AU2005299837A1 - Inhibitors of c-fms kinase - Google Patents
Inhibitors of c-fms kinase Download PDFInfo
- Publication number
- AU2005299837A1 AU2005299837A1 AU2005299837A AU2005299837A AU2005299837A1 AU 2005299837 A1 AU2005299837 A1 AU 2005299837A1 AU 2005299837 A AU2005299837 A AU 2005299837A AU 2005299837 A AU2005299837 A AU 2005299837A AU 2005299837 A1 AU2005299837 A1 AU 2005299837A1
- Authority
- AU
- Australia
- Prior art keywords
- cyano
- phenyl
- carboxylic acid
- amide
- enyl
- 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.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title description 9
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 287
- -1 chloro, fluoro, methyl Chemical group 0.000 claims description 145
- XTDRPNJABDWQFI-UHFFFAOYSA-N 5-cyano-1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC(C#N)=CN1 XTDRPNJABDWQFI-UHFFFAOYSA-N 0.000 claims description 104
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 86
- 238000000034 method Methods 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 125000003277 amino group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 239000012453 solvate Substances 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000002883 imidazolyl group Chemical group 0.000 claims description 23
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 22
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 22
- HHHCADSYQQJUGV-UHFFFAOYSA-N 5-cyanofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)O1 HHHCADSYQQJUGV-UHFFFAOYSA-N 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 20
- 150000004677 hydrates Chemical class 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 125000002541 furyl group Chemical group 0.000 claims description 19
- 125000003282 alkyl amino group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims description 12
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 11
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims description 9
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 150000001721 carbon Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 8
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- WTGVAXNQURZHCB-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-(1-methoxypiperidin-4-yl)phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(OC)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC=C(C#N)N1 WTGVAXNQURZHCB-UHFFFAOYSA-N 0.000 claims description 5
- 108091000080 Phosphotransferase Proteins 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 102000020233 phosphotransferase Human genes 0.000 claims description 5
- 229910052705 radium Inorganic materials 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- SWPGDCRPXQMSIA-UHFFFAOYSA-N 4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]-n-(2-hydroxyethyl)piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCCO)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 SWPGDCRPXQMSIA-UHFFFAOYSA-N 0.000 claims description 4
- SAEZQFNKTQKVSM-UHFFFAOYSA-N 4-cyano-1h-pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC(C#N)=CN1 SAEZQFNKTQKVSM-UHFFFAOYSA-N 0.000 claims description 4
- KTOXYKSULADVCY-UHFFFAOYSA-N 5-chloro-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-1,2,4-triazole-3-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N1C(Cl)=NC(C(=O)NC=2C(=CC(=CC=2)C2CCNCC2)C=2CCCCC=2)=N1 KTOXYKSULADVCY-UHFFFAOYSA-N 0.000 claims description 4
- XPCQXAQALLRVJQ-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C=C(C#N)NC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 XPCQXAQALLRVJQ-UHFFFAOYSA-N 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000037408 Device failure Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 208000037099 Prosthesis Failure Diseases 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- UTVBBKOAYGIQRC-UHFFFAOYSA-N n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-1,2,4-triazole-5-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.N=1C=NNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 UTVBBKOAYGIQRC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- NNTGWGBICNZZPA-UHFFFAOYSA-N 4-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-pyrrole-2-carboxamide Chemical compound C=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 NNTGWGBICNZZPA-UHFFFAOYSA-N 0.000 claims description 3
- GXQMEGDUUBFCFH-UHFFFAOYSA-N 5-cyano-n-[2-(2-methylphenyl)-4-(4-methylpiperazin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C=2C(=CC=CC=2)C)=CC=C1NC(=O)C1=CC=C(C#N)O1 GXQMEGDUUBFCFH-UHFFFAOYSA-N 0.000 claims description 3
- SPZDCHRXPBSIHM-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-methylsulfonylethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(CCS(=O)(=O)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 SPZDCHRXPBSIHM-UHFFFAOYSA-N 0.000 claims description 3
- ZSVFWIDDNJEWEB-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-pyridin-4-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CC=NC=C1 ZSVFWIDDNJEWEB-UHFFFAOYSA-N 0.000 claims description 3
- GUBJNPWVIUFSTR-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CN(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 GUBJNPWVIUFSTR-UHFFFAOYSA-N 0.000 claims description 3
- BKGAAMAFOWYKJB-UHFFFAOYSA-N 5-cyano-n-[4-(4-methylpiperazin-1-yl)-2-(3-methylthiophen-2-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C2=C(C=CS2)C)=CC=C1NC(=O)C1=CC=C(C#N)O1 BKGAAMAFOWYKJB-UHFFFAOYSA-N 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 3
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 3
- 201000005296 lung carcinoma Diseases 0.000 claims description 3
- GCPYRLIYCNLRAT-UHFFFAOYSA-N n-[4-(1-acetylpiperidin-4-yl)-2-(1,2,3,6-tetrahydropyridin-5-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)C)CCC1C(C=C1C=2CNCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 GCPYRLIYCNLRAT-UHFFFAOYSA-N 0.000 claims description 3
- UKGCAEYEQULSSN-UHFFFAOYSA-N n-[4-(1-acetylpiperidin-4-yl)-2-(cyclohexen-1-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 UKGCAEYEQULSSN-UHFFFAOYSA-N 0.000 claims description 3
- FFASJWSCBGYXQX-UHFFFAOYSA-N n-[4-[1-(2-amino-2-methylpropanoyl)piperidin-4-yl]-2-(cyclohexen-1-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)C(C)(N)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC=C(C#N)N1 FFASJWSCBGYXQX-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 206010046766 uterine cancer Diseases 0.000 claims description 3
- VTVVSHJUELMWBZ-UHFFFAOYSA-N 5-cyano-n-[2-(3,6-dihydro-2h-pyran-4-yl)-4-(4-methylpiperazin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C=2CCOCC=2)=CC=C1NC(=O)C1=CC=C(C#N)O1 VTVVSHJUELMWBZ-UHFFFAOYSA-N 0.000 claims description 2
- OFUKXOKMKQXPHK-UHFFFAOYSA-N 5-cyano-n-[2-(4,4-dimethylcyclohexen-1-yl)-6-piperidin-4-ylpyridin-3-yl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1C(C)(C)CCC(C=2C(=CC=C(N=2)C2CCNCC2)NC(=O)C=2NC=C(N=2)C#N)=C1 OFUKXOKMKQXPHK-UHFFFAOYSA-N 0.000 claims description 2
