EA021464B1 - Производные индол-пиридона, обладающие ингибиторной активностью в отношении киназы 1, содержащая их фармацевтическая композиция и их применение - Google Patents

Info

Publication number

EA021464B1

EA021464B1 EA201001197A EA201001197A EA021464B1 EA 021464 B1 EA021464 B1 EA 021464B1 EA 201001197 A EA201001197 A EA 201001197A EA 201001197 A EA201001197 A EA 201001197A EA 021464 B1 EA021464 B1 EA 021464B1

Authority

EA

Eurasian Patent Office

Prior art keywords

carboxylic acid

oxo

title compound

pyrazole

amide

Prior art date

2008-01-22

Links

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• 230000002401 inhibitory effect Effects 0.000 title claims abstract description 5
• 108091000080 Phosphotransferase Proteins 0.000 title claims description 9
• 102000020233 phosphotransferase Human genes 0.000 title claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
• NRGVEGWSRITVOR-UHFFFAOYSA-N 3-(1h-indol-2-yl)-1h-pyridin-2-one Chemical class OC1=NC=CC=C1C1=CC2=CC=CC=C2N1 NRGVEGWSRITVOR-UHFFFAOYSA-N 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 567
• 239000001257 hydrogen Substances 0.000 claims abstract description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 claims abstract description 29
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 claims abstract description 28
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 7
• 238000000034 method Methods 0.000 claims description 269
• -1 triftorometoksi Chemical group 0.000 claims description 120
• 239000000203 mixture Substances 0.000 claims description 72
• 229910052757 nitrogen Inorganic materials 0.000 claims description 37
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
• KGDOHXYALMXHLF-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1 KGDOHXYALMXHLF-UHFFFAOYSA-N 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 29
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 150000001408 amides Chemical class 0.000 claims description 26
• 206010028980 Neoplasm Diseases 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 201000011510 cancer Diseases 0.000 claims description 16
• 230000000694 effects Effects 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 125000002950 monocyclic group Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
• 239000001301 oxygen Substances 0.000 claims description 9
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• 150000002367 halogens Chemical class 0.000 claims description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 238000001959 radiotherapy Methods 0.000 claims description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 239000011737 fluorine Substances 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 208000023275 Autoimmune disease Diseases 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• ZHIONVHFUBBCKL-UHFFFAOYSA-N 1-(1-phenylethyl)pyrazole-4-carboxylic acid Chemical compound C1=C(C(O)=O)C=NN1C(C)C1=CC=CC=C1 ZHIONVHFUBBCKL-UHFFFAOYSA-N 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• 150000001412 amines Chemical group 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 238000002512 chemotherapy Methods 0.000 claims description 4
• 231100000433 cytotoxic Toxicity 0.000 claims description 4
• 230000001472 cytotoxic effect Effects 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
• YRNZHBVRTDDGNB-UHFFFAOYSA-N 1-benzyl-n-[5-(1h-indol-2-yl)-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1NC(=O)C(C=2NC3=CC=CC=C3C=2)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 YRNZHBVRTDDGNB-UHFFFAOYSA-N 0.000 claims description 3
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• 206010052779 Transplant rejections Diseases 0.000 claims description 3
• 239000000460 chlorine Substances 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 206010025135 lupus erythematosus Diseases 0.000 claims description 3
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
• 201000006417 multiple sclerosis Diseases 0.000 claims description 3
• 201000008482 osteoarthritis Diseases 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
• GEBXRQMORXJPGN-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]-n-[6-oxo-5-[5-(piperidin-1-ylmethyl)-1h-indol-2-yl]-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1=CC(C)=CC=C1CN1N=CC(C(=O)NC=2C=C(C(=O)NC=2)C=2NC3=CC=C(CN4CCCCC4)C=C3C=2)=C1 GEBXRQMORXJPGN-UHFFFAOYSA-N 0.000 claims description 2
• OUZSVHBSAIWGAB-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[1-(dimethylamino)-2-methylpropan-2-yl]oxy-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C=1C2=CC(OC(C)(C)CN(C)C)=CC=C2NC=1C(C(NC=1)=O)=CC=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 OUZSVHBSAIWGAB-UHFFFAOYSA-N 0.000 claims description 2
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 2
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
• SCQQENZFGAHTRF-BETUJISGSA-N 5-amino-3-[5-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]-1H-indol-2-yl]-1H-pyridin-2-one Chemical compound C1[C@@H](C)O[C@@H](C)CN1CC1=CC=C(NC(=C2)C=3C(NC=C(N)C=3)=O)C2=C1 SCQQENZFGAHTRF-BETUJISGSA-N 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 125000004122 cyclic group Chemical group 0.000 claims description 2
• 239000000824 cytostatic agent Substances 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 150000002825 nitriles Chemical class 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 210000000056 organ Anatomy 0.000 claims 2
