AU2010281368C1 - Novel bicyclic urea compounds - Google Patents

Info

Publication number

AU2010281368C1

AU2010281368C1 AU2010281368A AU2010281368A AU2010281368C1 AU 2010281368 C1 AU2010281368 C1 AU 2010281368C1 AU 2010281368 A AU2010281368 A AU 2010281368A AU 2010281368 A AU2010281368 A AU 2010281368A AU 2010281368 C1 AU2010281368 C1 AU 2010281368C1

Authority

AU

Australia

Prior art keywords

fluoro

oxo

phenyl

pyrimidin

benzamide

Prior art date

2009-08-06

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

• Espacenet
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• -1 bicyclic urea compounds Chemical class 0.000 title claims description 124
• 150000001875 compounds Chemical class 0.000 claims abstract description 362
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
• 201000010099 disease Diseases 0.000 claims abstract description 23
• 201000011510 cancer Diseases 0.000 claims abstract description 15
• 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 12
• 238000000034 method Methods 0.000 claims description 336
• 238000002360 preparation method Methods 0.000 claims description 325
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 100
• 150000003839 salts Chemical class 0.000 claims description 49
• 239000000651 prodrug Substances 0.000 claims description 34
• 229940002612 prodrug Drugs 0.000 claims description 34
• 239000012453 solvate Substances 0.000 claims description 32
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
• 229910052731 fluorine Inorganic materials 0.000 claims description 17
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 12
• 239000004480 active ingredient Substances 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 125000004434 sulfur atom Chemical group 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 125000001424 substituent group Chemical group 0.000 claims description 7
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 230000004054 inflammatory process Effects 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
• 201000004624 Dermatitis Diseases 0.000 claims description 4
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
• 208000032612 Glial tumor Diseases 0.000 claims description 4
• 206010018338 Glioma Diseases 0.000 claims description 4
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 4
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
• 230000033115 angiogenesis Effects 0.000 claims description 4
• 125000003118 aryl group Chemical group 0.000 claims description 4
• 208000010668 atopic eczema Diseases 0.000 claims description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims description 4
• 208000002780 macular degeneration Diseases 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 125000006362 methylene amino carbonyl group Chemical group [H]N(C([*:2])=O)C([H])([H])[*:1] 0.000 claims description 4
• 125000002950 monocyclic group Chemical group 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 208000017520 skin disease Diseases 0.000 claims description 4
• 230000005747 tumor angiogenesis Effects 0.000 claims description 4
• 230000004862 vasculogenesis Effects 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000000565 sulfonamide group Chemical group 0.000 claims description 2
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
• 208000002193 Pain Diseases 0.000 claims 3
• 206010033645 Pancreatitis Diseases 0.000 claims 3
• 201000011066 hemangioma Diseases 0.000 claims 3
• 206010020718 hyperplasia Diseases 0.000 claims 3
• 208000017169 kidney disease Diseases 0.000 claims 3
• 208000037803 restenosis Diseases 0.000 claims 3
• YOWGCQRWOILZBA-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]urea Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)NC1=CC=CC(Cl)=C1 YOWGCQRWOILZBA-UHFFFAOYSA-N 0.000 claims 1
• YXHURDDOXJYJCD-UHFFFAOYSA-N 1-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-(4-propan-2-ylphenyl)urea Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)NC(C=C1F)=CC=C1OC1=CC=NC2=C1CNC(=O)N2 YXHURDDOXJYJCD-UHFFFAOYSA-N 0.000 claims 1
• NLRJBIXXRDJCAU-UHFFFAOYSA-N 1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]urea Chemical compound FC(F)(F)C1=CC(F)=CC=C1NC(=O)NC(C=C1)=CC=C1NC1=CC=NC2=C1CNC(=O)N2 NLRJBIXXRDJCAU-UHFFFAOYSA-N 0.000 claims 1
• SPNNXEKFUAFBSG-UHFFFAOYSA-N 2,5-dichloro-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]pyridine-3-carboxamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC(Cl)=CN=C1Cl SPNNXEKFUAFBSG-UHFFFAOYSA-N 0.000 claims 1
• BSTCOMNDERKXIO-UHFFFAOYSA-N 2-cyclopropyl-n-[4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]acetamide Chemical compound C=1C=C(NC=2C=3CNC(=O)NC=3N=CC=2)C=CC=1NC(=O)CC1CC1 BSTCOMNDERKXIO-UHFFFAOYSA-N 0.000 claims 1
