KR20160148715A - B형 간염 바이러스 감염의 치료 또는 예방을 위한 신규한 다이하이드로퀴놀리진온 - Google Patents
B형 간염 바이러스 감염의 치료 또는 예방을 위한 신규한 다이하이드로퀴놀리진온 Download PDFInfo
- Publication number
- KR20160148715A KR20160148715A KR1020167034686A KR20167034686A KR20160148715A KR 20160148715 A KR20160148715 A KR 20160148715A KR 1020167034686 A KR1020167034686 A KR 1020167034686A KR 20167034686 A KR20167034686 A KR 20167034686A KR 20160148715 A KR20160148715 A KR 20160148715A
- Authority
- KR
- South Korea
- Prior art keywords
- methoxy
- ethyl
- dihydrobenzo
- oxo
- quinolizine
- 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.)
- Ceased
Links
- 238000011282 treatment Methods 0.000 title claims description 13
- 208000002672 hepatitis B Diseases 0.000 title description 2
- 238000011321 prophylaxis Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 32
- -1 di-C 1-6 alkylamino Chemical group 0.000 claims description 222
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 239000007821 HATU Substances 0.000 claims description 30
- BXWKHIIAMJBZMP-UHFFFAOYSA-N 4h-quinolizine-3-carboxamide Chemical compound C1=CC=CN2CC(C(=O)N)=CC=C21 BXWKHIIAMJBZMP-UHFFFAOYSA-N 0.000 claims description 28
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 208000015181 infectious disease Diseases 0.000 claims description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 150000003857 carboxamides Chemical class 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- CTAVYWUMTZFOFF-UHFFFAOYSA-N 6-ethyl-10-methoxy-3-(methoxymethyl)-9-(3-methoxypropoxy)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound C(C)C1CC2=C(C3=CC(C(=CN13)COC)=O)C=C(C(=C2)OCCCOC)OC CTAVYWUMTZFOFF-UHFFFAOYSA-N 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
- DGCWHOHVNONFSD-UHFFFAOYSA-N quinolizin-2-one Chemical compound C1=CC=CC2=CC(=O)C=CN21 DGCWHOHVNONFSD-UHFFFAOYSA-N 0.000 claims description 5
- KQRWNHQNWJAORD-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-6-ethyl-10-methoxy-9-(3-methoxypropoxy)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound CN(C)CC1=CN2C(CC3=C(C2=CC1=O)C=C(C(=C3)OCCCOC)OC)CC KQRWNHQNWJAORD-UHFFFAOYSA-N 0.000 claims description 4
- GBLRKIJYJPRMPG-UHFFFAOYSA-N 6-ethyl-10-methoxy-N-methylsulfonyl-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NS(=O)(=O)C)=O)C=C1OC GBLRKIJYJPRMPG-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 4
- LTCHJIOBMNJQHJ-UHFFFAOYSA-N 6-ethyl-10-methoxy-9-(3-methoxypropoxy)-3-(methylaminomethyl)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound C(C)C1CC2=C(C3=CC(C(=CN13)CNC)=O)C=C(C(=C2)OCCCOC)OC LTCHJIOBMNJQHJ-UHFFFAOYSA-N 0.000 claims description 3
- QZFVBHAZENHGMD-UHFFFAOYSA-N 6-ethyl-10-methoxy-9-(3-methoxypropoxy)-3-(piperidin-1-ylmethyl)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound C(C)C1CC2=C(C3=CC(C(=CN13)CN1CCCCC1)=O)C=C(C(=C2)OCCCOC)OC QZFVBHAZENHGMD-UHFFFAOYSA-N 0.000 claims description 3
- NEKMSUAEPJWNBY-UHFFFAOYSA-N N-benzyl-6-ethyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)NC(=O)C1=CN2C(CC3=C(C2=CC1=O)C=C(C(=C3)OCCCOC)OC)CC NEKMSUAEPJWNBY-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- TUTILOAXEMJXSI-UHFFFAOYSA-N 6-ethyl-10-methoxy-2-oxo-9-phenylmethoxy-N-propyl-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NCCC)=O)C=C1OC TUTILOAXEMJXSI-UHFFFAOYSA-N 0.000 claims description 2
- WFRHSVBYVIILQQ-UHFFFAOYSA-N 6-ethyl-10-methoxy-9-(3-methoxypropoxy)-3-(morpholin-4-ylmethyl)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound C(C)C1CC2=C(C3=CC(C(=CN13)CN1CCOCC1)=O)C=C(C(=C2)OCCCOC)OC WFRHSVBYVIILQQ-UHFFFAOYSA-N 0.000 claims description 2
- GXCZFHUFLBJDPH-UHFFFAOYSA-N 6-ethyl-10-methoxy-N-(2-methoxyethyl)-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NCCOC)=O)C=C1OC GXCZFHUFLBJDPH-UHFFFAOYSA-N 0.000 claims description 2
