WO2017064156A1 - Nouvelles 2-hétéroaryldihydropyrimidines fusionnées en position 6 pour le traitement et la prophylaxie de l'infection par le virus de l'hépatite b - Google Patents

Nouvelles 2-hétéroaryldihydropyrimidines fusionnées en position 6 pour le traitement et la prophylaxie de l'infection par le virus de l'hépatite b Download PDF

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WO2017064156A1
WO2017064156A1 PCT/EP2016/074526 EP2016074526W WO2017064156A1 WO 2017064156 A1 WO2017064156 A1 WO 2017064156A1 EP 2016074526 W EP2016074526 W EP 2016074526W WO 2017064156 A1 WO2017064156 A1 WO 2017064156A1
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methyl
fluoro
phenyl
imidazo
tetrahydro
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PCT/EP2016/074526
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English (en)
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Taishan HU
Buyu KOU
Gangqin LI
Hong Shen
Weixing Zhang
Zhisen ZHANG
Wei Zhu
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2017064156A1 publication Critical patent/WO2017064156A1/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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a human, and in particular to Hepatitis B virus (HBV) inhibitors by targeting on HBV capsid for the treatment of HBV infection.
  • HBV Hepatitis B virus
  • the present invention relates to novel 6-fused and 2-heteroaryldihydropyrimidines having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • the present invention relates to compounds of formula (I) or (la):
  • R 1 to R 7 are as described below, or to pharmaceutically acceptable salts, or to enantiomers or diastereomers thereof.
  • HBV is a species of the hepadnaviridae family of viruses. HBV is a serious public health problem worldwide, with more than 400 million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus. Although most individuals seem to resolve the infection following acute symptoms, 15-40% of HBV patients will finally develop clinical diseases during their lifespan, most notably, hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year 500,000 to 1 million people die from the end stage of liver diseases caused by HBV infection.
  • HBV lifecycle begins with the binding of the "Dane” particle with an unidentified receptor on the surface of hepatocyte. Following entry, viral genome is delivered into nucleus where a covalently closed circular DNA (cccDNA) is formed through DNA repair of viral relaxed circular DNA. Unlike the mechanisms of most other DNA viruses, HBV cccDNA replicates through the retrotranscription of a 1.1 -genome unit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interacts with other two viral components, capsid protein and polymerase, as well as some host factors, to form capsid particles where viral DNA replication occurs. Most copies of the encapsidated genome then efficiently associate with the envelope proteins for virion assembly and secretion; a minority of these genomes is shunted to the nucleus, where they are converted to cccDNA.
  • cccDNA covalently closed circular DNA
  • nucleoside (tide) analogs targeting viral polymerase (lamivudine, adefovir, tenofovir, telbivudine and entecavir) and interferon modulating host immune functions. Mutations in the primary sequence of the polymerase that confer resistance to lamivudine and adefovir have been identified clinically and underlie a rebound of serum virus titers that 70% of treated patients experience within 3 years of the start of lamivudine therapy. Although resistance to telbivudine, adefovir, and entecavir occurs more rarely, it has been recorded.
  • Interferon alpha is the other major therapy available for hepatitis B, but it is limited by a poor long-term response and debilitating side effects. Some viral genotypes do not show good responses to interferon therapy. Now, the standard of clinic cure of HBV infection is the loss and/or seroconversion of HBsAg. The majority (around or more than 90%) of treated patients fail to achieve this goal. This drawback is mainly due to the presence of a stable pool of viral cccDNA in nucleus that doesn't replicate itself, therefore, shows no accessibility to nucleoside (tide) analogs.
  • HBV capsid protein plays essential roles in HBV replication.
  • HBV has an icosahedral core comprising of 240 copies of the capsid (or core) protein.
  • the predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles in the cytoplasm. This step is prerequisite for viral DNA replication.
  • the HBV capsid spontaneously self-assembles from many copies of core dimers present in the cytoplasm. It has been shown that the formation of a trimeric nucleus and the subsequent elongation reactions occur by adding one dimeric subunit at a time until it is complete.
  • capsid protein regulates viral DNA synthesis through different phosphorylation status of its C-terminal phosphorylation sites.
  • capsid protein might facilitate the nuclear translocation of viral relaxed circular genome by means of the nuclear localization signals located in the Arginine-rich domain of the C-terminal region of capsid protein.
  • capsid protein could play a structural and regulatory role in the functionality of cccDNA minichromosomes.
