CA2771673C - Compounds and compositions as protein kinase inhibitors - Google Patents
Compounds and compositions as protein kinase inhibitors Download PDFInfo
- Publication number
- CA2771673C CA2771673C CA2771673A CA2771673A CA2771673C CA 2771673 C CA2771673 C CA 2771673C CA 2771673 A CA2771673 A CA 2771673A CA 2771673 A CA2771673 A CA 2771673A CA 2771673 C CA2771673 C CA 2771673C
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- alkyl
- imidazol
- chloro
- mmol
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 113
- 239000000203 mixture Substances 0.000 title description 107
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 92
- 125000000217 alkyl group Chemical group 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 61
- -1 -C(O)NH2 Chemical group 0.000 claims description 52
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000002947 alkylene group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000006442 t-butyl cyclopropyl group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- LGMVHJUXPHGDLP-NSHDSACASA-N methyl n-[(2s)-1-[[4-[2-cyclopropyl-4-[2,5-dichloro-3-(methanesulfonamido)phenyl]-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)Cl)=N1 LGMVHJUXPHGDLP-NSHDSACASA-N 0.000 claims 1
- HFOSTMUUQSEZEJ-NSHDSACASA-N methyl n-[(2s)-1-[[4-[2-cyclopropyl-4-[2,5-difluoro-3-(methanesulfonamido)phenyl]-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)F)=N1 HFOSTMUUQSEZEJ-NSHDSACASA-N 0.000 claims 1
- NKKOLHWQHWBPAP-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[2-cyclopropyl-4-[2-fluoro-3-(methanesulfonamido)-5-methylphenyl]-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(C)C=2)F)=N1 NKKOLHWQHWBPAP-ZDUSSCGKSA-N 0.000 claims 1
- GKCIDSIFAMSUJW-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[2-cyclopropyl-4-[2-fluoro-3-(methanesulfonamido)phenyl]-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=CC=2)F)=N1 GKCIDSIFAMSUJW-LBPRGKRZSA-N 0.000 claims 1
- OKGNZEREGSRADT-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-3-(cyclopropylsulfonylamino)-5-fluorophenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(=O)(=O)C3CC3)C=C(F)C=2)Cl)=N1 OKGNZEREGSRADT-LBPRGKRZSA-N 0.000 claims 1
- HKTFGEGWADCNRV-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-3-(ethylsulfonylamino)-5-fluorophenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCS(=O)(=O)NC1=CC(F)=CC(C2=C(NC(=N2)C2CC2)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1Cl HKTFGEGWADCNRV-LBPRGKRZSA-N 0.000 claims 1
- CCKVIZBHVHATDV-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-3-(methanesulfonamido)-5-methylphenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(C)C=2)Cl)=N1 CCKVIZBHVHATDV-ZDUSSCGKSA-N 0.000 claims 1
- QYXRSOAMFKXRCU-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-3-(methanesulfonamido)phenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=CC=2)Cl)=N1 QYXRSOAMFKXRCU-LBPRGKRZSA-N 0.000 claims 1
- USTQEUSYKXURJE-NSHDSACASA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-5-fluoro-3-(methanesulfonamido)phenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 USTQEUSYKXURJE-NSHDSACASA-N 0.000 claims 1
- RXVJOHHWPJUJPH-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[4-[2-fluoro-3-(methanesulfonamido)-5-methylphenyl]-2-(1-methylcyclopropyl)-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2(C)CC2)C=2C(=C(NS(C)(=O)=O)C=C(C)C=2)F)=N1 RXVJOHHWPJUJPH-AWEZNQCLSA-N 0.000 claims 1
- YCCLPJNCXZAVHV-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-2-fluoro-3-(3,3,3-trifluoropropylsulfonylamino)phenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2CC2)C=2C(=C(NS(=O)(=O)CCC(F)(F)F)C=C(Cl)C=2)F)=N1 YCCLPJNCXZAVHV-LBPRGKRZSA-N 0.000 claims 1
- YNMUPDMDSKNHHL-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-2-(1-methylcyclopropyl)-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2(C)CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 YNMUPDMDSKNHHL-LBPRGKRZSA-N 0.000 claims 1
