ES2461799T3 - Derivados de indolil-piridona que tienen actividad inhibidora de la quinasa de control 1 - Google Patents

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Publication number

ES2461799T3

ES2461799T3 ES09704645T ES09704645T ES2461799T3 ES 2461799 T3 ES2461799 T3 ES 2461799T3 ES 09704645 T ES09704645 T ES 09704645T ES 09704645 T ES09704645 T ES 09704645T ES 2461799 T3 ES2461799 T3 ES 2461799T3

Authority

ES

Spain

Prior art keywords

title compound

oxo

dihydro

alkyl

pyridin

Prior art date

2008-01-22

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.)

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• 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
• 108091000080 Phosphotransferase Proteins 0.000 title description 4
• 102000020233 phosphotransferase Human genes 0.000 title description 4
• 230000002401 inhibitory effect Effects 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 574
• -1 hydroxy, methyl Chemical group 0.000 claims abstract description 270
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
• 239000001257 hydrogen Substances 0.000 claims abstract description 56
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 50
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 36
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 15
• 150000003839 salts Chemical class 0.000 claims abstract description 15
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 14
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 13
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 11
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
• 239000001301 oxygen Substances 0.000 claims abstract description 11
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 9
• 125000005843 halogen group Chemical group 0.000 claims abstract description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
• 239000011593 sulfur Chemical group 0.000 claims abstract description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 7
• 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
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 4
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 4
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
• 239000002253 acid Substances 0.000 claims description 70
• 238000011282 treatment Methods 0.000 claims description 32
• 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 29
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 206010028980 Neoplasm Diseases 0.000 claims description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• 201000011510 cancer Diseases 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
• IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 238000001959 radiotherapy Methods 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 231100000433 cytotoxic Toxicity 0.000 claims description 4
• 230000001472 cytotoxic effect Effects 0.000 claims description 4
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 238000002512 chemotherapy Methods 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 2
• 239000000824 cytostatic 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
• 150000002431 hydrogen Chemical group 0.000 claims 10
• ZJGRIZMTPIORPO-UHFFFAOYSA-N 5-amino-3-[5-(piperidin-1-ylmethyl)-1H-indol-2-yl]-1H-pyridin-2-one Chemical compound NC1=CNC(=O)C(C=2NC3=CC=C(CN4CCCCC4)C=C3C=2)=C1 ZJGRIZMTPIORPO-UHFFFAOYSA-N 0.000 claims 1
• 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 1
• KJVRTFVBVVBAQD-UHFFFAOYSA-N 5-amino-3-[5-[[1-(diethylaminomethyl)cyclopropyl]methoxy]-1H-indol-2-yl]-1H-pyridin-2-one Chemical compound C=1C=C2NC(C=3C(NC=C(N)C=3)=O)=CC2=CC=1OCC1(CN(CC)CC)CC1 KJVRTFVBVVBAQD-UHFFFAOYSA-N 0.000 claims 1
• 239000002254 cytotoxic agent Substances 0.000 claims 1
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 543
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 365
• 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 201
• 238000005160 1H NMR spectroscopy Methods 0.000 description 179
• 238000002474 experimental method Methods 0.000 description 170
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 146
• 238000001665 trituration Methods 0.000 description 140
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 127
• 239000000243 solution Substances 0.000 description 81
• 238000002360 preparation method Methods 0.000 description 80
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
• 238000000034 method Methods 0.000 description 59
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 59
• 238000003818 flash chromatography Methods 0.000 description 58
• 239000000377 silicon dioxide Substances 0.000 description 58
• 239000011541 reaction mixture Substances 0.000 description 57
• 229910052681 coesite Inorganic materials 0.000 description 55
• 229910052906 cristobalite Inorganic materials 0.000 description 55
• 235000012239 silicon dioxide Nutrition 0.000 description 55
• 229910052682 stishovite Inorganic materials 0.000 description 55
• 229910052905 tridymite Inorganic materials 0.000 description 55
• 239000012043 crude product Substances 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
• 238000006243 chemical reaction Methods 0.000 description 41
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 40
