WO2024051667A1 - Composé triazole substitué inhibiteur d'axl - Google Patents
Composé triazole substitué inhibiteur d'axl Download PDFInfo
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- WO2024051667A1 WO2024051667A1 PCT/CN2023/116897 CN2023116897W WO2024051667A1 WO 2024051667 A1 WO2024051667 A1 WO 2024051667A1 CN 2023116897 W CN2023116897 W CN 2023116897W WO 2024051667 A1 WO2024051667 A1 WO 2024051667A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- membered heterocyclyl
- alkoxy
- membered
- Prior art date
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- -1 triazole compound Chemical class 0.000 title claims abstract description 46
- 230000002401 inhibitory effect Effects 0.000 title abstract description 12
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 claims abstract description 34
- 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 claims abstract description 23
- 108010023337 axl receptor tyrosine kinase Proteins 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 310
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 150
- 125000000623 heterocyclic group Chemical group 0.000 claims description 102
- 229910052757 nitrogen Inorganic materials 0.000 claims description 91
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 69
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical group 0.000 claims description 54
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 51
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 41
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 33
- 125000003368 amide group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 229910052731 fluorine Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 201000005787 hematologic cancer Diseases 0.000 claims 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 357
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 356
- 238000006243 chemical reaction Methods 0.000 description 350
- 238000002360 preparation method Methods 0.000 description 323
- 239000000243 solution Substances 0.000 description 231
- 239000000047 product Substances 0.000 description 224
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000004440 column chromatography Methods 0.000 description 108
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 80
- 239000012043 crude product Substances 0.000 description 80
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 73
- 239000012071 phase Substances 0.000 description 52
- 239000002994 raw material Substances 0.000 description 50
- 239000012074 organic phase Substances 0.000 description 44
- 238000003756 stirring Methods 0.000 description 41
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- 238000001514 detection method Methods 0.000 description 28
- 230000014759 maintenance of location Effects 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000002245 particle Substances 0.000 description 23
- 238000004007 reversed phase HPLC Methods 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 19
- 238000012856 packing Methods 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000004576 sand Substances 0.000 description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 6
- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 6
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- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
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- 101150098329 Tyro3 gene Proteins 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 5
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- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 4
- GZWVZXOFWQGSRB-UHFFFAOYSA-N 2-cyano-n-(4-fluorophenyl)acetamide Chemical compound FC1=CC=C(NC(=O)CC#N)C=C1 GZWVZXOFWQGSRB-UHFFFAOYSA-N 0.000 description 4
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- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 3
- PFMAFXYUHZDKPY-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(F)C=CC=1NC(=O)C1(C(=O)O)CC1 PFMAFXYUHZDKPY-UHFFFAOYSA-N 0.000 description 3
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- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
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- 239000007983 Tris buffer Substances 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
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- 238000004587 chromatography analysis Methods 0.000 description 3
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- LGMMJMDBRQXPIQ-UHFFFAOYSA-N (4-bromo-2-fluorophenyl)hydrazine;hydrochloride Chemical compound [Cl-].[NH3+]NC1=CC=C(Br)C=C1F LGMMJMDBRQXPIQ-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- BTPCWSQBSXUYHV-UHFFFAOYSA-N 1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 BTPCWSQBSXUYHV-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- AOYSLJHKVBSXRU-UHFFFAOYSA-N 1-(oxetan-3-yl)piperazine Chemical compound C1OCC1N1CCNCC1 AOYSLJHKVBSXRU-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
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- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- FEHLGOYZDFFMND-UHFFFAOYSA-N cyclopropane-1,1-dicarboxamide Chemical compound NC(=O)C1(C(N)=O)CC1 FEHLGOYZDFFMND-UHFFFAOYSA-N 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- SXLDHZFJMXLFJU-RNFRBKRXSA-N diethyl (1r,2r)-cyclopropane-1,2-dicarboxylate Chemical compound CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC SXLDHZFJMXLFJU-RNFRBKRXSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- LKMBJOCCSUMPJY-UHFFFAOYSA-N difluoromethylperoxy(trifluoro)methane Chemical compound FC(F)OOC(F)(F)F LKMBJOCCSUMPJY-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- RCRYEYMHBHPZQD-UHFFFAOYSA-N ditert-butyl-[2,3,4,5-tetramethyl-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=C(C)C(C)=C(C)C(C)=C1P(C(C)(C)C)C(C)(C)C RCRYEYMHBHPZQD-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- AZJAMMCCAZZXIK-UHFFFAOYSA-N ethyl 4-chloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=CN=C1Cl AZJAMMCCAZZXIK-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- JHMNJUQVLPODJN-UHFFFAOYSA-M magnesium;1-fluoro-4-methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=C(F)C=C1 JHMNJUQVLPODJN-UHFFFAOYSA-M 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000005673 monoalkenes Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- CHMBIJAOCISYEW-UHFFFAOYSA-N n-(4-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C=C1 CHMBIJAOCISYEW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- NPCBDQZLUSJKOW-UHFFFAOYSA-M sodium;4-[5-(4-chlorophenyl)-3,4-dihydropyrazol-2-yl]benzenesulfonate Chemical compound [Na+].C1=CC(S(=O)(=O)[O-])=CC=C1N1N=C(C=2C=CC(Cl)=CC=2)CC1 NPCBDQZLUSJKOW-UHFFFAOYSA-M 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
Definitions
- the present invention belongs to the field of medicine, and specifically relates to a substituted triazole compound with AXL inhibitory activity and a pharmaceutical composition thereof.
