WO2022161448A1 - Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le vhb ou de maladies induites par le vhb - Google Patents

Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le vhb ou de maladies induites par le vhb Download PDF

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WO2022161448A1
WO2022161448A1 PCT/CN2022/074479 CN2022074479W WO2022161448A1 WO 2022161448 A1 WO2022161448 A1 WO 2022161448A1 CN 2022074479 W CN2022074479 W CN 2022074479W WO 2022161448 A1 WO2022161448 A1 WO 2022161448A1
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compound
mmol
purity
alkyl
hbv
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PCT/CN2022/074479
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English (en)
Inventor
Yimin Jiang
Zhanling CHENG
Gang Deng
Zhiguo Liu
Chao Liang
Jianping Wu
Linglong KONG
Xiangjun DENG
Yanping Xu
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Janssen Sciences Ireland Unlimited Company
Johnson & Johnson (China) Investment Ltd.
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Publication of WO2022161448A1 publication Critical patent/WO2022161448A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • HBV infection chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5%of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S. ) .
  • HBV human immunodeficiency virus
  • Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase) ; drug resistance, low efficacy, and tolerability issues limit their impact.
  • the low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent.
  • persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma.
  • Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.
  • HBV capsid protein plays essential functions during the viral life cycle.
  • HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress.
  • Capsid structures also respond to environmental cues to allow un-coating after viral entry. Consistently, the appropriate timing of capsid assembly and dis-assembly, the appropriate capsid stability and the function of core protein have been found to be critical for viral infectivity.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, halogens, CN and C 1-3 alkyl,
  • R 4 is selected from the group consisting of thiazolyl, imidazolyl, oxazolyl and pyridyl, each of which may be optionally substituted with one or more substituents, each independently selected from CH 3 or halogens,
  • R 5 is C 1-4 alkyl
  • X is selected from CH 2 and O
  • R 6 and R 7 are independently selected from H and C 1-3 alkyl
  • R 8 is selected from H and C 1-6 alkyl
  • L is a C 1-6 alkylene substituted with
  • each of the above C 1-3 alkyl, C 1-3 alkoxyl, C 1-4 alkyl and C 1-6 alkyl can optionally be substituted with one, two or three halogens;
  • a pharmaceutical composition comprising at least one compound of Formula (I) , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one disclosed compound, together with a pharmaceutically acceptable carrier.
  • a method of treating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • provided herein is any of the compounds described herein, or the pharmaceutical composition of the invention, for use as a medicament.
  • provided herein is any of the compounds described herein, or the pharmaceutical composition of the invention, for use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof.
  • a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof, wherein said first compound is different from said second compound, wherein said first compound is the compound of Formula (I) or the pharmaceutical composition according to the invention, as described herein, and wherein said second compound is an HBV inhibitor.
  • Said HBV inhibitor may be chosen from among:
  • any of the methods provided herein can further comprise administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and any combination thereof.
  • R 1 -R 5 are as defined in Formula (I) , and LG represents a suitable leaving group, such as for example, bromo; with a compound of Formula (V)
  • R 6 -R 8 , X and L are as defined in Formula (I) ;
  • nucleophilic substitution conditions for example, in the presence of a suitable base, such as for example triethanolamine.
  • compounds e.g., the compounds of Formula (I) , or pharmaceutically acceptable salts thereof as described herein, that may be useful in the treatment and prevention of HBV infection in a subject.
  • these compounds are believed to modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles and/or may disrupt HBV capsid assembly leading to empty capsids with greatly reduced infectivity or replication capacity.
  • the compounds provided herein may act as capsid assembly modulators.
  • the disclosed compounds may modulate (e.g., accelerate, delay, inhibit, disrupt or reduce) normal viral capsid assembly or disassembly, bind capsid or alter metabolism of cellular polyproteins and precursors. The modulation may occur when the capsid protein is mature, or during viral infectivity.
  • Disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the generation or release of HBV RNA particles from within an infected cell.
  • the compounds described herein may be suitable for monotherapy and may be effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein may be suitable for use in combination therapy.
  • the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include” , “includes, ” and “included, ” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20%or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1%from the specified value, as such variations are appropriate to perform the disclosed methods.
