MX2011000925A - Amidofenoxiindazoles utiles como inhibidores de c-met. - Google Patents
Amidofenoxiindazoles utiles como inhibidores de c-met.Info
- Publication number
- MX2011000925A MX2011000925A MX2011000925A MX2011000925A MX2011000925A MX 2011000925 A MX2011000925 A MX 2011000925A MX 2011000925 A MX2011000925 A MX 2011000925A MX 2011000925 A MX2011000925 A MX 2011000925A MX 2011000925 A MX2011000925 A MX 2011000925A
- Authority
- MX
- Mexico
- Prior art keywords
- mmol
- methyl
- fluoro
- added
- pharmaceutically acceptable
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- -1 amino, dimethylamino, fluoro, cyclopropyl Chemical group 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 230000002440 hepatic effect Effects 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 201000010279 papillary renal cell carcinoma Diseases 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical group CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 201000005296 lung carcinoma Diseases 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 270
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 229
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 239000000243 solution Substances 0.000 description 118
- 235000019439 ethyl acetate Nutrition 0.000 description 114
- 238000002360 preparation method Methods 0.000 description 111
- 239000000203 mixture Substances 0.000 description 83
- 239000007787 solid Substances 0.000 description 82
- 239000000047 product Substances 0.000 description 76
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- 239000000741 silica gel Substances 0.000 description 60
- 229910002027 silica gel Inorganic materials 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 59
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 229910001868 water Inorganic materials 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 45
- 238000004440 column chromatography Methods 0.000 description 45
- 229920006395 saturated elastomer Polymers 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 34
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 30
- 239000011780 sodium chloride Substances 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 239000000725 suspension Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 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 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000007983 Tris buffer Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 9
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 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 6
- 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 6
- PVURLVXVVVMHMW-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methylindazole Chemical compound BrC=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F PVURLVXVVVMHMW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- 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 6
- ZKVBYEQUNGMVQI-UHFFFAOYSA-N 6-bromo-1h-indazol-5-ol Chemical compound C1=C(Br)C(O)=CC2=C1NN=C2 ZKVBYEQUNGMVQI-UHFFFAOYSA-N 0.000 description 5
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 5
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 4
- LYCMZDBJVXHTTB-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(1h-pyrazol-4-yl)indazole Chemical compound C1=NNC=C1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F LYCMZDBJVXHTTB-UHFFFAOYSA-N 0.000 description 4
- XMCCKWQPRKZJEB-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)Br)=CC2=C1N(C1OCCCC1)N=C2 XMCCKWQPRKZJEB-UHFFFAOYSA-N 0.000 description 4
- HHWVMMFGSBICIO-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1h-indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)Br)=CC2=C1NN=C2 HHWVMMFGSBICIO-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 229910002666 PdCl2 Inorganic materials 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- AFJLKSVKOPUXAK-UHFFFAOYSA-N ethyl 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazole-6-carboxylate Chemical compound CCOC(=O)C1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F AFJLKSVKOPUXAK-UHFFFAOYSA-N 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000011343 solid material Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- 238000003828 vacuum filtration Methods 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 3
