WO2021160087A1 - 喹啉基膦氧化合物及其组合物和用途 - Google Patents
喹啉基膦氧化合物及其组合物和用途 Download PDFInfo
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- WO2021160087A1 WO2021160087A1 PCT/CN2021/075994 CN2021075994W WO2021160087A1 WO 2021160087 A1 WO2021160087 A1 WO 2021160087A1 CN 2021075994 W CN2021075994 W CN 2021075994W WO 2021160087 A1 WO2021160087 A1 WO 2021160087A1
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- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- amino
- substituted
- alkoxy
- Prior art date
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- -1 Quinolyl phosphine oxide compound Chemical class 0.000 title claims description 20
- 239000000203 mixture Substances 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 1385
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 322
- 125000003545 alkoxy group Chemical group 0.000 claims description 163
- 125000001072 heteroaryl group Chemical group 0.000 claims description 137
- 229910052736 halogen Inorganic materials 0.000 claims description 123
- 150000002367 halogens Chemical class 0.000 claims description 123
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 102
- 125000003118 aryl group Chemical group 0.000 claims description 94
- 125000000623 heterocyclic group Chemical group 0.000 claims description 73
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 claims description 62
- 125000004043 oxo group Chemical group O=* 0.000 claims description 54
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 36
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
- 102200048955 rs121434569 Human genes 0.000 claims description 28
- 125000003107 substituted aryl group Chemical group 0.000 claims description 28
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 239000000651 prodrug Substances 0.000 claims description 23
- 229940002612 prodrug Drugs 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 230000035772 mutation Effects 0.000 claims description 16
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- 241000009298 Trigla lyra Species 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 12
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 12
- 102200048928 rs121434568 Human genes 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- QMIHJDCMHQDZSZ-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C)=C3)N3CCN(CC3)C3CCCC3)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C)=C3)N3CCN(CC3)C3CCCC3)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 QMIHJDCMHQDZSZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000013522 chelant Substances 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- OCZAYJYMQCKNPE-UHFFFAOYSA-N O=P(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C=4C=NN(C=4)C)=C3)NCC3CCOCC3)OC)=NC=C2Br)C=CC2=NC(C3CC3)=CC=C12 Chemical compound O=P(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C=4C=NN(C=4)C)=C3)NCC3CCOCC3)OC)=NC=C2Br)C=CC2=NC(C3CC3)=CC=C12 OCZAYJYMQCKNPE-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- LDHGVEIEAGAHFT-UHFFFAOYSA-N O=P(C)(C)C1=C(NC2=NC(NC3=C(OC)C=C(C(=C3)C)N3CCN(CC3)C)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound O=P(C)(C)C1=C(NC2=NC(NC3=C(OC)C=C(C(=C3)C)N3CCN(CC3)C)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 LDHGVEIEAGAHFT-UHFFFAOYSA-N 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- HJGBPXJZNWBODE-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)N3CCC(CC3)N3CCN(CC3)C)OC)=N2)Br)C=CC2=NC(=CC=C12)C(C)C Chemical compound P(=O)(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)N3CCC(CC3)N3CCN(CC3)C)OC)=N2)Br)C=CC2=NC(=CC=C12)C(C)C HJGBPXJZNWBODE-UHFFFAOYSA-N 0.000 claims description 4
- RQPDHMNTRKRFQL-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(=C3)CC)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(=C3)CC)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 RQPDHMNTRKRFQL-UHFFFAOYSA-N 0.000 claims description 4
- PWRXTHQJBQAVQH-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C)=C3)N3CCC(CC3)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C#C Chemical compound P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C)=C3)N3CCC(CC3)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C#C PWRXTHQJBQAVQH-UHFFFAOYSA-N 0.000 claims description 4
- VDUOCUWDCIZTDM-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(CC)=C3)N3CCC(CC3)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(C#C)=CC=C12 Chemical compound P(=O)(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(CC)=C3)N3CCC(CC3)N3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(C#C)=CC=C12 VDUOCUWDCIZTDM-UHFFFAOYSA-N 0.000 claims description 4
- NPASPGFIPYGSIT-UHFFFAOYSA-N P(=O)(C)(C)C1=C(NC2=NC(NC3=C(OC)C=C(C(C=4C=NN(N=4)C)=C3)N3CCC(CC3)N3CCN(CC3)C)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound P(=O)(C)(C)C1=C(NC2=NC(NC3=C(OC)C=C(C(C=4C=NN(N=4)C)=C3)N3CCC(CC3)N3CCN(CC3)C)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 NPASPGFIPYGSIT-UHFFFAOYSA-N 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- OQPCKBCTTWDNLE-UHFFFAOYSA-N C1(=C(C2=C(C=C1)N=C(C1=CN(N=C1)C)C=C2)P(=O)(C)C)NC1=NC(NC2=C(OC)C=C(C(=C2)CC)N2CCC(CC2)N2CCN(CC2)C)=NC=C1Br Chemical compound C1(=C(C2=C(C=C1)N=C(C1=CN(N=C1)C)C=C2)P(=O)(C)C)NC1=NC(NC2=C(OC)C=C(C(=C2)CC)N2CCC(CC2)N2CCN(CC2)C)=NC=C1Br OQPCKBCTTWDNLE-UHFFFAOYSA-N 0.000 claims description 3
- WDBBMRFZDOLNQW-UHFFFAOYSA-N C1C(C2=CC(N3CCC(N4CCN(CC4)C)CC3)=C(OC)C=C2NC2=NC=C(C(NC3=C(P(=O)(C)C)C4=C(C=C3)N=C(C=C4)C3CC3)=N2)Br)CCOC1 Chemical compound C1C(C2=CC(N3CCC(N4CCN(CC4)C)CC3)=C(OC)C=C2NC2=NC=C(C(NC3=C(P(=O)(C)C)C4=C(C=C3)N=C(C=C4)C3CC3)=N2)Br)CCOC1 WDBBMRFZDOLNQW-UHFFFAOYSA-N 0.000 claims description 3
- NXBHZNCPUIIEQJ-UHFFFAOYSA-N C1C(C2=CC(N3CCOCC3)=C(OC)C=C2NC2=NC=C(C(NC3=C(P(=O)(C)C)C4=C(C=C3)N=C(C3CC3)C=C4)=N2)Br)C1 Chemical compound C1C(C2=CC(N3CCOCC3)=C(OC)C=C2NC2=NC=C(C(NC3=C(P(=O)(C)C)C4=C(C=C3)N=C(C3CC3)C=C4)=N2)Br)C1 NXBHZNCPUIIEQJ-UHFFFAOYSA-N 0.000 claims description 3
- FPYWUZPSLFRDHG-UHFFFAOYSA-N N1(C)N=CC(C2=C(N3CCN(CC3)C3=NC(C(C)(O)C)=CC=C3)C=C(OC)C(NC3=NC=C(C(NC4=CC=C5N=C(C=CC5=C4P(=O)(C)C)C4CC4)=N3)Br)=C2)=C1 Chemical compound N1(C)N=CC(C2=C(N3CCN(CC3)C3=NC(C(C)(O)C)=CC=C3)C=C(OC)C(NC3=NC=C(C(NC4=CC=C5N=C(C=CC5=C4P(=O)(C)C)C4CC4)=N3)Br)=C2)=C1 FPYWUZPSLFRDHG-UHFFFAOYSA-N 0.000 claims description 3
