ES2392014T3 - Pirazolopiridinas como inhibidores de la cinasa - Google Patents

Info

Publication number

ES2392014T3

ES2392014T3 ES09701216T ES09701216T ES2392014T3 ES 2392014 T3 ES2392014 T3 ES 2392014T3 ES 09701216 T ES09701216 T ES 09701216T ES 09701216 T ES09701216 T ES 09701216T ES 2392014 T3 ES2392014 T3 ES 2392014T3

Authority

ES

Spain

Prior art keywords

mmol

pyrazolo

added

hydrogen

piperazin

Prior art date

2008-01-09

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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• 150000005229 pyrazolopyridines Chemical class 0.000 title description 3
• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• -1 -ORe Chemical group 0.000 claims abstract description 158
• 150000001875 compounds Chemical class 0.000 claims abstract description 154
• 239000001257 hydrogen Substances 0.000 claims abstract description 95
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 95
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 67
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 57
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 55
• 150000002367 halogens Chemical group 0.000 claims abstract description 52
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 44
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 43
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 43
• 150000003839 salts Chemical class 0.000 claims abstract description 36
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 24
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 19
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 10
• 125000004429 atom Chemical group 0.000 claims abstract description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 6
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 5
• 229910017711 NHRa Inorganic materials 0.000 claims abstract description 5
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract 2
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims abstract 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 35
• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• 229910052794 bromium Chemical group 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims 3
• 150000002431 hydrogen Chemical group 0.000 abstract description 32
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 342
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 278
• 239000000243 solution Substances 0.000 description 175
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 170
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 161
• 239000007787 solid Substances 0.000 description 159
• 238000006243 chemical reaction Methods 0.000 description 151
• 239000000203 mixture Substances 0.000 description 135
• 235000019439 ethyl acetate Nutrition 0.000 description 129
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 124
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 78
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 71
• 238000000034 method Methods 0.000 description 66
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
• 239000002904 solvent Substances 0.000 description 62
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 59
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 56
• 239000012044 organic layer Substances 0.000 description 56
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
• 229910052938 sodium sulfate Inorganic materials 0.000 description 49
• 235000011152 sodium sulphate Nutrition 0.000 description 49
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 46
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
• 238000011282 treatment Methods 0.000 description 38
• 238000005160 1H NMR spectroscopy Methods 0.000 description 35
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
• 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 35
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 35
• 238000004440 column chromatography Methods 0.000 description 34
• 239000011541 reaction mixture Substances 0.000 description 34
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 32
• 238000001914 filtration Methods 0.000 description 32
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 31
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
• 235000019341 magnesium sulphate Nutrition 0.000 description 31
• 239000003921 oil Substances 0.000 description 30
• 239000003112 inhibitor Substances 0.000 description 28
• 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 28
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
• 238000003756 stirring Methods 0.000 description 27
• 206010028980 Neoplasm Diseases 0.000 description 26
• 201000010099 disease Diseases 0.000 description 26
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 25
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 24
• 241000124008 Mammalia Species 0.000 description 24
• 125000003118 aryl group Chemical group 0.000 description 24
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 125000000217 alkyl group Chemical group 0.000 description 22
• 150000001413 amino acids Chemical class 0.000 description 22
• 238000004587 chromatography analysis Methods 0.000 description 21
• 239000002253 acid Substances 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 239000010410 layer Substances 0.000 description 20
• 125000006239 protecting group Chemical group 0.000 description 20
• 201000011510 cancer Diseases 0.000 description 19
• RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 18
• 230000003463 hyperproliferative effect Effects 0.000 description 16
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 238000000926 separation method Methods 0.000 description 15
• 239000000741 silica gel Substances 0.000 description 15
• 229910002027 silica gel Inorganic materials 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 15
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
• 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 14
• 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 14
• 239000012043 crude product Substances 0.000 description 14
• 238000003818 flash chromatography Methods 0.000 description 14
• 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 14
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
• 239000012317 TBTU Substances 0.000 description 13
• 239000007864 aqueous solution Substances 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
