KR20090018212A - 치환된 아미노피라졸로피리딘 및 그의 염, 이의 제조 방법 및 이를 포함하는 제약 조성물 - Google Patents
치환된 아미노피라졸로피리딘 및 그의 염, 이의 제조 방법 및 이를 포함하는 제약 조성물 Download PDFInfo
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- KR20090018212A KR20090018212A KR1020097000562A KR20097000562A KR20090018212A KR 20090018212 A KR20090018212 A KR 20090018212A KR 1020097000562 A KR1020097000562 A KR 1020097000562A KR 20097000562 A KR20097000562 A KR 20097000562A KR 20090018212 A KR20090018212 A KR 20090018212A
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- KR
- South Korea
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- alkyl
- phenyl
- heterocycloalkyl
- methyl
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 112
- MJEPPEQNLZSPAP-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridin-3-amine Chemical class C1=CN=C2C(N)=NNC2=C1 MJEPPEQNLZSPAP-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 238000000034 method Methods 0.000 claims abstract description 85
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 71
- 201000010099 disease Diseases 0.000 claims abstract description 59
- 238000011282 treatment Methods 0.000 claims abstract description 39
- 230000006444 vascular growth Effects 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 211
- 239000001257 hydrogen Substances 0.000 claims description 201
- -1 hydroxy, amino Chemical group 0.000 claims description 197
- 150000002431 hydrogen Chemical class 0.000 claims description 146
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 117
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 103
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 99
- 229910052736 halogen Inorganic materials 0.000 claims description 89
- 150000002367 halogens Chemical class 0.000 claims description 89
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 88
- 229910052799 carbon Inorganic materials 0.000 claims description 81
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 80
- 239000004202 carbamide Substances 0.000 claims description 70
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 54
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
- 206010028980 Neoplasm Diseases 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- 230000033115 angiogenesis Effects 0.000 claims description 26
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 24
- 239000000460 chlorine Chemical group 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 206010030113 Oedema Diseases 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 230000008482 dysregulation Effects 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 230000002491 angiogenic effect Effects 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 230000001419 dependent effect Effects 0.000 claims description 10
- 125000005549 heteroarylene group Chemical group 0.000 claims description 10
- 208000027866 inflammatory disease Diseases 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
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- 230000036573 scar formation Effects 0.000 claims description 10
- 206010027476 Metastases Diseases 0.000 claims description 9
- 201000004681 Psoriasis Diseases 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 150000002429 hydrazines Chemical class 0.000 claims description 9
- 239000012948 isocyanate Substances 0.000 claims description 9
- 150000002513 isocyanates Chemical class 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 125000000732 arylene group Chemical group 0.000 claims description 8
- 206010012442 Dermatitis contact Diseases 0.000 claims description 7
- 206010021143 Hypoxia Diseases 0.000 claims description 7
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- 208000010247 contact dermatitis Diseases 0.000 claims description 7
- 208000014674 injury Diseases 0.000 claims description 7
- 208000002780 macular degeneration Diseases 0.000 claims description 7
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- 208000037803 restenosis Diseases 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 230000008733 trauma Effects 0.000 claims description 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 6
