PT1784183E - Processos para a preparação de derivados de isotiazole - Google Patents
Processos para a preparação de derivados de isotiazole Download PDFInfo
- Publication number
- PT1784183E PT1784183E PT05778840T PT05778840T PT1784183E PT 1784183 E PT1784183 E PT 1784183E PT 05778840 T PT05778840 T PT 05778840T PT 05778840 T PT05778840 T PT 05778840T PT 1784183 E PT1784183 E PT 1784183E
- Authority
- PT
- Portugal
- Prior art keywords
- aryl
- isothiazole
- ureido
- carboxylic acid
- benzyloxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 39
- 238000002360 preparation method Methods 0.000 title claims description 25
- 150000003854 isothiazoles Chemical class 0.000 title description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 254
- 125000003118 aryl group Chemical group 0.000 claims description 226
- -1 C1 -C10 alkyl Chemical group 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 113
- 125000000217 alkyl group Chemical group 0.000 claims description 108
- 229910052760 oxygen Inorganic materials 0.000 claims description 84
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 80
- 125000004434 sulfur atom Chemical group 0.000 claims description 80
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 54
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 53
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 50
- 125000004122 cyclic group Chemical group 0.000 claims description 50
- 125000005842 heteroatom Chemical group 0.000 claims description 47
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 38
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 37
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 28
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910021529 ammonia Inorganic materials 0.000 claims description 18
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 150000004702 methyl esters Chemical class 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- PJXPORIRXYJDLD-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylic acid Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)O)=C1NC(=O)NCCCCN1CCCC1 PJXPORIRXYJDLD-UHFFFAOYSA-N 0.000 claims description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000003367 polycyclic group Chemical group 0.000 claims description 5
- MLTRVXNMTIBDJI-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(Cl)C=C1F MLTRVXNMTIBDJI-UHFFFAOYSA-N 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- FLTUSYTWLHGKSB-UHFFFAOYSA-N 5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound C1CN(C)CCN1CCCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(C)=CC=2F)F)=NS1 FLTUSYTWLHGKSB-UHFFFAOYSA-N 0.000 claims description 4
- NZLRJJCXOVYZRF-UHFFFAOYSA-N 5-[4-[bis(2-hydroxyethyl)amino]butylcarbamoylamino]-3-[(2,6-difluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound FC1=CC(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN(CCO)CCO)=C1C(O)=O NZLRJJCXOVYZRF-UHFFFAOYSA-N 0.000 claims description 4
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 claims description 4
- QBRJZYJMHZZQKY-UHFFFAOYSA-N methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylate Chemical group S1C(S(C)(=O)=O)=C(C(=O)OC)C(OCC=2C(=CC(Br)=CC=2F)F)=N1 QBRJZYJMHZZQKY-UHFFFAOYSA-N 0.000 claims description 4
- KGKURLCJVMTUAH-UHFFFAOYSA-N methyl 5-amino-3-[(4-bromo-2,6-difluorophenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical group COC(=O)C1=C(N)SN=C1OCC1=C(F)C=C(Br)C=C1F KGKURLCJVMTUAH-UHFFFAOYSA-N 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 claims description 3
- UOHVFUKYCPCDMK-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[3-[ethyl(2-hydroxyethyl)amino]propylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=C(NC(=O)NCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(Cl)C(F)=C1F UOHVFUKYCPCDMK-UHFFFAOYSA-N 0.000 claims description 3
