ES2765891T3 - Derivados de piridinona y pirimidinona como inhibidores del factor XIa - Google Patents
Derivados de piridinona y pirimidinona como inhibidores del factor XIa Download PDFInfo
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- ES2765891T3 ES2765891T3 ES17193874T ES17193874T ES2765891T3 ES 2765891 T3 ES2765891 T3 ES 2765891T3 ES 17193874 T ES17193874 T ES 17193874T ES 17193874 T ES17193874 T ES 17193874T ES 2765891 T3 ES2765891 T3 ES 2765891T3
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- Prior art keywords
- phenyl
- oxo
- imidazol
- chloro
- tetrazol
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims description 19
- 108010080805 Factor XIa Proteins 0.000 title description 22
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 5
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 3
- -1 cyano, oxo, amidino Chemical group 0.000 claims abstract description 768
- 150000001875 compounds Chemical class 0.000 claims abstract description 400
- 150000002367 halogens Chemical class 0.000 claims abstract description 167
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 158
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 137
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 125
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 120
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 115
- 239000001257 hydrogen Substances 0.000 claims abstract description 115
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims abstract description 112
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 100
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 79
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 76
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 66
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 61
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 55
- 125000003118 aryl group Chemical group 0.000 claims abstract description 26
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims abstract description 24
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 18
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 11
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 656
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 208
- 239000002253 acid Substances 0.000 claims description 149
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 102
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 61
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 44
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000001425 triazolyl group Chemical group 0.000 claims description 26
- 125000002883 imidazolyl group Chemical group 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 24
- 150000001204 N-oxides Chemical class 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 208000035475 disorder Diseases 0.000 claims description 22
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 21
- 230000009424 thromboembolic effect Effects 0.000 claims description 21
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 20
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 20
- 125000002971 oxazolyl group Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 20
- 208000001435 Thromboembolism Diseases 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 17
- 206010047249 Venous thrombosis Diseases 0.000 claims description 15
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- IHXNIOYEXQWUNI-UHFFFAOYSA-N 4,5-dihydro-1h-pyrimidin-6-one Chemical compound O=C1CCN=CN1 IHXNIOYEXQWUNI-UHFFFAOYSA-N 0.000 claims description 10
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 10
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 10
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims description 9
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- SUTGPOOOBVWLON-UHFFFAOYSA-N 2-ethoxyethyl carbamate Chemical compound CCOCCOC(N)=O SUTGPOOOBVWLON-UHFFFAOYSA-N 0.000 claims description 6
- QAQJKDRAJZWQCM-UHFFFAOYSA-N 2-methoxyethyl carbamate Chemical compound COCCOC(N)=O QAQJKDRAJZWQCM-UHFFFAOYSA-N 0.000 claims description 6
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 5
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 5
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 5
