JP6457697B2 - キナーゼ阻害剤としての縮合環式または三環式アリールピリミジン化合物 - Google Patents
キナーゼ阻害剤としての縮合環式または三環式アリールピリミジン化合物 Download PDFInfo
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- JP6457697B2 JP6457697B2 JP2018507763A JP2018507763A JP6457697B2 JP 6457697 B2 JP6457697 B2 JP 6457697B2 JP 2018507763 A JP2018507763 A JP 2018507763A JP 2018507763 A JP2018507763 A JP 2018507763A JP 6457697 B2 JP6457697 B2 JP 6457697B2
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- Prior art keywords
- dihydro
- amino
- ethyl
- methyl
- indol
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- 150000001875 compounds Chemical class 0.000 title claims description 369
- 125000004122 cyclic group Chemical group 0.000 title description 9
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 74
- 125000005842 heteroatom Chemical group 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical class 0.000 claims description 9
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
- -1 organic acid salt Chemical class 0.000 description 359
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 212
- 239000007787 solid Substances 0.000 description 168
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 166
- 238000000034 method Methods 0.000 description 166
- 238000005481 NMR spectroscopy Methods 0.000 description 156
- 239000000203 mixture Substances 0.000 description 155
- 238000006243 chemical reaction Methods 0.000 description 123
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 229910052757 nitrogen Inorganic materials 0.000 description 83
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000012043 crude product Substances 0.000 description 76
- 239000011541 reaction mixture Substances 0.000 description 71
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 64
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 62
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 39
- 239000003921 oil Substances 0.000 description 37
- 235000019198 oils Nutrition 0.000 description 37
- 238000004440 column chromatography Methods 0.000 description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 36
- 238000003756 stirring Methods 0.000 description 35
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 33
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 31
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 239000012141 concentrate Substances 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- 125000001424 substituent group Chemical group 0.000 description 26
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 20