- NKDLZDBLODZAES-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound OCC1CCCN1CCCCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(Cl)=CC=2F)F)=NS1 NKDLZDBLODZAES-UHFFFAOYSA-N 0.000 claims description 3
- NYYQETQHPXRWLV-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound CN1CCCC1CCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=CC(Cl)=CC=2F)F)=NS1 NYYQETQHPXRWLV-UHFFFAOYSA-N 0.000 claims description 3
- ZDEFKACGJVBKCO-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound C1CN(C)CCN1CCCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=CC(Cl)=CC=2F)F)=NS1 ZDEFKACGJVBKCO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- GAEFKHUAINDYPU-UHFFFAOYSA-N 5-[4-(4-methylpiperazin-1-yl)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound C1CN(C)CCN1CCCCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(C)=CC=2F)F)=NS1 GAEFKHUAINDYPU-UHFFFAOYSA-N 0.000 claims description 3
- CDXWXGJLRJUYAK-UHFFFAOYSA-N 5-[4-[4-(2-hydroxyethyl)piperazin-1-yl]butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound FC1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN2CCN(CCO)CC2)=C1C(O)=O CDXWXGJLRJUYAK-UHFFFAOYSA-N 0.000 claims description 3
- RTSXOONRXMLUQC-UHFFFAOYSA-N 5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F RTSXOONRXMLUQC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- WVHXBHFWYRJNKU-UHFFFAOYSA-N methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 WVHXBHFWYRJNKU-UHFFFAOYSA-N 0.000 claims description 3
- GRIBVKFHFTZOCK-UHFFFAOYSA-N 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-(3-hydroxypyrrolidin-1-yl)butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound C1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN2CC(O)CC2)=C1C(N)=O GRIBVKFHFTZOCK-UHFFFAOYSA-N 0.000 claims description 2
- JGVUZSYKCBQTGT-UHFFFAOYSA-N 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=CC(F)=C(C)C=C1F JGVUZSYKCBQTGT-UHFFFAOYSA-N 0.000 claims description 2
- OIJBFJNKDCYVCY-UHFFFAOYSA-N 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=CC(F)=C(C)C=C1F OIJBFJNKDCYVCY-UHFFFAOYSA-N 0.000 claims description 2
- QIMZMNAVSSZUFG-UHFFFAOYSA-N 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[6-(dimethylamino)hexylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCCCN(C)C)SN=C1OCC1=CC(F)=C(C)C=C1F QIMZMNAVSSZUFG-UHFFFAOYSA-N 0.000 claims description 2
- QYQQDBQNTUOFJL-UHFFFAOYSA-N 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound FC1=CC(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCN2CCCC2)=C1C(N)=O QYQQDBQNTUOFJL-UHFFFAOYSA-N 0.000 claims description 2
- ARMSUXIOUXKTQE-UHFFFAOYSA-N 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound CN1CCCC1CCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=CC(C)=CC=2F)F)=NS1 ARMSUXIOUXKTQE-UHFFFAOYSA-N 0.000 claims description 2
- GVJSWBMFVKGXAE-UHFFFAOYSA-N 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[3-(dimethylamino)propylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCN(C)C)SN=C1OCC1=C(F)C=C(C)C=C1F GVJSWBMFVKGXAE-UHFFFAOYSA-N 0.000 claims description 2
- HFCXEWPMPAOGBM-UHFFFAOYSA-N 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound C1CN(C)CCN1CCCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=CC(C)=CC=2)F)=NS1 HFCXEWPMPAOGBM-UHFFFAOYSA-N 0.000 claims description 2
- AMLIAESKGXHWSE-UHFFFAOYSA-N 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[5-(propan-2-ylamino)pentylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCCNC(C)C)SN=C1OCC1=CC=C(C)C=C1F AMLIAESKGXHWSE-UHFFFAOYSA-N 0.000 claims description 2
- QFICIQKWQFJJMF-UHFFFAOYSA-N 3-[(3-chloro-2,6-difluoro-4-methylphenyl)methoxy]-5-[4-(dimethylamino)butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCN(C)C)SN=C1OCC1=C(F)C=C(C)C(Cl)=C1F QFICIQKWQFJJMF-UHFFFAOYSA-N 0.000 claims description 2
- HCYLBNPHRUPOIC-UHFFFAOYSA-N 3-[(4-bromo-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=C(F)C(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HCYLBNPHRUPOIC-UHFFFAOYSA-N 0.000 claims description 2