- RPXMWNGPBSDKNC-UHFFFAOYSA-N 6-ethyl-10-methoxy-N-methyl-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NC)=O)C=C1OC RPXMWNGPBSDKNC-UHFFFAOYSA-N 0.000 claims description 2
- GPXUVVKDUSARDT-UHFFFAOYSA-N 6-ethyl-3-(hydroxymethyl)-10-methoxy-9-(3-methoxypropoxy)-6,7-dihydrobenzo[a]quinolizin-2-one Chemical compound CCC1CC2=C(C=C(OC)C(OCCCOC)=C2)C2=CC(=O)C(CO)=CN12 GPXUVVKDUSARDT-UHFFFAOYSA-N 0.000 claims description 2
- BJACRYHCFSBEHC-UHFFFAOYSA-N 6-ethyl-N-(2-hydroxyethyl)-10-methoxy-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NCCO)=O)C=C1OC BJACRYHCFSBEHC-UHFFFAOYSA-N 0.000 claims description 2
- RCBXYFZIDIIHRB-UHFFFAOYSA-N C1=CC=CN2CC=CC(C(=O)N)=C21 Chemical compound C1=CC=CN2CC=CC(C(=O)N)=C21 RCBXYFZIDIIHRB-UHFFFAOYSA-N 0.000 claims description 2
- LGAMUCNZDXWMTL-UHFFFAOYSA-N N-benzyl-6-ethyl-10-methoxy-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)NC(=O)C1=CN2C(CC3=C(C2=CC1=O)C=C(C(=C3)OCC3=CC=CC=C3)OC)CC LGAMUCNZDXWMTL-UHFFFAOYSA-N 0.000 claims description 2
- XFPYSNULJZXIPG-UHFFFAOYSA-N N-butan-2-yl-6-ethyl-10-methoxy-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxamide Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)NC(C)CC)=O)C=C1OC XFPYSNULJZXIPG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 230000024717 negative regulation of secretion Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 131
- 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 abstract description 7
- 239000000243 solution Substances 0.000 description 173
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 104
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 238000002360 preparation method Methods 0.000 description 89
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 239000012044 organic layer Substances 0.000 description 56
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 45
- 239000011734 sodium Substances 0.000 description 45
- 238000001819 mass spectrum Methods 0.000 description 44
- 238000002953 preparative HPLC Methods 0.000 description 41
- 241000700721 Hepatitis B virus Species 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 238000005259 measurement Methods 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 30
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 28
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- 238000000746 purification Methods 0.000 description 27
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- 239000007864 aqueous solution Substances 0.000 description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 20
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
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- WMNLMOUEXUARFU-UHFFFAOYSA-N 6-ethyl-10-methoxy-2-oxo-9-phenylmethoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC1=CC2=C(C3=CC(C(=CN3C(C2)CC)C(=O)O)=O)C=C1OC WMNLMOUEXUARFU-UHFFFAOYSA-N 0.000 description 11
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- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 10
- 235000019253 formic acid Nutrition 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 125000001424 substituent group Chemical group 0.000 description 9
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- FLPWBPAEWBUYLL-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)butan-2-amine Chemical compound CCC(N)CC1=CC=C(OC)C(OC)=C1 FLPWBPAEWBUYLL-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
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- 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
- A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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| CN2015074462 | 2015-03-18 | ||
| PCT/EP2015/060284 WO2015173164A1 (en) | 2014-05-13 | 2015-05-11 | Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection |
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