CA2897259C - Benzoheterocyclic compounds and use thereof - Google Patents
Benzoheterocyclic compounds and use thereof Download PDFInfo
- Publication number
- CA2897259C CA2897259C CA2897259A CA2897259A CA2897259C CA 2897259 C CA2897259 C CA 2897259C CA 2897259 A CA2897259 A CA 2897259A CA 2897259 A CA2897259 A CA 2897259A CA 2897259 C CA2897259 C CA 2897259C
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- CA
- Canada
- Prior art keywords
- fluoro
- amino
- compound
- alkyl
- carboxamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 399
- 150000003839 salts Chemical class 0.000 claims abstract description 165
- 238000000034 method Methods 0.000 claims abstract description 48
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 azido, hydroxy Chemical group 0.000 claims description 422
- 125000000217 alkyl group Chemical group 0.000 claims description 291
- 229910052739 hydrogen Inorganic materials 0.000 claims description 181
- 239000001257 hydrogen Substances 0.000 claims description 170
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 156
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 155
- 125000005843 halogen group Chemical group 0.000 claims description 115
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 100
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 98
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 79
- 125000004414 alkyl thio group Chemical group 0.000 claims description 74
- 125000001153 fluoro group Chemical group F* 0.000 claims description 71
- 239000012453 solvate Substances 0.000 claims description 66
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 50
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 49
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 49
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 47
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 43
- 125000005605 benzo group Chemical group 0.000 claims description 39
- 125000001246 bromo group Chemical group Br* 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 125000002346 iodo group Chemical group I* 0.000 claims description 37
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 35
- 230000008878 coupling Effects 0.000 claims description 31
- 238000010168 coupling process Methods 0.000 claims description 31
- 238000005859 coupling reaction Methods 0.000 claims description 31
- 125000000027 (C1-C10) alkoxy group Chemical class 0.000 claims description 28
- 125000004423 acyloxy group Chemical class 0.000 claims description 22
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 201000011510 cancer Diseases 0.000 claims description 17
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 14
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- KALDBJONLIOQJS-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-iodoanilino)-n-(2-hydroxyethoxy)-1,3-benzoxazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2OC=NC=2C(F)=C1NC1=CC=C(I)C=C1F KALDBJONLIOQJS-UHFFFAOYSA-N 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 150000002443 hydroxylamines Chemical class 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- NCXQEKULAYAEMA-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-iodoanilino)-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(I)C=C1F NCXQEKULAYAEMA-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000002147 killing effect Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- ZUNDYGYIUYOIAJ-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-n-(2,3-dihydroxypropoxy)-4-fluoro-1,3-benzoxazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2OC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl ZUNDYGYIUYOIAJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 2