- CRBQHUZGHXBQOI-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-(4-imidazol-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1C=CN=C1 CRBQHUZGHXBQOI-UHFFFAOYSA-N 0.000 claims description 2
- NKGBEPBSPHYERX-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCC(O)CCN1CCCC1 NKGBEPBSPHYERX-UHFFFAOYSA-N 0.000 claims description 2
- AVBLJLMYGYPZBD-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-imidazol-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1C=CN=C1 AVBLJLMYGYPZBD-UHFFFAOYSA-N 0.000 claims description 2
- KBASJCBTQBVBOG-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 KBASJCBTQBVBOG-UHFFFAOYSA-N 0.000 claims description 2
- AHTAYKWZFAVPQM-UHFFFAOYSA-N 5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound FC1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCN2CCCC2)=C1C(N)=O AHTAYKWZFAVPQM-UHFFFAOYSA-N 0.000 claims description 2
- PNLQTLDEFBVYHM-UHFFFAOYSA-N 5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound FC1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN2CCCC2)=C1C(N)=O PNLQTLDEFBVYHM-UHFFFAOYSA-N 0.000 claims description 2
- JZKSAVFKXZDXTQ-UHFFFAOYSA-N 5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound FC1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCC(O)CCN2CCCC2)=C1C(N)=O JZKSAVFKXZDXTQ-UHFFFAOYSA-N 0.000 claims description 2
- JAPPCINOHTZNJE-UHFFFAOYSA-N 5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical compound CN1CCCC1CCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(C)=CC=2F)F)=NS1 JAPPCINOHTZNJE-UHFFFAOYSA-N 0.000 claims description 2
- WXMYZVYEMXHCFL-UHFFFAOYSA-N 5-[3-(dimethylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCN(C)C)SN=C1OCC1=C(F)C=C(C)C(F)=C1F WXMYZVYEMXHCFL-UHFFFAOYSA-N 0.000 claims description 2
- ZLGQTFMQIQJIND-UHFFFAOYSA-N 5-[3-(methylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCNC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F ZLGQTFMQIQJIND-UHFFFAOYSA-N 0.000 claims description 2
- UFLMPWLAMMMPBH-UHFFFAOYSA-N 5-[3-(propan-2-ylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCNC(C)C)SN=C1OCC1=C(F)C=C(C)C(F)=C1F UFLMPWLAMMMPBH-UHFFFAOYSA-N 0.000 claims description 2
- WREMRCJTCVCTHZ-UHFFFAOYSA-N 5-[4-(diethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCN(CC)CC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F WREMRCJTCVCTHZ-UHFFFAOYSA-N 0.000 claims description 2
- NYNDSKDUQMPEHX-UHFFFAOYSA-N 5-[4-(dimethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCN(C)C)SN=C1OCC1=C(F)C=C(C)C(F)=C1F NYNDSKDUQMPEHX-UHFFFAOYSA-N 0.000 claims description 2
- RVEJKOFDHFCLKB-UHFFFAOYSA-N 5-[[3-aminopropyl(methyl)carbamoyl]amino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)N(CCCN)C)SN=C1OCC1=C(F)C=C(C)C(F)=C1F RVEJKOFDHFCLKB-UHFFFAOYSA-N 0.000 claims description 2
- CPIXYAJJCRHOTJ-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-(3-hydroxypyrrolidin-1-yl)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=C(F)C=2)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCC(O)C1 CPIXYAJJCRHOTJ-UHFFFAOYSA-N 0.000 claims description 2
- DFHHYJAARHLEQQ-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=C(F)C=2)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1CO DFHHYJAARHLEQQ-UHFFFAOYSA-N 0.000 claims description 2
- ZVCMMPDTVZXUNC-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[6-(dimethylamino)hexylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=C(F)C=2)F)=N1 ZVCMMPDTVZXUNC-UHFFFAOYSA-N 0.000 claims description 2
- JXGILVIQYAUXGQ-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C=C1F JXGILVIQYAUXGQ-UHFFFAOYSA-N 0.000 claims description 2
- DQFULOUGRNYPIT-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC(O)CCN1CCCC1 DQFULOUGRNYPIT-UHFFFAOYSA-N 0.000 claims description 2
- ZMEXDFWCAWIBTI-UHFFFAOYSA-N methyl 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCN(C)CC2)=C(C(=O)OC)C=1OCC1=CC=C(C)C=C1F ZMEXDFWCAWIBTI-UHFFFAOYSA-N 0.000 claims description 2
