JP5976778B2 - キナーゼ阻害剤としてのピラゾリル−ピリミジン誘導体 - Google Patents
キナーゼ阻害剤としてのピラゾリル−ピリミジン誘導体 Download PDFInfo
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- JP5976778B2 JP5976778B2 JP2014504251A JP2014504251A JP5976778B2 JP 5976778 B2 JP5976778 B2 JP 5976778B2 JP 2014504251 A JP2014504251 A JP 2014504251A JP 2014504251 A JP2014504251 A JP 2014504251A JP 5976778 B2 JP5976778 B2 JP 5976778B2
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- Prior art keywords
- pyrazole
- carboxamide
- formula
- compound
- pyrimidin
- Prior art date
- 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.)
- Expired - Fee Related
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- BWIHJLOBZMKPKS-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)pyrimidine Chemical class N1C=CC(C=2N=CC=CN=2)=N1 BWIHJLOBZMKPKS-UHFFFAOYSA-N 0.000 title description 4
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 357
- 238000000034 method Methods 0.000 claims description 132
- -1 methylenedioxy Chemical group 0.000 claims description 123
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 54
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 43
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 102000001253 Protein Kinase Human genes 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 108060006633 protein kinase Proteins 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 125000001769 aryl amino group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- RFJQYCNMCJJJSG-UHFFFAOYSA-N 1-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound CSC1=NC=CC(C=2N(N=C(C=2)C(N)=O)C(C)(C)C)=N1 RFJQYCNMCJJJSG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 5
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 5
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- SAZWNKNJUWDIKE-UHFFFAOYSA-N 3-(2-methylsulfanylpyrimidin-4-yl)-1h-pyrazole-5-carboxamide Chemical compound CSC1=NC=CC(C=2NN=C(C=2)C(N)=O)=N1 SAZWNKNJUWDIKE-UHFFFAOYSA-N 0.000 claims description 4
- WBRIZQWMKIXWSK-UHFFFAOYSA-N 5-[2-(4-bromo-2-methoxyanilino)pyrimidin-4-yl]-n-(2,6-diethylphenyl)-1-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C=2N=C(NC=3C(=CC(Br)=CC=3)OC)N=CC=2)=C1 WBRIZQWMKIXWSK-UHFFFAOYSA-N 0.000 claims description 4
- SIYHLKJVZNBAAO-UHFFFAOYSA-N 5-[2-(4-bromo-2-methoxyanilino)pyrimidin-4-yl]-n-(2,6-diethylphenyl)-2-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CC(C=2N=C(NC=3C(=CC(Br)=CC=3)OC)N=CC=2)=NN1C SIYHLKJVZNBAAO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 4
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 4
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YFPXKALYLATDPX-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]-2-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CC(C=2N=C(NC=3C(=CC(=CC=3)N3CCN(C)CC3)OC)N=CC=2)=NN1C YFPXKALYLATDPX-UHFFFAOYSA-N 0.000 claims description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- YIGPUXRGBBZKJW-UHFFFAOYSA-N 1-tert-butyl-5-(2-methoxypyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound COC1=NC=CC(C=2N(N=C(C=2)C(N)=O)C(C)(C)C)=N1 YIGPUXRGBBZKJW-UHFFFAOYSA-N 0.000 claims description 3
- NPAPHHQDTZZLSK-UHFFFAOYSA-N 1-tert-butyl-5-(2-morpholin-4-ylpyrimidin-4-yl)-n-phenylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC=2C=CC=CC=2)C=C1C(N=1)=CC=NC=1N1CCOCC1 NPAPHHQDTZZLSK-UHFFFAOYSA-N 0.000 claims description 3
- LLSIYQYYVAAHEN-UHFFFAOYSA-N 1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)-n-phenylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC=2C=CC=CC=2)C=C1C(N=1)=CC=NC=1OC1=CC=CC=C1 LLSIYQYYVAAHEN-UHFFFAOYSA-N 0.000 claims description 3
