WO2017173999A1 - 抗乙肝病毒的吡唑-噁唑烷酮类化合物 - Google Patents
抗乙肝病毒的吡唑-噁唑烷酮类化合物 Download PDFInfo
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- WO2017173999A1 WO2017173999A1 PCT/CN2017/079552 CN2017079552W WO2017173999A1 WO 2017173999 A1 WO2017173999 A1 WO 2017173999A1 CN 2017079552 W CN2017079552 W CN 2017079552W WO 2017173999 A1 WO2017173999 A1 WO 2017173999A1
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- fluorophenyl
- bromophenyl
- pyrazol
- ethyl
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- 0 Cc(cc1)ccc1C(C(C(*1CCc2c(C)c(*)c(**=C)cc2IC)OCC1=C)=C1)=**C1c1ccc(C(F)(F)F)cc1 Chemical compound Cc(cc1)ccc1C(C(C(*1CCc2c(C)c(*)c(**=C)cc2IC)OCC1=C)=C1)=**C1c1ccc(C(F)(F)F)cc1 0.000 description 12
- QEFIPPNXFHQYRO-PLNGDYQASA-N CC/C=C\C(C)N Chemical compound CC/C=C\C(C)N QEFIPPNXFHQYRO-PLNGDYQASA-N 0.000 description 2
- RBTKLZWNSRAZMG-UHFFFAOYSA-N CC(C1)C(F)=CC=C1c(c(C(N1C)OCC11OC1)c1)n[n]1-c(cc1)ccc1Br Chemical compound CC(C1)C(F)=CC=C1c(c(C(N1C)OCC11OC1)c1)n[n]1-c(cc1)ccc1Br RBTKLZWNSRAZMG-UHFFFAOYSA-N 0.000 description 1
- GDTXTZNKMPKMNV-WAYWQWQTSA-N CC/C=C\C(C)(C)N Chemical compound CC/C=C\C(C)(C)N GDTXTZNKMPKMNV-WAYWQWQTSA-N 0.000 description 1
- QNAAQRWAIUHJRB-PLNGDYQASA-N CC/C=C\C(C)[N+]([O-])=O Chemical compound CC/C=C\C(C)[N+]([O-])=O QNAAQRWAIUHJRB-PLNGDYQASA-N 0.000 description 1
- OCIFWLMAVANGIA-PLNGDYQASA-N CC/C=C\C([N+]([O-])=O)=C Chemical compound CC/C=C\C([N+]([O-])=O)=C OCIFWLMAVANGIA-PLNGDYQASA-N 0.000 description 1
- HRQYVRKPRJBXLJ-UHFFFAOYSA-N CC1(C=CC(c(c(C(N2C)OCC2=O)c2)n[n]2-c(cc2)ccc2Br)=CC1)F Chemical compound CC1(C=CC(c(c(C(N2C)OCC2=O)c2)n[n]2-c(cc2)ccc2Br)=CC1)F HRQYVRKPRJBXLJ-UHFFFAOYSA-N 0.000 description 1
- HDSBGAOTSDYOLA-FIWHBWSRSA-N CC1(C=CC(c(c([C@H](N2OC)OCC2=O)c2)n[n]2-c(cc2)ccc2Br)=CC1)F Chemical compound CC1(C=CC(c(c([C@H](N2OC)OCC2=O)c2)n[n]2-c(cc2)ccc2Br)=CC1)F HDSBGAOTSDYOLA-FIWHBWSRSA-N 0.000 description 1
- FCMXYTKYDHMJHD-LEMWZUJYSA-N CCC(C)OC(C[C@@H](/C=C(/CCNC(COCC)=O)\C=C/C)[N+]([O-])=O)=O Chemical compound CCC(C)OC(C[C@@H](/C=C(/CCNC(COCC)=O)\C=C/C)[N+]([O-])=O)=O FCMXYTKYDHMJHD-LEMWZUJYSA-N 0.000 description 1
- DNZQPIGBMLQDCU-UHFFFAOYSA-N CCOC(C(C1C=CC([N+]([O-])=O)=C(CC(OC)=O)C1C)C#N)OO Chemical compound CCOC(C(C1C=CC([N+]([O-])=O)=C(CC(OC)=O)C1C)C#N)OO DNZQPIGBMLQDCU-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N CCOC(CC#N)=O Chemical compound CCOC(CC#N)=O ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- OXYLCGRXCQARQV-UHFFFAOYSA-N COC(Cc1cc(F)ccc1)=O Chemical compound COC(Cc1cc(F)ccc1)=O OXYLCGRXCQARQV-UHFFFAOYSA-N 0.000 description 1
- ABJDBYCUWNTRFB-UHFFFAOYSA-N COC(Cc1cc(F)ccc1[N+]([O-])=O)=O Chemical compound COC(Cc1cc(F)ccc1[N+]([O-])=O)=O ABJDBYCUWNTRFB-UHFFFAOYSA-N 0.000 description 1
- SRFLOGMBHHIUCU-IBGZPJMESA-N CON([C@H](c1c[n](-c(cc2)ccc2Br)nc1-c(cc1)ccc1F)OC1)C1=O Chemical compound CON([C@H](c1c[n](-c(cc2)ccc2Br)nc1-c(cc1)ccc1F)OC1)C1=O SRFLOGMBHHIUCU-IBGZPJMESA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- GWRGXRSQECENII-UHFFFAOYSA-N N=C(C(CNc(cc1)ccc1Br)C=O)C(CC1)CC=C1F Chemical compound N=C(C(CNc(cc1)ccc1Br)C=O)C(CC1)CC=C1F GWRGXRSQECENII-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
- A61K31/41—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
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a class of pyrazole-oxazolidinone compounds having anti-hepatitis B virus activity.