- AOTNUPAPIGHNCS-UHFFFAOYSA-N methyl 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[5-(propan-2-ylamino)pentylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCCNC(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=CC=2)F)=N1 AOTNUPAPIGHNCS-UHFFFAOYSA-N 0.000 claims description 2
- HCBXWYPSNANGJD-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 HCBXWYPSNANGJD-UHFFFAOYSA-N 0.000 claims description 2
- SHHJPDMWHWCATJ-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-imidazol-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1C=CN=C1 SHHJPDMWHWCATJ-UHFFFAOYSA-N 0.000 claims description 2
- OXWAWKZUTJKCAD-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 OXWAWKZUTJKCAD-UHFFFAOYSA-N 0.000 claims description 2
- LYKMAZPRKPTOLB-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCN2C3CC(N(C3)C)C2)SN=C1OCC1=C(F)C=C(Cl)C=C1F LYKMAZPRKPTOLB-UHFFFAOYSA-N 0.000 claims description 2
- CPXGXRLEXKZTST-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1CO CPXGXRLEXKZTST-UHFFFAOYSA-N 0.000 claims description 2
- SCBHXFKLYDJABR-UHFFFAOYSA-N methyl 5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F SCBHXFKLYDJABR-UHFFFAOYSA-N 0.000 claims description 2
- CVUJQFCRESAPAB-UHFFFAOYSA-N methyl 5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F CVUJQFCRESAPAB-UHFFFAOYSA-N 0.000 claims description 2
- VBUKUTDXZLGLJK-UHFFFAOYSA-N methyl 5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC(O)CCN1CCCC1 VBUKUTDXZLGLJK-UHFFFAOYSA-N 0.000 claims description 2
- NXHHPBXWGZXXEJ-UHFFFAOYSA-N methyl 5-[(4-hydroxy-5-piperidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCC(O)CN1CCCCC1 NXHHPBXWGZXXEJ-UHFFFAOYSA-N 0.000 claims description 2
- DGTJIZCUMVPCGO-UHFFFAOYSA-N methyl 5-[3-(dimethylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 DGTJIZCUMVPCGO-UHFFFAOYSA-N 0.000 claims description 2
- CTFFWTVCFNCGMC-UHFFFAOYSA-N methyl 5-[3-(propan-2-ylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCNC(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 CTFFWTVCFNCGMC-UHFFFAOYSA-N 0.000 claims description 2
- HZGXQPTZUGIFPW-UHFFFAOYSA-N methyl 5-[4-(dimethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 HZGXQPTZUGIFPW-UHFFFAOYSA-N 0.000 claims description 2
- DGXJAGGCMLMDSU-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)piperidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCCC1CO DGXJAGGCMLMDSU-UHFFFAOYSA-N 0.000 claims 2
- KGDHVWRSIDVHLF-UHFFFAOYSA-N 3-[(4-bromo-2,3,6-trifluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound C1CN(C)CCN1CCCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(Br)=CC=2F)F)=NS1 KGDHVWRSIDVHLF-UHFFFAOYSA-N 0.000 claims 1
- RNBYFZPZEQJLQT-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound CN1CC2CC1CN2CCCNC(=O)NC(=C1C(N)=O)SN=C1OCC1=C(F)C=C(Cl)C(F)=C1F RNBYFZPZEQJLQT-UHFFFAOYSA-N 0.000 claims 1
- HLWZBOXPCYYJHT-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)piperidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCCC1CO HLWZBOXPCYYJHT-UHFFFAOYSA-N 0.000 claims 1
- ZPNJGUBDUYTZLI-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1CO ZPNJGUBDUYTZLI-UHFFFAOYSA-N 0.000 claims 1
- NWMFTCUVROERRS-UHFFFAOYSA-N 3-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-2H-1,2-thiazole-4-carboxamide Chemical compound FC=1C=C(C)C(F)=C(F)C=1COC1(NC(=O)NCCCCN(CCO)CC)NSC=C1C(N)=O NWMFTCUVROERRS-UHFFFAOYSA-N 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- LCHPYVGLOSGUFS-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C=C1F LCHPYVGLOSGUFS-UHFFFAOYSA-N 0.000 claims 1
- ZLAJKDDQOYZOGQ-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[3-(dimethylamino)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=CC=2F)F)=N1 ZLAJKDDQOYZOGQ-UHFFFAOYSA-N 0.000 claims 1
