ES2292461T3 - Derivados de quinazolina. - Google Patents

Info

Publication number

ES2292461T3

ES2292461T3 ES00953271T ES00953271T ES2292461T3 ES 2292461 T3 ES2292461 T3 ES 2292461T3 ES 00953271 T ES00953271 T ES 00953271T ES 00953271 T ES00953271 T ES 00953271T ES 2292461 T3 ES2292461 T3 ES 2292461T3

Authority

ES

Spain

Prior art keywords

alkyl

amino

group

underbar

pyrrolidin

Prior art date

1999-07-07

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.)

Expired - Lifetime

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• 125000000217 alkyl group Chemical group 0.000 claims abstract description 117
• 239000001257 hydrogen Substances 0.000 claims abstract description 75
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 75
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 56
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 53
• 125000003118 aryl group Chemical group 0.000 claims abstract description 52
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 42
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 31
• 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 30
• 238000011282 treatment Methods 0.000 claims abstract description 25
• 201000010099 disease Diseases 0.000 claims abstract description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
• 230000002265 prevention Effects 0.000 claims abstract description 15
• 239000003814 drug Substances 0.000 claims abstract description 12
• 230000001404 mediated effect Effects 0.000 claims abstract description 12
• 241001465754 Metazoa Species 0.000 claims abstract description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• 238000004519 manufacturing process Methods 0.000 claims abstract description 5
• 125000005843 halogen group Chemical group 0.000 claims abstract 2
• -1 cyano, isocyan, nitro, hydroxy, mercapto , amino, formyl Chemical group 0.000 claims description 425
• 150000001875 compounds Chemical class 0.000 claims description 129
• 229910052757 nitrogen Inorganic materials 0.000 claims description 129
• 125000001424 substituent group Chemical group 0.000 claims description 109
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 88
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 63
• 125000001072 heteroaryl group Chemical group 0.000 claims description 47
• 239000002253 acid Substances 0.000 claims description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 28
• 150000002367 halogens Chemical class 0.000 claims description 27
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 26
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
• 229920006395 saturated elastomer Polymers 0.000 claims description 25
• 229910052799 carbon Inorganic materials 0.000 claims description 23
• 229910052736 halogen Inorganic materials 0.000 claims description 23
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 20
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 239000001301 oxygen Chemical group 0.000 claims description 19
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 18
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 18
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
• 239000011593 sulfur Chemical group 0.000 claims description 18
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 17
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 15
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 14
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 14
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 14
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• 125000002619 bicyclic group Chemical group 0.000 claims description 14
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
• 125000001153 fluoro group Chemical group F* 0.000 claims description 14
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 14
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 13
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
• PDKQWNNPSOCARZ-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC(=O)NC1=CC=CC=C1 PDKQWNNPSOCARZ-UHFFFAOYSA-N 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 125000001246 bromo group Chemical group Br* 0.000 claims description 10
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 10
• 125000002950 monocyclic group Chemical group 0.000 claims description 10
• 125000001624 naphthyl group Chemical group 0.000 claims description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
• 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 10
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
• 229920002554 vinyl polymer Polymers 0.000 claims description 9
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
• 125000002947 alkylene group Chemical group 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 7
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
• 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 claims description 6
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
• 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 6
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 4
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 4
• 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 4
• 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
• LFKKTLUGAAHREA-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(Cl)C=CC=C1Cl LFKKTLUGAAHREA-UHFFFAOYSA-N 0.000 claims description 3
• MYGNHGMKCUOIOX-UHFFFAOYSA-N 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]thiourea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=S)NC1=C(C)C=CC=C1C MYGNHGMKCUOIOX-UHFFFAOYSA-N 0.000 claims description 3
• PWLOZSWLRKABAU-UHFFFAOYSA-N 1-benzyl-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NCC1=CC=CC=C1 PWLOZSWLRKABAU-UHFFFAOYSA-N 0.000 claims description 3
• 125000004423 acyloxy group Chemical group 0.000 claims description 3
• 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 3
• 125000006319 alkynyl amino group Chemical group 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
• XFMBZTKSOUNGDD-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]urea Chemical compound ClC1=CC=CC(Cl)=C1NC(=O)NC1=NC=NC2=CC(OCCCN3CCOCC3)=CC=C12 XFMBZTKSOUNGDD-UHFFFAOYSA-N 0.000 claims description 2
• VJPCAEOLFMRBIO-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-3-[7-[3-(1,1-dioxo-1,4-thiazinan-4-yl)propoxy]quinazolin-4-yl]urea Chemical compound ClC1=CC=CC(Cl)=C1NC(=O)NC1=NC=NC2=CC(OCCCN3CCS(=O)(=O)CC3)=CC=C12 VJPCAEOLFMRBIO-UHFFFAOYSA-N 0.000 claims description 2