- VZYACGCYABUZMD-UHFFFAOYSA-N 1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)-n-propan-2-ylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC(C)C)C=C1C1=CC=NC(OC=2C=CC=CC=2)=N1 VZYACGCYABUZMD-UHFFFAOYSA-N 0.000 claims description 3
- NXUZHSNCDIAGAY-UHFFFAOYSA-N 1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-n-methylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC)C=C1C1=CC=NC(OC=2C=CC(=CC=2)C#N)=N1 NXUZHSNCDIAGAY-UHFFFAOYSA-N 0.000 claims description 3
- DMLNFHDCCVVACO-UHFFFAOYSA-N 1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-n-phenylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC=2C=CC=CC=2)C=C1C(N=1)=CC=NC=1OC1=CC=C(C#N)C=C1 DMLNFHDCCVVACO-UHFFFAOYSA-N 0.000 claims description 3
- GLOLZXJNFUHZRR-UHFFFAOYSA-N 1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]-n-propan-2-ylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC(C)C)C=C1C1=CC=NC(OC=2C=CC(=CC=2)C#N)=N1 GLOLZXJNFUHZRR-UHFFFAOYSA-N 0.000 claims description 3
- AXRBYRBXIFSKIF-UHFFFAOYSA-N 1-tert-butyl-5-[2-(4-piperazin-1-ylphenoxy)pyrimidin-4-yl]pyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(N)=O)C=C1C1=CC=NC(OC=2C=CC(=CC=2)N2CCNCC2)=N1 AXRBYRBXIFSKIF-UHFFFAOYSA-N 0.000 claims description 3
- JPXVJHYKCAPQRA-UHFFFAOYSA-N 1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-n-methylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC)C=C1C1=CC=NC(N(C)C)=N1 JPXVJHYKCAPQRA-UHFFFAOYSA-N 0.000 claims description 3
- JGLZQEWJZMTROM-UHFFFAOYSA-N 1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-n-phenylpyrazole-3-carboxamide Chemical compound CN(C)C1=NC=CC(C=2N(N=C(C=2)C(=O)NC=2C=CC=CC=2)C(C)(C)C)=N1 JGLZQEWJZMTROM-UHFFFAOYSA-N 0.000 claims description 3
- KHJXLLUKAIABND-UHFFFAOYSA-N 1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]-n-propan-2-ylpyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC(C)C)C=C1C1=CC=NC(N(C)C)=N1 KHJXLLUKAIABND-UHFFFAOYSA-N 0.000 claims description 3
- STVXWMPMCBWAQK-UHFFFAOYSA-N 1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]pyrazole-3-carboxamide Chemical compound CN(C)C1=NC=CC(C=2N(N=C(C=2)C(N)=O)C(C)(C)C)=N1 STVXWMPMCBWAQK-UHFFFAOYSA-N 0.000 claims description 3
- NWLNDDCQBDCBGL-UHFFFAOYSA-N 2-[(3-methoxyphenyl)methyl]-5-(2-methylpyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound COC1=CC=CC(CN2C(=CC(=N2)C=2N=C(C)N=CC=2)C(N)=O)=C1 NWLNDDCQBDCBGL-UHFFFAOYSA-N 0.000 claims description 3
- GNDPCMBWJSMFDH-UHFFFAOYSA-N 2-[(3-methoxyphenyl)methyl]-5-(2-oxo-1h-pyrimidin-6-yl)pyrazole-3-carboxamide Chemical compound COC1=CC=CC(CN2C(=CC(=N2)C=2N=C(O)N=CC=2)C(N)=O)=C1 GNDPCMBWJSMFDH-UHFFFAOYSA-N 0.000 claims description 3
- LXAHIOJOUKGSMV-UHFFFAOYSA-N 5-[2-(4-bromo-2-methoxyanilino)pyrimidin-4-yl]-n-(2,6-diethylphenyl)-1-[(4-methoxyphenyl)methyl]pyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(CC=2C=CC(OC)=CC=2)C(C=2N=C(NC=3C(=CC(Br)=CC=3)OC)N=CC=2)=C1 LXAHIOJOUKGSMV-UHFFFAOYSA-N 0.000 claims description 3
- SXSDYPDWRFRBOK-UHFFFAOYSA-N 5-[2-(4-bromo-2-methoxyanilino)pyrimidin-4-yl]-n-(2,6-diethylphenyl)-2-[(4-methoxyphenyl)methyl]pyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CC(C=2N=C(NC=3C(=CC(Br)=CC=3)OC)N=CC=2)=NN1CC1=CC=C(OC)C=C1 SXSDYPDWRFRBOK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- JPKZTKMCHHNHCK-UHFFFAOYSA-N N-hydroxy-3-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide Chemical compound CSC1=NC=CC(C=2NN=C(C=2)C(=O)NO)=N1 JPKZTKMCHHNHCK-UHFFFAOYSA-N 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000004986 diarylamino group Chemical group 0.000 claims description 3