- LCZJCNBNQPPCNR-UHFFFAOYSA-N methyl 3-[(3-chloro-2,6-difluoro-4-methylphenyl)methoxy]-5-[4-(dimethylamino)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(Cl)C(C)=CC=2F)F)=N1 LCZJCNBNQPPCNR-UHFFFAOYSA-N 0.000 claims 1
- BYVKQFFUPQPZHS-UHFFFAOYSA-N methyl 3-[(4-bromo-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 BYVKQFFUPQPZHS-UHFFFAOYSA-N 0.000 claims 1
- YYRHDUCNMMIWGW-UHFFFAOYSA-N methyl 5-[3-(methylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCNC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F YYRHDUCNMMIWGW-UHFFFAOYSA-N 0.000 claims 1
- JTLGSPVHFRXHEH-UHFFFAOYSA-N methyl 5-[4-(diethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCCN(CC)CC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F JTLGSPVHFRXHEH-UHFFFAOYSA-N 0.000 claims 1
- ZLEFCSJAIHQAAR-UHFFFAOYSA-N methyl 5-[[3-aminopropyl(methyl)carbamoyl]amino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)N(C)CCCN)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 ZLEFCSJAIHQAAR-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000203 mixture Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical class C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- UWITWVXLWLBPCU-UHFFFAOYSA-N methyl 5-methylsulfonyl-3-oxo-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C(O)=NSC=1S(C)(=O)=O UWITWVXLWLBPCU-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- NNXMKFQFURUZQB-UHFFFAOYSA-N 1,2-thiazole-3-thione Chemical compound SC=1C=CSN=1 NNXMKFQFURUZQB-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 150000007513 acids Chemical group 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical class O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 description 3
- RZJCAPLYUBBPPE-UHFFFAOYSA-N methyl 3-methoxycarbonyloxy-5-methylsulfanyl-1,2-thiazole-4-carboxylate Chemical compound COC(=O)OC1=NSC(SC)=C1C(=O)OC RZJCAPLYUBBPPE-UHFFFAOYSA-N 0.000 description 3
- SBKINGHNPUEFHX-UHFFFAOYSA-N methyl 3-methoxycarbonyloxy-5-methylsulfonyl-1,2-thiazole-4-carboxylate Chemical compound COC(=O)OC1=NSC(S(C)(=O)=O)=C1C(=O)OC SBKINGHNPUEFHX-UHFFFAOYSA-N 0.000 description 3
- LELGRSWICDCODU-UHFFFAOYSA-N methyl 5-methylsulfanyl-3-oxo-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C(O)=NSC=1SC LELGRSWICDCODU-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OKRROXQXGNEUSS-UHFFFAOYSA-N 1h-imidazol-1-ium-1-carboxylate Chemical compound OC(=O)N1C=CN=C1 OKRROXQXGNEUSS-UHFFFAOYSA-N 0.000 description 2
- PINKTXRKCALTEU-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid Chemical group BrC1=CC(=C(COC2=NSC(=C2C(=O)O)S(=O)(=O)C)C(=C1)F)F PINKTXRKCALTEU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- HTZYETABNKXNNX-UHFFFAOYSA-N ethene-1,1-dithiol Chemical compound SC(S)=C HTZYETABNKXNNX-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- 230000004862 vasculogenesis Effects 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RSEKKXIUGAEHBG-UHFFFAOYSA-N 1-sulfonyl-1,2-thiazole Chemical compound S(=O)(=O)=S1N=CC=C1 RSEKKXIUGAEHBG-UHFFFAOYSA-N 0.000 description 1
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- WKCLDWBEDQOPTO-UHFFFAOYSA-N 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound C1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN2C(CCC2)CO)=C1C(N)=O WKCLDWBEDQOPTO-UHFFFAOYSA-N 0.000 description 1
- DYTGJDKRYVLILD-UHFFFAOYSA-N 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound FC1=CC(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCCN2CCCC2)=C1C(N)=O DYTGJDKRYVLILD-UHFFFAOYSA-N 0.000 description 1
- KOZFIMSVPMYVSF-UHFFFAOYSA-N 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[4-(dimethylamino)butylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound NC(=O)C1=C(NC(=O)NCCCCN(C)C)SN=C1OCC1=C(F)C=C(C)C=C1F KOZFIMSVPMYVSF-UHFFFAOYSA-N 0.000 description 1
- CQZGCMLNUGONKK-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxamide Chemical compound C1CN(C)CCN1CCCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=CC(Br)=CC=2F)F)=NS1 CQZGCMLNUGONKK-UHFFFAOYSA-N 0.000 description 1
