JP4869075B2 - Mekの複素環阻害剤及びその使用方法 - Google Patents
Mekの複素環阻害剤及びその使用方法 Download PDFInfo
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- JP4869075B2 JP4869075B2 JP2006541581A JP2006541581A JP4869075B2 JP 4869075 B2 JP4869075 B2 JP 4869075B2 JP 2006541581 A JP2006541581 A JP 2006541581A JP 2006541581 A JP2006541581 A JP 2006541581A JP 4869075 B2 JP4869075 B2 JP 4869075B2
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- JP
- Japan
- Prior art keywords
- oxo
- alkyl
- aryl
- carboxylic acid
- heteroaryl
- 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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- 238000000034 method Methods 0.000 title claims abstract description 71
- 239000003112 inhibitor Substances 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 238000011282 treatment Methods 0.000 claims abstract description 44
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 19
- 230000004968 inflammatory condition Effects 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims description 225
- 125000001072 heteroaryl group Chemical group 0.000 claims description 222
- 125000000623 heterocyclic group Chemical group 0.000 claims description 191
- 125000000217 alkyl group Chemical group 0.000 claims description 151
- -1 methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl Chemical group 0.000 claims description 140
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 138
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 126
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 118
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 106
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 93
- 150000002367 halogens Chemical class 0.000 claims description 91
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 85
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 79
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 61
- 125000003342 alkenyl group Chemical group 0.000 claims description 59
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 51
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 claims description 48
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 42
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 38
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 36
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 35
- 125000000304 alkynyl group Chemical group 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 150000001350 alkyl halides Chemical class 0.000 claims description 27
- 150000001412 amines Chemical class 0.000 claims description 25
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 25
- 125000004429 atom Chemical group 0.000 claims description 21
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 21
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 18
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 17
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 16
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 125000000539 amino acid group Chemical group 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- 150000001448 anilines Chemical class 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 5
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 4
- OEUDFZQKJRTOKB-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-1-methyl-6-oxopyridine-3-carboxylic acid Chemical compound C1=CC(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(O)=O OEUDFZQKJRTOKB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 3
- OBBCQHYXZOIRNT-UHFFFAOYSA-N azido(nitro)cyanamide Chemical group [O-][N+](=O)N(C#N)N=[N+]=[N-] OBBCQHYXZOIRNT-UHFFFAOYSA-N 0.000 claims 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- FDXXPGVUUMVTHN-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-1-ethyl-n-(2-hydroxyethoxy)-6-oxopyridine-3-carboxamide Chemical compound C1=CC(=O)N(CC)C(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)NOCCO FDXXPGVUUMVTHN-UHFFFAOYSA-N 0.000 claims 1
- WFMGYZPZHPBZOS-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-5-fluoro-n-(2-hydroxyethoxy)-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1=C(F)C(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)NOCCO WFMGYZPZHPBZOS-UHFFFAOYSA-N 0.000 claims 1
- SCSJIUZYMBEKRI-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-6-oxo-1h-pyridine-3-carboxylic acid Chemical compound C1=CC(=O)NC(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)O SCSJIUZYMBEKRI-UHFFFAOYSA-N 0.000 claims 1
- OZZVLOZIMNKALQ-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-n-(2-hydroxyethoxy)-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1=CC(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)NOCCO OZZVLOZIMNKALQ-UHFFFAOYSA-N 0.000 claims 1
- MLRXZLSTMKQNNP-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-n-(cyclopropylmethoxy)-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1CC1CONC(=O)C=1C=CC(=O)N(C)C=1NC1=CC=C(Br)C=C1F MLRXZLSTMKQNNP-UHFFFAOYSA-N 0.000 claims 1
- FXHXPQKYSJDDMN-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-n-(cyclopropylmethoxy)-6-oxo-1h-pyridine-3-carboxamide Chemical compound FC1=CC(Br)=CC=C1NC1=C(C(=O)NOCC2CC2)C=CC(=O)N1 FXHXPQKYSJDDMN-UHFFFAOYSA-N 0.000 claims 1
- WWWTWPXKLJTKPM-UHFFFAOYSA-N 2-aminooxyethanol Chemical compound NOCCO WWWTWPXKLJTKPM-UHFFFAOYSA-N 0.000 claims 1