- Hepatitis B is a disease caused by hepatitis B virus (HBV), which is mainly caused by inflammatory lesions of the liver and can cause damage to multiple organs. Hepatitis B is widely prevalent in all countries of the world, mainly invading children and young adults, and a small number of patients can be converted into cirrhosis or liver cancer. Therefore, it has become a worldwide disease that seriously threatens human health and is one of the most widespread and most harmful diseases. There is no certain epidemic period for hepatitis B virus, which can occur all year round, but it is mostly distributed. In recent years, the incidence of hepatitis B has increased significantly.
- HBV hepatitis B virus
- HBV inhibition is directly related to the therapeutic effects of hepatitis B (see, for example, Klaus Klumpp and Thibaut Crupin, Capsid proteins of enveloped viruses as antiviral drug targets, Current Opinion in Virology, 2014, 5: 63-71; Timothy M. Block, Siddhartha Rawat, Carol L. Brosgart, Chronic hepatitis B: A wave of new therapies on the horizon, Antiviral Research, 121, 2015, 69-81).
- interferon alpha has been widely used for the treatment of chronic HBV infection for many years, but interferon is only effective for certain types of patients and is poorly tolerated.
- lamivudine (3'-thio-2',3'-dideoxycytosine) has been used for the treatment of HBV infection because of its significant inhibitory effect on HBV replication, but the rate of resistance has gradually increased. High, thus limiting its efficacy for a large proportion of patients.
- adefovir dipivoxil (9-[2-[[bis[(pivaloyloxy)methyl]phosphinyl]methoxy]ethyl]adenine) is resistant to lamivudine
- the patient is effective, but the drug has the disadvantage of a low sustained viral response rate (less than 20%), and the maximum tolerated dose and duration of treatment are often limited by nephrotoxicity.
- Carbocyclic nucleoside compounds such as ketone monohydrate (Bristol-Myers Squibb) and acyclic nucleoside compounds having liver targeting such as Ribapharm also exhibit anti-HBV activity clinically.
- the existing therapeutic drugs of HBV have the limitations of limited therapeutic effect, high drug resistance and high toxicity. Therefore, there is an urgent need for new drugs with high efficiency, low toxicity and different drug resistance spectrum.
- Another object of the present invention is to provide a pharmaceutical use of the above compounds.
- One aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof,
- R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, optionally substituted alkyl, amino or hydroxy;
- R 4 and R 5 is an amino group, and the other is selected from hydrogen, halogen, amino or hydroxy; or
- R 6 is selected from the group consisting of hydrazine, halogen, amino or hydroxy
- n 0, 1 or 2;
- Q is an aryl or heteroaryl group optionally substituted with one or more halogens.
- the chiral carbon in formula I can be in the R configuration or the S configuration.
- Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, for use in inhibiting hepatitis B virus.
- Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, for use in the treatment of a mammalian, particularly human, hepatitis B virus infection.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, and a pharmaceutically acceptable carrier.
- Another aspect of the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, for the manufacture of a medicament for the inhibition of hepatitis B virus.
- Another aspect of the invention relates to a method of inhibiting hepatitis B virus comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof thereof body.
- One aspect of the invention relates to a compound of the formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof:
- R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, optionally substituted alkyl, amino or hydroxy;
- R 4 and R 5 is an amino group, and the other is selected from hydrogen, halogen, amino or hydroxy; or
- R 6 is selected from the group consisting of hydrazine, halogen, amino or hydroxy
- n 0, 1 or 2;
- Q is an aryl or heteroaryl group optionally substituted with one or more halogens.
- the compounds of the present application may have tautomers.
- the following two structural parts are identical to each other.
- the compounds of the present application may have one or more stereoisomeric centers, and each isomeric center may exist in the R or S configuration or a combination thereof.
- the chiral carbon of Formula I is in the R configuration and the structure is as shown in Formula I-R:
- enantiomers and tautomers of a particular compound are understood to include all possible isomers and mixtures thereof.
- the compounds of the present application include all conformationally different enantiomers, diastereomeric The conformation and tautomeric forms as well as their corresponding mixtures.
