DK2888241T3 - 2,4,5,6-Substituerede 3,6-dihydropyrimidinderivativer som hepatitis B-virus (HBV)-polymerasehæmmere til behandling af fx kronisk hepatitis - Google Patents

2,4,5,6-Substituerede 3,6-dihydropyrimidinderivativer som hepatitis B-virus (HBV)-polymerasehæmmere til behandling af fx kronisk hepatitis Download PDF

Info

Publication number
DK2888241T3
DK2888241T3 DK13830553.7T DK13830553T DK2888241T3 DK 2888241 T3 DK2888241 T3 DK 2888241T3 DK 13830553 T DK13830553 T DK 13830553T DK 2888241 T3 DK2888241 T3 DK 2888241T3
Authority
DK
Denmark
Prior art keywords
cr7r7a
methyl
independently
mmol
ethyl
Prior art date
Application number
DK13830553.7T
Other languages
English (en)
Inventor
Yingjun Zhang
Qingyun Ren
Xinchang Liu
Siegfried Goldmann
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Application granted granted Critical
Publication of DK2888241T3 publication Critical patent/DK2888241T3/da

Links

Classifications

    • 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
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (20)

1. Forbindelse med formlen (I) eller (la)
eller en enantiomer, en diastereoisomer, en tautomer, et hydrat, et solvat eller et farmaceutisk acceptabelt salt deraf, hvor: hver A er en binding, -O-, -S- eller -NR5-; hver R er -X-Z; X er -(CR7R7n)m- eller -C(=0)-; Z har formlen (II) eller (Ila):
hvor hver B er -CR7R7n-; hver W erN; hver Y er -O-; hver R1 er aryl eller heteroaryl; hver R2 er H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl eller alkoxycarbonyl; hver R3 er aryl eller heteroaryl; hver R4 er H eller Ci-4-alkyl; R5 er H, alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl eller alkynyl; hver R7a og R7 er uafhængigt H, F, Cl, Br, alkyl, haloalkyl, -(CH2)m-OH eller -(CH2)m-C(=0)0-R8; hver R8 og R8a er uafhængigt H, alkyl, haloalkyl, aminoalkyl, Boc-NH-alkyl, alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H eller -(CH2)m-0C(=0)-(CH2)m-H; Boc er tert-butyloxycarbonyl; hver R9 er uafhængigt -(CR7R7n)t-OH, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)t-0C(=0)-R8, triazolyl, tetrazolyl eller -(CR7R7a)m-C(=0)N(R8)2, med det forbehold, at når R9 er -(CR7R7a)tOH, er R3 aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl eller triazinyl; hver n er uafhængigt 1, 2 eller 3; hver t er uafhængigt 1,2,3 eller 4; hver m er uafhængigt 0, 1 eller 2; og hver af ovenfor beskrevne aryl, heteroaryl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxy, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, heterocyclyl og heterocyclylalkyl er eventuelt uafhængigt substitueret med en eller flere substituenter, som er de samme eller forskellige, hvor substituenten er H, F, Cl, Br, I, alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifluormethyl, trifluormethoxy, -(CR7R7a)m-C(=0)0-R8, haloalkylsubstitueret aryl, halogensubstitueret aryl, -(CR7R7a)m-C(=0)N(R8a)2 eller trifluormethylsulfonyl.
2. Forbindelse ifølge krav 1, hvor Z har formlen (III) eller (Illa):
hvor hver B er -CR7R7a-; hver Y er -O-; hver R7a og R7 er uafhængigt H, F, Cl, Br, Ci-4-alkyl, -(CH2)m-OH, Ci-4-haloalkyl eller -(CH2)m-C(=0)0-R8; hver R8 er uafhængigt H, Ci-6-alkyl, Ci-4-haloalkyl, amino-Ci-4-alkyl, Boc-NH-Cm-alkyl, Ci 4-alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)ni-H eller -(CH2)m-0C(=0)-(CH2)m-H; hver R9 er uafhængigt -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)t-0C(=0)-R8, triazolyl, tetrazolyl eller -(CR7R7a)m-C(=0)N(R8)2, med det forbehold, at når R9 er -(CR7R7a)t-OH, er R3 C6-10-aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl eller triazinyl; hver n er uafhængigt 1 eller 2; hver t er uafhængigt 1, 2, 3 eller 4; og hver m er uafhængigt 0, 1 eller 2.
3. Forbindelse ifølge krav 2, hvor Z er
hvor hver R6 er uafhængigt methyl, ethyl eller propyl; hver R7 og R7a er uafhængigt H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 eller propyl; hver R8 er uafhængigt H, methyl, ethyl, propyl, isopropyl, butyl, 1-mcthylpropyl, 2-methylpropyl, aminomethyl, 1-amino-2-methylpropyl, 1-aminoethyl, 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, l-Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-0C(=0)-(CH2)m-H eller tert-butyl; og hver R9 er uafhængigt triazolyl, tetrazolyl, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)-R8, -(CR7R7a)t-0C(=0)-R8 eller -(CR7R7a)m-C(=0)N(R8)2, med det forbehold, at når R9 er -(CR7R7a)t-OH, er R3 phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl eller triazinyl.