- YRXZENYHAZGPBF-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 YRXZENYHAZGPBF-UHFFFAOYSA-N 0.000 description 1
- KXZQJNNZLZSZEA-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound CN1CCCC1CCNC(=O)NC1=C(C(O)=O)C(OCC=2C(=C(F)C(Cl)=CC=2F)F)=NS1 KXZQJNNZLZSZEA-UHFFFAOYSA-N 0.000 description 1
- DCZUKMJDYHQFBY-UHFFFAOYSA-N 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylic acid Chemical compound CN1CC2CC1CN2CCCNC(=O)NC(=C1C(O)=O)SN=C1OCC1=C(F)C=C(Cl)C(F)=C1F DCZUKMJDYHQFBY-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 1
- ITUTYGOXGTZQRV-UHFFFAOYSA-N 4-chloro-5-[4-[2-(hydroxymethyl)piperidin-1-yl]butylcarbamoylamino]-3-[(2,3,6-trifluorophenyl)methoxy]-5H-1,2-thiazole-4-carboxylic acid Chemical compound ClC1(C(=NSC1NC(=O)NCCCCN1C(CCCC1)CO)OCC1=C(C(=CC=C1F)F)F)C(=O)O ITUTYGOXGTZQRV-UHFFFAOYSA-N 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 description 1
- LSDYCEIPEBJKPT-UHFFFAOYSA-N 4-pyrrolidin-1-ylbutan-1-amine Chemical compound NCCCCN1CCCC1 LSDYCEIPEBJKPT-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- RBHHELBRBWBBTD-UHFFFAOYSA-N 5-[(4-hydroxy-5-piperidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound FC1=C(F)C(C)=CC(F)=C1COC1=NSC(NC(=O)NCCCC(O)CN2CCCCC2)=C1C(N)=O RBHHELBRBWBBTD-UHFFFAOYSA-N 0.000 description 1
- SKYJJHBJQTTWCK-UHFFFAOYSA-N 5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxamide Chemical compound CN1CCCC1CCNC(=O)NC1=C(C(N)=O)C(OCC=2C(=C(F)C(C)=CC=2F)F)=NS1 SKYJJHBJQTTWCK-UHFFFAOYSA-N 0.000 description 1
- INTFUGIOGWXMCU-UHFFFAOYSA-N 5-amino-3-[(4-bromo-2,6-difluorophenyl)methoxy]-1,2-thiazole-4-carboxylic acid Chemical group NC1=C(C(=NS1)OCC1=C(C=C(C=C1F)Br)F)C(=O)O INTFUGIOGWXMCU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- PAHVXADNKOJZBW-UHFFFAOYSA-N COC(=O)C1(C(=NSC1NC(=O)NCCCCN1C(CCCC1)CO)OCC1=C(C(=CC=C1F)F)F)Cl Chemical compound COC(=O)C1(C(=NSC1NC(=O)NCCCCN1C(CCCC1)CO)OCC1=C(C(=CC=C1F)F)F)Cl PAHVXADNKOJZBW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 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
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 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
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical class CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- GPWFZNXSBNZLHU-UHFFFAOYSA-N S(=O)=S1N=CC=C1 Chemical compound S(=O)=S1N=CC=C1 GPWFZNXSBNZLHU-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- HYCQPBOMQVFBMK-UHFFFAOYSA-N [N].OCC1=C(F)C=C(Br)C=C1F Chemical compound [N].OCC1=C(F)C=C(Br)C=C1F HYCQPBOMQVFBMK-UHFFFAOYSA-N 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 description 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 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
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- URMDGTOVYDJCNM-UHFFFAOYSA-N dimethyl 2-[methylsulfanyl(sulfanyl)methylidene]propanedioate Chemical compound COC(=O)C(C(=O)OC)=C(S)SC URMDGTOVYDJCNM-UHFFFAOYSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000011967 lanthanide triflate Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 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
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KUHWVZGKCZLWSS-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC(O)CCN1CCCC1 KUHWVZGKCZLWSS-UHFFFAOYSA-N 0.000 description 1
- VCLBZKNPAWEHFI-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[3-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCN2C3CC(N(C3)C)C2)SN=C1OCC1=C(F)C=C(Cl)C(F)=C1F VCLBZKNPAWEHFI-UHFFFAOYSA-N 0.000 description 1
- WDFJVRHIASMJTB-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-(3,4-dihydroxypyrrolidin-1-yl)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CC(O)C(O)C1 WDFJVRHIASMJTB-UHFFFAOYSA-N 0.000 description 1