• 230000004952 protein activity Effects 0.000 claims 2
• DKDWHPAIWPQMDV-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[(4-fluoropiperidin-1-yl)methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CC(F)CCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 DKDWHPAIWPQMDV-UHFFFAOYSA-N 0.000 claims 1
• QENZBLJVRSQXHR-UHFFFAOYSA-N 1-benzyl-n-[5-[5-[(4-methylpiperidin-1-yl)methyl]-1h-indol-2-yl]-6-oxo-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1CC(C)CCN1CC1=CC=C(NC(=C2)C=3C(NC=C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)C=3)=O)C2=C1 QENZBLJVRSQXHR-UHFFFAOYSA-N 0.000 claims 1
• OEKPFDMUKNSTBS-UHFFFAOYSA-N 1-benzyl-n-[6-oxo-5-[5-(piperidin-1-ylmethyl)-1h-indol-2-yl]-1h-pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1=NN(CC=2C=CC=CC=2)C=C1C(=O)NC(C=1)=CNC(=O)C=1C(NC1=CC=2)=CC1=CC=2CN1CCCCC1 OEKPFDMUKNSTBS-UHFFFAOYSA-N 0.000 claims 1
• 125000004414 alkyl thio group Chemical group 0.000 claims 1
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 1
• 125000001309 chloro group Chemical group Cl* 0.000 claims 1
• 239000002254 cytotoxic agent Substances 0.000 claims 1
• 125000005843 halogen group Chemical group 0.000 claims 1
• 108010019244 Checkpoint Kinase 1 Proteins 0.000 abstract 1
• 125000001475 halogen functional group Chemical group 0.000 abstract 1
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 369
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
• 239000007787 solid Substances 0.000 description 220
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 216
• 238000005481 NMR spectroscopy Methods 0.000 description 188
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 187
• 238000002474 experimental method Methods 0.000 description 186
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
• 238000001665 trituration Methods 0.000 description 136
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
• 238000002360 preparation method Methods 0.000 description 87
• 239000011541 reaction mixture Substances 0.000 description 85
• 239000000243 solution Substances 0.000 description 77
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
• 239000012043 crude product Substances 0.000 description 59
• 238000003818 flash chromatography Methods 0.000 description 58
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 54
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• 239000010410 layer Substances 0.000 description 25
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• 239000012267 brine Substances 0.000 description 21
• 239000003921 oil Substances 0.000 description 21
• 235000019198 oils Nutrition 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 239000007864 aqueous solution Substances 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• 239000000047 product Substances 0.000 description 18
• 239000000725 suspension Substances 0.000 description 18
• 239000003112 inhibitor Substances 0.000 description 16
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 229960005277 gemcitabine Drugs 0.000 description 15
• SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 238000001816 cooling Methods 0.000 description 14
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 13
• 238000007792 addition Methods 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• UTWGRMYWDUMKNY-UHFFFAOYSA-N indole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)C=CC2=C1 UTWGRMYWDUMKNY-UHFFFAOYSA-N 0.000 description 11
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• 125000004965 chloroalkyl group Chemical group 0.000 description 10
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• 235000017557 sodium bicarbonate Nutrition 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 239000003814 drug Substances 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• 150000003254 radicals Chemical class 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
• HYBRAUPLUXQZEG-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=CC(C)=CC=C1CN1N=CC(C(O)=O)=C1 HYBRAUPLUXQZEG-UHFFFAOYSA-N 0.000 description 7
• HOJPHBAQGCFSQQ-UHFFFAOYSA-N 5-(1h-indol-2-yl)-6-oxo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)C(C=2NC3=CC=CC=C3C=2)=C1 HOJPHBAQGCFSQQ-UHFFFAOYSA-N 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 125000004429 atom Chemical group 0.000 description 7
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 7
• 238000010992 reflux Methods 0.000 description 7
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
• 229910021529 ammonia Inorganic materials 0.000 description 6
• 239000012065 filter cake Substances 0.000 description 6
• 239000012634 fragment Substances 0.000 description 6
• 239000012299 nitrogen atmosphere Substances 0.000 description 6
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 239000002244 precipitate Substances 0.000 description 6
• OWPIFQXNMLDXKW-UHFFFAOYSA-N tert-butyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1 OWPIFQXNMLDXKW-UHFFFAOYSA-N 0.000 description 6
• BVIVIYHTBNPNTF-UHFFFAOYSA-N 3-iodo-5-nitro-1-(2-trimethylsilylethoxymethyl)pyridin-2-one Chemical compound C[Si](C)(C)CCOCN1C=C([N+]([O-])=O)C=C(I)C1=O BVIVIYHTBNPNTF-UHFFFAOYSA-N 0.000 description 5
• 238000010511 deprotection reaction Methods 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 239000000741 silica gel Substances 0.000 description 5
• 229910002027 silica gel Inorganic materials 0.000 description 5
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