- 208000007814 Unstable Angina Diseases 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000000302 ischemic effect Effects 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 5
- AARCNTLPYLQRKZ-UHFFFAOYSA-N 4-[2-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C(C2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 AARCNTLPYLQRKZ-UHFFFAOYSA-N 0.000 claims description 4
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 4
- 206010002388 Angina unstable Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 206010014513 Embolism arterial Diseases 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 206010063544 Renal embolism Diseases 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 210000002216 heart Anatomy 0.000 claims description 4
- 239000007943 implant Substances 0.000 claims description 4
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
- 201000010849 intracranial embolism Diseases 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 230000003836 peripheral circulation Effects 0.000 claims description 4
- 230000002093 peripheral effect Effects 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 201000005060 thrombophlebitis Diseases 0.000 claims description 4
- SPLMRIALVABEDR-IBGZPJMESA-N (3s)-3-[4-(6-aminopyridin-3-yl)-5-chloro-1h-imidazol-2-yl]-7-[5-methyl-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound ClC=1NC([C@@H]2CCC3=CC(=CC(=O)N32)C=2C(=CC=C(C=2)C)N2N=NN=C2)=NC=1C1=CC=C(N)N=C1 SPLMRIALVABEDR-IBGZPJMESA-N 0.000 claims description 3
- ZJEGMSCNQOIVFF-DEOSSOPVSA-N (3s)-3-[5-(1-aminoisoquinolin-6-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C([C@H](N1C(=O)C=2)C3=NC=C(N3)C=3C=C4C=CN=C(C4=CC=3)N)CC1=CC=2C1=CC(Cl)=CC=C1N1C=NN=N1 ZJEGMSCNQOIVFF-DEOSSOPVSA-N 0.000 claims description 3
- PNCKFQMSPCUDHI-QFIPXVFZSA-N (3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[5-(4-hydroxyphenyl)-1h-imidazol-2-yl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C1=CC(O)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 PNCKFQMSPCUDHI-QFIPXVFZSA-N 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- JZDGKEHJCKHFOK-UHFFFAOYSA-N 3-[5-(3-amino-1h-indazol-6-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C=1C=C2C(N)=NNC2=CC=1C(N1)=CN=C1C(N1C(=O)C=2)CCC1=CC=2C1=CC(Cl)=CC=C1N1C=NN=N1 JZDGKEHJCKHFOK-UHFFFAOYSA-N 0.000 claims description 3
- ZGQDPLZUQSLSBO-SFHVURJKSA-N 5-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxamide Chemical compound S1C(C(=O)N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 ZGQDPLZUQSLSBO-SFHVURJKSA-N 0.000 claims description 3
- HMLYJELZUZPGSW-DEOSSOPVSA-N 6-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]-3,4-dihydro-1h-quinolin-2-one Chemical compound N1([C@H](C=2NC(=CN=2)C=2C=C3CCC(=O)NC3=CC=2)CCC1=C1)C(=O)C=C1C1=CC(Cl)=CC=C1N1C=NN=N1 HMLYJELZUZPGSW-DEOSSOPVSA-N 0.000 claims description 3
- HMLYJELZUZPGSW-UHFFFAOYSA-N 6-[2-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=C2CCC(C=3NC(=CN=3)C=3C=C4CCC(=O)NC4=CC=3)N2C(=O)C=C1C1=CC(Cl)=CC=C1N1C=NN=N1 HMLYJELZUZPGSW-UHFFFAOYSA-N 0.000 claims description 3
- 200000000007 Arterial disease Diseases 0.000 claims description 3
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- ZLUJIRVHZOKYMM-QFIPXVFZSA-N n-[4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-5-fluoro-1h-imidazol-4-yl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=C(F)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 ZLUJIRVHZOKYMM-QFIPXVFZSA-N 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- RYBNRCILNRLUPI-SFHVURJKSA-N (3s)-3-[4-(6-aminopyridin-3-yl)-5-chloro-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C1=NC(N)=CC=C1C1=C(Cl)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 RYBNRCILNRLUPI-SFHVURJKSA-N 0.000 claims description 2
- MGFOTRWELFFSCU-IBGZPJMESA-N (3s)-3-[5-(6-amino-2-chloropyridin-3-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound ClC1=NC(N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 MGFOTRWELFFSCU-IBGZPJMESA-N 0.000 claims description 2
- GAAMYHWRTMVMAJ-IBGZPJMESA-N (3s)-3-[5-(6-amino-2-fluoropyridin-3-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound FC1=NC(N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 GAAMYHWRTMVMAJ-IBGZPJMESA-N 0.000 claims description 2