- R 1 , R 2 and R 3 are each independently hydrogen or halogen; preferably, R 1 and R 3 are both hydrogen and R 2 is halogen; more preferably, R 1 and R 3 are both hydrogen and R 2 is bromine ;
- the substituent is selected from the group consisting of halogen and alkoxycarbonylamino;
- R 6 is hydrazine or halogen
- Q is an aryl or heteroaryl group optionally substituted by one or more halogens, especially fluoro, said aryl being phenyl, said heteroaryl being selected from furanyl, pyrrolyl or thienyl.
- R 6 in Formula I and Formula IR is fluoro.
- Q in Formula I and Formula I-R is p-fluorophenyl.
- Q in Formula I and Formula I-R is thienyl or furanyl, preferably furan-2-yl.
- the compound of formula I is selected from the group consisting of
- the compound of formula I is selected from the group consisting of
- the compound of formula I is selected from the group consisting of
- R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, halogen;
- R 4 and R 5 is an amino group, and the other is selected from the group consisting of hydrogen, halogen, especially fluorine, amino group;
- R 6 is halogen, especially fluorine
- Q is an aryl or heteroaryl group optionally substituted by one or more halogens, especially fluoro, said aryl being phenyl, said heteroaryl being selected from furanyl, pyrrolyl, thienyl or pyridyl.
- the alkyl group as R 1 , R 2 or R 3 is methyl.
- the halogen as R 4 or R 5 is fluorine.
- the halogen as R 6 is fluorine.
- Q in Formula I and Formula I-R is p-fluorophenyl.
- R 4 in Formula I and Formula IR is an amino group
- R 5 is hydrogen
- n is 0.
- the compound of formula I is selected from the group consisting of
- alkyl denotes a straight or branched saturated hydrocarbon group.
- an alkyl group may include 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.
- C 1 -C 3 alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 3 carbon atoms, including methyl, ethyl, n-propyl, isopropyl.
- C 1 -C 3 alkyl is preferably a methyl group.
- alkoxy denotes -O-alkyl, wherein the term “alkyl” is as defined above.
- C 1 -C 3 alkoxy refers to -OC 1 -C 3 alkyl.
- halogen is fluoro, chloro, bromo or iodo. In some embodiments, the halogen is fluorine.
- trifluoromethyl is a -CF 3 group.
- trifluoromethoxy is a -OCF 3 group.
- amino is a -NH 2 group.
- heterocyclyl refers to a non-aromatic cyclic group formed from one or more heteroatoms selected from nitrogen, oxygen, sulfur, and one or more carbon atoms.
- the heterocyclic group may be a 3- to 8-membered ring system containing 1 to 3 selected from the group consisting of nitrogen, oxygen, and sulfur, and preferably at least one of the hetero atoms is selected from nitrogen.
- heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolinone, oxazolidinyl, oxazolidinone, oxazolinyl, oxazolinone, thiazolidinyl
- a thiazolidinone group, a thiazolinyl group, a thiazolinone group can be bonded to the rest of the molecule through any suitable site on the ring.
- aryl refers to a monocyclic or fused aromatic cyclic hydrocarbon group containing from six to ten carbon atoms.
- examples of the aryl group include a phenyl group and a naphthyl group, of which a phenyl group is preferred.
- heteroaryl refers to a fused or non-fused aromatic cyclic group formed by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and one or more carbon atoms, at least one of which The ring is a five to eight membered ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least one heteroatom selected from nitrogen.
- the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other, provided that The ring of the group does not contain two adjacent O or S atoms.
- heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl , pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, fluorenyl and the like.
- a heteroaryl group can be bonded to the rest of the molecule through any suitable site on the ring.
- the pyrrolyl group may be pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl;
- the furyl group may be furan-2-yl, furan-3-yl;
- the thienyl group may be thiophen-2-yl, Thiophen-3-yl.
- salts refers to those salts which retain the biological effectiveness and properties of the parent compound, which possess the desired pharmaceutical activity and which are not biologically and otherwise undesirable.
- Such salts include, but are not limited to: (1) salt formation with an acid (acid salt), obtained by reaction of a free base of the parent compound with an inorganic or organic acid; inorganic acids including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, Methanesulfonic acid, organic acids including but not limited to acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid , digluconic acid, aspartic acid, tartaric acid; (2) a salt (basic salt) formed by the acidic protons present in the parent compound being replaced by metal ions or complexed with an organic base.
- Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, for use in inhibiting hepatitis B virus.
- Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, for use in the treatment of a mammalian, particularly human, hepatitis B virus infection.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, and a pharmaceutically acceptable carrier.
- the compounds of the invention may be combined with one or A wide variety of pharmaceutically acceptable carriers form suitable dosage forms for administration.
- These dosage forms are suitable for oral administration, rectal administration, topical administration, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
- dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
- the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
- the above dosage forms can be prepared from the active compounds with one or more pharmaceutically acceptable carriers via conventional pharmaceutical methods.
- a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
- the above carriers need to be compatible with the active compound or other excipients.
- commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, calcium carbonate, calcium phosphate, starch, cellulose and its derivatives, glucose, sucrose, gelatin, and the like.
- Carriers for liquid preparations include water, physiological saline, aqueous dextrose, vegetable oil, ethylene glycol, polyethylene glycol, and the like.
- the active compound can form a solution or suspension with the above carriers.
- the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
- the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In some embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day.
- a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required.
- the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day.
- the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
- the pharmaceutical composition further comprises at least one anti-HBV drug. In other embodiments, the pharmaceutical composition and the at least one anti-HBV drug are each combined into a combined product in separate dosage forms.
- HBV drugs which may be HBV polymerase inhibitors, immunomodulators or interferons
- the other HBV drugs may be lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfafone, alloferon, celmoleukin, claf Ding, emtricitabine, famciclovir, Feilong, Baoganling CP, intepropen, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, leukocytes Interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, interferon-A, sirolimus, euforavac, veldona, rintatolimod
- additional drugs can be administered separately from the pharmaceutical compositions containing the compounds of the invention as part of a multi-dose regimen.
- a drug may be part of a single dosage form, mixed with a compound of the invention in a single composition.
- the two active agents can be administered simultaneously, sequentially or at intervals between each other to produce the desired activity of these agents.
- Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the inhibition of hepatitis B virus the use of.
- the medicament is for treating a hepatitis B virus infection in a mammal, particularly a human.
- Another aspect of the invention relates to a method of inhibiting replication of hepatitis B virus comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer or tautomer thereof thereof A construct or a pharmaceutical composition of the invention.
- the method is for treating a hepatitis B virus infection in a mammal, particularly a human.
- the term "therapeutically effective amount” may be one or more physiology that alleviates one or more symptoms of a disease or condition in a subject, causes a disease or condition, or its etiology. Or an amount of biochemical parameter that partially or completely returns to normal, and/or reduces the likelihood of a disease or condition.
- diseases involved in hepatitis B virus infection include acute hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
- Symptoms of acute hepatitis B virus infection can be asymptomatic or can be the same as acute hepatitis.
- a patient with a chronic viral infection may develop an active disease that can progress to cirrhosis or liver cancer.
- PCR and enzyme-linked immunosorbent assay can be used to quantitatively detect the effect of the compounds of the present application on HBV replication.
- the present invention also provides a process for the preparation of the above compounds, and a similar preparation process is disclosed in PCT/US/06/28343, filed on Jul. 21, 2006.
- the preparation of the compounds of the invention may be referred to, but not limited to, the following methods:
- the chiral resolution method of Berger can be summarized as follows: A racemic mixture (60 mg) is dissolved in methanol (2 mL), and the resulting solution is injected into a chiral column (ChiralPak AD-H SFC, id 1 cm x 25 cm). The conditions of the SFC were as follows: mobile phase: 65% CO 2 and 35% methanol, flow rate: 10 mL/min, detection wavelength: 220 nm. Stereoisomers can be separated at different retention times.
- Phosphorus oxychloride 83.5 mL was slowly added dropwise to anhydrous DMF (68.75 mL) under anhydrous and ice-cooling conditions. After stirring for 30 min, 1-(4-bromophenyl) was taken under nitrogen. 2-(1-(4-fluorophenyl)ethylidene) ruthenium (125 g, 407.2 mmol) was dissolved in a small amount of DMF, and slowly added dropwise to the reaction mixture, stirred at room temperature for 1 h, and warmed to 70 ° C.
- Step 8 3-(2-(1H-Benzo[d]imidazol-5-yl)ethyl)-2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H -pyrazol-4-yl)oxazolin-4-one
- the reaction mixture was stirred at room temperature for 2 hours, and 50 mL of water was added, and the mixture was extracted with ethyl acetate (60 mL), and the mixture was extracted with 10% sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate and evaporated to dryness.
- the crude product was purified by reversed column chromatography to afford white crystals.
- 1,2-Difluoro-4-nitro (20 g, 0.13 mol), ethyl cyanoacetate (19 g, 0.16 mol), potassium carbonate (35 g, 0.25 mol) was dissolved in acetonitrile and heated to 90 ° C overnight.
- the reaction mixture was dried with EtOAc EtOAc m.
- the combined ethyl acetate phases were washed twice with brine, dried over anhydrous sodium sulfate and filtered and evaporated.
- reaction mixture was concentrated by flash evaporation and purified using silica gel column (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc a crude product of -1H-pyrazolyl-4-yl)-3-(2-fluoro-4-nitrophenethyl)oxazolin-4one, which was then beaten with ethyl acetate and filtered, and dried in a filter cake oven. Solid (4.5 g, yield: 48%); MS: 569.1 [M+H] + .
