PT1487806E - Derivados de 4-anilino-quinazolina como agentes antiproliferativos - Google Patents

Info

Publication number

PT1487806E

PT1487806E PT03710015T PT03710015T PT1487806E PT 1487806 E PT1487806 E PT 1487806E PT 03710015 T PT03710015 T PT 03710015T PT 03710015 T PT03710015 T PT 03710015T PT 1487806 E PT1487806 E PT 1487806E

Authority

PT

Portugal

Prior art keywords

alkyl

group

chloro

alkanoyl

formula

Prior art date

2002-03-28

Links

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• Global Dossier
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• 230000001028 anti-proliverative effect Effects 0.000 title claims description 16
• MTSNDBYBIZSILH-UHFFFAOYSA-N n-phenylquinazolin-4-amine Chemical class N=1C=NC2=CC=CC=C2C=1NC1=CC=CC=C1 MTSNDBYBIZSILH-UHFFFAOYSA-N 0.000 title description 3
• -1 trifluoromethoxy, cyano, nitro, amino, carbamoyl Chemical group 0.000 claims description 574
• 125000000217 alkyl group Chemical group 0.000 claims description 378
• 125000001424 substituent group Chemical group 0.000 claims description 316
• 229910052757 nitrogen Inorganic materials 0.000 claims description 286
• 125000002252 acyl group Chemical group 0.000 claims description 179
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 161
• 150000001875 compounds Chemical class 0.000 claims description 157
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 101
• 229910052736 halogen Inorganic materials 0.000 claims description 100
• 150000002367 halogens Chemical group 0.000 claims description 100
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 98
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 86
• 238000000034 method Methods 0.000 claims description 82
• 239000001257 hydrogen Substances 0.000 claims description 81
• 229910052739 hydrogen Inorganic materials 0.000 claims description 81
• 150000003246 quinazolines Chemical class 0.000 claims description 76
• 150000003839 salts Chemical class 0.000 claims description 74
• 125000003545 alkoxy group Chemical group 0.000 claims description 71
• 125000004423 acyloxy group Chemical group 0.000 claims description 66
• 125000001153 fluoro group Chemical group F* 0.000 claims description 66
• 229910052799 carbon Inorganic materials 0.000 claims description 62
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 58
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 58
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 57
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 55
• 238000006243 chemical reaction Methods 0.000 claims description 54
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 53
• 125000001589 carboacyl group Chemical group 0.000 claims description 52
• 230000008569 process Effects 0.000 claims description 51
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 50
• 125000005842 heteroatom Chemical group 0.000 claims description 50
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 49
• 229920006395 saturated elastomer Polymers 0.000 claims description 49
• 229910052705 radium Inorganic materials 0.000 claims description 48
• 229910052701 rubidium Inorganic materials 0.000 claims description 48
• 150000001721 carbon Chemical group 0.000 claims description 47
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 47
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 44
• 206010028980 Neoplasm Diseases 0.000 claims description 44
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
• 125000006239 protecting group Chemical group 0.000 claims description 37
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 35
• 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 35
• 125000000623 heterocyclic group Chemical group 0.000 claims description 34
• 238000011282 treatment Methods 0.000 claims description 34
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 33
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 32
• 125000003282 alkyl amino group Chemical group 0.000 claims description 32
• 125000003342 alkenyl group Chemical group 0.000 claims description 31
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
• 229910052717 sulfur Chemical group 0.000 claims description 30
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
• 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 29
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 28
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 28
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• 239000011593 sulfur Chemical group 0.000 claims description 28
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 27
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
• 239000001301 oxygen Substances 0.000 claims description 27
• 238000002360 preparation method Methods 0.000 claims description 27
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 25
• 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 25
• 125000004414 alkyl thio group Chemical group 0.000 claims description 24
