, 1H), 4.20-4.13 (m, 2H), 3.73 (dd,J= 8.7, 4.2 Hz, 2H), 2.21 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.67, 158.41, 157.59, 156.39, 155.68, 153.17, 151.55, 149.63, 138.20, 136.15,131.48, 128.89, 125.79, 124.44, 122.08, 117.13, 117.04, 116.84,112.99, 109.04, 106.44, 98.57, 60.15, 59.98, 56.49.
According to the method of example 78, intermediate e of different substituents is reacted with a different substituted carboxylic acid (D 1 -D 4 ) The compound of examples 79-93 was prepared by reaction.
Example 79: n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-1, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 537.1702. 1 H NMR (600 MHz, DMSO-d6) 10.72 (s, 1H), 9.84 (s, 1H), 9.17 (s, 1H), 8.12 (d,J= 5.7 Hz, 1H), 7.89 (dd,J= 13.0, 2.4 Hz, 1H), 7.49 (d,J= 2.3 Hz, 1H), 7.46 (ddd,J= 7.1, 5.2, 2.7 Hz, 3H), 7.37 (ddd,J= 9.0, 4.9, 2.7 Hz,3H), 6.62 (dd,J= 5.7, 2.4 Hz, 1H), 5.61 (d,J= 5.8 Hz, 1H), 4.38 (d,J= 5.1 Hz, 1H), 4.19-4.07 (m, 2H), 3.69 (dd,J= 8.7, 4.2 Hz, 2H), 2.23 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.67, 161.13, 158.47, 156.39, 155.67, 154.79, 153.04, 151.92, 149.63, 138.02, 136.21, 130.61 (d,J= 216 Hz, 1C), 129.18, 124.41, 116.75, 116.58 (d,J= 22.6 Hz, 1C), 112.28, 108.74 (d,J= 23.3 Hz, 1C), 106.43, 98.57, 60.15, 59.84, 55.63.
Example 80:1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 571.1305. 1 H NMR (600 MHz, DMSO-d6) 10.87 (s, 1H), 9.98 (s, 1H), 9.19 (s, 1H), 8.13 (t,J= 6.2 Hz, 1H), 7.92 (dd,J= 13.0, 2.3 Hz, 1H), 7.78 (dd,J= 6.7, 2.5 Hz, 1H), 7.61 (t,J= 8.9 Hz, 1H), 7.56-7.52 (m, 1H), 7.52-7.46 (m, 2H), 7.37 (t,J= 9.0 Hz, 1H), 6.64 (dd,J= 5.7, 2.4 Hz, 1H), 5.63 (d,J= 6.4 Hz, 1H), 4.44-4.36 (m, 1H), 4.14 (t,J= 7.4 Hz, 2H), 3.71 (dd,J= 8.5, 4.0 Hz, 2H), 2.28 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.67, 158.42, 156.42, 155.67, 154.84, 153.38, 151.72, 149.63, 138.35, 136.20, 131.48, 130.75, 129.41 (d,J= 202 Hz, 1C), 129.11, 124.39, 120.39 (d,J= 18.6 Hz, 1C), 117.84 (d,J= 22.2 Hz, 1C), 116.81, 112.43, 108.77 (d,J= 23.0 Hz,1C), 106.43, 98.58, 60.15, 59.92, 52.57.
Example 81:1- (2, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxylic acid methyl esterAmides and their use
ESI-MS[M+H] (m/z): 555.1608. 1 H NMR (600 MHz, DMSO-d6) 11.03 (s, 1H), 10.15 (s, 1H), 9.19 (s, 1H), 8.13 (d,J= 5.7 Hz, 1H), 7.93 (dd,J= 13.0, 2.4 Hz, 1H), 7.64 (td,J= 8.8, 6.1 Hz, 1H), 7.58 (ddd,J= 13.8, 10.5, 2.0 Hz, 2H), 7.51 (d,J= 2.3 Hz, 1H), 7.36 (t,J= 9.0 Hz, 1H), 7.33-7.28 (m, 1H), 6.63 (dd,J= 5.7, 2.4 Hz, 1H), 5.63 (s, 1H), 4.39 (dd,J= 10.0, 5.4 Hz, 1H), 4.20-4.09 (m, 2H), 3.71 (dd,J= 8.7, 4.2 Hz, 2H), 2.20 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) 165.67, 163.72, 158.44, 157.84, 156.39, 155.67, 154.79, 153.21, 151.55, 149.63, 138.34, 136.14,132.76, 129.07, 124.36, 118.75, 116.86, 113.04, 112.99, 108.80 (d,J= 23.3 Hz, 1C), 106.40, 98.59, 60.15, 59.74, 57.99.