- the present invention also relates to the use of such compounds and compositions to treat diseases and disease states associated with AXL activity.
- AXL (also known as UFO, ARK and Tyro7 or JTK11) is a member of the TAM family of receptor tyrosine kinases (RTKs).
- RTKs receptor tyrosine kinases
- AXL was originally identified as a transforming gene expressed in cells from patients with chronic myelogenous leukemia or chronic myeloproliferative disorders.
- AXL overexpression has been reported to be associated with a variety of cancers, including non-small cell lung cancer (NSCLC), breast cancer, prostate cancer, gastric cancer, renal cell carcinoma, and glioblastoma.
- NSCLC non-small cell lung cancer
- AXL has increasingly been recognized as a key mediator of resistance to many approved tyrosine kinase inhibitor therapies. Therefore, AXL can serve as a potential target for cancer treatment.
- Patent documents WO2008083357A1, WO2008083353A1, WO2008083354A1, WO2010005879A1, CN101622252A, CN104860930A, CN101622246A and WO2015082887A2 all disclose compounds used as AXL inhibitors.
- the invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
- Y is selected from NR 3 or O;
- R 2 is selected from -C(O)NH-R 2a , 6-15 membered aryl group, 3-18 membered heterocyclyl group or benzo(C3-C8) cycloalkyl group, wherein the 6-15 membered aryl group , 3-18 membered heterocyclyl or benzo (C3-C8) cycloalkyl optionally substituted by amide group, cyano group, nitro, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1- C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, 3-10 membered heterocyclyl or 6-10 membered aryl group, the amide group is optionally substituted by C1-C3 Alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl substituted, wherein the 3-10 membered heterocyclyl is optionally substituted by C1-
- R 2a is selected from 6-15-membered aryl, 3-18-membered heterocyclyl or benzo(C3-C8) cycloalkyl, wherein the 6-15-membered aryl, 3-18-membered heterocyclyl or benzene And (C3-C8) cycloalkyl is optionally substituted by cyano, nitro, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy , 3-10 membered heterocyclyl or 6-10 membered aryl substituted, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 3-8 membered heterocyclyl or C1-C3 alkoxy Substituted with a base, the 3-10 membered heterocyclic group is optionally substituted by a C1-C3 alkyl group or halogen;
- R 3 is selected from hydrogen, C1-C6 alkyl or 3-10 membered heterocyclyl
- R 4 is selected from -C(O)-R 10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by amide group, C1-C6 alkyl, halogenated C1-C6 alkyl base, halogen, nitro, cyano, amino, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, 6-10 membered aryl, 5-7 membered heterocyclyl or C3-C6 cycloalkyl substituted, the 6-10-membered aryl group or 5-7-membered heterocyclyl group is optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy group, the C1-C6 alkyl group is optionally substituted by Phenyl, C3-C6 cycloalkyl or 3-10 membered heterocyclyl substituted, the amide group is optionally substituted by C1-C3 al
- R 10 is selected from a 6-10-membered aryl group, a 3-10-membered heterocyclyl group or a C3-C8 cycloalkyl group, wherein the 6-10-membered aryl group, a 3-10-membered heterocyclyl group or a C3-C8 cycloalkyl group
- the base is optionally substituted by a 6-8-membered aryl group, a 5-7-membered heterocyclyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, an amide group, a halogen, a nitro group or a cyano group, wherein the C1 -C6 alkyl is optionally substituted by halogen or 3-8-membered heterocyclyl, and the 6-8-membered aryl or 5-7-membered heterocyclyl is optionally substituted by halogen, C1-C3 alkyl, C1- C3 al
- R 7 and R 8 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, halo Generation (C2-C6) alkynyl, hydroxy (C1-C6) alkyl, 6-10-membered aryl, 6-10-membered aryl (C1-C6) alkyl, 6-10-membered aryl (C2-C6) alkenyl , 6-10 yuan aryl (C2-C6) alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C3-C8 cycloalkyl (C2-C6) alkenyl, C3 -C8 cycloalkyl (C2-C6) alkynyl, 3-10 membered heterocyclyl, 3-10 membered hetero
- R 9 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, halo(C2-C6) )alkynyl, hydroxy (C1-C6) alkyl, 6-10-membered aryl, 6-10-membered aryl (C1-C6) alkyl, 6-10-membered aryl (C2-C6) alkenyl, 6-10-membered Aryl (C2-C6) alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C3-C8 cycloalkyl (C2-C6) alkenyl, C3-C8 cycloalkyl (C2-C6)alkynyl, 3-10-membered heterocyclyl, 3-10-membered heterocyclyl (
- Y is NR 3 and R 3 is as defined above.
- R3 is hydrogen or C1-C6 alkyl; in some typical embodiments, R3 is hydrogen.