- Step 7 3-(2-Fluoro-5-nitro-4-acetamidophenethyl)-2-(3-(4-fluorophenyl)-1-(4-bromophenyl)-1H-pyridyl Oxazol-4-yl)oxazolidin-4-one
- Step X 2-(1-(4-Bromophenyl)-3-(4-fluorophenyl)1H-pyrazol-4-yl)-3-(2-(5-fluoro-1H-benzo[ d] imidazolium-6-yl)ethyl)oxazolin-4-one
- N-(2,6-Difluoro-4-nitrophenethyl)-2-hydroxyacetamide (2.5 g, 9.6 mmol) and 1-(4-bromophenyl)-3-(4-fluorobenzene -1H-pyrazole-4-carbaldehyde (3.3 g, 9.6 mmol) was dissolved in toluene (60 mL), and p-toluenesulfonic acid (825 mg, 4.8 mmol) was added. The reaction mixture was concentrated. The extract was washed with a 10% sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness.
- Step 7 3-(2,6-Difluoro-5-nitro-4-acetamidophenethyl)-2-(3-(4-fluorophenyl)-1-(4-bromophenyl)- 1H-pyrazol-4-yl)oxazolidin-4-one
- Step 8 3-(2,6-Difluoro-5-nitro-4-acetamidophenethyl)-2-(3-(4-fluorophenyl)-1-(4-bromophenyl)- 1H-pyrazol-4-yl)oxazolidin-4-one
- Step X 2-(1-(4-Bromophenyl)-3-(4-fluorophenyl)1H-pyrazol-4-yl)-3-(3,4-diamino-2,6-di Fluorophenethyl)oxazolin-4-one
- Example 11 2-(1-(4-Bromophenyl)-3-(4-fluorophenyl)1H-pyrazol-4-yl)-3-(2-(4,6-difluoro-2) -carbonyl-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)oxazolin-4-one
- Example 12 2-(1-(4-Bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(2-(5,7-difluoro-) 1H hydrogen-benzo[d][1,2,3]triazol-6-yl)ethyl)oxazolin-4-one
- Methyl methyl-2-(2-nitrophenyl)cyanocarboxylate (1.0 g, 3.26 mmol) was dissolved in DMSO (10 mL), sodium chloride (0.57 g, 9.80 mmol) and The reaction was carried out at 140 ° C for 1.5 hours, cooled to room temperature, water was added, EtOAc (EtOAc) 700 mg, yield: 76%).
- Example 14 2-(1-(4-Bromophenyl)-3-(4-difluorophenyl)-1H-pyrazole)-3-(2-(3,3-difluoro-2-oxo) Porphyrin-5-ethyl)oxorphyrin-4-one
- Step 8 2-(1-(4-Fluorophenyl)-3-(4-fluorophenyl)1H-pyrazol-4-yl)-3-(2-(6-fluoro-2-carbonyl-2) ,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)oxazolin-4-one
- Example 16 6-(2- ⁇ 2-[1-(4-Bromo-phenyl)-3-(4-fluoro-phenyl)-1-hydro-pyrazol-4-yl]-4-carbonyl -oxazolin-3-yl ⁇ -ethyl)-3-hydro-2-carbonyl-benzoxazole
- Step 8 6-(2- ⁇ 2-[1-(4-Bromo-phenyl)-3-(4-fluoro-phenyl)-1-hydro-pyrazol-4-yl]-4-carbonyl- Oxazolin-3-yl ⁇ -ethyl)-3-hydro-2-carbonyl-benzoxazole
- Step X 5-(2-(2-(1-(4-Bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxazoline-3- Ethyl)benzo[d]oxazole-2(3H)-one
- the reaction solution was cooled to room temperature, and 3 mL of glacial acetic acid was added via a syringe, and then heated to 130 ° C under a nitrogen atmosphere, and stirred for 3 hours.
- the reaction mixture was cooled to room temperature, filtered over Celite, filtered, and ethyl acetate (50 mL), and the filtrate was washed once with 100 mL of water, and the aqueous phase was extracted once with ethyl acetate (50 mL) and the organic phase was washed three times with saturated brine.
- the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
- Step I O-(4-(2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxazoline) -3-yl)ethyl)-2-nitrophenyl)dimethylaminothiocarboxylic acid
- N-(4-(2-Acetylaminoethyl)phenyl)acetamide (4.9 g, 22.3 mmol) was dissolved in concentrated sulfuric acid (30 mL), cooled to 0 ° C in an ice bath, and fuming nitric acid (2.1 g, 33.3 mmol) was slowly added dropwise to the reaction solution, and the ice bath was removed, and the mixture was reacted at room temperature for 1 hour.
- reaction solution was slowly added to 400 mL of ice water by the wall of the bottle, stirred for 15 min, filtered, and the filter cake was washed with 50 mL of water, and the filter cake was dried to obtain crude N-(4-acetamido-3-nitrophenethyl)acetamide (5.2 g), used directly in the next reaction.
- tert-Butyl-4-amino-3-nitrophenylcarbamate (1.8 g, 6.4 mmol) was dissolved in methanol (100 mL), Pd / C (0.36 g) was added, hydrogen was passed, and stirred at 30 ° C 16 After a while, filtration and concentration gave tert-butyl tert-butyl 3,4-diaminophenethylcarbamate (1.6 g, 6.4 mmol, yield: 100%). MS: 274.3 [M + Na] + .