- CHMNOKLWJZUOBM-UHFFFAOYSA-N O=P(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)C3=CC=C(N4CCN(CC4)C)C=C3)OC)=N2)Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound O=P(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)C3=CC=C(N4CCN(CC4)C)C=C3)OC)=N2)Br)C=CC2=NC(=CC=C12)C1CC1 CHMNOKLWJZUOBM-UHFFFAOYSA-N 0.000 claims description 3
- DKMXEBIKMPYHST-UHFFFAOYSA-N O=P(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)N3CCC(CC3)N3CCN(CC3)C)OC)=N2)Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound O=P(C)(C)C1=C(NC2=C(C=NC(NC3=C(C=C(C(=C3)C)N3CCC(CC3)N3CCN(CC3)C)OC)=N2)Br)C=CC2=NC(=CC=C12)C1CC1 DKMXEBIKMPYHST-UHFFFAOYSA-N 0.000 claims description 3
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- QQPPMMCBLREFCF-UHFFFAOYSA-N O=P(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C4=CN(N=C4)C)=C3)NCC3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 Chemical compound O=P(C)(C)C1=C(NC2=NC(NC3=C(C=C(C(C4=CN(N=C4)C)=C3)NCC3CCN(CC3)C)OC)=NC=C2Br)C=CC2=NC(=CC=C12)C1CC1 QQPPMMCBLREFCF-UHFFFAOYSA-N 0.000 claims description 3
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 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
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940121646 third-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Definitions
- the present invention relates to pharmaceutically active compounds, deuterated compounds (hydrogen replaced by deuterium) and pharmaceutically acceptable salts thereof, which can be used to treat or prevent diseases or medical conditions mediated by certain mutant forms of epidermal growth factor receptor ( For example, L858R activating mutant, Exon19 deletion activating mutant, T790M resistance mutant, and C797S resistance mutant).
- the present invention also relates to a pharmaceutical composition containing the compound and a method of using the compound, deuterated compound and salt thereof to treat diseases mediated by various forms of EGFR mutants.
- Epidermal growth factor receptor is a transmembrane glycoprotein that belongs to the ErbB family of tyrosine kinase receptors.
- the activation of EGFR leads to the autophosphorylation of receptor tyrosine kinases, which initiates a cascade of downstream signaling pathways involved in regulating cell proliferation, differentiation, and survival.
- EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation, and is related to the development of a variety of human cancers.
- Inhibition of EGFR is one of the key goals of cancer treatment.
- the previous generations of EGFR-TKIs have developed rapidly, the problem of drug resistance has also emerged with the development of drugs.
- Most of the resistance was due to the T790M mutation in the ATP binding domain.
- Recently developed third-generation irreversible inhibitors against T790M, such as osimertinib, have very good inhibitory activity, and drug resistance inevitably appears.
- the EGFR-C797S mutation is the most common secondary mutation that causes the third-generation EGFR-TKI resistance.
- the C797S mutation refers to a missense mutation in which the cysteine at position 797 of exon 20 of EGFR is replaced by serine. It is located in the tyrosine kinase region of EGFR.
- the mutation of C797S prevents osimertinib from continuing to form a coexistence in the ATP binding domain. Valence bond, thereby losing the effect of inhibiting EGFR activation, leading to the occurrence of drug resistance.
- the present invention relates to a quinolinyl phosphine oxide compound, which can inhibit EGFR, and these compounds can be used to treat cancer and infectious diseases.
- the first object of the present invention is to provide a compound represented by formula I, or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-co- Valence complex or solvate:
- the -C 1-6 alkyl, -C 1-6 alkoxy, 3-6 membered heterocyclyl, aryl and heteroaryl are optionally halogen, OH, NH 2 , aryl, heteroaryl , -C 1-6 alkyl, -C 3-6 cycloalkyl substituted or unsubstituted;
- R ', R ", R 7 , R 8 and R 9 are independently selected from H, CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; the -C 1-6 alkyl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , aryl, heteroaryl, -C 1-6 alkyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclic group is substituted or unsubstituted;
- R 1 is selected from H, halogen, CN, -NR 10 R 11 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocycle
- the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl substituted or unsubstituted;
- R 10 and R 11 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 2 , R 3 and R 6 are each independently selected from H, halogen, CN, -NR 12 R 13 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 ring Alkyl group and 3-6 membered heterocyclic group; the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally Halogen, OH, NH 2 , -C 1-6 alkyl is substituted or unsubstituted; and R 2 , R 3 and R 6 are not H at the same time;
- R 12 and R 13 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy , -C 3-6 cycloalkyl and 3-8 membered heterocyclic group; wherein the -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy, -C 3- 6 -cycloalkyl and 3-8 membered heterocyclic groups are optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted 3-6 membered heterocyclic ring , aryl, substituted ary
- R 14 and R 15 are each independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl; wherein, the -C 1-6 alkyl, -C 3-6 cycloalkyl and -C 3-6 heterocyclyl are selectively substituted by -C 1-6 alkyl, -C 1-6 alkoxy, -NR 16 R 17 and -C 3-6 hetero Cyclic group, substituted by one or more C 1-6 alkyl substituted heterocyclic group; R 16 and R 17 are each independently selected from H and -C 1-6 alkyl;
- n is selected from any integer of 1 to 3;
- p is selected from any integer of 1 to 3;
- q is selected from any integer of 0 to 3;
- r is selected from any integer of 1 to 3.
- n 1
- n is 2.
- n 3.
- R are each independently selected from halogen, CN, NO 2 , OH, -C 1-6 alkyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, heteroaryl ,with
- the definition of R 9 is as described in any embodiment of the present invention.
- R is each independently selected from halogen, CN, NO 2 , OH, -CF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,
- R 1 is selected from halogen, CN, -NR 10 R 11 and OH; the definitions of R 10 and R 11 are as described in any embodiment of the present invention.