- Y is NH
- X is selected from hydrogen or halogen.
- X is selected from hydrogen or fluorine.
- R 1 , R 5 and R 6 are each hydrogen.
- R 2 is selected from -C(O)NH-R 2a , 6-15 membered aryl, 3-18 membered heterocyclyl, or benzo(C3-C8)cycloalkyl, wherein 6-15-membered aryl, 3-18-membered heterocyclyl or benzo (C3-C8) cycloalkyl is optionally substituted by amide group, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1 -C6 alkoxy or 3-10 membered heterocyclyl substituted, wherein the amide group is optionally substituted by C1-C3 alkyl, wherein the 3-10 membered heterocyclyl is optionally substituted by C1-C3 Alkyl or 3-8 membered heterocyclyl substituted, wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclyl or C1-C3 al
- R 2a is a 6-10 membered aryl group, the 6-10 membered aryl group is optionally substituted by a 3-10 membered heterocyclyl group, wherein the 3-10 membered heterocyclyl group is optionally substituted by a C1-C3 alkyl group replace.
- R is selected from And R 2 is optionally substituted by amide group, halogen, C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-10 membered heterocyclyl Substituted, wherein the 3-10 membered heterocyclyl group is optionally substituted by a C1-C3 alkyl group or a 3-8 membered heterocyclyl group, wherein the amide group is optionally substituted by a C1-C3 alkyl group, wherein the The above-mentioned C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclic groups or C1-C3 alkoxy groups.
- R is selected from and R 2 is optionally -F, -Cl, methyl, methoxy, replace.
- R is selected from
- R is selected from
- R is selected from
- R 4 is selected from -C(O)-R 10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by amide, C1-C6 alkyl , C1-C6 alkoxy, halogen, 6-10 membered aryl, 5-7 membered heterocyclyl or C3-C6 cycloalkyl substitution, the 6-10 membered aryl or 5-7 membered heterocyclyl is optional optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy, the C1-C6 alkyl is optionally substituted by phenyl, C3-C6 cycloalkyl or 3-8 membered heterocyclyl, so
- the amide group is optionally substituted by C1-C3 alkyl, phenyl or halogen-substituted phenyl;
- R 10 is selected from 3-10 membered heterocyclyl or C3-C8 cycloalkyl, wherein the 3-10 membered heterocyclyl or C3-C8 cycloalkyl is optionally replaced by 6-8 membered aryl, 5-7 6-membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy or amide substituted, wherein the 6-8-membered aryl or 5-7-membered heterocyclyl is optionally substituted by halogen or C1-C3 alkyl
- the C1-C6 alkyl group is optionally substituted by a 3-8 membered heterocyclyl group
- the amide group is optionally substituted by a phenyl group or a halogen-substituted phenyl group.
- R4 is selected from -C(O) -R10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by Ethoxy, methyl, isopropyl, Br, F, Cl, phenyl, pyridyl, cyclopropyl or cyclopentyl, the methyl optionally being substituted by phenyl, cyclopropyl or Substituted, the phenyl or pyridyl is optionally substituted by F, methyl or methoxy;
- R 10 is selected from 3-10 membered heterocyclyl or C3-C8 cycloalkyl, wherein the 3-10 membered heterocyclyl or C3-C8 cycloalkyl is optionally replaced by phenyl, pyridyl, methyl, isopropyl, ethoxy or substituted, wherein said methyl group is optionally replaced by Substituted, the phenyl or pyridyl group is optionally substituted by halogen or methyl.
- R 4 is selected from stated therein optionally F, Cl, Br, methyl, 4-fluorophenyl, 4-methoxyphenyl, replace;
- R4 is selected from Preferably, R 4 is selected from More preferably, R 4 is selected from
- the aforementioned compound of Formula I has a structure shown in Formula II,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
- the aforementioned compound of Formula I has a structure shown in Formula III,
- R 3 , R 4 , R 5 and R 6 are each defined as described in Formula I; W is selected from CH or N;
- R Y1 is selected from amide group, 3-10 membered heterocyclyl group, 3-10 membered heterocyclyl (C1-C6) alkyl group or C1-C6 alkoxy group, wherein the amide group is optionally replaced by C1-C3 Alkyl substitution, wherein the 3-10 membered heterocyclyl or 3-10 membered heterocyclyl (C1-C6) alkyl is optionally substituted by a C1-C6 alkyl or 3-8 membered heterocyclyl, the The C1-C6 alkoxy group is optionally substituted by a 3-8 membered heterocyclyl group;
- R Y2 is selected from hydrogen, halogen, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl (C1-C6) alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy or halogenated C1 -C6 alkoxy, wherein the 3-10 membered heterocyclyl or 3-10 membered heterocyclyl (C1-C6)alkyl is optionally substituted by C1-C6 alkyl or 3-8 membered heterocyclyl, The C1-C6 alkoxy group is optionally substituted by a 3-8 membered heterocyclyl group;
- R Y3 are selected from hydrogen, halogen, C1-C6 alkoxy or halogenated C1-C6 alkoxy; R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
- W is CH.