- FAGJFBOKLUFLLZ-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-2-fluoro-3-[(3-fluorophenyl)sulfonylamino]phenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2CC2)C=2C(=C(NS(=O)(=O)C=3C=C(F)C=CC=3)C=C(Cl)C=2)F)=N1 FAGJFBOKLUFLLZ-AWEZNQCLSA-N 0.000 claims 1
- AFASZXUNTTVSQE-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-2-fluoro-3-[(4-fluorophenyl)sulfonylamino]phenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2CC2)C=2C(=C(NS(=O)(=O)C=3C=CC(F)=CC=3)C=C(Cl)C=2)F)=N1 AFASZXUNTTVSQE-AWEZNQCLSA-N 0.000 claims 1
- PSDDRKAIAAMWIZ-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-3-(cyclopropylsulfonylamino)-2-fluorophenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=C(NC(=N2)C2CC2)C=2C(=C(NS(=O)(=O)C3CC3)C=C(Cl)C=2)F)=N1 PSDDRKAIAAMWIZ-LBPRGKRZSA-N 0.000 claims 1
- PWMKVDVQZIUERF-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-3-(ethylsulfonylamino)-2-fluorophenyl]-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(N=C(N2)C2CC2)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F PWMKVDVQZIUERF-LBPRGKRZSA-N 0.000 claims 1
- VDVHEBQEJCHLCN-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound ClC=1C(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=CC(F)=CC=1NS(=O)(=O)C1=C(F)C=CC=C1F VDVHEBQEJCHLCN-UHFFFAOYSA-N 0.000 claims 1
- XJNXDPBTZPNVPO-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(F)=CC(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=C1Cl XJNXDPBTZPNVPO-UHFFFAOYSA-N 0.000 claims 1
- DMNKAFXXZZAQNF-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=C1Cl DMNKAFXXZZAQNF-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 224
- 238000006243 chemical reaction Methods 0.000 description 166
- 239000000243 solution Substances 0.000 description 161
- 238000002360 preparation method Methods 0.000 description 134
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
- 230000014759 maintenance of location Effects 0.000 description 96
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- 239000011541 reaction mixture Substances 0.000 description 85
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 81
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 67
- 239000012267 brine Substances 0.000 description 65
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000010410 layer Substances 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 45
- 238000003818 flash chromatography Methods 0.000 description 42
- 238000000034 method Methods 0.000 description 42
- 238000000746 purification Methods 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 101150041968 CDC13 gene Proteins 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000003921 oil Substances 0.000 description 35
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 34
- 229910052681 coesite Inorganic materials 0.000 description 34
- 229910052906 cristobalite Inorganic materials 0.000 description 34
- 229910052682 stishovite Inorganic materials 0.000 description 34
- 229910052905 tridymite Inorganic materials 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000007792 addition Methods 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 28
- 239000000543 intermediate Substances 0.000 description 28
- 239000000463 material Substances 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 25
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 229940124530 sulfonamide Drugs 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 description 17
- 235000017550 sodium carbonate Nutrition 0.000 description 17
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 125000001207 fluorophenyl group Chemical group 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 11
- 108091000080 Phosphotransferase Proteins 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 102000020233 phosphotransferase Human genes 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 10
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- VQGISNOMGHCEPX-UHFFFAOYSA-N propanenitrile Chemical compound C[CH]C#N VQGISNOMGHCEPX-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000013058 crude material Substances 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 8