4. Forbindelse ifølge krav 1, hvor R3 er C6-io-aryl eller 5-6-leddet heteroaryl, og hver af heteroaryl og aryl eventuelt er uafhængigt substitueret med en eller flere substituenter, som er de samme eller forskellige, hvor substituenten er H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluormethyl, trifluormethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 eller trifluormethylsulfonyl; hver R7a og R7 er uafhængigt H, F, Cl, Br, Ci-4-alkyl, Ci-4-haloalkyl, -(CFbV-OFl eller -(CH2)m-C(=0)0-R8; og hver R8a og R8 er uafhængigt H, Ci-4-alkyl, Ci-4-haloalkyl, amino-Ci4-alkyl, Boc-NH-Ci-4-alkyl, Ci-4-alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H eller -(CH2)m-0C(=0)-(CH2)m-H.
5. Forbindelse ifølge krav 4, hvor R3 har en af følgende formler:
hvor hver X1 er uafhængigt O, S, NR11 eller CR12R12a; hver X2, X3, X4, X5 og X6 er uafhængigt N eller CR12; hvor højst tre eller fire af X2, X3,X4, X5 og X6 er N; hver R10 er uafhængigt H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluormethyl, trifluormethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 eller trifluormethylsulfonyl; hver R11 er uafhængigt H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, -(CR7R7a)m-C(=0)N(R8a)2 eller -(CR7R7a)m-C(=0)0-R8a; hver R12 og R12a er uafhængigt H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluormethyl, trifluormethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 eller trifluormethylsulfonyl; hver R7a og R7 er uafhængigt H, F, Cl, Br, Ci-4-alkyl, -(CFFV-OFI, Ci-4-haloalkyl eller -(CH2)m-C(=0)0-R8; hver R8a og R8 er uafhængigt H, Ci-4-alkyl, Ci-4-haloalkyl, amino-Ci-4-alkyl, Boc-NH- Ci-4-alkyl, Ci-4-alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H eller -(CH2)m- 0C(=0)-(CH2)m-H; hver m er uafhængigt 0, 1 eller 2; og hver p er uafhængigt 0, 1, 2 eller 3.
6. Forbindelse ifølge krav 5, hvor R ' har en af følgende formler:
hvor hver R10 er uafhængigt H, F, Cl, methyl, ethyl, cyano, hydroxy, nitro, amino, methoxy, ethoxy, trifluormethyl, trifluormethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 eller trifluormethylsulfonyl; hver R11 er uafhængigt H, methyl, ethyl, propyl, isopropyl, butyl, trifluormethyl eller -(CR7R7a)m-C(=0)0-R8a; hver R7a og R7 er uafhængigt H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 eller propyl; hver R8 og R8a er uafhængigt H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1 -methylpropyl, aminomethyl, 1 -amino-2-methylpropyl, 1-aminoethy), 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, l-Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, - (C H 2) m - O C O) - (C H 2) m - H eller tert-butyl; og hver p er uafhængigt 0, 1, 2 eller 3.
7. Forbindelse ifølge krav 1, hvor R1 er C6-io-aryl, og arylgruppen er uafhængigt substitueret med en eller flere substituenter, som er de samme eller forskellige, hvor substituenten er H, F, Cl, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluormethyl)phenyl, 3,5-b/.s(trifluormcthyl)phcnyl eller trifluormethyl; R2 er H eller Ci-4-alkyl; og R5 er H eller Ci-4-alkyl.
8. Forbindelse ifølge krav 7, hvor R1 er phenyl eller en phenyl substitueret med en eller flere substituenter, som er de samme eller forskellige, hvor substituenten er H, F, Cl, Br, nitro, 4-(trifluormethyl)phenyl, 3,5-b/.sftrifluormcthyl)phcnyl eller trifluormethyl.
9. Forbindelse ifølge krav 1, som har formlen (IV) eller (IVa),
eller en enantiomer, en diastereoisomer, en tautomer, et hydrat, et solvat eller et farmaceutisk acceptabelt salt deraf, hvor Z har formlen (II) eller (Ila):