- R Y1 is selected from amide, 3-10 membered heterocyclyl, 3-10 membered heterocyclylmethylene, or C1-C6 alkoxy, wherein the amide group is optionally replaced by C1 -C3 alkyl substituted, wherein the 3-10 membered heterocyclyl is optionally substituted by methyl or Substituted, the C1-C6 alkoxy group is optionally replaced by replace.
- R Y1 is methoxy
- R Y1 is methoxy
- R Y1 is methoxy
- R Y2 is selected from hydrogen, halogen, 3-10 membered heterocyclyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, or halogenated C1-C6 alkoxy.
- R Y2 is selected from hydrogen, F, Cl, methoxy
- R Y2 is selected from hydrogen or methoxy.
- R Y3 is selected from hydrogen, halogen, or C1-C6 alkoxy.
- R Y3 is selected from hydrogen, F, Cl, or methoxy.
- the compound represented by the aforementioned formula I has a structure represented by formula IV,
- R 3 , R 4 , R 5 and R 6 are each defined as described in Formula I;
- R q is selected from C1-C6 alkyl or 3-6 membered heterocyclyl;
- Rm is selected from hydrogen, halogen or C1-C6 alkoxy
- R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
- R q is selected from methyl or
- Rm is selected from hydrogen, F, Cl, or methoxy.
- the compound represented by the aforementioned formula I has a structure represented by formula V,
- R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
- the compound represented by the aforementioned formula I has a structure represented by formula VI,
- -C6 alkoxy group, R v3 is selected from hydrogen, C1-C6 alkyl group, 6-10-membered aryl group or 5-7-membered heterocyclyl group, the 6-10-membered aryl group or 5-7-membered heterocyclyl group can be any Optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy.
- R v1 is selected from hydrogen or halogen.
- R v1 is selected from hydrogen, -Cl or -Br.
- R v2 is selected from hydrogen or C1-C6 alkyl.
- R v2 is selected from hydrogen or methyl.
- R v3 is selected from 6-10 membered aryl or 5-7 membered heterocyclyl optionally substituted by halogen or C1-C3 Alkoxy substitution.
- R v3 is selected from phenyl or pyridyl, which is optionally substituted by halogen or C1-C3 alkoxy.
- R v3 is selected from
- R v3 is
- the present invention provides the following compounds or pharmaceutically acceptable salts thereof:
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or Formula VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the invention provides compounds of Formula I, II, III, IV, V or Formula VI, or pharmaceutically acceptable salts thereof, for use in the treatment and/or prevention of AXL receptor tyrosine kinase.
- Use of drugs to induce disease are known in the art.
- the present invention provides a method for treating AXL receptor tyrosine kinase-induced disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, II, III, IV, V or Formula VI or a pharmaceutical agent thereof. Acceptable salts or steps of the pharmaceutical compositions described above.
- the AXL receptor tyrosine kinase-induced disorder is a disorder caused by, associated with, and/or accompanied by hyperfunction of AXL kinase.
- the condition induced by the AXL receptor tyrosine kinase is cancer, and the cancer is a solid tumor or a hematological cancer.
- the AXL receptor tyrosine kinase induced disorder is a solid tumor cancer.
- C1-C3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms
- C1-C6 means that the group can have 1 carbon atom, 2 carbon atoms , 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
- substituted by means that any one or more hydrogen atoms on a specific group are replaced by a substituent, as long as the valence state of the specific group is normal and the substituted compound is stable.
- substituted by halogen means that any one or more hydrogen atoms on a specific group are replaced by halogen, as long as the specific group The valence state of the group is normal and the substituted compound is stable.
- middle It refers to the connection point of chemical bond.
- cyano refers to the -CN group; the term “nitro” refers to the -NO group; the term “amino” refers to the -NH group; the term “ hydroxy " refers to the -OH group; the term “halogen” ” refers to fluorine, chlorine, bromine and iodine, and the term “halo” refers to fluoro, chlorine, bromo and iodine.
- alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the number of carbon atoms shown.
- C1-C3 alkyl includes C1 alkyl, C2 alkyl, C3 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl; such as the term “C1-C6 alkyl” "Basic” includes C1-C3 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-he
- alkoxy refers to a group having the structure alkyl-O-, alkyl being an alkyl group as defined above.
- C1-C3 alkoxy includes C1 alkoxy, C2 alkoxy, C3 alkoxy, examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyl Oxygen;
- C1-C6 alkoxy includes C1-C3 alkoxy, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy , examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy base, 2-pentyloxy, 3-pentyloxy, n-hexyloxy
- R is a saturated aliphatic hydrocarbon group, including linear or branched saturated hydrocarbon groups, for example, examples of the term “C1-C3 alkanoyl” include However, it is not limited to, for example, formyl, acetyl, 2-methylacetyl, propionyl, etc.
- C2-C6 alkenyl refers to a group formed by losing one or two hydrogen atoms from an alkene having 2 to 6 carbon atoms.
- C2-C6 alkynyl refers to a straight or branched hydrocarbon chain group consisting only of 2 to 6 carbon atoms and hydrogen atoms, which contains at least one triple bond, optionally at least one double bond, and which Attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.