- R 1 is selected from halogen; wherein said halogen is fluorine, chlorine, bromine or iodine.
- R 1 is fluorine or bromine.
- R 2 and R 3 are each independently selected from H, halogen, CN, -NR 12 R 13 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group; the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group Optionally substituted or unsubstituted by halogen, OH, NH 2 , -C 1-6 alkyl; and R 2 and R 3 are not H at the same time; R 12 and R 13 are defined as described in any embodiment of the present invention .
- R 2 is selected from H, -C 1-6 alkyl, and -C 1-6 alkoxy.
- R 2 is selected from -C 1-6 alkoxy.
- R 2 is selected from H, -CH 3 or -OCH 3 .
- R 3 is selected from H or -C 1-6 alkoxy.
- R 3 is selected from H or -OCH 3 .
- R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , -C 1-6 alkyl, aryl, heteroaryl,- C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group; the -C 1-6 alkyl group, aryl group, heteroaryl group -C 1-6 alkoxy group, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally substituted by halogen, OH, NH 2 , -C 1-6 alkoxy, -C 3-6 cycloalkyl, substituted C 3- 6 -cycloalkyl, 3-6-membered heterocyclyl and substituted 3-6-membered heterocyclyl, aryl, and heteroaryl are substituted or unsubstituted; and R 4 and R 5 are not H at the same time.
- R 4 is selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , aryl, heteroaryl, -C 3-6 cycloalkyl, and 3-6 membered heterocycle
- the aryl, heteroaryl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1 -6 alkyl, hydroxy substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15, aryl, substituted aryl, heteroaryl, substituted with one or more C 1-6 alkyl,
- R 4 is selected from -NR 14 R 15 , aryl, heteroaryl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; the aryl, heteroaryl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1- 6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, with one or more A C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, one or more A C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, hydroxy
- R 14 and R 15 are each independently selected from H, -C 1-6 alkyl, and -C 3-6 cycloalkyl.
- R 4 is selected from
- R 5 is selected from H, halogen, CN, NO 2 , OH, -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy; 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy is optionally halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy Substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group , 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 , aryl, substituted aryl, heteroaryl , by one or more C 1-6 alkyl, hydroxy substituted C 1-6 alkyl,
- R 5 is selected from H, halogen, CN, -C 1-6 alkyl, heteroaryl, -C 1-6 alkoxy; the -C 1-6 alkyl, heteroaryl Group, -C 1-6 alkoxy optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted by one or more C 1-6 alkane Group, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, and one or more C 1-6 alkane Group, hydroxy substituted C 1-6 alkyl, oxo, C 1-6 alkoxy,
- R 5 is selected from H, CN, CH 3 , CH 2 CH 3 , F, OCH 3 ,
- R 6 is selected from H, CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; the -C 1-6 alkyl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl optionally substituted with halogen, OH, NH 2, -C 1- 6 alkyl substituted or not substituted.
- R 6 is selected from H, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
- the compound of formula I or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or
- the solvate is selected from formula II:
- the -C 1-6 alkyl, -C 1-6 alkoxy, 3-6 membered heterocyclyl, aryl and heteroaryl are optionally halogen, OH, NH 2 , aryl, heteroaryl , -C 1-6 alkyl, -C 3-6 cycloalkyl substituted or unsubstituted;
- R ', R ", R 7 , R 8 and R 9 are independently selected from H, CN, -C 1-6 alkyl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; the -C 1-6 alkyl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , aryl, heteroaryl, -C 1-6 alkyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclic group is substituted or unsubstituted;
- R 1 is selected from H, halogen, CN, -NR 10 R 11 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocycle
- the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl substituted or unsubstituted;
- R 10 and R 11 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 2 is selected from H, halogen, CN, -NR 12 R 13 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocycle
- the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl is substituted or unsubstituted; and R 2 , R 3 and R 6 are not H at the same time;
- R 12 and R 13 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy , -C 3-6 cycloalkyl and 3-8 membered heterocyclic group; the -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy, -C 3-6 ring Alkyl and 3-8 membered heterocyclic groups are optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted by one or more C 1-6 alkane Group, C 1-6 alkoxy, oxo,
- R 14 and R 15 are each independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl; the -C 1-6 alkyl, -C 3-6 cycloalkyl and -C 3-6 heterocyclyl are optionally selected by -C 1-6 alkyl, -C 1-6 alkoxy, -NR 16 R 17 and -C 3-6 heterocyclyl , Substituted by one or more C 1-6 alkyl substituted heterocyclyl; R 16 and R 17 are each independently selected from H and -C 1-6 alkyl;
- n is selected from any integer of 1 to 3;
- p is selected from any integer of 1 to 3;
- q is selected from any integer of 0 to 3;
- r is selected from any integer of 1 to 3.
- n 1
- R are each independently selected from halogen, CN, NO 2 , OH, -C 1-6 alkyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, heteroaryl ,with
- the definition of R 9 is as described in any embodiment of the present invention.
- R is each independently selected from halogen, CN, NO 2 , OH, -CF 3 -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,
- R 1 is selected from halogen, CN, -NR 10 R 11 and OH; the definitions of R 10 and R 11 are as described in any embodiment of the present invention.
- R 1 is selected from halogen; wherein said halogen is fluorine, chlorine, bromine or iodine.
- R 1 is fluorine or bromine.
- R 2 is selected from H, halogen, CN, -NR 12 R 13 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl And 3-6 membered heterocyclic group; the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , and -C 1-6 alkyl are substituted or unsubstituted; R 12 and R 13 are defined as described in any embodiment of the present invention.
- R 2 is selected from H, -C 1-6 alkyl, and -C 1-6 alkoxy.
- R 2 is selected from -C 1-6 alkoxy.
- R 2 is selected from H, -CH 3 or -OCH 3 .
