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
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- 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
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- 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
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- 239000012279 sodium borohydride Substances 0.000 description 1
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- 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
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- 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
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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 |
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| US9498471B2 (en) | 2011-10-20 | 2016-11-22 | The Regents Of The University Of California | Use of CDK9 inhibitors to reduce cartilage degradation |
| CA2855243C (en) | 2011-11-11 | 2020-04-14 | Novartis Ag | Method of treating a proliferative disease |
| PE20141994A1 (es) | 2011-11-23 | 2014-12-24 | Novartis Ag | Formulaciones farmaceuticas |
| 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 |
| RU2015149937A (ru) | 2013-05-30 | 2017-07-06 | Плексксикон Инк. | Соединения для модулирования киназы и показания к их применению |
| EP3013815B1 (en) | 2013-06-25 | 2017-05-03 | Bristol-Myers Squibb Company | Carbazole carboxamide compounds useful as kinase inhibitors |
| UY35625A (es) | 2013-06-25 | 2014-12-31 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Compuestos de tetrahidrocarbazol y carbazol carboxamida sustituidos como inhibidores de quinasa |
| TR201809185T4 (tr) * | 2013-08-28 | 2018-07-23 | Medivation Tech Llc | Heterosiklik bileşikler ve kullanım yöntemleri. |
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| 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 |
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| WO2022036176A1 (en) * | 2020-08-13 | 2022-02-17 | Albert Einstein College Of Medicine | N-cyclyl-sulfonamides useful for inhibiting raf |
| EP4499634A1 (en) | 2022-03-28 | 2025-02-05 | Nikang Therapeutics, Inc. | Sulfonamido derivatives as cyclin-dependent kinase 2 inhibitors |
| EP4536363A1 (en) | 2022-06-08 | 2025-04-16 | Nikang Therapeutics, Inc. | Sulfamide derivatives as cyclin-dependent kinase 2 inhibitors |
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| KR20120092577A (ko) | 2012-08-21 |
| JP2013503139A (ja) | 2013-01-31 |
| CN102596937B (zh) | 2014-02-12 |
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| US20120225899A1 (en) | 2012-09-06 |
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| AR077977A1 (es) | 2011-10-05 |
| TW201111365A (en) | 2011-04-01 |
| CA2771673A1 (en) | 2011-03-03 |
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| PL2470528T3 (pl) | 2015-03-31 |
| US8242260B2 (en) | 2012-08-14 |
| AU2010288455B2 (en) | 2013-01-31 |
| AU2010288455A1 (en) | 2012-02-23 |
| US8859548B2 (en) | 2014-10-14 |
| KR101714107B1 (ko) | 2017-03-08 |
| CN102596937A (zh) | 2012-07-18 |
| JO3007B1 (ar) | 2016-09-05 |
| PT2470528E (pt) | 2014-12-29 |
| WO2011023773A1 (en) | 2011-03-03 |
| EP2470528A1 (en) | 2012-07-04 |
| IN2012DN00869A (cg-RX-API-DMAC7.html) | 2015-07-10 |
| EA201200323A1 (ru) | 2012-09-28 |
| EP2470528B1 (en) | 2014-10-01 |
| ES2527176T3 (es) | 2015-01-21 |
| US20110052578A1 (en) | 2011-03-03 |
| EA020479B1 (ru) | 2014-11-28 |
| BR112012004448A2 (pt) | 2017-05-30 |
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