hvor hver B er -CR7R7a-; hver W er N; hver Y er -O-; hver R2 er H eller Ci-4-alkyl; hver R3 er C6-io-aryl eller 5-6-leddet heteroaryl, og hver af heteroaryl og aryl eventuelt er uafhængigt substitueret med en eller flere substituenter, som er de samme eller forskellige, hvor substituenten er H, F, Cl, methyl, ethyl, propyl, cyano, trifluormethyl, methoxy, -(CR7R7a)m-C(=0)N(R8a)2 eller -(CR7R7a)m-C(=0)0-R8a; hver R7a og R7 er uafhængigt H, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 eller Ci-4-alkyl; hver R8 og R8a cr uafhængigt H, Ci-4-alkyl, Ci-4-haloalkyl, amino-Ci-4-alkyl, Boc-NH-Cl-4-alkyl, Ci_4-alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H eller -(CH2)m-0C(=0)-(CH2)m-H eller Ci-6-alkyl; hver R9 er uafhængigt triazolyl, tetrazolyl, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)0-R8, -(CR7R7a-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)-R8, -(CR7R7a)t-0C(=0)-R8 eller -(CR7R7a)m-C(=0)N(R8)2, med det forbehold, at når R9 er -(CR7R7a)t-OH, er R3 C6-io-aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl eller triazinyl; hver R13 er uafhængigt H, F, Cl, Br, cyano, nitro, 4-(trifluormethyl)phenyl, 3,5-/v'v(trifluormcthyl)phcnyl eller trifluormethyl; hver n er uafhængigt 1 eller 2; hver t er uafhængigt 1, 2, 3 eller 4; og hver m er uafhængigt 0, 1 eller 2.
10. Forbindelse ifølge krav 9, hvor Z har formlen (II) eller (Ila):
hvor hver B er -CR7R7a-; hver W erN; hver Y er -O-; hver R7a og R7 er uafhængigt H, methyl, ethyl, -(CFhV-OH, -(CH2)m-C(=0)0-R8, ethyl eller propyl; hver R8 er uafhængigt H, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, aminomethyl, 1-amino-2-methylpropyl, 1-aminoethyl, 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, 1-Boc-NH-2-mcthylpropyl, 1-Boc-NH-cthyl, 2-Boc-NH-cthyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CFFV-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-0C(=0)-(CH2)m-H; hver R8a er uafhængigt H, methyl, ethyl, isopropyl eller propyl; hver R9 er uafhængigt triazolyl, tetrazolyl, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-R8, - (CR7R7a)m-C(=0)0-(CR7R7a)m-0C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m- 0C(=0)-R8, -(CR7R7a)t-0C(=0)-R8, triazolyl, tetrazolyl eller -(CR7R7a)m- C(=0)N(R8)2, med det forbehold, at når R9 er -(CR7R7a)t-OH, er R3 phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl eller triazinyl; hver m er uafhængigt 0, 1 eller 2; og hver t er uafhængigt 1,2,3 eller 4.
11. Forbindelse ifølge krav 10, hvor Z er:
12. Forbindelse ifølge krav 9, hvor hver R3 er uafhængigt:
13. Forbindelse ifølge krav 1, som har en af følgende strukturer:
eller en enantiomer, en diastereoisomer, en tautomer, et hydrat, et solvat eller et farmaceutisk acceptabelt salt deraf.
14. Farmaceutisk sammensætning, som omfatter forbindelsen ifølge et hvilket som helst af kravene 1-13 og en farmaceutisk acceptabel bærer, excipiens, adjuvans eller et farmaceutisk acceptabelt vehikel eller en kombination deraf.
15. Farmaceutisk sammensætning ifølge krav 14, som yderligere omfatter et anti-HBV-middel.
16. Farmaceutisk sammensætning ifølge krav 15, hvor anti-HBV-midlet er en HBV-polymerasehæmmer, -immunmodulator eller interferon.
17. Farmaceutisk sammensætning ifølge krav 15, hvor anti-HBV-midlet er lamivudin, telbivudin, tenofovir, entecavir, adefovir dipivoxil, alfaferon, alloferon, celmoleukin, clevudin, emtricitabin, famciclovir, feron, hepatect CP, intefen, interferon α-lb, interferon a, interferon a-2a, interferon β-la, interferon a-2, interleukin-2, mivotilat, nitazoxanid, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, veldona, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisol eller propagermanium.
18. Forbindelse ifølge et hvilket som helst af kravene 1-13 eller farmaceutisk sammensætning ifølge et hvilket som helst af kravene 14-17 til anvendelse ved forebyggelse, håndtering, behandling eller lindring af en virussygdom eller en HBV-sygdom.
19. Forbindelse til anvendelse eller farmaceutisk sammensætning til anvendelse ifølge krav 18, hvor virussygdommen eller HBV-sygdommen er hepatitis B-infektion eller en sygdom, der er forårsaget af hepatitis B-infektion.
20. Forbindelse til anvendelse eller farmaceutisk sammensætning til anvendelse ifølge krav 19, hvor sygdommen, der er forårsaget af hepatitis B-infektion, er cirrose eller hepatocellulært karcinom.
DK13830553.7T 2012-08-24 2013-08-23 2,4,5,6-Substituerede 3,6-dihydropyrimidinderivativer som hepatitis B-virus (HBV)-polymerasehæmmere til behandling af fx kronisk hepatitis DK2888241T3 (da)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201210303033 2012-08-24
CN201310116949 2013-04-03
PCT/CN2013/001001 WO2014029193A1 (en) 2012-08-24 2013-08-23 Dihydropyrimidine compounds and their application in pharmaceuticals