- R 4 is selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , aryl, heteroaryl, -C 3-6 cycloalkyl, and 3-6 membered heterocycle
- the aryl, heteroaryl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1 -6 alkyl, hydroxy substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15, aryl, substituted aryl, heteroaryl, substituted with one or more C 1-6 alkyl,
- R 4 is selected from -NR 14 R 15 , aryl, heteroaryl, -C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; the aryl, heteroaryl, -C 3-6 cycloalkyl and 3-6 membered heterocyclic group optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1- 6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, with one or more A C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, one or more A C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, hydroxy
- R 4 is selected from
- R 5 is selected from H, halogen, CN, NO 2 , OH, -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy; 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy is optionally halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy Substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group , 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 , aryl, substituted aryl, heteroaryl , by one or more C 1-6 alkyl, hydroxy substituted C 1-6 alkyl,
- R 5 is selected from H, halogen, CN, -C 1-6 alkyl, heteroaryl, -C 1-6 alkoxy; the -C 1-6 alkyl, heteroaryl Group, -C 1-6 alkoxy optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted by one or more C 1-6 alkane Group, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, and one or more C 1-6 alkane Group, hydroxy substituted C 1-6 alkyl, oxo, C 1-6 alkoxy,
- R 5 is selected from H, CN, CH 3 , CH 2 CH 3 , F, OCH 3 ,
- the compound of formula I or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or
- the solvate is selected from formula III:
- R 1 is selected from H, halogen, CN, -NR 10 R 11 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocycle
- the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl substituted or unsubstituted;
- R 10 and R 11 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 2 is selected from H, halogen, CN, -NR 12 R 13 , OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-6 cycloalkyl and 3-6 membered heterocycle
- the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 3-6 cycloalkyl group and 3-6 membered heterocyclic group are optionally halogen, OH, NH 2 , -C 1-6 alkyl substituted or unsubstituted;
- R 12 and R 13 are each independently selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
- R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, -NR 14 R 15 , -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy , -C 3-6 cycloalkyl and 3-8 membered heterocyclic group; the -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy, -C 3-6 ring Alkyl and 3-8 membered heterocyclic groups are optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted by one or more C 1-6 alkane Group, C 1-6 alkoxy, oxo,
- R 14 and R 15 are each independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl; the -C 1-6 alkyl, -C 3-6 cycloalkyl and -C 3-6 heterocyclyl are optionally selected by -C 1-6 alkyl, -C 1-6 alkoxy, -NR 16 R 17 and -C 3-6 heterocyclyl , Substituted by one or more C 1-6 alkyl substituted heterocyclic groups; wherein R 16 and R 17 are independently selected from H and -C 1-6 alkyl.
- R 1 is selected from halogen; wherein said halogen is fluorine, chlorine, bromine or iodine.
- R 1 is fluorine or bromine.
- R 2 is selected from -C 1-6 alkyl and -C 1-6 alkoxy.
- R 2 is selected from -C 1-6 alkoxy.
- R 2 is selected from -CH 3 or -OCH 3 .
- R 4 is selected from -NR 14 R 15 , aryl, heteroaryl, -C 3-6 cycloalkyl and 3-8 membered heterocyclyl; the aryl, heteroaryl, -C 3-6 cycloalkyl and 3-8 membered heterocyclic group optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1- 6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, with one or more A C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, one or more A C 1-6 alkyl group, a hydroxy substituted C 1-6 alkyl group
- R 4 is selected from a 3-8 membered heterocyclic group; the 3-8 membered heterocyclic group is optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 , aryl, substituted aryl, heteroaryl, substituted with one or more C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, oxo, C 1-6 alkoxy, -NR 14 R 15 substituted heteroaryl
- the group is substituted or unsubstituted.
- R 14 and R 15 are each independently selected from H and -C 1-6 alkyl; said -C 1-6 alkyl is optionally selected from -C 1-6 alkoxy,- NR 16 R 17 and -C 3-6 heterocyclyl, substituted by one or more C 1-6 alkyl substituted heterocyclic groups; wherein R 16 and R 17 are independently selected from H and -C 1- 6 alkyl.
- R 4 is selected from
- R 5 is selected from H, halogen, CN, NO 2 , OH, -C 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy; 1-6 alkyl, aryl, heteroaryl, -C 1-6 alkoxy is optionally halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy Substituted C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group , 3-6 membered heterocyclic group substituted by one or more C 1-6 alkyl, C 1-6 alkoxy, oxo, -NR 14 R 15 , aryl, substituted aryl, heteroaryl , by one or more C 1-6 alkyl, hydroxy substituted C 1-6 alkyl,
- R 5 is selected from H, halogen, CN, -C 1-6 alkyl, heteroaryl, -C 1-6 alkoxy; the -C 1-6 alkyl, heteroaryl Group, -C 1-6 alkoxy optionally substituted by halogen, OH, NH 2 , -C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, -C 1-6 alkoxy, -NR 14 R 15 , -C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, 3-6 membered heterocyclic group, substituted by one or more C 1-6 alkane Group, C 1-6 alkoxy, oxo, -NR 14 R 15 substituted 3-6 membered heterocyclic group, aryl, substituted aryl, heteroaryl, and one or more C 1-6 alkane Group, hydroxy substituted C 1-6 alkyl, oxo, C 1-6 alkoxy,
- R 5 is selected from H, CN, CH 3 , CH 2 CH 3 , F, OCH 3 ,
- the compound of formula I is selected from:
- the second object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising: the compound represented by formula I, formula II or formula III, or its stereoisomers, tautomers, deuterium Compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates are used as active ingredients and at least one pharmaceutically acceptable excipient, such as a carrier or excipient.
- the third object of the present invention is to provide a method for inhibiting various forms of EGFR mutations, including one or more of L858R, ⁇ 19del, T790M and C797S mutations, and the method includes administering to a patient the formula I Any compound, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof.
- the fourth object of the present invention is to provide a method for the treatment of EGFR-driven cancer, which comprises administering to a patient in need a therapeutically effective amount of any compound represented by formula I, or its stereoisomers, tautomers Isomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates.
- the EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M, and C797S, or (v) ⁇ 19del, T790M and C797S.
- the EGFR-driven cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.
- the cancer to carry EGFR L858R / T790M / C797S or EGFR ⁇ 19del / T790M / C797S mutant NSCLC.
- the fifth object of the present invention is to provide a method for inhibiting mutant EGFR in a patient, the method comprising administering to a patient in need a therapeutically effective amount of any compound represented by formula I, or its stereoisomers, mutual Mutants, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates.
- the sixth object of the present invention is to provide any compound represented by formula I of the present invention, or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, chelate Use of compounds, non-covalent complexes, solvates or their pharmaceutical compositions in the preparation of medicines.
- the medicament is used to treat or prevent cancer.
- cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.
- the cancer to carry EGFR L858R / T790M / C797S or EGFR ⁇ 19del / T790M / C797S mutant NSCLC.
- halogen refers to fluorine, chlorine, bromine, or iodine.
- Preferred halogen groups include F, Cl and Br.
- alkyl group used herein includes a saturated monovalent hydrocarbon group having a straight or branched chain.
- alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl.
- C 1-8 alkyl C 1-8 is defined as the group identified as having a straight-chain or branched 1,2,3,4,5,6,7 or 8 carbon atoms, Chain arrangement.
- the alkoxy group is an oxyether formed from the aforementioned linear, branched or cyclic alkyl group.