• NJIDQBULLAICNP-UHFFFAOYSA-N 2-fluoro-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-(trifluoromethyl)benzamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC=CC(C(F)(F)F)=C1F NJIDQBULLAICNP-UHFFFAOYSA-N 0.000 claims 1
• KOEIPWCNSYGSKR-UHFFFAOYSA-N 3-bromo-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]benzamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC=CC(Br)=C1 KOEIPWCNSYGSKR-UHFFFAOYSA-N 0.000 claims 1
• FODQLNUOVCCYQE-UHFFFAOYSA-N 3-cyano-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]benzamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC=CC(C#N)=C1 FODQLNUOVCCYQE-UHFFFAOYSA-N 0.000 claims 1
• KEKYRXMBJRDZSS-UHFFFAOYSA-N 3-fluoro-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=C1 KEKYRXMBJRDZSS-UHFFFAOYSA-N 0.000 claims 1
• UGLWODDRRMZTFH-UHFFFAOYSA-N 3-fluoro-n-[3-fluoro-4-[(3-methyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(C)CC2=C1NC(C(=C1)F)=CC=C1NC(=O)C1=CC=CC(F)=C1 UGLWODDRRMZTFH-UHFFFAOYSA-N 0.000 claims 1
• QJJQEDFOKVFOHG-UHFFFAOYSA-N 4-bromo-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]benzamide Chemical compound C=1C=C(OC=2C=3CNC(=O)NC=3N=CC=2)C(F)=CC=1NC(=O)C1=CC=C(Br)C=C1 QJJQEDFOKVFOHG-UHFFFAOYSA-N 0.000 claims 1
• HOIMGBNXXXHZFV-UHFFFAOYSA-N 4-fluoro-n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]-2-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC(F)=CC=C1C(=O)NC(C=C1F)=CC=C1NC1=CC=NC2=C1CNC(=O)N2 HOIMGBNXXXHZFV-UHFFFAOYSA-N 0.000 claims 1
• GNITVJCZUNIVSR-UHFFFAOYSA-N 4-fluoro-n-[3-fluoro-4-[[3-[(4-methoxyphenyl)methyl]-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]amino]phenyl]-2-(trifluoromethyl)benzamide Chemical compound C1=CC(OC)=CC=C1CN1C(=O)NC2=NC=CC(NC=3C(=CC(NC(=O)C=4C(=CC(F)=CC=4)C(F)(F)F)=CC=3)F)=C2C1 GNITVJCZUNIVSR-UHFFFAOYSA-N 0.000 claims 1
• LDMZAJAFEJXKRF-UHFFFAOYSA-N 4-fluoro-n-[4-[[3-(1-methylpyrazol-3-yl)-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]amino]phenyl]-2-(trifluoromethyl)benzamide Chemical compound CN1C=CC(N2C(NC3=NC=CC(NC=4C=CC(NC(=O)C=5C(=CC(F)=CC=5)C(F)(F)F)=CC=4)=C3C2)=O)=N1 LDMZAJAFEJXKRF-UHFFFAOYSA-N 0.000 claims 1
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
• XCMVCFHQUUNMEG-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=CC=C1 XCMVCFHQUUNMEG-UHFFFAOYSA-N 0.000 claims 1
• AVKARBOPQCYVOP-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-methoxybenzamide Chemical compound COC1=CC=CC(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=C1 AVKARBOPQCYVOP-UHFFFAOYSA-N 0.000 claims 1
• JUWMAKCBIVNAFD-UHFFFAOYSA-N n-[3-fluoro-4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)oxy]phenyl]-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2C=C(F)C(OC=3C=4CNC(=O)NC=4N=CC=3)=CC=2)=C1 JUWMAKCBIVNAFD-UHFFFAOYSA-N 0.000 claims 1
• AXSBWPJEDXDHBM-UHFFFAOYSA-N n-[3-fluoro-4-[(6-oxo-3,4,7,11b-tetrahydro-2h-pyrido[1,2]pyrimido[3,6-b][1,3]oxazin-11-yl)oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4C5OCCCN5C(=O)NC=4N=CC=3)=CC=2)=CC=C1 AXSBWPJEDXDHBM-UHFFFAOYSA-N 0.000 claims 1
• BZNMSNRKROOLNQ-UHFFFAOYSA-N n-[3-fluoro-4-[[2-oxo-3-(2,2,2-trifluoroethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CC(F)=CC=C1N1C(=O)C(C(=O)NC=2C=C(F)C(OC=3C=4CN(CC(F)(F)F)C(=O)NC=4N=CC=3)=CC=2)=CC=C1 BZNMSNRKROOLNQ-UHFFFAOYSA-N 0.000 claims 1
• CSZLHAZTZZCCEL-UHFFFAOYSA-N n-[4-[(2-oxo-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C=1C=C(NC=2C=3CNC(=O)NC=3N=CC=2)C=CC=1NC(=O)C1=CC=CC=C1 CSZLHAZTZZCCEL-UHFFFAOYSA-N 0.000 claims 1
• XTXULARVLBAOQE-UHFFFAOYSA-N n-[4-[(3-ethyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(CC)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 XTXULARVLBAOQE-UHFFFAOYSA-N 0.000 claims 1
• OPZMCVRYMSWKMH-UHFFFAOYSA-N n-[4-[(3-ethyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)oxy]-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound C1=CN=C2NC(=O)N(CC)CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=CC=CN1C1=CC=C(F)C=C1 OPZMCVRYMSWKMH-UHFFFAOYSA-N 0.000 claims 1
• LJKYTSCKMNOCHV-UHFFFAOYSA-N n-[4-[(3-methyl-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl)amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(C)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 LJKYTSCKMNOCHV-UHFFFAOYSA-N 0.000 claims 1
• JHNPANQOHNYANI-UHFFFAOYSA-N n-[4-[[2-oxo-3-(2,2,2-trifluoroethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-5-yl]amino]phenyl]benzamide Chemical compound C1=CN=C2NC(=O)N(CC(F)(F)F)CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 JHNPANQOHNYANI-UHFFFAOYSA-N 0.000 claims 1
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