DK3087070T3 - PYRAZOLO [1,5-A] PYRIDINE DERIVATIVES AND PROCEDURES FOR THEIR USE - Google Patents

Info

Publication number

DK3087070T3

DK3087070T3 DK14824711.7T DK14824711T DK3087070T3 DK 3087070 T3 DK3087070 T3 DK 3087070T3 DK 14824711 T DK14824711 T DK 14824711T DK 3087070 T3 DK3087070 T3 DK 3087070T3

Authority

DK

Denmark

Prior art keywords

fluoro

phenyl

pyrazolo

pyridin

carboxylic acid

Prior art date

2013-12-26

Links

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• 238000000034 method Methods 0.000 title claims description 184
• DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical class C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 213
• -1 substituted Chemical class 0.000 claims description 103
• GDDMXXIYSLJCRK-UHFFFAOYSA-N 3-(4-fluorophenyl)-2,4-dioxo-1-propan-2-ylpyrimidine-5-carboxylic acid Chemical compound O=C1N(C(C)C)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 GDDMXXIYSLJCRK-UHFFFAOYSA-N 0.000 claims description 80
• IGIJOGBLFJFFHO-UHFFFAOYSA-N 1-ethyl-3-(4-fluorophenyl)-2,4-dioxopyrimidine-5-carboxylic acid Chemical compound O=C1N(CC)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 IGIJOGBLFJFFHO-UHFFFAOYSA-N 0.000 claims description 73
• 229910052757 nitrogen Inorganic materials 0.000 claims description 52
• 150000003839 salts Chemical class 0.000 claims description 30
• 150000001408 amides Chemical class 0.000 claims description 28
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
• 206010028980 Neoplasm Diseases 0.000 claims description 16
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• JTZSVYCKAYMNCT-UHFFFAOYSA-N 3-(4-fluorophenyl)-2,4-dioxo-1h-pyrimidine-5-carboxylic acid Chemical compound O=C1C(C(=O)O)=CNC(=O)N1C1=CC=C(F)C=C1 JTZSVYCKAYMNCT-UHFFFAOYSA-N 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
• 125000004385 trihaloalkyl group Chemical group 0.000 claims description 8
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 6
• 206010017758 gastric cancer Diseases 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 201000011549 stomach cancer Diseases 0.000 claims description 5
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
• OYOBTADHXXTSKP-UHFFFAOYSA-N 1-(2-ethoxyethyl)-3-(4-fluorophenyl)-2,4-dioxopyrimidine-5-carboxylic acid Chemical compound O=C1N(CCOCC)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 OYOBTADHXXTSKP-UHFFFAOYSA-N 0.000 claims description 4
• AZIKNCZQDXXEIS-UHFFFAOYSA-N 3-(4-fluorophenyl)-1-methyl-2,4-dioxopyrimidine-5-carboxylic acid Chemical compound O=C1N(C)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 AZIKNCZQDXXEIS-UHFFFAOYSA-N 0.000 claims description 4
• NUPJSSQUUCZNLZ-UHFFFAOYSA-N 3-(4-fluorophenyl)-2,4-dioxo-1-(2-phenylmethoxyethyl)pyrimidine-5-carboxylic acid Chemical compound O=C1N(C=2C=CC(F)=CC=2)C(=O)C(C(=O)O)=CN1CCOCC1=CC=CC=C1 NUPJSSQUUCZNLZ-UHFFFAOYSA-N 0.000 claims description 4
• QAPUOJJJKOPDFV-UHFFFAOYSA-N 3-(4-fluorophenyl)-2,4-dioxo-1-pentylpyrimidine-5-carboxylic acid Chemical compound O=C1N(CCCCC)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 QAPUOJJJKOPDFV-UHFFFAOYSA-N 0.000 claims description 4
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 206010009944 Colon cancer Diseases 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 125000002971 oxazolyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• KVTUSMPNLUCCQO-UHFFFAOYSA-N 3,3-difluoropyrrolidine Chemical compound FC1(F)CCNC1 KVTUSMPNLUCCQO-UHFFFAOYSA-N 0.000 claims description 3
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 3
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
• 206010038389 Renal cancer Diseases 0.000 claims description 3
• 208000029742 colonic neoplasm Diseases 0.000 claims description 3
• 201000010982 kidney cancer Diseases 0.000 claims description 3
• 208000032839 leukemia Diseases 0.000 claims description 3
• 201000007270 liver cancer Diseases 0.000 claims description 3
• 208000014018 liver neoplasm Diseases 0.000 claims description 3
