KR20110029161A - Ｍｅｋ 키나제 억제제로서의 비시클릭 헤테로사이클 - Google Patents
Ｍｅｋ 키나제 억제제로서의 비시클릭 헤테로사이클 Download PDFInfo
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- KR20110029161A KR20110029161A KR1020117002481A KR20117002481A KR20110029161A KR 20110029161 A KR20110029161 A KR 20110029161A KR 1020117002481 A KR1020117002481 A KR 1020117002481A KR 20117002481 A KR20117002481 A KR 20117002481A KR 20110029161 A KR20110029161 A KR 20110029161A
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- compound
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- fluoro
- alkyl
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 5
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 378
- 238000000034 method Methods 0.000 claims abstract description 70
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
- 241000124008 Mammalia Species 0.000 claims abstract description 39
- 230000002159 abnormal effect Effects 0.000 claims abstract description 14
- 230000010261 cell growth Effects 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 10
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 101
- 229920006395 saturated elastomer Polymers 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 24
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 13
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 12
- 239000002246 antineoplastic agent Substances 0.000 claims description 12
- 229940127089 cytotoxic agent Drugs 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 8
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 81
- 238000011282 treatment Methods 0.000 abstract description 31
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 abstract description 6
- 108060006687 MAP kinase kinase kinase Proteins 0.000 abstract description 6
- 238000003745 diagnosis Methods 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 4
- 210000004962 mammalian cell Anatomy 0.000 abstract description 4
- 230000001575 pathological effect Effects 0.000 abstract description 4
- 230000001093 anti-cancer Effects 0.000 abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 349
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 183
- 239000000243 solution Substances 0.000 description 172
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
- 239000011541 reaction mixture Substances 0.000 description 142
- 235000019439 ethyl acetate Nutrition 0.000 description 117
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 108
- 239000007787 solid Substances 0.000 description 104
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
- 239000002904 solvent Substances 0.000 description 88
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 59
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 58
- 239000011734 sodium Substances 0.000 description 57
- 238000003818 flash chromatography Methods 0.000 description 54
- 239000012267 brine Substances 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 239000002585 base Substances 0.000 description 34
- 238000010992 reflux Methods 0.000 description 34
- 150000003839 salts Chemical class 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 30
- 235000017557 sodium bicarbonate Nutrition 0.000 description 30
- 239000002253 acid Substances 0.000 description 29
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 28
- 239000000284 extract Substances 0.000 description 27
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- 206010028980 Neoplasm Diseases 0.000 description 26
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 208000035475 disorder Diseases 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 18
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 18
- 201000010099 disease Diseases 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 239000012453 solvate Substances 0.000 description 18
- 229940002612 prodrug Drugs 0.000 description 17
- 239000000651 prodrug Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
- 239000012223 aqueous fraction Substances 0.000 description 14
- 238000003556 assay Methods 0.000 description 14