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- 0 CCC(*c(cc(c(OC)c1)Nc2nc(-c3c(C*CC4)[n]4c4ccccc34)ccn2)c1N(C)CC(C)(C)*C)=O Chemical compound CCC(*c(cc(c(OC)c1)Nc2nc(-c3c(C*CC4)[n]4c4ccccc34)ccn2)c1N(C)CC(C)(C)*C)=O 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- DJHMLTIIKOUPKJ-UHFFFAOYSA-N CC1(COC=CN1)C Chemical compound CC1(COC=CN1)C DJHMLTIIKOUPKJ-UHFFFAOYSA-N 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- YEEGQDGJIXWFIQ-UHFFFAOYSA-N 3,4-dihydro-2h-1,4-oxazine Chemical compound C1COC=CN1 YEEGQDGJIXWFIQ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- YHWMFDLNZGIJSD-UHFFFAOYSA-N 2h-1,4-oxazine Chemical compound C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 description 8
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 102000003746 Insulin Receptor Human genes 0.000 description 7
- 108010001127 Insulin Receptor Proteins 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HVZAFNRIZAKUQS-UHFFFAOYSA-N 3,4-dihydro-1h-[1,4]oxazino[4,3-a]indole Chemical compound C1=CC=C2N3CCOCC3=CC2=C1 HVZAFNRIZAKUQS-UHFFFAOYSA-N 0.000 description 6
- XVAABNBFDQAMLE-UHFFFAOYSA-N 4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine Chemical compound C1OCCN2C1=C(C=1C=CC=CC2=1)C1=NC(=NC=C1)NC1=C(C=C(C(=C1)[N+](=O)[O-])F)OC XVAABNBFDQAMLE-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 6
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229940121647 egfr inhibitor Drugs 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 108060006698 EGF receptor Proteins 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- JFGGGDPBBGGVRJ-UHFFFAOYSA-N N-[5-[[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=C(C(=C1)NC1=NC=C(C(=C1)C1=C2N(C=3C=CC=CC1=3)CCOC2)F)OC)N(C)CCN(C)C JFGGGDPBBGGVRJ-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 150000001412 amines Chemical group 0.000 description 5
- 125000005605 benzo group Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000006911 enzymatic reaction Methods 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 5
- 229960003278 osimertinib Drugs 0.000 description 5
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 4
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical class ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 4
- FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 4
- ADCCQZQWHLXYQU-UHFFFAOYSA-N 4-pyrimidin-4-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indole Chemical compound C1CC2=C(C3=CC=CC=C3N2C1)C4=NC=NC=C4 ADCCQZQWHLXYQU-UHFFFAOYSA-N 0.000 description 4
- WTXBRZCVLDTWLP-UHFFFAOYSA-N 5-fluoro-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C2NC(C(=O)O)=CC2=C1 WTXBRZCVLDTWLP-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 238000011729 BALB/c nude mouse Methods 0.000 description 4