  • Capsid protein also interacts with viral large envelope protein in endoplasmic reticulum and triggers the release of intact viral particles from hepatocytes.
  • capsid related anti-HBV inhibitors There has been a couple of capsid related anti-HBV inhibitors reported. For example, phenylpropenamide derivatives, including compounds named AT-61 and AT- 130 (Feld J. et al. Antiviral Research 2007, 168-177), and a class of thiazolidin-4-ones from Valeant R&D
  • HAP Heteroaryldihydropyrimidines or HAP, including compounds named Bay 41-4109, Bay
  • HAP analogs 38-7690 and Bay 39-5493 were discovered in a tissue culture-based screening (Deres K. et al. Science 2003, 893). These HAP analogs act as synthetic allosteric activators and are able to induce aberrant capsid formation that leads to degradation of the core protein. HAP analogs also reorganized core protein from preassembled capsids into noncapsid polymers, presumably by interaction of HAP with dimers freed during capsid 'breathing', the transitory breaking of individual intersubunit bonds. Bay 41-4109 was administered to HBV infected transgenic mouse or humanized mouse models and demonstrated in vivo efficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893; Brezillon N.
  • the present invention relates to novel compounds of formula (I) or (la),
  • R 1 is heteroaryl
  • R 2 R 3 J and IT 4 are independently selected from halogen and C 1-6 alkyl
  • R 5 is Ci_ 6 alkyl
  • R 6 is hydrogen or carboxy
  • R is Ci_ 6 alkyl or carboxyCi- 6 alkyl
  • R 1 is not unsubstituted thiazolyl.
  • the invention is also relates to their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or other compounds of the present invention for the treatment or prophylaxis of HBV infection.
  • Ci_ 6 alkyl signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, ie/t-butyl and the like.
  • Particular "Ci_ 6 alkyl” groups are methyl, ethyl, isopropyl and tert-butyl.
  • Ci_6alkoxy refers to a group Ci_6alkyl-0-, wherein the "Ci_6alkyl” is as defined above; for example methoxy, ethoxy, propoxy, zsopropoxy, w-butoxy, zsobutoxy, 2-butoxy, ie/t-butoxy and the like.
  • Particular "Ci_ 6 alkoxy” groups are methoxy and ethoxy.
  • C 3 _ 7 Cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Particular "C 3 _ 7 Cycloalkyl” groups are cyclopropyl, cyclopentyl and cyclohexyl.
  • carbonyl refers to the group -C(O)-.
  • halogen and "halo” are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.
  • haloCi_ 6 alkyl refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloCi_ 6 alkyl include monofluoro-, difluoro- or trifluoro-methyl, - ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoroethyl or trifluoromethyl.
  • Ci_ 6 alkoxycarbonyl refers to a group Ci_ 6 alkoxy-C(0)-, wherein the "Ci_ 6alkoxy” is as defined above.
  • heterocyclic ring or heterocyclyl refers to a saturated or partly unsaturated monocyclic or bicyclic ring containing from 3 to 10 ring atoms which can comprise one, two or three atoms selected from nitrogen, oxygen and/or sulfur.
  • Examples of monocyclic heterocyclyl rings containing in particular from 3 to 7 ring atoms include, but not limited to, aziridinyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, azepinyl, diazepanyl, pyrrolidinyl, morpholinyl, dihydrofuryl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and thiomorpholinyl.
  • Bicyclic heterocyclyl can be bicyclic fused ring or bicyclic bridged ring.
  • bicyclic heterocyclyl examples include oxohexahydroimidazo[l,5-a]pyrazinyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3- thia-9-aza-bicyclo[3.3.1]nonyl, or difluoroazabicyclo[3.2.1]octyl.
  • Monocyclic and bicyclic heterocyclyl can be further substituted by halogen, Ci_ 6 alkyl, cyano, carboxy, carboxyCi_ 6 alkyl.
  • heteroaryl denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • heteroaryl moieties include, but not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzo isothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quina
  • Heteroaryl can be further substituted by halogen, Ci_ 6 alkyl, haloCi_ 6 alkyl, cyano, C3_ 7 cycloalkyl, (Ci_ 6 alkyl) 2 amino or Ci- 6 alkoxy.
  • enantiomer denotes two stereoisomers of a compound which are non- superimpo sable mirror images of one another.
  • diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and activities.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) or other compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Acid- addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid,
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability,
  • Racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • the present invention relates to (i) a compound of formula (I),
  • R 1 is heteroaryl
  • R 3 J and R 4" are independently selected from halogen and Ci_ 6 alkyl;
  • R 5 is Ci_ 6 alkyl
  • R 6 is hydrogen or carboxy
  • R is Ci- 6 alkyl or carboxyCi_ 6 alkyl
  • R 1 is not unsubstituted thiazolyl.
  • Another embodiment of present invention relates to (ii) a compound of formula (la),
  • R 1 is heteroaryl
  • R 2", R 3 J and R 4" are independently selected from hydrogen, halogen and Ci_ 6 alkyl;
  • R 5 is Ci_ 6 alkyl
  • R 6 is hydrogen or carboxy
  • R is Ci_ 6 alkyl or carboxyCi- 6 alkyl
  • R 1 is not unsubstituted thiazolyl.
  • a further embodiment of the present invention is (iii) a compound of formula (I) or (la), wherein R 1 is
  • thiazolyl said thiazolyl being substituted with one to three substituents independently selected from halogen, Ci- 6 alkyl, haloCi_ 6 alkyl, C 3 _ 7 cycloalkyl and Ci_
  • a further embodiment of the present invention is (iv) a compound of formula (I) or (la), wherein R 1 is cyclopropyl, fluoro thiazolyl, methylthiazolyl, isopropylthiazolyl,
  • difluoromethylthiazolyl trifluoromethylthiazolyl, methylsulfanylthiazolyl, cyclopropylthiazolyl, chlorothienyl, fluorothienyl, methylthienyl, difluorophenyl, trifluorophenyl, fluoropyridyl, difluoropyridyl, methylpyridyl, methylimidazolyl, methyloxazolyl, thiadiazolyl,
  • a further embodiment of the present invention is (v) a compound of formula (I) or (la), wherein R 1 is methylimidazolyl, methylthiazolyl or difluoropyridyl.
  • a further embodiment of the present invention is (vi) a compound of formula (I) or (la), wherein R 2 , R 3 and R 4 are independently selected from hydrogen, fluoro, chloro and methyl.
  • a further embodiment of the present invention is (vii) a compound of formula (I) or (la), wherein R 5 is methyl or ethyl.
  • a further embodiment of the present invention is (viii) a compound of formula (I) or (la), wherein R is ethyl, isopropyl, tert-butyl or carboxydimethylethyl.
  • Particular compounds of the present invention according to the invention are the following:
  • the compounds of the present invention can be prepared by any conventional means.
  • dihydropyrimidine V can be prepared through a one-pot condensation reaction. Bromination of Compound V provides bromide VI. Coupling bromide VI with selected bicyclic amine VII provides compound I. HPLC chiral separation of compound I provides two single diastereomers of interest la and lb.
  • dihydropyrimidine V can be prepared through one pot condensation and cyclization reaction of acetyl acetate II, aldehyde III and amidine IV. The reaction can be carried out in a suitable alcoholic solvent such as trifluoroethanol in the presence of a base like potassium acetate under a heating condition over several hours.
  • Bromide VI can be prepared by reaction of V with a bromination reagent, such as N- bromosuccinimide, in a suitable inert solvent such as carbon tetrachloride at 80-100°C for about 1 hour.
  • a bromination reagent such as N- bromosuccinimide
  • a suitable inert solvent such as carbon tetrachloride
  • Compound I can be obtained by coupling bromide VI with selected bicyclic amine VII.
  • the reaction is typically performed in a suitable solvent like 1,2-dichloroethane at room temperature over several hours in the presence of an organic base such as N,N- diisopropylethylamine .
  • the two single diastereomers of interest la and lb are obtained by preparative HPLC separation of diastereomeric mixture of I.
  • the stereochemistry of la and lb is assigned based on the comparison of the 1H NMR data and HPLC retention time with Examples disclosed in patent WO2015132276.
  • Specifically dihydropyrimidine V can be prepared through one pot condensation and cyclization reaction of acetyl acetate II, aldehyde III and amidine IV.
  • the reaction can be carried out in a suitable alcoholic solvent such as trifluoroethanol in the presence of a base like potassium acetate under a heating condition over several hours.
  • the (-)-enatiomer dihydropyrimidine Va can be obtained by SFC chiral separation of racemic dihydropyrimidine V.
  • the chiral bromide Via can be prepared by reaction of Va with a bromination reagent, such as N-bromosuccinimide, in a suitable inert solvent such as carbon tetrachloride at 80-100°C for about 1 hour.