- tert-Butyl 3,4-diaminophenethylcarbamic acid tert-butyl ester (1.6 g, 6.4 mmol) was added to acetonitrile (30 mL) and N,N'-carbonyldiimidazole (CDI) (1.2) was added with stirring. g, 7.4 mmol). The reaction solution was warmed to 60 ° C and stirred for 3 hours.
- Phosphorus oxychloride (3.78 g, 24.6 mmol) was slowly added dropwise to anhydrous DMF (3.3 mL) under ice-cooling. After stirring for 30 min, 1-(4-bromophenyl)- 2-(1-(Thien-2-yl)ethylidene) hydrazine (3.3 g, 11.18 mmol) was dissolved in a small amount of anhydrous DMF, and slowly added dropwise to the reaction mixture, stirred at room temperature for 1 hour, and warmed to 70 The reaction was continued for 5 hours at ° C. The reaction solution was poured into ice water and extracted with ethyl acetate.
- reaction solution was concentrated by rotary distillation and purified by preparative HPLC to give 2-(1-(4-bromophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-3-(2) -(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)oxazolidin-4-one (3.6 mg).
- Phosphorus oxychloride (1.14 g, 7.46 mmol) was slowly added dropwise to anhydrous DMF (2 mL) under ice-cooling. After stirring for 30 min, 1-(4-bromophenyl)-2 -(1-(furan-3-yl)ethylidene)anthracene (1.0g, 3.39mmol) was dissolved in a small amount of anhydrous DMF, and slowly added dropwise to the reaction mixture, stirred at room temperature for 1 hour, warmed to 70 The reaction was continued for 5 hours at ° C. The reaction solution was poured into ice water and extracted with ethyl acetate.
- Step 2 (5-(2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)oxazolin-4-one- Methyl 3-yl)ethyl)-1H-benzo[d]imidazol-2-yl)carbamate
- the initial concentration of all compounds used in the in vitro anti-HBV activity assay was 1 ⁇ M, 3 fold dilution, 8 concentrations; the initial concentration of all compounds used in the cytotoxicity experiments was 100 ⁇ M, 3 fold dilution, 8 Concentration; the mother liquor of the compound was diluted with DMSO.
- the control compound was lamivudine, which was set to 100 nM in the anti-HBV activity assay in vitro, and the initial concentration in the cytotoxicity experiment was 100 ⁇ M, 3-fold dilution, and 8 concentrations.
- HepG2.2.15 cells (4 x 10 4 cells/well) were seeded into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added. On the eighth day, the supernatant in the culture well was collected for extracting HBV DNA from the supernatant. The qPCR assay was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
- Example 26 Activity test of anti-nucleoside anti-HBV resistant strains in vitro
- the compound was tested for the activity of anti-nucleoside anti-HBV resistant strains in vitro using a transient transfected cell model.
- HepG2 cells (4 x 10 4 cells/well) transfected with the nucleoside HBV resistant strain were seeded into 96-well plates and cultured overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added. On the eighth day, the supernatant in the culture well was collected for extracting HBV DNA from the supernatant. The qPCR assay was used to detect the HBV DNA content in the supernatant of HepG2. The experimental results are shown in the following table (EC 50 nM):
- IV and PO oral administration of test compounds in Sprague Dawley rats
- blood samples were taken at different time points, and LC/MS/MS was used to determine the concentration of the test substance in the plasma of rats after administration of the test substance and calculate the correlation. parameter.
- the time points of animal blood collection were: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration.
- Each animal was subjected to a jugular vein puncture or other suitable vein for about 0.3 mL of blood, and heparin sodium was anticoagulated.
- Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 min, 4 ° C). Plasma samples were stored in a -70 ° C refrigerator before storage.
- Mass Spectrometer API 4000, Applied Biosystems, Inc., Electrospray Ionization (ESI), Tandem Quadrupole Mass Analyzer.
- ESI Electrospray Ionization
- Mass spectrometry conditions ion source: electrospray ion source (ESI); auxiliary gas (Gas1): 60 psi; auxiliary gas (Gas2): 60 psi; curtain gas (CUR): 14 psi; collision gas (CAD): 6; ion source voltage ( IS): 5500V; ion source temperature (TEM): 550 ° C
- the pharmacokinetic parameters of the test compound were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2.
- mice Female BALB/c mice were given a single subcutaneous test compound, blood samples were taken at different time points, LC/MS/MS was used to determine the concentration of the test substance in the rat plasma after administration of the test substance and the relevant parameters were calculated.
- the time points of animal blood collection were: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration.
- Mass spectrometer Triple Quad 5500. Mass spectrometry conditions: SRM detection
- the pharmacokinetic parameters of the test compound were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2.