• 201000011510 cancer Diseases 0.000 claims description 24
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 24
• 125000000304 alkynyl group Chemical group 0.000 claims description 23
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 22
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 22
• 125000000524 functional group Chemical group 0.000 claims description 22
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 21
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 125000003386 piperidinyl group Chemical group 0.000 claims description 18
• 239000002253 acid Substances 0.000 claims description 17
• 241001465754 Metazoa Species 0.000 claims description 16
• 238000004519 manufacturing process Methods 0.000 claims description 16
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 15
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 14
• 229910003827 NRaRb Inorganic materials 0.000 claims description 13
• 239000000460 chlorine Substances 0.000 claims description 13
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 11
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 10
• 238000010494 dissociation reaction Methods 0.000 claims description 10
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 238000010561 standard procedure Methods 0.000 claims description 8
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 7
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
• 125000002950 monocyclic group Chemical group 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
• VZBZUFGPXJGXNJ-UHFFFAOYSA-N 4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-ol Chemical compound C=12C=C(O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F VZBZUFGPXJGXNJ-UHFFFAOYSA-N 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 6
• 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 6
• 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 5
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
• 125000005108 alkenylthio group Chemical group 0.000 claims description 5
• 230000029936 alkylation Effects 0.000 claims description 5
• 238000005804 alkylation reaction Methods 0.000 claims description 5
• 125000005139 alkynylsulfonyl group Chemical group 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 230000005593 dissociations Effects 0.000 claims description 5
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 4
• 125000005136 alkenylsulfinyl group Chemical group 0.000 claims description 4
• 125000005137 alkenylsulfonyl group Chemical group 0.000 claims description 4
• 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 4
• DFNJBNWBONZOQL-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-piperidin-4-yloxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCNCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DFNJBNWBONZOQL-UHFFFAOYSA-N 0.000 claims description 4
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
• QEBRMJTUPMNDKF-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QEBRMJTUPMNDKF-UHFFFAOYSA-N 0.000 claims description 3
• DWMAXHFKQQZRDD-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)CN(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DWMAXHFKQQZRDD-UHFFFAOYSA-N 0.000 claims description 3
• XLKMNDIRQXLLRJ-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethanone Chemical compound C=12C=C(OC3CCN(CC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F XLKMNDIRQXLLRJ-UHFFFAOYSA-N 0.000 claims description 3
• DIBGTMXGHUALIU-UHFFFAOYSA-N 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]acetamide Chemical compound C=12C=C(OC3CCN(CC(N)=O)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DIBGTMXGHUALIU-UHFFFAOYSA-N 0.000 claims description 3
• FKIGKBRONDNFSA-UHFFFAOYSA-N 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]acetonitrile Chemical compound C=12C=C(OC3CCN(CC#N)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FKIGKBRONDNFSA-UHFFFAOYSA-N 0.000 claims description 3
• SBAGQHZIOBAMDV-UHFFFAOYSA-N 4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-n,n-dimethylpiperidine-1-sulfonamide Chemical compound C=12C=C(OC3CCN(CC3)S(=O)(=O)N(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F SBAGQHZIOBAMDV-UHFFFAOYSA-N 0.000 claims description 3
• 125000005134 alkynylsulfinyl group Chemical group 0.000 claims description 3
• 125000005109 alkynylthio group Chemical group 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
• PUGRPTFZBHHZPM-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F PUGRPTFZBHHZPM-UHFFFAOYSA-N 0.000 claims description 3
• QBSXCQDYNHLCCN-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylpyrrolidin-3-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QBSXCQDYNHLCCN-UHFFFAOYSA-N 0.000 claims description 3