- VLLHEPHWWIDUSS-ONEGZZNKSA-N (e)-4-methoxybut-3-en-2-one Chemical compound CO\C=C\C(C)=O VLLHEPHWWIDUSS-ONEGZZNKSA-N 0.000 description 3
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 3
- ONKHOVUNSYXIJY-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F ONKHOVUNSYXIJY-UHFFFAOYSA-N 0.000 description 3
- SKMANSKZDGFVAR-UHFFFAOYSA-N 6-bromo-1-(oxan-2-yl)-5-phenylmethoxyindazole Chemical compound BrC1=CC=2N(C3OCCCC3)N=CC=2C=C1OCC1=CC=CC=C1 SKMANSKZDGFVAR-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 3
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940076286 cupric acetate Drugs 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 3
- DVIGICXZLWQQCP-UHFFFAOYSA-N ethyl 3-(4-fluoroanilino)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=C(F)C=C1 DVIGICXZLWQQCP-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 230000017066 negative regulation of growth Effects 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- OSLAYKKXCYSJSF-ARJAWSKDSA-N (Z)-4-aminopent-3-en-2-one Chemical compound C\C(N)=C\C(C)=O OSLAYKKXCYSJSF-ARJAWSKDSA-N 0.000 description 2
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- BTPCWSQBSXUYHV-UHFFFAOYSA-N 1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 BTPCWSQBSXUYHV-UHFFFAOYSA-N 0.000 description 2
- GOJIMMZYKNSSHZ-UHFFFAOYSA-N 1-(oxan-2-yl)-n-(oxan-4-yl)-5-phenylmethoxyindazol-6-amine Chemical compound C=1C=CC=CC=1COC(C(=CC=12)NC3CCOCC3)=CC=1C=NN2C1CCCCO1 GOJIMMZYKNSSHZ-UHFFFAOYSA-N 0.000 description 2
- HVCAUTAOQALMGO-UHFFFAOYSA-N 1-(oxan-2-yl)indazole Chemical compound O1CCCCC1N1C2=CC=CC=C2C=N1 HVCAUTAOQALMGO-UHFFFAOYSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- HGYSQMDBNTXXKV-UHFFFAOYSA-N 2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC1=CC(C=O)=C(Br)C=C1Br HGYSQMDBNTXXKV-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- QQGASDUNUSWZNJ-UHFFFAOYSA-N 4-(4-bromo-2-fluorophenoxy)-5-fluoro-2-methylaniline Chemical compound C1=C(N)C(C)=CC(OC=2C(=CC(Br)=CC=2)F)=C1F QQGASDUNUSWZNJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 2
- YKSDZJRDPZBOOL-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)-6-pyridin-4-ylindazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)C=2C=CN=CC=2)=CC2=C1N(C1OCCCC1)N=C2 YKSDZJRDPZBOOL-UHFFFAOYSA-N 0.000 description 2
- VTTUOCVDCFUPFW-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)-n-(oxan-4-yl)indazole-6-carboxamide Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)C(=O)NC2CCOCC2)=CC2=C1N(C1OCCCC1)N=C2 VTTUOCVDCFUPFW-UHFFFAOYSA-N 0.000 description 2
- WOPIGYXKNFAQLS-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-methylindazole-6-carboxylic acid Chemical compound OC(=O)C=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F WOPIGYXKNFAQLS-UHFFFAOYSA-N 0.000 description 2
- BARMSCKCCFMLTF-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-6-pyridin-4-yl-1h-indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)C=2C=CN=CC=2)=CC2=C1NN=C2 BARMSCKCCFMLTF-UHFFFAOYSA-N 0.000 description 2
- XYZJGLBENWCVMK-UHFFFAOYSA-N 5-(4-amino-2-fluorophenoxy)-n-benzhydryl-1-methylindazol-6-amine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)NC=1C=C2N(C)N=CC2=CC=1OC1=CC=C(N)C=C1F XYZJGLBENWCVMK-UHFFFAOYSA-N 0.000 description 2
- HPKUEMDLRKISJY-UHFFFAOYSA-N 5-(4-bromo-2-fluorophenoxy)-6-fluoro-1-(oxan-2-yl)indazole Chemical compound FC1=CC(Br)=CC=C1OC(C(=C1)F)=CC2=C1N(C1OCCCC1)N=C2 HPKUEMDLRKISJY-UHFFFAOYSA-N 0.000 description 2
- RWOIXOWVCBWVSB-UHFFFAOYSA-N 5-[1-(oxan-2-yl)-5-phenylmethoxyindazol-6-yl]pyridin-2-amine Chemical compound C1=NC(N)=CC=C1C(C(=C1)OCC=2C=CC=CC=2)=CC2=C1C=NN2C1OCCCC1 RWOIXOWVCBWVSB-UHFFFAOYSA-N 0.000 description 2
- KSSWHWHADJOWJF-UHFFFAOYSA-N 5-bromo-4-methoxy-2-methylaniline Chemical compound COC1=CC(C)=C(N)C=C1Br KSSWHWHADJOWJF-UHFFFAOYSA-N 0.000 description 2
- IMSBOOOUCNENSM-UHFFFAOYSA-N 6-(6-methylpyridin-3-yl)-1-(oxan-2-yl)-5-phenylmethoxyindazole Chemical compound C1=NC(C)=CC=C1C(C(=C1)OCC=2C=CC=CC=2)=CC2=C1C=NN2C1OCCCC1 IMSBOOOUCNENSM-UHFFFAOYSA-N 0.000 description 2
- NQZSGBCLGLWIDU-UHFFFAOYSA-N 6-bromo-2-(oxan-2-yl)indazol-5-ol Chemical compound N1=C2C=C(Br)C(O)=CC2=CN1C1CCCCO1 NQZSGBCLGLWIDU-UHFFFAOYSA-N 0.000 description 2
- SDMGDLJUCCODOM-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC1=CC2=CN(C3OCCCC3)N=C2C=C1Br SDMGDLJUCCODOM-UHFFFAOYSA-N 0.000 description 2