Publications (1)

Publication Number Publication Date
DK2888241T3 true DK2888241T3 (da) 2017-10-23

Family

ID=50149385

Family Applications (1)

Application Number Title Priority Date Filing Date
DK13830553.7T DK2888241T3 (da) 2012-08-24 2013-08-23 2,4,5,6-Substituerede 3,6-dihydropyrimidinderivativer som hepatitis B-virus (HBV)-polymerasehæmmere til behandling af fx kronisk hepatitis

Country Status (21)

Country Link
US (1) US9340538B2 (da)
EP (1) EP2888241B1 (da)
JP (1) JP6263533B2 (da)
KR (1) KR102148678B1 (da)
CN (2) CN104926808B (da)
AU (1) AU2013305390C1 (da)
BR (1) BR112015002858A2 (da)
CA (1) CA2876690C (da)
DK (1) DK2888241T3 (da)
ES (1) ES2640049T3 (da)
HK (1) HK1206027A1 (da)
HU (1) HUE034919T2 (da)
MX (1) MX2015002511A (da)
MY (1) MY182403A (da)
PL (1) PL2888241T3 (da)
PT (1) PT2888241T (da)
RU (1) RU2655914C9 (da)
SG (1) SG11201408791TA (da)
TW (1) TWI668217B (da)
WO (1) WO2014029193A1 (da)
ZA (1) ZA201500451B (da)