  • capsid assembly modulator refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function.
  • a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology.
  • a capsid assembly modulator interacts (e.g.
  • a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like) , which attenuates viral infectivity or is lethal to the virus.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a disclosed compound (alone or in combination with another pharmaceutical agent) , to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications) , who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection, or the potential to develop an HBV infection.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the term “patient, ” “individual” or “subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, subject, or individual is human.
  • the terms “effective amount, ” “pharmaceutically effective amount, ” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445 and Journal of Pharmaceutical Science, 66, 1-19 (1977) , each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1990, Easton, PA) , which is incorporated herein by reference.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1-3 alkyl means an alkyl having one to three carbon atoms, C 1-4 alkyl means an alkyl having one to four carbons and includes straight and branched chains, C 1-6 alkyl means an alkyl having one to six carbon atoms and includes straight and branched chains, C 1 -C 9 alkyl means an alkyl having one to nine carbon atoms and includes straight and branched chains) .
  • C 1-3 alkyl means an alkyl having one to three carbon atoms
  • C 1-4 alkyl means an alkyl having one to four carbons and includes straight and branched chains
  • C 1-6 alkyl means an alkyl having one to six carbon atoms and includes straight and branched chains
  • C 1 -C 9 alkyl means an alkyl having one to nine carbon atoms and includes
  • alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
  • alkyl examples include, but are not limited to, C 1-9 alkyl, C 1-6 alkyl, C 1-4 alkyl.
  • alkylene alone or as part of another substituent means, refers to a divalent alkyl linking group.
  • An alkylene group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • C n-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-1, 2-diyl, ethan-1, 1-diyl, propan-1, 3-diyl, propan-1, 2-diyl, propan-1, 1 -diyl, butan-1, 4-diyl, butan-1, 3-diyl, butan-1, 2-diyl, 2-methyl-propan-1, 3-diyl and the like.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • substituted is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • substituents When two or more substituents are present on a moiety they may, unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.
  • a dashed line across a bond indicates the position where a moiety is attached to another moiety.
  • L is a group of formula (a)
  • R a1 is selected from OH and C 1-3 alkyloxyl
  • R a2 is selected from C 1-3 alkyl
  • R a1 is selected from halogen
  • R a2 is selected from C 1-3 alkyl.
  • L is a group of formula (a)
  • R a1 is selected from OH, CH 3 O and C 2 H 5 O, and
  • R a2 is CH 3 or C 2 H 5 ,
  • R a1 is F or Cl
  • R a2 is CH 3 or C 2 H 5 .
  • L is a group of formula (b)
  • R b1 is selected from halogen, OH and C 1-3 alkyloxyl,
  • R b2 is selected from C 1-3 alkyl
  • R b3 and R b4 are H
  • R b1 and R b2 are independently selected from H and C 1-3 alkyl
  • R b3 is selected from halogen, OH and C 1-3 alkyloxyl,
  • R b4 is H
  • R b1 and R b2 are independently selected from H and C 1-3 alkyl
  • R b3 is selected from halogen
  • R b4 is selected from halogen and C 1-3 alkyl
  • R b1 and R b2 are independently selected from H and C 1-3 alkyl
  • R b3 is selected from OH and C 1-3 alkyloxyl
  • R b4 is C 1-3 alkyl.
  • L is a group of formula (b)
  • R b1 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R b2 is CH 3 or C 2 H 5 ,
  • R b3 and R b4 are H
  • R b1 and R b2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R b3 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R b4 is H
  • R b1 and R b2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R b3 is F or Cl
  • R b4 is selected from F, Cl, CH 3 and C 2 H 5 ,
  • R b1 and R b2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R b3 is selected from OH, CH 3 O and C 2 H 5 O,
  • R b4 is CH 3 or C 2 H 5 .
  • L is a group of formula (c)
  • R c1 is selected from halogen, OH and C 1-3 alkyloxyl,
  • R c2 is selected from C 1-3 alkyl
  • R c3 , R c4 , R c5 and R c6 are H
  • R c1 and R c2 are independently selected from H and C 1-3 alkyl
  • R c3 is selected from halogen, OH and C 1-3 alkyloxyl,
  • R c4 , R c5 and R c6 are H
  • R c1 and R c2 are independently selected from H and C 1-3 alkyl
  • R c3 and R c4 are H
  • R c5 is selected from halogen, OH and C 1-3 alkyloxyl
  • R c6 is selected from H and C 1-3 alkyl
  • R c1 and R c2 are independently selected from H and C 1-3 alkyl
  • R c3 and R c4 are H
  • R c5 and R c6 are halogen.