• 239000000203 mixture Substances 0.000 description 35
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
• 239000007832 Na2SO4 Substances 0.000 description 28
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
• 238000002953 preparative HPLC Methods 0.000 description 28
• 229910052938 sodium sulfate Inorganic materials 0.000 description 28
• 235000011152 sodium sulphate Nutrition 0.000 description 28
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 26
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 26
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• 239000010410 layer Substances 0.000 description 23
• 239000012267 brine Substances 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
• 239000003921 oil Substances 0.000 description 20
• 235000019198 oils Nutrition 0.000 description 20
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 18
• 239000000725 suspension Substances 0.000 description 18
• 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 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
• 229960005277 gemcitabine Drugs 0.000 description 17
• 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 17
• 239000003112 inhibitor Substances 0.000 description 17
• 238000007792 addition Methods 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 238000001816 cooling Methods 0.000 description 15
• 239000000047 product Substances 0.000 description 15
• 239000002904 solvent Substances 0.000 description 15
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
• 238000005481 NMR spectroscopy Methods 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 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
• AGBUHNSJFSPPNR-UHFFFAOYSA-N tert-butyl 5-(2-tert-butylsilyloxypropan-2-yl)indole-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C=CC2=CC(=CC=C12)C(O[SiH2]C(C)(C)C)(C)C AGBUHNSJFSPPNR-UHFFFAOYSA-N 0.000 description 12
• 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 11
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
• 239000007864 aqueous solution Substances 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
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 9
• 238000012360 testing method Methods 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
• 239000000843 powder Substances 0.000 description 8
• 235000017557 sodium bicarbonate Nutrition 0.000 description 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• 230000006866 deterioration Effects 0.000 description 7
• 239000003814 drug Substances 0.000 description 7
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 7
• 150000003254 radicals Chemical class 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
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
• 239000003795 chemical substances by application Substances 0.000 description 6
• 235000019441 ethanol Nutrition 0.000 description 6
• 239000012065 filter cake Substances 0.000 description 6
• 239000012634 fragment Substances 0.000 description 6
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• 239000011368 organic material 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
• 238000010992 reflux Methods 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
• 238000005406 washing Methods 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
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• 229910021529 ammonia Inorganic materials 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 235000019253 formic acid Nutrition 0.000 description 5
• 230000005764 inhibitory process Effects 0.000 description 5
• 230000004048 modification Effects 0.000 description 5
• 238000012986 modification Methods 0.000 description 5
• 230000005855 radiation Effects 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
• 239000003826 tablet Substances 0.000 description 5
• 239000003981 vehicle Substances 0.000 description 5
• YGVIIKNFIFDTKW-UHFFFAOYSA-N 1-[(3,4-difluorophenyl)methyl]pyrazol-4-amine Chemical compound C1=C(N)C=NN1CC1=CC=C(F)C(F)=C1 YGVIIKNFIFDTKW-UHFFFAOYSA-N 0.000 description 4
• AKKPGUPOFLAXRN-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=C(F)C=C1 AKKPGUPOFLAXRN-UHFFFAOYSA-N 0.000 description 4
• NAIULCJIOKEMOQ-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]pyrazole-4-carbonyl chloride Chemical compound C1=CC(C)=CC=C1CN1N=CC(C(Cl)=O)=C1 NAIULCJIOKEMOQ-UHFFFAOYSA-N 0.000 description 4
• LNYMJXVFIFMSOW-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxamide Chemical compound C1=C(C(=O)N)C=NN1CC1=CC=CC=C1 LNYMJXVFIFMSOW-UHFFFAOYSA-N 0.000 description 4
• BVSGXWCTWBZFEV-UHFFFAOYSA-N 1h-indol-4-ylmethanol Chemical compound OCC1=CC=CC2=C1C=CN2 BVSGXWCTWBZFEV-UHFFFAOYSA-N 0.000 description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
• 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 description 4
• SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 4
• UKMSJQSYTPUZOS-UHFFFAOYSA-N 5-amino-3-[5-[(4-fluoropiperidin-1-yl)methyl]-1H-indol-2-yl]-1H-pyridin-2-one Chemical compound NC1=CNC(=O)C(C=2NC3=CC=C(CN4CCC(F)CC4)C=C3C=2)=C1 UKMSJQSYTPUZOS-UHFFFAOYSA-N 0.000 description 4
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• 229910014455 Ca-Cb Inorganic materials 0.000 description 4
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
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