- 208000006313 Delayed Hypersensitivity Diseases 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims description 6
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 6
- 208000017442 Retinal disease Diseases 0.000 claims description 6
- 206010038923 Retinopathy Diseases 0.000 claims description 6
- 208000029078 coronary artery disease Diseases 0.000 claims description 6
- 230000007954 hypoxia Effects 0.000 claims description 6
- 230000002062 proliferating effect Effects 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
- 206010003445 Ascites Diseases 0.000 claims description 5
- 206010061692 Benign muscle neoplasm Diseases 0.000 claims description 5
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010048962 Brain oedema Diseases 0.000 claims description 5
- 206010011017 Corneal graft rejection Diseases 0.000 claims description 5
- 201000009273 Endometriosis Diseases 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 5
- 208000001344 Macular Edema Diseases 0.000 claims description 5
- 206010025415 Macular oedema Diseases 0.000 claims description 5
- 201000004458 Myoma Diseases 0.000 claims description 5
- 206010055870 Postmenopausal haemorrhage Diseases 0.000 claims description 5
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 5
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 5
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 5
- 208000006752 brain edema Diseases 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 201000010230 macular retinal edema Diseases 0.000 claims description 5
- 210000005036 nerve Anatomy 0.000 claims description 5
- 201000011461 pre-eclampsia Diseases 0.000 claims description 5
- 208000005333 pulmonary edema Diseases 0.000 claims description 5
- 230000008929 regeneration Effects 0.000 claims description 5
- 238000011069 regeneration method Methods 0.000 claims description 5
- 208000023516 stroke disease Diseases 0.000 claims description 5
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 4
- 208000006386 Bone Resorption Diseases 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 230000024279 bone resorption Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 208000028774 intestinal disease Diseases 0.000 claims description 4
- 230000029663 wound healing Effects 0.000 claims description 4
- QBEWEBNLZYGINF-UHFFFAOYSA-N 1-[4-(1-methyl-6-propan-2-ylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C(C)C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1 QBEWEBNLZYGINF-UHFFFAOYSA-N 0.000 claims description 3
- XFNWQFGHTRDOQD-UHFFFAOYSA-N 1-[4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C1=CN=C2N(C)N=CC2=C1C(C=C1)=CC=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1 XFNWQFGHTRDOQD-UHFFFAOYSA-N 0.000 claims description 3
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 claims description 3
- 208000037824 growth disorder Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- AEIWZOSNKPYSJF-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]urea Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC(=O)NC1=CC=C(C=2C=3C=NN(C)C=3N=C(C)C=2)C=C1 AEIWZOSNKPYSJF-UHFFFAOYSA-N 0.000 claims description 2
- MWEMKZUFOBTGSZ-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1 MWEMKZUFOBTGSZ-UHFFFAOYSA-N 0.000 claims description 2
- BYBSGHVXSJFZCS-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-phenylurea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC=C1 BYBSGHVXSJFZCS-UHFFFAOYSA-N 0.000 claims description 2
- QHWBHEYMIKAPRK-UHFFFAOYSA-N 1-[4-(6-propan-2-yl-1h-pyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NNC2=NC(C(C)C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1 QHWBHEYMIKAPRK-UHFFFAOYSA-N 0.000 claims description 2
- XGTVOKJZLRYVCR-UHFFFAOYSA-N 1-[4-(6-tert-butyl-1h-pyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-(3-ethylphenyl)urea Chemical compound CCC1=CC=CC(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NNC=3N=C(C=2)C(C)(C)C)=C1 XGTVOKJZLRYVCR-UHFFFAOYSA-N 0.000 claims description 2
- PCLDEOPUBVOTMW-UHFFFAOYSA-N 1-[4-[1-methyl-6-(morpholin-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]-3-(3-methylphenyl)urea Chemical compound CC1=CC=CC(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CCOCC3)C=2)=C1 PCLDEOPUBVOTMW-UHFFFAOYSA-N 0.000 claims description 2