Example 82: n- (4- ((2- (3- (dimethylamino) propyl) urea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 566.2249.
Example 83: n- (4- ((2- (3- ((diethylamino) methyl) -3-methylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 580.2406.
Example 84: n- (3-fluoro-4- ((2- (3-hydroxycyclopentyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 565.1933.
Example 85: n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro) -1H-imidazole-4-carboxamide) phenoxy) pyridin-2-yl) -4-hydroxypiperidine-1-carboxamide
ESI-MS[M+H] (m/z): 565.1933.
Example 86: n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro)-1H-imidazole-4-carboxy) phenoxy) pyridin-2-yl) -4-methylpiperazine-1-carboxamide
ESI-MS[M+H] (m/z): 564.2093.
Example 87: n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro)-1H-imidazole-4-carboxamide) phenoxy) pyridin-2-yl) -4- (2-hydroxyethyl) piperazine-1-carboxamide
ESI-MS[M+H] (m/z): 594.2198.
Example 88: n- (3-fluoro-4- ((2- (3- (2-methoxyethyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 539.1766..
Example 89: n- (4- ((2- (3-ethoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 579.2089.
Example 90: n- (4- ((2- (3- ((dimethylamino) methyl) azetidin-1-yl) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 578.2249.
Example 91: (R) -3-amino-N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro)-1H-imidazole-4-carboxamido) phenoxy) pyridin-2-yl) piperidine-1-carboxamide
ESI-MS[M+H] (m/z): 564.2093.
Example 92:4- (3- (dimethylamino) azetidin-1-yl) -N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro) -1H-imidazole-4-formyl) phenoxy) pyridin-2-yl) piperidine-1-carboxamide
ESI-MS[M+H] (m/z): 647.2828.
Example 93: n- (3-fluoro-4- ((2- (3-fluoropyrrolidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide
ESI-MS[M+H] (m/z): 553.1733.
Test example 1: compound pair constructed BaF for stably expressing FLT3-ITD 3 In vitro antiproliferation of tool cellsActivity(s)
Cell lines: baF (Baf) 3 -FLT3-ITD
The method comprises the following steps: cell proliferation was detected by CellTiter-Glo method, method: taking cells in exponential proliferation phase, counting, and then counting according to 210 3 The wells were seeded in 96-well plates, 95 l per well, and a row of wells plus cell-free medium was left as a blank. Cell plates were placed in a 5% carbon dioxide cell incubator overnight at 37 . The next day, 5 l 20X labeled concentration gradient of compound was added to the cells, with 3 duplicate wells per concentration. DMSO levels are generally below 1% unless otherwise indicated. After placing the cell plates in a cell incubator for incubation 72 h, the supernatant was removed, the formulated CellTiter-Glo substrate was added, mixed and shaken for 5 minutes, and the chemiluminescent value was measured using a multi-labeled microplate detector (EnVision).
Cell Inhibition Rate (Inhibition Rate) was calculated by subtracting the blank control of the wells of the different cells from all well readings:
Inhibition ratio (Inhibition%) =100% (Control Lum-sample Lum)/Control Lum
Sampe Lum: administration group Control Lum: DMSO control group
The resulting data was used as software to map and calculate IC 50 Value of
The compound of the general formula I of the invention corresponds to BaF 3 The results of the in vitro antiproliferative activity of FLT3-ITD cells are shown in Table 1.