- ZXDBGBMTKSZKCT-UHFFFAOYSA-N 5-(4-bromo-2-fluoroanilino)-4-fluoro-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(Br)C=C1F ZXDBGBMTKSZKCT-UHFFFAOYSA-N 0.000 claims 2
- IVGFMRMTHAGJIO-UHFFFAOYSA-N 1-(2,3-dihydroxypropyl)-n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,2,3-benzothiadiazol-6-yl]cyclopropane-1-sulfonamide Chemical compound C=1C=2SN=NC=2C(F)=C(NC=2C(=CC(I)=CC=2)F)C=1NS(=O)(=O)C1(CC(O)CO)CC1 IVGFMRMTHAGJIO-UHFFFAOYSA-N 0.000 claims 1
- YLABLNGZCLLPKS-UHFFFAOYSA-N 1-(2,3-dihydroxypropyl)-n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzothiazol-6-yl]cyclopropane-1-sulfonamide Chemical compound C=1C=2SC=NC=2C(F)=C(NC=2C(=CC(I)=CC=2)F)C=1NS(=O)(=O)C1(CC(O)CO)CC1 YLABLNGZCLLPKS-UHFFFAOYSA-N 0.000 claims 1
- XYUZRPLYJMFXPG-UHFFFAOYSA-N 1-(2,3-dihydroxypropyl)-n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzoxazol-6-yl]cyclopropane-1-sulfonamide Chemical compound C=1C=2OC=NC=2C(F)=C(NC=2C(=CC(I)=CC=2)F)C=1NS(=O)(=O)C1(CC(O)CO)CC1 XYUZRPLYJMFXPG-UHFFFAOYSA-N 0.000 claims 1
- UIJWBOBUIYVDMP-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-methylsulfanylanilino)-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound FC1=CC(SC)=CC=C1NC(C(=C1)C(=O)NOCCO)=C(F)C2=C1SN=N2 UIJWBOBUIYVDMP-UHFFFAOYSA-N 0.000 claims 1
- JVFOJFCPIFTUMY-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-methylsulfanylanilino)-n-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide Chemical compound FC1=CC(SC)=CC=C1NC(C(=C1)C(=O)NOCCO)=C(F)C2=C1SC=N2 JVFOJFCPIFTUMY-UHFFFAOYSA-N 0.000 claims 1
- RHEUZYIHCYUISE-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-methylsulfanylanilino)-n-(2-hydroxyethoxy)-1,3-benzoxazole-6-carboxamide Chemical compound FC1=CC(SC)=CC=C1NC(C(=C1)C(=O)NOCCO)=C(F)C2=C1OC=N2 RHEUZYIHCYUISE-UHFFFAOYSA-N 0.000 claims 1
- HZEXVFCJGPUEAN-UHFFFAOYSA-N 4-fluoro-5-[2-fluoro-4-(trifluoromethyl)anilino]-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(C(F)(F)F)C=C1F HZEXVFCJGPUEAN-UHFFFAOYSA-N 0.000 claims 1
- JZCAXROVSARZIU-UHFFFAOYSA-N 4-fluoro-5-[2-fluoro-4-(trifluoromethyl)anilino]-n-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(C(F)(F)F)C=C1F JZCAXROVSARZIU-UHFFFAOYSA-N 0.000 claims 1
- ZEVWANKJVWLMBU-UHFFFAOYSA-N 4-fluoro-5-[2-fluoro-4-(trifluoromethyl)anilino]-n-(2-hydroxyethoxy)-1,3-benzoxazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2OC=NC=2C(F)=C1NC1=CC=C(C(F)(F)F)C=C1F ZEVWANKJVWLMBU-UHFFFAOYSA-N 0.000 claims 1
- BXJHQOBQJCTEBE-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-4-fluoro-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl BXJHQOBQJCTEBE-UHFFFAOYSA-N 0.000 claims 1
- VRBLKDMPRBQKCZ-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-4-fluoro-n-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl VRBLKDMPRBQKCZ-UHFFFAOYSA-N 0.000 claims 1
- GNCVQXJQAMRTTQ-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-n-(2,3-dihydroxypropoxy)-4-fluoro-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl GNCVQXJQAMRTTQ-UHFFFAOYSA-N 0.000 claims 1
- RDSLUYCJFHGBFK-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-n-(2,3-dihydroxypropoxy)-4-fluoro-1,3-benzothiazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl RDSLUYCJFHGBFK-UHFFFAOYSA-N 0.000 claims 1