- MNLVPEGAWGXIMT-UHFFFAOYSA-N 6-bromo-5-(4-nitrophenoxy)-1h-indazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)Br)=CC2=C1NN=C2 MNLVPEGAWGXIMT-UHFFFAOYSA-N 0.000 description 2
- USRTZJDWQCNIEN-UHFFFAOYSA-N 6-bromo-5-methoxy-1h-indazole Chemical compound C1=C(Br)C(OC)=CC2=C1NN=C2 USRTZJDWQCNIEN-UHFFFAOYSA-N 0.000 description 2
- GUHSZAAKYDZXIH-UHFFFAOYSA-N 6-bromo-5-phenylmethoxy-1h-indazole Chemical compound BrC1=CC=2NN=CC=2C=C1OCC1=CC=CC=C1 GUHSZAAKYDZXIH-UHFFFAOYSA-N 0.000 description 2
- SYTVWQAYOSKDTP-UHFFFAOYSA-N 6-methyl-2-oxo-1-phenylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1C1=CC=CC=C1 SYTVWQAYOSKDTP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 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
- 241001465754 Metazoa Species 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- REVDPJKCGIMABK-UHFFFAOYSA-N ethyl 5-(2-fluoro-4-nitrophenoxy)-1-methylindazole-6-carboxylate Chemical compound CCOC(=O)C1=CC=2N(C)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F REVDPJKCGIMABK-UHFFFAOYSA-N 0.000 description 2
- XWLADEBJTGAAFF-UHFFFAOYSA-N ethyl 5-hydroxy-1h-indazole-6-carboxylate Chemical compound C1=C(O)C(C(=O)OCC)=CC2=C1C=NN2 XWLADEBJTGAAFF-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- AYRUKGQCGNNMLA-UHFFFAOYSA-N n-(4-methoxy-2-methylphenyl)acetamide Chemical compound COC1=CC=C(NC(C)=O)C(C)=C1 AYRUKGQCGNNMLA-UHFFFAOYSA-N 0.000 description 2
- PNZHTGLCLCATLF-UHFFFAOYSA-N n-(5-bromo-4-methoxy-2-methylphenyl)acetamide Chemical compound COC1=CC(C)=C(NC(C)=O)C=C1Br PNZHTGLCLCATLF-UHFFFAOYSA-N 0.000 description 2
- HNBUWOMBTCXHLB-UHFFFAOYSA-N n-[3-fluoro-4-[6-fluoro-1-(oxan-2-yl)indazol-5-yl]oxyphenyl]-1,1-diphenylmethanimine Chemical compound FC1=CC(N=C(C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1OC(C(=CC=12)F)=CC=1C=NN2C1CCCCO1 HNBUWOMBTCXHLB-UHFFFAOYSA-N 0.000 description 2
- JGSZSPHWWCFJHH-UHFFFAOYSA-N n-[5-(2-fluoro-4-nitrophenoxy)-1-methylindazol-6-yl]-1,1-diphenylmethanimine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)=NC=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F JGSZSPHWWCFJHH-UHFFFAOYSA-N 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 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 2
- 239000008188 pellet Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- WHYQCQRHPQBZHM-UHFFFAOYSA-N pyrazole-1-carboxylic acid Chemical compound OC(=O)N1C=CC=N1 WHYQCQRHPQBZHM-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- OZSBEAZSPLJSJB-UHFFFAOYSA-N 1,2-dihydropyridine-2-carboxamide Chemical compound NC(=O)C1NC=CC=C1 OZSBEAZSPLJSJB-UHFFFAOYSA-N 0.000 description 1
- DHFYEFAILLBNHD-UHFFFAOYSA-N 1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxylic acid Chemical compound CN1C(C)=C(C(O)=O)C(=O)N1C1=CC=CC=C1 DHFYEFAILLBNHD-UHFFFAOYSA-N 0.000 description 1
- TUYNAVAKTQTOQC-UHFFFAOYSA-N 1-(4-bromo-2-fluorophenoxy)-2-fluoro-5-methyl-4-nitrobenzene Chemical compound C1=C([N+]([O-])=O)C(C)=CC(OC=2C(=CC(Br)=CC=2)F)=C1F TUYNAVAKTQTOQC-UHFFFAOYSA-N 0.000 description 1
- OCRYOEXMQQJDRA-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-methylhydrazine Chemical compound CNNC1=CC=C(F)C=C1 OCRYOEXMQQJDRA-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- BVVMNSNLWMCMOP-UHFFFAOYSA-N 2,2-dimethylmorpholin-4-ium;chloride Chemical compound Cl.CC1(C)CNCCO1 BVVMNSNLWMCMOP-UHFFFAOYSA-N 0.000 description 1
- YYYLLTIYDVSUDA-UHFFFAOYSA-N 2,4-dibromo-5-hydroxybenzaldehyde Chemical compound OC1=CC(C=O)=C(Br)C=C1Br YYYLLTIYDVSUDA-UHFFFAOYSA-N 0.000 description 1
- UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical compound OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 description 1
- PJYFXNZOOMGPIL-UHFFFAOYSA-N 2-methylmorpholin-4-ium;chloride Chemical compound Cl.CC1CNCCO1 PJYFXNZOOMGPIL-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- IEEHKTFVUIVORU-UHFFFAOYSA-N 2-methylpropanedioyl dichloride Chemical compound ClC(=O)C(C)C(Cl)=O IEEHKTFVUIVORU-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- RAHNMIAKHIOWFL-UHFFFAOYSA-N 3-fluoro-4-[(6-pyridin-4-yl-1h-indazol-5-yl)oxy]aniline Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)C=2C=CN=CC=2)=CC2=C1NN=C2 RAHNMIAKHIOWFL-UHFFFAOYSA-N 0.000 description 1
- LXRCXJIRKLIRQD-UHFFFAOYSA-N 3-fluoro-4-[1-methyl-6-(1h-pyrazol-4-yl)indazol-5-yl]oxyaniline Chemical compound C1=NNC=C1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C(N)C=C1F LXRCXJIRKLIRQD-UHFFFAOYSA-N 0.000 description 1