- WLWUADABAAOKCE-UHFFFAOYSA-N 1-[4-[1-methyl-6-(morpholin-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]-3-phenylurea Chemical compound N1=C2N(C)N=CC2=C(C=2C=CC(NC(=O)NC=3C=CC=CC=3)=CC=2)C=C1CN1CCOCC1 WLWUADABAAOKCE-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- HXIOTKBQHXRMOX-UHFFFAOYSA-N ethyl 1-[4-[4-(phenylcarbamoylamino)phenyl]-1h-pyrazolo[3,4-b]pyridin-6-yl]cyclopropane-1-carboxylate Chemical compound C=1C(C=2C=CC(NC(=O)NC=3C=CC=CC=3)=CC=2)=C2C=NNC2=NC=1C1(C(=O)OCC)CC1 HXIOTKBQHXRMOX-UHFFFAOYSA-N 0.000 claims description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims 4
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 claims 2
- 238000006193 diazotization reaction Methods 0.000 claims 2
- MUXXBBUGTINDOI-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=CC=2)=C1 MUXXBBUGTINDOI-UHFFFAOYSA-N 0.000 claims 1
- AJVQQDDBJULLHT-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-(1h-pyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NNC=3N=CC=2)=C1 AJVQQDDBJULLHT-UHFFFAOYSA-N 0.000 claims 1
- KKSQNQFHTYAYMO-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-(methylsulfonylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CS(C)(=O)=O)C=2)=C1 KKSQNQFHTYAYMO-UHFFFAOYSA-N 0.000 claims 1
- BUUYBOOVFSIJCN-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-(morpholin-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CCOCC3)C=2)=C1 BUUYBOOVFSIJCN-UHFFFAOYSA-N 0.000 claims 1
- YBYWJWSXJXWZGJ-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-(piperidin-1-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CCCCC3)C=2)=C1 YBYWJWSXJXWZGJ-UHFFFAOYSA-N 0.000 claims 1
- GGPSYMHKBXFSEN-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-[(3-oxopiperazin-1-yl)methyl]pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CC(=O)NCC3)C=2)=C1 GGPSYMHKBXFSEN-UHFFFAOYSA-N 0.000 claims 1
- NHXXPINLNYZVMB-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-[(4-methylpiperazin-1-yl)methyl]pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound C1CN(C)CCN1CC1=CC(C=2C=CC(NC(=O)NC=3C(=CC=C(C)C=3)F)=CC=2)=C(C=NN2C)C2=N1 NHXXPINLNYZVMB-UHFFFAOYSA-N 0.000 claims 1
- BAVHPORQMZFSDD-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[1-methyl-6-[1-(pyrrolidine-1-carbonyl)cyclopropyl]pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(C=2)C2(CC2)C(=O)N2CCCC2)=C1 BAVHPORQMZFSDD-UHFFFAOYSA-N 0.000 claims 1
- AVGZPQAQXMDFTB-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[6-(methoxymethyl)-1-methylpyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound C=12C=NN(C)C2=NC(COC)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC(C)=CC=C1F AVGZPQAQXMDFTB-UHFFFAOYSA-N 0.000 claims 1
- IPUYRXHKXNKBPD-UHFFFAOYSA-N 1-(2-fluoro-5-methylphenyl)-3-[4-[6-[(4-hydroxypiperidin-1-yl)methyl]-1-methylpyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CCC(O)CC3)C=2)=C1 IPUYRXHKXNKBPD-UHFFFAOYSA-N 0.000 claims 1
- XTXFBKQCSKAZLS-UHFFFAOYSA-N 1-(3-ethylphenyl)-3-[4-[1-methyl-6-(morpholin-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound CCC1=CC=CC(NC(=O)NC=2C=CC(=CC=2)C=2C=3C=NN(C)C=3N=C(CN3CCOCC3)C=2)=C1 XTXFBKQCSKAZLS-UHFFFAOYSA-N 0.000 claims 1
- NIAAGVAFAREREG-UHFFFAOYSA-N 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound C1=CN=C2N(C)N=CC2=C1C(C=C1)=CC=C1NC(=O)NC1=CC(C(F)(F)F)=CC=C1F NIAAGVAFAREREG-UHFFFAOYSA-N 0.000 claims 1
- VABXSELRSOOYNM-UHFFFAOYSA-N 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(1h-pyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound FC1=CC=C(C(F)(F)F)C=C1NC(=O)NC1=CC=C(C=2C=3C=NNC=3N=CC=2)C=C1 VABXSELRSOOYNM-UHFFFAOYSA-N 0.000 claims 1
- USRPRZRMZCCBLZ-UHFFFAOYSA-N 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-[1-methyl-6-(morpholin-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-yl]phenyl]urea Chemical compound N1=C2N(C)N=CC2=C(C=2C=CC(NC(=O)NC=3C(=CC=C(C=3)C(F)(F)F)F)=CC=2)C=C1CN1CCOCC1 USRPRZRMZCCBLZ-UHFFFAOYSA-N 0.000 claims 1