- CZHIHAHCJCNHLP-KRWDZBQOSA-N (6s)-6-[5-(6-amino-2-chloropyridin-3-yl)-1h-imidazol-2-yl]-2-[5-chloro-2-(tetrazol-1-yl)phenyl]-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidin-4-one Chemical compound ClC1=NC(N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(N=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 CZHIHAHCJCNHLP-KRWDZBQOSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- RYJFTFGBRPTACZ-UHFFFAOYSA-N 3-methoxypropyl carbamate Chemical compound COCCCOC(N)=O RYJFTFGBRPTACZ-UHFFFAOYSA-N 0.000 claims description 2
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- PMTAHALAIWMBCV-KRWDZBQOSA-N 4-[2-[(6s)-2-[5-chloro-2-(tetrazol-1-yl)phenyl]-4-oxo-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidin-6-yl]-1h-imidazol-5-yl]thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(N=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 PMTAHALAIWMBCV-KRWDZBQOSA-N 0.000 claims description 2
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 claims description 2
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- KYDJQJAIHCVQPO-UHFFFAOYSA-N tert-butyl n-tert-butylcarbamate Chemical compound CC(C)(C)NC(=O)OC(C)(C)C KYDJQJAIHCVQPO-UHFFFAOYSA-N 0.000 description 1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
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- IXZKXMBYXUENQN-UHFFFAOYSA-N tributyl(2h-triazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CNN=N1 IXZKXMBYXUENQN-UHFFFAOYSA-N 0.000 description 1
- YEMJHNYABQHWHL-UHFFFAOYSA-N tributyl(ethynyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C#C YEMJHNYABQHWHL-UHFFFAOYSA-N 0.000 description 1
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- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1122139.7A GB2497806A (en) | 2011-12-21 | 2011-12-21 | Pyridinone and pyrimidinone derivatives as factor XIa inhibitors |
| GB201217290A GB201217290D0 (en) | 2012-09-27 | 2012-09-27 | Compounds |
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| ES2765891T3 true ES2765891T3 (es) | 2020-06-11 |
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| ES17193874T Active ES2765891T3 (es) | 2011-12-21 | 2012-12-20 | Derivados de piridinona y pirimidinona como inhibidores del factor XIa |
| ES12813423.6T Active ES2655669T3 (es) | 2011-12-21 | 2012-12-20 | Derivados de piridinona y pirimidinona como inhibidores del factor XIa |
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| ES12813423.6T Active ES2655669T3 (es) | 2011-12-21 | 2012-12-20 | Derivados de piridinona y pirimidinona como inhibidores del factor XIa |
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| TWI520965B (zh) | 2010-02-11 | 2016-02-11 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之巨環類 |
| KR20140036312A (ko) * | 2011-07-13 | 2014-03-25 | 산텐 세이야꾸 가부시키가이샤 | Ｐａｒｐ 저해 활성을 갖는 신규 화합물 |
| ES2625256T3 (es) | 2011-10-14 | 2017-07-19 | Bristol-Myers Squibb Company | Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIA |
| ES2579832T3 (es) | 2011-10-14 | 2016-08-17 | Bristol-Myers Squibb Company | Compuestos de tetrahidroisoquinolina sustituida como inhibidores del factor XIa |
| EP2766345B1 (en) | 2011-10-14 | 2016-03-16 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| SG11201403402VA (en) * | 2011-12-21 | 2015-01-29 | Ono Pharmaceutical Co | Compounds |
| UY34538A (es) * | 2011-12-23 | 2013-06-28 | Millennium Pharm Inc | Heteroarilos y usos de los mismos |
| HK1209747A1 (en) | 2012-07-19 | 2016-04-08 | 大日本住友制药株式会社 | 1-(cycloalkyl-carbonyl)proline derivative |
| TW201410667A (zh) | 2012-08-03 | 2014-03-16 | 必治妥美雅史谷比公司 | 二氫吡啶酮ｐ１作爲凝血因子ｘｉａ抑制劑 |
| EP2882734B1 (en) | 2012-08-03 | 2016-10-12 | Bristol-Myers Squibb Company | Dihydropyridone as factor xia inhibitors |
| PT2906551T (pt) | 2012-10-12 | 2018-05-10 | Bristol Myers Squibb Co | Formas cristalinas de um inibidor de fator xia |
| US9403774B2 (en) | 2012-10-12 | 2016-08-02 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| US9315519B2 (en) | 2012-10-12 | 2016-04-19 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors |
| EP2978751B1 (en) | 2013-03-25 | 2018-12-05 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors |
| US9809545B2 (en) | 2013-03-27 | 2017-11-07 | Merck Sharp & Dohme Corp. | Factor XIa inhibitors |
| TWI633089B (zh) * | 2013-03-28 | 2018-08-21 | 拜耳製藥股份有限公司 | 經取代的酮基吡啶衍生物 |
| US9475809B2 (en) * | 2013-07-23 | 2016-10-25 | Bayer Pharma Aktiengesellschaft | Substituted oxopyridine derivatives and use thereof as factor xia/plasma |