- ANWOMOBMTBNCGP-UHFFFAOYSA-N n-(2,6-diethylphenyl)-3-[2-(2-methoxyanilino)pyrimidin-4-yl]-1h-pyrazole-5-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NNC(C=2N=C(NC=3C(=CC=CC=3)OC)N=CC=2)=C1 ANWOMOBMTBNCGP-UHFFFAOYSA-N 0.000 claims description 3
- GXEHCAYTZFZPQF-UHFFFAOYSA-N n-(2,6-diethylphenyl)-3-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1h-pyrazole-5-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NNC(C=2N=C(NC=3C(=CC(=CC=3)N3CCN(C)CC3)OC)N=CC=2)=C1 GXEHCAYTZFZPQF-UHFFFAOYSA-N 0.000 claims description 3
- UTWAVTYOSXACBH-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-(2-methoxyanilino)pyrimidin-4-yl]-1-[(4-methoxyphenyl)methyl]pyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(CC=2C=CC(OC)=CC=2)C(C=2N=C(NC=3C(=CC=CC=3)OC)N=CC=2)=C1 UTWAVTYOSXACBH-UHFFFAOYSA-N 0.000 claims description 3
- HVTSGLCSESUTKX-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-(2-methoxyanilino)pyrimidin-4-yl]-1-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C=2N=C(NC=3C(=CC=CC=3)OC)N=CC=2)=C1 HVTSGLCSESUTKX-UHFFFAOYSA-N 0.000 claims description 3
- AIXGHQIUKRVEAX-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-(2-methoxyanilino)pyrimidin-4-yl]-2-[(4-methoxyphenyl)methyl]pyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=CC(C=2N=C(NC=3C(=CC=CC=3)OC)N=CC=2)=NN1CC1=CC=C(OC)C=C1 AIXGHQIUKRVEAX-UHFFFAOYSA-N 0.000 claims description 3
- LPNFVFRZLDAJHS-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-[(4-methoxyphenyl)methyl]pyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(CC=2C=CC(OC)=CC=2)C(C=2N=C(NC=3C(=CC(=CC=3)N3CCN(C)CC3)OC)N=CC=2)=C1 LPNFVFRZLDAJHS-UHFFFAOYSA-N 0.000 claims description 3
- WZKSKKZREXLPGE-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C=2N=C(NC=3C(=CC(=CC=3)N3CCN(C)CC3)OC)N=CC=2)=C1 WZKSKKZREXLPGE-UHFFFAOYSA-N 0.000 claims description 3
- ZFRAYIYRRCRCJI-UHFFFAOYSA-N n-(2,6-diethylphenyl)-5-[2-[4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]-1-methylpyrazole-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C=2N=C(NC=3C(=CC(=CC=3)N3CCN(CCO)CC3)OC)N=CC=2)=C1 ZFRAYIYRRCRCJI-UHFFFAOYSA-N 0.000 claims description 3
- WYBUJUAJMUSILH-UHFFFAOYSA-N n-benzyl-1-tert-butyl-5-(2-phenoxypyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NCC=2C=CC=CC=2)C=C1C(N=1)=CC=NC=1OC1=CC=CC=C1 WYBUJUAJMUSILH-UHFFFAOYSA-N 0.000 claims description 3
- IUPQGRJRSIZORG-UHFFFAOYSA-N n-benzyl-1-tert-butyl-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]pyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NCC=2C=CC=CC=2)C=C1C(N=1)=CC=NC=1OC1=CC=C(C#N)C=C1 IUPQGRJRSIZORG-UHFFFAOYSA-N 0.000 claims description 3
- KXJJQDWQTVXFCT-UHFFFAOYSA-N n-benzyl-1-tert-butyl-5-[2-(dimethylamino)pyrimidin-4-yl]pyrazole-3-carboxamide Chemical compound CN(C)C1=NC=CC(C=2N(N=C(C=2)C(=O)NCC=2C=CC=CC=2)C(C)(C)C)=N1 KXJJQDWQTVXFCT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- YNJNLGYPTQPTPW-UHFFFAOYSA-N 1-(6-methoxypyridin-3-yl)-5-pyrimidin-4-ylpyrazole-3-carboxylic acid Chemical compound C1=NC(OC)=CC=C1N1C(C=2N=CN=CC=2)=CC(C(O)=O)=N1 YNJNLGYPTQPTPW-UHFFFAOYSA-N 0.000 claims description 2
- XWSQCSJHYIBIPB-UHFFFAOYSA-N 1-tert-butyl-5-(2-phenylpyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(N)=O)C=C1C1=CC=NC(C=2C=CC=CC=2)=N1 XWSQCSJHYIBIPB-UHFFFAOYSA-N 0.000 claims description 2