- JIDSZGYCIOEQPC-UHFFFAOYSA-N 3-fluoro-4-[6-(2-methylmorpholin-4-yl)-2-(oxan-2-yl)indazol-5-yl]oxyaniline Chemical compound C1COC(C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC1=CC=C(N)C=C1F JIDSZGYCIOEQPC-UHFFFAOYSA-N 0.000 description 1
- VZKAICSEZGOTLW-UHFFFAOYSA-N 3-fluoro-4-[6-(4-methylsulfonylphenyl)-1-(oxan-2-yl)indazol-5-yl]oxyaniline Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=C1)OC=2C(=CC(N)=CC=2)F)=CC2=C1C=NN2C1OCCCC1 VZKAICSEZGOTLW-UHFFFAOYSA-N 0.000 description 1
- KPMZFHFDWQTKEQ-UHFFFAOYSA-N 3-fluoro-4-[6-fluoro-1-(oxan-2-yl)indazol-5-yl]oxyaniline Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)F)=CC2=C1N(C1OCCCC1)N=C2 KPMZFHFDWQTKEQ-UHFFFAOYSA-N 0.000 description 1
- OFOQADCDNADADH-UHFFFAOYSA-N 3-fluoro-4-[[6-(1h-pyrazol-4-yl)-1h-indazol-5-yl]oxy]aniline Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)C2=CNN=C2)=CC2=C1NN=C2 OFOQADCDNADADH-UHFFFAOYSA-N 0.000 description 1
- FMOVQBLLFFJJBQ-UHFFFAOYSA-N 3-fluoro-4-[[6-(2-methoxypyrimidin-5-yl)-1h-indazol-5-yl]oxy]aniline Chemical compound C1=NC(OC)=NC=C1C(C(=C1)OC=2C(=CC(N)=CC=2)F)=CC2=C1C=NN2 FMOVQBLLFFJJBQ-UHFFFAOYSA-N 0.000 description 1
- BHFMDRKKCBCYAJ-UHFFFAOYSA-N 3-fluoro-4-[[6-(6-methylpyridin-3-yl)-1h-indazol-5-yl]oxy]aniline Chemical compound C1=NC(C)=CC=C1C(C(=C1)OC=2C(=CC(N)=CC=2)F)=CC2=C1C=NN2 BHFMDRKKCBCYAJ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- QMVGZGWXCPHJFW-UHFFFAOYSA-N 4,6-dimethyl-2-oxo-1-phenylpyridine-3-carboxylic acid Chemical compound O=C1C(C(O)=O)=C(C)C=C(C)N1C1=CC=CC=C1 QMVGZGWXCPHJFW-UHFFFAOYSA-N 0.000 description 1
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 1
- QFYZFYDOEJZMDX-UHFFFAOYSA-N 4-Formyl-antipyrine Chemical compound CN1C(C)=C(C=O)C(=O)N1C1=CC=CC=C1 QFYZFYDOEJZMDX-UHFFFAOYSA-N 0.000 description 1
- SQCZLBUBQMUZLZ-UHFFFAOYSA-N 4-[5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazol-6-yl]morpholine Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)N2CCOCC2)=CC2=C1N(C1OCCCC1)N=C2 SQCZLBUBQMUZLZ-UHFFFAOYSA-N 0.000 description 1
- ISOHPMZBBGGHER-UHFFFAOYSA-N 4-[5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazol-6-yl]-2-methylmorpholine Chemical compound C1COC(C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC1=CC=C([N+]([O-])=O)C=C1F ISOHPMZBBGGHER-UHFFFAOYSA-N 0.000 description 1
- RYXDPDZQYMSLQM-UHFFFAOYSA-N 4-[6-cyclopropyl-2-(oxan-2-yl)indazol-5-yl]oxy-3-fluoroaniline Chemical compound FC1=CC(N)=CC=C1OC1=CC2=CN(C3OCCCC3)N=C2C=C1C1CC1 RYXDPDZQYMSLQM-UHFFFAOYSA-N 0.000 description 1
- NSUDULRGVVELFX-UHFFFAOYSA-N 4-bromo-2,6-dimethylpyridine;hydrobromide Chemical compound Br.CC1=CC(Br)=CC(C)=N1 NSUDULRGVVELFX-UHFFFAOYSA-N 0.000 description 1
- GSNIJDQXKCLKCD-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)-6-(1h-pyrazol-4-yl)indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)C2=CNN=C2)=CC2=C1N(C1OCCCC1)N=C2 GSNIJDQXKCLKCD-UHFFFAOYSA-N 0.000 description 1
- OANGSIYETCZDON-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-pyridin-3-ylindazole Chemical compound C=1C=CN=CC=1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F OANGSIYETCZDON-UHFFFAOYSA-N 0.000 description 1
- ODUQOXSRGALJQU-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-6-(4-methylsulfonylphenyl)-1-(oxan-2-yl)indazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=C1)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=CC2=C1C=NN2C1OCCCC1 ODUQOXSRGALJQU-UHFFFAOYSA-N 0.000 description 1
- HOKMDFBPXLOXRT-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-6-(6-methylpyridin-3-yl)-1-(oxan-2-yl)indazole Chemical compound C1=NC(C)=CC=C1C(C(=C1)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=CC2=C1C=NN2C1OCCCC1 HOKMDFBPXLOXRT-UHFFFAOYSA-N 0.000 description 1
- BWINSBZKRALPQA-UHFFFAOYSA-N 5-(4-amino-2-fluorophenoxy)-1-(oxan-2-yl)-n-(oxan-4-yl)indazole-6-carboxamide Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)C(=O)NC2CCOCC2)=CC2=C1N(C1OCCCC1)N=C2 BWINSBZKRALPQA-UHFFFAOYSA-N 0.000 description 1
- CWWYKGMOBDVCOM-UHFFFAOYSA-N 5-(4-amino-2-fluorophenoxy)-n-(oxan-4-yl)-1h-indazol-6-amine Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)NC2CCOCC2)=CC2=C1NN=C2 CWWYKGMOBDVCOM-UHFFFAOYSA-N 0.000 description 1
- AQXKQOHAQDKIAN-UHFFFAOYSA-N 5-(4-bromo-2-fluorophenoxy)-6-fluoro-1h-indazole Chemical compound FC1=CC(Br)=CC=C1OC(C(=C1)F)=CC2=C1NN=C2 AQXKQOHAQDKIAN-UHFFFAOYSA-N 0.000 description 1