- aryl refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms.
- Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
- heteroaryl refers to an unsubstituted or substituted stable five- or six-membered monocyclic aromatic ring system or an unsubstituted or substituted nine- or ten-membered benzo-fused heteroaromatic ring Department or bicyclic heteroaromatic ring system.
- Heteroaryl groups can be attached to any heteroatom or carbon atom to produce a stable structure.
- heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl , Benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
- cycloalkyl refers to a cyclic saturated alkyl chain having carbon atoms, such as cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl.
- heterocyclic group refers to a stable monocyclic, bicyclic or tricyclic ring containing heteroatom groups. They may be saturated or partially unsaturated, and they contain carbon atoms and 1-4 options. Heteroatoms from N, O or S, and wherein nitrogen or sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized.
- the heterocyclic group can be attached to any heteroatom or carbon atom to produce a stable structure. Examples of heterocyclic groups include, but are not limited to, oxiranyl, piperazinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, and the like.
- substituted refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents.
- the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy , Isobutoxy, t-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl.
- substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
- substituted alkoxy groups include, but are not limited to, aminomethoxy, tetrafluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
- composition is intended to encompass products that contain specific ingredients in specific amounts, as well as any product produced directly or indirectly from a combination of specific ingredients in specific amounts. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound of the present invention are also part of the present invention.
- some crystalline forms of the compound may exist as polymorphs and are therefore intended to be included in the present invention.
- some compounds may form solvates (ie, hydrates) or common organic solvents with water, and these solvates are also included in the scope of the present invention.
- the compounds of the present invention may also exist in the form of pharmaceutically acceptable salts.
- the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts".
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anionic or basic/cationic salts.
- the pharmaceutically acceptable acid/anionic salt usually takes a form in which the basic nitrogen is protonated with an inorganic acid or an organic acid.
- organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, apple Acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid , Salicylic acid, saccharin or trifluoroacetic acid.
- Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.
- the prodrug of the compound of the present invention is included in the protection scope of the present invention.
- the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, in the treatment method of the present invention, the term "administration" shall include the treatment of various conditions described by the specific disclosed compound or the use of a compound that may not be specifically disclosed, but is converted into a specific compound in vivo after administration to the subject. Compound.
- the conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
- the compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this.
- the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
- the above formula I does not exactly define the three-dimensional structure of a certain position of the compound.
- the present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of racemization or epimerization known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
- the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
- the present invention includes any possible solvate and polymorph.
- the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
- water, ethanol, propanol, acetone and similar solvents can be used.
- pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
- the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium, and sodium.
- Non-toxic organic bases that can be derivatized into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
- non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
- the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid.
- citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula I will be used as a pharmaceutical application, it is preferable to use a certain purity, for example, at least 60% purity, a more suitable purity of at least 75%, and a particularly suitable purity of at least 98% (% is a weight ratio) .
- the pharmaceutical composition provided by the present invention includes the compound of Formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants.
- the pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
- the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
- the compound represented by formula I of the present invention can be used as an active component and mixed with a drug carrier to form a pharmaceutical composition.
- the pharmaceutical carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may adopt a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
- the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
- the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
- the pharmaceutical composition is prepared through uniform and intimate mixing of the active ingredient and a liquid carrier or a finely divided solid carrier or a mixture of the two.
- the product can be easily prepared into the desired appearance.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof, Its prodrug.
- a pharmaceutically acceptable carrier and a compound represented by formula I or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof, Its prodrug.
- the combination of the compound represented by formula I or its pharmaceutically acceptable salt, and one or more other compounds with therapeutic activity is also included in the pharmaceutical composition of the present invention.
- the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
- Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- Liquid carriers include syrup, peanut oil, olive oil and water.
- the gas carrier includes carbon dioxide and nitrogen.
- any pharmacologically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
- standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
- the tablet containing the compound or pharmaceutical composition of the present invention can be compressed or molded, and optionally, can be made into a tablet together with one or more auxiliary components or adjuvants.
- the active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to make compressed tablets.
- the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to make a molded tablet.
- each tablet contains about 0.05 mg to 5 g of active ingredient
- each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
- a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
- the unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
- the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
- the above-mentioned pharmaceutical composition can be prepared into a sterile powder form for immediate preparation of sterile injections or dispersions.
- the final injection form must be sterile, and for easy injection, it must be easy to flow.
- the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferred that the pharmaceutical composition be stored under conditions of anti-microbial contamination such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
- the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
- These preparations can be prepared by using the compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods.
- a cream or ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to produce a cream or ointment with the desired consistency.
- the pharmaceutical composition provided by the present invention can take a solid as a carrier and is suitable for rectal administration.
- the unit dose suppository is the most typical dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.
- the above formulations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
- additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc.
- other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
- the pharmaceutical composition containing the compound represented by formula I, or a pharmaceutically acceptable salt thereof can be prepared in the form of a powder or a concentrated solution.
- the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
- the effective treatment drug dosage level is 0.01 mg/kg body weight to 50 mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.
- the specific dosage level and treatment plan for any particular patient will depend on many factors, including the activity of the specific compound used, age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, drug combination The condition and the severity of the specific disease being treated.
- the present invention will be described in more detail through specific examples.
- the following examples are provided for illustrative purposes, but not to limit the present invention in any way.
- Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results.
- the compounds of the examples have been found to inhibit any one or more mutations of L858R, ⁇ 19del, T790M, and C797S.
- DIEA N,N-diisopropylethylamine
- DMSO dimethyl sulfoxide
- HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid
- Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
- n-BuOH n-butanol
- PTSA p-toluenesulfonic acid
- Pd/C Palladium on carbon
- NMP N-methyl-2-pyrrolidone
- Pd(dppf)Cl 2 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride
- Pd(PPh 3 ) 4 Tetratriphenylphosphine palladium
- Pd-Ruphos G 3 Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl) Phen-2-yl)palladium(II);
- Ruphos 2-Dicyclohexylphosphine-2',6'-diisopropoxybiphenyl
- ACN Acetonitrile
- compound 1-5 (10.00g, 32.84mmol), dimethylphosphine oxide (2.69g, 34.48mmol), Xantphos (3.80g, 6.57mmol), palladium acetate (737.27mg, 3.28mmol) And anhydrous potassium phosphate (13.94g, 65.68mmol) were dissolved in 1,4-dioxane (100mL), replaced with nitrogen 3 times, heated to 100°C and stirred overnight.
- the synthesis method of compound 4-1 is the same as that of compound 3-2, except that the raw material compound potassium trifluoro(vinyl)borate is replaced with cyclopropylboronic acid.