| CA2928867A1 (en) * | 2013-10-30 | 2015-05-07 | Bayer Pharma Aktiengesellschaft | Substituted oxopyridine derivatives |
| NO2760821T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 2014-01-31 | 2018-03-10 | ||
| ES2687498T3 (es) * | 2014-01-31 | 2018-10-25 | Bristol-Myers Squibb Company | Macrociclos con grupos P2¿ heterocíclicos como inhibidores del factor XIa |
| US9676723B2 (en) | 2014-02-11 | 2017-06-13 | Merck Sharp & Dohme Corp | Factor XIa inhibitors |
| EP3104703B1 (en) | 2014-02-11 | 2020-11-18 | Merck Sharp & Dohme Corp. | Factor xia inhibitors |
| EP3138839B1 (en) | 2014-02-14 | 2020-10-28 | Sichuan Haisco Pharmaceutical Co., Ltd. | Pyridone or pyrimidone derivative, preparation method therefor and application thereof |
| EP3134408B1 (en) | 2014-04-22 | 2020-08-12 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
| WO2016011940A1 (zh) * | 2014-07-25 | 2016-01-28 | 江苏恒瑞医药股份有限公司 | 氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 |
| EP3180317B1 (en) | 2014-07-28 | 2021-04-14 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
| ES2714283T3 (es) | 2014-09-04 | 2019-05-28 | Bristol Myers Squibb Co | Macrociclos de diamida que son inhibidores de FXIa |
| CN104311537B (zh) * | 2014-09-19 | 2016-08-24 | 广东东阳光药业有限公司 | 含有嘧啶酮乙酰基取代基吡唑类化合物及其组合物及用途 |
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| US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
| NO2721243T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) * | 2014-10-01 | 2018-10-20 | ||
| RU2707887C2 (ru) | 2014-12-10 | 2019-12-02 | Оно Фармасьютикал Ко., Лтд. | Производное дигидроиндолизинона |
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| CN111727186B (zh) * | 2018-11-11 | 2022-11-08 | 上海海雁医药科技有限公司 | 双杂环取代的吡啶-2(1h)-酮衍生物、其制法与医药上的用途 |
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| CN109836360B (zh) * | 2019-03-19 | 2021-08-13 | 南京恩泰医药科技有限公司 | 一种甲苯磺酸依度沙班中间体的制备方法及中间体化合物 |
| CN112028877B (zh) * | 2019-06-04 | 2021-11-26 | 江西济民可信集团有限公司 | 烷氧吡啶酮化合物及其制备方法和用途 |
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| CN112778277B (zh) * | 2019-11-11 | 2024-04-02 | 江西济民可信集团有限公司 | 环酮并吡啶酮联杂芳环化合物及其制备方法和用途 |
| JP2023534704A (ja) * | 2020-07-22 | 2023-08-10 | ヤンセン ファーマシューティカ エヌ．ベー． | 第ｘｉａ因子阻害剤として有用な化合物 |
| JP2024125436A (ja) * | 2021-07-20 | 2024-09-19 | 小野薬品工業株式会社 | イミダゾール化合物の製造方法 |
| US20230097157A1 (en) * | 2021-07-22 | 2023-03-30 | Janssen Pharmaceutica Nv | Bicyclic Pyridin-2-one and pyrimidin-4-one Derivatives Useful As a Factor XIa Inhibitors |
| US11958856B2 (en) | 2021-07-22 | 2024-04-16 | Janssen Pharmaceutica Nv | Substituted 1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-ones as factor XIa inhibitors |
| CN113735770B (zh) * | 2021-09-30 | 2023-06-06 | 四川大学 | 一种铑催化的4-苯基噁二唑酮与碳酸亚乙烯酯合成1-氨基异喹啉骨架的方法 |
| CN118974045A (zh) * | 2022-03-21 | 2024-11-15 | 上海济煜医药科技有限公司 | 三并环类化合物制备方法及其中间体 |
| CN116283908A (zh) * | 2023-03-10 | 2023-06-23 | 合肥工业大学 | 一种n-芳香甲基吡啶酮类衍生物及其制备方法与应用 |
| CN118406037B (zh) * | 2024-06-25 | 2025-02-25 | 四川师范大学 | 一种三氮唑类衍生物及其制备方法和用途 |
| CN118894814B (zh) * | 2024-07-15 | 2025-09-12 | 上海康鹏科技股份有限公司 | 1-(2-溴-4-氯苯基)-4-(三氟甲基)-1h-1，2，3-三唑的制备方法 |
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| EP0407342A3 (en) * | 1989-07-06 | 1991-07-10 | Ciba-Geigy Ag | Pyrimidine derivatives |
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| DE4407488A1 (de) * | 1994-03-07 | 1995-09-14 | Bayer Ag | Verwendung von Biphenyl- und Pyridylmethylpyridonen |
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| ATE511502T1 (de) | 2005-12-14 | 2011-06-15 | Bristol Myers Squibb Co | Arylpropionamid-, arylacrylamid-, arylpropinamid- oder arylmethylharnstoffanaloge als faktor-xia- inhibitoren |
| KR20090085117A (ko) * | 2006-11-24 | 2009-08-06 | 다케다 야쿠힌 고교 가부시키가이샤 | 헤테로모노시클릭 화합물 및 이의 용도 |
| WO2008076805A2 (en) | 2006-12-15 | 2008-06-26 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors |
| JP2011506460A (ja) | 2007-12-11 | 2011-03-03 | シェーリング コーポレイション | γ−セクレターゼモジュレーター |
| US8324199B2 (en) * | 2008-03-13 | 2012-12-04 | Bristol-Myers Squibb Company | Pyridazine derivatives as factor xia inhibitors |
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| EP2625170A1 (en) | 2010-10-07 | 2013-08-14 | Takeda Pharmaceutical Company Limited | 1,4-oxazepane derivatives |
| SG11201403402VA (en) * | 2011-12-21 | 2015-01-29 | Ono Pharmaceutical Co | Compounds |
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