TABLE 1 example Compound pair BaF 3 In vitro inhibitory Activity of FLT3-ITD cells
| Examples | IC 50 (M) | Examples | IC 50 (M) | Examples | IC 50 (M) |
| Example 1 | B | Example 32 | B | Example 63 | C |
| Example 2 | D | Example 33 | B | Example 64 | C |
| Example 3 | D | Example 34 | C | Example 65 | D |
| Example 4 | B | Example 35 | C | Example 66 | D |
| Example 5 | B | Example 36 | D | Example 67 | C |
| Example 6 | B | Example 37 | C | Example 68 | D |
| Example 7 | B | Example 38 | D | Example 69 | C |
| Example 8 | B | Example 39 | C | Example 70 | D |
| Example 9 | B | Example 40 | D | Example 71 | C |
| Example 10 | B | Example 41 | C | Example 72 | D |
| Example 11 | B | Example 42 | C | Example 73 | C |
| Example 12 | C | Example 43 | D | Example 74 | C |
| Example 13 | B | Example 44 | D | Example 75 | D |
| Example 14 | D | Example 45 | C | Example 76 | D |
| Example 15 | D | Example 46 | C | Example 77 | A |
| Example 16 | B | Example 47 | D | Example 78 | A |
| Example 17 | D | Example 48 | C | Example 79 | A |
| Example 18 | B | Example 49 | D | Example 80 | A |
| Example 19 | B | Example 50 | C | Example 81 | A |
| Example 20 | B | Example 51 | D | Example 82 | A |
| Example 21 | B | Example 52 | C | Example 83 | B |
| Example 22 | D | Example 53 | C | Example 84 | A |
| Example 23 | B | Example 54 | D | Example 85 | A |
| Example 24 | A | Example 55 | C | Example 86 | A |
| Example 25 | B | Example 56 | C | Example 87 | B |
| Example 26 | B | Example 57 | C | Example 88 | A |
| Example 27 | B | Example 58 | C | Example 89 | A |
| Example 28 | A | Example 59 | C | Example 90 | A |
| Example 29 | D | Example 60 | C | Example 91 | A |
| Example 30 | B | Example 61 | D | Example 92 | A |
| Example 31 | B | Example 62 | D | Example 93 | A |
| Sorafenib | A |
Remarks: a: 0.01-0.1. Mu.M; b is 0.1-0.3 mu M; c: 0.3-1. Mu.M; d: 1 mu M
Analysis of results: the 2, 4-disubstituted pyridine compound of the invention is used for BaF 3 FLT3-ITD cells exhibit moderate to strong inhibitory activity.
Test example 2: inhibitory Activity of Compounds against leukemia cells MOLM-13, MV4-11 and HL60 containing FLT3-ITD mutations and without FLT3-ITD mutations
Cell lines: MOLM-13, MV4-11 and HL60
The method comprises the following steps: cellTiter-Glo method, the concrete operation is the same as the previous one;
as can be seen from the results of Table 2, several compounds tested showed better activity against leukemia cells (MV 4-11 and MOLM-13) containing the FLT3-ITD mutation, comparable to the positive drug Sorafenib, and the compounds of the present invention were more sensitive to MOLM-13 leukemia cells. The inhibition activity on leukemia cells (HL 60) without FLT3-ITD is weak, which shows that the compound has better selectivity instead of cytotoxic drugs.
TABLE 2 inhibitory Activity of partial Compounds against three leukemia cells
| Compounds of formula (I) | MOLM-13 IC 50 (M) | MV4-11 IC 50 (M) | HL60 IC 50 (M) |
| Example 5 | 0.084 | 0.49 | >5 |
| Example 10 | 0.092 | 0.40 | >5 |
| Example 11 | 0.089 | 0.32 | >5 |
| Example 24 | 0.14 | 0.33 | >5 |
| Example 28 | 0.062 | 0.15 | >5 |
| Example 31 | 0.11 | 0.38 | >5 |
| Example 50 | 0.22 | 0.63 | >5 |
| Example 61 | 0.50 | 0.96 | >5 |
| Example 62 | 0.41 | 0.89 | >5 |
| Example 67 | 0.52 | 0.91 | >5 |
| Example 69 | 0.60 | 1.12 | >5 |
| Example 77 | 0.019 | 0.037 | >5 |
| Example 78 | 0.011 | 0.020 | >5 |
| Example 81 | 0.032 | 0.065 | >5 |
| Example 82 | 0.015 | 0.033 | >5 |
| Example 83 | 0.039 | 0.070 | >5 |
| Example 84 | 0.028 | 0.052 | >5 |
| Example 85 | 0.017 | 0.031 | >5 |
| Example 86 | 0.025 | 0.049 | >5 |
| Example 87 | 0.043 | 0.097 | >5 |
| Example 88 | 0.022 | 0.041 | >5 |
| Example 90 | 0.027 | 0.055 | >5 |
| Example 92 | 0.013 | 0.022 | >5 |
| Example 93 | 0.030 | 0.073 | >5 |
| Sorafenib | 0.014 | 0.011 | - |
Test example 3: inhibitory Activity of partial Compounds on c-KIT and FLT3 kinase
The method comprises the following steps: the inhibitory activity of the compounds against c-KIT, FLT3 kinase was evaluated using mobility detection assay (Mobility shift assay). Kinase was added to a 96-well plate at 50 l per well. Compounds were formulated with 100% DMSO at 500. Mu. Mol.L 1 In addition, a 96-well plate was used, and 10. Mu.L of the above solution and 90. Mu.L of kinase buffer (50 mmol.L) were added to each well 1 HEPES10 mmolL 1 MgCl 2 0.0015% Brij-35 and 2 mmol.L 1 DTT). mu.L of each well is added into 384-well plates, and FAM-labeled peptide, ATP, kinase solution and the like are addedCulturing at room temperature for 10 min, adding 10 l of the above peptide solution into each well, culturing at 28deg.C for a period of time, adding 25 l of stop buffer (100 mmol.L) 1 HEPES, 0.015% Brij-35 and 50 mmol.L 1 EDTA) to terminate the reaction. Measuring the conversion value, converting the conversion value into inhibition rate, fitting an inhibition rate curve to obtain the IC 50 Values.