- CAPUBLNUXUNCRT-UHFFFAOYSA-N 5-cyano-n-[2-(4-methylcyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1C(C)CCC(C=2C(=CC=C(C=2)C2CCN(CC=3N=CC=CC=3)CC2)NC(=O)C=2NC=C(N=2)C#N)=C1 CAPUBLNUXUNCRT-UHFFFAOYSA-N 0.000 claims description 2
- IIYSPOQOLUOWON-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(CO)CO)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 IIYSPOQOLUOWON-UHFFFAOYSA-N 0.000 claims description 2
- QPSVRPUGGFUWCH-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(CCO)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 QPSVRPUGGFUWCH-UHFFFAOYSA-N 0.000 claims description 2
- AOPYRPVBZZQJMJ-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-methylsulfonylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CS(=O)(=O)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 AOPYRPVBZZQJMJ-UHFFFAOYSA-N 0.000 claims description 2
- PSWOVPWZYVUKKW-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(pyridine-3-carbonyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CC2)C(=O)C=2C=NC=CC=2)C=C1C1=CCCCC1 PSWOVPWZYVUKKW-UHFFFAOYSA-N 0.000 claims description 2
- JIOJSZFBTLBPHK-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(methylamino)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CNC)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 JIOJSZFBTLBPHK-UHFFFAOYSA-N 0.000 claims description 2
- JJZWAMOLUCACLS-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-[2-hydroxyethyl(methyl)amino]acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CN(CCO)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 JJZWAMOLUCACLS-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000006386 Bone Resorption Diseases 0.000 claims description 2
- 206010006002 Bone pain Diseases 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 208000031886 HIV Infections Diseases 0.000 claims description 2
- 208000037357 HIV infectious disease Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 208000011623 Obstructive Lung disease Diseases 0.000 claims description 2
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 208000027868 Paget disease Diseases 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 2
- 206010046851 Uveitis Diseases 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 230000024279 bone resorption Effects 0.000 claims description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 208000027202 mammary Paget disease Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 230000000010 osteolytic effect Effects 0.000 claims description 2
- 201000000306 sarcoidosis Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 230000009278 visceral effect Effects 0.000 claims description 2
- NYKFOPZIAYDJHT-UHFFFAOYSA-N 2-[4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]acetic acid Chemical compound C1CN(CC(=O)O)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 NYKFOPZIAYDJHT-UHFFFAOYSA-N 0.000 claims 2
- NRRNXHWXRHOSFE-UHFFFAOYSA-N 5-cyano-n-[2-(4-methylcyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-imidazole-2-carboxamide Chemical compound C1C(C)CCC(C=2C(=CC=C(C=2)C2CCNCC2)NC(=O)C=2NC=C(N=2)C#N)=C1 NRRNXHWXRHOSFE-UHFFFAOYSA-N 0.000 claims 2
- DJXBOGHWDLVTJM-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-(1-pyridin-2-ylpiperidin-4-yl)phenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CC2)C=2N=CC=CC=2)C=C1C1=CCCCC1 DJXBOGHWDLVTJM-UHFFFAOYSA-N 0.000 claims 2
- MVPRWLBKNHWFPM-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CCN3CCOCC3)CC2)C=C1C1=CCCCC1 MVPRWLBKNHWFPM-UHFFFAOYSA-N 0.000 claims 2
- KMNMIWIJQSLPMT-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(3-morpholin-4-ylpropanoyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CCN1CCOCC1 KMNMIWIJQSLPMT-UHFFFAOYSA-N 0.000 claims 2
- KWLXMAXTGKZBPW-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CC=3N=CC=CC=3)CC2)C=C1C1=CCCCC1 KWLXMAXTGKZBPW-UHFFFAOYSA-N 0.000 claims 2
- FXFXHNQBLWHYDI-UHFFFAOYSA-N 5-cyano-n-[2-(cyclopenten-1-yl)-4-piperidin-4-ylphenyl]-1h-imidazole-2-carboxamide Chemical compound N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCC1 FXFXHNQBLWHYDI-UHFFFAOYSA-N 0.000 claims 2
- ZWRCMAAVANOLOT-UHFFFAOYSA-N 5-cyano-n-[4-(4-methylpiperazin-1-yl)-2-(2-methylthiophen-3-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C2=C(SC=C2)C)=CC=C1NC(=O)C1=CC=C(C#N)O1 ZWRCMAAVANOLOT-UHFFFAOYSA-N 0.000 claims 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- YSACTRAHIJTMLP-UHFFFAOYSA-N 1-[4-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]-2-(1H-imidazol-5-yl)ethanone Chemical compound NC1=CC=C(C2CCN(CC2)C(=O)CC=2NC=NC=2)C=C1C1=CCCCC1 YSACTRAHIJTMLP-UHFFFAOYSA-N 0.000 claims 1
- CEQVSLWTDOIJFZ-UHFFFAOYSA-N 2-(4-methylcyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]aniline Chemical compound C1C(C)CCC(C=2C(=CC=C(C=2)C2CCN(CC=3N=CC=CC=3)CC2)N)=C1 CEQVSLWTDOIJFZ-UHFFFAOYSA-N 0.000 claims 1
- HCKNMNCOHLVBKP-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-[1-(2-methylsulfonylethyl)piperidin-4-yl]aniline Chemical compound C1CN(CCS(=O)(=O)C)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 HCKNMNCOHLVBKP-UHFFFAOYSA-N 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- SLAJWIKQRQPMOS-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-pyridin-3-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CC=CN=C1 SLAJWIKQRQPMOS-UHFFFAOYSA-N 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 206010065390 Inflammatory pain Diseases 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 208000009935 visceral pain Diseases 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 279
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 190
- 239000000203 mixture Substances 0.000 description 122
- 239000000243 solution Substances 0.000 description 120
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 107
- 238000001819 mass spectrum Methods 0.000 description 96
- 235000019439 ethyl acetate Nutrition 0.000 description 92
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
- 238000006243 chemical reaction Methods 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 239000007787 solid Substances 0.000 description 78
- 238000005160 1H NMR spectroscopy Methods 0.000 description 76
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 72
- 239000011734 sodium Substances 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 239000002904 solvent Substances 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 33
- 239000000377 silicon dioxide Substances 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- 230000002829 reductive effect Effects 0.000 description 25
- 238000000746 purification Methods 0.000 description 19