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- DWBWMAAYLWUXQK-UHFFFAOYSA-N 2,3-difluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(F)=C1F DWBWMAAYLWUXQK-UHFFFAOYSA-N 0.000 description 6
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
- 101150009274 nhr-1 gene Proteins 0.000 description 6
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229940015043 glyoxal Drugs 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 5
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- JQXZBJAAOLPTKP-LURJTMIESA-N tert-butyl n-[(2s)-1-aminopropan-2-yl]carbamate Chemical compound NC[C@H](C)NC(=O)OC(C)(C)C JQXZBJAAOLPTKP-LURJTMIESA-N 0.000 description 5
- HIZADWSSPWORHH-UHFFFAOYSA-N 3-bromo-2,6-difluoroaniline Chemical compound NC1=C(F)C=CC(Br)=C1F HIZADWSSPWORHH-UHFFFAOYSA-N 0.000 description 4
- YZGMWJRUAGKYER-UHFFFAOYSA-N 3-bromo-2-chloro-5-fluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1Cl YZGMWJRUAGKYER-UHFFFAOYSA-N 0.000 description 4
- CSHMFIIPOVGVDN-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluoroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1F CSHMFIIPOVGVDN-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- 108010077182 raf Kinases Proteins 0.000 description 4
- 102000009929 raf Kinases Human genes 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 239000003039 volatile agent Substances 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 3
- XTTZFLRDPMATAY-UHFFFAOYSA-N 1-bromo-2,5-dichloro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(Br)=C1Cl XTTZFLRDPMATAY-UHFFFAOYSA-N 0.000 description 3
- AUAXYMOBWXOEQD-UHFFFAOYSA-N 2,5-dichloro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl AUAXYMOBWXOEQD-UHFFFAOYSA-N 0.000 description 3
- AXHRGVJWDJDYPO-UHFFFAOYSA-N 2-bromo-1h-imidazole Chemical compound BrC1=NC=CN1 AXHRGVJWDJDYPO-UHFFFAOYSA-N 0.000 description 3
- GDIMNXJSMJSDSB-UHFFFAOYSA-N 3-amino-2-methylpropanenitrile Chemical compound NCC(C)C#N GDIMNXJSMJSDSB-UHFFFAOYSA-N 0.000 description 3
- WEBVJSPIUIPJKV-UHFFFAOYSA-N 3-bromo-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(Br)=C1F WEBVJSPIUIPJKV-UHFFFAOYSA-N 0.000 description 3
- HKNLHCGTRMCOLV-UHFFFAOYSA-N 3-bromo-2-chloroaniline Chemical compound NC1=CC=CC(Br)=C1Cl HKNLHCGTRMCOLV-UHFFFAOYSA-N 0.000 description 3
- HYPQOSVTIONWSN-UHFFFAOYSA-N 3-bromo-2-fluoroaniline Chemical compound NC1=CC=CC(Br)=C1F HYPQOSVTIONWSN-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000006286 aqueous extract Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Chemical class Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Chemical class 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 238000006138 lithiation reaction Methods 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- OTOUMEDPEMHRQN-UHFFFAOYSA-N n-(3-bromo-2,6-difluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=C(F)C=CC(Br)=C1F OTOUMEDPEMHRQN-UHFFFAOYSA-N 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- ROQBTCYBYFOFJH-UHFFFAOYSA-N tert-butyl n-(3-bromo-5-chloro-2-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Cl)=CC(Br)=C1F ROQBTCYBYFOFJH-UHFFFAOYSA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- PZKDJJMHRYNBOR-UHFFFAOYSA-N 1,3-dibromo-2-chloro-5-fluorobenzene Chemical compound FC1=CC(Br)=C(Cl)C(Br)=C1 PZKDJJMHRYNBOR-UHFFFAOYSA-N 0.000 description 2
- WICRKCABAQJKSY-UHFFFAOYSA-N 1-(aminomethyl)cyclopropane-1-carbonitrile Chemical compound NCC1(C#N)CC1 WICRKCABAQJKSY-UHFFFAOYSA-N 0.000 description 2
- JNIDAGAFFKAPRV-UHFFFAOYSA-N 1-bromo-2-chloro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1Cl JNIDAGAFFKAPRV-UHFFFAOYSA-N 0.000 description 2
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 2
- JCGGPCDDFXIVQB-UHFFFAOYSA-N 2,4,5-tribromo-1h-imidazole Chemical compound BrC1=NC(Br)=C(Br)N1 JCGGPCDDFXIVQB-UHFFFAOYSA-N 0.000 description 2
- CTUNHIMNHSKDBN-UHFFFAOYSA-N 2-tert-butyl-1h-imidazole Chemical compound CC(C)(C)C1=NC=CN1 CTUNHIMNHSKDBN-UHFFFAOYSA-N 0.000 description 2