- HOCULWJPJJSOON-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-n-(cyclopropylmethyl)-4-fluoro-1,2,3-benzothiadiazole-6-carboxamide Chemical compound C1CC1CNC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl HOCULWJPJJSOON-UHFFFAOYSA-N 0.000 claims 1
- ZZSVOGPSNAWCAK-UHFFFAOYSA-N 5-[2-chloro-4-(trifluoromethoxy)anilino]-4-fluoro-n-(2-hydroxyethoxy)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(OC(F)(F)F)C=C1Cl ZZSVOGPSNAWCAK-UHFFFAOYSA-N 0.000 claims 1
- MFLVMEMEZXFVQF-UHFFFAOYSA-N 5-[2-chloro-4-(trifluoromethoxy)anilino]-4-fluoro-n-(2-hydroxyethoxy)-1,3-benzothiazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(OC(F)(F)F)C=C1Cl MFLVMEMEZXFVQF-UHFFFAOYSA-N 0.000 claims 1
- AMXONGHWJLVQTL-UHFFFAOYSA-N 5-[2-chloro-4-(trifluoromethoxy)anilino]-4-fluoro-n-(2-hydroxyethoxy)-1,3-benzoxazole-6-carboxamide Chemical compound OCCONC(=O)C1=CC=2OC=NC=2C(F)=C1NC1=CC=C(OC(F)(F)F)C=C1Cl AMXONGHWJLVQTL-UHFFFAOYSA-N 0.000 claims 1
- YVKXPLMHOZUAJJ-UHFFFAOYSA-N n-(2,3-dihydroxypropoxy)-4-fluoro-5-(2-fluoro-4-iodoanilino)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2SN=NC=2C(F)=C1NC1=CC=C(I)C=C1F YVKXPLMHOZUAJJ-UHFFFAOYSA-N 0.000 claims 1
- ZPIQKRUUBSNJIV-UHFFFAOYSA-N n-(2,3-dihydroxypropoxy)-4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzothiazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(I)C=C1F ZPIQKRUUBSNJIV-UHFFFAOYSA-N 0.000 claims 1
- XHPSQAJXPCJPIP-UHFFFAOYSA-N n-(2,3-dihydroxypropoxy)-4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzoxazole-6-carboxamide Chemical compound OCC(O)CONC(=O)C1=CC=2OC=NC=2C(F)=C1NC1=CC=C(I)C=C1F XHPSQAJXPCJPIP-UHFFFAOYSA-N 0.000 claims 1
- SJHCMRCSWRLRJV-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-fluoro-5-(2-fluoro-4-iodoanilino)-1,2,3-benzothiadiazole-6-carboxamide Chemical compound FC1=CC(I)=CC=C1NC(C(=C1)C(=O)NCC2CC2)=C(F)C2=C1SN=N2 SJHCMRCSWRLRJV-UHFFFAOYSA-N 0.000 claims 1
- MZYPAEXPISOZOC-UHFFFAOYSA-N n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,2,3-benzothiadiazol-6-yl]cyclopropanesulfonamide Chemical compound FC1=CC(I)=CC=C1NC(C(=C1N=NSC1=C1)F)=C1NS(=O)(=O)C1CC1 MZYPAEXPISOZOC-UHFFFAOYSA-N 0.000 claims 1
- CWBQVQKLFOWIQT-UHFFFAOYSA-N n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzothiazol-6-yl]cyclopropanesulfonamide Chemical compound FC1=CC(I)=CC=C1NC(C(=C1)NS(=O)(=O)C2CC2)=C(F)C2=C1SC=N2 CWBQVQKLFOWIQT-UHFFFAOYSA-N 0.000 claims 1
- AQUXUXBXROMQDQ-UHFFFAOYSA-N n-[4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzoxazol-6-yl]cyclopropanesulfonamide Chemical compound FC1=CC(I)=CC=C1NC(C(=C1)NS(=O)(=O)C2CC2)=C(F)C2=C1OC=N2 AQUXUXBXROMQDQ-UHFFFAOYSA-N 0.000 claims 1
- QIUSAXDTVFDSSC-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,2,3-benzothiadiazol-6-yl]-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Chemical compound C=1C=2SN=NC=2C(F)=C(NC=2C(=CC(Br)=CC=2)Cl)C=1NS(=O)(=O)C1(CC(O)CO)CC1 QIUSAXDTVFDSSC-UHFFFAOYSA-N 0.000 claims 1
- LFUHXJFYAXLVKX-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,2,3-benzothiadiazol-6-yl]cyclopropanesulfonamide Chemical compound C1CC1S(=O)(=O)NC1=CC=2SN=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl LFUHXJFYAXLVKX-UHFFFAOYSA-N 0.000 claims 1
- AITYBOUARXLEQK-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,3-benzothiazol-6-yl]-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Chemical compound C=1C=2SC=NC=2C(F)=C(NC=2C(=CC(Br)=CC=2)Cl)C=1NS(=O)(=O)C1(CC(O)CO)CC1 AITYBOUARXLEQK-UHFFFAOYSA-N 0.000 claims 1
- RFWUBRVJSLVOKP-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,3-benzothiazol-6-yl]cyclopropanesulfonamide Chemical compound C1CC1S(=O)(=O)NC1=CC=2SC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl RFWUBRVJSLVOKP-UHFFFAOYSA-N 0.000 claims 1