- OFKWIQJLYCKDNY-UHFFFAOYSA-N 5-bromo-2-methylpyridine Chemical compound CC1=CC=C(Br)C=N1 OFKWIQJLYCKDNY-UHFFFAOYSA-N 0.000 description 1
- JWEWFFCNXFUXTI-UHFFFAOYSA-N 6-(2,6-dimethylpyridin-4-yl)-5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazole Chemical compound CC1=NC(C)=CC(C=2C(=CC=3C=NN(C=3C=2)C2OCCCC2)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=C1 JWEWFFCNXFUXTI-UHFFFAOYSA-N 0.000 description 1
- RCDSRIRFKIZYKL-UHFFFAOYSA-N 6-(6-methylpyridin-3-yl)-1-(oxan-2-yl)indazol-5-ol Chemical compound C1=NC(C)=CC=C1C(C(=C1)O)=CC2=C1C=NN2C1OCCCC1 RCDSRIRFKIZYKL-UHFFFAOYSA-N 0.000 description 1
- NPOCSHUVRWAFRT-UHFFFAOYSA-N 6-bromo-1-methyl-5-(4-nitrophenoxy)indazole Chemical compound BrC=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1 NPOCSHUVRWAFRT-UHFFFAOYSA-N 0.000 description 1
- OULUXGINIIHCPV-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazole 4-[5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazol-6-yl]-2,2-dimethylmorpholine Chemical compound BrC=1C(=CC2=CN(N=C2C1)C1OCCCC1)OC1=C(C=C(C=C1)[N+](=O)[O-])F.FC1=C(OC2=CC3=CN(N=C3C=C2N2CC(OCC2)(C)C)C2OCCCC2)C=CC(=C1)[N+](=O)[O-] OULUXGINIIHCPV-UHFFFAOYSA-N 0.000 description 1
- WMKZCTDNUMLOGO-UHFFFAOYSA-N 6-cyclopropyl-5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC1=CC2=CN(C3OCCCC3)N=C2C=C1C1CC1 WMKZCTDNUMLOGO-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- DOSLSUYPGVYQAT-UHFFFAOYSA-N C1=NN(C(O)=O)C=C1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F Chemical compound C1=NN(C(O)=O)C=C1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F DOSLSUYPGVYQAT-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 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 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 240000005125 Myrtus communis Species 0.000 description 1
- 235000013418 Myrtus communis Nutrition 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 description 1
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- KKSWNPQYEQSECG-UHFFFAOYSA-N aniline 1H-indazole Chemical class NC1=CC=CC=C1.N1N=CC2=CC=CC=C12 KKSWNPQYEQSECG-UHFFFAOYSA-N 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- WOBLPDAWNVAVAS-UHFFFAOYSA-N butyl carboxy carbonate Chemical compound CCCCOC(=O)OC(O)=O WOBLPDAWNVAVAS-UHFFFAOYSA-N 0.000 description 1
- PMMVBIXTBBOSKH-UHFFFAOYSA-N butyl-[2-(2-methylphenyl)phenyl]phosphane Chemical group CCCCPC1=CC=CC=C1C1=CC=CC=C1C PMMVBIXTBBOSKH-UHFFFAOYSA-N 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SQAUUQRBOCJRCW-UHFFFAOYSA-N diethyl 2-acetylpropanedioate Chemical compound CCOC(=O)C(C(C)=O)C(=O)OCC SQAUUQRBOCJRCW-UHFFFAOYSA-N 0.000 description 1
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 1
- WEISAZNMMVPNTH-UHFFFAOYSA-N diethyl 2-propan-2-ylidenepropanedioate Chemical compound CCOC(=O)C(=C(C)C)C(=O)OCC WEISAZNMMVPNTH-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AXZRBQFPDMSQDG-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(C)N(C)N1C1=CC=C(F)C=C1 AXZRBQFPDMSQDG-UHFFFAOYSA-N 0.000 description 1
- MOJBHDUYXPZIFZ-UHFFFAOYSA-N ethyl 2-[(4-fluorophenyl)carbamoyl]-3-methylbut-2-enoate Chemical compound CCOC(=O)C(=C(C)C)C(=O)NC1=CC=C(F)C=C1 MOJBHDUYXPZIFZ-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- PELDSVQWAWPQCG-UHFFFAOYSA-N ethyl 3-(bromomethyl)-1-(4-fluorophenyl)-2-methyl-5-oxopyrazole-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(CBr)N(C)N1C1=CC=C(F)C=C1 PELDSVQWAWPQCG-UHFFFAOYSA-N 0.000 description 1
- KJSKGJKEWQJVHV-UHFFFAOYSA-N ethyl 3-anilino-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=CC=C1 KJSKGJKEWQJVHV-UHFFFAOYSA-N 0.000 description 1
- YQOSIYRTYFQAAK-UHFFFAOYSA-N ethyl 5-(2-fluoro-4-nitrophenoxy)-1h-indazole-6-carboxylate Chemical compound CCOC(=O)C1=CC=2NN=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F YQOSIYRTYFQAAK-UHFFFAOYSA-N 0.000 description 1
- FTNJFJJLGCPDCF-UHFFFAOYSA-N ethyl 5-hydroxy-1-(oxan-2-yl)indazole-6-carboxylate Chemical compound N1=CC=2C=C(O)C(C(=O)OCC)=CC=2N1C1CCCCO1 FTNJFJJLGCPDCF-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- ASLLHKMBHRQSCB-UHFFFAOYSA-N ethyl n-(4-fluoroanilino)carbamate Chemical compound CCOC(=O)NNC1=CC=C(F)C=C1 ASLLHKMBHRQSCB-UHFFFAOYSA-N 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