- PCALPXHVQPTOER-UHFFFAOYSA-N 3,6-dichloro-2-nitrobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC(Cl)=C1[N+]([O-])=O PCALPXHVQPTOER-UHFFFAOYSA-N 0.000 description 2
- ZEQKZRGDHYMUHS-UHFFFAOYSA-N 3-bromo-2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1Cl ZEQKZRGDHYMUHS-UHFFFAOYSA-N 0.000 description 2
- JBGGFYZUDGDHMN-UHFFFAOYSA-N 3-bromo-2,5-difluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1F JBGGFYZUDGDHMN-UHFFFAOYSA-N 0.000 description 2
- RXLNTBOIPLOOEA-UHFFFAOYSA-N 3-bromo-2-chloro-5-methylaniline Chemical compound CC1=CC(N)=C(Cl)C(Br)=C1 RXLNTBOIPLOOEA-UHFFFAOYSA-N 0.000 description 2
- KNPUHWXDXJQPOD-UHFFFAOYSA-N 3-bromo-2-fluoro-5-methylaniline Chemical compound CC1=CC(N)=C(F)C(Br)=C1 KNPUHWXDXJQPOD-UHFFFAOYSA-N 0.000 description 2
- JFAQBRSYTNDGBL-UHFFFAOYSA-N 3-bromo-2-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(Br)=C(F)C(C(O)=O)=C1 JFAQBRSYTNDGBL-UHFFFAOYSA-N 0.000 description 2
- ZSCAXCZFFCKFAE-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Br)=C1F ZSCAXCZFFCKFAE-UHFFFAOYSA-N 0.000 description 2
- MYYYOBVDIRECDX-UHFFFAOYSA-N 4,5-dibromo-1h-imidazole Chemical compound BrC=1N=CNC=1Br MYYYOBVDIRECDX-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- QYZBCWXZSYTIOY-UHFFFAOYSA-N Mercuric oxide Chemical compound [O-2].[Hg+2] QYZBCWXZSYTIOY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical class [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
- 239000012965 benzophenone Substances 0.000 description 2
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- XNPLKJNMBAWPTC-UHFFFAOYSA-N n-(3-bromo-2-fluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(Br)=C1F XNPLKJNMBAWPTC-UHFFFAOYSA-N 0.000 description 2
- TYVZMDXOAAZCMM-UHFFFAOYSA-N n-(3-bromo-5-methylphenyl)propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)NC1=CC(C)=CC(Br)=C1 TYVZMDXOAAZCMM-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- BSBUYMURKFVOJK-UHFFFAOYSA-N tert-butyl n-(3-bromo-2-fluoro-5-methylphenyl)carbamate Chemical compound CC1=CC(Br)=C(F)C(NC(=O)OC(C)(C)C)=C1 BSBUYMURKFVOJK-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- NREKOPMQTPPZNS-UHFFFAOYSA-N (3-bromo-2,6-difluorophenyl)carbamic acid Chemical compound OC(=O)NC1=C(F)C=CC(Br)=C1F NREKOPMQTPPZNS-UHFFFAOYSA-N 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QTZSKHCRRPXONC-UHFFFAOYSA-N 1,3-dibromo-2,5-difluorobenzene Chemical compound FC1=CC(Br)=C(F)C(Br)=C1 QTZSKHCRRPXONC-UHFFFAOYSA-N 0.000 description 1
- HVPWZGWQKWAJMQ-UHFFFAOYSA-N 1,3-dibromo-2-chloro-5-methylbenzene Chemical compound CC1=CC(Br)=C(Cl)C(Br)=C1 HVPWZGWQKWAJMQ-UHFFFAOYSA-N 0.000 description 1
- HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
- XTCIFWCZYRHDOF-UHFFFAOYSA-N 1-[(1,3-dioxoisoindol-2-yl)methyl]cyclopropane-1-carbonitrile Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1(C#N)CC1 XTCIFWCZYRHDOF-UHFFFAOYSA-N 0.000 description 1
- ZHWWPRBSUHITHG-UHFFFAOYSA-N 1-aminopropan-2-ylcarbamic acid Chemical compound NCC(C)NC(O)=O ZHWWPRBSUHITHG-UHFFFAOYSA-N 0.000 description 1
- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 1
- MWYFDHRLYOKUMH-UHFFFAOYSA-N 1-bromo-2-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1F MWYFDHRLYOKUMH-UHFFFAOYSA-N 0.000 description 1
- OOWPZKIOAPIRQZ-UHFFFAOYSA-N 1-bromo-3-(difluoromethoxy)-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC(OC(F)F)=C1 OOWPZKIOAPIRQZ-UHFFFAOYSA-N 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
- QVTQYSFCFOGITD-UHFFFAOYSA-N 2,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1Cl QVTQYSFCFOGITD-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- GBESIUPWXGQOFP-UHFFFAOYSA-N 2-bromo-1-chloro-3-fluorobenzene Chemical compound FC1=CC=CC(Cl)=C1Br GBESIUPWXGQOFP-UHFFFAOYSA-N 0.000 description 1
- QLRKALMVPCQTMU-UHFFFAOYSA-N 2-bromo-1-fluoro-4-methylbenzene Chemical compound CC1=CC=C(F)C(Br)=C1 QLRKALMVPCQTMU-UHFFFAOYSA-N 0.000 description 1
- YFFUYGSLQXVHMB-UHFFFAOYSA-N 2-bromo-4-chloro-1-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1Br YFFUYGSLQXVHMB-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BWAYZLJQQXIODW-UHFFFAOYSA-N 3-bromo-2-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Br)=C1Cl BWAYZLJQQXIODW-UHFFFAOYSA-N 0.000 description 1