- the synthesis method of compound 5-1 is the same as that of compound 3-2, except that the raw material compound potassium trifluoro(vinyl) borate is replaced with 4,4,5,5-tetramethyl-2-(prop-1- (En-2-yl)-1,3,2-dioxaborane.
- the synthesis method of compound 9-2 is the same as that of compound 3-2, except that the raw material compound potassium trifluoro(vinyl)borate is replaced with compound 9-1.
- reaction solution was reduced to room temperature, diluted with water, extracted twice with DCM, combined the organic phases, washed three times with water, washed once with saturated aqueous sodium chloride solution, dried, filtered, the filtrate was concentrated, mixed with silica gel, and passed Flash silica gel Column purification (DCM/MeOH, 0-10% MeOH, 20 minutes), concentration of the eluent to obtain compound 16-1 (300 mg, 1.22 mmol, yield: 51.92%) as a solid. MS:246.07[M+H] +
- the synthesis method of compound 25-1 is the same as that of compound 2-3, except that the raw material compound 2-2 is replaced with compound 3-1.
- the synthesis method of compound 27-2 is the same as that of compound 3-2, except that the raw material compound 3-1 is replaced with compound 27-1.
- reaction solution was cooled to room temperature, concentrated, mixed with silica gel and purified by flash silica gel column (DCM/MeOH; MeOH from 0-5%, 20 minutes) to obtain compound J-043-4 (1.20 g, 2.87 mmol, yield: 73.03%) )MS:418.20[M+H] +
- compound J-043-8 (164mg, 0.415mmol), compound 1-8 (156mg, 0.346mmol), PTSA (149mg, 0.864mmol) were dissolved in n-butanol (5ml) and heated to Stir at 110°C for 3 hours.
- J-049-1 (1.17g, 3.92mmol, 1.00eq) was dissolved in MeOH (20mL), and sodium methoxide (2.11g, 39.16mmoL, 10.00eq) was added and refluxed for 4 days.
- J-049-3 The synthesis method of J-049-3 is the same as that of J-048-2. Just replace the starting material J-048-2 with the compound J-049-2. MS of J-049-3: 195.12[M+H] +
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Abstract
Description
Claims (61)
- 一种式I所示化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物:其中,每一个R分别独立地选自H、卤素、CN、NO 2、OH、-NR'R"、-C 1-6烷基、-C 1-6烷氧基、-(CH 2) p(O(CH 2) q) rCH 3、-C 3-6环烷基、3-6元杂环基、芳基、杂芳基、-CR 7=CR 8和 所述-C 1-6烷基、-C 1-6烷氧基、3-6元杂环基、芳基和杂芳基任选地被卤素、OH、NH 2、芳基、杂芳基、-C 1-6烷基、-C 3-6环烷基取代或不被取代;R'、R"、R 7、R 8和R 9分别独立地选自H、CN、-C 1-6烷基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、芳基、杂芳基、-C 1-6烷基、-C 3-6环烷基、3-6元杂环基取代或不被取代;R 1选自H、卤素、CN、-NR 10R 11、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;R 10和R 11分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 2、R 3和R 6分别独立地选自H、卤素、CN、-NR 12R 13、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;且R 2、R 3和R 6不同时为H;R 12和R 13分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 4和R 5分别独立地选自H,卤素,CN,NO 2,OH,-NR 14R 15,-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基;其中,所述-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代;且R 4和R 5不同时为H;R 14和R 15分别独立地选自H、-C 1-6烷基、-C 3-6环烷基、-C 3-6杂环基;所述-C 1-6烷基、-C 3-6环烷基和-C 3-6杂环基选择性地被-C 1-6烷基、-C 1-6烷氧基、-NR 16R 17和-C 3-6杂环基、被一个或多个C 1-6烷基取代的杂环基取代;R 16和R 17分别独立地选自H和-C 1-6烷基;n选自1~3任一整数;p选自1~3任一整数;q选自0~3任一整数;r选自1~3任一整数。
- 根据权利要求1所述的化合物,其特征在于,n为1。
- 根据权利要求1-4任一项所述的化合物,其特征在于,R 1选自卤素、CN、-NR 10R 11和OH。
- 根据权利要求5所述的化合物,其特征在于,R 1选自卤素;其中,所述卤素为氟、氯、溴或碘。
- 根据权利要求1-6任一项所述的化合物,其特征在于,R 2和R 3分别独立地选自H、卤素、CN、-NR 12R 13、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;其中,所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;且R 2和R 3不同时为H。
- 根据权利要求7所述的化合物,其特征在于,R 2选自H、-C 1-6烷基和-C 1-6烷氧基。
- 根据权利要求8所述的化合物,其特征在于,R 2选自H、-CH 3或-OCH 3。
- 根据权利要求7所述的化合物,其特征在于,R 3选自H或-C 1-6烷氧基。
- 根据权利要求10所述的化合物,其特征在于,R 3选自H或-OCH 3。
- 根据权利要求1-11任一项所述的化合物,其特征在于,R 4和R 5分别独立地选自H、卤素、CN、NO 2、OH、-NR 14R 15、-C 1-6烷基、芳基、杂芳基、- C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、芳基、杂芳基-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷氧基、-C 3- 6环烷基、取代的C 3-6环烷基、3-6元杂环基和取代的3-6元杂环基、芳基、和杂芳基取代或不被取代;且R 4和R 5不同时为H。
- 根据权利要求1-12任一项所述的化合物,其特征在于,R 4选自-NR 14R 15、芳基、杂芳基、-C 3-6环烷基和3-6元杂环基;所述芳基,杂芳基,-C 3- 6环烷基和3-6元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求1-13任一项所述的化合物,其特征在于,R 14和R 15分别独立地选自H、-C 1-6烷基和-C 3-6环烷基。
- 根据权利要求1-15任一项所述的化合物,其特征在于,R 5选自H、卤素、CN、-C 1-6烷基、杂芳基、-C 1-6烷氧基;所述-C 1-6烷基,杂芳基,-C 1-6烷氧基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求1-17任一项所述的化合物,其特征在于,R 6选自H、CN、-C 1-6烷基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代。
- 根据权利要求1所述的化合物,其特征在于,式I所示化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物选自式II:其中,R分别独立地选自H、卤素、CN、NO 2、OH、-NR'R"、-C 1-6烷基、-C 1-6烷氧基、-(CH 2) p(O(CH 2) q) rCH 3、-C 3-6环烷基、3-6元杂环基、芳基、杂芳基、-CR 7=CR 8和 所述-C 1-6烷基、-C 1-6烷氧基、3-6元杂环基、芳基和杂 芳基任选地被卤素、OH、NH 2、芳基、杂芳基、-C 1-6烷基、-C 3-6环烷基取代或不被取代;R'、R"、R 7、R 8和R 9分别独立地选自H、CN、-C 1-6烷基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、芳基、杂芳基、-C 1-6烷基、-C 3-6环烷基、3-6元杂环基取代或不被取代;R 1选自H、卤素、CN、-NR 10R 11、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;R 10和R 11分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 2选自H、卤素、CN、-NR 12R 13、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;且R 2、R 3和R 6不同时为H;R 12和R 13分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 4和R 5分别独立地选自H,卤素,CN,NO 2,OH,-NR 14R 15,-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基;所述-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代;且R 4和R 5不同时为H;R 14和R 15分别独立地选自H、-C 1-6烷基、-C 3-6环烷基、-C 3-6杂环基;所述-C 1-6烷基、-C 3-6环烷基和-C 3-6杂环基选择性地被-C 1-6烷基、-C 1-6烷氧基、-NR 16R 17和-C 3-6杂环基、被一个或多个C 1-6烷基取代的杂环基取代;R 16和R 17分别独立地选自H和-C 1-6烷基;n选自1~3任一整数;p选自1~3任一整数;q选自0~3任一整数;r选自1~3任一整数。
