CN115867539A - 2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 - Google Patents
2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 Download PDFInfo
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- CN115867539A CN115867539A CN202180048966.0A CN202180048966A CN115867539A CN 115867539 A CN115867539 A CN 115867539A CN 202180048966 A CN202180048966 A CN 202180048966A CN 115867539 A CN115867539 A CN 115867539A
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- Prior art keywords
- deuterium
- radical
- substituted
- alkyl
- cycloalkyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 68
- JKWQHCSGMTWRIQ-UHFFFAOYSA-N 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine Chemical class C1=CC=C2NCCC2=N1 JKWQHCSGMTWRIQ-UHFFFAOYSA-N 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 230000035772 mutation Effects 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000003780 insertion Methods 0.000 claims abstract description 15
- 230000037431 insertion Effects 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 11
- 238000012217 deletion Methods 0.000 claims abstract description 9
- 230000037430 deletion Effects 0.000 claims abstract description 9
- 230000030833 cell death Effects 0.000 claims abstract description 7
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 6
- 230000001939 inductive effect Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 3
- 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 claims abstract 3
- -1 Alkyl radical Chemical class 0.000 claims description 737
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 414
- 229910052805 deuterium Inorganic materials 0.000 claims description 414
- 125000000217 alkyl group Chemical group 0.000 claims description 231
- 125000000623 heterocyclic group Chemical group 0.000 claims description 222
- 229910052739 hydrogen Inorganic materials 0.000 claims description 183
- 239000001257 hydrogen Substances 0.000 claims description 183
- 229910052736 halogen Inorganic materials 0.000 claims description 169
- 150000002367 halogens Chemical class 0.000 claims description 169
- 150000002431 hydrogen Chemical class 0.000 claims description 167
- 125000000304 alkynyl group Chemical group 0.000 claims description 142
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 138
- 125000001424 substituent group Chemical group 0.000 claims description 136
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 124
- 125000001072 heteroaryl group Chemical group 0.000 claims description 106
- 150000001875 compounds Chemical class 0.000 claims description 105
- 125000003118 aryl group Chemical group 0.000 claims description 104
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 89
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 69
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 67
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 67
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 66
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 62
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 62
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 57
- 150000005840 aryl radicals Chemical class 0.000 claims description 54
- 125000004104 aryloxy group Chemical group 0.000 claims description 54
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 49
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 48
- 125000002393 azetidinyl group Chemical group 0.000 claims description 45
- 125000003566 oxetanyl group Chemical group 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 125000001153 fluoro group Chemical group F* 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 29
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 28
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 28
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 27
- 229920002554 vinyl polymer Polymers 0.000 claims description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 12
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000005475 oxolanyl group Chemical group 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 201000010536 head and neck cancer Diseases 0.000 claims description 7
- 208000003154 papilloma Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 5
- 206010029098 Neoplasm skin Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 4
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 4
- 208000009849 Female Genital Neoplasms Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 201000011523 endocrine gland cancer Diseases 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 208000025426 neoplasm of thorax Diseases 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 201000003957 thoracic cancer Diseases 0.000 claims description 4
- 125000004069 aziridinyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 201000010151 inverted papilloma Diseases 0.000 claims 2
- 230000002124 endocrine Effects 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 210000000115 thoracic cavity Anatomy 0.000 claims 1
- 229940121647 egfr inhibitor Drugs 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 150000003222 pyridines Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 354
- 238000006243 chemical reaction Methods 0.000 description 167