- alkylene refers to a saturated linear or branched divalent hydrocarbon group, such as methylene, ethylene, propylene, n-butylene, and the like.
- alkenylene refers to a linear or branched divalent hydrocarbon group containing at least one double bond, such as vinylene, propenylene, n-butenylene, and the like.
- alkynylene refers to a linear or branched divalent hydrocarbon group containing at least one triple bond, such as propynylene, n-butynylene, and the like.
- haloalkyl refers to an alkyl group as defined above substituted by one or more halogen atoms.
- halo C1-C3 alkyl includes trifluoromethyl, difluoromethyl, trichloro Methyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc.
- haloalkoxy refers to an alkoxy group as defined above substituted by one or more halogen atoms.
- halo C1-C6 alkoxy includes trifluoromethoxy, difluoromethyl Oxygen, trichloromethoxy, 2,2,2-trifluoroethoxy, etc.
- halo(C2-C6)alkenyl refers to a C2-C6 alkenyl group as defined above substituted by one or more halogen atoms.
- halogenated (C2-C6)alkynyl refers to a C2-C6 alkynyl group as defined above substituted by one or more halogen atoms.
- hydroxyalkyl refers to an alkyl group as defined above substituted by one or more hydroxyl groups (-OH).
- hydroxy(C1-C3)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
- aryl refers to an all-carbon monocyclic group with a conjugated ⁇ electron system or a bicyclic group in which an all-carbon monocyclic ring with a conjugated ⁇ electron system is fused with an aromatic carbocyclic ring, which is obtained by converting the parent aromatic It is obtained by removing one hydrogen atom from a single carbon atom of the ring system.
- the "6-10-membered aryl group” defined in the present invention refers to a group formed by losing one hydrogen atom from a 6-10-membered aryl group. Examples include, but are not limited to, phenyl, naphthyl.
- 6-10 membered aryl(C1-C6)alkyl refers to a group having the general formula -Rb - Rc , wherein Rb is (C1-C6)alkylene as defined above and Rc Is one or more 6-10 membered aryl groups as defined above, such as benzyl, diphenylmethyl, etc.
- 6-10 membered aryl(C2-C6)alkenyl refers to a group having the general formula -Rd - Rc , wherein Rd is a C2-C6alkenylene group as defined above and Rc is a or a plurality of 6-10 membered aryl groups as defined above.
- 6-10 membered aryl(C2-C6)alkynyl refers to a group having the general formula -Re - Rc , wherein Re is a C2-C6 alkynylene as defined above and Rc is a or a plurality of 6-10 membered aryl groups as defined above.
- cycloalkyl refers to a stable saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include spiro or bridged ring systems, having from three to fifteen carbon atoms.
- C3-C8 cycloalkyl refers to a cyclic alkyl group with 3-8 carbon atoms, which may further be a C3-C6 cycloalkyl group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- C3-C8 cycloalkyl(C1-C6)alkyl refers to a group of the general formula -Rb - Rg , where Rb is a C1-C6 alkylene chain as defined above and Rg is C3-C8 cycloalkyl group as defined above.
- C3-C8 cycloalkyl(C2-C6)alkenyl refers to a group of the general formula -Rd - Rg , where Rd is a C2-C6 alkenylene chain as defined above and Rg is C3-C8 cycloalkyl group as defined above.
- C3-C8 cycloalkyl(C2-C6)alkynyl refers to a group of the general formula -R e -R g , wherein R e is a C2-C6 alkynylene group as defined above and R g is a C3-C8 cycloalkyl group as defined above.
- heterocyclyl refers to a stable saturated, partially unsaturated or fully unsaturated non-aromatic or aromatic ring group containing at least one ring heteroatom or heteroatom group independently selected from Nitrogen, sulfur, oxygen, sulfoxide, sulfone,
- the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, in which two or more rings exist in the form of spiro, joined or bridged rings.
- the heterocycle is two or more rings, at least one of the rings contains at least one heteroatom or heteroatom group, which can be two or more rings formed by a ring containing heteroatoms or heteroatom groups and a ring that does not contain heteroatoms or heteroatom groups.
- heteroatom when the heteroatom is nitrogen, the nitrogen can serve as a point of attachment to other groups.
- heterocyclic group of the atom can further be a 5-7 membered monocyclic heterocyclic group, an 8-10 membered bicyclic heterocyclic group or a 10-18 membered tricyclic or tetracyclic heterocyclic group.
- the "3-18 membered heterocyclic group""Basic optionally contains 1, 2, 3, or 4 heteroatoms or heteroatom groups as ring atoms, including but not limited to ethylene oxide, furyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyrrolyl , tetrahydrothiophenyl, piperidinyl, morpholinyl, pyridyl, benzimidazolyl,
- heterocyclyl(C1-C6)alkyl refers to a group of the general formula -Rb - Rh , wherein Rb is a C1-C6 alkylene chain as defined above and Rh is as defined above Heterocyclyl group as defined, and if the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group may be connected to an alkyl group at the nitrogen atom.