Families Citing this family (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130267517A1 (en) 2012-03-31 2013-10-10 Hoffmann-La Roche Inc. Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
WO2014037480A1 (en) * 2012-09-10 2014-03-13 F. Hoffmann-La Roche Ag 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CN103664899B (zh) * 2012-09-11 2017-06-16 广东东阳光药业有限公司 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用
CN104650069B (zh) * 2013-11-19 2019-04-19 广东东阳光药业有限公司 4-甲基二氢嘧啶类化合物及其在药物中的应用
WO2015074546A1 (en) 2013-11-19 2015-05-28 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
RU2688193C1 (ru) 2013-11-27 2019-05-21 Саншайн Лейк Фарма Ко., Лтд. Процессы приготовления производных дигидропиримидина и их промежуточных соединений
CA2935811C (en) * 2014-03-07 2018-09-18 F. Hoffmann-La Roche Ag 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
MY196243A (en) * 2014-03-28 2023-03-24 Sunshine Lake Pharma Co Ltd Dihydropyrimidine Compounds and Their Application In Pharmaceuticals
KR102428878B1 (ko) * 2014-05-30 2022-08-04 치루 파머수티컬 컴퍼니 리미티드 Hbv억제제인 디히드로피리미도 축합환 유도체
CN105153164B (zh) * 2014-05-30 2018-10-30 齐鲁制药有限公司 作为hbv抑制剂的二氢嘧啶并环衍生物
WO2016012470A1 (en) * 2014-07-25 2016-01-28 F. Hoffmann-La Roche Ag New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
CN105859709B (zh) * 2015-02-07 2018-12-04 广东东阳光药业有限公司 二氢嘧啶衍生物的复合物及其在药物中的应用
PT3270915T (pt) 2015-03-16 2020-06-17 H Hoffnabb La Roche Ag Tratamento combinado com um agonista do tlr7 e um inibidor da montagem da cápside do vhb
WO2016161268A1 (en) 2015-04-01 2016-10-06 Enanta Pharmaceuticals, Inc. Hepatitis b antviral agents
WO2016183266A1 (en) 2015-05-13 2016-11-17 Enanta Pharmaceuticals, Inc. Ehpatitis b antiviral agents
US10179131B2 (en) 2015-07-13 2019-01-15 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US10301255B2 (en) 2015-07-22 2019-05-28 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
EP3370759A1 (en) * 2015-11-03 2018-09-12 H. Hoffnabb-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and an interferon
WO2017136403A1 (en) 2016-02-02 2017-08-10 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
AR107633A1 (es) 2016-02-19 2018-05-16 Hoffmann La Roche Procedimiento para la preparación del ácido 4-fenil-5-alcoxicarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il-[metil]-3-oxo-5,6,8,8a-tetrahidro-1h-imidazo[1,5a]pirazin-2-il-carboxílico
ES2938341T3 (es) 2016-03-07 2023-04-10 Enanta Pharm Inc Agentes antivirales contra la hepatitis B
WO2017198201A1 (en) * 2016-05-19 2017-11-23 Sunshine Lake Pharma Co., Ltd. Crystalline form, salt and complex of dihydropyrimidine derivative, and uses thereof in medicine
JP2019521972A (ja) * 2016-06-10 2019-08-08 エナンタ ファーマシューティカルズ インコーポレイテッド Ｂ型肝炎抗ウイルス剤
CN107674072B (zh) * 2016-08-01 2020-11-24 广东东阳光药业有限公司 二氢嘧啶衍生物及其酸加成物的制备方法
CN109689059A (zh) * 2016-08-24 2019-04-26 豪夫迈·罗氏有限公司 Hbv衣壳组装抑制剂和核苷或核苷酸类似物的组合疗法
CN107793409B (zh) * 2016-09-05 2022-09-27 广东东阳光药业有限公司 二氢嘧啶类化合物及其在药物中的应用
WO2018045911A1 (zh) * 2016-09-09 2018-03-15 浙江海正药业股份有限公司 二氢嘧啶类化合物及其制备方法和用途
US11166954B2 (en) 2016-11-18 2021-11-09 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
CA3037218A1 (en) 2016-11-18 2018-05-24 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
AU2018291688B2 (en) * 2017-06-27 2022-02-03 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
RU2745431C1 (ru) 2017-07-27 2021-03-25 Цзянсу Хэнжуй Медицин Ко., Лтд. Гетероарильное производное пиперазина, способ его получения и применение в медицине
CA3073986A1 (en) 2017-08-28 2019-03-07 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
RU2020112854A (ru) 2017-11-30 2021-12-30 Арракис Терапьютикс, Инк. Фотозонды, связывающие нуклеиновые кислоты, и способы их применения
TW201936192A (zh) 2017-12-06 2019-09-16 美商因那塔製藥公司 B 型肝炎抗病毒試劑
WO2019113173A1 (en) 2017-12-06 2019-06-13 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
US11058678B2 (en) 2018-01-22 2021-07-13 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2019191166A1 (en) 2018-03-29 2019-10-03 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
CA3097784A1 (en) * 2018-05-08 2019-11-14 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
EP3814326A4 (en) * 2018-06-26 2022-03-16 Janssen Sciences Ireland Unlimited Company DIHYDROPYRIMIDE DERIVATIVES AND USES THEREOF IN THE TREATMENT OF HBV INFECTION OR HBV-INDUCED DISEASE
CN108947996B (zh) * 2018-07-12 2022-01-18 山东大学 二氢嘧啶-磺酰胺类衍生物及其制备方法与应用
US11053235B2 (en) 2018-08-09 2021-07-06 Janssen Sciences Ireland Unlimited Company Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases
CN112955142A (zh) 2018-09-21 2021-06-11 英安塔制药有限公司 官能化杂环化合物作为抗病毒剂
US20210395751A1 (en) 2018-10-31 2021-12-23 The University Of Sydney Compositions and methods for treating viral infections
CN109251201B (zh) * 2018-11-03 2020-06-02 深圳市第二人民医院 一种抗hbv的含氮杂环化合物
CN109232555B (zh) * 2018-11-03 2020-06-02 深圳市第二人民医院 一种抗hbv的含氧杂环化合物
