ES2379587T3 - Amidofenoxiindazoles como inhibidores de C-Met - Google Patents
Amidofenoxiindazoles como inhibidores de C-Met Download PDFInfo
- Publication number
- ES2379587T3 ES2379587T3 ES09790440T ES09790440T ES2379587T3 ES 2379587 T3 ES2379587 T3 ES 2379587T3 ES 09790440 T ES09790440 T ES 09790440T ES 09790440 T ES09790440 T ES 09790440T ES 2379587 T3 ES2379587 T3 ES 2379587T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- mmol
- fluoro
- indazol
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title description 9
- -1 amino, dimethylamino, fluoro, cyclopropyl Chemical group 0.000 claims abstract description 150
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 6
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 201000002689 pediatric hepatocellular carcinoma Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 208000027927 Hereditary papillary renal cell carcinoma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- QHADVLVFMKEIIP-UHFFFAOYSA-N n-[3-fluoro-4-[1-methyl-6-(1h-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound O=C1N(C=2C=CC(F)=CC=2)C(C)=CC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=2C=NN(C)C=2C=C1C=1C=NNC=1 QHADVLVFMKEIIP-UHFFFAOYSA-N 0.000 claims 1
- XCPSZMLNENDLKG-UHFFFAOYSA-N n-[3-fluoro-4-[1-methyl-6-(1h-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-6-methyl-2-oxo-1-phenylpyridine-3-carboxamide Chemical compound O=C1N(C=2C=CC=CC=2)C(C)=CC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=2C=NN(C)C=2C=C1C=1C=NNC=1 XCPSZMLNENDLKG-UHFFFAOYSA-N 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 279
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 225
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 144
- 239000000243 solution Substances 0.000 description 118
- 235000019439 ethyl acetate Nutrition 0.000 description 112
- 238000002360 preparation method Methods 0.000 description 112
- 239000000203 mixture Substances 0.000 description 82
- 239000000047 product Substances 0.000 description 77
- 239000007787 solid Substances 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 57
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 229910001868 water Inorganic materials 0.000 description 46
- 229920006395 saturated elastomer Polymers 0.000 description 43
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 39
- 238000000034 method Methods 0.000 description 37
- 239000012074 organic phase Substances 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 238000003756 stirring Methods 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 239000011780 sodium chloride Substances 0.000 description 28
- 239000000126 substance Substances 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000000725 suspension 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 239000007832 Na2SO4 Substances 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 235000019270 ammonium chloride 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
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000002244 precipitate Substances 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
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-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
- 239000010410 layer Substances 0.000 description 9
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 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 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
- 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 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 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 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
- 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
- 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
- 230000015572 biosynthetic process Effects 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 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
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 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 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 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
- 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 5
- 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000011343 solid material Substances 0.000 description 5
- 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 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 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000010438 heat treatment Methods 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
- 239000006166 lysate Substances 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000000523 sample Substances 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