• VAEZBGLPEMZOBD-UHFFFAOYSA-N 3-(4-fluorophenyl)-N-[3-fluoro-4-(6-pyridin-4-ylpyrazolo[1,5-a]pyridin-4-yl)oxyphenyl]-2,4-dioxo-1H-pyrimidine-5-carboxamide Chemical compound FC=1C=C(C=CC=1OC=1C=2N(C=C(C=1)C1=CC=NC=C1)N=CC=2)NC(=O)C=1C(N(C(NC=1)=O)C1=CC=C(C=C1)F)=O VAEZBGLPEMZOBD-UHFFFAOYSA-N 0.000 claims description 2
• MJOUJKDTBGXKIU-UHFFFAOYSA-N 4,4-difluoropiperidine Chemical compound FC1(F)CCNCC1 MJOUJKDTBGXKIU-UHFFFAOYSA-N 0.000 claims description 2
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
• UYRQRUQFWZWMBY-UHFFFAOYSA-N methyl N-[4-[4-[[1-ethyl-3-(4-fluorophenyl)-2,4-dioxopyrimidine-5-carbonyl]amino]-2-fluorophenoxy]pyrazolo[1,5-a]pyridin-6-yl]carbamate Chemical compound COC(NC=1C=C(C=2N(C1)N=CC2)OC2=C(C=C(C=C2)NC(=O)C=2C(N(C(N(C2)CC)=O)C2=CC=C(C=C2)F)=O)F)=O UYRQRUQFWZWMBY-UHFFFAOYSA-N 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 20
• MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims 7
• NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims 2
• FDEAXGCAOSGCNC-UHFFFAOYSA-N 3-(4-fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxopyrimidine-5-carboxylic acid Chemical compound O=C1N(CCO)C=C(C(O)=O)C(=O)N1C1=CC=C(F)C=C1 FDEAXGCAOSGCNC-UHFFFAOYSA-N 0.000 claims 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
• YBBLOADPFWKNGS-UHFFFAOYSA-N 1,1-dimethylurea Chemical compound CN(C)C(N)=O YBBLOADPFWKNGS-UHFFFAOYSA-N 0.000 claims 1
• FWCRQKIZZVMWID-UHFFFAOYSA-N N-[3-fluoro-4-[6-(methanesulfonamido)pyrazolo[1,5-a]pyridin-4-yl]oxyphenyl]-3-(4-fluorophenyl)-2,4-dioxo-1-propan-2-ylpyrimidine-5-carboxamide Chemical compound CC(C)N1C=C(C(=O)NC2=CC(F)=C(OC3=CC(NS(C)(=O)=O)=CN4N=CC=C34)C=C2)C(=O)N(C1=O)C1=CC=C(F)C=C1 FWCRQKIZZVMWID-UHFFFAOYSA-N 0.000 claims 1
• GBUIETYJWKMBJO-UHFFFAOYSA-N N-[4-(6-acetamidopyrazolo[1,5-a]pyridin-4-yl)oxy-3-fluorophenyl]-1-ethyl-3-(4-fluorophenyl)-2,4-dioxopyrimidine-5-carboxamide Chemical compound CCN1C=C(C(=O)NC2=CC(F)=C(OC3=CC(NC(C)=O)=CN4N=CC=C34)C=C2)C(=O)N(C1=O)C1=CC=C(F)C=C1 GBUIETYJWKMBJO-UHFFFAOYSA-N 0.000 claims 1
• ARKIHKJYXHLMKG-UHFFFAOYSA-N N-[4-(6-acetamidopyrazolo[1,5-a]pyridin-4-yl)oxy-3-fluorophenyl]-3-(4-fluorophenyl)-2,4-dioxo-1-propan-2-ylpyrimidine-5-carboxamide Chemical compound CC(C)N1C=C(C(=O)NC2=CC(F)=C(OC3=CC(NC(C)=O)=CN4N=CC=C34)C=C2)C(=O)N(C1=O)C1=CC=C(F)C=C1 ARKIHKJYXHLMKG-UHFFFAOYSA-N 0.000 claims 1
• NBZVXQLJFLPHNC-UHFFFAOYSA-N N-[4-[6-[acetyl(methyl)amino]pyrazolo[1,5-a]pyridin-4-yl]oxy-3-fluorophenyl]-1-ethyl-3-(4-fluorophenyl)-2,4-dioxopyrimidine-5-carboxamide Chemical compound CCN1C=C(C(=O)NC2=CC(F)=C(OC3=CC(=CN4N=CC=C34)N(C)C(C)=O)C=C2)C(=O)N(C1=O)C1=CC=C(F)C=C1 NBZVXQLJFLPHNC-UHFFFAOYSA-N 0.000 claims 1
• UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims 1
• YGGWPDLYLUHWIQ-UHFFFAOYSA-N n,n-dimethylpyridine-2-carboxamide Chemical compound CN(C)C(=O)C1=CC=CC=N1 YGGWPDLYLUHWIQ-UHFFFAOYSA-N 0.000 claims 1
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 275
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 268
• 238000005160 1H NMR spectroscopy Methods 0.000 description 183
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 171
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 168
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 93
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 90
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
• 239000000047 product Substances 0.000 description 69
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 68
• 235000019439 ethyl acetate Nutrition 0.000 description 66
• 239000000203 mixture Substances 0.000 description 62
• 238000006243 chemical reaction Methods 0.000 description 60
• 239000012267 brine Substances 0.000 description 59
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
• 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 54
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
• 229910052938 sodium sulfate Inorganic materials 0.000 description 51
• 235000011152 sodium sulphate Nutrition 0.000 description 51
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
• 239000012298 atmosphere Substances 0.000 description 45