- 201000011510 cancer Diseases 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- NTMYBIBHUDSSPP-UHFFFAOYSA-N 4-(2-fluoro-4-iodoanilino)-1h-indazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NN=CC2=C1NC1=CC=C(I)C=C1F NTMYBIBHUDSSPP-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 0 COC(C1=C(*)C(F)=C(C=O)C=*C1)=O Chemical compound COC(C1=C(*)C(F)=C(C=O)C=*C1)=O 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 230000004913 activation Effects 0.000 description 11
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 235000019253 formic acid Nutrition 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- JVRFBQWDCLHODS-UHFFFAOYSA-N 4-(2-fluoro-4-iodoanilino)-1,2-benzothiazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2SN=CC2=C1NC1=CC=C(I)C=C1F JVRFBQWDCLHODS-UHFFFAOYSA-N 0.000 description 7
- GVEGPCDSCGCKOI-UHFFFAOYSA-N 4-(2-fluoro-4-iodoanilino)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CN1C2=NC=C(C(O)=O)C(NC=3C(=CC(I)=CC=3)F)=C2C=N1 GVEGPCDSCGCKOI-UHFFFAOYSA-N 0.000 description 7
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- 241000282412 Homo Species 0.000 description 7
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- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 7
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- 125000001424 substituent group Chemical group 0.000 description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
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- YZYUSDXDWKOENV-DFWYDOINSA-N (2s)-1-aminooxypropan-2-ol;hydrochloride Chemical compound Cl.C[C@H](O)CON YZYUSDXDWKOENV-DFWYDOINSA-N 0.000 description 6
- SRIRADNHFQTPFR-UHFFFAOYSA-N 2-fluoro-4-trimethylsilylaniline Chemical compound C[Si](C)(C)C1=CC=C(N)C(F)=C1 SRIRADNHFQTPFR-UHFFFAOYSA-N 0.000 description 6
- HVLCPDJWHVAVOA-UHFFFAOYSA-N 7-(2-fluoro-4-iodoanilino)-1,2-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C=NSC2=C1NC1=CC=C(I)C=C1F HVLCPDJWHVAVOA-UHFFFAOYSA-N 0.000 description 6
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- 206010007559 Cardiac failure congestive Diseases 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 6
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- 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 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 5
- AIDLDBHFMPYPKF-UHFFFAOYSA-N 4-(2-fluoro-4-iodoanilino)-1-(4-methylphenyl)sulfonylindazole-5-carboxylic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC=C(C(O)=O)C(NC=3C(=CC(I)=CC=3)F)=C2C=N1 AIDLDBHFMPYPKF-UHFFFAOYSA-N 0.000 description 5
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7742608P | 2008-07-01 | 2008-07-01 | |
| US61/077,426 | 2008-07-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20110029161A true KR20110029161A (ko) | 2011-03-22 |
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| JP (1) | JP5544358B2 (enExample) |
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| CN (1) | CN102137847B (enExample) |
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| BR (1) | BRPI0910175A2 (enExample) |
| CA (1) | CA2727250A1 (enExample) |
| CL (1) | CL2010001641A1 (enExample) |
| IL (1) | IL209931A0 (enExample) |
| MX (1) | MX2010014559A (enExample) |
| PE (1) | PE20110570A1 (enExample) |
| RU (1) | RU2509078C2 (enExample) |
| WO (1) | WO2010003025A1 (enExample) |
| ZA (1) | ZA201008963B (enExample) |
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| MX2012005293A (es) | 2009-11-04 | 2012-06-19 | Novartis Ag | Derivados de sulfonamida heterociclicos utiles como inhibidores de mek. |
| CN102020651B (zh) | 2010-11-02 | 2012-07-18 | 北京赛林泰医药技术有限公司 | 6-芳基氨基吡啶酮甲酰胺mek抑制剂 |
| JP2014517004A (ja) * | 2011-06-09 | 2014-07-17 | ノバルティス アーゲー | 複素環スルホンアミド誘導体 |
| CA2890238A1 (en) | 2012-11-02 | 2014-05-08 | Merck Patent Gmbh | Method of reducing adverse effects in a cancer patient undergoing treatment with a mek inhibitor |
| US9227969B2 (en) | 2013-08-14 | 2016-01-05 | Novartis Ag | Compounds and compositions as inhibitors of MEK |