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- AYFFPEOVSJSGAT-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 AYFFPEOVSJSGAT-UHFFFAOYSA-N 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000006069 Suzuki reaction reaction Methods 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 238000004007 reversed phase HPLC Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- PAMSSXMKTNVDCR-UHFFFAOYSA-N 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(Br)=C1 PAMSSXMKTNVDCR-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- SQMINWFWFXVWHK-UHFFFAOYSA-N 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid Chemical compound C[Si](C)(C)CCOCN1C=C(C#N)N=C1C(O)=O SQMINWFWFXVWHK-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- XZWQKJXJNKYMAP-UHFFFAOYSA-N cyclohexen-1-ylboronic acid Chemical compound OB(O)C1=CCCCC1 XZWQKJXJNKYMAP-UHFFFAOYSA-N 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 7
- BNQGKHUEVQWESM-UHFFFAOYSA-M potassium;4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate Chemical compound [K+].C[Si](C)(C)CCOCN1C=C(C#N)N=C1C([O-])=O BNQGKHUEVQWESM-UHFFFAOYSA-M 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 6
- 238000012552 review Methods 0.000 description 6
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000006619 Stille reaction Methods 0.000 description 5
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 125000005620 boronic acid group Chemical class 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 4
- FIVQWANVHJBLAY-UHFFFAOYSA-N 1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile Chemical compound C[Si](C)(C)CCOCN1C=NC(C#N)=C1 FIVQWANVHJBLAY-UHFFFAOYSA-N 0.000 description 4
- ABXBBEBCOITZEX-UHFFFAOYSA-N 2-methylsulfonylethyl methanesulfonate Chemical compound CS(=O)(=O)CCOS(C)(=O)=O ABXBBEBCOITZEX-UHFFFAOYSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 229960001456 adenosine triphosphate Drugs 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical class OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006880 cross-coupling reaction Methods 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- NWVGXXPWOYZODV-UHFFFAOYSA-N 1h-imidazole-5-carbonitrile Chemical compound N#CC1=CN=CN1 NWVGXXPWOYZODV-UHFFFAOYSA-N 0.000 description 3
- UILABPRUJFPVHW-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-(1-methoxypiperidin-4-yl)aniline Chemical compound C1CN(OC)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 UILABPRUJFPVHW-UHFFFAOYSA-N 0.000 description 3
- SVVAEQDRNMUYKO-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-piperidin-4-ylaniline 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 SVVAEQDRNMUYKO-UHFFFAOYSA-N 0.000 description 3
- XDLFZSWZSHTGJY-UHFFFAOYSA-N 2-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile Chemical compound C[Si](C)(C)CCOCN1C=C(C#N)N=C1Br XDLFZSWZSHTGJY-UHFFFAOYSA-N 0.000 description 3
- ZMDCEXLCDOPKGH-UHFFFAOYSA-N 3,6-dihydro-2h-thiopyran-4-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CCSCC1 ZMDCEXLCDOPKGH-UHFFFAOYSA-N 0.000 description 3
- BPMBNLJJRKCCRT-UHFFFAOYSA-N 4-phenylbenzonitrile Chemical compound C1=CC(C#N)=CC=C1C1=CC=CC=C1 BPMBNLJJRKCCRT-UHFFFAOYSA-N 0.000 description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 101000933374 Gallus gallus Brain-specific homeobox/POU domain protein 3 Proteins 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RQMDFPGLTPLVTH-UHFFFAOYSA-N ethyl 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC(C#N)=CN1COCC[Si](C)(C)C RQMDFPGLTPLVTH-UHFFFAOYSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002875 fluorescence polarization Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 230000022244 formylation Effects 0.000 description 3
- 238000006170 formylation reaction Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 238000000527 sonication Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 3
- 108010072897 transcription factor Brn-2 Proteins 0.000 description 3
- UKVHGOODDMJJFN-UHFFFAOYSA-N (1-methoxy-3,6-dihydro-2h-pyridin-4-yl) trifluoromethanesulfonate Chemical compound CON1CCC(OS(=O)(=O)C(F)(F)F)=CC1 UKVHGOODDMJJFN-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- WIKBZUXHNPONPP-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-iodo-2-(trifluoromethyl)propane Chemical compound FC(F)(F)C(I)(C(F)(F)F)C(F)(F)F WIKBZUXHNPONPP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- ZSKXYSCQDWAUCM-UHFFFAOYSA-N 1-(chloromethyl)-2-dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1CCl ZSKXYSCQDWAUCM-UHFFFAOYSA-N 0.000 description 2
- GPMQQQHSEZPMTH-UHFFFAOYSA-N 1-[3-(2-fluorophenyl)-4-nitrophenyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C=2C(=CC=CC=2)F)=C1 GPMQQQHSEZPMTH-UHFFFAOYSA-N 0.000 description 2
- NARDFLCWIXQUGJ-UHFFFAOYSA-N 1-[3-(cyclohexen-1-yl)-4-nitrophenyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C=2CCCCC=2)=C1 NARDFLCWIXQUGJ-UHFFFAOYSA-N 0.000 description 2
- VKWQPILRYYGNQD-UHFFFAOYSA-N 1-methyl-4-[3-(2-methylphenyl)-4-nitrophenyl]piperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C=2C(=CC=CC=2)C)=C1 VKWQPILRYYGNQD-UHFFFAOYSA-N 0.000 description 2
- ZMZJUDLTGOZNMY-UHFFFAOYSA-N 1-methyl-4-[3-(4-methylthiophen-3-yl)-4-nitrophenyl]piperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C=2C(=CSC=2)C)=C1 ZMZJUDLTGOZNMY-UHFFFAOYSA-N 0.000 description 2
- ZHCKPJGJQOPTLB-UHFFFAOYSA-N 1-methyl-4-imidazoleacetic acid Chemical compound CN1C=NC(CC(O)=O)=C1 ZHCKPJGJQOPTLB-UHFFFAOYSA-N 0.000 description 2
- WJCZFVSGSDOFHR-UHFFFAOYSA-N 2-(3,6-dihydro-2h-thiopyran-4-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1C1=CCSCC1 WJCZFVSGSDOFHR-UHFFFAOYSA-N 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- VGYVBEJDXIPSDL-UHFFFAOYSA-N 2-bromo-4-fluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1Br VGYVBEJDXIPSDL-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- DGJCULPYCMEHFZ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(3-methylthiophen-2-yl)-1,3,2-dioxaborolane Chemical compound C1=CSC(B2OC(C)(C)C(C)(C)O2)=C1C DGJCULPYCMEHFZ-UHFFFAOYSA-N 0.000 description 2
- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 description 2
- GGVGHKJUVVDGHB-UHFFFAOYSA-N 4-(1-methoxy-3,6-dihydro-2h-pyridin-4-yl)aniline Chemical compound C1N(OC)CCC(C=2C=CC(N)=CC=2)=C1 GGVGHKJUVVDGHB-UHFFFAOYSA-N 0.000 description 2
- WGVVKADFKMTIRZ-UHFFFAOYSA-N 4-(1-methoxypiperidin-4-yl)aniline Chemical compound C1CN(OC)CCC1C1=CC=C(N)C=C1 WGVVKADFKMTIRZ-UHFFFAOYSA-N 0.000 description 2
- XJRFYOGZLQKKIL-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-(3-methylthiophen-2-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C(C2=C(C=CS2)C)=C1 XJRFYOGZLQKKIL-UHFFFAOYSA-N 0.000 description 2
- KMVOPBQPFUYFHA-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-(4-methylthiophen-3-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C(C=2C(=CSC=2)C)=C1 KMVOPBQPFUYFHA-UHFFFAOYSA-N 0.000 description 2
- GJYJDYXPUHRJLS-UHFFFAOYSA-N 4-(4-nitrophenyl)-3,6-dihydro-2h-thiopyran 1,1-dioxide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CCS(=O)(=O)CC1 GJYJDYXPUHRJLS-UHFFFAOYSA-N 0.000 description 2