As shown in the results of Table 3, the compounds have weaker activities on c-KIT and FLT3 kinase, and compared with sorafenib, the compounds have better selectivity on both kinases, and have lower possibility of causing side effects related to targets, thus having better safety.
TABLE 3 inhibitory Activity of partial Compounds on c-KIT and FLT3 kinase
| Compounds of formula (I) | c-KIT IC 50 (nM) | FLT3 IC 50 (nM) |
| Example 11 | >10,000 | >10,000 |
| Example 28 | >10,000 | 9,357 |
| Example 31 | >10,000 | >10,000 |
| Example 50 | >10,000 | >10,000 |
| Example 67 | >10,000 | >10,000 |
| Example 77 | 7,086 | 8,035 |
| Example 78 | 8,125 | 7,550 |
| Example 81 | >10,000 | >10,000 |
| Example 83 | >10,000 | >10,000 |
| Example 88 | 9,201 | 9,133 |
| Example 92 | 6,966 | 7,563 |
| Sorafenib | 28 | 35 |
Claims (6)
1. A 2, 4-bipyridine compound having a structure of the general formula I:
wherein:
R 1 is a six-membered aryl or heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, and R 1 Optionally 1-3R 4 Substitution;
R 2 is hydrogen or methyl;
R 3 is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-7 membered saturated heterocycle containing 1-3 members selected from N, O or S, - (CH) 2 )nNR 5 R 6 N is an integer of 1 to 4; the substitution means substitution with one or more substituents selected from the following:
hydroxy, C 1 -C 4 Straight-chain or branched alkyl, C 1 -C 4 Linear or branched alkoxy groups;
Or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally being substituted with one or more R 7 Substitution;
R 4 is halogen, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, - (CH) 2 ) m is an integer of 1 to 4, and is a substituted or unsubstituted 5-7 membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, said substitution being (C 1 -C 6 ) Alkyl or alkoxy;
R 5 and R is 6 Independently selected from C 1 -C 6 An alkyl group;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally further being substituted with one or more (C 1 -C 6 ) Alkyl substituted;
R 7 selected from hydroxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino, C 1 -C 6 Straight-chain or branched alkyl, C 1 -C 6 Linear or branched alkoxy groups, 0 to 3 4-8 membered saturated heterocyclic rings selected from N, O, S, said heterocyclic rings being substituted with 1 to 3 groups selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino;
a is selected from:
R 8 selected from hydrogen, methyl, trifluoromethyl.
2. A 2, 4-bipyridine compound according to claim 1 wherein: r is R 1 Is phenyl or pyridyl, and R 1 Optionally 1-3R 4 Substitution;
R 2 is hydrogen or methyl;
R 3 is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-7 membered saturated heterocycle containing 1-3 members selected from N, O or S, - (CH) 2 )nNR 5 R 6 The substitution means substitution by one or more substituents selected from the following: hydroxy, C 1 -C 4 An alkyl group;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring containing 1-3N and 0-3 members selected from O, S, said heterocyclic ring optionally being substituted with one or more R 7 Substitution;
R 4 is halogen;
R 7 selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino, 0-3 4-8 membered saturated heterocycles selected from N, O, S, said heterocycles being substituted with 1-3 groups selected from hydroxy, methyl, methoxy, mono-or di (C) 1 -C 6 Alkyl) substituted amino.
3. A 2, 4-bipyridine compound according to claim 2 wherein: r is R 2 And R is 3 And the nitrogen atom to which they are attached are selected from the following structures:
R 4 f or Cl.