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 41
• 229910000029 sodium carbonate Inorganic materials 0.000 description 41
• 125000005843 halogen group Chemical group 0.000 description 40
• 239000000243 solution Substances 0.000 description 38
• 229940093499 ethyl acetate Drugs 0.000 description 37
• 239000007787 solid Substances 0.000 description 33
• 238000010168 coupling process Methods 0.000 description 32
• 239000000543 intermediate Substances 0.000 description 32
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 27
• 229910002027 silica gel Inorganic materials 0.000 description 27
• COJCNRWONZZIHV-UHFFFAOYSA-N 6-bromo-4-(2-fluoro-4-nitrophenoxy)pyrazolo[1,5-a]pyridine Chemical compound BrC=1C=C(C=2N(C1)N=CC2)OC2=C(C=C(C=C2)[N+](=O)[O-])F COJCNRWONZZIHV-UHFFFAOYSA-N 0.000 description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
• 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 description 22
• 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 22
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 21
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 20
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
• 239000002480 mineral oil Substances 0.000 description 19
• 235000010446 mineral oil Nutrition 0.000 description 19
• NSIBFUPUJYMBJZ-UHFFFAOYSA-N 3-fluoro-4-[6-(1-methylimidazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyaniline Chemical compound FC=1C=C(C=CC1OC=1C=2N(C=C(C1)C=1N=CN(C1)C)N=CC2)N NSIBFUPUJYMBJZ-UHFFFAOYSA-N 0.000 description 18
• 239000006229 carbon black Substances 0.000 description 18
• ZXFBBQJGPRZCHS-UHFFFAOYSA-N 6-bromopyrazolo[1,5-a]pyridin-4-ol Chemical compound OC1=CC(Br)=CN2N=CC=C12 ZXFBBQJGPRZCHS-UHFFFAOYSA-N 0.000 description 17
• 229910052801 chlorine Inorganic materials 0.000 description 17
• 229910052731 fluorine Inorganic materials 0.000 description 17
• 230000009467 reduction Effects 0.000 description 17
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 15
• 239000012312 sodium hydride Substances 0.000 description 15
• 229910000104 sodium hydride Inorganic materials 0.000 description 15
• 125000001624 naphthyl group Chemical group 0.000 description 14
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 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 11
• VDFROLGDZZETHN-UHFFFAOYSA-N 3-fluoro-4-pyrazolo[1,5-a]pyridin-4-yloxyaniline Chemical compound FC=1C=C(C=CC1OC=1C=2N(C=CC1)N=CC2)N VDFROLGDZZETHN-UHFFFAOYSA-N 0.000 description 11
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• 238000003756 stirring Methods 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
• 241000282414 Homo sapiens Species 0.000 description 10
• 239000004480 active ingredient Substances 0.000 description 10
• 238000005859 coupling reaction Methods 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 108091000080 Phosphotransferase Proteins 0.000 description 9
• 230000008878 coupling Effects 0.000 description 9
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
• 239000000546 pharmaceutical excipient Substances 0.000 description 9
• 102000020233 phosphotransferase Human genes 0.000 description 9
• ZXYAAVBXHKCJJB-UHFFFAOYSA-N uracil-5-carboxylic acid Chemical class OC(=O)C1=CNC(=O)NC1=O ZXYAAVBXHKCJJB-UHFFFAOYSA-N 0.000 description 9
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 8
• 239000006185 dispersion Substances 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 239000000463 material Substances 0.000 description 8
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
• 108091008598 receptor tyrosine kinases Proteins 0.000 description 8
• 102000027426 receptor tyrosine kinases Human genes 0.000 description 8
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
• WCEWCRAPSCLFOV-UHFFFAOYSA-N tributyl-(1-methylimidazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN(C)C=N1 WCEWCRAPSCLFOV-UHFFFAOYSA-N 0.000 description 8
• 125000005500 uronium group Chemical group 0.000 description 8
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