• BDLUIKGKNQFJIO-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylsulfonylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(CC3)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F BDLUIKGKNQFJIO-UHFFFAOYSA-N 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• VERFDPCLRFVYAD-ZDUSSCGKSA-N (3s)-3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-n,n-dimethylpyrrolidine-1-sulfonamide Chemical compound C=12C=C(O[C@@H]3CN(CC3)S(=O)(=O)N(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F VERFDPCLRFVYAD-ZDUSSCGKSA-N 0.000 claims description 2
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
• JSBUNBCORFPCOC-GFCCVEGCSA-N 1-[(3r)-3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypyrrolidin-1-yl]-2-hydroxyethanone Chemical compound C=12C=C(O[C@H]3CN(CC3)C(=O)CO)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F JSBUNBCORFPCOC-GFCCVEGCSA-N 0.000 claims description 2
• BGJVGJZKZPYAMV-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-pyrrolidin-1-ylethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN3CCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F BGJVGJZKZPYAMV-UHFFFAOYSA-N 0.000 claims description 2
• FEGFNGQBRZUWHV-UHFFFAOYSA-N 2-(4-acetylpiperazin-1-yl)-1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN3CCN(CC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FEGFNGQBRZUWHV-UHFFFAOYSA-N 0.000 claims description 2
• DUZUWJLVYVKTKY-UHFFFAOYSA-N 2-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-n,n-dimethylacetamide Chemical compound C=12C=C(OC3CN(CC(=O)N(C)C)CCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DUZUWJLVYVKTKY-UHFFFAOYSA-N 0.000 claims description 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
• IIPZVWOEYKWBAM-IWPPFLRJSA-N [(4r)-4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-1-methylpyrrolidin-2-yl]-morpholin-4-ylmethanone Chemical compound C=12C=C(O[C@H]3CN(C)C(C3)C(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F IIPZVWOEYKWBAM-IWPPFLRJSA-N 0.000 claims description 2
• 238000009833 condensation Methods 0.000 claims description 2
• 230000005494 condensation Effects 0.000 claims description 2
• 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 2
• MORFQDRARBOZSN-LBPRGKRZSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3s)-piperidin-3-yl]oxyquinazolin-4-amine Chemical compound C=12C=C(O[C@@H]3CNCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MORFQDRARBOZSN-LBPRGKRZSA-N 0.000 claims description 2
• VAGCDXKHNHUMSZ-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[1-(2-methoxyethyl)piperidin-4-yl]oxyquinazolin-4-amine Chemical compound C1CN(CCOC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F VAGCDXKHNHUMSZ-UHFFFAOYSA-N 0.000 claims description 2
• 150000003335 secondary amines Chemical class 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 2
• VZFHDUMFRVSURN-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-(3,3-difluoropyrrolidin-1-yl)ethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN3CC(F)(F)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F VZFHDUMFRVSURN-UHFFFAOYSA-N 0.000 claims 1
• BWYJJZBRYSADRP-UHFFFAOYSA-N 2-methoxyquinazoline Chemical compound C1=CC=CC2=NC(OC)=NC=C21 BWYJJZBRYSADRP-UHFFFAOYSA-N 0.000 claims 1
• MDBOZMACAZGNHS-UHFFFAOYSA-N 4,5,6,6a-tetrahydro-3ah-[1,3]dioxolo[4,5-c]pyrrole Chemical compound C1NCC2OCOC21 MDBOZMACAZGNHS-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 231
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
• 229960005419 nitrogen Drugs 0.000 description 67
• 239000000047 product Substances 0.000 description 64
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
• 239000000243 solution Substances 0.000 description 53
• 239000000203 mixture Substances 0.000 description 52
• 210000004027 cell Anatomy 0.000 description 41
• 150000001335 aliphatic alkanes Chemical class 0.000 description 40
• WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
• 238000001819 mass spectrum Methods 0.000 description 32
• 239000002904 solvent Substances 0.000 description 31
• 239000000377 silicon dioxide Substances 0.000 description 30
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
• 239000011541 reaction mixture Substances 0.000 description 29
• 239000007787 solid Substances 0.000 description 29
• 239000007858 starting material Substances 0.000 description 29
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 28
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 28
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 27
• YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 26
• 238000004440 column chromatography Methods 0.000 description 25
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
• 238000005481 NMR spectroscopy Methods 0.000 description 24
• 229960004132 diethyl ether Drugs 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• 239000002585 base Substances 0.000 description 22
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 21
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 21
• 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 21
• 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 21
• 230000000694 effects Effects 0.000 description 21
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