- PMVLFBLYAWKVTH-UHFFFAOYSA-N 1-tert-butyl-n-methyl-5-(2-phenoxypyrimidin-4-yl)pyrazole-3-carboxamide Chemical compound CC(C)(C)N1N=C(C(=O)NC)C=C1C1=CC=NC(OC=2C=CC=CC=2)=N1 PMVLFBLYAWKVTH-UHFFFAOYSA-N 0.000 claims description 2
- LPPNOCWWUZTIKG-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-ethylphenyl)pyrazole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C=C1N1C(C=2N=C(N)N=CC=2)=CC(C(N)=O)=N1 LPPNOCWWUZTIKG-UHFFFAOYSA-N 0.000 claims description 2
- HOURAQDXNPRUJS-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-1-(5-chloro-2-methylphenyl)pyrazole-3-carboxamide Chemical compound CC1=CC=C(Cl)C=C1N1C(C=2N=C(N)N=CC=2)=CC(C(N)=O)=N1 HOURAQDXNPRUJS-UHFFFAOYSA-N 0.000 claims description 2
- ZYDBWXADPWQAMI-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)pyrazole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C=C1N1C(C(N)=O)=CC(C=2N=C(N)N=CC=2)=N1 ZYDBWXADPWQAMI-UHFFFAOYSA-N 0.000 claims description 2
- MGCJYRVJINHYAP-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)pyrazole-3-carboxamide Chemical compound CC1=CC=C(Cl)C=C1N1C(C(N)=O)=CC(C=2N=C(N)N=CC=2)=N1 MGCJYRVJINHYAP-UHFFFAOYSA-N 0.000 claims description 2
- IFXSYLKWEVEJIA-UHFFFAOYSA-N 5-(2-methylsulfanylpyrimidin-4-yl)-1-piperidin-4-ylpyrazole-3-carboxamide Chemical compound CSC1=NC=CC(C=2N(N=C(C=2)C(N)=O)C2CCNCC2)=N1 IFXSYLKWEVEJIA-UHFFFAOYSA-N 0.000 claims description 2
- OHTRSASACJDQCI-UHFFFAOYSA-N 5-(2-methylsulfanylpyrimidin-4-yl)-2-piperidin-4-ylpyrazole-3-carboxamide Chemical compound CSC1=NC=CC(C2=NN(C(C(N)=O)=C2)C2CCNCC2)=N1 OHTRSASACJDQCI-UHFFFAOYSA-N 0.000 claims description 2
- YNEYAILCVWIGMT-UHFFFAOYSA-N [1-(6-methoxypyridin-3-yl)-5-pyrimidin-4-ylpyrazol-3-yl]-(4-methylpiperazin-1-yl)methanone Chemical compound C1=NC(OC)=CC=C1N1C(C=2N=CN=CC=2)=CC(C(=O)N2CCN(C)CC2)=N1 YNEYAILCVWIGMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000011319 anticancer therapy Methods 0.000 claims description 2
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| EP11161925.0 | 2011-04-11 | ||
| EP11161925 | 2011-04-11 | ||
| PCT/EP2012/056047 WO2012139930A1 (en) | 2011-04-11 | 2012-04-03 | Pyrazolyl-pyrimidine derivatives as kinase inhibitors |
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| JP (1) | JP5976778B2 (enExample) |
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| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| JO3215B1 (ar) | 2012-08-09 | 2018-03-08 | Phenex Pharmaceuticals Ag | حلقات غير متجانسة بها 5 ذرات تحتوي على النيتروجين بها استبدال بكربوكساميد أو سلفوناميد كمعدلات لمستقبل نووي غير محمي RORy |
| WO2014108337A1 (en) * | 2013-01-10 | 2014-07-17 | Grünenthal GmbH | Pyrazolyl-based carboxamides i as crac channel inhibitors |
| AU2014204977A1 (en) | 2013-01-10 | 2015-08-20 | Grunenthal Gmbh | Pyrazolyl-based carboxamides II as CRAC channel inhibitors |
| EP2943485B1 (en) | 2013-01-14 | 2017-09-20 | Incyte Holdings Corporation | Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors |
| HUE050215T2 (hu) | 2013-01-15 | 2020-11-30 | Incyte Holdings Corp | Pim kináz inhibitorokként hasznos tiazolkarboxamid és piridinkarboxamid vegyületek |
| SI3660013T1 (sl) * | 2013-03-15 | 2022-05-31 | Cyclerion Therapeutics, Inc. | SGC stimulatorji |
| WO2014147203A1 (en) * | 2013-03-21 | 2014-09-25 | Bayer Pharma Aktiengesellschaft | 3-heteroaryl substituted indazoles |
| HK1222852A1 (zh) * | 2013-06-21 | 2017-07-14 | Bayer Pharma Aktiengesellschaft | 二氨基杂芳基取代的吡唑 |
| JP2016522232A (ja) * | 2013-06-21 | 2016-07-28 | バイエル ファーマ アクチエンゲゼルシャフト | ヘテロアリール置換されたピラゾール類 |
| TW201605866A (zh) | 2013-08-23 | 2016-02-16 | 英塞特公司 | 可用作ｐｉｍ激酶抑制劑之呋喃并－及噻吩并－吡啶甲醯胺化合物 |