- Example 28 In vivo pharmacodynamic assay
- HBV DNA tail vein hypertension injection and administration methods are HBV DNA tail vein hypertension injection and administration methods:
- HBV plasmid DNA solution into mouse tail vein:
- the plasmid DNA was previously dissolved in physiological saline (10 ⁇ g / 1.4 ml, 10 ⁇ g / 1.5 ml) before injection. Store at 4 ° C until use.
- a mouse 8% plasmid DNA solution was injected from the tail vein within 5 seconds. If the injection volume is less than or equal to 1.4 ml, 10 ⁇ g / 1.4 ml of the plasmid solution is used; if the injection volume is greater than or equal to 1.5 ml, 10 ⁇ g / 1.5 ml of the plasmid solution is used.
- mice On days 1-7, mice were injected intraperitoneally with the test compound or solvent for 7 days. Blood was collected from the submandibular vein on days 1, 3, and 5, and heparin sodium was anticoagulated, 7,000 x g, and centrifuged at 4 ° C for 10 min to prepare plasma. The plasma was divided into two parts, one was sent to the in vitro anti-infective group of the Ministry of Biology for HBV DNA testing, and the other was used.
- liver tissues were collected.
- the liver tissue was divided into three parts. Two of the left leaves were collected and immediately frozen in liquid nitrogen, and transferred to -80 degrees for storage until the anti-infective group of WuXi PharmaTech was tested for HBV DNA; the remaining liver tissue was frozen in dry ice. Medium, and transferred to -80 degrees to save the spare.
- Quantitative PCR was used to detect the amount of HBV DNA in mouse plasma.
- DNA in mouse plasma was extracted according to the QIAamp 96 DNA Blood Kit instructions.
- HBV DNA sequence HBV primer
- pAAV2 primer pAAV2 vector sequence
- HBV DNA content DNA content of HBV primer detection - DNA content detected by pAAV2 primer
- the dose of the test compound (the compound of Example 3, the R isomer) was 25 mpk.
- the HBV DNA content in mouse plasma decreased significantly on days 1 and 3, with a decrease of 0.55 log and 1.84 log, respectively, with statistical differences.
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Abstract
Description
PK参数 | 实施例3,R异构体 |
Cmax(ng/mL) | 643 |
Tmax(h) | 1.33 |
T1/2(h) | 1.19 |
AUC0-inf(ng·h/mL) | 2079 |
MRT0-inf(h) | 2.40 |
Claims (13)
- 根据权利要求1或2所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中:R1、R2和R3各自独立地为氢或卤素;R4和R5与它们所连接的碳原子一起形成任选取代的含有至少一个氮原子的五元杂环基或杂芳基,其中所述杂环基中的-CH2-任选地被-C(=O)-、-C(=S)-或-C(=NH)-替换;R6为氘或卤素;Q为任选地被一个或多个卤素取代的芳基或杂芳基,所述芳基为苯基,所述杂芳基选自呋喃基、吡咯基或噻吩基。
- 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐或其对映异构体 或互变异构体,其中Q为对-氟苯基或者为噻吩基或呋喃基。
- 根据权利要求1或2所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中:R1、R2和R3各自独立地选自氢、C1-C3烷基、卤素;R4和R5中的一个为氨基,另一个选自氢、卤素、氨基;R6为卤素;Q为任选地被一个或多个卤素尤其是氟取代的芳基或杂芳基,所述芳基为苯基,所述杂芳基选自呋喃基、吡咯基、噻吩基或吡啶基。
- 根据权利要求1-2、7中任一项所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中Q为对-氟苯基。
- 根据权利要求1-2、7-8中任一项所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,其中R4为氨基,R5为氢;n为0。
- 一种药物组合物,其含有权利要求1-10中任一项所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体,和药学上可接受的载体。
- 权利要求1-10中任一项所述的化合物或其药学上可接受的盐或其对映异构体或互变异构体或者权利要求11所述的药物组合物在制备用于抗乙型肝炎病毒的药物中的用途。
- 根据权利要求12所述的用途,其中所述药物用于治疗哺乳动物的乙型肝炎病毒感染。
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RS20211423A RS62597B1 (sr) | 2016-04-06 | 2017-04-06 | Jedinjenje pirazol-oksazolidinona protiv virusa hepatitisa b |
HRP20211907TT HRP20211907T1 (hr) | 2016-04-06 | 2017-04-06 | Pirazol – oksazolidinon spoj za anti – hepatitis b virus |
LTEPPCT/CN2017/079552T LT3441389T (lt) | 2016-04-06 | 2017-04-06 | Pirazol-oksazolidinono junginys prieš hepatito b virusą |