- BGENEXHSQIGPRB-UHFFFAOYSA-N tert-butyl 4-[5-(2-fluoro-4-nitrophenoxy)-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+]([O-])=O)C=C1F BGENEXHSQIGPRB-UHFFFAOYSA-N 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
- 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 3
- 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 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
- 238000005481 NMR spectroscopy Methods 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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 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
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940076286 cupric acetate Drugs 0.000 description 3
- UJONYAVMBYXBJQ-UHFFFAOYSA-N ditert-butyl-[2-(2-methylphenyl)phenyl]phosphane Chemical group CC1=CC=CC=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C UJONYAVMBYXBJQ-UHFFFAOYSA-N 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
- GZBUMXFWJBMWEE-UHFFFAOYSA-N ethyl 4,6-dimethyl-2-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)C=C(C)NC1=O GZBUMXFWJBMWEE-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- OUCYWJAACMAXQD-UHFFFAOYSA-N pyridin-2-ylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=N1 OUCYWJAACMAXQD-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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 3
- ULMJHNMTKSEWKX-UHFFFAOYSA-N (1-acetyl-6-bromoindazol-5-yl) acetate Chemical compound C1=C(Br)C(OC(=O)C)=CC2=C1N(C(C)=O)N=C2 ULMJHNMTKSEWKX-UHFFFAOYSA-N 0.000 description 2
- VTTWLUICORCDCK-BJMVGYQFSA-N (2e)-2-[(4-fluorophenyl)hydrazinylidene]acetaldehyde Chemical compound FC1=CC=C(N\N=C\C=O)C=C1 VTTWLUICORCDCK-BJMVGYQFSA-N 0.000 description 2
- 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
- OCRYOEXMQQJDRA-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-methylhydrazine Chemical compound CNNC1=CC=C(F)C=C1 OCRYOEXMQQJDRA-UHFFFAOYSA-N 0.000 description 2
- WPJGHIVGAOVUAT-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=C(F)C=C1 WPJGHIVGAOVUAT-UHFFFAOYSA-N 0.000 description 2
- KZSMSENQGGQIQF-UHFFFAOYSA-N 1-(4-fluorophenyl)-4,6-dimethyl-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(O)=O)=C(C)C=C(C)N1C1=CC=C(F)C=C1 KZSMSENQGGQIQF-UHFFFAOYSA-N 0.000 description 2
- XTTOEOZCZCIDFY-UHFFFAOYSA-N 1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound CC1=CC=C(C(N)=O)C(=O)N1C1=CC=C(F)C=C1 XTTOEOZCZCIDFY-UHFFFAOYSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 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
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 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
- 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
- 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 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
- 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 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
- 238000002965 ELISA Methods 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 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
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000000113 differential scanning calorimetry 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
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 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 2
- KXXQRJOFAUVHQU-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-5-methyl-2-oxopyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=CC(C)=CN1C1=CC=C(F)C=C1 KXXQRJOFAUVHQU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- KJSKGJKEWQJVHV-UHFFFAOYSA-N ethyl 3-anilino-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NC1=CC=CC=C1 KJSKGJKEWQJVHV-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 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 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
- ASLLHKMBHRQSCB-UHFFFAOYSA-N ethyl n-(4-fluoroanilino)carbamate Chemical compound CCOC(=O)NNC1=CC=C(F)C=C1 ASLLHKMBHRQSCB-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- WLGIETJZWGQIDX-UHFFFAOYSA-N methyl 1-(4-fluorophenyl)-2-oxopyridine-3-carboxylate Chemical compound O=C1C(C(=O)OC)=CC=CN1C1=CC=C(F)C=C1 WLGIETJZWGQIDX-UHFFFAOYSA-N 0.000 description 2
- SILBTMNCGYLTOK-UHFFFAOYSA-N methyl 2-oxo-1h-pyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1O SILBTMNCGYLTOK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 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
- 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
- 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 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000011580 nude mouse model Methods 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