- XTKQSZLRPSAAHE-UHFFFAOYSA-N 1-[3-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-[4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound C1CN(C)CCN1CC(C(=C1)C)=CC=C1NC(=O)NC1=CC=C(C=2C=3C=NN(C)C=3N=CC=2)C=C1 XTKQSZLRPSAAHE-UHFFFAOYSA-N 0.000 claims 1
- YNTJLHUPRRHFKN-UHFFFAOYSA-N 1-[3-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-[4-(1h-pyrazolo[3,4-b]pyridin-4-yl)phenyl]urea Chemical compound C1CN(C)CCN1CC(C(=C1)C)=CC=C1NC(=O)NC1=CC=C(C=2C=3C=NNC=3N=CC=2)C=C1 YNTJLHUPRRHFKN-UHFFFAOYSA-N 0.000 claims 1
- SROYUQLUYMEPGP-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[2-fluoro-3-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=CC(C(F)(F)F)=C1F SROYUQLUYMEPGP-UHFFFAOYSA-N 0.000 claims 1
- SDAXQKNDRGNTHA-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC(C(F)(F)F)=CC=C1F SDAXQKNDRGNTHA-UHFFFAOYSA-N 0.000 claims 1
- KZRRCZBJCRGRBT-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[3-fluoro-5-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC(F)=CC(C(F)(F)F)=C1 KZRRCZBJCRGRBT-UHFFFAOYSA-N 0.000 claims 1
- JUNBZVWIJGYHTJ-UHFFFAOYSA-N 1-[4-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)phenyl]-3-[4-fluoro-3-(trifluoromethyl)phenyl]urea Chemical compound C=12C=NN(C)C2=NC(C)=CC=1C(C=C1)=CC=C1NC(=O)NC1=CC=C(F)C(C(F)(F)F)=C1 JUNBZVWIJGYHTJ-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Immunology (AREA)
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- Pulmonology (AREA)
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06090109A EP1867648A1 (en) | 2006-06-13 | 2006-06-13 | Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them. |
| EP06090109.7 | 2006-06-13 | ||
| EP07090020 | 2007-02-15 | ||
| EP07090020.4 | 2007-02-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20090018212A true KR20090018212A (ko) | 2009-02-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1020097000562A Withdrawn KR20090018212A (ko) | 2006-06-13 | 2007-06-12 | 치환된 아미노피라졸로피리딘 및 그의 염, 이의 제조 방법 및 이를 포함하는 제약 조성물 |
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| EP (1) | EP2061790B1 (enExample) |
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| BR (1) | BRPI0711961A2 (enExample) |
| CA (1) | CA2654789C (enExample) |
| CL (1) | CL2007001711A1 (enExample) |
| CR (1) | CR10505A (enExample) |
| EA (1) | EA200802407A1 (enExample) |
| EC (1) | ECSP088963A (enExample) |
| ES (1) | ES2515117T3 (enExample) |
| GT (1) | GT200800285A (enExample) |
| IL (1) | IL195813A0 (enExample) |
| MX (1) | MX2008015955A (enExample) |
| NO (1) | NO20090171L (enExample) |
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| PE20061119A1 (es) * | 2005-01-19 | 2006-11-27 | Aventis Pharma Sa | PIRAZOLO PIRIDINAS SUSTITUIDAS COMO INHIBIDORES DE CINASAS FAK, KDR Y Tie |
| WO2009073300A1 (en) | 2007-11-02 | 2009-06-11 | Vertex Pharmaceuticals Incorporated | [1h- pyrazolo [3, 4-b] pyridine-4-yl] -phenyle or -pyridin-2-yle derivatives as protein kinase c-theta |
| JP2011520809A (ja) * | 2008-05-05 | 2011-07-21 | アムジエン・インコーポレーテツド | γセクレターゼモジュレーターとしての尿素化合物 |
| CA2729012A1 (en) | 2008-06-27 | 2009-12-30 | Amgen Inc. | Ang-2 inhibition to treat multiple sclerosis |
| ES2392488T3 (es) | 2008-11-20 | 2012-12-11 | Genentech, Inc. | Compuestos inhibidores de PI3K de tipo pirazolopiridina y sus procedimientos de uso |
| EP2789615B1 (en) | 2009-08-11 | 2017-05-03 | Bristol-Myers Squibb Company | Azaindazoles as Btk kinase modulators and use thereof |
| US8742106B2 (en) | 2009-12-21 | 2014-06-03 | Novartis Ag | Disubstituted heteroaryl-fused pyridines |
| US9663511B2 (en) | 2012-03-26 | 2017-05-30 | Arroyo BioSciences, LLC | Sphingosine 1-phosphate receptor antagonists |
| US20150164910A1 (en) * | 2012-06-15 | 2015-06-18 | The Regents Of The University Of Califonia | Antiviral compounds and methods of use |
| US11059817B2 (en) | 2015-09-23 | 2021-07-13 | The Regents Of The University Of California | Potent antiviral pyrazolopyridine compounds |
| JOP20190024A1 (ar) | 2016-08-26 | 2019-02-19 | Gilead Sciences Inc | مركبات بيروليزين بها استبدال واستخداماتها |
| US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
| CA3091142C (en) | 2018-02-26 | 2023-04-11 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds and uses thereof |