UY38483A (es) 2018-11-21 2020-06-30 Enanta Pharm Inc Heterociclos funcionalizados como agentes antivirales
CN113614088A (zh) 2019-03-25 2021-11-05 豪夫迈·罗氏有限公司 Hbv核心蛋白变构修饰剂化合物的固体形式
KR20210145787A (ko) 2019-04-02 2021-12-02 알리고스 테라퓨틱스 인코포레이티드 Prmt5를 표적으로 하는 화합물
US11236111B2 (en) 2019-06-03 2022-02-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
WO2020247561A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
WO2020247575A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
WO2020255015A1 (en) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators
CN110204539B (zh) * 2019-07-03 2021-07-23 山东大学 一种二氢嘧啶类前药及其制备方法和应用
WO2021007488A1 (en) 2019-07-11 2021-01-14 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
EP4003355A4 (en) * 2019-07-31 2023-07-26 Janssen Sciences Ireland Unlimited Company DIHYDROPYRIMIDE DERIVATIVES AND USES THEREOF IN THE TREATMENT OF HBV INFECTION OR HBV-INDUCED DISEASE
WO2021055425A2 (en) 2019-09-17 2021-03-25 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
WO2021121363A1 (en) * 2019-12-20 2021-06-24 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
US11802125B2 (en) 2020-03-16 2023-10-31 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
WO2022052923A1 (zh) * 2020-09-08 2022-03-17 和博医药有限公司 二氢嘧啶类化合物、其应用
AR124719A1 (es) 2021-01-29 2023-04-26 Janssen Sciences Ireland Unlimited Co Derivados de dihidropirimidina y usos de estos en el tratamiento de la infección por vhb o de enfermedades inducidas por vhb
CN116888118A (zh) * 2021-02-05 2023-10-13 和博医药有限公司 苯基二氢嘧啶类化合物及其应用
WO2022257942A1 (en) 2021-06-09 2022-12-15 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61271278A (ja) 1985-05-20 1986-12-01 イ−　ア−ル　スクイブ　アンド　サンズ　インコ−ポレ−テツド ２−置換チオまたはオキソ−４−アリ−ルまたはヘテロシクロ−５−カルボキシ−１，４−ジヒドロピリミジン
GB8906168D0 (en) 1989-03-17 1989-05-04 Pfizer Ltd Therapeutic agents
CA2154633A1 (en) * 1995-01-25 1996-07-26 Paul Harry Sandstrom Silica reinforced rubber composition and use in tires
SE9702563D0 (sv) 1997-07-02 1997-07-02 Astra Ab Compounds
SE9702564D0 (sv) 1997-07-02 1997-07-02 Astra Ab New compounds
DE19817265A1 (de) 1998-04-18 1999-10-21 Bayer Ag Verwendung von Dihydropyrimidinen als Arzneimittel und neue Stoffe
DE19817262A1 (de) 1998-04-18 1999-10-21 Bayer Ag Neue 2-heterocyclisch substituierte Dihydropyrimidine
DE19817264A1 (de) * 1998-04-18 1999-10-21 Bayer Ag Neue Dihydropyrimidine
AU4289100A (en) 1999-03-25 2000-10-16 Bayer Aktiengesellschaft Dihydropyrimidines and their use in the treatment of hepatitis
DE10012549A1 (de) 2000-03-15 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
DE10012823A1 (de) * 2000-03-16 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
DE10012824A1 (de) 2000-03-16 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
DE10013126A1 (de) * 2000-03-17 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
DE10013125A1 (de) 2000-03-17 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
WO2005007124A2 (en) 2003-07-23 2005-01-27 Bristol-Myers Squibb Company Substituted dihydropyrimidine inhibitors of calcium channel function
AR056871A1 (es) * 2005-10-04 2007-10-31 Aventis Pharma Inc Compuestos de pirimidina amida como inhibidores de pgds
CN101104617B (zh) 2006-07-10 2010-06-23 北京摩力克科技有限公司 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途
CN101104604B (zh) 2006-07-10 2011-03-02 北京摩力克科技有限公司 光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途
WO2008024692A1 (en) 2006-08-23 2008-02-28 Neurogen Corporation N-oxide aryl sulfones and sulfoxides
CN101225084A (zh) 2007-01-16 2008-07-23 北京摩力克科技有限公司 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途
WO2008154819A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
KR101173892B1 (ko) * 2007-06-18 2012-08-16 선샤인 레이크 파르마 컴퍼니 리미티드 브로모-페닐 치환된 티아졸릴 디하이드로피리미딘
WO2008154820A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
CN101328170B (zh) * 2007-06-18 2011-09-14 张中能 一种氟苯基-取代噻唑二氢嘧啶
WO2010069147A1 (zh) * 2008-12-17 2010-06-24 张中能 二氢嘧啶类化合物、其组合物及其应用
CN101744823B (zh) * 2008-12-17 2013-06-19 广东东阳光药业有限公司 一种二氢嘧啶类化合物的固体分散体及其药用制剂
CN101575318B (zh) 2009-06-25 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 二氢嘧啶类化合物及其用于制备治疗和/或预防病毒性疾病的药物的用途
WO2013010069A1 (en) * 2011-07-13 2013-01-17 Indiana University Research And Technology Corporation Modified viral structural protein with antiviral activity
US9487534B2 (en) 2011-08-02 2016-11-08 Scripps Research Institute, A Not-For-Profit Public Benefit Corporation Of California Modulators of virus assembly as antiviral agents
WO2013102655A1 (en) 2012-01-06 2013-07-11 Janssen R&D Ireland 4,4-disubstituted-1,4-dihydropyrimidines and the use thereof as medicaments for the treatment of hepatitis b
US20130267517A1 (en) 2012-03-31 2013-10-10 Hoffmann-La Roche Inc. Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
WO2014037480A1 (en) * 2012-09-10 2014-03-13 F. Hoffmann-La Roche Ag 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