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000011734 sodium Substances 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
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OWVWACFCIIHCOQ-UHFFFAOYSA-N tert-butyl n-[5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazol-6-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F OWVWACFCIIHCOQ-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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
- 239000003039 volatile agent Substances 0.000 description 2
- 230000004580 weight loss Effects 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
- ISOHPMZBBGGHER-NKTHEXPSSA-N (2r)-4-[5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazol-6-yl]-2-methylmorpholine Chemical compound C1CO[C@H](C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC1=CC=C([N+]([O-])=O)C=C1F ISOHPMZBBGGHER-NKTHEXPSSA-N 0.000 description 1
- NJQRAAHKQQPUIT-UHFFFAOYSA-N 1,2-dihydropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CNC1 NJQRAAHKQQPUIT-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-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
- DBVQFPOKBRTQMT-UHFFFAOYSA-N 1-(4-fluorophenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxylic acid Chemical compound CN1C(C)=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 DBVQFPOKBRTQMT-UHFFFAOYSA-N 0.000 description 1
- VRHLXKGWXCAERP-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-methyl-3-(morpholin-4-ylmethyl)-5-oxopyrazole-4-carboxylic acid Chemical compound OC(=O)C=1C(=O)N(C=2C=CC(F)=CC=2)N(C)C=1CN1CCOCC1 VRHLXKGWXCAERP-UHFFFAOYSA-N 0.000 description 1
- ZXNZHVDQMZJUKH-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound O=C1C(C(=O)N)=CC=CN1C1=CC=C(F)C=C1 ZXNZHVDQMZJUKH-UHFFFAOYSA-N 0.000 description 1
- HYPPRVKRONOGKR-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-methyl-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(O)=O)=C(C)C=CN1C1=CC=C(F)C=C1 HYPPRVKRONOGKR-UHFFFAOYSA-N 0.000 description 1
- CMDFYEPURQYWPK-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(morpholin-4-ylmethyl)-2-oxopyridine-3-carboxylic acid Chemical compound C=1N(C=2C=CC(F)=CC=2)C(=O)C(C(=O)O)=CC=1CN1CCOCC1 CMDFYEPURQYWPK-UHFFFAOYSA-N 0.000 description 1
- GIQNJKXLSIEOME-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-methyl-2-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 GIQNJKXLSIEOME-UHFFFAOYSA-N 0.000 description 1
- YQCIBHNPQJZLOT-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-[3-fluoro-4-[(6-pyridin-3-yl-1h-indazol-5-yl)oxy]phenyl]-2-methyl-3-(morpholin-4-ylmethyl)-5-oxopyrazole-4-carboxamide Chemical compound C=1C=C(OC=2C(=CC=3NN=CC=3C=2)C=2C=NC=CC=2)C(F)=CC=1NC(=O)C=1C(=O)N(C=2C=CC(F)=CC=2)N(C)C=1CN1CCOCC1 YQCIBHNPQJZLOT-UHFFFAOYSA-N 0.000 description 1
- KAANTNXREIRLCT-UHFFFAOYSA-N 1-(triphenyl-$l^{5}-phosphanylidene)propan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)C)C1=CC=CC=C1 KAANTNXREIRLCT-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
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-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
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-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
- IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-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
- IEEHKTFVUIVORU-UHFFFAOYSA-N 2-methylpropanedioyl dichloride Chemical compound ClC(=O)C(C)C(Cl)=O IEEHKTFVUIVORU-UHFFFAOYSA-N 0.000 description 1
- XLGOPZMMTOJEQX-UHFFFAOYSA-N 3-fluoro-4-(1-methyl-6-pyridin-3-ylindazol-5-yl)oxyaniline Chemical compound C=1C=CN=CC=1C=1C=C2N(C)N=CC2=CC=1OC1=CC=C(N)C=C1F XLGOPZMMTOJEQX-UHFFFAOYSA-N 0.000 description 1
- DZZZKMWSQBCWDS-UHFFFAOYSA-N 3-fluoro-4-[(6-morpholin-4-yl-1h-indazol-5-yl)oxy]aniline Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)N2CCOCC2)=CC2=C1NN=C2 DZZZKMWSQBCWDS-UHFFFAOYSA-N 0.000 description 1
- LJXGCVMRIYXROZ-UHFFFAOYSA-N 3-fluoro-4-[(6-pyridin-3-yl-1h-indazol-5-yl)oxy]aniline Chemical compound FC1=CC(N)=CC=C1OC(C(=C1)C=2C=NC=CC=2)=CC2=C1NN=C2 LJXGCVMRIYXROZ-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
- OPCPUWRUFNSGJS-UHFFFAOYSA-N 3-fluoro-4-[1-methyl-6-(2-methylpyridin-4-yl)indazol-5-yl]oxyaniline Chemical compound C1=NC(C)=CC(C=2C(=CC=3C=NN(C)C=3C=2)OC=2C(=CC(N)=CC=2)F)=C1 OPCPUWRUFNSGJS-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
- FYTQTUYGMCRKGB-UHFFFAOYSA-N 3-fluoro-4-[[6-(2-methylpyridin-4-yl)-1h-indazol-5-yl]oxy]aniline Chemical compound C1=NC(C)=CC(C=2C(=CC=3C=NNC=3C=2)OC=2C(=CC(N)=CC=2)F)=C1 FYTQTUYGMCRKGB-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
- 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
- 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