- DWUFOSZUVFTSQA-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)piperidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCCC1CO DWUFOSZUVFTSQA-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- DMTUQTRZIMTUQV-UHFFFAOYSA-N potassium;ethenylideneazanide Chemical compound [K+].[CH2-]C#N DMTUQTRZIMTUQV-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 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
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229910021381 transition metal chloride Inorganic materials 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- 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
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60454204P | 2004-08-26 | 2004-08-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT1784183E true PT1784183E (pt) | 2012-03-09 |
Family
ID=36000502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT05778840T PT1784183E (pt) | 2004-08-26 | 2005-08-02 | Processos para a preparação de derivados de isotiazole |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US8884025B2 (https=) |
| EP (1) | EP1784183B1 (https=) |
| JP (2) | JP5100390B2 (https=) |
| KR (1) | KR100893977B1 (https=) |
| CN (1) | CN101043888B (https=) |
| AR (1) | AR050613A1 (https=) |
| AT (1) | ATE542533T1 (https=) |
| AU (1) | AU2005280451B2 (https=) |
| BR (1) | BRPI0514667A (https=) |
| CA (1) | CA2578023C (https=) |
| DK (1) | DK1784183T3 (https=) |
| ES (1) | ES2378994T3 (https=) |
| IL (1) | IL181063A0 (https=) |
| MX (1) | MX2007002246A (https=) |
| NO (1) | NO20071319L (https=) |
| PL (1) | PL1784183T3 (https=) |
| PT (1) | PT1784183E (https=) |
| RU (1) | RU2349588C2 (https=) |
| TW (1) | TWI361688B (https=) |
| WO (1) | WO2006026034A2 (https=) |
| ZA (1) | ZA200701016B (https=) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1784183E (pt) | 2004-08-26 | 2012-03-09 | Pfizer | Processos para a preparação de derivados de isotiazole |
| ES2623652T3 (es) | 2011-12-28 | 2017-07-11 | Allergan, Inc. | Derivados de 3-fenil-5-ureidoisotiazol-4-carboximida y 3-amino-5-fenilisotiazol como inhibidores de cinasa |
| CN103833665B (zh) * | 2014-02-24 | 2015-09-23 | 杰达维（上海）医药科技发展有限公司 | 一种新的合成异噻唑的方法 |
| US9353093B2 (en) | 2014-10-07 | 2016-05-31 | Allergan, Inc. | Indole-1-carboxamides as kinase inhibitors |
| US9403803B2 (en) | 2014-10-08 | 2016-08-02 | Allergan, Inc. | Indole-3-carboxamides as kinase inhibitors |
| US9359336B2 (en) | 2014-10-09 | 2016-06-07 | Allergan, Inc. | Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors |
| US9371314B2 (en) | 2014-10-09 | 2016-06-21 | Allergan, Inc. | Pyridyl benzothiophenes as kinase inhibitors |
| AU2023416218A1 (en) * | 2022-12-28 | 2025-07-10 | Beyang Therapeutics Co., Ltd. | Protein tyrosine kinase inhibitor and medical use thereof |
| WO2026002126A1 (zh) * | 2024-06-27 | 2026-01-02 | 苏州必扬医药科技有限公司 | 一种蛋白酪氨酸激酶抑制剂及其眼用制剂 |
| WO2026002137A1 (zh) * | 2024-06-27 | 2026-01-02 | 苏州必扬医药科技有限公司 | 一种蛋白酪氨酸激酶抑制剂游离碱的晶型 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2408234A1 (de) * | 1974-02-21 | 1975-09-04 | Celamerck Gmbh & Co Kg | Isothiazolylharnstoffe |
| US4059433A (en) * | 1976-06-18 | 1977-11-22 | Fmc Corporation | 3-Alkoxyisothiazole derivatives as herbicides |
| IL72093A0 (en) * | 1983-06-20 | 1984-10-31 | Lilly Co Eli | N'-substituted(3-alkyl-5-isothiazolyl)urea derivatives |
| UA60365C2 (uk) * | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
| HN2000000051A (es) * | 1999-05-19 | 2001-02-02 | Pfizer Prod Inc | Derivados heterociclicos utiles como agentes anticancerosos |
| GB0010188D0 (en) * | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
| EP1527071A1 (en) * | 2002-07-25 | 2005-05-04 | Pfizer Products Inc. | Isothiazole derivatives useful as anticancer agents |
| US20060035954A1 (en) * | 2004-08-11 | 2006-02-16 | Sharma Padam N | Ammonolysis process for the preparation of intermediates for DPP IV inhibitors |
| PT1784183E (pt) | 2004-08-26 | 2012-03-09 | Pfizer | Processos para a preparação de derivados de isotiazole |