• 150000002148 esters Chemical class 0.000 description 13
• 125000001424 substituent group Chemical group 0.000 description 13
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• 239000003153 chemical reaction reagent Substances 0.000 description 12
• 238000005859 coupling reaction Methods 0.000 description 12
• 125000000753 cycloalkyl group Chemical group 0.000 description 12
• 238000002360 preparation method Methods 0.000 description 12
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
• 239000000543 intermediate Substances 0.000 description 11
• 238000010992 reflux Methods 0.000 description 11
• 239000000377 silicon dioxide Substances 0.000 description 11
• 238000003786 synthesis reaction Methods 0.000 description 11
• 239000007832 Na2SO4 Substances 0.000 description 10
• 239000003814 drug Substances 0.000 description 10
• 230000014759 maintenance of location Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• 230000002829 reductive effect Effects 0.000 description 10
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 9
• 208000009956 adenocarcinoma Diseases 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• GQWRBNJRKSPGTF-CQSZACIVSA-N (2s)-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(C(C)C)C[C@@H](C(O)=O)C1=CC=C(Cl)C=C1 GQWRBNJRKSPGTF-CQSZACIVSA-N 0.000 description 8
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
• 201000009030 Carcinoma Diseases 0.000 description 8
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
• 206010025323 Lymphomas Diseases 0.000 description 8
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
• 108091000080 Phosphotransferase Proteins 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 8
• 102000020233 phosphotransferase Human genes 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• DRTZAIDVOGUYSP-UHFFFAOYSA-N pyridin-1-ium;chloride;hydrochloride Chemical compound Cl.Cl.C1=CC=NC=C1 DRTZAIDVOGUYSP-UHFFFAOYSA-N 0.000 description 8
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 7
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
• 230000002159 abnormal effect Effects 0.000 description 7
• 125000006242 amine protecting group Chemical group 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 239000000843 powder Substances 0.000 description 7
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 7
• 206010041823 squamous cell carcinoma Diseases 0.000 description 7
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• 206010039491 Sarcoma Diseases 0.000 description 6
• 150000001336 alkenes Chemical class 0.000 description 6
• 239000002246 antineoplastic agent Substances 0.000 description 6
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
• 239000000460 chlorine Substances 0.000 description 6
• 230000008878 coupling Effects 0.000 description 6
• 238000010168 coupling process Methods 0.000 description 6
• 239000000706 filtrate Substances 0.000 description 6
• 238000005984 hydrogenation reaction Methods 0.000 description 6
• JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 6
• 239000012074 organic phase Substances 0.000 description 6
• LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 6
• 150000003141 primary amines Chemical class 0.000 description 6
• NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 6
• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• 235000011006 sodium potassium tartrate Nutrition 0.000 description 6
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
• 238000004809 thin layer chromatography Methods 0.000 description 6
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 6
• 229910052727 yttrium Inorganic materials 0.000 description 6
• DCAYZHRQQFCZGT-KBPBESRZSA-N (2s)-2-(4-chlorophenyl)-2-[(2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]acetic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(O)=O)C1=CC=C(Cl)C=C1 DCAYZHRQQFCZGT-KBPBESRZSA-N 0.000 description 5
• MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 5
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 5
• PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
• 150000001412 amines Chemical class 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• 239000012267 brine Substances 0.000 description 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
• 230000010261 cell growth Effects 0.000 description 5
• 229910052681 coesite Inorganic materials 0.000 description 5
• 229910052593 corundum Inorganic materials 0.000 description 5
• 229910052906 cristobalite Inorganic materials 0.000 description 5
• 238000010511 deprotection reaction Methods 0.000 description 5
• 238000001035 drying Methods 0.000 description 5
• 238000010438 heat treatment Methods 0.000 description 5
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
• 229910052740 iodine Inorganic materials 0.000 description 5
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
• 230000004048 modification Effects 0.000 description 5
• 238000012986 modification Methods 0.000 description 5
• 229910052763 palladium Inorganic materials 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
• 230000005855 radiation Effects 0.000 description 5
• 229920006395 saturated elastomer Polymers 0.000 description 5
• 239000012047 saturated solution Substances 0.000 description 5
• 235000012239 silicon dioxide Nutrition 0.000 description 5
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
• 229910052682 stishovite Inorganic materials 0.000 description 5
• 229910052905 tridymite Inorganic materials 0.000 description 5
• 229910001845 yogo sapphire Inorganic materials 0.000 description 5
• 239000011701 zinc Substances 0.000 description 5
• BETBOAZCLSJOBQ-LLVKDONJSA-N (2r)-3-(4-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CC1=CC=C(Cl)C=C1 BETBOAZCLSJOBQ-LLVKDONJSA-N 0.000 description 4
• DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 4
• XQBXNRCFGZPQLH-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]-7H-pyrazolo[3,4-b]pyridin-4-one Chemical compound C1=CC(OC)=CC=C1CN1C2=NC=CC(O)=C2C=N1 XQBXNRCFGZPQLH-UHFFFAOYSA-N 0.000 description 4
• JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
• CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 4
• 230000033616 DNA repair Effects 0.000 description 4
• 239000002841 Lewis acid Substances 0.000 description 4
• 229910013596 LiOH—H2O Inorganic materials 0.000 description 4
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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