- DYEFGKDRCUZYNU-UHFFFAOYSA-N CC1(COCC=2N1C=1C=CC=CC=1C=2C1=CC(=NC=C1F)NC=1C=C(C(=CC=1OC)N(C)CCN(C)C)N)C Chemical compound CC1(COCC=2N1C=1C=CC=CC=1C=2C1=CC(=NC=C1F)NC=1C=C(C(=CC=1OC)N(C)CCN(C)C)N)C DYEFGKDRCUZYNU-UHFFFAOYSA-N 0.000 description 4
- 229940126639 Compound 33 Drugs 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical group NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D498/14—Ortho-condensed systems
Description
nは、0、1または2であり、
mは、1、2または3であり、
Y1、Y2、Y3及びY4は、それぞれ独立的に-O-、-S-、-C(R)2-、-N(R)-、-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-から選択され、
X1は、CRX1、Nから選択され、
X2は、CRX2、Nから選択され、
X3は、CRX3、Nから選択され、
RX1、RX2、RX3は、それぞれ独立的にH、F、Cl、Br、I、CN、OH、SH、NH2から選択され、またはRX1、RX2、RX3は、それぞれ独立的に、任意に1、2、3または4個のRに置換されたC1-6アルキル基(C1-6alkyl group)、C1-6ヘテロアルキル(C1-6heteroalkyl group)から選択され、
R1は、H、F、Cl、Me、CN、CF3から選択され、
R2は、R02、OR02、SR02から選択され、
R02は、独立的に、任意に1、2、3または4個のRに置換されたC1-4アルキル基(C1-4alkyl group)、C1-4ヘテロアルキル基(C1-4heteroalkyl group)、C3-5シクロアルキル-(CH2)0-3-(C3-5cycloalkyl-(CH2)0-3-)から選択され、
R3は、任意に1、2、3または4個のRに置換されたC1-6アルキル基、C1-6ヘテロアルキル基、C2-4アルキニル(C2-4alkynyl group)、3〜7員シクロアルキル、3〜7員シクロアルキル-L-、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル-L-から選択され、
Lは、-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、またはLは、任意に1、2、3または4個のRに置換されたNH、C1-4アルキル、C1-4ヘテロアルキルから選択され、
「ヘテロ」は、-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-から選択されたヘテロ原子またはヘテロ原子団を代表し、
ヘテロ原子またはヘテロ原子団の数は、それぞれ独立的に0、1、2、3から選択され、
Rは、H、F、Cl、Br、I、OH、CNから選択され、またはRは、任意に1、2、3または4個のR’に置換されたNH2、C1-4アルキル、C1-4ヘテロアルキル、3〜7員シクロアルキル、または 3〜7員ヘテロシクロアルキルから選択され、
R’は、F、Cl、Br、I、CN、OH、NH2、CF3、NHCH3、CH2OCH3、N(CH3)2から選択される。
試験化合物を3倍階段エタンアミンし、最終濃度は、300nMから0.015nMの10回の用量である。
0.05nMの野生型EGFR、1uMbiotin-TK1peptide、25uMのATP酵素の緩衝液は、合計10uLである。反応プレートは、whiteProxiplate384-Plusplate(PerkinElmer)であり、23℃で60分間反応させる。
0.04nMEGFRT790M/L858R、1uMbiotin-TK1peptide、20uMATPの酵素の緩衝液は、合計10uLである。反応プレートは、whiteProxiplate384-Plusplate(PerkinElmer)であり、23℃で60分間反応させる。
0.025nMEGFRd746-750/T790M、1uMbiotin-TK1peptide、40uMATPの酵素の緩衝液は、合計10uLである。反応プレートは、whiteProxiplate384-Plusplate(PerkinElmer)であり、23℃で60分間反応させる。
0.03nMEGFRT790M,1uMbiotin-TK1peptide,10uMATPの酵素の緩衝液は、合計10uLである。反応プレートは、whiteProxiplate384-Plusplate(PerkinElmer)であり、23℃で60分間反応させる。
0.5nMINSR、1uMbiotin-TK1peptide、35uMATPの酵素の緩衝液は、合計10uLである。反応プレートは、whiteProxiplate384-Plusplate(PerkinElmer)であり、23℃で60分間反応させる。
以下の式により、読み取り値を、抑制率(%)(Min-Ratio)/(Max-Min)*100%に変換する。4パラメーターロジスティック曲線フィッティング(Model205inXLFIT5,iDBS)により、IC50データを検出する。
RPMI1640、ウシ胎児血清,ペニシリン/ストレプトマイシン溶液は、すべてLifeTechnology(Madison,WI)から購入し、CellTiter-Gloluminescentcellviabilityreagentsは、Promega(Madison,WI)から購入した。A431cellline及びNCI-H1975celllineは、すべてEuropeanCollectionofCellCultures(ECACC)から購入した。プレートリーダー:Envision(PerkinElmer)。