- 239000000243 solution Substances 0.000 description 156
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 120
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 119
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 102
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 91
- 230000015572 biosynthetic process Effects 0.000 description 84
- 238000003786 synthesis reaction Methods 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000000543 intermediate Substances 0.000 description 71
- 239000000203 mixture Substances 0.000 description 68
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
- 239000003208 petroleum Substances 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 57
- 239000012074 organic phase Substances 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 52
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- 239000012043 crude product Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 239000003480 eluent Substances 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 26
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 23
- 102000001301 EGF receptor Human genes 0.000 description 21
- 108060006698 EGF receptor Proteins 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 125000006413 ring segment Chemical group 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000001721 carbon Chemical group 0.000 description 15
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- 125000003367 polycyclic group Chemical group 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- CXEIVUUBMRPVDP-UHFFFAOYSA-N ethyl 2-(6-methyl-3-nitropyridin-2-yl)acetate Chemical compound CCOC(=O)CC1=NC(C)=CC=C1[N+]([O-])=O CXEIVUUBMRPVDP-UHFFFAOYSA-N 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000003003 spiro group Chemical group 0.000 description 5
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004280 Sodium formate Substances 0.000 description 4
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 4
- 235000019254 sodium formate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
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Classifications
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- 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
- 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
- C07D471/02—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
- C07D471/10—Spiro-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
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
Abstract
涉及了2,3‑二氢‑1H‑吡咯并[3,2‑b]吡啶衍生物、其制备方法和应用。特别地涉及一种具有式(I)结构的EGFR抑制剂及其制备方法、含有其的药物组合物，以及其作为EGFR抑制剂的用途和其在治疗和/或预防至少部分由与EGFR外显子20插入或缺失突变相关的癌症、肿瘤或转移性疾病中的用途，特别是在治疗过度增殖性疾病和诱导细胞死亡障碍疾病中的用途。其中式(I)的各取代基与说明书中的定义相同。
Description
PCT国内申请，说明书已公开。
Claims (22)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020114004319 | 2020-12-02 | ||
| CN202011400431 | 2020-12-02 | ||
| PCT/CN2021/134790 WO2022116995A1 (zh) | 2020-12-02 | 2021-12-01 | 2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115867539A true CN115867539A (zh) | 2023-03-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180048966.0A Pending CN115867539A (zh) | 2020-12-02 | 2021-12-01 | 2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20240109885A1 (zh) |
| EP (1) | EP4257584A1 (zh) |
| JP (1) | JP2023545571A (zh) |
| CN (1) | CN115867539A (zh) |
| CA (1) | CA3196068A1 (zh) |
| TW (1) | TW202227439A (zh) |
| WO (1) | WO2022116995A1 (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| CN106928150A (zh) * | 2015-12-31 | 2017-07-07 | 恩瑞生物医药科技（上海）有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
| CN108864079A (zh) * | 2017-05-15 | 2018-11-23 | 深圳福沃药业有限公司 | 一种三嗪化合物及其药学上可接受的盐 |
| CN109328059A (zh) * | 2016-01-07 | 2019-02-12 | Cs制药技术有限公司 | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 |
| WO2022033455A1 (zh) * | 2020-08-13 | 2022-02-17 | 上海和誉生物医药科技有限公司 | 具有egfr抑制活性的三嗪衍生物及其制备方法和应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016029839A1 (zh) * | 2014-08-25 | 2016-03-03 | 四川海思科制药有限公司 | 一种（取代的苯基）（取代的嘧啶）胺基衍生物及其制备方法和药物用途 |
-
2021
- 2021-12-01 WO PCT/CN2021/134790 patent/WO2022116995A1/zh active Application Filing
- 2021-12-01 CA CA3196068A patent/CA3196068A1/en active Pending
- 2021-12-01 TW TW110144851A patent/TW202227439A/zh unknown
- 2021-12-01 EP EP21900025.4A patent/EP4257584A1/en active Pending
- 2021-12-01 US US18/253,503 patent/US20240109885A1/en active Pending
- 2021-12-01 CN CN202180048966.0A patent/CN115867539A/zh active Pending
- 2021-12-01 JP JP2023524135A patent/JP2023545571A/ja active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| CN106928150A (zh) * | 2015-12-31 | 2017-07-07 | 恩瑞生物医药科技（上海）有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
| CN109328059A (zh) * | 2016-01-07 | 2019-02-12 | Cs制药技术有限公司 | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 |
| CN108864079A (zh) * | 2017-05-15 | 2018-11-23 | 深圳福沃药业有限公司 | 一种三嗪化合物及其药学上可接受的盐 |
| WO2022033455A1 (zh) * | 2020-08-13 | 2022-02-17 | 上海和誉生物医药科技有限公司 | 具有egfr抑制活性的三嗪衍生物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP4257584A1 (en) | 2023-10-11 |
| WO2022116995A1 (zh) | 2022-06-09 |
| US20240109885A1 (en) | 2024-04-04 |
| CA3196068A1 (en) | 2022-06-09 |
| JP2023545571A (ja) | 2023-10-30 |
| TW202227439A (zh) | 2022-07-16 |
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