| US9532987B2 (en) | 2013-09-05 | 2017-01-03 | Genentech, Inc. | Use of a combination of a MEK inhibitor and an ERK inhibitor for treatment of hyperproliferative diseases |
| NO2714752T3 (enExample) | 2014-05-08 | 2018-04-21 | ||
| WO2015196072A2 (en) | 2014-06-19 | 2015-12-23 | Whitehead Institute For Biomedical Research | Uses of kinase inhibitors for inducing and maintaining pluripotency |
| CN104119332B (zh) * | 2014-07-08 | 2019-03-29 | 上海科州药物研发有限公司 | 作为蛋白激酶抑制剂的苯并杂环化合物及其制备方法和用途 |
| CN104860869B (zh) * | 2015-04-03 | 2017-11-03 | 北京大学 | 具有mek激酶抑制功能的化合物及其制备方法与应用 |
| TN2017000483A1 (en) | 2015-05-20 | 2019-04-12 | Amgen Inc | Triazole agonists of the apj receptor. |
| WO2017033113A1 (en) | 2015-08-21 | 2017-03-02 | Acerta Pharma B.V. | Therapeutic combinations of a mek inhibitor and a btk inhibitor |
| GB201516504D0 (en) | 2015-09-17 | 2015-11-04 | Astrazeneca Ab | Imadazo(4,5-c)quinolin-2-one Compounds and their use in treating cancer |
| KR20180134347A (ko) | 2016-04-15 | 2018-12-18 | 제넨테크, 인크. | 암의 진단 및 치료 방법 |
| WO2017192485A1 (en) | 2016-05-03 | 2017-11-09 | Amgen Inc. | Heterocyclic triazole compounds as agonists of the apj receptor |
| AU2017348826B2 (en) | 2016-10-28 | 2021-12-02 | Centaurus Biopharma Co., Ltd. | Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor |
| MA46827A (fr) | 2016-11-16 | 2019-09-25 | Amgen Inc | Composés de triazole à substitution cycloalkyle en tant qu'agonistes du récepteur apj |
| EP3541792B1 (en) | 2016-11-16 | 2020-12-23 | Amgen Inc. | Triazole furan compounds as agonists of the apj receptor |
| US10906890B2 (en) | 2016-11-16 | 2021-02-02 | Amgen Inc. | Triazole phenyl compounds as agonists of the APJ receptor |
| WO2018093580A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Triazole pyridyl compounds as agonists of the apj receptor |
| WO2018097945A1 (en) | 2016-11-16 | 2018-05-31 | Amgen Inc. | Heteroaryl-substituted triazoles as apj receptor agonists |
| US11191762B2 (en) | 2016-11-16 | 2021-12-07 | Amgen Inc. | Alkyl substituted triazole compounds as agonists of the APJ Receptor |
| US11859252B2 (en) | 2017-09-08 | 2024-01-02 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
| WO2019089335A1 (en) | 2017-11-03 | 2019-05-09 | Amgen Inc. | Fused triazole agonists of the apj receptor |
| EP3752200A1 (en) | 2018-02-13 | 2020-12-23 | Vib Vzw | Targeting minimal residual disease in cancer with rxr antagonists |
| WO2019213006A1 (en) | 2018-05-01 | 2019-11-07 | Amgen Inc. | Substituted pyrimidinones as agonists of the apj receptor |
| WO2021113436A1 (en) * | 2019-12-04 | 2021-06-10 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha |
| US12371667B2 (en) | 2021-05-13 | 2025-07-29 | Washington University | Enhanced methods for inducing and maintaining naive human pluripotent stem cells |
| JP2024521788A (ja) | 2021-05-27 | 2024-06-04 | ミラティ セラピューティクス， インコーポレイテッド | 併用療法 |
| CN113336786B (zh) * | 2021-05-31 | 2022-10-18 | 南京工业大学 | 一种非对映选择性的多取代环烷基化合物及其制备方法 |
| WO2024033381A1 (en) | 2022-08-10 | 2024-02-15 | Vib Vzw | Inhibition of tcf4/itf2 in the treatment of cancer |
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| DE2017853C3 (de) | 1970-04-14 | 1975-12-11 | Standard Elektrik Lorenz Ag, 7000 Stuttgart | Steuerverfahren zur Sicherung der Informationsverarbeitung und -Übertragung |
| ZA711710B (en) * | 1970-05-28 | 1971-12-29 | Squibb & Sons Inc | Amino derivatives of purazolo-pyridine carboxylic acids and esters |
| US3736326A (en) * | 1971-03-29 | 1973-05-29 | Squibb & Sons Inc | Isoxazolopyridine carboxylic acids and esters |
| US3780047A (en) * | 1972-07-05 | 1973-12-18 | Squibb & Sons Inc | Derivatives of pyrazolo(3',4'-2,3)pyrido(4,5-e)b-benzo-1,5-diazepines |
| US4012373A (en) * | 1972-09-22 | 1977-03-15 | E. R. Squibb & Sons, Inc. | Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones |
| GB8404586D0 (en) * | 1984-02-22 | 1984-03-28 | Beecham Group Plc | Compounds |
| JP2002020386A (ja) * | 2000-07-07 | 2002-01-23 | Ono Pharmaceut Co Ltd | ピラゾロピリジン誘導体 |
