AU2002337142B2 - Indolizines as kinase protein inhibitors - Google Patents

Info

Publication number

AU2002337142B2

AU2002337142B2 AU2002337142A AU2002337142A AU2002337142B2 AU 2002337142 B2 AU2002337142 B2 AU 2002337142B2 AU 2002337142 A AU2002337142 A AU 2002337142A AU 2002337142 A AU2002337142 A AU 2002337142A AU 2002337142 B2 AU2002337142 B2 AU 2002337142B2

Authority

AU

Australia

Prior art keywords

phenyl

compounds

amide

formula

optionally substituted

Prior art date

2001-09-19

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.)

Ceased

Links

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• 108091000080 Phosphotransferase Proteins 0.000 title claims description 35
• 102000020233 phosphotransferase Human genes 0.000 title claims description 35
• 150000002478 indolizines Chemical class 0.000 title 1
• 229940121649 protein inhibitor Drugs 0.000 title 1
• 239000012268 protein inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 439
• -1 cyclolalkyl Chemical group 0.000 claims description 489
• 150000001408 amides Chemical class 0.000 claims description 377
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 227
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 175
• 150000003839 salts Chemical class 0.000 claims description 113
• 229940002612 prodrug Drugs 0.000 claims description 87
• 239000000651 prodrug Substances 0.000 claims description 87
• 150000001204 N-oxides Chemical class 0.000 claims description 84
• 125000001072 heteroaryl group Chemical group 0.000 claims description 83
• 125000000217 alkyl group Chemical group 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 125000003118 aryl group Chemical group 0.000 claims description 58
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
• 239000001257 hydrogen Substances 0.000 claims description 55
• 238000000034 method Methods 0.000 claims description 52
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 44
• 150000004677 hydrates Chemical class 0.000 claims description 44
• 239000012453 solvate Substances 0.000 claims description 43
• 238000011282 treatment Methods 0.000 claims description 41
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 39
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
• HWGYCYYNKQMGNG-UHFFFAOYSA-N 7-chloro-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid Chemical compound C1N(C(=O)O)CCN2C1=C(C(O)=O)C(Cl)=C2C1=CC=CC=C1 HWGYCYYNKQMGNG-UHFFFAOYSA-N 0.000 claims description 38
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 36
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
• 125000004076 pyridyl group Chemical group 0.000 claims description 35
• 206010028980 Neoplasm Diseases 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 30
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 30
• 201000010099 disease Diseases 0.000 claims description 30
• 229940126601 medicinal product Drugs 0.000 claims description 30
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 26
• 125000003107 substituted aryl group Chemical group 0.000 claims description 24
• 238000002360 preparation method Methods 0.000 claims description 23
• 125000001424 substituent group Chemical group 0.000 claims description 23
• 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 claims description 22
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 22
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 21
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 17
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 17
• 229910052500 inorganic mineral Inorganic materials 0.000 claims description 17
• 239000011707 mineral Substances 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 230000000694 effects Effects 0.000 claims description 16
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 16
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 15
• FGPTZSNPAUOIAM-UHFFFAOYSA-N 7-cyano-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid Chemical compound C1N(C(=O)O)CCN2C1=C(C(O)=O)C(C#N)=C2C1=CC=CC=C1 FGPTZSNPAUOIAM-UHFFFAOYSA-N 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 15
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 15
• 239000003112 inhibitor Substances 0.000 claims description 14
• 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 239000003795 chemical substances by application Substances 0.000 claims description 10
• NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 10
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 9
• 206010006187 Breast cancer Diseases 0.000 claims description 9
• 208000026310 Breast neoplasm Diseases 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000002541 furyl group Chemical group 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 208000020816 lung neoplasm Diseases 0.000 claims description 9
• 150000007522 mineralic acids Chemical class 0.000 claims description 9
• 150000007524 organic acids Chemical class 0.000 claims description 9
• 235000005985 organic acids Nutrition 0.000 claims description 9
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
• 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 8
• 201000005202 lung cancer Diseases 0.000 claims description 8
• 150000007530 organic bases Chemical class 0.000 claims description 8
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 7
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• 208000029742 colonic neoplasm Diseases 0.000 claims description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 7
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 6
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 6
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 6
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 238000002512 chemotherapy Methods 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 229940124783 FAK inhibitor Drugs 0.000 claims description 5
• 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 claims description 5
• 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims description 5
• 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 claims description 5
• 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims description 5
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 5
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 5
• 229910005965 SO 2 Inorganic materials 0.000 claims description 5
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 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 description 5
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 5
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 5
• 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 claims description 5
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 210000002307 prostate Anatomy 0.000 claims description 5
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
• 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 4
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 4
• 101100481408 Danio rerio tie2 gene Proteins 0.000 claims description 4
• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
• 101150017750 FGFRL1 gene Proteins 0.000 claims description 4
• 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 claims description 4
• 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 claims description 4
• 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims description 4
• 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims description 4
• 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims description 4
• 102100026149 Fibroblast growth factor receptor-like 1 Human genes 0.000 claims description 4
• 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims description 4
• 101000852966 Rattus norvegicus Interleukin-1 receptor-like 1 Proteins 0.000 claims description 4
• 108091008605 VEGF receptors Proteins 0.000 claims description 4
• UBLYEVLMRSPMOG-UHFFFAOYSA-N cyclopentylmethanamine Chemical compound NCC1CCCC1 UBLYEVLMRSPMOG-UHFFFAOYSA-N 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 239000000138 intercalating agent Substances 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
• 125000005936 piperidyl group Chemical group 0.000 claims description 4
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
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