- SMWXBKRWRZKILZ-UHFFFAOYSA-N 3-bromo-2-chloro-5-fluoroaniline;hydron;chloride Chemical compound Cl.NC1=CC(F)=CC(Br)=C1Cl SMWXBKRWRZKILZ-UHFFFAOYSA-N 0.000 description 1
- BSJSHGSLFVAXAK-UHFFFAOYSA-N 3-bromo-5-(difluoromethoxy)aniline Chemical compound NC1=CC(Br)=CC(OC(F)F)=C1 BSJSHGSLFVAXAK-UHFFFAOYSA-N 0.000 description 1
- YYBRLVWWPRAQDX-UHFFFAOYSA-N 3-bromo-5-chloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1 YYBRLVWWPRAQDX-UHFFFAOYSA-N 0.000 description 1
- YIZRPAWCIFTHNA-UHFFFAOYSA-N 3-bromo-5-methylaniline Chemical compound CC1=CC(N)=CC(Br)=C1 YIZRPAWCIFTHNA-UHFFFAOYSA-N 0.000 description 1
- VJQGLUHOAIZTNK-UHFFFAOYSA-N 3-bromo-5-nitrophenol Chemical compound OC1=CC(Br)=CC([N+]([O-])=O)=C1 VJQGLUHOAIZTNK-UHFFFAOYSA-N 0.000 description 1
- JRQDVRIQJJPHEQ-UHFFFAOYSA-N 3970-35-2 Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl JRQDVRIQJJPHEQ-UHFFFAOYSA-N 0.000 description 1
- MQWXUMPGBOMYOC-UHFFFAOYSA-N 4,5-dibromo-2-tert-butyl-1h-imidazole Chemical compound CC(C)(C)C1=NC(Br)=C(Br)N1 MQWXUMPGBOMYOC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- XTZNLELDRXUAOX-UHFFFAOYSA-N 5-bromo-1-methoxy-2-methyl-3-nitrobenzene Chemical compound COC1=CC(Br)=CC([N+]([O-])=O)=C1C XTZNLELDRXUAOX-UHFFFAOYSA-N 0.000 description 1
- 101150019464 ARAF gene Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100029381 CMRF35-like molecule 5 Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101100127166 Escherichia coli (strain K12) kefB gene Proteins 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 101000990038 Homo sapiens CMRF35-like molecule 5 Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108700012928 MAPK14 Proteins 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101150003567 Mapk12 gene Proteins 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- GYCMBHHDWRMZGG-UHFFFAOYSA-N Methylacrylonitrile Chemical compound CC(=C)C#N GYCMBHHDWRMZGG-UHFFFAOYSA-N 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 1
- 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 1
- 102000054819 Mitogen-activated protein kinase 14 Human genes 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910021120 PdC12 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 240000006413 Prunus persica var. persica Species 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 229940123690 Raf kinase inhibitor Drugs 0.000 description 1
- 101150105578 SAPK3 gene Proteins 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 101150082971 Sgk1 gene Proteins 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 241000287181 Sturnus vulgaris Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ALMFIOZYDASRRC-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(C(F)(F)F)C=C1 ALMFIOZYDASRRC-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- FDZLCIITHLSEQK-UHFFFAOYSA-N ethyl 1-cyanocyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(C#N)CC1 FDZLCIITHLSEQK-UHFFFAOYSA-N 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- DTVBZYSSZUCODC-WCCKRBBISA-N methyl n-[(2s)-1-aminopropan-2-yl]carbamate;hydrochloride Chemical compound Cl.COC(=O)N[C@@H](C)CN DTVBZYSSZUCODC-WCCKRBBISA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- DJQVTWXPVHCLSW-UHFFFAOYSA-N n-(3-bromo-2-chloro-5-fluorophenyl)-1,1-diphenylmethanimine Chemical compound FC1=CC(Br)=C(Cl)C(N=C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 DJQVTWXPVHCLSW-UHFFFAOYSA-N 0.000 description 1
- KJUFNBQYBZTFRU-UHFFFAOYSA-N n-(3-bromo-2-chlorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(Br)=C1Cl KJUFNBQYBZTFRU-UHFFFAOYSA-N 0.000 description 1
- RYQGTYVUUPMJQF-UHFFFAOYSA-N n-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(Br)=C1F RYQGTYVUUPMJQF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 description 1
- 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- SJMCLWCCNYAWRQ-UHFFFAOYSA-N propane-2-sulfonamide Chemical compound CC(C)S(N)(=O)=O SJMCLWCCNYAWRQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 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