- NRFSMURTCRAWRK-UHFFFAOYSA-N 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=C1 NRFSMURTCRAWRK-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
- YIDVTJXHCSBUKP-UHFFFAOYSA-N 4-[5-(2-fluoro-4-nitrophenoxy)-2-(oxan-2-yl)indazol-6-yl]-2,2-dimethylmorpholine Chemical compound C1COC(C)(C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC1=CC=C([N+]([O-])=O)C=C1F YIDVTJXHCSBUKP-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
- NQYNATPARYNZHK-UHFFFAOYSA-N 4-[6-(2,2-dimethylmorpholin-4-yl)-2-(oxan-2-yl)indazol-5-yl]oxy-3-fluoroaniline Chemical compound C1COC(C)(C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC1=CC=C(N)C=C1F NQYNATPARYNZHK-UHFFFAOYSA-N 0.000 description 1
- SCYDNBIYENGVRL-UHFFFAOYSA-N 4-[[6-(2,5-dimethylpyrazol-3-yl)-1h-indazol-5-yl]oxy]-3-fluoroaniline Chemical compound CN1N=C(C)C=C1C(C(=C1)OC=2C(=CC(N)=CC=2)F)=CC2=C1C=NN2 SCYDNBIYENGVRL-UHFFFAOYSA-N 0.000 description 1
- WBOBUZFGMWDEPU-UHFFFAOYSA-N 4-[[6-(2,6-dimethylpyridin-4-yl)-1h-indazol-5-yl]oxy]-3-fluoroaniline Chemical compound CC1=NC(C)=CC(C=2C(=CC=3C=NNC=3C=2)OC=2C(=CC(N)=CC=2)F)=C1 WBOBUZFGMWDEPU-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
- ZQKLDXDMRSBWMC-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)-6-pyridin-3-ylindazole Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)C=2C=NC=CC=2)=CC2=C1N(C1OCCCC1)N=C2 ZQKLDXDMRSBWMC-UHFFFAOYSA-N 0.000 description 1
- XVUUSVDXEWYUFD-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(2-methylpyridin-4-yl)indazole Chemical compound C1=NC(C)=CC(C=2C(=CC=3C=NN(C)C=3C=2)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=C1 XVUUSVDXEWYUFD-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
- KDJPVLZJBQCYCD-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-6-(2-methoxypyrimidin-5-yl)-1-(oxan-2-yl)indazole Chemical compound C1=NC(OC)=NC=C1C(C(=C1)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=CC2=C1C=NN2C1OCCCC1 KDJPVLZJBQCYCD-UHFFFAOYSA-N 0.000 description 1
- ZESVMGPZXZQIGU-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-6-(2-methylpyridin-4-yl)-1-(oxan-2-yl)indazole Chemical compound C1=NC(C)=CC(C=2C(=CC=3C=NN(C=3C=2)C2OCCCC2)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=C1 ZESVMGPZXZQIGU-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
- UNDGASQSGFZFFV-UHFFFAOYSA-N 5-(2-fluoro-4-nitrophenoxy)-n,n-dimethyl-1-(oxan-2-yl)indazol-6-amine Chemical compound CN(C)C1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1F UNDGASQSGFZFFV-UHFFFAOYSA-N 0.000 description 1
- YFTAUNOLAHRUIE-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N)N=C1 YFTAUNOLAHRUIE-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
- IOZMPEKXTVBCNP-UHFFFAOYSA-N 5-(4-amino-2-fluorophenoxy)-n,n-dimethyl-1h-indazol-6-amine Chemical compound CN(C)C1=CC=2NN=CC=2C=C1OC1=CC=C(N)C=C1F IOZMPEKXTVBCNP-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
- KMYDMRSJNVQRJK-UHFFFAOYSA-N 5-(4-aminophenoxy)-n,n-dimethyl-1h-indazol-6-amine Chemical compound CN(C)C1=CC=2NN=CC=2C=C1OC1=CC=C(N)C=C1 KMYDMRSJNVQRJK-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
- JVBBTOOJZQKVED-UHFFFAOYSA-N 5-methyl-2-oxo-1-phenylpyridine-3-carboxylic acid Chemical compound C1=C(C)C=C(C(O)=O)C(=O)N1C1=CC=CC=C1 JVBBTOOJZQKVED-UHFFFAOYSA-N 0.000 description 1
- WYINCEUDAPKKKD-UHFFFAOYSA-N 6-(2,5-dimethylpyrazol-3-yl)-5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazole Chemical compound CN1N=C(C)C=C1C(C(=C1)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=CC2=C1C=NN2C1OCCCC1 WYINCEUDAPKKKD-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
- 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 1
- GEKVAMNXBCJIFH-UHFFFAOYSA-N 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methylindazole Chemical class BrC1=CC2=NN(C)C=C2C=C1OC1=CC=C([N+]([O-])=O)C=C1F GEKVAMNXBCJIFH-UHFFFAOYSA-N 0.000 description 1
- NQZFITKAOXEEKZ-UHFFFAOYSA-N 6-bromo-5-(4-nitrophenoxy)-1-(oxan-2-yl)indazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(C(=C1)Br)=CC2=C1N(C1OCCCC1)N=C2 NQZFITKAOXEEKZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 239000004135 Bone phosphate Substances 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
- 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
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 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
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 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
- 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
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-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
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient 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