- heterocyclyl(C2-C6)alkenyl refers to a group of the general formula -Rd - Rh , wherein Rd is a C2-C6 alkenylene chain as defined above and Rh is a C2-C6 alkenylene chain as defined above.
- Rd is a C2-C6 alkenylene chain as defined above
- Rh is a C2-C6 alkenylene chain as defined above.
- a defined heterocyclyl group and if the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group may be connected to an alkenylene chain at the nitrogen atom.
- heterocyclyl(C2-C6)alkynyl refers to a group of the general formula -Re - Rh , wherein Re is a C2-C6 alkynylene chain as defined above and Rh is as defined above Heterocyclyl as defined, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be linked to an alkynyl group at the nitrogen atom.
- benzo(C3-C8)cycloalkyl refers to a group formed by fusion of a benzene ring and a C3-C8 cycloalkyl group as defined above.
- the benzene ring and the cycloalkyl group share two adjacent ring carbon atoms, And the connection site with the parent core structure is located in the benzene ring part. Examples include, but are not limited to:
- pharmaceutically acceptable salt refers to a salt that retains the biological potency of the free acid and base of a particular compound without adverse biological effects.
- acid including organic acids and inorganic acids
- base addition salts including organic bases and inorganic bases.
- the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- ⁇ ективное amount refers to a nontoxic amount of a drug or agent that is sufficient to achieve the desired effect.
- pharmaceutically acceptable carrier refers to those carriers that have no obvious irritating effect on the body and do not impair the biological activity and performance of the active compound. Including but not limited to any diluent, disintegrant, binder, glidant, and wetting agent approved by the State Food and Drug Administration for use on humans or animals.
- v/v refers to the volume ratio
- SEB Supplemented Enzymatic Buffer (SEB), a component in the kit;
- DMF-DMA N,N-dimethylformamide dimethyl acetal
- Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
- N or M represents concentration, mol/L.
- concentration mol/L.
- concentration of hydrochloric acid 6mol/L.
- 1,2-Difluoro-4-nitrobenzene (795 mg), 80% hydrazine hydrate (400 mg) and ethanol (15 mL) were placed in a 25 mL single-mouth bottle and reacted at 80 degrees Celsius. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness, then slurried with methyl tert-butyl ether, and filtered. The filter cake was dried to obtain 500 mg of the title product.
- Trimethyl orthoformate (324.7 mg) and intermediate compound M6-1 (580 mg) were placed in a 100 mL single-neck bottle, and stirred at 100 degrees Celsius for 1.5 hours. Then 4-dimethylaminopyridine (26.7 mg) was added, and the reaction was continued overnight. When the reaction is complete, the reaction solution is lowered to room temperature, and a large amount of solid precipitates. Filter with suction, and wash the filter cake with isopropyl alcohol. The filter cake was dried to obtain 206 mg of the title product.
- Preparation Example 7 replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with 2-cyano-N-(5-methylpyridin-2-yl)acetamide. That is Yes, the same subsequent reaction as step b) to step d) in Preparation Example 7 was carried out to obtain 169 mg of the title product.
- step a) of Example 3 to replace 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid with 3-(4-fluorophenyl)-1-isopropyl-2,4 -Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid is sufficient to obtain 110 mg of the title product.
- the aqueous phase was extracted twice with ethyl acetate (20 mL).
- the aqueous phase was then extracted once with ethyl acetate (50 mL).
- the organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
- step b) in Example 18 Referring to the method of step b) in Example 18, replacing 18-1 with 19-1, 11 mg of the title product was prepared.
- step d) 22-3 just replace step d) 22-3 with 24-5.
- the reaction solution was then desolvated to dryness.
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18 column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 10mmol/L HCl aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min; Gradient: 10% B ⁇ 62% B, 10 min; detection wavelength: 220 nm; target compound retention time: 7.75 min), and 5.3 mg of the title product was obtained.
- Example 26 just replace 26-5 in step f) with 27-3.
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate :100mL/min; Gradient: 25%B ⁇ 65%B, 40min; Detection wavelength: 220nm; Target compound retention time: 35min) to obtain 3 mg of the title product.
- reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate :100mL/min; Gradient: 25%B ⁇ 65%B, 40min; Detection wavelength: 220nm; Target
- step c was replaced with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline to obtain 160 mg of the title product.
- Example 26 replace 26-5 in step f) with 28-3.
- the crude product obtained is purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCl), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 10%B ⁇ 62%B, 8min; detection wavelength: 220nm; target compound retention time: 7.75 min), 4.1 mg of the title product was obtained.
- reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCl), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 10%B ⁇ 62%B, 8min; detection wavelength: 220nm; target compound retention time: 7.75 min
- Example 26 replace 26-5 in step f) with 29-3.
- the crude product obtained is purified by reversed-phase high performance liquid chromatography (column: XSelect CSH Fluoro Phenyl, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (0.1% FA), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B ⁇ 50%B, 8min; detection wavelength: 220nm; target compound retention time: 6.25min ), 6.9 mg of the title product was obtained.