4. A 2, 4-bipyridine compound according to claim 1, wherein the specific compound is as follows:
1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-chloro-3-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1-phenyl-1H-1, 2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (p-tolyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-fluoro-3-methylphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1, 2-3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (3, 4-dimethoxyphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4 ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-hydroxyphenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-ethynylphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (2, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-cyanophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -1H-1,2, 3-triazole-4-carboxamide;
N- (4- (4- (1- (3-chloro-4-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide) -2-fluorophenoxy) pyridin-2-yl) morpholine-4-carboxamide;
n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide;
n- (4- (2-fluoro-4- (1- (3-fluorophenyl) -1H-1,2, 3-triazole-4-carboxamide) phenoxy) pyridin-2-yl) morpholine-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-morpholinophenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-iodophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (4-bromophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4- (morpholinomethyl) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
1- (2, 3-dichloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidin-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-2-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (6-fluoropyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3- (tetrahydro-2H-pyran-4-yl) urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (4- ((2- (3- (dimethylamino) azetidin-1-amide) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (4- (2-fluoro-4- (1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxylic) phenoxy) pyridin-2-yl) -4-methoxypiperidine-1-carboxamide;
n- (3-fluoro-4- ((2- (3- (1-methylpiperidin-4-yl) urea) pyridin-4-yl) oxy) phenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
n- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (pyridin-3-yl) -1H-1,2, 3-triazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4-trifluoromethylphenyl) -1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 6-dihydropyridazine-3-carboxamide;
1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-3-methylphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-cyanophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-2-methoxyphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-fluoro-2-methylphenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxypyridine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-iodophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (2-chloro-5-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-bromophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (4-chloro-3-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-1- (4- (methylsulfonyl) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 5-dichloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-methoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (2-hydroxypropan-2-yl) piperidine-1-carbonyl) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3, 5-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-5-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (4- ((2- (3-cyclopropylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxy-3-methylpyrrolidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (3- (tetrahydro-2H-pyran-4-yl) urea) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (4- (4-methylpiperazin-1-yl) piperidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (5-chloro-2-fluorophenyl) -N- (3-fluoro-4- ((2- (4-methylpiperidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -4-trifluoromethyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1- (p-tolyl) -2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (4-chlorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (3-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -3, 5-dimethyl-2-oxo-1-phenyl-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -3, 5-dimethyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (2-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
1- (2, 4-difluorophenyl) -N- (3-fluoro-4- ((2- (3-hydroxyazetidine-1-carboxamido) pyridin-4-yl) oxy) phenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (4- ((2- (3- (dimethylamino) propyl) urea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (4- ((2- (3- ((diethylamino) methyl) -3-methylurea) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (3-fluoro-4- ((2- (3-hydroxycyclopentyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide) phenoxy) pyridin-2-yl) -4-hydroxypiperidine-1-carboxamide;
N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxylic) phenoxy) pyridin-2-yl) -4-methylpiperazine-1-carboxamide;
n- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide) phenoxy) pyridin-2-yl) -4- (2-hydroxyethyl) piperazine-1-carboxamide;
n- (3-fluoro-4- ((2- (3- (2-methoxyethyl) urea) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (4- ((2- (3-ethoxypyrrolidine-1-carboxamido) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
n- (4- ((2- (3- ((dimethylamino) methyl) azetidin-1-carboxylic) pyridin-4-yl) oxy) -3-fluorophenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide;
(R) -3-amino-N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamido) phenoxy) pyridin-2-yl) piperidine-1-carboxamide;
4- (3- (dimethylamino) azetidin-1-yl) -N- (4- (2-fluoro-4- (1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-formyl) phenoxy) pyridin-2-yl) piperidine-1-carboxamide;
N- (3-fluoro-4- ((2- (3-fluoropyrrolidine-1-carboxamide) pyridin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -5-methyl-2-oxo-2, 3-dihydro-1H-imidazole-4-carboxamide.
5. The use of a 2, 4-bipyridine compound according to claim 4 and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof in the preparation of FLT3-ITD kinase inhibitors.
6. The use of a 2, 4-bipyridine compound according to claim 4 and pharmaceutically acceptable salts, stereoisomers or prodrug molecules thereof for the preparation of a medicament for the treatment and/or prophylaxis of leukemia.
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| WO2014022116A2 (en) * | 2012-07-28 | 2014-02-06 | Calitor Sciences, Llc | Substituted pyrazolone compounds and methods of use |
| WO2019101178A1 (en) * | 2017-11-24 | 2019-05-31 | 南京明德新药研发股份有限公司 | Uracil compound as c-met/axl inhibitor |
| CN111372925A (en) * | 2017-11-24 | 2020-07-03 | 南京明德新药研发有限公司 | Uracil compounds as c-MET/AXL inhibitors |
| CN111886228A (en) * | 2019-05-24 | 2020-11-03 | 南京明德新药研发有限公司 | Crystal form of c-MET/AXL inhibitor |
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