  • L is a group of formula (c)
  • R c1 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R c2 is CH 3 or C 2 H 5 ,
  • R c3 , R c4 , R c5 and R c6 are H
  • R c1 and R c2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R c3 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R c4 , R c5 and R c6 are H
  • R c1 and R c2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R c3 and R c4 are H
  • R c5 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R c6 is selected from H, CH 3 and C 2 H 5 ,
  • R c1 and R c2 are independently selected from H, CH 3 and C 2 H 5,
  • R c3 and R c4 are H
  • R c5 and R c6 are F or Cl.
  • L is a group of formula (d)
  • R d1 and R d2 are independently selected from C 1-3 alkyl
  • R d3 R d4 , R d5 and R d6 are H
  • R d8 is selected from halogen, OH and C 1-3 alkyloxyl
  • R d9 is selected from H and C 1-3 alkyl
  • R d1 and R d2 are independently selected from H and C 1-3 alkyl
  • R d3 , R d4 , R d5 and R d6 are H
  • R d8 and R d9 are halogen.
  • L is a group of formula (d)
  • R d1 and R d2 are independently selected from CH 3 and C 2 H 5 ,
  • R d3 R d4 , R d5 and R d6 are H
  • R d8 is selected from F, Cl, OH, CH 3 O and C 2 H 5 O,
  • R d9 is selected from H, CH 3 and C 2 H 5,
  • R d1 and R d2 are independently selected from H, CH 3 and C 2 H 5 ,
  • R d3 , R d4 , R d5 and R d6 are H
  • R d8 and R d9 are F or Cl.
  • R 8 is H.
  • L-COOR 8 is selected from the group consisting of the following:
  • X is O.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, CN and CH 3 .
  • R 4 is selected from the group consisting of thiazolyl, imidazolyl, and oxazolyl, each of which may be optionally substituted with one CH 3 .
  • R 4 is selected from the group consisting of thiazol-2-yl, 1-methyl-imidazol-2-yl and 5-methyl-oxazol-4-yl; more in particular, thiazol-2-yl and 5-methyl-oxazol-4-yl.
  • R 5 is CH 3 or C 2 H 5 ..
  • R 6 and R 7 are independently selected from H and CH 3 .
  • An embodiment relates to a compound is selected from the group consisting of the following compounds:
  • Preferred compounds according to the invention are compounds or a stereoisomer or tautomeric form thereof with a formula as represented in the synthesis of compounds section and Table 1, and of which the activity is displayed in Table 3.
  • the disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
  • the stereochemical configuration may be assigned at indicated centers as (*) when the absolute stereochemistry is undetermined at the stereocenter although the compound itself has been isolated as a single stereoisomer and is enatiomerically/diastereomerically pure.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the disclosed compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the stereochemical configuration at indicated centres has been assigned as “R*” , “S*” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically/diastereomerically pure.
  • the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements) .
  • substitution with positron emitting isotopes is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • R 1 -R 5 are as defined in Formula (I) , and LG represents a suitable leaving group, such as for example, bromo; with a compound of Formula (V)
  • R 6 -R 8 , X and L are as defined in Formula (I) ;
  • nucleophilic substitution conditions for example, in the presence of a suitable base, such as for example triethanolamine.
  • a method of treating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • Also provided herein is a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of reducing viral load associated with an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of reducing reoccurrence of an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • the invention is said to relate to a method of treating an individual, it is understood that such method is to be interpreted in certain jurisdictions as a medical use, e.g. a compound or a composition according to the invention for use in treating an individual; or a use of the compound or the composition according to the invention, for the manufacture of a medicament, in particular for treating an individual. Therefore, for example, the invention also relates to a compound or a pharmaceutical composition as disclosed herein for use in the prevention or treatment of an HBV infection. Also provided herein, is a compound or a pharmaceutical composition as disclosed herein for use in the reduction of viral load associated with an HBV infection.