  • a bromination reagent such as N-bromosuccinimide
  • a suitable inert solvent such as carbon tetrachloride
  • the bromide Via is further reacted with a selected bicyclic amine VII in a suitable solvent such as 1,2-dichloroethane at room temperature over several hours in the presence of an organic base such as N,N-diisopropylethylamine.
  • a suitable solvent such as 1,2-dichloroethane at room temperature over several hours in the presence of an organic base such as N,N-diisopropylethylamine.
  • Compound la is obtained after chromatographic purification.
  • the commercial unavailable amidine building block IV can be prepared from the corresponding nitrile VIII by reacting with sodium methoxide followed by treatment with ammonium chloride in Scheme 3.
  • This invention also relates to a process for the preparation of a compound of formula (I) or other compounds of the present invention comprising the reaction of:
  • the base can be for example N,N-diisopropylethylamine.
  • a compound of formula (I) or (la) or other compounds of the present invention when manufactured according to the above process is also an object of the invention.
  • the invention also relates to a compound of formula (I) or (la) or other compounds of the present invention for use as therapeutically active substance.
  • compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula (I) or (la) or other compounds of the present invention may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) or (la) or a compound of the present invention is formulated in an acetate buffer, at pH 5.
  • the compounds of formula (I), (la) and other compounds of the present invention are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular human being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to the suppression of serum HBV DNA levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or normalization of alanine aminotransferase levels and improvement in liver histology. For example, such amount may be below the amount that is toxic to normal cells, or the human as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical
  • composition thereof or aid in the manufacturing of the pharmaceutical product (i.e.,
  • An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 1000 mg of the compound of the invention compounded with about 30 mg to 90 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using
  • an example of an aerosol formulation can be prepared by dissolving the compound, for example 5 mg to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g. a phosphate buffer
  • a tonicifier e.g. a salt such sodium chloride
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula (I) or (la), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of formula (I) or (la), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a
  • a compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
  • a compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
  • the compounds of the invention can inhibit HBV's de novo DNA synthesis and reduce
  • the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.
  • the compounds of inventions are useful as HBV capsid inhibitors.
  • the invention relates to the use of a compound of formula (I) or (la) or a compound of the present invention for the treatment or prophylaxis of HBV infection.
  • the invention relates in particular to the use of a compound of formula (I) or (la) or a compound of the present invention for the preparation of a medicament for the treatment or prophylaxis of HBV infection.
  • Another embodiment includes a method for the treatment or prophylaxis of HBV infection which method comprises administering an effective amount of a compound of formula (I) or (la), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • LC/MS spectra of compounds were obtained using a LC/MS (WatersTM Alliance 2795- Micromass ZQ), LC/MS conditions were as follows (running time 6 min): Acidic condition: A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • the microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer.
  • Example la and lb are prepared according to Scheme 1 by using bromide intermediate VI- and bicyclic amine VII- 1 as shown below.
  • Example la was obtained as a light yellow solid (28 mg).
  • Example lb was obtained as a light yellow solid (28 mg). 1H NMR (400 MHz,
  • Example 2a and 2b are prepared in analogy to Example la and Example lb by using bromide intermediate VI-2 and bicyclic amine VII-1 as shown below.
  • Example 2a was obtained as a light yellow solid (16 mg).
  • Example 2b was obtained as a light yellow solid (16 mg).
  • Example 3 are prepared in analogy to compound 1 by using bromide intermediate VI-3 and bicyclic amine VII-1 as shown below.
  • Example 3 was obtained as a light yellow solid (7 mg).
  • 1H NMR (400 MHz, METHANOL-d 4 ) ⁇ ppm 7.13-7.27 (m, 2H), 5.91 (d, / 2.5 Hz, 1H), 3.93-4.02 (m, 1H), 3.72-3.91 (m, 3H), 3.65 (s, 3H), 3.49-3.60 (m, 1H), 3.36-3.46 (m, 1H), 2.88-3.22 (m,6H), 2.20-2.39 (m, 3H), 1.99-2.15 (m, 1H), 1.30-1.49 (m, 4H), 1.21 (m, 6H), 0.97-1.13 ppm (m, 1H).
  • Compound VI-3 was prepared according to general procedure B in Scheme 2 and in analogy to compound C of Example 1 in WO2015132276 by using cyclopropyl amidine instead of thiazolyl amidine and 3,4-difluoro-2-methyl-benzaldehyde instead of 2-chloro-4-fluoro- benzaldehyde.