- LMOJIIIBWFTGPF-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,3-benzoxazol-6-yl]-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Chemical compound C=1C=2OC=NC=2C(F)=C(NC=2C(=CC(Br)=CC=2)Cl)C=1NS(=O)(=O)C1(CC(O)CO)CC1 LMOJIIIBWFTGPF-UHFFFAOYSA-N 0.000 claims 1
- NDQJPHQEBUKDIR-UHFFFAOYSA-N n-[5-(4-bromo-2-chloroanilino)-4-fluoro-1,3-benzoxazol-6-yl]cyclopropanesulfonamide Chemical compound C1CC1S(=O)(=O)NC1=CC=2OC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl NDQJPHQEBUKDIR-UHFFFAOYSA-N 0.000 claims 1
- 239000000651 prodrug Substances 0.000 abstract description 64
- 229940002612 prodrug Drugs 0.000 abstract description 64
- 238000011282 treatment Methods 0.000 abstract description 19
- 241000124008 Mammalia Species 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 102000001253 Protein Kinase Human genes 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 108060006633 protein kinase Proteins 0.000 abstract description 5
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 abstract description 3
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 abstract description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract 2
- 230000004054 inflammatory process Effects 0.000 abstract 2
- 229940000406 drug candidate Drugs 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 184
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 156
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 128
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 120
- 239000002585 base Substances 0.000 description 110
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 125000001072 heteroaryl group Chemical group 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000006243 chemical reaction Methods 0.000 description 72
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 71
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 63
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 63
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 239000003153 chemical reaction reagent Substances 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 59
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 52
- 238000010626 work up procedure Methods 0.000 description 52
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- 239000002253 acid Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 125000003545 alkoxy group Chemical group 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
- 239000000460 chlorine Substances 0.000 description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 40
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 40
- 125000003342 alkenyl group Chemical group 0.000 description 40
- 125000000304 alkynyl group Chemical group 0.000 description 39
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 38
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 36
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 35
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 34
- 239000003054 catalyst Substances 0.000 description 34
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Landscapes
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| CN201210014021.X | 2012-01-17 | ||
| CN201210014021 | 2012-01-17 | ||
| CN201210189087.2 | 2012-06-08 | ||
| CN201210190520.4 | 2012-06-08 | ||
| CN201210189086.8A CN103204822B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噁唑化合物及其制备方法和用途 |
| CN201210189087.2A CN103204827B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噻二唑化合物及其制备方法和用途 |