- 238000004458 analytical method Methods 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
- 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 210000001072 colon Anatomy 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 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
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 230000009089 cytolysis Effects 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 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
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- WDUDHEOUGWAKFD-UHFFFAOYSA-N ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+) Chemical compound [Fe+2].CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 WDUDHEOUGWAKFD-UHFFFAOYSA-N 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
- JTZNWONOSXFPQK-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-2-methyl-3-(morpholin-4-ylmethyl)-5-oxopyrazole-4-carboxylate Chemical compound CN1N(C=2C=CC(F)=CC=2)C(=O)C(C(=O)OCC)=C1CN1CCOCC1 JTZNWONOSXFPQK-UHFFFAOYSA-N 0.000 description 1
- IIQZGXAZOSJAAD-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-2-methyl-5-oxo-3-(piperidin-1-ylmethyl)pyrazole-4-carboxylate Chemical compound CN1N(C=2C=CC(F)=CC=2)C(=O)C(C(=O)OCC)=C1CN1CCCCC1 IIQZGXAZOSJAAD-UHFFFAOYSA-N 0.000 description 1
- DULHKPXUZJYPJG-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-4,6-dimethyl-2-oxopyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(C)C=C(C)N1C1=CC=C(F)C=C1 DULHKPXUZJYPJG-UHFFFAOYSA-N 0.000 description 1
- OQEBGEOZZFMBAA-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-4-methyl-2-oxopyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(C)C=CN1C1=CC=C(F)C=C1 OQEBGEOZZFMBAA-UHFFFAOYSA-N 0.000 description 1
- LIVQXBUMORWIEC-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-5-(morpholin-4-ylmethyl)-2-oxopyridine-3-carboxylate Chemical compound C=1N(C=2C=CC(F)=CC=2)C(=O)C(C(=O)OCC)=CC=1CN1CCOCC1 LIVQXBUMORWIEC-UHFFFAOYSA-N 0.000 description 1
- HFHIARHKWVOWHA-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=CC=C(C)N1C1=CC=C(F)C=C1 HFHIARHKWVOWHA-UHFFFAOYSA-N 0.000 description 1
- SXDVPXMWCYSYEW-UHFFFAOYSA-N ethyl 2-(4-fluorophenyl)-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=CC=NN1C1=CC=C(F)C=C1 SXDVPXMWCYSYEW-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
- JVRMHJVBDNCXMM-UHFFFAOYSA-N ethyl 4,6-dimethyl-2-oxo-1-phenylpyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(C)C=C(C)N1C1=CC=CC=C1 JVRMHJVBDNCXMM-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
- ZYTMNQWDIYZICM-UHFFFAOYSA-N ethyl 5-methyl-2-oxo-1-phenylpyridine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)=CC(C)=CN1C1=CC=CC=C1 ZYTMNQWDIYZICM-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 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
- 239000008187 granular material Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 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
- 230000009545 invasion Effects 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
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 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
- 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
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- WUQISXVGQIMJFV-UHFFFAOYSA-N n,n-dimethyl-5-(4-nitrophenoxy)-1-(oxan-2-yl)indazol-6-amine Chemical compound CN(C)C1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C([N+]([O-])=O)C=C1 WUQISXVGQIMJFV-UHFFFAOYSA-N 0.000 description 1
- XZUYDGFVJWMSRH-UHFFFAOYSA-N n-[3-fluoro-4-[(6-fluoro-1h-indazol-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.CC1=CC=C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)F)=CC=2)C(=O)N1C1=CC=C(F)C=C1 XZUYDGFVJWMSRH-UHFFFAOYSA-N 0.000 description 1
- NFZZEALYNZKYKR-UHFFFAOYSA-N n-[3-fluoro-4-[(6-morpholin-4-yl-1h-indazol-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)N3CCOCC3)=CC=2)=CC=C1 NFZZEALYNZKYKR-UHFFFAOYSA-N 0.000 description 1
- FZQADZJEKFXROT-UHFFFAOYSA-N n-[3-fluoro-4-[(6-morpholin-4-yl-1h-indazol-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-4,6-dimethyl-2-oxopyridine-3-carboxamide Chemical compound O=C1C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)N3CCOCC3)=CC=2)=C(C)C=C(C)N1C1=CC=C(F)C=C1 FZQADZJEKFXROT-UHFFFAOYSA-N 0.000 description 1
- RWDMRHSYWFEFLL-UHFFFAOYSA-N n-[3-fluoro-4-[(6-morpholin-4-yl-1h-indazol-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-4-methyl-2-oxopyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.O=C1C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)N3CCOCC3)=CC=2)=C(C)C=CN1C1=CC=C(F)C=C1 RWDMRHSYWFEFLL-UHFFFAOYSA-N 0.000 description 1