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- GFFALKCIACMPPO-UHFFFAOYSA-N tert-butyl n-(3-bromo-2,6-difluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(F)C=CC(Br)=C1F GFFALKCIACMPPO-UHFFFAOYSA-N 0.000 description 1
- PDAFIZPRSXHMCO-ZCFIWIBFSA-N tert-butyl n-[(2r)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-ZCFIWIBFSA-N 0.000 description 1
- PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23808309P | 2009-08-28 | 2009-08-28 | |
| US61/238,083 | 2009-08-28 | ||
| US31306110P | 2010-03-11 | 2010-03-11 | |
| US61/313,061 | 2010-03-11 | ||
| PCT/EP2010/062495 WO2011023773A1 (en) | 2009-08-28 | 2010-08-26 | Compounds and compositions as protein kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2771673A1 CA2771673A1 (en) | 2011-03-03 |
| CA2771673C true CA2771673C (en) | 2016-07-12 |
Family
ID=42829939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2771673A Expired - Fee Related CA2771673C (en) | 2009-08-28 | 2010-08-26 | Compounds and compositions as protein kinase inhibitors |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US8242260B2 (https=) |
| EP (1) | EP2470528B1 (https=) |
| JP (1) | JP5726190B2 (https=) |
| KR (1) | KR101714107B1 (https=) |
| CN (1) | CN102596937B (https=) |
| AR (1) | AR077977A1 (https=) |
| AU (1) | AU2010288455B2 (https=) |
| BR (1) | BR112012004448A2 (https=) |
| CA (1) | CA2771673C (https=) |
| EA (1) | EA020479B1 (https=) |
| ES (1) | ES2527176T3 (https=) |
| IN (1) | IN2012DN00869A (https=) |
| JO (1) | JO3007B1 (https=) |
| MX (1) | MX2012002542A (https=) |
| PL (1) | PL2470528T3 (https=) |
| PT (1) | PT2470528E (https=) |
| TW (1) | TWI487701B (https=) |
| UY (1) | UY32859A (https=) |
| WO (1) | WO2011023773A1 (https=) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO3002B1 (ar) | 2009-08-28 | 2016-09-05 | Irm Llc | مركبات و تركيبات كمثبطات كيناز بروتين |
| EP3028699B1 (en) | 2010-02-25 | 2018-03-21 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
| WO2013059634A1 (en) | 2011-10-20 | 2013-04-25 | The Regents Of The University Of California | Use of cdk9 inhibitors to reduce cartilage degradation |
| CN108542906A (zh) | 2011-11-11 | 2018-09-18 | 诺华股份有限公司 | 治疗增生性疾病的方法 |
| ES2695099T3 (es) | 2011-11-23 | 2019-01-02 | Array Biopharma Inc | Formulaciones farmacéuticas |
| US9408885B2 (en) | 2011-12-01 | 2016-08-09 | Vib Vzw | Combinations of therapeutic agents for treating melanoma |
| US20150232452A1 (en) * | 2012-09-19 | 2015-08-20 | Ruga Corporation | Novel raf kinase inhibitors |
| US9242969B2 (en) | 2013-03-14 | 2016-01-26 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
| EP3004060B1 (en) * | 2013-05-30 | 2019-11-27 | Plexxikon Inc. | Compounds for kinase modulation, and indications therefor |
| WO2014210087A1 (en) | 2013-06-25 | 2014-12-31 | Bristol-Myers Squibb Company | Carbazole carboxamide compounds useful as kinase inhibitors |
| TWI648272B (zh) | 2013-06-25 | 2019-01-21 | 美商必治妥美雅史谷比公司 | 經取代之四氫咔唑及咔唑甲醯胺化合物 |
| SG10201806370QA (en) * | 2013-08-28 | 2018-08-30 | Medivation Tech Llc | Heterocyclic compounds and methods of use |
| GB2517988A (en) * | 2013-09-09 | 2015-03-11 | Redx Pharma Ltd | Compounds |
| UY36294A (es) | 2014-09-12 | 2016-04-29 | Novartis Ag | Compuestos y composiciones como inhibidores de quinasa |
| JP6930913B2 (ja) | 2014-10-14 | 2021-09-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニアＴｈｅ Ｒｅｇｅｎｔｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｃａｌｉｆｏｒｎｉａ | 炎症を阻害するためのｃｄｋ９及びｂｒｄ４阻害剤の使用法 |
| CN104402920B (zh) * | 2014-11-27 | 2018-04-03 | 河南科技学院 | 一种合成2‑卤代‑3‑频那醇硼酸酯‑5‑氯苯胺的方法 |
| AU2017329090B9 (en) | 2016-09-19 | 2019-09-05 | Novartis Ag | Therapeutic combinations comprising a RAF inhibitor and a ERK inhibitor |
| JP7341060B2 (ja) | 2017-02-10 | 2023-09-08 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | Ｍａｐｋ経路の活性化に関連付けられる癌の処置のための方法及び医薬組成物 |
| ES2952265T3 (es) | 2017-05-02 | 2023-10-30 | Novartis Ag | Terapia combinada que comprende un inhibidor de Raf y trametinib |