- MNQDGSQOILXNDX-UHFFFAOYSA-N 4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]piperidine-1-carboxamide Chemical compound C1CN(C(=O)N)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 MNQDGSQOILXNDX-UHFFFAOYSA-N 0.000 description 2
- CXGJRXKBDMAGFL-UHFFFAOYSA-N 4-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-pyrrole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 CXGJRXKBDMAGFL-UHFFFAOYSA-N 0.000 description 2
- YEEBLJFZYXYIOQ-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-morpholin-4-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CN1CCOCC1 YEEBLJFZYXYIOQ-UHFFFAOYSA-N 0.000 description 2
- WWJOJLYTHINHLM-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(2-hydroxyethylamino)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)CNCCO)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 WWJOJLYTHINHLM-UHFFFAOYSA-N 0.000 description 2
- SQFWFCVKVHKBSA-UHFFFAOYSA-N 5-cyano-n-[4-(4-methylpiperazin-1-yl)-2-(4-methylthiophen-3-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C=2C(=CSC=2)C)=CC=C1NC(=O)C1=CC=C(C#N)O1 SQFWFCVKVHKBSA-UHFFFAOYSA-N 0.000 description 2
- VLZZMVPPSQPHMQ-UHFFFAOYSA-N 5-cyanofuran-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)O1 VLZZMVPPSQPHMQ-UHFFFAOYSA-N 0.000 description 2
- SHNRXUWGUKDPMA-UHFFFAOYSA-N 5-formyl-2-furoic acid Chemical compound OC(=O)C1=CC=C(C=O)O1 SHNRXUWGUKDPMA-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical compound OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 238000005700 Stille cross coupling reaction Methods 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- AUNARHLSDQIJGY-UHFFFAOYSA-N methyl 1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C=1N=CN(COCC[Si](C)(C)C)N=1 AUNARHLSDQIJGY-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WVJQGZYKOZGBMB-UHFFFAOYSA-N n-[4-[1-(3-amino-3-methylbutanoyl)piperidin-4-yl]-2-(cyclohexen-1-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)CC(C)(N)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 WVJQGZYKOZGBMB-UHFFFAOYSA-N 0.000 description 2
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BVSQXIYDLVVEQR-UHFFFAOYSA-M potassium;1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-carboxylate Chemical compound [K+].C[Si](C)(C)CCOCN1C=NC(C([O-])=O)=N1 BVSQXIYDLVVEQR-UHFFFAOYSA-M 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- HFDGFACRWPWRPN-UHFFFAOYSA-N tert-butyl 4-(4-amino-3-bromophenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C(Br)=C1 HFDGFACRWPWRPN-UHFFFAOYSA-N 0.000 description 2
- PKYRLRVLXYAKPM-UHFFFAOYSA-N tert-butyl 4-(4-nitrophenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1 PKYRLRVLXYAKPM-UHFFFAOYSA-N 0.000 description 2
- OYYCRSFYWJMOHI-UHFFFAOYSA-N tert-butyl 4-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(cyclohexen-1-yl)phenyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1COCC[Si](C)(C)C OYYCRSFYWJMOHI-UHFFFAOYSA-N 0.000 description 2
- NXZKMPZVGNXFAM-UHFFFAOYSA-N tert-butyl 4-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 NXZKMPZVGNXFAM-UHFFFAOYSA-N 0.000 description 2
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 1
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- SJZMIZIVYIOMIW-UHFFFAOYSA-N (4-methylcyclohexen-1-yl)boronic acid Chemical group CC1CCC(B(O)O)=CC1 SJZMIZIVYIOMIW-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical compound B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dithiothreitol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- LTSLRXQWWJWZQP-UHFFFAOYSA-N 1-[3-(3,6-dihydro-2h-pyran-4-yl)-4-nitrophenyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C=2CCOCC=2)=C1 LTSLRXQWWJWZQP-UHFFFAOYSA-N 0.000 description 1
- DQYHXRIBRCXGDJ-UHFFFAOYSA-N 1-[4-(4-amino-3-bromophenyl)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CC=C(N)C(Br)=C1 DQYHXRIBRCXGDJ-UHFFFAOYSA-N 0.000 description 1
- JLHKBGOWYGVITM-UHFFFAOYSA-N 1-[4-(4-aminophenyl)piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CC=C(N)C=C1 JLHKBGOWYGVITM-UHFFFAOYSA-N 0.000 description 1
- VRECWKIFBMUMHU-UHFFFAOYSA-N 1-[4-[4-amino-3-(1,2,3,6-tetrahydropyridin-5-yl)phenyl]piperidin-1-yl]ethanone 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)C)CCC1C1=CC=C(N)C(C=2CNCCC=2)=C1 VRECWKIFBMUMHU-UHFFFAOYSA-N 0.000 description 1
- PGPDHIFTNPJUBA-UHFFFAOYSA-N 1-[4-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 PGPDHIFTNPJUBA-UHFFFAOYSA-N 0.000 description 1
- PPFHNDLIIBTERG-UHFFFAOYSA-N 1-[4-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)pyridin-2-yl]piperidin-1-yl]-2-(dimethylamino)ethanone 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)CN(C)C)CCC1C1=CC=C(N)C(C=2CCC(C)(C)CC=2)=N1 PPFHNDLIIBTERG-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- GKRUJRHSPLFHBC-UHFFFAOYSA-N 1-methoxypiperidin-2-one Chemical compound CON1CCCCC1=O GKRUJRHSPLFHBC-UHFFFAOYSA-N 0.000 description 1
- PMEKKJJZHNQEIZ-UHFFFAOYSA-N 1-methyl-1,2,4-triazole-3-carboxylic acid Chemical compound CN1C=NC(C(O)=O)=N1 PMEKKJJZHNQEIZ-UHFFFAOYSA-N 0.000 description 1
- UVSSPVUTAPEUNF-UHFFFAOYSA-N 1-methyl-4-[3-(3-methylthiophen-2-yl)-4-nitrophenyl]piperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(C2=C(C=CS2)C)=C1 UVSSPVUTAPEUNF-UHFFFAOYSA-N 0.000 description 1
- UEBFLTZXUXZPJO-UHFFFAOYSA-N 1-methylimidazole-2-carbaldehyde Chemical compound CN1C=CN=C1C=O UEBFLTZXUXZPJO-UHFFFAOYSA-N 0.000 description 1
- LJVQHXICFCZRJN-UHFFFAOYSA-N 1h-1,2,4-triazole-5-carboxylic acid Chemical compound OC(=O)C1=NC=NN1 LJVQHXICFCZRJN-UHFFFAOYSA-N 0.000 description 1
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 description 1
- ASFQDNDZFGFMMP-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxan-5-one Chemical compound CC1(C)OCC(=O)CO1 ASFQDNDZFGFMMP-UHFFFAOYSA-N 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- MDNDJMCSXOXBFZ-UHFFFAOYSA-N 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1B1OCC(C)(C)CO1 MDNDJMCSXOXBFZ-UHFFFAOYSA-N 0.000 description 1
- DDHAFYWTHXVSLP-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]aniline Chemical compound NC1=CC=C(C2CCN(CC=3N=CC=CC=3)CC2)C=C1C1=CCCCC1 DDHAFYWTHXVSLP-UHFFFAOYSA-N 0.000 description 1
- MVAXDKDOPWPFML-UHFFFAOYSA-N 2-(dimethylamino)acetyl chloride;hydrochloride Chemical compound [Cl-].C[NH+](C)CC(Cl)=O MVAXDKDOPWPFML-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- GDJRXHVOCNOCNI-UHFFFAOYSA-N 2-[4-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]acetamide Chemical compound C1CN(CC(=O)N)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 GDJRXHVOCNOCNI-UHFFFAOYSA-N 0.000 description 1
- YYJBWYBULYUKMR-UHFFFAOYSA-N 2-bromo-3-methylthiophene Chemical compound CC=1C=CSC=1Br YYJBWYBULYUKMR-UHFFFAOYSA-N 0.000 description 1
- HUUFTVUBFFESEN-UHFFFAOYSA-N 2-bromo-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)N=C1 HUUFTVUBFFESEN-UHFFFAOYSA-N 0.000 description 1
- GVLQQPDTOWRBRC-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)ethanamine Chemical compound BrCCNCCBr GVLQQPDTOWRBRC-UHFFFAOYSA-N 0.000 description 1