-
2005
- 2005-08-02 PT PT05778840T patent/PT1784183E/pt unknown
- 2005-08-02 MX MX2007002246A patent/MX2007002246A/es active IP Right Grant
- 2005-08-02 BR BRPI0514667-4A patent/BRPI0514667A/pt active Search and Examination
- 2005-08-02 CA CA2578023A patent/CA2578023C/en not_active Expired - Fee Related
- 2005-08-02 RU RU2007106847/04A patent/RU2349588C2/ru not_active IP Right Cessation
- 2005-08-02 JP JP2007537876A patent/JP5100390B2/ja not_active Expired - Fee Related
- 2005-08-02 AT AT05778840T patent/ATE542533T1/de active
- 2005-08-02 EP EP05778840A patent/EP1784183B1/en not_active Expired - Lifetime
- 2005-08-02 ES ES05778840T patent/ES2378994T3/es not_active Expired - Lifetime
- 2005-08-02 AU AU2005280451A patent/AU2005280451B2/en not_active Ceased
- 2005-08-02 CN CN2005800284337A patent/CN101043888B/zh not_active Expired - Fee Related
- 2005-08-02 US US11/574,046 patent/US8884025B2/en not_active Expired - Fee Related
- 2005-08-02 DK DK05778840.8T patent/DK1784183T3/da active
- 2005-08-02 PL PL05778840T patent/PL1784183T3/pl unknown
- 2005-08-02 KR KR1020077004371A patent/KR100893977B1/ko not_active Expired - Fee Related
- 2005-08-02 WO PCT/US2005/027398 patent/WO2006026034A2/en not_active Ceased
- 2005-08-22 TW TW094128618A patent/TWI361688B/zh not_active IP Right Cessation
- 2005-08-23 AR ARP050103539A patent/AR050613A1/es not_active Application Discontinuation
-
2007
- 2007-01-30 IL IL181063A patent/IL181063A0/en unknown
- 2007-02-02 ZA ZA200701016A patent/ZA200701016B/xx unknown
- 2007-03-09 NO NO20071319A patent/NO20071319L/no not_active Application Discontinuation
-
2012
- 2012-03-30 JP JP2012079463A patent/JP5498524B2/ja not_active Expired - Fee Related
-
2014
- 2014-11-10 US US14/537,093 patent/US9371298B2/en not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5498524B2 (ja) | イソチアゾール誘導体の製造方法 | |
| ES2870524T3 (es) | Derivado de piridina como inhibidor de ASK1, y método de preparación y uso del mismo | |
| ES2278578T3 (es) | Procedimientos y compuestos intermedios para preparar compuestos anticancerigenos. | |
| ES2379076T3 (es) | Derivados de pirazol útiles como inhibidores de COX-I | |
| ES2442369T3 (es) | Derivados de quinolina y quinoxalina como inhibidores de cinasa | |
| CN114685460A (zh) | Kras g12c抑制剂及其在医药上的应用 | |
| BR112021015639A2 (pt) | Compostos, composições e métodos | |
| ES2874656T3 (es) | Compuesto tricíclico y aplicaciones del mismo | |
| BRPI0912878B1 (pt) | Compostos derivados de indazóis substituídos por fenila e benzodioxinila e composição farmacêutica que os compreende | |
| JP2023166434A (ja) | 細胞毒性ベンゾジアゼピン誘導体の調製方法 | |
| BR112015031004A2 (pt) | Processos para fabricação e formas cristalinas de um inibidor de mdm2 | |
| ES2774363T3 (es) | Proceso para preparar cicloserinas sustituidas | |
| ES2261721T3 (es) | Formulaciones de 3,7-diazabiciclo(3.3.1) como compuestos antiarritmicos. | |
| ES2908240T3 (es) | Inhibidores de la enzima amida hidrolasa de ácidos grasos (FAAH) con biodisponibilidad oral mejorada y su uso como medicamentos | |
| ES2641258T3 (es) | Compuesto heterocíclico bicíclico | |
| BRPI0706493A2 (pt) | antagonistas de receptor de urotensina ii, composição farmcêutica e veterinária que os contém e uso dos mesmos | |
| PT1854789E (pt) | Derivado de quinazolina possuindo actividade inibidora de tirosina-cinase | |
| ES2861050T3 (es) | Procedimiento de producción de derivado de tiazol | |
| HK1111359B (en) | Processes for the preparation of isothiazole derivatives | |
| BR102015005344A2 (pt) | processo e intermediários para a preparação de dasatinib | |
| Sun et al. | Synthesis and antiproliferative activity of novel 4-substituted-phenoxy-benzamide derivatives | |
| CN102712582A (zh) | (e)-羟基亚氨基苯基乙酸衍生物的制备方法 | |
| ES2351574A1 (es) | Bibliotecas de n-fenetisulfonamidas-n-sustituidas para el descubrimiento de farmacos. |