- XCDYVZNWMIGERD-UHFFFAOYSA-N n-[3-fluoro-4-[(6-morpholin-4-yl-1h-indazol-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-5-(morpholin-4-ylmethyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)N3CCOCC3)=CC=2)=CC(CN2CCOCC2)=C1 XCDYVZNWMIGERD-UHFFFAOYSA-N 0.000 description 1
- ZUDIUTCQQYDLQT-UHFFFAOYSA-N n-[3-fluoro-4-[6-(2-methylmorpholin-4-yl)-2-(oxan-2-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1COC(C)CN1C1=CC2=NN(C3OCCCC3)C=C2C=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=CN1C1=CC=C(F)C=C1 ZUDIUTCQQYDLQT-UHFFFAOYSA-N 0.000 description 1
- QPKKBIHANPCFTH-UHFFFAOYSA-N n-[3-fluoro-4-[[6-(2-methylmorpholin-4-yl)-1h-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1COC(C)CN1C(C(=C1)OC=2C(=CC(NC(=O)C=3C(N(C=4C=CC(F)=CC=4)C=CC=3)=O)=CC=2)F)=CC2=C1C=NN2 QPKKBIHANPCFTH-UHFFFAOYSA-N 0.000 description 1
- ZFSIWGKHOUJUCB-UHFFFAOYSA-N n-[3-fluoro-4-[[6-(4-methylsulfonylphenyl)-1h-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=C1)OC=2C(=CC(NC(=O)C=3C(N(C=4C=CC(F)=CC=4)C=CC=3)=O)=CC=2)F)=CC2=C1C=NN2 ZFSIWGKHOUJUCB-UHFFFAOYSA-N 0.000 description 1
- QPKKBIHANPCFTH-GOSISDBHSA-N n-[3-fluoro-4-[[6-[(2r)-2-methylmorpholin-4-yl]-1h-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1CO[C@H](C)CN1C(C(=C1)OC=2C(=CC(NC(=O)C=3C(N(C=4C=CC(F)=CC=4)C=CC=3)=O)=CC=2)F)=CC2=C1C=NN2 QPKKBIHANPCFTH-GOSISDBHSA-N 0.000 description 1
- WKZVZNPZZIDILN-LJQANCHMSA-N n-[3-fluoro-4-[[6-[(2r)-2-methylmorpholin-4-yl]-1h-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound C1CO[C@H](C)CN1C(C(=C1)OC=2C(=CC(NC(=O)C=3C(N(C=4C=CC(F)=CC=4)C(C)=CC=3)=O)=CC=2)F)=CC2=C1C=NN2 WKZVZNPZZIDILN-LJQANCHMSA-N 0.000 description 1
- PXBUQGWRVQCXOD-UHFFFAOYSA-N n-[4-(6-amino-1-methylindazol-5-yl)oxy-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.NC=1C=C2N(C)N=CC2=CC=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=CN1C1=CC=C(F)C=C1 PXBUQGWRVQCXOD-UHFFFAOYSA-N 0.000 description 1
- IZDYXXIXARDGML-UHFFFAOYSA-N n-[4-(6-amino-1-methylindazol-5-yl)oxy-3-fluorophenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound CC1=CC=C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4N(C)N=CC=4C=3)N)=CC=2)C(=O)N1C1=CC=C(F)C=C1 IZDYXXIXARDGML-UHFFFAOYSA-N 0.000 description 1
- JHXDFJMBVKHOBF-UHFFFAOYSA-N n-[4-[(6-amino-1h-indazol-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound NC1=CC=2NN=CC=2C=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=CN1C1=CC=C(F)C=C1 JHXDFJMBVKHOBF-UHFFFAOYSA-N 0.000 description 1
- KKUFGQPLIZDMTR-UHFFFAOYSA-N n-[4-[(6-amino-1h-indazol-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-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=C(F)C=C1 KKUFGQPLIZDMTR-UHFFFAOYSA-N 0.000 description 1
- LPRTYTPOWJPYOM-UHFFFAOYSA-N n-[4-[(6-cyclopropyl-1h-indazol-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C(=CC=4NN=CC=4C=3)C3CC3)=CC=2)=CC=C1 LPRTYTPOWJPYOM-UHFFFAOYSA-N 0.000 description 1
- GKBORAGJEVYVKP-UHFFFAOYSA-N n-[4-[(6-cyclopropyl-1h-indazol-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound O=C1N(C=2C=CC(F)=CC=2)C(C)=CC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=2C=NNC=2C=C1C1CC1 GKBORAGJEVYVKP-UHFFFAOYSA-N 0.000 description 1
- AIVFTAPXWGSQGN-UHFFFAOYSA-N n-[4-[6-(benzhydrylamino)-1-methylindazol-5-yl]oxy-3-fluorophenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound O=C1N(C=2C=CC(F)=CC=2)C(C)=CC=C1C(=O)NC(C=C1F)=CC=C1OC1=CC=2C=NN(C)C=2C=C1NC(C=1C=CC=CC=1)C1=CC=CC=C1 AIVFTAPXWGSQGN-UHFFFAOYSA-N 0.000 description 1
- JBADSHVNTXRSST-UHFFFAOYSA-N n-[4-[[6-(dimethylamino)-1h-indazol-5-yl]oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-4,6-dimethyl-2-oxopyridine-3-carboxamide Chemical compound CN(C)C1=CC=2NN=CC=2C=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)C=C(C)N1C1=CC=C(F)C=C1 JBADSHVNTXRSST-UHFFFAOYSA-N 0.000 description 1
- UUKXKKZNCUOJER-UHFFFAOYSA-N n-[4-[[6-(dimethylamino)-1h-indazol-5-yl]oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound CN(C)C1=CC=2NN=CC=2C=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=C(C)N1C1=CC=C(F)C=C1 UUKXKKZNCUOJER-UHFFFAOYSA-N 0.000 description 1
- NHSXYYXJGQLCGO-UHFFFAOYSA-N n-[4-[[6-(dimethylamino)-1h-indazol-5-yl]oxy]-3-fluorophenyl]-6-methyl-2-oxo-1-phenylpyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.CN(C)C1=CC=2NN=CC=2C=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=C(C)N1C1=CC=CC=C1 NHSXYYXJGQLCGO-UHFFFAOYSA-N 0.000 description 1
- XKVZRZKBRNMBOU-UHFFFAOYSA-N n-[4-[[6-(dimethylamino)-1h-indazol-5-yl]oxy]phenyl]-6-methyl-2-oxo-1-phenylpyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.CN(C)C1=CC=2NN=CC=2C=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=CC=C(C)N1C1=CC=CC=C1 XKVZRZKBRNMBOU-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
- 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