- XTQPPYUFHHLQSR-UHFFFAOYSA-N 5-bromo-2-(4-bromo-2-fluoroanilino)-1-methyl-6-oxopyridine-3-carboxylic acid Chemical compound C1=C(Br)C(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(O)=O XTQPPYUFHHLQSR-UHFFFAOYSA-N 0.000 claims 1
- AKZQKYBWJARSLG-UHFFFAOYSA-N 5-bromo-2-(4-bromo-2-fluoroanilino)-n-(2-hydroxyethoxy)-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1=C(Br)C(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)NOCCO AKZQKYBWJARSLG-UHFFFAOYSA-N 0.000 claims 1
- BLQOLWHCGVTVNJ-UHFFFAOYSA-N N-methoxy-1-methyl-6-oxopyridine-3-carboxamide Chemical compound CONC(=O)C1=CN(C(C=C1)=O)C BLQOLWHCGVTVNJ-UHFFFAOYSA-N 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 51
- 239000000651 prodrug Substances 0.000 abstract description 51
- 229940002612 prodrug Drugs 0.000 abstract description 51
- 241000124008 Mammalia Species 0.000 abstract description 35
- 201000010099 disease Diseases 0.000 abstract description 29
- 206010028980 Neoplasm Diseases 0.000 abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 20
- 201000011510 cancer Diseases 0.000 abstract description 11
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 157
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 144
- 239000011541 reaction mixture Substances 0.000 description 80
- 239000000243 solution Substances 0.000 description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 72
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- 239000000203 mixture Substances 0.000 description 61
- 239000000047 product Substances 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
- 238000002360 preparation method Methods 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
- 239000003960 organic solvent Substances 0.000 description 50
- 230000002829 reductive effect Effects 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000002585 base Substances 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 150000001408 amides Chemical class 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 28
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 28
- 238000003756 stirring Methods 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 25
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 24
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 23
- 239000000284 extract Substances 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 22
- 239000012267 brine Substances 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 208000035475 disorder Diseases 0.000 description 21
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
- 230000029936 alkylation Effects 0.000 description 20
- 238000005804 alkylation reaction Methods 0.000 description 20
- 239000000460 chlorine Chemical group 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- 238000005859 coupling reaction Methods 0.000 description 19
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 19
- 230000001404 mediated effect Effects 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 230000002159 abnormal effect Effects 0.000 description 17
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 16
- 238000006880 cross-coupling reaction Methods 0.000 description 16
- 238000007363 ring formation reaction Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 230000004913 activation Effects 0.000 description 15
- 150000001299 aldehydes Chemical class 0.000 description 15
- 150000004702 methyl esters Chemical class 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 14
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 14
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 230000010261 cell growth Effects 0.000 description 12
- 230000008878 coupling Effects 0.000 description 12
- 238000010168 coupling process Methods 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 238000005660 chlorination reaction Methods 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- 230000026030 halogenation Effects 0.000 description 10
- 238000005658 halogenation reaction Methods 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 238000001665 trituration Methods 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000003682 fluorination reaction Methods 0.000 description 8
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000007127 saponification reaction Methods 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- KQLHRXQKORXSTC-UHFFFAOYSA-N 3-amino-1h-pyrazin-2-one Chemical compound NC1=NC=CNC1=O KQLHRXQKORXSTC-UHFFFAOYSA-N 0.000 description 7
- 229940124647 MEK inhibitor Drugs 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 125000002837 carbocyclic group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 239000003102 growth factor Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 239000002207 metabolite Substances 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical compound O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 239000003765 sweetening agent Substances 0.000 description 7
- AJPKQSSFYHPYMH-UHFFFAOYSA-N 2,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1Cl AJPKQSSFYHPYMH-UHFFFAOYSA-N 0.000 description 6
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
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Classifications
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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