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- VNWHJJCHHGPAEO-UHFFFAOYSA-N fluoroboronic acid Chemical compound OB(O)F VNWHJJCHHGPAEO-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 102000057308 human HGF Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- CDGNLUSBENXDGG-UHFFFAOYSA-N meta-Cresidine Chemical compound COC1=CC=C(N)C(C)=C1 CDGNLUSBENXDGG-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- WDLMEQGFKXXCRX-UHFFFAOYSA-N methyl 3-(4-fluoroanilino)-3-oxopropanoate Chemical compound COC(=O)CC(=O)NC1=CC=C(F)C=C1 WDLMEQGFKXXCRX-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- KQUMPVACLCUODY-UHFFFAOYSA-N n-[4-[(6-amino-1h-indazol-5-yl)oxy]-3-fluorophenyl]-6-methyl-2-oxo-1-phenylpyridine-3-carboxamide Chemical compound CC1=CC=C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)N)=CC=2)C(=O)N1C1=CC=CC=C1 KQUMPVACLCUODY-UHFFFAOYSA-N 0.000 description 1
- SZLNIFNJINCJSX-UHFFFAOYSA-N n-[[2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)phenyl]methylideneamino]methanamine Chemical compound C1=C(Br)C(C=NNC)=CC(OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=C1Br SZLNIFNJINCJSX-UHFFFAOYSA-N 0.000 description 1
- XHXVAJHZTIXQQD-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-5-[(4-butoxyphenyl)methyl]-2,6-dimethylpyrimidin-4-amine Chemical compound C1=CC(OCCCC)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 XHXVAJHZTIXQQD-UHFFFAOYSA-N 0.000 description 1
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- XITQUSLLOSKDTB-UHFFFAOYSA-N nitrofen Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(Cl)C=C1Cl XITQUSLLOSKDTB-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000012026 peptide coupling reagents Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UZBYXBPZESUCBE-UHFFFAOYSA-N tert-butyl 4-[5-(4-amino-2-fluorophenoxy)-1-methylindazol-6-yl]pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C(N)C=C1F UZBYXBPZESUCBE-UHFFFAOYSA-N 0.000 description 1
- CMNHMRCJSHRCRI-UHFFFAOYSA-N tert-butyl n-[5-(2-fluoro-4-nitrophenoxy)-1-methylindazol-6-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC=1C=C2N(C)N=CC2=CC=1OC1=CC=C([N+]([O-])=O)C=C1F CMNHMRCJSHRCRI-UHFFFAOYSA-N 0.000 description 1
- YRWMJOLPABFTDZ-UHFFFAOYSA-N tert-butyl n-[5-[2-fluoro-4-[(6-methyl-2-oxo-1-phenylpyridine-3-carbonyl)amino]phenoxy]-1h-indazol-6-yl]carbamate Chemical compound CC1=CC=C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)NC(=O)OC(C)(C)C)=CC=2)C(=O)N1C1=CC=CC=C1 YRWMJOLPABFTDZ-UHFFFAOYSA-N 0.000 description 1
- ORUGTGTZBRUQIT-UHFFFAOYSA-N tert-butyl n-pyridin-2-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=N1 ORUGTGTZBRUQIT-UHFFFAOYSA-N 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- 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
- C07D403/14—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 three or more hetero rings
-
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8329408P | 2008-07-24 | 2008-07-24 | |
| US8508208P | 2008-07-31 | 2008-07-31 | |
| US10865908P | 2008-10-27 | 2008-10-27 | |
| PCT/US2009/050640 WO2010011538A1 (en) | 2008-07-24 | 2009-07-15 | Amidophenoxyindazoles useful as inhibitors of c-met |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2011000925A true MX2011000925A (es) | 2011-03-21 |
Family
ID=41010247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2011000925A MX2011000925A (es) | 2008-07-24 | 2009-07-15 | Amidofenoxiindazoles utiles como inhibidores de c-met. |
Country Status (35)
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110075016A (ko) | 2008-10-14 | 2011-07-05 | 닝 시 | 화합물 및 사용 방법 |
| EP2408300B1 (en) | 2009-03-21 | 2016-05-11 | Sunshine Lake Pharma Co., Ltd. | Amino ester derivatives, salts thereof and methods of use |
| CA2820709C (en) | 2011-02-28 | 2016-02-16 | Sunshine Lake Pharma Co., Ltd. | Substituted quinoline compounds and methods of use |
| JP5970003B2 (ja) * | 2011-03-04 | 2016-08-17 | ローカス ファーマシューティカルズ インコーポレイテッド | アミノピラジン化合物 |
| KR20130118612A (ko) * | 2012-04-20 | 2013-10-30 | (주)네오믹스 | 신규한 아미노피리딘 유도체 및 이의 용도 |
| CN104334581B (zh) * | 2012-05-09 | 2018-02-02 | 伊莱利利公司 | 抗‑c‑Met抗体 |
| EP2961744B1 (en) * | 2013-02-27 | 2017-06-28 | Array Biopharma, Inc. | Intermediates for use in the preparation of indazole derivatives and processes for the preparation thereof |
| CN104140393B (zh) * | 2013-12-10 | 2016-09-21 | 郑州泰基鸿诺医药股份有限公司 | 一种芳环/芳杂环叔丁醇酯类化合物的制备方法 |