| ES2988920T3 (es) | 2018-05-17 | 2024-11-22 | Forma Therapeutics Inc | Compuestos bicíclicos fusionados útiles como inhibidores de la peptidasa 30 específica de ubiquitina |
| MX2021002981A (es) | 2018-10-05 | 2021-05-14 | Forma Therapeutics Inc | Pirrolinas fusionadas que actuan como inhibidores de la proteasa 30 especifica de la ubiquitina (usp30). |
| TW202136238A (zh) * | 2020-01-06 | 2021-10-01 | 大陸商廣東東陽光藥業有限公司 | RORγt抑制劑及其製備方法和用途 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6670364B2 (en) * | 2001-01-31 | 2003-12-30 | Telik, Inc. | Antagonists of MCP-1 function and methods of use thereof |
| EP1638941B1 (en) | 2003-05-22 | 2010-06-02 | Abbott Laboratories | Indazole, benzisoxazole, and benzisothiazole kinase inhibitors |
| US20070293511A1 (en) * | 2003-12-22 | 2007-12-20 | Sb Pharmco Puerto Rico Inc. And Neurocrine Biosciences, Inc., A Corporation | Crf Receptor Antagonists and Methods |
| FR2876691B1 (fr) * | 2004-10-18 | 2006-12-29 | Sanofi Aventis Sa | Derives de pyridine, leur preparation, leur application en therapeutique |
| US7812166B2 (en) * | 2004-10-29 | 2010-10-12 | Abbott Laboratories | Kinase inhibitors |
| PE20061119A1 (es) * | 2005-01-19 | 2006-11-27 | Aventis Pharma Sa | PIRAZOLO PIRIDINAS SUSTITUIDAS COMO INHIBIDORES DE CINASAS FAK, KDR Y Tie |
| EP1683796A1 (en) * | 2005-01-24 | 2006-07-26 | Schering Aktiengesellschaft | Pyrazolopyridines, their preparation and their medical use |
| EP1899333B1 (en) * | 2005-06-27 | 2009-02-18 | Sanofi-Aventis | Pyrazolopyridine derivatives as inhibitors of beta-adrenergic receptor kinase 1 |
-
2007
- 2007-06-11 TW TW096121006A patent/TW200815438A/zh unknown
- 2007-06-12 JP JP2009514716A patent/JP5475442B2/ja not_active Expired - Fee Related
- 2007-06-12 EA EA200802407A patent/EA200802407A1/ru unknown
- 2007-06-12 CL CL2007001711A patent/CL2007001711A1/es unknown
- 2007-06-12 US US11/761,672 patent/US7846928B2/en not_active Expired - Fee Related
- 2007-06-12 UY UY30409A patent/UY30409A1/es not_active Application Discontinuation
- 2007-06-12 ES ES07764753.5T patent/ES2515117T3/es active Active
- 2007-06-12 WO PCT/EP2007/005432 patent/WO2007144204A1/en not_active Ceased
- 2007-06-12 BR BRPI0711961-5A patent/BRPI0711961A2/pt not_active IP Right Cessation
- 2007-06-12 AR ARP070102552A patent/AR061346A1/es unknown
- 2007-06-12 EP EP07764753.5A patent/EP2061790B1/en active Active
- 2007-06-12 PE PE2007000741A patent/PE20080205A1/es not_active Application Discontinuation
- 2007-06-12 KR KR1020097000562A patent/KR20090018212A/ko not_active Withdrawn
- 2007-06-12 CA CA2654789A patent/CA2654789C/en not_active Expired - Fee Related
- 2007-06-12 AU AU2007260216A patent/AU2007260216A1/en not_active Abandoned
- 2007-06-12 MX MX2008015955A patent/MX2008015955A/es not_active Application Discontinuation
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2008
- 2008-12-09 IL IL195813A patent/IL195813A0/en unknown
- 2008-12-12 CR CR10505A patent/CR10505A/es not_active Application Discontinuation
- 2008-12-12 EC EC2008008963A patent/ECSP088963A/es unknown
- 2008-12-12 GT GT200800285A patent/GT200800285A/es unknown
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2009
- 2009-01-12 NO NO20090171A patent/NO20090171L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CL2007001711A1 (es) | 2008-01-04 |
| US20080058326A1 (en) | 2008-03-06 |
| EA200802407A1 (ru) | 2009-06-30 |
| BRPI0711961A2 (pt) | 2012-01-17 |
| MX2008015955A (es) | 2009-01-09 |
| GT200800285A (es) | 2009-03-09 |
| US7846928B2 (en) | 2010-12-07 |
| CA2654789A1 (en) | 2007-12-21 |
| ECSP088963A (es) | 2009-01-30 |
| JP5475442B2 (ja) | 2014-04-16 |
| NO20090171L (no) | 2009-03-12 |
| EP2061790B1 (en) | 2014-08-13 |
| PE20080205A1 (es) | 2008-06-01 |
| UY30409A1 (es) | 2008-01-31 |
| JP2009539914A (ja) | 2009-11-19 |
| EP2061790A1 (en) | 2009-05-27 |
| CA2654789C (en) | 2014-08-05 |
| TW200815438A (en) | 2008-04-01 |
| WO2007144204A1 (en) | 2007-12-21 |
| AU2007260216A1 (en) | 2007-12-21 |
| ES2515117T3 (es) | 2014-10-29 |
| AR061346A1 (es) | 2008-08-20 |
| IL195813A0 (en) | 2009-09-22 |
| CR10505A (es) | 2009-03-20 |
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