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- MFNXWZGIFWJHMI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C(O)=O MFNXWZGIFWJHMI-UHFFFAOYSA-N 0.000 description 1
- NYEHUAQIJXERLP-UHFFFAOYSA-N 2-methylsulfonylacetic acid Chemical compound CS(=O)(=O)CC(O)=O NYEHUAQIJXERLP-UHFFFAOYSA-N 0.000 description 1
- KFTYFTKODBWKOU-UHFFFAOYSA-N 2-methylsulfonylethanol Chemical compound CS(=O)(=O)CCO KFTYFTKODBWKOU-UHFFFAOYSA-N 0.000 description 1
- MQVISALTZUNQSK-UHFFFAOYSA-N 2-pyridin-2-ylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CC=N1 MQVISALTZUNQSK-UHFFFAOYSA-N 0.000 description 1
- PAEXAIBDCHBNDC-UHFFFAOYSA-N 2-pyridin-4-ylacetic acid Chemical compound OC(=O)CC1=CC=NC=C1 PAEXAIBDCHBNDC-UHFFFAOYSA-N 0.000 description 1
- QMDFJHAAWUGVKQ-UHFFFAOYSA-N 2h-thiopyran Chemical compound C1SC=CC=C1 QMDFJHAAWUGVKQ-UHFFFAOYSA-N 0.000 description 1
- XHJCXZBDOGPBNJ-UHFFFAOYSA-N 3-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile Chemical compound C[Si](C)(C)CCOCN1C=NC=C1C#N XHJCXZBDOGPBNJ-UHFFFAOYSA-N 0.000 description 1
- XXZWPMDKWCOJMD-UHFFFAOYSA-N 3-[4-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]propanenitrile Chemical compound NC1=CC=C(C2CCN(CCC#N)CC2)C=C1C1=CCCCC1 XXZWPMDKWCOJMD-UHFFFAOYSA-N 0.000 description 1
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
- MBUSOPVRLCFJCS-UHFFFAOYSA-N 3-bromo-4-methylthiophene Chemical compound CC1=CSC=C1Br MBUSOPVRLCFJCS-UHFFFAOYSA-N 0.000 description 1
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 description 1
- YCOQKTIMEQOYNN-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(2-methylthiophen-3-yl)-1,3,2-dioxaborolane Chemical compound S1C=CC(B2OC(C)(C)C(C)(C)O2)=C1C YCOQKTIMEQOYNN-UHFFFAOYSA-N 0.000 description 1
- NBJHDLKSWUDGJG-UHFFFAOYSA-N 4-(2-chloroethyl)morpholin-4-ium;chloride Chemical compound Cl.ClCCN1CCOCC1 NBJHDLKSWUDGJG-UHFFFAOYSA-N 0.000 description 1
- XJKVNNVFOSWOLC-UHFFFAOYSA-N 4-(4-amino-3-bromophenyl)piperidine-1-carboxylic acid Chemical compound NC1=C(C=C(C=C1)C1CCN(CC1)C(=O)O)Br XJKVNNVFOSWOLC-UHFFFAOYSA-N 0.000 description 1
- JGOCTECQSPZHFX-UHFFFAOYSA-N 4-(4-nitrophenyl)-3,6-dihydro-2h-thiopyran Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CCSCC1 JGOCTECQSPZHFX-UHFFFAOYSA-N 0.000 description 1
- MALWZYJMHUQQGE-UHFFFAOYSA-N 4-[4-amino-3-(4-methylcyclohexen-1-yl)phenyl]piperidine-1-carboxylic acid Chemical compound C1C(C)CCC(C=2C(=CC=C(C=2)C2CCN(CC2)C(O)=O)N)=C1 MALWZYJMHUQQGE-UHFFFAOYSA-N 0.000 description 1
- KQIVOLPIONLMKC-UHFFFAOYSA-N 4-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide Chemical compound C[Si](C)(C)CCOCN1C=C(C#N)N=C1C(=O)NC1=CC=C(C2CCN(CCN3CCOCC3)CC2)C=C1C1=CCCCC1 KQIVOLPIONLMKC-UHFFFAOYSA-N 0.000 description 1
- MDULNJMHRIEHFQ-UHFFFAOYSA-N 4-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C[Si](C)(C)CCOCN1C=C(C#N)N=C1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 MDULNJMHRIEHFQ-UHFFFAOYSA-N 0.000 description 1
- FVYYZAZCLYZXQC-UHFFFAOYSA-N 5-cyano-n-[2-(2-fluorophenyl)-4-(4-methylpiperazin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C=2C(=CC=CC=2)F)=CC=C1NC(=O)C1=CC=C(C#N)O1 FVYYZAZCLYZXQC-UHFFFAOYSA-N 0.000 description 1
- DQTPMDFKSNCUCH-UHFFFAOYSA-N 5-cyano-n-[2-(4,4-dimethylcyclohexen-1-yl)-6-piperidin-4-ylpyridin-3-yl]-1h-imidazole-2-carboxamide Chemical compound C1C(C)(C)CCC(C=2C(=CC=C(N=2)C2CCNCC2)NC(=O)C=2NC=C(N=2)C#N)=C1 DQTPMDFKSNCUCH-UHFFFAOYSA-N 0.000 description 1
- HULKRSSUPOPJDE-UHFFFAOYSA-N 5-cyano-n-[2-(4-methylcyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1C(C)CCC(C=2C(=CC=C(C=2)C2CCN(CC=3N=CC=CC=3)CC2)NC(=O)C=2NC=C(N=2)C#N)=C1 HULKRSSUPOPJDE-UHFFFAOYSA-N 0.000 description 1
- HJPNOILTFHHVJV-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-(1-pyridin-2-ylpiperidin-4-yl)phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CC2)C=2N=CC=CC=2)C=C1C1=CCCCC1 HJPNOILTFHHVJV-UHFFFAOYSA-N 0.000 description 1
- RHAURHVPLMBUOW-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-(4-methylpiperazin-1-yl)phenyl]furan-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=CC=C(C#N)O1 RHAURHVPLMBUOW-UHFFFAOYSA-N 0.000 description 1
- GMGSCVRVUCUBON-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1OC(C)(C)OCC1N1CCC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CC1 GMGSCVRVUCUBON-UHFFFAOYSA-N 0.000 description 1
- HHWVFSWVBWNOSV-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(CCO)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 HHWVFSWVBWNOSV-UHFFFAOYSA-N 0.000 description 1
- CHHSNJOVTNQKLL-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CCN3CCOCC3)CC2)C=C1C1=CCCCC1 CHHSNJOVTNQKLL-UHFFFAOYSA-N 0.000 description 1
- BJMQKWRHLJKHOC-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-pyridin-2-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CC=CC=N1 BJMQKWRHLJKHOC-UHFFFAOYSA-N 0.000 description 1
- WSCJUWSIRSXLAX-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-pyridin-2-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CC=CC=N1 WSCJUWSIRSXLAX-UHFFFAOYSA-N 0.000 description 1
- RTJYMLBUXWIKOD-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(2-pyridin-4-ylacetyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CC=NC=C1 RTJYMLBUXWIKOD-UHFFFAOYSA-N 0.000 description 1
- OVVUFMBJASGSMT-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CC=3N=CC=CC=3)CC2)C=C1C1=CCCCC1 OVVUFMBJASGSMT-UHFFFAOYSA-N 0.000 description 1
- YNQPJFIFZLTSCH-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(1-methylimidazol-4-yl)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CN1C=NC(CC(=O)N2CCC(CC2)C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)=C1 YNQPJFIFZLTSCH-UHFFFAOYSA-N 0.000 description 1
- ZDZWIYNKACEWQC-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(1h-imidazol-5-yl)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CC(C=2C=C(C(NC(=O)C=3NC=C(N=3)C#N)=CC=2)C=2CCCCC=2)CCN1C(=O)CC1=CN=CN1 ZDZWIYNKACEWQC-UHFFFAOYSA-N 0.000 description 1
- LWRKMHOVENKMIL-UHFFFAOYSA-N 5-cyano-n-[4-[1-(2-cyanoethyl)piperidin-4-yl]-2-(cyclohexen-1-yl)phenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCN(CCC#N)CC2)C=C1C1=CCCCC1 LWRKMHOVENKMIL-UHFFFAOYSA-N 0.000 description 1
- GIIQBDSNDJOXAW-UHFFFAOYSA-N 6-piperidin-4-ylpyridin-3-amine Chemical group N1=CC(N)=CC=C1C1CCNCC1 GIIQBDSNDJOXAW-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- SKJMAJSHCQYEIA-UHFFFAOYSA-N C1(=CCCCC1)OBOC1=CCCCC1 Chemical compound C1(=CCCCC1)OBOC1=CCCCC1 SKJMAJSHCQYEIA-UHFFFAOYSA-N 0.000 description 1
- GPHJJHNSOAMOQE-UHFFFAOYSA-N CN1CCN(CC1)C1=CC(=C(C=C1)[N+](=O)[O-])C=1SC=CC1C.CN1CCN(CC1)C1=CC(=C(C=C1)NC(=O)C=1OC(=CC1)C#N)C=1SC=CC1C Chemical compound CN1CCN(CC1)C1=CC(=C(C=C1)[N+](=O)[O-])C=1SC=CC1C.CN1CCN(CC1)C1=CC(=C(C=C1)NC(=O)C=1OC(=CC1)C#N)C=1SC=CC1C GPHJJHNSOAMOQE-UHFFFAOYSA-N 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 1