| US9718841B2 (en) | 2014-04-22 | 2017-08-01 | Calitor Sciences, Llc | Bicyclic pyrazolone compounds and methods of use |
| TW201716085A (zh) * | 2015-08-12 | 2017-05-16 | 應克隆公司 | 癌症之組合療法 |
| EP3442573A1 (en) * | 2016-04-15 | 2019-02-20 | Eli Lilly and Company | Combination of ramucirumab and merestinib for use in treatment of colorectal cancer |
| ES3008636T3 (en) | 2016-06-02 | 2025-03-24 | Immunocore Ltd | Dosing regimen for gp100-specific tcr - anti-cd3 scfv fusion protein |
| EP3490676A1 (en) * | 2016-07-29 | 2019-06-05 | Eli Lilly and Company | Combination therapy with merestinib and anti-pd-l1 or anti-pd-1 inhibitors for use in the treatment of cancer |
| CN108069938A (zh) * | 2016-11-15 | 2018-05-25 | 中国药科大学 | 2,4-二取代吡啶类化合物及其制备方法和应用 |
| US20210283249A1 (en) | 2016-11-16 | 2021-09-16 | Eli Lilly And Company | Combination therapy for cancer with exon 14 skipping mutation(s) or exon 14 skipping phenotype |
| WO2018093654A1 (en) | 2016-11-16 | 2018-05-24 | Eli Lilly And Company | Treatment of cancer with exon 14 skipping mutation(s) or exon 14 skipping phenotype |
| CN107382968A (zh) * | 2017-07-06 | 2017-11-24 | 北京万全德众医药生物技术有限公司 | 一种吲哚类c‑Met抑制剂的制备方法 |
| CN107311983A (zh) * | 2017-07-06 | 2017-11-03 | 北京万全德众医药生物技术有限公司 | 吲哚类小分子c‑met抑制剂 |
| US10180422B1 (en) | 2017-08-22 | 2019-01-15 | Scripps Health | Methods of treating a neuroendocrine tumor |
| EP3480201A1 (en) | 2017-11-06 | 2019-05-08 | Oncostellae, S.L. | New analogs as androgen receptor and glucocorticoid receptor modulators |
| JP7377798B2 (ja) | 2017-11-24 | 2023-11-10 | 南京明徳新薬研発有限公司 | c-MET/AXL阻害剤としてのウラシル系化合物 |
| CN110041316B (zh) * | 2018-01-17 | 2022-04-19 | 药捷安康(南京)科技股份有限公司 | Tam家族激酶/和csf1r激酶抑制剂及其用途 |
| CN111295386B (zh) | 2018-03-08 | 2022-09-06 | 伟迈可生物有限公司 | 噻吩并吡啶衍生物及含有该衍生物的药物组合物 |
| CA3109891A1 (en) * | 2018-08-24 | 2020-02-27 | Nanjing Transthera Biosciences Co., Ltd. | Quinoline derivative inhibitor: tam, ntrk, and csf1r kinases |
| JP7443373B2 (ja) * | 2018-09-03 | 2024-03-05 | タイリガンド バイオサイエンス(シャンハイ)リミテッド | 抗がん性薬物としてのtrk阻害剤 |
| CN112771053A (zh) | 2019-09-06 | 2021-05-07 | 伟迈可生物有限公司 | 基于生物标志物的治疗组合物 |
| CN117355533A (zh) * | 2021-06-22 | 2024-01-05 | 株式会社Lg化学 | 作为蛋白激酶抑制剂的新型化合物 |
| WO2023110936A1 (en) | 2021-12-14 | 2023-06-22 | Netherlands Translational Research Center Holding B.V | Reversible macrocyclic kinase inhibitors |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO155316C (no) * | 1982-04-23 | 1987-03-11 | Sintef | Fremgangsmaate for fremstilling av magnetiske polymerpartikler. |
| US5484681A (en) * | 1994-10-31 | 1996-01-16 | Xerox Corporation | Conductive composite particles and processes for the preparation thereof |
| IL114149A0 (en) * | 1995-06-14 | 1995-10-31 | Yeda Res & Dev | Modified avidin and streptavidin molecules and use thereof |
| US5747577A (en) * | 1995-12-27 | 1998-05-05 | Xerox Corporation | Conductive particles containing carbon black and processes for the preparation thereof |
| DE10046029A1 (de) | 2000-09-18 | 2002-03-28 | Bayer Ag | Indazole |
| ES2268015T3 (es) * | 2001-05-18 | 2007-03-16 | Srl, Inc. | Procedimiento de inmunoensayo. |
| US6956084B2 (en) * | 2001-10-04 | 2005-10-18 | Bridgestone Corporation | Nano-particle preparation and applications |
| JP2004067703A (ja) * | 2002-04-24 | 2004-03-04 | Japan Science & Technology Corp | 架橋ポリマー、微粒子および製造方法 |
| US7192780B2 (en) * | 2002-10-23 | 2007-03-20 | Evident Technologies | Fluorescent lifetime biological detection and imaging using water-stable semiconductor nanocrystals |
| EP1562935B1 (de) | 2002-10-28 | 2006-09-06 | Bayer HealthCare AG | Heteroaryloxy-substituierte phenylaminopyrimidine als rho-kinaseinhibitoren |
| DE602004010525T2 (de) * | 2003-07-17 | 2008-11-27 | Invitrogen Dynal As | Verfahren zur herstellung von ummantelten magnetischen teilchen |
| US7163998B2 (en) * | 2003-09-09 | 2007-01-16 | Eastman Kodak Company | Stabilized polymer beads and method of preparation |
| US7173031B2 (en) * | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US7439246B2 (en) * | 2004-06-28 | 2008-10-21 | Bristol-Myers Squibb Company | Fused heterocyclic kinase inhibitors |
| JO2787B1 (en) | 2005-04-27 | 2014-03-15 | امجين إنك, | Alternative amide derivatives and methods of use |
| ES2612377T3 (es) | 2005-12-21 | 2017-05-16 | Janssen Pharmaceutica N.V. | Triazolopiridazinas como moduladores de tirosina cinasas |