  • a compound or a pharmaceutical composition as disclosed herein for use in the reduction of reoccurrence of an HBV infection in an individual. Also provided herein, is a compound or a pharmaceutical composition as disclosed herein, for use in the inhibition or reduction of the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual.
  • HBV-associated particles may contain HBV DNA (i.e., linear and/or covalently closed circular DNA (cccDNA) ) and/or HBV RNA (i.e., pre-genomic RNA and/or sub-genomic RNA) .
  • HBV-associated particles include HBV DNA-containing particles or HBV RNA-containing particles.
  • HBV-asociated particles refer to both infectious HBV virions (i.e., Dane particles) and non-infectious HBV subviral particles (i.e., HBV filaments and/or HBV spheres) .
  • HBV virions comprise an outer envelope including surface proteins, a nucleocapsid comprising core proteins, at least one polymerase protein, and an HBV genome.
  • HBV filaments and HBV spheres comprise HBV surface proteins, but lack core proteins, polymerase and an HBV genome.
  • HBV filaments and HBV spheres are also known collectively as surface antigen (HBsAg) particles.
  • HBV spheres comprise middle and small HBV surface proteins.
  • HBV filaments also include middle, small and large HBV surface proteins.
  • HBV subviral particles can include the nonparticulate or secretory HBeAg, which serves as a marker for active replication of HBV.
  • a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • Also provided herein is a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of inducing reversal of hepatic injury from an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection comprising administering to the individual a therapeutically effective amount of a disclosed compound.
  • a compound or a pharmaceutical composition as disclosed herein for use in the reduction of an adverse physiological impact of an HBV infection in an individual. Also provided herein is a compound or a pharmaceutical composition as disclosed herein, for use in the reduction, slowing or inhibition of an HBV infection in an individual. Also provided herein, is a compound or a pharmaceutical composition as disclosed herein for use in inducing reversal of hepatic injury from an HBV infection in an individual.
  • a compound or a pharmaceutical composition as disclosed herein for use in reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual. Further provided herein is a compound or a pharmaceutical composition as disclosed herein for use in the prophylactic treatment of an HBV infection in an individual, wherein the individual is afflicted with a latent HBV infection.
  • the individual is refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof) .
  • HBV drugs e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof.
  • the disclosed method or use reduces viral load in an individual suffering from an HBV infection to a greater extent or at a faster rate compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual.
  • the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
  • the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof reduces the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.
  • the disclosed method or use reduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.
  • the disclosed method or use causes a lower incidence of viral mutation or viral resistance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regimens.
  • the administering of a compound the invention, or a pharmaceutically acceptable salt thereof causes a lower incidence of viral mutation or viral resistance than the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • the disclosed method or use increases the seroconversion rate from HBV infected to non-HBV infected or from detectable HBV viral load to non-detectable HBV viral load beyond that of current treatment regimens.
  • seroconversion refers to the period of time during which HBV antibodies develop and become detectable.
  • the disclosed method or use increases or normalizes or restores normal health, elicits full recovery of normal health, restores life expectancy, or resolves the viral infection in the individual in need thereof.
  • the disclosed method or use eliminates or decreases the number of HBV RNA particles that are released from HBV infected cells thus enhancing, prolonging, or increasing the therapeutic benefit of the disclosed compounds.
  • the disclosed method or use eradicates HBV from an individual infected with HBV, thereby obviating the need for long term or life-long treatment, or shortening the duration of treatment, or allowing for reduction in dosing of other antiviral agents.
  • the disclosed method or use further comprises monitoring or detecting the HBV viral load of the subject, and wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.
  • provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof. Accordingly, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to the invention, e.g. those of Table 1, or a pharmaceutically acceptable salt thereof.
  • the method or use can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.
  • the disclosed compounds may be useful in combination with one or more additional compounds useful for treating HBV infection.
  • additional compounds may comprise other disclosed compounds and/or compounds known to treat, prevent, or reduce the symptoms or effects of HBV infection.
  • Such compounds include, but are not limited to, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitors, immunomodulatory agents, TLR-agonists, and other agents with distinct or unknown mechanisms that affect the HBV life cycle or affect the consequences of HBV infection, e.g.