- reversed-phase high performance liquid chromatography columnumn: XSelect CSH Fluoro Phenyl, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (0.1% FA), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B ⁇ 50%B, 8min; detection wavelength: 220nm; target compound retention time: 6.25min ), 6.9 mg
- Acetonitrile (15mL), potassium carbonate (3.92g), 4-fluoronitrobenzene (2g), and 1-(oxetan-3-yl)piperazine (2.02g) were placed in a sealed tube. Reaction was carried out overnight at 100°C. When the raw materials disappear, add water (10 mL) to the reaction solution. Extract three times with dichloromethane (20 mL). The combined organic phases were extracted with n-hexane (3 mL) and dried over anhydrous sodium sulfate. Filter, and the filtrate is desolvated to dryness to obtain 3.6 g of the title product.
- Example 26 just replace 26-5 in step f) with 31-3.
- the reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: XBridge Shield RP18 OBD, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.53 min) to obtain 15.7 mg of the title product.
- reversed-phase high performance liquid chromatography columnumn: XBridge Shield RP18 OBD, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10
- Example 26 just replace 26-5 in step f) with 32-2.
- the reaction solution was cooled to room temperature, concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD, 30 ⁇ 150 mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (0.1% trifluoroacetic acid), Mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 8.62 min) to obtain 19.1 mg of the title product.
- reversed-phase high performance liquid chromatography columnumn: Xselect CSH C18 OBD, 30 ⁇ 150 mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (0.1% trifluoroacetic acid), Mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 40% B
- step f just replace 30-5 in step f) with 33-5.
- the reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO prep C18, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 60% B, 7.88 min; detection wavelength: 220 nm; target compound retention time: 7.75 min) to obtain 9.6 mg of the title product.
- reversed-phase high performance liquid chromatography columnumn: Kinetex EVO prep C18, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 60% B, 7.88 min; detection
- N-(4-aminophenyl)acetamide 150mg
- hydrochloric acid solution 2M, 5mL
- sodium nitrite 73mg
- Tin dichloride 380 mg was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the product was filtered with suction, the filter cake was washed with water, and 142 mg of the title product was obtained after drying the filter cake.
- Example 26 replace 26-5 in step f) with 47-6.
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min) to obtain 17.5 mg of the title product.
- reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min), and 34.1 mg of the title product was obtained.
- the obtained crude product (250 mg crude product) was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate : 60 mL/min; gradient: 10% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.18 min), and 100 mg of the mixture was obtained (Example 50 and Example 53).
- Embodiment 50 is purified by reversed-phase chiral high performance liquid chromatography (column: CHIRALPAK IA C18 column, 2 ⁇ 25mm packing particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B : ethanol; flow rate: 20 mL/min; gradient: 50% B ⁇ 50% B, 22 min; detection wavelength: 256/220 nm; target compound retention time: 9.08 min), and 29.3 mg of the title compound was obtained.
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO C18 column, 21.2 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 10mmol/L ammonium bicarbonate solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 20% B ⁇ 50% B, 10 min; detection wavelength: 220 nm; target compound retention time: 10.15 min), and 7.1 mg of the title product was obtained.
- the obtained crude product (250 mg crude product) was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate : 60 mL/min; gradient: 10% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.18 min), and 100 mg of the mixture was obtained (Example 50 and Example 53).
- Embodiment 53 is purified by reversed-phase chiral high performance liquid chromatography (column: CHIRALPAK IA C18 column, 2 ⁇ 25mm packing particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B : ethanol; flow rate: 20 mL/min; gradient: 50% B ⁇ 50% B, 22 min; detection wavelength: 256/220 nm; target compound retention time: 19.32 min), and 36 mg of the title compound was obtained.
- Example 50 replace 5-nitro-1H-benzo[d]imidazole in step a) with 6-nitro-2H-indazole to obtain 800 mg of the title product.
- the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO prep C18 column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.68 min), and 16.4 mg of the title product was obtained.
- the positive drug BGB-324 used in the activity test was purchased from Hubei Kele Fine Chemical Co., Ltd.
- ATP, substrate preparation and sample addition Use 1 ⁇ enzyme buffer to prepare ATP (Sigma, A7699) working solution for AXL, Mer and Tyro3 kinase reactions in sequence: dilute sequentially from 10mM to 75 ⁇ M (5 ⁇ , final concentration 15 ⁇ M) , 50 ⁇ M (5 ⁇ , final concentration 10 ⁇ M), 2 ⁇ M (5 ⁇ , final concentration 0.4 ⁇ M), use 1 ⁇ enzyme buffer to dilute the substrate TK Substrate-biotin (Cisbio, 61TK0BLC) from 500 ⁇ M to 5 ⁇ M (5 ⁇ , final concentration The concentration is 1 ⁇ M); mix ATP and substrate in equal volumes, and add 4 ⁇ L to each well using a BioTek automatic dispenser; centrifuge at 2500 rpm for 30 seconds, and react at 25°C for 45 min (AXL kinase reaction time) and 45 min (Mer kinase reaction time), respectively. 30min (Tyro3 kinase reaction time);
- Detection reagent preparation and sample addition Use detection buffer (Cisbio, 62SDBRDF) to dilute Streptavidin-XL665 (Cisbio, 610SAXLG) from 16.67 ⁇ M to 250nM (4 ⁇ , final concentration is 62.5nM); use detection buffer to dilute TK Antibody-Cryptate (Cisbio) was diluted from 100 ⁇ to 1 ⁇ ; mix Streptavidin-XL665 and TK Antibody-Cryptate in equal volumes, add 10 ⁇ L to each well using a BioTek automatic liquid dispenser, centrifuge at 2500 rpm for 30 s, and react at 25°C for 1 hour. After the reaction, the HTRF module of a multifunctional plate reader (PerkinElmer, Envision) was used for detection;
- Inhibition rate (%) (Ratio negative control group - Ratio compound group)/(Ratio negative control group - Ratio blank control group) ⁇ 100%
- the experimental results are shown in Table 1.