| EP3732285A1 (en) | 2017-12-28 | 2020-11-04 | Tract Pharmaceuticals, Inc. | Stem cell culture systems for columnar epithelial stem cells, and uses related thereto |
| WO2020124397A1 (en) * | 2018-12-19 | 2020-06-25 | Inventisbio Shanghai Ltd. | C-terminal src kinase inhibitors |
| ES3025633T3 (en) | 2019-05-13 | 2025-06-09 | Novartis Ag | New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl)isonicotinamide as raf inhibitors for the treatment of cancer |
| WO2022036176A1 (en) * | 2020-08-13 | 2022-02-17 | Albert Einstein College Of Medicine | N-cyclyl-sulfonamides useful for inhibiting raf |
| CN119053595A (zh) | 2022-03-28 | 2024-11-29 | 尼坎治疗公司 | 作为细胞周期蛋白依赖性激酶2抑制剂的磺酰氨基衍生物 |
| EP4536363A1 (en) | 2022-06-08 | 2025-04-16 | Nikang Therapeutics, Inc. | Sulfamide derivatives as cyclin-dependent kinase 2 inhibitors |
| WO2025072462A1 (en) | 2023-09-27 | 2025-04-03 | Nikang Therapeutics, Inc. | Sulfonamide derivatives as cyclin-dependent kinase 2 inhibitors |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2659739A (en) | 1950-04-14 | 1953-11-17 | Eastman Kodak Co | 1-hydroxy-4-beta-cyanopropylamino-anthraquinone and process for preparing same |
| US6358932B1 (en) | 1994-05-31 | 2002-03-19 | Isis Pharmaceticals, Inc. | Antisense oligonucleotide inhibition of raf gene expression |
| US6391636B1 (en) | 1994-05-31 | 2002-05-21 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of raf gene expression |
| US6037136A (en) | 1994-10-24 | 2000-03-14 | Cold Spring Harbor Laboratory | Interactions between RaF proto-oncogenes and CDC25 phosphatases, and uses related thereto |
| US5717100A (en) | 1995-10-06 | 1998-02-10 | Merck & Co., Inc. | Substituted imidazoles having anti-cancer and cytokine inhibitory activity |
| GB2306108A (en) * | 1995-10-13 | 1997-04-30 | Merck & Co Inc | Treatment of Raf-mediated cancers with imidazole derivatives |
| AU728701B2 (en) | 1996-05-23 | 2001-01-18 | Applied Research Systems Ars Holding N.V. | Compounds that inhibit the binding of Raf-1 or 14-3-3 proteins to the beta chain of IL-2 receptor, and pharmaceutical compositions containing same |
| AR012634A1 (es) | 1997-05-02 | 2000-11-08 | Sugen Inc | Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion |
| US6187799B1 (en) | 1997-05-23 | 2001-02-13 | Onyx Pharmaceuticals | Inhibition of raf kinase activity using aryl ureas |
| GB9716557D0 (en) | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
| US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
| US6204467B1 (en) | 1998-03-24 | 2001-03-20 | Ford Global Technologies, Inc. | Method and apparatus for resistive welding |
| US7351834B1 (en) | 1999-01-13 | 2008-04-01 | Bayer Pharmaceuticals Corporation | ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| AU2001285349A1 (en) | 2000-08-30 | 2002-03-13 | The Board Of Trustees Of The University Of Arkansas | Induction of ldl receptor expression by extracellular-signal regulated kinase, erk-1/2 |
| SG2013013339A (en) | 2002-03-13 | 2014-12-30 | Array Biopharma Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
| US6644516B1 (en) | 2002-11-06 | 2003-11-11 | Continental Afa Dispensing Company | Foaming liquid dispenser |
| AU2006217744A1 (en) | 2005-02-25 | 2006-08-31 | Kudos Pharmaceuticals Limited | 2,4-diamino-pyridopyrimidine derivatives and their use as MTOR inhibitors |
| AU2006217742A1 (en) | 2005-02-25 | 2006-08-31 | Kudos Pharmaceuticals Limited | Hydrazinomethyl, HYDR zonomethyl and 5-membered heterocylic compounds which act as MTOR inhibitors and their use as anti cancer agents |
| PL1954699T3 (pl) | 2005-11-22 | 2013-01-31 | Kudos Pharm Ltd | Pochodne pirydo-, pirazo- i pirymidopirymidyny jako inhibitory mTOR |
| JP2009523161A (ja) | 2006-01-11 | 2009-06-18 | アストラゼネカ アクチボラグ | モルホリノピリミジン誘導体と療法におけるその使用 |
| KR101438245B1 (ko) | 2006-08-23 | 2014-09-04 | 쿠도스 파마슈티칼스 리미티드 | Ｍｔｏｒ 억제제로서의 2-메틸모르폴린 피리도-, 피라조- 및 피리미도-피리미딘 유도체 |
| TW200922582A (en) | 2007-08-20 | 2009-06-01 | Organon Nv | N-benzyl, N'-arylcarbonylpiperazine derivatives |