| RU2008139599A (ru) * | 2006-03-07 | 2010-04-20 | Эррэй Биофарма Инк. (Us) | Гетеробициклические производные пиразола и способы их применения |
| JP2009542862A (ja) * | 2006-06-29 | 2009-12-03 | インヴィトロジェン ダイナル エーエス | マルチブロックポリマーを含む粒子 |
| PE20080403A1 (es) | 2006-07-14 | 2008-04-25 | Amgen Inc | Derivados heterociclicos fusionados y metodos de uso |
| US8507489B2 (en) | 2006-10-23 | 2013-08-13 | Sgx Pharmaceuticals, Inc. | Bicyclic triazoles as protein kinase modulators |
| WO2009003084A1 (en) | 2007-06-27 | 2008-12-31 | Arkema Inc. | Process for the manufacture of hydrofluoroolefins |
-
2009
- 2009-07-10 TW TW098123519A patent/TWI365185B/zh not_active IP Right Cessation
- 2009-07-12 JO JO2009256A patent/JO2788B1/en active
- 2009-07-13 AR ARP090102636A patent/AR074632A1/es active IP Right Grant
- 2009-07-15 PE PE2011000061A patent/PE20110150A1/es active IP Right Grant
- 2009-07-15 SI SI200930193T patent/SI2310382T1/sl unknown
- 2009-07-15 PL PL09790440T patent/PL2310382T3/pl unknown
- 2009-07-15 RS RS20120176A patent/RS52261B/sr unknown
- 2009-07-15 MX MX2011000925A patent/MX2011000925A/es active IP Right Grant
- 2009-07-15 NZ NZ590013A patent/NZ590013A/en not_active IP Right Cessation
- 2009-07-15 CA CA2731773A patent/CA2731773C/en not_active Expired - Fee Related
- 2009-07-15 ES ES09790440T patent/ES2379587T3/es active Active
- 2009-07-15 MY MYPI2011000343A patent/MY163852A/en unknown
- 2009-07-15 EA EA201170252A patent/EA018385B1/ru not_active IP Right Cessation
- 2009-07-15 CN CN200980128694.4A patent/CN102105462B/zh not_active Expired - Fee Related
- 2009-07-15 KR KR1020117001628A patent/KR101334456B1/ko not_active Expired - Fee Related
- 2009-07-15 PT PT09790440T patent/PT2310382E/pt unknown
- 2009-07-15 HR HR20120202T patent/HRP20120202T1/hr unknown
- 2009-07-15 AT AT09790440T patent/ATE546444T1/de active
- 2009-07-15 JP JP2011520095A patent/JP5414794B2/ja not_active Expired - Fee Related
- 2009-07-15 WO PCT/US2009/050640 patent/WO2010011538A1/en not_active Ceased
- 2009-07-15 AU AU2009274256A patent/AU2009274256B2/en not_active Ceased
- 2009-07-15 US US12/503,223 patent/US8030302B2/en not_active Ceased
- 2009-07-15 DK DK09790440.3T patent/DK2310382T3/da active
- 2009-07-15 EP EP09790440A patent/EP2310382B1/en active Active
- 2009-07-15 BR BRPI0916286A patent/BRPI0916286B8/pt not_active IP Right Cessation
-
2011
- 2011-01-06 IL IL210490A patent/IL210490A/en active IP Right Grant
- 2011-01-07 ZA ZA2011/00219A patent/ZA201100219B/en unknown
- 2011-01-07 DO DO2011000009A patent/DOP2011000009A/es unknown
- 2011-01-19 CO CO11005437A patent/CO6351737A2/es not_active Application Discontinuation
- 2011-01-21 EC EC2011010778A patent/ECSP11010778A/es unknown
- 2011-01-21 SV SV2011003816A patent/SV2011003816A/es active IP Right Grant
- 2011-01-21 CL CL2011000134A patent/CL2011000134A1/es unknown
- 2011-01-24 CR CR20110046A patent/CR20110046A/es unknown
- 2011-01-24 MA MA33555A patent/MA32594B1/fr unknown
- 2011-12-08 US US13/374,053 patent/USRE43878E1/en not_active Expired - Fee Related
-
2012
- 2012-04-04 CY CY20121100337T patent/CY1112595T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2009274256B2 (en) | Amidophenoxyindazoles useful as inhibitors of c-Met | |
| CN110573500B (zh) | N-(氮杂芳基)环内酰胺-1-甲酰胺衍生物及其制备方法和应用 | |
| AU2020255100C1 (en) | N-heteroaromatic amide derivatives for treatment of cancer | |
| DK2137162T3 (en) | Organic compounds and their applications | |
| CN105189480A (zh) | 在治疗由IKKε和/或TBK-1机制介导的疾病中有用的嘧啶化合物 | |
| CN103951658A (zh) | 用于治疗异常细胞生长的磺酰胺衍生物 | |
| HUE033177T2 (en) | Pyrazine carboxamide compound | |
| AU2005300736B2 (en) | Anthranilamide pyridinureas as VEGF receptor kinase inhibitors | |
| MX2011005177A (es) | Antagonistas de la trayectoria hedgehog de piridazinas tetrasustituidas. | |
| CA3039919A1 (en) | Quinoxaline compounds as type iii receptor tyrosine kinase inhibitors | |
| MX2011005176A (es) | Antagonistas de la trayectoria hedgehog de piridazinas tetrasustituidas. | |
| KR102815874B1 (ko) | 피롤리딘 유도체 | |
| JP2023547346A (ja) | セロトニン1b受容体モジュレーターとしての強力で選択的な新規化合物 | |
| TW201116515A (en) | Dihydrobenzoindazoles | |
| HK1155172B (en) | Amidophenoxyindazoles useful as inhibitors of c-met | |
| CN120957978A (zh) | 作为pkmyt1激酶抑制剂的吲唑化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Grant or registration |