- 101100149678 Caenorhabditis elegans snr-3 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102100035861 Cytosolic 5'-nucleotidase 1A Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000054300 EC 2.7.11.- Human genes 0.000 description 1
- 108700035490 EC 2.7.11.- Proteins 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000802744 Homo sapiens Cytosolic 5'-nucleotidase 1A Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- PVBZBWFXVGEYGV-UHFFFAOYSA-N N-(cyclohexen-1-yl)-4-(1-methoxypiperidin-4-yl)aniline Chemical compound C1(=CCCCC1)NC1=CC=C(C=C1)C1CCN(CC1)OC PVBZBWFXVGEYGV-UHFFFAOYSA-N 0.000 description 1
- FQOIXJRSXNOPMI-UHFFFAOYSA-N N-[chloro(hydroxy)methyl]-4H-benzotriazole-5-sulfonamide Chemical compound OC(NS(=O)(=O)C1=CC=C2C(=NN=N2)C1)Cl FQOIXJRSXNOPMI-UHFFFAOYSA-N 0.000 description 1
- STYGYWFTBXIFEE-UHFFFAOYSA-N N-bromo-4-(1-methoxy-3,6-dihydro-2H-pyridin-4-yl)aniline Chemical compound BrNC1=CC=C(C=C1)C=1CCN(CC1)OC STYGYWFTBXIFEE-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- JSFGZPUFCTXDJY-UHFFFAOYSA-N [2-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]phenyl]methanol Chemical compound OCC1=CC=CC=C1N1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JSFGZPUFCTXDJY-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 201000011529 cardiovascular cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- YBGPLLGDLFUUOU-UHFFFAOYSA-N cyano 1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate;potassium Chemical compound [K].C[Si](C)(C)CCOCN1C=CN=C1C(=O)OC#N YBGPLLGDLFUUOU-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UZBHNSVUMGIKLU-UHFFFAOYSA-N cyclopenten-1-ylboronic acid Chemical group OB(O)C1=CCCC1 UZBHNSVUMGIKLU-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- BLEBFDYUDVZRFG-UHFFFAOYSA-N dichloromethane;propan-2-ol Chemical compound ClCCl.CC(C)O BLEBFDYUDVZRFG-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- SITMDWHJQROIPF-UHFFFAOYSA-N ethyl 2-morpholin-4-ylacetate Chemical compound CCOC(=O)CN1CCOCC1 SITMDWHJQROIPF-UHFFFAOYSA-N 0.000 description 1
- WRBIQTVRBWJCQT-UHFFFAOYSA-N ethyl 3-morpholin-4-ylpropanoate Chemical compound CCOC(=O)CCN1CCOCC1 WRBIQTVRBWJCQT-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- MSMGXWFHBSCQFB-UHFFFAOYSA-N ethyl cyanoformate Chemical compound CCOC(=O)C#N MSMGXWFHBSCQFB-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- DOWWCCDWPKGNGX-RXMQYKEDSA-N methyl (4r)-2,2-dimethyl-1,3-dioxolane-4-carboxylate Chemical compound COC(=O)[C@H]1COC(C)(C)O1 DOWWCCDWPKGNGX-RXMQYKEDSA-N 0.000 description 1
- QMPFMODFBNEYJH-UHFFFAOYSA-N methyl 1h-1,2,4-triazole-5-carboxylate Chemical compound COC(=O)C1=NC=NN1 QMPFMODFBNEYJH-UHFFFAOYSA-N 0.000 description 1
- NDZVUEAMBRJIIJ-UHFFFAOYSA-N methyl 5-chloro-1h-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C1=NNC(Cl)=N1 NDZVUEAMBRJIIJ-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- ROSJKFFLIXTTAW-UHFFFAOYSA-N n,n-bis(2-chloroethyl)aniline Chemical compound ClCCN(CCCl)C1=CC=CC=C1 ROSJKFFLIXTTAW-UHFFFAOYSA-N 0.000 description 1
- MCILBTNZXCIEIJ-UHFFFAOYSA-N n-[4-(1-acetylpiperidin-4-yl)-2-(1,2,3,6-tetrahydropyridin-5-yl)phenyl]-5-cyano-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(C(=O)C)CCC1C(C=C1C=2CNCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 MCILBTNZXCIEIJ-UHFFFAOYSA-N 0.000 description 1
- JIKRFINZEAWXLY-UHFFFAOYSA-N n-[4-(1-acetylpiperidin-4-yl)-2-(cyclohexen-1-yl)phenyl]-4-cyano-1h-pyrrole-2-carboxamide Chemical compound C1CN(C(=O)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=CC(C#N)=CN1 JIKRFINZEAWXLY-UHFFFAOYSA-N 0.000 description 1
- JOWMUPQBELRFRZ-UHFFFAOYSA-N n-carbamoylformamide Chemical compound NC(=O)NC=O JOWMUPQBELRFRZ-UHFFFAOYSA-N 0.000 description 1
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000010644 positive regulation of cell differentiation Effects 0.000 description 1
- 230000034918 positive regulation of cell growth Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- KCLRQVLKAFJSCC-UHFFFAOYSA-M potassium 1,3-dioxolane-4-carboxylate Chemical compound [K+].O1COC(C1)C(=O)[O-] KCLRQVLKAFJSCC-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- IBSDZPFCOZILOM-UHFFFAOYSA-M potassium;2-morpholin-4-ylacetate Chemical compound [K+].[O-]C(=O)CN1CCOCC1 IBSDZPFCOZILOM-UHFFFAOYSA-M 0.000 description 1
- VAGNPDJJIASJFD-UHFFFAOYSA-M potassium;3-morpholin-4-ylpropanoate Chemical compound [K+].[O-]C(=O)CCN1CCOCC1 VAGNPDJJIASJFD-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ADBYGASBXODWTQ-DTORHVGOSA-N tert-butyl (2r,6s)-2,6-dimethyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@H]1CC(=O)C[C@@H](C)N1C(=O)OC(C)(C)C ADBYGASBXODWTQ-DTORHVGOSA-N 0.000 description 1
- ADBYGASBXODWTQ-IUCAKERBSA-N tert-butyl (2s,6s)-2,6-dimethyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@H]1CC(=O)C[C@H](C)N1C(=O)OC(C)(C)C ADBYGASBXODWTQ-IUCAKERBSA-N 0.000 description 1
- XFHDOSGLKQJYLP-UHFFFAOYSA-N tert-butyl 2,6-dimethylpiperidine-1-carboxylate Chemical compound CC1CCCC(C)N1C(=O)OC(C)(C)C XFHDOSGLKQJYLP-UHFFFAOYSA-N 0.000 description 1
- ZAQYBHOQALRPSJ-UHFFFAOYSA-N tert-butyl 2-[4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OC(C)(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 ZAQYBHOQALRPSJ-UHFFFAOYSA-N 0.000 description 1
- DUFOMYZIZHKJPV-UHFFFAOYSA-N tert-butyl 2-[4-amino-3-(cyclohexen-1-yl)phenyl]piperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(CCCC1)C1=CC(=C(C=C1)N)C1=CCCCC1 DUFOMYZIZHKJPV-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 1
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 description 1
- OPUJDGNICJVMDV-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)-2,6-dimethyl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC1N(C(=O)OC(C)(C)C)C(C)CC(C=2C=CC(N)=CC=2)=C1 OPUJDGNICJVMDV-UHFFFAOYSA-N 0.000 description 1
- ATHDMVJLLBLTME-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)-2,6-dimethylpiperidine-1-carboxylate Chemical compound C1C(C)N(C(=O)OC(C)(C)C)C(C)CC1C1=CC=C(N)C=C1 ATHDMVJLLBLTME-UHFFFAOYSA-N 0.000 description 1
- CNCSOOBVWRVUSB-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C=CC(N)=CC=2)=C1 CNCSOOBVWRVUSB-UHFFFAOYSA-N 0.000 description 1
- YRLQFRXDWBFGMK-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C=C1 YRLQFRXDWBFGMK-UHFFFAOYSA-N 0.000 description 1
- NDSINOHTMDHVGE-UHFFFAOYSA-N tert-butyl 4-(5-amino-6-bromopyridin-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C(Br)=N1 NDSINOHTMDHVGE-UHFFFAOYSA-N 0.000 description 1
- XVFBFTRNOMROEW-UHFFFAOYSA-N tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C=N1 XVFBFTRNOMROEW-UHFFFAOYSA-N 0.000 description 1
- GLHFLLITEDOHNU-UHFFFAOYSA-N tert-butyl 4-(5-nitropyridin-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2N=CC(=CC=2)[N+]([O-])=O)=C1 GLHFLLITEDOHNU-UHFFFAOYSA-N 0.000 description 1
- YLIVTRYLLZJHIM-UHFFFAOYSA-N tert-butyl 4-[4-[[5-chloro-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3-carbonyl]amino]-3-(cyclohexen-1-yl)phenyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NN(COCC[Si](C)(C)C)C(Cl)=N1 YLIVTRYLLZJHIM-UHFFFAOYSA-N 0.000 description 1