- 根据权利要求20所述的化合物,其特征在于,n为1。
- 根据权利要求20-23任一项所述的化合物,其特征在于,R 1选自卤素、CN、-NR 10R 11和OH。
- 根据权利要求24所述的化合物,其特征在于,R 1选自卤素;其中,所述卤素为氟、氯、溴或碘。
- 根据权利要求25所述的化合物,其特征在于,R 1为氟或溴。
- 根据权利要求20-26任一项所述的化合物,其特征在于,R 2选自H、卤素、CN、-NR 12R 13、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;R 12和R 13的定义如本发明任意实施方案所述。
- 根据权利要求27所述的化合物,其特征在于,R 2选自H、-C 1-6烷基和-C 1-6烷氧基。
- 根据权利要求28所述的化合物,其特征在于,R 2选自-C 1-6烷氧基。
- 根据权利要求28所述的化合物,其特征在于,R 2选自H、-CH 3或-OCH 3。
- 根据权利要求20-30任一项所述的化合物,其特征在于,R 4选自H、卤素、CN、NO 2、OH、-NR 14R 15、芳基、杂芳基、-C 3-6环烷基和3-6元杂环基;所述芳基,杂芳基,-C 3-6环烷基和3-6元杂环基任选地被卤素,OH,NH 2,-C 1- 6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求31所述的化合物,其特征在于,R 4选自-NR 14R 15、芳基、杂芳基、-C 3-6环烷基和3-6元杂环基;所述芳基,杂芳基,-C 3-6环烷基和3-6元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳 基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求20-33任一项所述的化合物,其特征在于,R 5选自H、卤素、CN、NO 2、OH、-C 1-6烷基、芳基、杂芳基、-C 1-6烷氧基;所述-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求34所述的化合物,其特征在于,R 5选自H、卤素、CN、-C 1-6烷基、杂芳基、-C 1-6烷氧基;所述-C 1-6烷基,杂芳基,-C 1-6烷氧基任选地 被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求1所述的化合物,其特征在于,式I所示化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物选自式III:其中,R 1选自H、卤素、CN、-NR 10R 11、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;R 10和R 11分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 2选自H、卤素、CN、-NR 12R 13、OH、-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基;所述-C 1-6烷基、-C 1-6烷氧基、-C 3-6环烷基和3-6元杂环基任选地被卤素、OH、NH 2、-C 1-6烷基取代或不被取代;R 12和R 13分别独立地选自H、-C 1-6烷基和-C 3-6环烷基;R 4和R 5分别独立地选自H,卤素,CN,NO 2,OH,-NR 14R 15,-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基;所述-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基,-C 3-6环烷基和3-8元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代;且R 4和R 5不同时为H;R 14和R 15分别独立地选自H、-C 1-6烷基、-C 3-6环烷基、-C 3-6杂环基;所述-C 1-6烷基、-C 3-6环烷基和-C 3-6杂环基选择性地被-C 1-6烷基、-C 1-6烷氧基、-NR 16R 17和-C 3-6杂环基、被一个或多个C 1-6烷基取代的杂环基取代;其中,R 16和R 17分别独立地选自H和-C 1-6烷基。
- 根据权利要求37所述的化合物,其特征在于,R 1选自卤素;其中,所述卤素为氟、氯、溴或碘。
- 根据权利要求38所述的化合物,其特征在于,R 1为氟或溴。
- 根据权利要求37-39任一项所述的化合物,其特征在于,R 2选自-C 1-6烷基和-C 1-6烷氧基。
- 根据权利要求40所述的化合物,其特征在于,R 2选自-C 1-6烷氧基。
- 根据权利要求40所述的化合物,其特征在于,R 2选自-CH 3或-OCH 3。
- 根据权利要求37-42任一项所述的化合物,其特征在于,R 4选自-NR 14R 15,芳基,杂芳基,-C 3-6环烷基和3-8元杂环基;所述芳基,杂芳基,-C 3- 6环烷基和3-8元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求37-43任一项所述的化合物,其特征在于,R 4选自3-8元杂环基;所述3-8元杂环基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求37-44任一项所述的化合物,其特征在于,R 14和R 15分别独立地选自H和-C 1-6烷基;所述-C 1-6烷基选择性地被-C 1-6烷氧基、-NR 16R 17和-C 3-6杂环基、被一个或多个C 1-6烷基取代的杂环基取代;其中,R 16和R 17分别独立地选自H和-C 1-6烷基。
- 根据权利要求37-46任一项所述的化合物,其特征在于,R 5选自H、卤素、CN、NO 2、OH、-C 1-6烷基、芳基、杂芳基、-C 1-6烷氧基;所述-C 1-6烷基,芳基,杂芳基,-C 1-6烷氧基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
- 根据权利要求37-47任一项所述的化合物,其特征在于,R 5选自H、卤素、CN、-C 1-6烷基、杂芳基、-C 1-6烷氧基;所述-C 1-6烷基,杂芳基,-C 1-6烷氧基任选地被卤素,OH,NH 2,-C 1-6烷基,卤代C 1-6烷基,羟基取代的C 1-6烷基,-C 1-6烷氧基,-NR 14R 15,-C 3-6环烷基,取代的C 3-6环烷基,3-6元杂环基,被一个或多个C 1-6烷基、C 1-6烷氧基、氧代、-NR 14R 15取代的3-6元杂环基,芳基、取代的芳基、杂芳基、被一个或多个C 1-6烷基、羟基取代的C 1-6烷基、氧代、C 1-6烷氧基、-NR 14R 15取代的杂芳基取代或不被取代。
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根据权利要求1-49任一项所述的化合物,其特征在于,所述式I所述化合物选自:(6-((5-溴-2-((5-甲氧基-2-甲基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;5-((5-溴-4-((2-环丙基-5-(二甲基氧化膦)喹啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-吗啉苯甲腈;(6-((5-溴-2-((2-乙基-5-甲氧基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-环丙基-5-甲氧基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-异丙基-5-甲氧基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((3-甲氧基-5-甲基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-甲氧基-2-甲基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-(1-甲基-1H-吡唑-4-基)喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-(1-乙基-1H-吡唑-4-基)-2-甲氧基-4-吗啉苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-(二甲基氨基)哌啶-1-基)-5-甲氧基-2-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;5-((5-溴-4-((2-环丙基-5-(二甲基氧化膦)喹啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌嗪-1-基)苯甲腈;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-乙炔基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-乙炔基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-甲氧基-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-乙炔基喹啉-5-基)二甲基氧化膦;6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-5-(二甲基氧化膦)喹啉-2-甲腈;(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-(1-甲基-1H-吡唑-4-基)喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-氟-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2,5-二甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;5-((5-溴-4-((2-环丙基-5-(二甲基氧化膦)喹啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯甲腈;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-甲氧基-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