  • the reaction mixture was flushed with nitrogen and heated to 55 °C for 2 hours.
  • the reaction mixture was quenched by adding ice- water.
  • the mixture was extracted with ethyl acetate (30 mL) for three times.
  • the combined organic layers were dried over Na 2 S0 4 and concentrated in vacuo.
  • the residue was purified by HPLC to give a mixture of two isomers which were further separated by SFC to give two single isomers: 4a- 1 (faster eluting, 77 mg, yield: 25%) and 4b-l (slower eluting, 76 mg, yield: 25%) with 30% isopropanol (0.05%DEA)/CO 2 on ChiralPak AD-3 column.
  • Example 4b (30 mg) was prepared in analogy to Example 4a.
  • Compound VI-4 was prepared according to Scheme 2 and in analogy to compound C of Example 1 in WO2015132276 by using 4-methylthiazole-2-carbonitrile instead of thiazole-2- carbonitrile, 2-chloro-3-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde and ethyl acetoacetate instead of methyl acetoacetate.
  • Example 5a was obtained as a light yellow solid (13.5 mg). 1H NMR (400 MHz,
  • Example 5b was obtained as a light yellow solid (29 mg). 1H NMR (400 MHz,
  • Example 5a was synthesized from compound 5a-l (faster eluting) and Example 5b was synthesized from compound 5b-l (slower eluting) on ChiralCel OJ-H column eluting with 25% methanol (0.05%DEA)/CO 2 .
  • Compound VII-5 was prepared in analogy to compound VII- 1 by the procedure described in WO2015132276 (compound Q in Example 19).
  • Example 6b was obtained as a light yellow solid (12 mg). 1H NMR (400 MHz,
  • Example 6a was synthesized from compound 6a-l (faster eluting) and Example 6b was synthesized from compound 6b-l (slower eluting) on ChiralCel OJ-H column eluting with 25% methanol (0.05%DEA)/CO 2 .
  • Compound VII-6 was prepared in analogy to compound VII- 1 by the procedure described in WO2015132276 (compound Q in Example 19).
  • HepG2.2.15 and HepDE19 are stably-transfected cell lines containing the HBV genome. Both cell lines are derived from the hepatoblastoma cell line Hep G2 (American Type Culture Collection, ATCC® HB-8065TM) by the published procedures described in references: MA Selles et al. Proc. Natl. Acad. Sci. USA 1987, 84, 1005-1009 and H Guo et al. Journal of Virology 2007, 81, 12472-12484, respectively.
  • Both cell lines were maintained in Dulbecco's modified Eagle's medium (DMEM)-F12 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ / ⁇ streptomycin, and 0.5 mg/mL of G418.
  • DMEM Dulbecco's modified Eagle's medium
  • HepG2.2.15 cells constitutively support HBV replication and production of virus particles
  • HepDE19 cells are inducible by tetracycline. Addition of ⁇ g/mL tetracycline in culture medium suppresses HBV replication in HepDE19 cells, whereas switching to tetracycline- free medium resumes this process.
  • HepG2.2.15 cells were seeded into 96-well plates (3 x 10 4 cells in 100 ⁇ L ⁇ media per well) and incubated overnight at 37 °C.
  • the test compounds were serially half-log diluted in DMSO, then diluted 100 times in culture media. 100 ⁇ _, of diluted compounds were added into the plates to reach 0.5% final concentration of DMSO in every well. Five days after compound treatment, culture supernatant was collected for further analysis.
  • the compounds of the present invention were tested for their capacity to inhibit a HBV activity and activation as described herein.
  • the Examples were tested in the above assays as described herein and found to have EC 50 ⁇ 0.2 ⁇ in HepG2.2.15 assay.
  • Particular compounds of formula (I) or (la) were found to have EC 50 ⁇ 0.02 ⁇ in HepG2.2.15 assay.
  • HepDE19 cells were seeded into 96-well plates (5 x 10 cells per well) and treated with compounds for EC 50 determination. Five days after treatment, cell viability was measured by addition of 20 ⁇ _, of CCK-8 reagent. Two hours after incubation at 37°C, the absorbance at wavelengths of 450 nm and 630 nm (OD 450 and OD 6 3o) was recorded by a plate reader. The concentration results in the death of 50% of the host cells (CC 50 ) of each compound were determined.