| AU2009227013B2 (en) | 2008-03-21 | 2013-01-10 | Novartis Ag | Novel heterocyclic compounds and uses therof |
| UA103319C2 (en) * | 2008-05-06 | 2013-10-10 | Глаксосмитклайн Ллк | Thiazole- and oxazole-benzene sulfonamide compounds |
| SI2324008T1 (sl) * | 2008-07-24 | 2012-08-31 | Nerviano Medical Sciences Srl | 3,4-diarilpirazoli kot protein-kinazni inhibitorji |
-
2010
- 2010-08-24 US US12/862,418 patent/US8242260B2/en not_active Expired - Fee Related
- 2010-08-26 EA EA201200323A patent/EA020479B1/ru not_active IP Right Cessation
- 2010-08-26 CN CN201080038235.XA patent/CN102596937B/zh active Active
- 2010-08-26 WO PCT/EP2010/062495 patent/WO2011023773A1/en not_active Ceased
- 2010-08-26 PT PT107452807T patent/PT2470528E/pt unknown
- 2010-08-26 CA CA2771673A patent/CA2771673C/en not_active Expired - Fee Related
- 2010-08-26 JP JP2012526067A patent/JP5726190B2/ja active Active
- 2010-08-26 ES ES10745280.7T patent/ES2527176T3/es active Active
- 2010-08-26 BR BR112012004448A patent/BR112012004448A2/pt not_active Application Discontinuation
- 2010-08-26 JO JOP/2010/0298A patent/JO3007B1/ar active
- 2010-08-26 PL PL10745280T patent/PL2470528T3/pl unknown
- 2010-08-26 AR ARP100103125A patent/AR077977A1/es unknown
- 2010-08-26 AU AU2010288455A patent/AU2010288455B2/en not_active Ceased
- 2010-08-26 MX MX2012002542A patent/MX2012002542A/es active IP Right Grant
- 2010-08-26 KR KR1020127007838A patent/KR101714107B1/ko not_active Expired - Fee Related
- 2010-08-26 IN IN869DEN2012 patent/IN2012DN00869A/en unknown
- 2010-08-26 EP EP10745280.7A patent/EP2470528B1/en active Active
- 2010-08-27 UY UY0001032859A patent/UY32859A/es not_active Application Discontinuation
- 2010-08-27 TW TW099128938A patent/TWI487701B/zh not_active IP Right Cessation
-
2012
- 2012-05-16 US US13/473,230 patent/US8563553B2/en active Active
-
2013
- 2013-09-10 US US14/022,540 patent/US8859548B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013503139A (ja) | 2013-01-31 |
| EA020479B1 (ru) | 2014-11-28 |
| MX2012002542A (es) | 2012-04-02 |
| US8563553B2 (en) | 2013-10-22 |
| AR077977A1 (es) | 2011-10-05 |
| JP5726190B2 (ja) | 2015-05-27 |
| US8242260B2 (en) | 2012-08-14 |
| EA201200323A1 (ru) | 2012-09-28 |
| EP2470528B1 (en) | 2014-10-01 |
| ES2527176T3 (es) | 2015-01-21 |
| JO3007B1 (ar) | 2016-09-05 |
| PL2470528T3 (pl) | 2015-03-31 |
| US20120225899A1 (en) | 2012-09-06 |
| WO2011023773A1 (en) | 2011-03-03 |
| CA2771673A1 (en) | 2011-03-03 |
| TWI487701B (zh) | 2015-06-11 |
| EP2470528A1 (en) | 2012-07-04 |
| IN2012DN00869A (https=) | 2015-07-10 |
| UY32859A (es) | 2011-03-31 |
| US20110052578A1 (en) | 2011-03-03 |
| BR112012004448A2 (pt) | 2017-05-30 |
| US8859548B2 (en) | 2014-10-14 |
| KR20120092577A (ko) | 2012-08-21 |
| PT2470528E (pt) | 2014-12-29 |
| KR101714107B1 (ko) | 2017-03-08 |
| US20140011825A1 (en) | 2014-01-09 |
| CN102596937B (zh) | 2014-02-12 |
| AU2010288455B2 (en) | 2013-01-31 |
| CN102596937A (zh) | 2012-07-18 |
| AU2010288455A1 (en) | 2012-02-23 |
| TW201111365A (en) | 2011-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2771673C (en) | Compounds and compositions as protein kinase inhibitors | |
| AU2016282837B2 (en) | New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them | |
| CN107709333B (zh) | 羟基酯衍生物、其制备方法以及含有它们的药物组合物 | |
| JP2024020220A (ja) | 免疫調節剤としての複素環式化合物 | |
| MXPA05005477A (es) | Pirimidinas 2,4,6-trisustituidas como inhibidores de fosfotidilinositol (pi) 3-cinasa y su uso en el tratamiento del cancer. | |
| JP2021512161A (ja) | Ｃｄｋ４およびｃｄｋ６阻害剤としての２ｈ−インダゾール誘導体およびその治療上の使用 | |
| EP2145877B1 (en) | Aurora Kinase inhibitors | |
| TW202400148A (zh) | 作為trpa1抑制劑之吡啶酮化合物 | |
| JP6920553B2 (ja) | Ｂｔｋ阻害剤化合物 | |
| WO2022138792A1 (ja) | Ｅｐ２拮抗活性を有する化合物の塩、溶媒和物および結晶 | |
| HK40026624B (en) | Btk inhibitor compounds | |
| HK40026624A (en) | Btk inhibitor compounds | |
| OA18890A (en) | New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them | |
| OA18889A (en) | New Hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20150528 |
|
| MKLA | Lapsed |
Effective date: 20200831 |