  • the additional compounds may comprise HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, famesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-induc
  • the disclosed compounds may be used in combination with one or more drugs (or a salt thereof) selected from the group comprising:
  • HBV reverse transcriptase inhibitors HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors.
  • the additional therapeutic agent is an interferon.
  • interferon or “IFN” refers to any member of the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are grouped into three classes: Type I, Type II, and Type III. Recombinant forms of interferons that have been developed and are commercially available are encompassed by the term “interferon” as used herein. Subtypes of interferons, such as chemically modified or mutated interferons, are also encompassed by the term “interferon” as used herein.
  • the compounds of Formula (I) can be administered in combination with an interferon.
  • the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class.
  • the additional therapeutic agent may be an agent of distinct or unknown mechanism including agents that disrupt the function of other essential viral protein (s) or host proteins required for HBV replication or persistence.
  • the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets the HBV polymerase such as nucleoside or nucleotide or non-nucleos (t) ide polymerase inhibitors.
  • the additional therapeutic agent is an immunomodulatory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses.
  • the immunomodulatory agent can effect maturation of antigen presenting cells, proliferation of T-cells and cytokine release (e.g., IL-12, IL-18, IFN-alpha, -beta, and -gamma and TNF-alpha among others) .
  • the additional therapeutic agent is a TLR modulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist.
  • the method may further comprise administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.
  • the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.
  • provided herein is method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine.
  • a method of treating an HBV infection in an individual in need thereof comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a antisense oligonucleotide or RNA interference agent that targets HBV nucleic acids; and further administering to the individual a therapeutically effective amount of HBV vaccine.
  • the antisense oligonucleotide or RNA interference agent possesses sufficient complementarity to the target HBV nucleic acids to inhibit replication of the viral genome, transcription of viral RNAs, or translation of viral proteins.
  • the disclosed compound and the at least one additional therapeutic agent are co-formulated. In yet another embodiment, the disclosed compound and the at least one additional therapeutic agent are co-administered.
  • synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E max equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453) , the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55) .
  • Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • the method can further comprise monitoring or detecting the HBV viral load of the subject, wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.
  • composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of HBV infection in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • illustrating the invention is a process for preparing a pharmaceutical composition, comprising mixing at least one pharmaceutically acceptable carrier with a therapeutically effective amount of a disclosed compound.
  • the dose of a disclosed compound is from about 1 mg to about 2,500 mg.
  • a dose of a second compound (i.e., another drug for HBV treatment) as described herein is less than about 1,000 mg.
  • the present invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a disclosed compound, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.
  • routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans) buccal, (trans) urethral, vaginal (e.g., trans-and perivaginally) , (intra) nasal and (trans) rectal) , intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • ACN means acetonitrile
  • AcOH means acetic acid
  • Boc means tert-butyloxycarbonyl
  • Bn means benzyl
  • calcd. means calculated
  • Cbz means benzyloxycarbonyl
  • col. means column, conc.
  • m-CPBA 3-chloroperbenzoic acid
  • DAST diethylamino) sulfur trifluoride
  • DCM means dichloromethane
  • DEA diethanolamine
  • DIEA means N, N-diisopropylethyl amine
  • DMAP means 4- (dimethylamino) pyridine
  • DMF means dimethylformamide
  • DMP means Dess-Martin periodinane
  • EA means ethyl acetate
  • ee means enantiomeric excess
  • ESI electrospray ionization
  • HATU means 2- (7-azabenzotriazol-1-yl) -N, N, N’, N’-tetramethyluronium hexafluorophosphate
  • Hex means hexane
  • HNMR means 1 HNMR
  • HPLC means high performance liquid chromatography
  • IPA isopropyl alcohol
  • LC-MS or LCMS means liquid chromatography-mass
  • Prep-HPLC means preparative
  • R T or Rt mean retention time
  • sat. means saturated
  • TBAF means tetrabutylammonium fluoride
  • TBS means tert-butyldimethylsilyl
  • TEA means triethylamine
  • THF means tetrahydrofuran
  • T or Temp mean temperature
  • TsCl means 4-toluenesulfonyl chloride
  • t-BuOK means potassium tert-butoxide
  • W means wavelength.
