ZA200307466B - Novel tyrosine kinase inhibitors. - Google Patents

Info

Publication number

ZA200307466B

ZA200307466B ZA200307466A ZA200307466A ZA200307466B ZA 200307466 B ZA200307466 B ZA 200307466B ZA 200307466 A ZA200307466 A ZA 200307466A ZA 200307466 A ZA200307466 A ZA 200307466A ZA 200307466 B ZA200307466 B ZA 200307466B

Authority

ZA

South Africa

Prior art keywords

methyl

ethylamino

pyridin

phenyl

hydroxy

Prior art date

2001-03-28

Links

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• Global Dossier
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• 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 7
• 229940121358 tyrosine kinase inhibitor Drugs 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims description 151
• 229910052739 hydrogen Inorganic materials 0.000 claims description 116
• 239000001257 hydrogen Substances 0.000 claims description 107
• 125000000217 alkyl group Chemical group 0.000 claims description 102
• 150000002431 hydrogen Chemical class 0.000 claims description 75
• -1 sulfoxy, sulfonyl Chemical group 0.000 claims description 74
• 125000001072 heteroaryl group Chemical group 0.000 claims description 60
• 125000003118 aryl group Chemical group 0.000 claims description 55
• 125000003545 alkoxy group Chemical group 0.000 claims description 52
• 238000000034 method Methods 0.000 claims description 46
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
• 125000003342 alkenyl group Chemical group 0.000 claims description 44
• 239000000203 mixture Substances 0.000 claims description 43
• 125000005843 halogen group Chemical group 0.000 claims description 42
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 41
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 35
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 32
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 30
• 229910052799 carbon Inorganic materials 0.000 claims description 28
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 27
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 25
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 24
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 24
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• 206010028980 Neoplasm Diseases 0.000 claims description 22
• 125000000304 alkynyl group Chemical group 0.000 claims description 22
• 239000000126 substance Substances 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 20
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 150000002367 halogens Chemical class 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
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• 201000011510 cancer Diseases 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000003282 alkyl amino group Chemical group 0.000 claims description 12
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
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• 150000003839 salts Chemical class 0.000 claims description 11
• 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
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• 229940022353 herceptin Drugs 0.000 claims description 5
• XPTAUSRPHWOZPN-UHFFFAOYSA-N morpholin-4-yl hydrogen sulfate Chemical group OS(=O)(=O)ON1CCOCC1 XPTAUSRPHWOZPN-UHFFFAOYSA-N 0.000 claims description 5
• 230000002062 proliferating effect Effects 0.000 claims description 5
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• 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
• 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
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• 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 claims description 4
• 229960004679 doxorubicin Drugs 0.000 claims description 4
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• VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
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• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
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• 150000004677 hydrates Chemical class 0.000 claims description 4
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• 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 claims description 3
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• ODUJFBNSLMAOSE-AUSIDOKSSA-N 4-[[(2S)-2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[(2R)-2-(methoxymethyl)morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1CO[C@@H](COC)CN1C1=CC(C)=C(N=C(N2)C=3C(NC=CC=3NC[C@@H](O)C=3C=C(Br)C(OC)=CC=3)=O)C2=C1 ODUJFBNSLMAOSE-AUSIDOKSSA-N 0.000 claims 1
• PKNHVWJAADMUFX-AUSIDOKSSA-N 4-[[(2S)-2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[(2R)-2-(methoxymethyl)morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1CO[C@@H](COC)CN1C1=CC(C)=C(N=C(N2)C=3C(NC=CC=3NC[C@@H](O)C=3C=C(Cl)C(OC)=CC=3)=O)C2=C1 PKNHVWJAADMUFX-AUSIDOKSSA-N 0.000 claims 1
• XNQQOBWDWJLPKE-XMSQKQJNSA-N 4-[[(2S)-2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1=C(Cl)C(OC)=CC=C1[C@H](O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2C[C@@H](CF)OCC2)C(=O)NC=C1 XNQQOBWDWJLPKE-XMSQKQJNSA-N 0.000 claims 1
• PKNHVWJAADMUFX-WMZHIEFXSA-N 4-[[(2S)-2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[(2S)-2-(methoxymethyl)morpholin-4-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1CO[C@H](COC)CN1C1=CC(C)=C(N=C(N2)C=3C(NC=CC=3NC[C@@H](O)C=3C=C(Cl)C(OC)=CC=3)=O)C2=C1 PKNHVWJAADMUFX-WMZHIEFXSA-N 0.000 claims 1
• IIJGLRWTELJRPH-OPAMFIHVSA-N 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-[(2R)-2-methylmorpholin-4-yl]-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1CO[C@H](C)CN1C1=CC(C)=C(N=C(N2)C=3C(NC=CC=3NC[C@@H](O)C=3C=C(Cl)C=CC=3)=O)C2=C1 IIJGLRWTELJRPH-OPAMFIHVSA-N 0.000 claims 1
• KPFSRAAWPJUHQV-OAQYLSRUSA-N 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[6-(5,6-dihydro-4H-pyrimidin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)N2C=NCCC2)=CC=CC(Cl)=C1 KPFSRAAWPJUHQV-OAQYLSRUSA-N 0.000 claims 1
• FSDYMRXZPHZFJS-UHFFFAOYSA-N 4-[[2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound C1=C(Br)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2CCOCC2)C(=O)NC=C1 FSDYMRXZPHZFJS-UHFFFAOYSA-N 0.000 claims 1
• IMMXVSIPHLGTTG-UHFFFAOYSA-N 4-[[2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[4-(3-fluoropropyl)piperazin-1-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1=C(Br)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2CCN(CCCF)CC2)C(=O)NC=C1 IMMXVSIPHLGTTG-UHFFFAOYSA-N 0.000 claims 1
• MQPZCABORBJAFW-UHFFFAOYSA-N 4-[[2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound N=1C=2C(C)=CC(N3CCOCC3)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=C(F)C(Cl)=C1 MQPZCABORBJAFW-UHFFFAOYSA-N 0.000 claims 1
• MQKSVRLGJFYTRI-UHFFFAOYSA-N 4-[[2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound N=1C=2C(C)=CC(N3CCNCC3)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=C(F)C(Cl)=C1 MQKSVRLGJFYTRI-UHFFFAOYSA-N 0.000 claims 1
• IYAZTZOPWLFGSM-UHFFFAOYSA-N 4-[[2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound C1=C(Cl)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2CCOCC2)C(=O)NC=C1 IYAZTZOPWLFGSM-UHFFFAOYSA-N 0.000 claims 1
• VTMIHYCOXBGSOX-UHFFFAOYSA-N 4-[[2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-[4-(3-fluoropropyl)piperazin-1-yl]-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1=C(Cl)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2CCN(CCCF)CC2)C(=O)NC=C1 VTMIHYCOXBGSOX-UHFFFAOYSA-N 0.000 claims 1
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• GLPQSWLXLBIVRM-UHFFFAOYSA-N 4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(6-imidazol-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound C=1C=CC(Cl)=CC=1C(O)CNC=1C=CNC(=O)C=1C(NC1=C2)=NC1=CC=C2N1C=CN=C1 GLPQSWLXLBIVRM-UHFFFAOYSA-N 0.000 claims 1
• ODKOFIIUMZVPOY-UHFFFAOYSA-N 4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-[4-(2-methylsulfonylacetyl)piperazin-1-yl]-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound N=1C=2C(C)=CC(N3CCN(CC3)C(=O)CS(C)(=O)=O)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=CC(Cl)=C1 ODKOFIIUMZVPOY-UHFFFAOYSA-N 0.000 claims 1
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