SG184882A1 - Inhibitors of protein tyrosine kinase activity - Google Patents

Info

Publication number

SG184882A1

SG184882A1 SG2012076725A SG2012076725A SG184882A1 SG 184882 A1 SG184882 A1 SG 184882A1 SG 2012076725 A SG2012076725 A SG 2012076725A SG 2012076725 A SG2012076725 A SG 2012076725A SG 184882 A1 SG184882 A1 SG 184882A1

Authority

SG

Singapore

Prior art keywords

heterocyclyl

cealkyl

csalkyl

cgalkyl

formula

Prior art date

2010-04-16

Links

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• 230000000694 effects Effects 0.000 title claims abstract description 52
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 title abstract description 38
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 title abstract description 38
• 239000003112 inhibitor Substances 0.000 title description 13
• 150000001875 compounds Chemical class 0.000 claims abstract description 740
• 239000000203 mixture Substances 0.000 claims abstract description 135
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 120
• 201000010099 disease Diseases 0.000 claims abstract description 89
• 238000000034 method Methods 0.000 claims abstract description 49
• 230000005764 inhibitory process Effects 0.000 claims abstract description 39
• 230000002062 proliferating effect Effects 0.000 claims abstract description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 453
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 242
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 180
• -1 -O-aryl Chemical group 0.000 claims description 156
• 125000003118 aryl group Chemical group 0.000 claims description 122
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 121
• 125000000217 alkyl group Chemical group 0.000 claims description 120
• 229910052739 hydrogen Inorganic materials 0.000 claims description 118
• 125000001072 heteroaryl group Chemical group 0.000 claims description 96
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 87
• 229910052799 carbon Inorganic materials 0.000 claims description 82
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
• 229920006395 saturated elastomer Polymers 0.000 claims description 69
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 68
• 125000001424 substituent group Chemical group 0.000 claims description 67
• 150000003839 salts Chemical class 0.000 claims description 64
• 229910052757 nitrogen Inorganic materials 0.000 claims description 63
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
• 229940002612 prodrug Drugs 0.000 claims description 50
• 239000000651 prodrug Substances 0.000 claims description 50
• 239000012453 solvate Substances 0.000 claims description 47
• 125000005843 halogen group Chemical group 0.000 claims description 45
• 229910052760 oxygen Inorganic materials 0.000 claims description 44
• 150000001204 N-oxides Chemical class 0.000 claims description 41
• 229910052717 sulfur Inorganic materials 0.000 claims description 41
• 108091000080 Phosphotransferase Proteins 0.000 claims description 39
• 150000004677 hydrates Chemical class 0.000 claims description 39
• 125000002883 imidazolyl group Chemical group 0.000 claims description 39
• 102000020233 phosphotransferase Human genes 0.000 claims description 39
• 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 38
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
• 230000002401 inhibitory effect Effects 0.000 claims description 25
• 125000003342 alkenyl group Chemical group 0.000 claims description 24
• 125000000304 alkynyl group Chemical group 0.000 claims description 23
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
• 230000033115 angiogenesis Effects 0.000 claims description 21
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
• 229910052731 fluorine Inorganic materials 0.000 claims description 18
• 229910052792 caesium Inorganic materials 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 12
• 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 12
• VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 11
• 125000004414 alkyl thio group Chemical group 0.000 claims description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
• 125000002947 alkylene group Chemical group 0.000 claims description 10
• 150000001768 cations Chemical class 0.000 claims description 10
• 125000004122 cyclic group Chemical group 0.000 claims description 10
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000003107 substituted aryl group Chemical group 0.000 claims description 6
• 125000004953 trihalomethyl group Chemical group 0.000 claims description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 150000004885 piperazines Chemical class 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
• JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 150000003053 piperidines Chemical class 0.000 claims description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• 150000002460 imidazoles Chemical group 0.000 claims 2
• 230000011664 signaling Effects 0.000 abstract description 32
• 208000035475 disorder Diseases 0.000 abstract description 30
• 102000005962 receptors Human genes 0.000 abstract description 22
• 108020003175 receptors Proteins 0.000 abstract description 22
• 108091008605 VEGF receptors Proteins 0.000 abstract description 17
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 abstract description 17
• 102000009465 Growth Factor Receptors Human genes 0.000 abstract description 11
• 108010009202 Growth Factor Receptors Proteins 0.000 abstract description 11
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 351
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 202
• 239000011541 reaction mixture Substances 0.000 description 116
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 104
• 229910001868 water Inorganic materials 0.000 description 103
• 239000007787 solid Substances 0.000 description 95
• 239000000243 solution Substances 0.000 description 95
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
• 238000005481 NMR spectroscopy Methods 0.000 description 93
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 84
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 54
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 46
• 125000004043 oxo group Chemical group O=* 0.000 description 44
• 239000007864 aqueous solution Substances 0.000 description 40
• 239000000725 suspension Substances 0.000 description 39
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
• 210000004027 cell Anatomy 0.000 description 34
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
• 235000019439 ethyl acetate Nutrition 0.000 description 31
• 238000010992 reflux Methods 0.000 description 30
• 239000004202 carbamide Substances 0.000 description 27
• 238000000746 purification Methods 0.000 description 27
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 26
• 239000011734 sodium Substances 0.000 description 26
• 125000002837 carbocyclic group Chemical group 0.000 description 25
• 238000001914 filtration Methods 0.000 description 25
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• 241001465754 Metazoa Species 0.000 description 24
• 239000012074 organic phase Substances 0.000 description 24
• 238000012512 characterization method Methods 0.000 description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• 210000004204 blood vessel Anatomy 0.000 description 22
• 241000124008 Mammalia Species 0.000 description 21
• 235000019270 ammonium chloride Nutrition 0.000 description 21
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 20
• 206010028980 Neoplasm Diseases 0.000 description 20
• 125000004432 carbon atom Chemical group C* 0.000 description 20
• 125000000392 cycloalkenyl group Chemical group 0.000 description 20
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
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• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
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• 239000012044 organic layer Substances 0.000 description 18
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• 239000012267 brine Substances 0.000 description 16
• 239000012043 crude product Substances 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
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• 150000003217 pyrazoles Chemical group 0.000 description 15
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• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 12
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• 229910000104 sodium hydride Inorganic materials 0.000 description 10
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