- Ba/F3 (mouse-derived B lymphocytes, culture medium: RPMI1640+10% FBS+IL-3 (10ng/ml)), purchased from Peking Union Cell Resource Center.
- Ba/F3-TEL-AXL (mouse-derived B lymphocytes stably expressing TEL-AXL, culture medium: RPMI1640+10% FBS), self-built from Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd., cells were placed at 37°C, 5% Culture in a CO 2 incubator. The above cells in the logarithmic growth phase were plated in a 96-well plate at a cell density of 3000 cells/well/150 ⁇ L, and a blank control group was set at the same time.
- DMSO dimethyl sulfoxide
- Test substance signal value mean fluorescence signal value of cells + culture medium + compound group
- Signal value of blank group mean fluorescence signal value of culture medium group (containing 0.3% DMSO);
- Signal value of negative control group mean fluorescence signal value of cells + culture medium group (containing 0.3% DMSO).
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Abstract
L'invention concerne un composé triazole substitué inhibiteur d'AXL représenté par la formule (I), qui est utilisé pour traiter et/ou prévenir des troubles induits par le récepteur tyrosine kinase AXL.
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004046120A2 (fr) * | 2002-11-15 | 2004-06-03 | Vertex Pharmaceuticals Incorporated | Diaminotriazoles convenant comme inhibiteurs de proteine kinases |
WO2007030680A2 (fr) * | 2005-09-07 | 2007-03-15 | Rigel Pharmaceuticals, Inc. | Derives de triazole utiles comme inhibiteurs d'axl |
WO2008083367A2 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs de axl |
WO2008083357A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par aryle bicyclique ponté et hétéroaryle bicyclique ponté utilisés comme inhibiteurs d'axl |
WO2008083354A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par n3-hétéroaryle et triazoles substitués par n5-hétéroaryle utiles comme inhibiteurs de axl |
WO2008083356A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués utilisés comme inhibiteurs d'axl |
WO2008083353A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles à substitution aryle bicycliques et hétéroaryle bicycliques utiles en tant qu'inhibiteurs axl |
WO2009054864A1 (fr) * | 2007-10-26 | 2009-04-30 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par aryle polycyclique et triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs d'axl |
WO2010005876A2 (fr) * | 2008-07-09 | 2010-01-14 | Rigel Pharmaceuticals, Inc. | Triazoles à substitution hétéroaryle polycycliques utiles en tant qu’inhibiteurs d’axl |
WO2016197009A1 (fr) * | 2015-06-05 | 2016-12-08 | Vertex Pharmaceuticals Incorporated | Triazoles pour le traitement de maladies liées à la démyélinisation |
-
2023
- 2023-09-05 WO PCT/CN2023/116897 patent/WO2024051667A1/fr unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004046120A2 (fr) * | 2002-11-15 | 2004-06-03 | Vertex Pharmaceuticals Incorporated | Diaminotriazoles convenant comme inhibiteurs de proteine kinases |
WO2007030680A2 (fr) * | 2005-09-07 | 2007-03-15 | Rigel Pharmaceuticals, Inc. | Derives de triazole utiles comme inhibiteurs d'axl |
WO2008083367A2 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs de axl |
WO2008083357A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par aryle bicyclique ponté et hétéroaryle bicyclique ponté utilisés comme inhibiteurs d'axl |
WO2008083354A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par n3-hétéroaryle et triazoles substitués par n5-hétéroaryle utiles comme inhibiteurs de axl |
WO2008083356A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles substitués utilisés comme inhibiteurs d'axl |
WO2008083353A1 (fr) * | 2006-12-29 | 2008-07-10 | Rigel Pharmaceuticals, Inc. | Triazoles à substitution aryle bicycliques et hétéroaryle bicycliques utiles en tant qu'inhibiteurs axl |
WO2009054864A1 (fr) * | 2007-10-26 | 2009-04-30 | Rigel Pharmaceuticals, Inc. | Triazoles substitués par aryle polycyclique et triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs d'axl |
WO2010005876A2 (fr) * | 2008-07-09 | 2010-01-14 | Rigel Pharmaceuticals, Inc. | Triazoles à substitution hétéroaryle polycycliques utiles en tant qu’inhibiteurs d’axl |
WO2016197009A1 (fr) * | 2015-06-05 | 2016-12-08 | Vertex Pharmaceuticals Incorporated | Triazoles pour le traitement de maladies liées à la démyélinisation |
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