384ウェルプレート、各ウェルに300個のA431cells及びNCI-H1975cells細胞を移植し、45ulの体積である。CO2のインキュベーターの中で、37℃で、一晩インキュベートする。試験化合物を3回希釈して、10μMから0.508nMの2つのウェルの10回分の濃度を得るまで検出する。中間プレートには、1ウェル当たりに49μlの培地を置く。階段希釈化合物プレートから1ulの化合物を、中間プレートに移動させて、充分に混ぜる。また中間プレートから、5ulの液体を細胞プレートに移動する。細胞を、CO2インキュベーターの中で、6日間インキュベートする。6日後、25μlの検出試薬を加える。室温で、10分間インキュベートし、Envisionのプレートリーダーである。
以下の式により、読み取り値を抑制率(%)(Max-Sample)/(Max-Min)*100%に変換する。4パラメーターロジスティック曲線フィッティング(Model205inXLFIT5,iDBS)により、IC50データを検出する。
Claims (19)
-
nは、0、1または2であり、
mは、1、2または3であり、
Y1、Y3及びY4は、それぞれ独立的に-O-、-S-、-C(R)2-、-N(R)-、-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-から選択され、
Y2は、-O-、-S-、-N(R)-、-S(=O)2-、-S(=O)-、-C(=O)-、または-C(=S)-であり、
X1は、CRX1、Nから選択され、
X2は、CRX2、Nから選択され、
X3は、CRX3、Nから選択され、
RX1、RX2、RX3は、それぞれ独立的にH、F、Cl、Br、I、CN、OH、SH、NH2から選択され、またはRX1、RX2、RX3は、それぞれ独立的に、任意に1、2、3または4個のRに置換されたC1-6アルキル基(C1-6alkyl group)、C1-6ヘテロアルキル(C1-6heteroalkyl group)から選択され、
R1は、H、F、Cl、Me、CN、CF3から選択され、
R2は、R02、OR02、SR02から選択され、
R02は、独立的に、任意に1、2、3または4個のRに置換されたC1-4アルキル基(C1-4alkyl group)、C1-4ヘテロアルキル基(C1-4heteroalkyl group)、C3-5シクロアルキル-(CH2)0-3-(C3-5cycloalkyl-(CH2)0-3-)から選択され、
R3は、任意に1、2、3または4個のRに置換されたC1-6アルキル基、C1-6ヘテロアルキル基、C2-4アルキニル(C2-4alkynyl group)、3〜7員シクロアルキル、3〜7員シクロアルキル-L-、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル-L-から選択され、
Lは、-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、またはLは、任意に1、2、3または4個のRに置換されたNH、C1-4アルキル、C1-4ヘテロアルキルから選択され、
「ヘテロ」は、-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-から選択されたヘテロ原子またはヘテロ原子団を代表し、
ヘテロ原子またはヘテロ原子団の数は、それぞれ独立的に0、1、2、3から選択され、
Rは、H、F、Cl、Br、I、OH、CNから選択され、またはRは、任意に1、2、3または4個のR’に置換されたNH2、C1-4アルキル、C1-4ヘテロアルキル、3〜7員シクロアルキル、または3〜7員ヘテロシクロアルキルから選択され、
R’は、F、Cl、Br、I、CN、OH、NH2、CF3、NHCH3、CH2OCH3、N(CH3)2から選択されることを特徴とする式(I)で示される化合物またはその薬理学的に許容される塩。 -
nは、0または2であり、
mは、1、2または3であり、
Y1、Y3及びY4は、それぞれ独立的に-O-、-S-、-C(R)2-、-N(R)-、-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-から選択され、
Y2は、-C(R)2- であり、
X1は、CRX1、Nから選択され、
X2は、CRX2、Nから選択され、
X3は、CRX3、Nから選択され、
RX1、RX2、RX3は、それぞれ独立的にH、F、Cl、Br、I、CN、OH、SH、NH2から選択され、またはRX1、RX2、RX3は、それぞれ独立的に、任意に1、2、3または4個のRに置換されたC1-6アルキル基、C1-6ヘテロアルキルから選択され、
R1は、H、F、Cl、Me、CN、CF3から選択され、
R2は、R02、OR02、SR02から選択され、R02は、独立的に、任意に1、2、3または4個のRに置換されたC1-4アルキル基、C1-4ヘテロアルキル基、C3-5シクロアルキル-(CH2)0-3-から選択され、
R3は、任意に1、2、3または4個のRに置換されたC1-6アルキル基、C1-6ヘテロアルキル基、C2-4アルキニル、3〜7員シクロアルキル、3〜7員シクロアルキル-L-、3〜7員ヘテロシクロアルキル、3〜7員ヘテロシクロアルキル-L-から選択され、
Lは、-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、またはLは、任意に1、2、3または4個のRに置換されたNH、C1-4アルキル、C1-4ヘテロアルキルから選択され、
「ヘテロ」は、-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-から選択されたヘテロ原子またはヘテロ原子団を代表し、
ヘテロ原子またはヘテロ原子団の数は、それぞれ独立的に0、1、2、3から選択され、