CN201780035186.6A CN109311865B (zh) | 2016-04-06 | 2017-04-06 | 抗乙肝病毒的吡唑-噁唑烷酮类化合物 |
KR1020187031104A KR102083818B1 (ko) | 2016-04-06 | 2017-04-06 | 항 b형 간염 바이러스 피라졸-옥사졸리디논계 화합물 |
EP17778663.9A EP3441389B1 (en) | 2016-04-06 | 2017-04-06 | Pyrazole-oxazolidinone compound for anti-hepatitis b virus |
US16/091,320 US10519145B2 (en) | 2016-04-06 | 2017-04-06 | Pyrazole-oxazolidinone compound for anti-hepatitis B virus |
DK17778663.9T DK3441389T3 (da) | 2016-04-06 | 2017-04-06 | Pyrazol-oxazolidinonforbindelse mod anti-hepatitis b-virus |
PL17778663T PL3441389T3 (pl) | 2016-04-06 | 2017-04-06 | Związek pirazolo-oksazolidynonowy przeciwko wirusowi zapalenia wątroby typu B |
SI201730993T SI3441389T1 (sl) | 2016-04-06 | 2017-04-06 | Pirazol-oksazolidinonska spojina proti virusu hepatitisa B |
ES17778663T ES2893208T3 (es) | 2016-04-06 | 2017-04-06 | Compuesto de pirazoloxazolidinona contra el virus de la hepatitis B |
JP2019503613A JP6581745B2 (ja) | 2016-04-06 | 2017-04-06 | 抗b型肝炎ウイルスのピラゾール−オキサゾリジノン系化合物 |
CY20211100903T CY1124671T1 (el) | 2016-04-06 | 2021-10-19 | Ενωση πυραζολο-οξαζολιδινονης για αντι-ηπατιτιδας β ιο |
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EP (1) | EP3441389B1 (zh) |
JP (1) | JP6581745B2 (zh) |
KR (1) | KR102083818B1 (zh) |
CN (1) | CN109311865B (zh) |
CY (1) | CY1124671T1 (zh) |
DK (1) | DK3441389T3 (zh) |
ES (1) | ES2893208T3 (zh) |
HR (1) | HRP20211907T1 (zh) |
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WO2023001298A1 (zh) | 2021-07-23 | 2023-01-26 | 上海挚盟医药科技有限公司 | 一种乙肝病毒核衣壳抑制剂的制备方法 |
WO2023001299A1 (zh) | 2021-07-23 | 2023-01-26 | 上海挚盟医药科技有限公司 | 式i化合物的晶型及其制备和应用 |
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WO2020221816A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel phenyl and pyridyl ureas active against the hepatitis b virus (hbv) |
WO2020221811A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel oxalyl piperazines active against the hepatitis b virus (hbv) |
WO2020221826A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel indole-2-carboxamides active against the hepatitis b virus (hbv) |
WO2020221824A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv) |
CN112574188A (zh) * | 2019-09-29 | 2021-03-30 | 苏州爱科百发生物医药技术有限公司 | 一种吡唑类化合物及其应用 |
WO2021057994A1 (zh) * | 2019-09-29 | 2021-04-01 | 苏州爱科百发生物医药技术有限公司 | 一种吡唑类化合物及其应用 |
CN112574188B (zh) * | 2019-09-29 | 2022-05-06 | 苏州爱科百发生物医药技术有限公司 | 一种吡唑类化合物及其应用 |
WO2022135601A1 (zh) * | 2020-12-25 | 2022-06-30 | 杭州百新生物医药科技有限公司 | 5-烷基-2-吡唑-恶唑烷-4-酮类衍生物及其用途 |
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WO2023001299A1 (zh) | 2021-07-23 | 2023-01-26 | 上海挚盟医药科技有限公司 | 式i化合物的晶型及其制备和应用 |
TWI827152B (zh) * | 2021-07-23 | 2023-12-21 | 大陸商上海摯盟醫藥科技有限公司 | 式i化合物的晶型及其製備和應用 |
TWI845992B (zh) | 2021-07-23 | 2024-06-21 | 大陸商上海摯盟醫藥科技有限公司 | 一種b肝病毒核衣殼抑制劑的製備方法 |
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US10519145B2 (en) | 2019-12-31 |
PL3441389T3 (pl) | 2022-01-24 |
EP3441389B1 (en) | 2021-09-08 |
CY1124671T1 (el) | 2022-07-22 |
EP3441389A1 (en) | 2019-02-13 |
KR20180128953A (ko) | 2018-12-04 |
ES2893208T3 (es) | 2022-02-08 |
KR102083818B1 (ko) | 2020-03-03 |
US20190152963A1 (en) | 2019-05-23 |
CN109311865B (zh) | 2021-08-31 |
RS62597B1 (sr) | 2021-12-31 |
PT3441389T (pt) | 2021-11-11 |
HRP20211907T1 (hr) | 2022-03-18 |
CN109311865A (zh) | 2019-02-05 |
JP2019513830A (ja) | 2019-05-30 |
EP3441389A4 (en) | 2019-09-04 |
SI3441389T1 (sl) | 2022-01-31 |
DK3441389T3 (da) | 2021-11-08 |
JP6581745B2 (ja) | 2019-09-25 |
LT3441389T (lt) | 2021-10-11 |
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