• KSNTYYGPIMDEGF-UHFFFAOYSA-N 1-(2,6-difluorophenyl)-3-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC(=O)NC1=C(F)C=CC=C1F KSNTYYGPIMDEGF-UHFFFAOYSA-N 0.000 claims description 2
• BVQIOKJOQYMERO-UHFFFAOYSA-N 1-(2,6-difluorophenyl)-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(F)C=CC=C1F BVQIOKJOQYMERO-UHFFFAOYSA-N 0.000 claims description 2
• VQANQTNLUVCABE-UHFFFAOYSA-N 1-(2,6-difluorophenyl)-3-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(F)C=CC=C1F VQANQTNLUVCABE-UHFFFAOYSA-N 0.000 claims description 2
• WEHHOPRHJGOSQH-UHFFFAOYSA-N 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1NC(=O)NC1=C(C)C=CC=C1C WEHHOPRHJGOSQH-UHFFFAOYSA-N 0.000 claims description 2
• QGOLHIOJZCVCEQ-UHFFFAOYSA-N 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(C)C=CC=C1C QGOLHIOJZCVCEQ-UHFFFAOYSA-N 0.000 claims description 2
• HJRYVXJYTOOIHN-UHFFFAOYSA-N 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(C)C=CC=C1C HJRYVXJYTOOIHN-UHFFFAOYSA-N 0.000 claims description 2
• VEVFYAOTCNGEQL-UHFFFAOYSA-N 1-(2-chloro-6-methylphenyl)-2-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]guanidine Chemical compound N1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC(=N)NC1=C(C)C=CC=C1Cl VEVFYAOTCNGEQL-UHFFFAOYSA-N 0.000 claims description 2
• METZVMMERANODX-UHFFFAOYSA-N 1-(2-chloro-6-methylphenyl)-3-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC1=C(C)C=CC=C1Cl METZVMMERANODX-UHFFFAOYSA-N 0.000 claims description 2
• ARDYBEPURLDBAR-UHFFFAOYSA-N 1-[6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl]-3-(1-phenylethyl)urea Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=O)NC(C)C1=CC=CC=C1 ARDYBEPURLDBAR-UHFFFAOYSA-N 0.000 claims description 2
• 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
• 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([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
• 125000001589 carboacyl group Chemical group 0.000 claims 17
• 150000003246 quinazolines Chemical class 0.000 claims 8
• 238000000034 method Methods 0.000 abstract description 124
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 32
• 238000002360 preparation method Methods 0.000 abstract description 12
• 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
• 239000000203 mixture Substances 0.000 description 324
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 270
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 268
• 238000001819 mass spectrum Methods 0.000 description 255
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 219
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 196
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 186
• 239000000047 product Substances 0.000 description 177
• 239000007858 starting material Substances 0.000 description 125
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 107
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 106
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 94
• 239000000463 material Substances 0.000 description 92
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
• 239000000243 solution Substances 0.000 description 82
• 239000007787 solid Substances 0.000 description 69
• 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 62
• 238000001228 spectrum Methods 0.000 description 57
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 53
• 239000007864 aqueous solution Substances 0.000 description 52
• 239000000377 silicon dioxide Substances 0.000 description 51
• 239000003480 eluent Substances 0.000 description 48
• 238000004440 column chromatography Methods 0.000 description 45
• 229910021529 ammonia Inorganic materials 0.000 description 43
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
• 239000011541 reaction mixture Substances 0.000 description 42
• 238000006243 chemical reaction Methods 0.000 description 40
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
• 239000007810 chemical reaction solvent Substances 0.000 description 29
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
• 235000019341 magnesium sulphate Nutrition 0.000 description 28
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 28
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 28
• 125000002252 acyl group Chemical group 0.000 description 27
• 239000000706 filtrate Substances 0.000 description 26
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• 239000002244 precipitate Substances 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 21
• 238000012360 testing method Methods 0.000 description 21
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
• 102000036243 Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Human genes 0.000 description 20
• 108010002481 Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Proteins 0.000 description 20
• 238000005481 NMR spectroscopy Methods 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 239000002585 base Substances 0.000 description 19
• 230000000694 effects Effects 0.000 description 19
• 239000012948 isocyanate Substances 0.000 description 19
• 150000002513 isocyanates Chemical class 0.000 description 19
• UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 19
• 125000006239 protecting group Chemical group 0.000 description 19
• 239000000126 substance Substances 0.000 description 19
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
• 239000012267 brine Substances 0.000 description 18
• 125000000524 functional group Chemical group 0.000 description 18
• 150000003949 imides Chemical class 0.000 description 18
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
• 238000010992 reflux Methods 0.000 description 17
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 16
• 239000012044 organic layer Substances 0.000 description 14
• 230000004913 activation Effects 0.000 description 13
• 150000001412 amines Chemical class 0.000 description 13
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
• 230000005764 inhibitory process Effects 0.000 description 12
• 239000002904 solvent Substances 0.000 description 12
• WQNYJBJUJKUATO-UHFFFAOYSA-N 6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound COC1=CC2=C(N)N=CN=C2C=C1OCC1CCN(C)CC1 WQNYJBJUJKUATO-UHFFFAOYSA-N 0.000 description 11
• 239000003112 inhibitor Substances 0.000 description 11
• 229910052751 metal Inorganic materials 0.000 description 11
• 239000002184 metal Substances 0.000 description 11
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