-环丙基-5-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;2-((5-溴-4-((2-环丙基-5-(二甲基氧化膦)喹啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯甲腈;(6-((5-溴-2-((5-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2-(四氢-2H-吡喃-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-乙基-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-乙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((3-甲氧基-5-甲基l-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-乙基-2-甲氧基-4-(1'-甲基-[4,4'-联哌啶]-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-乙基-5-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-环戊基哌嗪-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-甲氧基-4-(4-甲氧基哌啶-1-基)-2-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-异丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-氟-2-甲基-4-吗啉代苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2,5-二甲基-4-吗啉代苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-环戊基哌嗪-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-环丙基哌嗪-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-环戊基哌嗪-1-基)-5-甲氧基-2-甲基苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-甲氧基-2-甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-4-(4-(2-甲氧基吡啶-4-基)哌嗪-1-基)-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)吡啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-4-(4-(2-甲氧基嘧啶-5-基)哌嗪-1-基)-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)胺基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-(5-(二甲氨基)吡嗪-2-基)哌嗪-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(2-甲基-2H-1,2,3-三唑-4-基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)胺基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(2-甲基-2H-1,2,3-三唑-4-基)-4-(4-(吡啶-4-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)胺基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(噻唑-2-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-4-(4-(6-甲氧基吡嗪-2-基)哌嗪-1-基)-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;6-(4-(4-((5-溴-4-((2-环丙基-5-(二甲基磷酰基)喹啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌嗪-1-基)-1-甲基吡啶-2(1H)-酮;(6-((5-溴-2-((4-(4-(6-(2-羟基丙烷-2-基)吡啶-2-基)哌嗪-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(((1-甲基哌啶-4-基)甲基)氨基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-(4-环戊基哌嗪-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(吡啶-3-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(吡啶-4-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(吡嗪-2-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-吗啉基哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(嘧啶-4-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(3-甲基-3,6-二氮杂双环[3.1.1]庚基-6-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;4-(4-(4-((5-溴-4-((2-环丙基-5-(二甲基磷酰基)喹啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌嗪-1-基)吡啶-2(1H)酮;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡咯-3-基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(2-环丙基-6-((5-氟-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基嘧啶-4-基)氨基)喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;(6-((5-溴-2-((5-(1-(二氟甲基)-1H-吡唑-4-基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦;和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2-环丙基喹啉-5-基)二甲基氧化膦。
- 一种药物组合物,所述药物组合物包括:权利要求1-50任一项所述式I所示化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物作为活性成分及至少一种药学上可接受的辅料。
- 一种抑制各种不同形式EGFR突变的方法,包括L858R、△19del、T790M和C797S突变中的一种或多种,所述方法包括给患者施用权利要求1-50任一项所述式I所示任一化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物。
- 一种治疗EGFR驱动的癌症的方法,所述方法包括给予有此需要的患者治疗有效量的权利要求1-50任一项所述式I所示任一化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物。
- 根据权利要求53所述的方法,其特征在于,EGFR驱动的癌症的特征在于存在选自以下的一种或多种突变:(i)C797S,(ii)L858R和C797S,(iii)C797S和T790M,(iv)L858R,T790M,和C797S,或(v)△19del,T790M和C797S。
- 根据权利要求53或54所述的方法,其特征在于,EGFR驱动的癌症是结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑素瘤、脑癌、肾癌、前列腺癌、卵巢癌或乳腺癌。
- 根据权利要求53-55任一项所述的方法,其特征在于,所述肺癌为携带EGFR L858R/T790M/C797S或EGFR △19del/T790M/C797S突变的非小细胞肺癌。
- 一种抑制患者体内突变型EGFR的方法,所述方法包括给予有此需要的患者治疗有效量的权利要求1-50任一项所述式I所示任一化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物或溶剂化物。
- 一种权利要求1-50任一项所述式I、所示任一化合物,或其立体异构体、互变异构体、氘化化合物、药学上可接受的盐、前药、螯合物、非共价复合物、溶剂化物或其药物组合物在制备药物中的用途。
- 根据权利要求58所述的用途,其特征在于,其中所述药物用于治疗或预防癌症。
- 根据权利要求58或59所述的用途,其特征在于,其中癌症是结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑素瘤、脑癌、肾癌、前列腺癌、卵巢癌或乳腺癌。
- 根据权利要求60所述的用途,其特征在于,所述肺癌为携带EGFR L858R/T790M/C797S或EGFR △19del/T790M/C797S突变的非小细胞肺癌。
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BR112022016045A BR112022016045A2 (pt) | 2020-02-14 | 2021-02-08 | Composto de óxido de fosfina quinolina, e composição e aplicação do mesmo. |
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WO2023020600A1 (zh) * | 2021-08-19 | 2023-02-23 | 贝达药业股份有限公司 | Egfr抑制剂的盐、晶型及其组合物和应用 |
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US20230131025A1 (en) | 2023-04-27 |
BR112022016045A2 (pt) | 2022-10-04 |
TW202140446A (zh) | 2021-11-01 |
CA3167899A1 (en) | 2021-08-19 |
KR20220141838A (ko) | 2022-10-20 |
CN114885607A (zh) | 2022-08-09 |
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