  • Compound I-1 can be prepared by the condensation of aldehyde II, acetoacetate III and amidine IV in the presence of a base such as NaOAc.
  • Compound I-2 was prepared from compound I-1 using brominating reagent such as for example, N-bromosuccinimide, in a suitable solvent, such as carbon tetrachloride, under suitable reaction conditions, such as for example at a temperature of about room temperature to about 60 °C under an inert atmosphere, e.g. nitrogen, for a sufficient period of time, typically 1 hour.
  • the filtrate was concentrated under reduced pressure to give the crude product.
  • the combined organic phases were washed with brine (50 mL) , dried over sodium sulfate and filtered. The filtrate was concentrated in vacuum.
  • Step 1 To a solution of 4- ( (cis) -4- (tert-butoxycarbonyl) -6, 6-difluorohexahydropyrrolo [3, 2-b] pyrrol-1 (2H) -yl) -2- (methoxymethoxy) -2-methylbutanoic acid S4-6 (2.30 g, 95 %purity, 5.35 mmol) and potassium carbonate (1.50 g, 10.9 mmol) in N, N-dimethylformamide (10 mL) was added 3-bromoprop-1-ene (700 mg, 5.79 mmol) and the reaction mixture was stirred at 25°C overnight.
  • Step 2 A solution of (cis) -tert-butyl 4- (4- (allyloxy) -3- (methoxymethoxy) -3-methyl-4-oxobutyl) -3, 3-difluorohexahydropyrrolo [3, 2-b] pyrrole-1 (2H) -carboxylate (900 mg, 95%purity, 1.91 mmol) in 2 M hydrochloric acid in 1, 4-dioxane solution (50 mL, 100 mmol) was stirred at room temperature for 6 hours. The mixture was poured into saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (50 mL) twice. The combined organic phases were washed with brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the titled product (640 mg, 99.3%yield) as colorless oil.
  • N-dimethylformamide (20 mL) was added N-bromosuccinimide (2.72 g, 15.3 mmol) .
  • the mixture was heated to 80 °C and stirred under nitrogen atmosphere overnight.
  • the mixture was diluted with ethyl acetate (20 mL) and washed with water (50 mL) .
  • the aqueous layer was extracted with ethyl acetate (20 mL) for three times.
  • the pH of the solution was adjusted to 5 using 1N HCl aqueous solution.
  • the mixture was concentrated under reduced pressure to remove MeOH. It was extracted with EtOAc. The organic layers were collected, washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the crude was purified by prep-HPLC (Column: Waters Xbrige C18 (5 ⁇ m 19 *150 mm) , Mobile phase A: water (0.1 %ammomium bicarbonate) , Mobile phase B: acetonitrile, UV: 214 nm, Flow rate: 15 mL/min, Gradient: 20 -70% (%B) ) to get the title compound (65.8 mg, 97.8 %purity from LCMS, 51 %yield) as a yellow solid.
  • reaction mixture was neutralized with 1 M hydrochloride aqueous solution (about 4 mL) to pH 6 -7 and extracted with ethyl acetate (100 mL) twice.
  • Compound 39 was made from Intermediate H6A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 40A was made from Intermediate H17A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 40B was prepared analogous to compound 40A.
  • Compound 41 was made from Intermediate H3B and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 42 was made from Intermediate H5A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 43 was made from Intermediate H4A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 44 was made from Intermediate H2A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 45 was made from Intermediate H15A and Intermediate M1 according to typical method 1 and typical method 2 successively.
  • Compound 46 was made from Intermediate H7B and Intermediate M1 according to typical method 1 and typical method 2 successively.

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Abstract

L'invention concerne des dérivés de dihydropyrimidine qui sont utiles dans le traitement ou la prévention d'une infection par le VHB ou de maladies induites par le VHB, plus particulièrement d'une infection chronique par HBV ou de maladies induites par une infection chronique par HBV, ainsi que des applications pharmaceutiques ou médicales de celles-ci.
PCT/CN2022/074479 2021-01-29 2022-01-28 Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le vhb ou de maladies induites par le vhb WO2022161448A1 (fr)

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