| CN201210190520.4A CN103204825B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噻唑化合物及其制备方法和用途 |
| CN201210189086.8 | 2012-06-08 | ||
| PCT/CN2013/000037 WO2013107283A1 (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
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| CN104710417B (zh) * | 2013-12-11 | 2020-09-08 | 上海科州药物研发有限公司 | 氮杂吲哚类衍生物及其合成方法 |
| CN105384738B (zh) * | 2014-08-21 | 2017-08-29 | 上海科州药物研发有限公司 | 作为蛋白激酶抑制剂的杂环类化合物及其制备方法和用途 |
| CN105859543A (zh) * | 2016-05-06 | 2016-08-17 | 蚌埠中实化学技术有限公司 | 一种2,6-二氟-4-溴苯甲酰氯的制备方法 |
| CN111205244B (zh) * | 2018-11-22 | 2023-08-18 | 上海科技大学 | 噻唑并环类化合物、其制备方法、中间体和应用 |
| AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
| KR20220098759A (ko) | 2019-11-08 | 2022-07-12 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 키나제 억제제에 대해 내성을 획득한 암의 치료 방법 |
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| CN113440616A (zh) * | 2020-03-25 | 2021-09-28 | 上海科州药物研发有限公司 | Ras或raf突变型癌症的联合疗法 |
| EP4663631A1 (en) * | 2023-02-10 | 2025-12-17 | Shanghai Kechow Pharma, Inc. | Polymorph as protein kinase mek inhibitor, and preparation method therefor and use thereof |
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| WO2005007616A1 (en) | 2003-07-23 | 2005-01-27 | Warner-Lambert Company Llc | Diphenylamino ketone derivatives as mek inhibitors |
| WO2005009975A2 (en) | 2003-07-24 | 2005-02-03 | Warner-Lambert Company Llc | Benzimidazole derivatives as mek inhibitors |
| US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| WO2005046665A1 (en) | 2003-11-13 | 2005-05-26 | Warner-Lambert Company Llc | Combination chemotherapy comprising a mek inhibitor and a erbb1/2 receptor inhibitor |
| JP4869075B2 (ja) | 2003-11-19 | 2012-02-01 | アレイ バイオファーマ、インコーポレイテッド | Mekの複素環阻害剤及びその使用方法 |
| RU2500673C2 (ru) | 2005-05-18 | 2013-12-10 | Астразенека Аб | Гетероциклические ингибиторы мек и способы их применения |
| WO2006134469A1 (en) | 2005-06-14 | 2006-12-21 | Warner-Lambert Company Llc | Methods of preparing mek inhibitor |
| FR2887882B1 (fr) * | 2005-07-01 | 2007-09-07 | Sanofi Aventis Sa | Derives de pyrido[2,3-d] pyrimidine, leur preparation, leur application en therapeutique |
| US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
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2012
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- 2012-06-08 CN CN201210190520.4A patent/CN103204825B/zh active Active
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2013
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- 2013-01-16 WO PCT/CN2013/000037 patent/WO2013107283A1/en not_active Ceased
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| WO2013107283A1 (en) | 2013-07-25 |
| CN103204822A (zh) | 2013-07-17 |
| CN103204822B (zh) | 2014-12-03 |
| CA2897259A1 (en) | 2013-07-25 |
| AU2013201455B2 (en) | 2015-07-23 |
| US20160235721A1 (en) | 2016-08-18 |
| US9290468B2 (en) | 2016-03-22 |
| CN103204825B (zh) | 2015-03-04 |
| CN103204825A (zh) | 2013-07-17 |
| AU2013201455A8 (en) | 2016-04-14 |
| NZ627631A (en) | 2016-10-28 |
| CN103204827B (zh) | 2014-12-03 |
| HK1203486A1 (en) | 2015-10-30 |
| EP2804855A1 (en) | 2014-11-26 |
| EP2804855B1 (en) | 2017-09-20 |
| JP2015503597A (ja) | 2015-02-02 |
| AU2013201455A1 (en) | 2013-08-01 |
| EP2804855A4 (en) | 2015-07-29 |
| US9937158B2 (en) | 2018-04-10 |
| AU2013201455C1 (en) | 2016-01-21 |
| CN103204827A (zh) | 2013-07-17 |
| US20140371278A1 (en) | 2014-12-18 |
| JP6077006B2 (ja) | 2017-02-08 |
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