- BEPXSLFEEFMMJS-UHFFFAOYSA-N tert-butyl 4-[4-amino-3-(3,6-dihydro-2h-thiopyran-4-yl)phenyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C(C=2CCSCC=2)=C1 BEPXSLFEEFMMJS-UHFFFAOYSA-N 0.000 description 1
- BHEZRLRYVAVOAI-UHFFFAOYSA-N tert-butyl 4-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)pyridin-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C(C=2CCC(C)(C)CC=2)=N1 BHEZRLRYVAVOAI-UHFFFAOYSA-N 0.000 description 1
- KEEIJBAOTMNSEN-UHFFFAOYSA-N tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC=C1B1OC(C)(C)C(C)(C)O1 KEEIJBAOTMNSEN-UHFFFAOYSA-N 0.000 description 1
- JWIOZKDQPDVJNT-UHFFFAOYSA-N tert-butyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1 JWIOZKDQPDVJNT-UHFFFAOYSA-N 0.000 description 1
- IGYUUOODUQUIOM-UHFFFAOYSA-N tert-butyl 5-[5-(1-acetylpiperidin-4-yl)-2-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]phenyl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1CN(C(=O)C)CCC1C(C=C1C=2CN(CCC=2)C(=O)OC(C)(C)C)=CC=C1NC(=O)C1=NC(C#N)=CN1COCC[Si](C)(C)C IGYUUOODUQUIOM-UHFFFAOYSA-N 0.000 description 1
- OMYDCXUICVZTMA-UHFFFAOYSA-N tert-butyl n-[2-[4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]-2-oxoethyl]carbamate Chemical compound C1CN(C(=O)CNC(=O)OC(C)(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 OMYDCXUICVZTMA-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- JTFJPZUTHAZKCK-UHFFFAOYSA-N tert-butyl n-[4-[4-[4-[(5-cyano-1h-imidazole-2-carbonyl)amino]-3-(cyclohexen-1-yl)phenyl]piperidin-1-yl]-2-methyl-4-oxobutan-2-yl]carbamate Chemical compound C1CN(C(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 JTFJPZUTHAZKCK-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- BDTOTMBOHYUNSQ-UHFFFAOYSA-N triazole-1-carboxylic acid Chemical compound OC(=O)N1C=CN=N1 BDTOTMBOHYUNSQ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Virology (AREA)
- AIDS & HIV (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Urology & Nephrology (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2011203515A AU2011203515B2 (en) | 2004-10-22 | 2011-07-12 | Inhibitors of c-fms kinase |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62121104P | 2004-10-22 | 2004-10-22 | |
| US60/621,211 | 2004-10-22 | ||
| US60/670,172 | 2005-04-11 | ||
| PCT/US2005/037868 WO2006047277A2 (en) | 2004-10-22 | 2005-10-20 | Inhibitors of c-fms kinase |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2011203515A Division AU2011203515B2 (en) | 2004-10-22 | 2011-07-12 | Inhibitors of c-fms kinase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2005299837A1 true AU2005299837A1 (en) | 2006-05-04 |
Family
ID=36228272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2005299837A Abandoned AU2005299837A1 (en) | 2004-10-22 | 2005-10-20 | Inhibitors of c-fms kinase |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1807077B1 (enExample) |
| JP (1) | JP5046950B2 (enExample) |
| KR (1) | KR101273434B1 (enExample) |
| CN (1) | CN101437514B (enExample) |
| AU (1) | AU2005299837A1 (enExample) |
| BR (1) | BRPI0516947A (enExample) |
| CA (1) | CA2585053C (enExample) |
| DK (1) | DK1807077T3 (enExample) |
| EA (1) | EA013250B1 (enExample) |
| ES (1) | ES2611604T3 (enExample) |
| HU (1) | HUE033089T2 (enExample) |
| MX (1) | MX2007004784A (enExample) |
| NO (1) | NO339555B1 (enExample) |
| PL (1) | PL1807077T3 (enExample) |
| PT (1) | PT1807077T (enExample) |
| UA (1) | UA88648C2 (enExample) |
| WO (1) | WO2006047277A2 (enExample) |
| ZA (1) | ZA200704106B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006304897B2 (en) * | 2005-10-18 | 2012-07-12 | Janssen Pharmaceutica N.V. | Method of inhibiting FLT3 kinase |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1631560A2 (en) | 2003-04-25 | 2006-03-08 | 3-Dimensional Pharmaceuticals, Inc. | C-fms kinase inhibitors |
| US7427683B2 (en) | 2003-04-25 | 2008-09-23 | Ortho-Mcneil Pharmaceutical, Inc. | c-fms kinase inhibitors |
| US7790724B2 (en) | 2003-04-25 | 2010-09-07 | Janssen Pharmaceutica N.V. | c-fms kinase inhibitors |
| TW200526626A (en) | 2003-09-13 | 2005-08-16 | Astrazeneca Ab | Chemical compounds |
| JP5008569B2 (ja) * | 2004-10-22 | 2012-08-22 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | C−fmsキナーゼのインヒビターとしての芳香族アミド |
| WO2006087543A1 (en) | 2005-02-18 | 2006-08-24 | Astrazeneca Ab | Antibacterial piperidine derivatives |
| US20080269214A1 (en) * | 2005-03-04 | 2008-10-30 | Astrazeneca Ab | Pyrrole Derivatives as Dna Gyrase and Topoisomerase Inhibitors |
| JP2008540665A (ja) * | 2005-05-19 | 2008-11-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | イオンチャネルのモジュレーターとして有用なビアリール |
| EP1904491A2 (en) | 2005-05-31 | 2008-04-02 | Vertex Pharmaceuticals Incorporated | Heterocycles useful as modulators of ion channels |
| US20060281788A1 (en) * | 2005-06-10 | 2006-12-14 | Baumann Christian A | Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor |
| US20070004660A1 (en) * | 2005-06-10 | 2007-01-04 | Baumann Christian A | Synergistic Modulation of Flt3 Kinase Using Alkylquinolines and Alkylquinazolines |
| ES2458291T3 (es) | 2006-04-20 | 2014-04-30 | Janssen Pharmaceutica Nv | Derivados de amidas aromáticas como inhibidores de la cinasa C-KIT |
| KR101367645B1 (ko) * | 2006-04-20 | 2014-02-27 | 얀센 파마슈티카 엔.브이. | C-fms 키나제의 저해제로서의 복소환식 화합물 |
| US8697716B2 (en) * | 2006-04-20 | 2014-04-15 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
| KR101367646B1 (ko) | 2006-04-20 | 2014-02-27 | 얀센 파마슈티카 엔.브이. | C-fms 키나제의 저해제 |
| JP2009534380A (ja) * | 2006-04-20 | 2009-09-24 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | c−fmsキナーゼインヒビター |
| JP5443342B2 (ja) | 2007-06-08 | 2014-03-19 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ピペリジン/ピペラジン誘導体 |
| AU2008258487B2 (en) | 2007-06-08 | 2012-11-15 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
| JP5464709B2 (ja) | 2007-06-08 | 2014-04-09 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ピペリジン/ピペラジン誘導体 |
| JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
| JO3240B1 (ar) * | 2007-10-17 | 2018-03-08 | Janssen Pharmaceutica Nv | c-fms مثبطات كيناز |
| AU2013203813B2 (en) * | 2007-10-17 | 2014-07-31 | Janssen Pharmaceutica, N.V. | Inhibitors of C-FMS kinase |
| CA2704517A1 (en) * | 2007-11-02 | 2009-05-07 | Janssen Pharmaceutica, N.V. | Use of cfms inhibitor for treating or preventing bone cancer and the bone loss and bone pain associated with bone cancer |
| TWI498115B (zh) | 2007-12-27 | 2015-09-01 | Daiichi Sankyo Co Ltd | 咪唑羰基化合物 |
| ES2617619T3 (es) | 2008-06-05 | 2017-06-19 | Janssen Pharmaceutica, N.V. | Combinaciones de fármacos que comprenden un inhibidor de DGAT y un agonista de PPAR |
| WO2011149841A1 (en) | 2010-05-25 | 2011-12-01 | Janssen Pharmaceutica Nv | SUBSTITUTED THIAZOLIDINEDIONE INDAZOLES, INDOLES AND BENZOTRIAZOLES AS ESTROGEN-RELATED RECEPTOR-α MODULATORS |