| EE05450B1 (et) | 2000-07-19 | 2011-08-15 | Warner-Lambert Company | 4-jodofenlaminobenshdroksaamhapete oksgeenitud estrid, nende kristallvormid ja farmatseutilised kompositsioonid ning kasutamine |
| US20050009876A1 (en) * | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
| PL401638A1 (pl) | 2002-03-13 | 2013-05-27 | Array Biopharma Inc. | N3 alkilowane pochodne benzimidazolu jako inhibitory MEK |
| AR038972A1 (es) | 2002-03-13 | 2005-02-02 | Array Biopharma Inc | Derivados de bencimidazol n3 alquilado como inhibidores de mek |
| GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
| CL2003002287A1 (es) * | 2002-11-25 | 2005-01-14 | Wyeth Corp | COMPUESTOS DERIVADOS DE TIENO[3,2-b]-PIRIDINA-6-CARBONITRILOS Y TIENEO[2,3-b]-PIRIDINA-5-CARBONITRILOS, COMPOSICION FARMACEUTICA, PROCEDIMIENTO DE PREPARACION Y COMPUESTOS INTERMEDIARIOS, Y SU USO EN EL TRATAMIENTO DEL CANCER, APOPLEJIA, OSTEOPOROSIS |
| GB0316237D0 (en) | 2003-07-11 | 2003-08-13 | Astrazeneca Ab | Therapeutic agents |
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| US20050049276A1 (en) | 2003-07-23 | 2005-03-03 | Warner-Lambert Company, Llc | Imidazopyridines and triazolopyridines |
| SI1663242T1 (sl) | 2003-08-07 | 2011-09-30 | Rigel Pharmaceuticals Inc | 2,4-pirimidindiaminske spojine in uporabe kot antiproliferativna sredstva |
| US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
| US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| JP4768628B2 (ja) | 2003-11-19 | 2011-09-07 | アレイ バイオファーマ、インコーポレイテッド | Ｍｅｋの二環系阻害剤及びその使用方法 |
| WO2005054176A1 (en) | 2003-11-25 | 2005-06-16 | Eli Lilly And Company | Peroxisome proliferator activated receptor modulators |
| EP1694663A1 (en) | 2003-12-19 | 2006-08-30 | Biovitrum Aktiebolag | Novel benzofuran derivatives, which can be used in prophylaxis or treatment of 5-ht6 receptor-related disorder |
| ES2338060T3 (es) | 2003-12-22 | 2010-05-03 | Basilea Pharmaceutica Ag | Componentes de tipo ariloxi y ariltoxia-cetofenona para el tratamiento del cancer. |
| MXPA06007213A (es) | 2003-12-23 | 2006-08-18 | Pfizer Prod Inc | Combinacion terapeutica para la mejora de la cognicion y trastornos sicoticos. |
| AU2006284751A1 (en) | 2005-09-01 | 2007-03-08 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
| HRP20110498T1 (hr) * | 2005-10-07 | 2011-08-31 | Exelixis | Azetidini kao inhibitori mek za liječenje proliferativnih bolesti |
| CA2662285A1 (en) | 2006-08-31 | 2008-03-06 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
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- 2009-07-01 MX MX2010014559A patent/MX2010014559A/es active IP Right Grant
- 2009-07-01 JP JP2011516860A patent/JP5544358B2/ja not_active Expired - Fee Related
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- 2009-07-01 RU RU2011103454/04A patent/RU2509078C2/ru not_active IP Right Cessation
- 2009-07-01 PE PE2010001198A patent/PE20110570A1/es not_active Application Discontinuation
- 2009-07-01 US US12/999,003 patent/US8841462B2/en not_active Expired - Fee Related
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- 2009-07-01 WO PCT/US2009/049453 patent/WO2010003025A1/en not_active Ceased
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2010
- 2010-12-12 IL IL209931A patent/IL209931A0/en unknown
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| JP5544358B2 (ja) | 2014-07-09 |
| CL2010001641A1 (es) | 2011-07-15 |
| RU2509078C2 (ru) | 2014-03-10 |
| ZA201008963B (en) | 2012-03-28 |
| EP2310373A1 (en) | 2011-04-20 |
| MX2010014559A (es) | 2011-03-04 |
| PE20110570A1 (es) | 2011-08-26 |
| BRPI0910175A2 (pt) | 2017-03-21 |
| US20110190257A1 (en) | 2011-08-04 |
| CN102137847A (zh) | 2011-07-27 |
| AU2009266956B2 (en) | 2014-03-20 |
| CA2727250A1 (en) | 2010-01-07 |
| IL209931A0 (en) | 2011-02-28 |
| AU2009266956A2 (en) | 2011-03-10 |
| JP2011526926A (ja) | 2011-10-20 |
| WO2010003025A1 (en) | 2010-01-07 |
| AU2009266956A1 (en) | 2010-01-07 |
| CN102137847B (zh) | 2015-06-10 |
| US8841462B2 (en) | 2014-09-23 |
| RU2011103454A (ru) | 2012-08-10 |
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