Also Published As

Publication number Publication date
SG11201408791TA (en) 2015-01-29
EP2888241A4 (en) 2016-05-25
AU2013305390B2 (en) 2015-09-17
EP2888241A1 (en) 2015-07-01
CN104926808A (zh) 2015-09-23
AU2013305390C1 (en) 2015-12-24
CN103626752A (zh) 2014-03-12
HK1206027A1 (en) 2015-12-31
EP2888241B1 (en) 2017-07-12
US9340538B2 (en) 2016-05-17
CA2876690A1 (en) 2014-02-27
PL2888241T3 (pl) 2017-12-29
PT2888241T (pt) 2017-09-14
MY182403A (en) 2021-01-25
RU2655914C2 (ru) 2018-05-30
CN104926808B (zh) 2018-09-14
US20150152096A1 (en) 2015-06-04
ZA201500451B (en) 2016-10-26
JP6263533B2 (ja) 2018-01-17
MX2015002511A (es) 2016-03-08
WO2014029193A1 (en) 2014-02-27
BR112015002858A2 (pt) 2017-08-08
AU2013305390A1 (en) 2015-01-15
HUE034919T2 (en) 2018-03-28
JP2015526448A (ja) 2015-09-10
RU2015110082A (ru) 2016-10-10
KR102148678B1 (ko) 2020-08-27
KR20150044859A (ko) 2015-04-27
TWI668217B (zh) 2019-08-11
TW201408662A (zh) 2014-03-01
RU2655914C9 (ru) 2018-07-24
ES2640049T3 (es) 2017-10-31
CN103626752B (zh) 2015-08-12
CA2876690C (en) 2020-06-09

Similar Documents

Publication Publication Date Title
DK2888241T3 (da) 2,4,5,6-Substituerede 3,6-dihydropyrimidinderivativer som hepatitis B-virus (HBV)-polymerasehæmmere til behandling af fx kronisk hepatitis
AU2015236982B2 (en) Dihydropyrimidine compounds and their application in pharmaceuticals
KR102667040B1 (ko) 디하이드로피리미딘 화합물 및 약제에서의 이의 용도
AU2014352404B2 (en) Dihydropyrimidine compounds and their application in pharmaceuticals
KR102665544B1 (ko) 디하이드로피리미딘 화합물 및 약제에서의 이의 용도
KR20180133461A (ko) 피라졸로[1,5-a]피리미디닐 카르복스아미드 화합물 및 의학적 장애의 치료에서의 그의 용도