| DK2822656T3 (en) | 2012-03-07 | 2017-01-30 | Inst Of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
| US9303046B2 (en) | 2012-08-07 | 2016-04-05 | Janssen Pharmaceutica Nv | Process for the preparation of heterocyclic ester derivatives |
| JOP20180012A1 (ar) | 2012-08-07 | 2019-01-30 | Janssen Pharmaceutica Nv | عملية السلفنة باستخدام نونافلوروبوتانيسولفونيل فلوريد |
| KR101676208B1 (ko) * | 2012-09-17 | 2016-11-14 | 에프. 호프만-라 로슈 아게 | 트라이아졸 카복스아미드 유도체 |
| CN103664957A (zh) * | 2012-09-25 | 2014-03-26 | 杨子娇 | 一类治疗房角狭窄的化合物及其用途 |
| CN103804349A (zh) * | 2012-11-01 | 2014-05-21 | 杨子娇 | 一类治疗青光眼的化合物及其用途 |
| CN104370881A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类具有神经保护作用的化合物及其制备方法和用途 |
| CN104370882A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类降低眼压的化合物及其制备方法和用途 |
| CN104370880A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类蛋白酶抑制剂及其制备方法和用途 |
| ES2662600T3 (es) | 2013-03-15 | 2018-04-09 | Janssen Pharmaceutica, N.V. | Derivados de piridina sustituidos útiles como inhibidores de c-fms quinasa |
| PL3024832T3 (pl) | 2013-07-22 | 2018-10-31 | Idorsia Pharmaceuticals Ltd | Pochodne 1-(piperazyn-1-ylo)-2-([1,2,4]triazol-1-ilo)-etanonu |
| CN105722835B (zh) | 2013-09-11 | 2018-07-31 | 癌症研究协会:皇家癌症医院 | 3-芳基-5-取代的-异喹啉-1-酮化合物及它们的疗法应用 |
| PL3245203T3 (pl) | 2015-01-15 | 2019-05-31 | Idorsia Pharmaceuticals Ltd | Pochodne hydroksyalkilopiperazyny jako modulatory receptora cxcr3 |
| AR103399A1 (es) | 2015-01-15 | 2017-05-10 | Actelion Pharmaceuticals Ltd | Derivados de (r)-2-metil-piperazina como moduladores del receptor cxcr3 |
| JP7012822B2 (ja) * | 2017-08-10 | 2022-02-14 | 中国科学院上海薬物研究所 | フタラジノン系化合物、その製造方法、医薬組成物及びその使用 |
| US10930064B2 (en) | 2018-02-08 | 2021-02-23 | Covidien Lp | Imaging reconstruction system and method |
| AU2019407650B2 (en) | 2018-12-17 | 2022-10-27 | Tolremo Therapeutics Ag | Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment, amelioration or prevention of cancer |
| WO2021144360A1 (en) | 2020-01-17 | 2021-07-22 | F. Hoffmann-La Roche Ag | Small molecule csf-1r inhibitors in therapeutic and cosmetic uses |
| WO2024254440A1 (en) * | 2023-06-09 | 2024-12-12 | Modulo Bio, Inc. | 5-cyano-1h-imidazole-2-carboxamide compounds as csf1r inhibitors |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| JP2002520324A (ja) * | 1998-07-10 | 2002-07-09 | メルク エンド カムパニー インコーポレーテッド | 新規な血管形成インヒビター |
| GB9824579D0 (en) * | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
| EP1140938B1 (en) * | 1999-01-11 | 2003-08-27 | Princeton University | High affinity inhibitors for target validation and uses thereof |
| CA2396693A1 (en) * | 1999-12-28 | 2001-07-05 | Stephen T. Wrobleski | Cytokine, especially tnf-alpha, inhibitors |
| US7105682B2 (en) * | 2001-01-12 | 2006-09-12 | Amgen Inc. | Substituted amine derivatives and methods of use |
| IL165264A0 (en) * | 2002-05-23 | 2005-12-18 | Cytopia Pty Ltd | Protein kinase inhibitors |
| EP1549614A4 (en) * | 2002-10-03 | 2008-04-16 | Targegen Inc | VASCULATORY AGENTS AND METHODS FOR THEIR APPLICATION |
| US20050113566A1 (en) * | 2003-04-25 | 2005-05-26 | Player Mark R. | Inhibitors of C-FMS kinase |
| EP1631560A2 (en) * | 2003-04-25 | 2006-03-08 | 3-Dimensional Pharmaceuticals, Inc. | C-fms kinase inhibitors |
| JP5008569B2 (ja) * | 2004-10-22 | 2012-08-22 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | C−fmsキナーゼのインヒビターとしての芳香族アミド |
| EP1951234A2 (en) * | 2005-10-18 | 2008-08-06 | Janssen Pharmaceutica N.V. | Method of inhibiting flt3 kinase |
-
2005
- 2005-10-20 ES ES05815361.0T patent/ES2611604T3/es not_active Expired - Lifetime
- 2005-10-20 HU HUE05815361A patent/HUE033089T2/en unknown
- 2005-10-20 KR KR1020077011145A patent/KR101273434B1/ko not_active Expired - Fee Related
- 2005-10-20 UA UAA200704498A patent/UA88648C2/ru unknown
- 2005-10-20 CN CN2005800435040A patent/CN101437514B/zh not_active Expired - Fee Related
- 2005-10-20 AU AU2005299837A patent/AU2005299837A1/en not_active Abandoned
- 2005-10-20 BR BRPI0516947-0A patent/BRPI0516947A/pt not_active Application Discontinuation
- 2005-10-20 JP JP2007538060A patent/JP5046950B2/ja not_active Expired - Fee Related
- 2005-10-20 CA CA2585053A patent/CA2585053C/en not_active Expired - Fee Related
- 2005-10-20 PL PL05815361T patent/PL1807077T3/pl unknown
- 2005-10-20 EP EP05815361.0A patent/EP1807077B1/en not_active Expired - Lifetime
- 2005-10-20 WO PCT/US2005/037868 patent/WO2006047277A2/en not_active Ceased
- 2005-10-20 EA EA200700918A patent/EA013250B1/ru not_active IP Right Cessation
- 2005-10-20 DK DK05815361.0T patent/DK1807077T3/en active
- 2005-10-20 PT PT58153610T patent/PT1807077T/pt unknown
- 2005-10-20 MX MX2007004784A patent/MX2007004784A/es active IP Right Grant
-
2007
- 2007-05-15 NO NO20072489A patent/NO339555B1/no not_active IP Right Cessation
- 2007-05-21 ZA ZA200704106A patent/ZA200704106B/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006304897B2 (en) * | 2005-10-18 | 2012-07-12 | Janssen Pharmaceutica N.V. | Method of inhibiting FLT3 kinase |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0516947A (pt) | 2008-09-23 |
| ZA200704106B (en) | 2009-09-30 |
| EP1807077A2 (en) | 2007-07-18 |
| KR20070085382A (ko) | 2007-08-27 |
| ES2611604T3 (es) | 2017-05-09 |
| UA88648C2 (en) | 2009-11-10 |
| DK1807077T3 (en) | 2017-01-23 |
| NO20072489L (no) | 2007-06-29 |
| JP5046950B2 (ja) | 2012-10-10 |
| EA200700918A1 (ru) | 2008-06-30 |
| MX2007004784A (es) | 2007-09-11 |
| HUE033089T2 (en) | 2017-11-28 |
| JP2008517926A (ja) | 2008-05-29 |
| WO2006047277A2 (en) | 2006-05-04 |
| KR101273434B1 (ko) | 2013-06-11 |
| WO2006047277A3 (en) | 2009-05-07 |
| CA2585053C (en) | 2011-07-12 |
| EP1807077A4 (en) | 2011-09-21 |
| CA2585053A1 (en) | 2006-05-04 |
| PL1807077T3 (pl) | 2017-05-31 |
| CN101437514A (zh) | 2009-05-20 |
| CN101437514B (zh) | 2012-04-25 |
| EA013250B1 (ru) | 2010-04-30 |
| EP1807077B1 (en) | 2016-11-23 |
| NO339555B1 (no) | 2017-01-02 |
| PT1807077T (pt) | 2017-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2585053C (en) | Substituted n-acyl (hetero)aryl compounds as c-fms kinase inhibitors | |
| US7645755B2 (en) | Inhibitors of c-fms kinase | |
| EP1807407B1 (en) | Aromatic amides as inhibitors of c-fms kinase | |
| AU2007240440B2 (en) | Inhibitors of c-fms kinase | |
| EP2029570B1 (en) | Fused thiophene derivatives as kinase inhibitors | |
| IL182735A (en) | C – fms kinase inhibitors | |
| JPWO2008029825A1 (ja) | イミダゾール誘導体 | |
| AU2007240400B2 (en) | Method of inhibiting C KIT kinase | |
| AU2011203515B2 (en) | Inhibitors of c-fms kinase | |
| HK1109342A (en) | Inhibitors of c-fms kinase | |
| HK1109342B (en) | Inhibitors of c-fms kinase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: ADD PRIORITY DETAILS 60/670,172 11 APR 2005 US |
|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |