ES2823127T3 - Compuestos tricíclicos de quinolina y azaquinolina sustituidos con heteroarilo como inhibidores de PAR4 - Google Patents
Compuestos tricíclicos de quinolina y azaquinolina sustituidos con heteroarilo como inhibidores de PAR4 Download PDFInfo
- Publication number
- ES2823127T3 ES2823127T3 ES17742926T ES17742926T ES2823127T3 ES 2823127 T3 ES2823127 T3 ES 2823127T3 ES 17742926 T ES17742926 T ES 17742926T ES 17742926 T ES17742926 T ES 17742926T ES 2823127 T3 ES2823127 T3 ES 2823127T3
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- ES
- Spain
- Prior art keywords
- ethyl
- thiazol
- ethoxy
- benzo
- dioxino
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 191
- 101001113471 Homo sapiens Proteinase-activated receptor 4 Proteins 0.000 title description 56
- 102100023710 Proteinase-activated receptor 4 Human genes 0.000 title description 56
- 101000613565 Homo sapiens PRKC apoptosis WT1 regulator protein Proteins 0.000 title description 52
- 239000003112 inhibitor Substances 0.000 title description 13
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
- -1 -S (O) 2NRaRa Chemical group 0.000 claims abstract description 796
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 222
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 56
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 55
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 48
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 42
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 39
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 39
- 125000001424 substituent group Chemical group 0.000 claims abstract description 37
- 239000012453 solvate Substances 0.000 claims abstract description 29
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims abstract description 28
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 28
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 25
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 21
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 21
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 19
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 18
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 18
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 16
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 16
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims abstract description 16
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 16
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 claims abstract description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 11
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 10
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims abstract description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 9
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims abstract description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 9
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims abstract description 9
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 8
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims abstract description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 4
- 125000002541 furyl group Chemical group 0.000 claims abstract description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 230
- 238000000034 method Methods 0.000 claims description 189
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 176
- 235000013350 formula milk Nutrition 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
- 239000000460 chlorine Substances 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 208000035475 disorder Diseases 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 230000009424 thromboembolic effect Effects 0.000 claims description 38
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 30
- 208000007536 Thrombosis Diseases 0.000 claims description 21
- 210000004369 blood Anatomy 0.000 claims description 15
- 239000008280 blood Substances 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 206010047249 Venous thrombosis Diseases 0.000 claims description 14
- 125000004532 benzofuran-3-yl group Chemical group O1C=C(C2=C1C=CC=C2)* 0.000 claims description 14
- 125000005605 benzo group Chemical group 0.000 claims description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 11
- 201000001320 Atherosclerosis Diseases 0.000 claims description 11
- 208000006011 Stroke Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 229920006358 Fluon Polymers 0.000 claims description 9
- RTLYCOOENXHEGT-UHFFFAOYSA-N [2-(2-hydroxyethoxy)pyrimidin-5-yl] carbamate Chemical compound C(N)(OC=1C=NC(=NC=1)OCCO)=O RTLYCOOENXHEGT-UHFFFAOYSA-N 0.000 claims description 9
- 239000007943 implant Substances 0.000 claims description 8
- OKGVGUUEFJXBGT-UHFFFAOYSA-N (3-cyanophenyl) carbamate Chemical compound NC(=O)Oc1cccc(c1)C#N OKGVGUUEFJXBGT-UHFFFAOYSA-N 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 206010002388 Angina unstable Diseases 0.000 claims description 5
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 5
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 5
- 206010011091 Coronary artery thrombosis Diseases 0.000 claims description 5
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 5
- 206010063544 Renal embolism Diseases 0.000 claims description 5
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 5
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 5
- 208000002528 coronary thrombosis Diseases 0.000 claims description 5
- 201000010849 intracranial embolism Diseases 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 201000005060 thrombophlebitis Diseases 0.000 claims description 5
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 5
- DOHQSYULTPMCOG-UHFFFAOYSA-N (6-cyanopyridin-3-yl) carbamate Chemical compound NC(=O)OC1=CC=C(C#N)N=C1 DOHQSYULTPMCOG-UHFFFAOYSA-N 0.000 claims description 4
- BYWHPNJRQASNFX-ZDUSSCGKSA-N 1-cyclopropyl-3-[[(7S)-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrofuro[2,3-g][1,3]benzothiazol-7-yl]methyl]urea Chemical compound C1(CC1)NC(=O)NC[C@H]1OC2=C(C1)C1=C(N=C(S1)C1=C3N=CC(=NC3=CC(=C1)C)OC)C=C2F BYWHPNJRQASNFX-ZDUSSCGKSA-N 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- VOYIQZJXBICUOX-NSHDSACASA-N [(7S)-2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluoro-7,8-dihydrofuro[2,3-g][1,3]benzothiazol-7-yl]methanol Chemical compound C(C)OC1=NC2=CC(=CC(=C2N=C1)C=1SC2=C(N=1)C=C(C1=C2C[C@H](O1)CO)F)C VOYIQZJXBICUOX-NSHDSACASA-N 0.000 claims description 4
- INLUMHLYFJRCGX-UHFFFAOYSA-N [2-(2-methoxy-7-methylquinoxalin-5-yl)-8-methyl-7,8-dihydrofuro[2,3-g][1,3]benzothiazol-7-yl]methanol Chemical compound COC1=NC2=CC(=CC(=C2N=C1)C=1SC2=C(N=1)C=CC1=C2C(C(O1)CO)C)C INLUMHLYFJRCGX-UHFFFAOYSA-N 0.000 claims description 4
- YVTYOJPYNLAXHP-UHFFFAOYSA-N [2-[2-(difluoromethoxy)-7-methylquinoxalin-5-yl]-4-fluoro-7,8-dihydro-[1,4]dioxino[2,3-g][1,3]benzothiazol-8-yl]methanol Chemical compound FC(OC1=NC2=CC(=CC(=C2N=C1)C=1SC2=C(N=1)C(=CC1=C2OC(CO1)CO)F)C)F YVTYOJPYNLAXHP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000006393 methylpyrimidinyl group Chemical group 0.000 claims description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 claims description 4
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims description 4
- APJYETRMZMJYLZ-RFAUZJTJSA-N 8-[(7S,8S)-5-fluoro-7-(hydroxymethyl)-8-methyl-7,8-dihydrofuro[2,3-g][1,3]benzothiazol-2-yl]-3-methoxyquinoxaline-6-carbonitrile Chemical compound FC1=CC=2N=C(SC=2C=2[C@@H]([C@H](OC=21)CO)C)C=1C=C(C=C2N=C(C=NC=12)OC)C#N APJYETRMZMJYLZ-RFAUZJTJSA-N 0.000 claims description 3
- 241000534944 Thia Species 0.000 claims description 3
- FGZXSIJJADHBRO-UHFFFAOYSA-N [6-(dimethylamino)pyridin-3-yl] carbamate Chemical compound C(N)(OC=1C=NC(=CC=1)N(C)C)=O FGZXSIJJADHBRO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 claims description 3
- DXGPLGPVXNBIQZ-UHFFFAOYSA-L copper;2-hydroxybenzoate;methyl n-(1h-benzimidazol-2-yl)carbamate;6-methyl-n-phenyl-2,3-dihydro-1,4-oxathiine-5-carboxamide;quinolin-8-olate Chemical compound [Cu+2].OC1=CC=CC=C1C([O-])=O.C1=CN=C2C([O-])=CC=CC2=C1.C1=CC=C2NC(NC(=O)OC)=NC2=C1.S1CCOC(C)=C1C(=O)NC1=CC=CC=C1 DXGPLGPVXNBIQZ-UHFFFAOYSA-L 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 3
- 238000011324 primary prophylaxis Methods 0.000 claims description 3
- HBJCINXCGUYMGB-UHFFFAOYSA-N (2-phenylpyridin-4-yl) carbamate Chemical compound NC(OC1=CC(C2=CC=CC=C2)=NC=C1)=O HBJCINXCGUYMGB-UHFFFAOYSA-N 0.000 claims description 2
- CYKFBZKEZZXXPP-UHFFFAOYSA-N 2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrofuro[2,3-g][1,3]benzothiazole-7-carboxylic acid Chemical compound COc1cnc2c(cc(C)cc2n1)-c1nc2ccc3OC(Cc3c2s1)C(O)=O CYKFBZKEZZXXPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 230000003836 peripheral circulation Effects 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- KXSIUJJLRBAPGB-UHFFFAOYSA-N 2-ethylquinoxaline Chemical compound C1=CC=CC2=NC(CC)=CN=C21 KXSIUJJLRBAPGB-UHFFFAOYSA-N 0.000 claims 12
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 5
- MJIPSRRYLBPEGR-UHFFFAOYSA-N C1CC2=C(O1)C=CC=1N=C(SC2=1)CC Chemical compound C1CC2=C(O1)C=CC=1N=C(SC2=1)CC MJIPSRRYLBPEGR-UHFFFAOYSA-N 0.000 claims 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 4
- BZWGPEOBQUNEDP-UHFFFAOYSA-N (5-fluoropyridin-3-yl) carbamate Chemical compound C(N)(OC=1C=NC=C(C=1)F)=O BZWGPEOBQUNEDP-UHFFFAOYSA-N 0.000 claims 3
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims 3
- 101100021281 Caenorhabditis elegans lin-8 gene Proteins 0.000 claims 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 3
- RUOJLMWDYMDFTL-INIZCTEOSA-N 1-[[(7S)-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrofuro[2,3-g][1,3]benzothiazol-7-yl]methyl]-3-phenylurea Chemical compound FC1=CC=2N=C(SC=2C=2C[C@H](OC=21)CNC(=O)NC1=CC=CC=C1)C1=C2N=CC(=NC2=CC(=C1)C)OC RUOJLMWDYMDFTL-INIZCTEOSA-N 0.000 claims 2
- UQSIEHVSHVIAPB-UHFFFAOYSA-N [1-(trifluoromethyl)cyclobutyl]methanol Chemical compound OCC1(C(F)(F)F)CCC1 UQSIEHVSHVIAPB-UHFFFAOYSA-N 0.000 claims 2
- YYWSKSKIJXVNTH-UHFFFAOYSA-N [1-(trifluoromethyl)cyclopropyl]methanol Chemical compound OCC1(C(F)(F)F)CC1 YYWSKSKIJXVNTH-UHFFFAOYSA-N 0.000 claims 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 2
- AFCCDDWKHLHPDF-UHFFFAOYSA-M metam-sodium Chemical compound [Na+].CNC([S-])=S AFCCDDWKHLHPDF-UHFFFAOYSA-M 0.000 claims 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims 2
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- 200000000007 Arterial disease Diseases 0.000 claims 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
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- 206010037437 Pulmonary thrombosis Diseases 0.000 claims 1
- DECIPOUIJURFOJ-UHFFFAOYSA-N ethoxyquin Chemical compound N1C(C)(C)C=C(C)C2=CC(OCC)=CC=C21 DECIPOUIJURFOJ-UHFFFAOYSA-N 0.000 claims 1
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- 230000002093 peripheral effect Effects 0.000 claims 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims 1
- WDZVYHXDNNXLFP-UHFFFAOYSA-N pyridin-3-yl carbamate Chemical compound NC(=O)OC1=CC=CN=C1 WDZVYHXDNNXLFP-UHFFFAOYSA-N 0.000 claims 1
- YPTJZFKTXNUWIN-UHFFFAOYSA-N pyridin-3-yl hydrogen carbonate Chemical compound OC(=O)OC1=CC=CN=C1 YPTJZFKTXNUWIN-UHFFFAOYSA-N 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract description 19
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract description 10
- 125000005348 fluorocycloalkyl group Chemical group 0.000 abstract description 8
- 125000002971 oxazolyl group Chemical group 0.000 abstract description 8
- 125000004103 aminoalkyl group Chemical group 0.000 abstract description 4
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- 101150017724 Crhr1 gene Proteins 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 366
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 269
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- 235000019439 ethyl acetate Nutrition 0.000 description 133
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 124
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- 239000000203 mixture Substances 0.000 description 115
- 239000007787 solid Substances 0.000 description 98
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 238000005160 1H NMR spectroscopy Methods 0.000 description 77
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000002904 solvent Substances 0.000 description 76
- 239000012267 brine Substances 0.000 description 75
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 75
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 71
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- 238000006243 chemical reaction Methods 0.000 description 50
- 239000012044 organic layer Substances 0.000 description 48
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 46
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D515/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
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| US201662362121P | 2016-07-14 | 2016-07-14 | |
| PCT/US2017/041880 WO2018013776A1 (en) | 2016-07-14 | 2017-07-13 | Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors |
Publications (1)
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| ES2823127T3 true ES2823127T3 (es) | 2021-05-06 |
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| WO2018013772A1 (en) * | 2016-07-14 | 2018-01-18 | Bristol-Myers Squibb Company | Monocyclic heteroaryl substituted compounds |
| KR102494647B1 (ko) | 2016-07-14 | 2023-01-31 | 브리스톨-마이어스 스큅 컴퍼니 | 비시클릭 헤테로아릴 치환된 화합물 |
| JP7058256B2 (ja) | 2016-07-14 | 2022-04-21 | ブリストル－マイヤーズ スクイブ カンパニー | 二環式ヘテロアリール置換化合物 |
| CN111440146B (zh) * | 2020-05-15 | 2022-10-21 | 中国药科大学 | 一种具有par4拮抗活性的苯并三嗪类化合物及其应用 |
| CN117285527A (zh) * | 2023-09-25 | 2023-12-26 | 中国药科大学 | 一种噌啉类par4拮抗剂及其医药应用 |
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| CA1164459A (en) * | 1980-11-11 | 1984-03-27 | Yung-Hsiung Yang | Process for preparing (imidazo¬1,2-a|pyridine- 2-yl)-carbostyril or -3,4-dihydrocarbostyryl derivatives |
| TW279162B (cg-RX-API-DMAC7.html) * | 1991-09-26 | 1996-06-21 | Mitsubishi Chem Corp | |
| JP2928079B2 (ja) | 1994-02-14 | 1999-07-28 | 永信薬品工業股▲ふん▼有限公司 | １−（置換ベンジル）−３−（置換アリール）縮合ピラゾール類、その製造法及びその用途 |
| US6166041A (en) | 1995-10-11 | 2000-12-26 | Euro-Celtique, S.A. | 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma |
| US6387942B2 (en) * | 2000-06-19 | 2002-05-14 | Yung Shin Pharmaceutical Ind. Co. Ltd | Method of treating disorders related to protease-activated receptors-induced cell activation |
| EP1348701A1 (en) | 2002-03-28 | 2003-10-01 | Warner-Lambert Company LLC | (2,4-disubstituted-thiazol-5-yl) amine compounds as PDE7 inhibitors |
| JP2007501189A (ja) | 2003-08-01 | 2007-01-25 | ジェネラブス テクノロジーズ，インコーポレイテッド | フラビウイルス科に対する二環式イミダゾール誘導体 |
| US20050272784A1 (en) | 2004-05-07 | 2005-12-08 | Xiaobing Li | Inhibitors of bacterial Type III protein secretion systems |
| AU2005267798A1 (en) | 2004-07-28 | 2006-02-09 | Irm Llc | Compounds and compositions as modulators of steroid hormone nuclear receptors |
| KR20070098914A (ko) | 2005-01-14 | 2007-10-05 | 제네랩스 테크놀로지스, 인코포레이티드 | 바이러스 감염을 치료하기 위한 인돌 유도체 |
| WO2007149395A2 (en) | 2006-06-20 | 2007-12-27 | Amphora Discovery Corporation | 2,5-substituted oxazole derivatives as protein kinase inhibitors for the treatment of cancer |
| CN101479249B (zh) | 2006-06-29 | 2012-10-10 | 霍夫曼-拉罗奇有限公司 | 苯并咪唑衍生物、其制备方法、它们作为fxr激动剂的用途及含有它们的药物制剂 |
| WO2008073451A2 (en) | 2006-12-11 | 2008-06-19 | Sirtris Pharmaceuticals, Inc. | Benzoimidazole derivatives as sirtuin (sir) modulating compounds |
| AU2008331480A1 (en) | 2007-11-30 | 2009-06-11 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
| ES2586459T3 (es) | 2008-05-01 | 2016-10-14 | Glaxosmithkline Llc | Quinolinas y análogos relacionados como moduladores de sirtuina |
| EA021421B1 (ru) | 2008-05-23 | 2015-06-30 | Новартис Аг | Производные хинолинов и хиноксалинов в качестве ингибиторов протеинтирозинкиназы, способ их получения, содержащая их фармацевтическая композиция и способ лечения заболеваний с применением таких соединений |
| JP5631310B2 (ja) | 2008-07-23 | 2014-11-26 | 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Ｖｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ | 三環式ピラゾロピリジンキナーゼ阻害剤 |
| US20130072473A1 (en) | 2011-05-09 | 2013-03-21 | Proteostasis Therapeutics, Inc. | Compounds for treating protein folding disorders |
| WO2013130660A1 (en) | 2012-02-28 | 2013-09-06 | Amgen Inc. | Amides as pim inhibitors |
| RS59882B1 (sr) | 2012-04-26 | 2020-03-31 | Bristol Myers Squibb Co | Derivati imidazotiadiazola i imidazopirazina kao inhibitori proteazom aktiviranog receptora 4 (par4) za lečenje agregacije trombocita |
| WO2013163244A1 (en) * | 2012-04-26 | 2013-10-31 | Bristol-Myers Squibb Company | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| AU2013251680A1 (en) * | 2012-04-26 | 2014-11-13 | Bristol-Myers Squibb Company | Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CA2922542A1 (en) * | 2013-11-22 | 2015-05-28 | University Of Kentucky Research Foundation | Arylquinoline and analog compounds and use thereof to treat cancer |
| US9598419B1 (en) | 2014-06-24 | 2017-03-21 | Universite De Montreal | Imidazotriazine and imidazodiazine compounds |
| US9617279B1 (en) | 2014-06-24 | 2017-04-11 | Bristol-Myers Squibb Company | Imidazooxadiazole compounds |
| WO2016138199A1 (en) | 2015-02-26 | 2016-09-01 | Bristol-Myers Squibb Company | Benzothiazole and benzothiophne compounds |
| ES2929208T3 (es) | 2015-02-26 | 2022-11-25 | Univ Montreal | Compuestos de imidazotiadiazol como inhibidores de PAR4 |
| WO2017019828A1 (en) * | 2015-07-30 | 2017-02-02 | Bristol-Myers Squibb Company | Aryl substituted bicyclic heteroaryl compounds |
| WO2018013772A1 (en) | 2016-07-14 | 2018-01-18 | Bristol-Myers Squibb Company | Monocyclic heteroaryl substituted compounds |
| KR102494647B1 (ko) | 2016-07-14 | 2023-01-31 | 브리스톨-마이어스 스큅 컴퍼니 | 비시클릭 헤테로아릴 치환된 화합물 |
| JP7058256B2 (ja) * | 2016-07-14 | 2022-04-21 | ブリストル－マイヤーズ スクイブ カンパニー | 二環式ヘテロアリール置換化合物 |
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- 2017-07-13 EP EP17742926.3A patent/EP3484894B1/en active Active
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| US11932658B2 (en) | 2024-03-19 |
| EP3484894A1 (en) | 2019-05-22 |
| EP3484894B1 (en) | 2020-08-19 |
| CN109689664B (zh) | 2022-04-15 |
| CN109689664A (zh) | 2019-04-26 |
| US20210188877A1 (en) | 2021-06-24 |
| WO2018013776A1 (en) | 2018-01-18 |
| KR102468661B1 (ko) | 2022-11-17 |
| KR20190026906A (ko) | 2019-03-13 |
| US20190315774A1 (en) | 2019-10-17 |
| JP6903732B2 (ja) | 2021-07-14 |
| US20240309019A1 (en) | 2024-09-19 |
| JP2019524732A (ja) | 2019-09-05 |
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