| LT3828173T (lt) | 2014-03-07 | 2022-11-10 | Biocryst Pharmaceuticals, Inc. | Pakeistieji pirazolai kaip žmogaus plazmos kalikreino inhibitoriai |
| WO2016010897A1 (en) | 2014-07-14 | 2016-01-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as pim kinase inhibitors |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| US11208696B2 (en) | 2015-04-17 | 2021-12-28 | Netherlands Translational Research Center B.V. | Prognostic biomarkers for TTK inhibitor chemotherapy |
| HK1248070A1 (zh) * | 2015-05-18 | 2018-10-12 | 转化药物开发有限责任公司 | 作为激酶抑制剂的杂环化合物 |
| US9540347B2 (en) | 2015-05-29 | 2017-01-10 | Incyte Corporation | Pyridineamine compounds useful as Pim kinase inhibitors |
| JP6816100B2 (ja) | 2015-07-16 | 2021-01-20 | アレイ バイオファーマ、インコーポレイテッド | ＲＥＴキナーゼ阻害物質としての置換ピラゾロ［１，５−ａ］ピリジン化合物 |
| TWI734699B (zh) | 2015-09-09 | 2021-08-01 | 美商英塞特公司 | Ｐｉｍ激酶抑制劑之鹽 |
| WO2017059251A1 (en) | 2015-10-02 | 2017-04-06 | Incyte Corporation | Heterocyclic compounds useful as pim kinase inhibitors |
| US10724102B2 (en) | 2015-10-26 | 2020-07-28 | Loxo Oncology, Inc. | Point mutations in TRK inhibitor-resistant cancer and methods relating to the same |
| WO2017157991A1 (en) * | 2016-03-18 | 2017-09-21 | Bayer Pharma Aktiengesellschaft | 1-alkyl-pyrazoles and -indazoles as bub1 inhibitors for the treatment of hyperproliferative diseases |
| PL3439663T3 (pl) | 2016-04-04 | 2024-11-18 | Loxo Oncology, Inc. | Sposoby leczenia nowotworów wieku dziecięcego |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| SG11201808559PA (en) | 2016-04-04 | 2018-10-30 | Loxo Oncology Inc | Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
| FI3800189T3 (fi) | 2016-05-18 | 2023-07-31 | Loxo Oncology Inc | (s)-n-(5-((r)-2-(2,5-difluorifenyyli)pyrrolidin-1-yyli)pyratsolo[1,5-a]pyrimidin-3-yyli)-3-hydroksipyrrolidiini-1-karboksamidin valmistaminen |
| TWI704148B (zh) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | 作為ｒｅｔ激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
| JOP20190077A1 (ar) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret |
| JOP20190092A1 (ar) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها |
| WO2018094362A1 (en) * | 2016-11-21 | 2018-05-24 | Translational Drug Development, Llc | Heterocyclic compounds as kinase inhibitors |
| WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
| ES2948194T3 (es) | 2017-01-18 | 2023-09-01 | Array Biopharma Inc | Compuestos de pirazolo[1,5-a]pirazina sustituida como inhibidores de la cinasa RET |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| WO2018207881A1 (ja) * | 2017-05-12 | 2018-11-15 | 武田薬品工業株式会社 | 複素環化合物 |
| CN109516955B (zh) * | 2017-09-20 | 2022-07-26 | 华东师范大学 | 含氮五元芳香杂环化合物及其制备方法和应用 |
| TWI791053B (zh) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物 |
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| WO2003011837A1 (en) * | 2001-08-01 | 2003-02-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
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| HRP20160243T1 (hr) | 2008-06-26 | 2016-04-08 | Les Laboratoires Servier | Pirazolo-kinazolini kao modulatori aktivnosti protein kinaze |
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| WO2010108921A1 (en) * | 2009-03-27 | 2010-09-30 | Nerviano Medical Sciences S.R.L. | N-aryl-2-(2-arylaminopyrimidin-4-yl)pyrrol-4-carboxamide derivatives as mps1 kinase inhibitors |
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| JP2014511869A (ja) | 2014-05-19 |
| WO2012139930A1 (en) | 2012-10-18 |
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