Rは、H、F、Cl、Br、I、OH、CNから選択され、またはRは、任意に1、2、3または4個のR’に置換されたNH2、C1-4アルキル、C1-4ヘテロアルキル、3〜7員シクロアルキル、または3〜7員ヘテロシクロアルキルから選択され、
R’は、F、Cl、Br、I、CN、OH、NH2、CF3、NHCH3、CH2OCH3、N(CH3)2から選択されることを特徴とする式(I)で示される化合物またはその薬理学的に許容される塩。 - Y1、Y3及びY4は、それぞれ独立的に、-O-、-S-、-CH2-、-CF2-、-CHF-、-C(Me)2-、-CH(Me)-、-CH(OH)-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、
Y2は、-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-から選択されることを特徴とする、請求項1に記載の式(I)で示される化合物またはその薬理学的に許容される塩。 - Y 1 及びY 3 は、それぞれ独立的に、-CH 2 -、-C(Me) 2 -、-CH(Me)-、-C(=O)-、-CF 2 -、-CHF-、-CH(OH)-から選択され、
Y 2 は、-O-、-S-、-S(=O) 2 -、-C(=O)-から選択され、
Y 4 は、-O-、-S-、-S(=O) 2 -、-CH 2 -、-C(Me) 2 -、-C(=O)-、-CF 2 -、-CH(OH)-、-CH(Me)-、-CHF-から選択されることを特徴とする請求項1に記載の式(I)で示される化合物またはその薬理学的に許容される塩。 - Y1、Y3及びY4は、それぞれ独立的に、-O-、-S-、-CH2-、-CF2-、-CHF-、-C(Me)2-、-CH(Me)-、-CH(OH)-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、
Y2は、-CH2-、-CF2-、-CHF-、-C(Me)2-、-CH(Me)-、-CH(OH)-から選択されることを特徴とする、請求項2に記載の式(I)で示される化合物またはその薬理学的に許容される塩。 - Y1及びY3は、それぞれ独立的に、-CH2-、-C(Me)2-、-CH(Me)-、-C(=O)-、-CF2-、-CHF-、-CH(OH)-から選択され、
Y2は、-CH2-、-C(Me)2-、-CF2-、-CH(OH)-、-CH(Me)-、-CHF-から選択され、
Y4は、-O-、-S-、-S(=O)2-、-CH2-、-C(Me)2-、-C(=O)-、-CF2-、-CH(OH)-、-CH(Me)-、-CHF-から選択されることを特徴とする請求項2に記載の式(I)で示される化合物またはその薬理学的に許容される塩。 - Lは、-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-から選択され、またはLは、任意に1、2または3個のRに置換されたNH、C1-3アルキル基、-O-C1-3アルキル基、-S-C1-3アルキル基、-NH-C1-3アルキル基から選択されることを特徴とする、請求項1または請求項2に記載の式(I)で示される化合物またはその薬理学的に許容される塩。
- R3は、任意に1、2、3または4個のRに置換された-C1-4アルキル、-NH-C1-4アルキル、-NH-C(=O)-C1-4アルキル、-O-C1-4アルキル、-S-C1-4アルキル、-S(=O)-C1-4アルキル、-S(=O)2-C1-4アルキル、C2-3アルキニル、3〜6員シクロアルキル、3〜6員シクロアルキル-L-、3〜6員ヘテロシクロアルキル、3〜6員ヘテロシクロアルキル-L-から選択され、
前記「ヘテロ」は、-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-から選択されるヘテロ原子またはヘテロ原子団を代表し、ヘテロ原子またはヘテロ原子団の数は、それぞれ独立的に、0、1、2、3から選択されることを特徴とする、請求項1または請求項2に記載の式(I)で示される化合物またはその薬理学的に許容される塩。 - R02は、Me、CHF2、CH2CH3、CH(CH3)2から選択されることを特徴とする請求項1または請求項2に記載の式(I)で示される化合物またはその薬理学的に許容される塩。
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CN106749267B (zh) * | 2015-11-23 | 2020-08-21 | 南京圣和药业股份有限公司 | 新的表皮生长因子受体抑制剂及其应用 |
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CA2988896C (en) | 2023-08-15 |
HK1246294A1 (zh) | 2018-09-07 |
CN107614503A (zh) | 2018-01-19 |
CN107973791A (zh) | 2018-05-01 |
CA2984586C (en) | 2021-02-16 |
KR20170141772A (ko) | 2017-12-26 |
EP3312179A1 (en) | 2018-04-25 |
JP2018087245A (ja) | 2018-06-07 |
KR102604425B1 (ko) | 2023-11-22 |
EP3290419B1 (en) | 2019-08-07 |
US10494373B2 (en) | 2019-12-03 |
EP3312179B1 (en) | 2019-07-10 |
CN107973791B (zh) | 2020-04-07 |
US20180354953A1 (en) | 2018-12-13 |
WO2016173438A1 (zh) | 2016-11-03 |
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