- 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 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
- 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
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 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
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 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
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 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
- IPISOFJLWYBCAV-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 IPISOFJLWYBCAV-UHFFFAOYSA-N 0.000 description 1
- INAOIWOVFLKRCX-UHFFFAOYSA-N tert-butyl 4-[5-(2-fluoro-4-nitrophenoxy)-1-(oxan-2-yl)indazol-6-yl]pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1C(C(=C1)OC=2C(=CC(=CC=2)[N+]([O-])=O)F)=CC2=C1C=NN2C1OCCCC1 INAOIWOVFLKRCX-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
- YVJHHCDMLDCHAE-UHFFFAOYSA-N tert-butyl n-[5-(4-amino-2-fluorophenoxy)-1-(oxan-2-yl)indazol-6-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=2N(C3OCCCC3)N=CC=2C=C1OC1=CC=C(N)C=C1F YVJHHCDMLDCHAE-UHFFFAOYSA-N 0.000 description 1
- JDDZBVOSDZEVBG-UHFFFAOYSA-N tert-butyl n-[5-(4-amino-2-fluorophenoxy)-1-methylindazol-6-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC=1C=C2N(C)N=CC2=CC=1OC1=CC=C(N)C=C1F JDDZBVOSDZEVBG-UHFFFAOYSA-N 0.000 description 1
- JFFMFNNEPBNHBL-UHFFFAOYSA-N tert-butyl n-[5-(4-amino-2-fluorophenoxy)-1h-indazol-6-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=2NN=CC=2C=C1OC1=CC=C(N)C=C1F JFFMFNNEPBNHBL-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
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 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
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000005406 washing Methods 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 (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8329408P | 2008-07-24 | 2008-07-24 | |
| US83294P | 2008-07-24 | ||
| US8508208P | 2008-07-31 | 2008-07-31 | |
| US85082P | 2008-07-31 | ||
| US10865908P | 2008-10-27 | 2008-10-27 | |
| US108659P | 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 |
|---|---|
| ES2379587T3 true ES2379587T3 (es) | 2012-04-27 |
Family
ID=41010247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09790440T Active ES2379587T3 (es) | 2008-07-24 | 2009-07-15 | Amidofenoxiindazoles como inhibidores de C-Met |
Country Status (35)
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8293897B2 (en) | 2008-10-14 | 2012-10-23 | Ning Xi | Compounds comprising a spiro-ring and methods of use |
| AU2010229147B2 (en) | 2009-03-21 | 2012-07-05 | Sunshine Lake Pharma Co., Ltd. | Amino ester derivatives, salts thereof and methods of use |
| ES2590778T3 (es) | 2011-02-28 | 2016-11-23 | Calitor Sciences, Llc | Compuestos de quinolina sustituida |
| US8962623B2 (en) * | 2011-03-04 | 2015-02-24 | Locus Pharmaceuticals, Inc. | Aminopyrazine compounds |
| KR20130118612A (ko) * | 2012-04-20 | 2013-10-30 | (주)네오믹스 | 신규한 아미노피리딘 유도체 및 이의 용도 |
| EP2870178B1 (en) * | 2012-05-09 | 2017-07-12 | Eli Lilly and Company | Anti-c-met antibodies |
| JP6433922B2 (ja) * | 2013-02-27 | 2018-12-05 | アレイ バイオファーマ、インコーポレイテッド | インダゾール誘導体の調製に使用するための中間体およびその調製方法 |
| 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 |
| WO2015164161A1 (en) | 2014-04-22 | 2015-10-29 | Calitor Sciences, Llc | Bicylcic 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 |
| US20190336599A1 (en) * | 2016-04-15 | 2019-11-07 | Eli Lilly And Company | Combination of ramucirumab and merestinib for use in treatment of colorectal cancer |
| EP3464380B1 (en) | 2016-06-02 | 2024-11-06 | Immunocore Limited | Dosing regimen for gp100-specific tcr - anti-cd3 scfv fusion protein |
| CN109562282A (zh) * | 2016-07-29 | 2019-04-02 | 伊莱利利公司 | 用于治疗癌症的使用merestinib和抗-pd-l1或抗-pd-1抑制剂的组合疗法 |
| 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 |
| CN109982700A (zh) * | 2016-11-16 | 2019-07-05 | 伊莱利利公司 | 具有外显子14跳跃突变或外显子14跳跃表型的癌症的治疗 |
| EP3541383B1 (en) | 2016-11-16 | 2021-01-06 | Eli Lilly and Company | Combination therapy for 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 |
| EP3719012B1 (en) | 2017-11-24 | 2024-03-06 | Medshine Discovery Inc. | N-[4-[(2-amino-4-pyridinyl)oxy]-3-fluorophenyl]-3-(4-fluorophenyl)-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamide derivatives as c-met/axl inhibitors for the treatment of tumors |
| US20210177828A1 (en) * | 2018-01-17 | 2021-06-17 | Nanjing Transthera Biosciences Co., Ltd. | Tam family kinase /and csf1r kinase inhibitor and use thereof |
| AU2019237715B2 (en) | 2018-03-08 | 2021-01-28 | Wellmarker Bio Co., Ltd. | Thienopyridine derivatives and pharmaceutical composition comprising same |
| EP3842425B1 (en) * | 2018-08-24 | 2024-05-22 | TransThera Sciences (Nanjing), Inc. | Novel quinoline derivative inhibitor |
| CN112739691B (zh) * | 2018-09-03 | 2023-05-23 | 泰励生物科技（上海）有限公司 | 用作抗癌药的trk抑制剂 |
| 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 |
| US6964872B2 (en) * | 2001-05-18 | 2005-11-15 | Srl, Inc. | Immunoassay method |
| 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 |
| JP4681451B2 (ja) | 2002-10-28 | 2011-05-11 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | Ｒｈｏ−キナーゼ阻害剤としてのヘテロアリールオキシ置換フェニルアミノピリミジン類 |
| AU2004264038B2 (en) * | 2003-07-17 | 2010-09-23 | Life Technologies As | Process for preparing coated magnetic particles |
| 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 |
| EP1966214B9 (en) | 2005-12-21 | 2017-09-13 | Janssen Pharmaceutica N.V. | Triazolopyridazines as tyrosine kinase modulators |
| WO2007103308A2 (en) * | 2006-03-07 | 2007-09-13 | Array Biopharma Inc. | Heterobicyclic pyrazole compounds and methods of use |
| EP2230264B1 (en) * | 2006-06-29 | 2019-10-09 | Life Technologies AS | Particles containing multi-block polymers |
| PE20121506A1 (es) | 2006-07-14 | 2012-11-26 | Amgen Inc | Compuestos triazolopiridinas como inhibidores de c-met |
| DK2084162T3 (da) | 2006-10-23 | 2012-10-01 | Sgx Pharmaceuticals Inc | Bicykliske triazoler som proteinkinasemodulatorer |
| JP5337799B2 (ja) | 2007-06-27 | 2013-11-06 | アーケマ・インコーポレイテッド | ヒドロフルオロオレフィンの製造方法 |
-
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 EA EA201170252A patent/EA018385B1/ru not_active IP Right Cessation
- 2009-07-15 PL PL09790440T patent/PL2310382T3/pl unknown
- 2009-07-15 EP EP09790440A patent/EP2310382B1/en active Active
- 2009-07-15 US US12/503,223 patent/US8030302B2/en not_active Ceased
- 2009-07-15 WO PCT/US2009/050640 patent/WO2010011538A1/en not_active Ceased
- 2009-07-15 NZ NZ590013A patent/NZ590013A/en not_active IP Right Cessation
- 2009-07-15 MY MYPI2011000343A patent/MY163852A/en unknown
- 2009-07-15 CA CA2731773A patent/CA2731773C/en not_active Expired - Fee Related
- 2009-07-15 PT PT09790440T patent/PT2310382E/pt unknown
- 2009-07-15 PE PE2011000061A patent/PE20110150A1/es active IP Right Grant
- 2009-07-15 BR BRPI0916286A patent/BRPI0916286B8/pt not_active IP Right Cessation
- 2009-07-15 AU AU2009274256A patent/AU2009274256B2/en not_active Ceased
- 2009-07-15 CN CN200980128694.4A patent/CN102105462B/zh not_active Expired - Fee Related
- 2009-07-15 ES ES09790440T patent/ES2379587T3/es active Active
- 2009-07-15 SI SI200930193T patent/SI2310382T1/sl unknown
- 2009-07-15 MX MX2011000925A patent/MX2011000925A/es active IP Right Grant
- 2009-07-15 AT AT09790440T patent/ATE546444T1/de active
- 2009-07-15 KR KR1020117001628A patent/KR101334456B1/ko not_active Expired - Fee Related
- 2009-07-15 HR HR20120202T patent/HRP20120202T1/hr unknown
- 2009-07-15 RS RS20120176A patent/RS52261B/sr unknown
- 2009-07-15 DK DK09790440.3T patent/DK2310382T3/da active
- 2009-07-15 JP JP2011520095A patent/JP5414794B2/ja not_active Expired - Fee Related
-
2011
- 2011-01-06 IL IL210490A patent/IL210490A/en active IP Right Grant
- 2011-01-07 DO DO2011000009A patent/DOP2011000009A/es unknown
- 2011-01-07 ZA ZA2011/00219A patent/ZA201100219B/en unknown
- 2011-01-19 CO CO11005437A patent/CO6351737A2/es not_active Application Discontinuation
- 2011-01-21 SV SV2011003816A patent/SV2011003816A/es active IP Right Grant
- 2011-01-21 EC EC2011010778A patent/ECSP11010778A/es unknown
- 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 |
|---|---|---|
| ES2379587T3 (es) | Amidofenoxiindazoles como inhibidores de 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 | |
| CN101657430B (zh) | 有机化合物及其用途 | |
| 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 | |
| ES2687475T3 (es) | Nuevos derivados de indol y de pirrol, su procedimiento de preparación y las composiciones farmacéuticas que los contienen | |
| TW200302221A (en) | Quinazoline derivatives | |
| TW200530229A (en) | Novel compounds | |
| JP2004508365A (ja) | 抗細胞増殖薬としてのイミダゾロ−５−イル−２−アニリノ−ピリミジン類 | |
| US9353107B2 (en) | 3-(pyrazolyl)-1H-pyrrolo[2,3-b]pyridine derivatives as kinase inhibitors | |
| CN111511750A (zh) | 新的大环衍生物、其制备方法以及包含其的药物组合物 | |
| WO2023125877A1 (zh) | 三并环类衍生物抑制剂、其制备方法和应用 | |
| CN116969923B (zh) | 杂芳基氨基化合物及其制备方法和应用 | |
| WO2009010794A1 (en) | 2,4-diamino-pyrimidine derivatives | |
| WO2024254490A1 (en) | Pyrazolo-pyrimidinone compounds for use in methods of inhibiting wee1 a kinase | |
| TWI673268B (zh) | 作為ｆｇｆｒ４抑制劑之稠環雙環吡啶基衍生物 | |
| HK1155172B (en) | Amidophenoxyindazoles useful as inhibitors of c-met | |
| HK40033080B (zh) | 大环衍生物、其制备方法以及包含其的药物组合物 | |
| HK1138844A (en) | 8-oxy-quinoline derivatives as bradykinin b2 receptor modulators |