  • selectivity index (CC 50 value/ECso value). Based on CC 50 and EC 50 data, selectivity indexes were determined.
  • Example No. CC50 ( ⁇ ) Example No. CC50 ( ⁇ )
  • the final incubations contained 1 ⁇ test compound, 0.5 mg/mL liver microsomal protein, 1 mM NADPH in 100 mM phosphate buffer, pH 7.4
  • the final incubations contained 1 ⁇ test compound, 0.5 mg/mL liver microsomal protein, 3 mM glucose 6-phosphate, 1 mM NADP, 3 mM MgCl 2 and 0.05 mg/mL glucose 6-phosphate dehydrogenase in 100 mM phosphate buffer, pH 7.4.
  • Samples were prepared in duplicate from 10 mM DMSO stock solutions. After evaporation of DMSO with a centrifugal vacuum evaporator, the residue was solved in 0.05 M phosphate buffer (pH 6.5), stirred for one hour and shook for two hours. After one night, the solution was filtered using a microtiter filter plate. Then the filtrate and its 1/10 dilution were analyzed by direct UV measurement or by HPLC-UV. In addition a four-point calibration curve was prepared from the 10 mM stock solutions and used for the solubility determination of the compounds. The results were in ⁇ g/mL. In case the percentage of sample measured in solution after evaporation divided by the calculated maximum of sample amount was over 80%, the solubility was reported as higher than this value.
  • Example No. Lysa ⁇ g/mL Example No. Lysa ⁇ g/mL

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Abstract

La présente invention concerne de nouvelles 2-hétéroaryldihydropyrimidines fusionnées en position 6 ayant une activité pharmaceutique, leur fabrication, des compositions pharmaceutiques les contenant et leur utilisation potentielle en tant que médicaments. La présente invention concerne des composés de formule (I), dans laquelle R1 à R7 sont tels que décrits ci-dessus, ou des sels pharmaceutiquement acceptables, ou les énantiomères ou diastéréoisomères correspondants.
PCT/EP2016/074526 2015-10-16 2016-10-13 Nouvelles 2-hétéroaryldihydropyrimidines fusionnées en position 6 pour le traitement et la prophylaxie de l'infection par le virus de l'hépatite b WO2017064156A1 (fr)

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US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
WO2019076310A1 (fr) * 2017-10-18 2019-04-25 Sunshine Lake Pharma Co., Ltd. Composés dihydropyrimidine et utilisations de ceux-ci en médecine
WO2019129681A1 (fr) * 2017-12-28 2019-07-04 F. Hoffmann-La Roche Ag Dihydropyrimidinylthiazole pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci
WO2020125729A1 (fr) 2018-12-20 2020-06-25 Janssen Pharmaceutica Nv Dérivés d'hétéroaryldihydropyrimidine et procédés de traitement d'infections par le virus de l'hépatite b
WO2020135439A1 (fr) * 2018-12-25 2020-07-02 广东东阳光药业有限公司 Composé dihydropyrimidine deutéré et son utilisation en tant que médicament
CN111386127A (zh) * 2017-11-30 2020-07-07 阿拉基斯医疗公司 核酸结合光探针和其用途
JP2020525453A (ja) * 2017-06-26 2020-08-27 ノース・アンド・サウス・ブラザー・ファーマシー・インベストメント・カンパニー・リミテッド ジヒドロピリミジン化合物、及び医薬におけるその使用
CN111825676A (zh) * 2019-04-15 2020-10-27 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
WO2020255016A1 (fr) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combinaison de vaccins contre le virus de l'hépatite b (vhb) et de dérivés de dihydropyrimidine en tant que modulateurs de l'assemblage des capsides
WO2021018239A1 (fr) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b
WO2021018238A1 (fr) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b
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WO2021063852A1 (fr) * 2019-09-30 2021-04-08 F. Hoffmann-La Roche Ag Pyrimidine substituée pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
WO2021078221A1 (fr) * 2019-10-24 2021-04-29 广东东阳光药业有限公司 Composé dihydropyrimidine et son utilisation en tant que médicament
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
CN114026095A (zh) * 2019-06-06 2022-02-08 豪夫迈·罗氏有限公司 用于制备4-苯基-5-烷氧基羰基-2-噻唑-2-基-1,4-二氢嘧啶-6-基]甲基]-3-氧代-5,6,8,8a-四氢-1H-咪唑并[1,5-a]吡嗪-2-基]-甲酸的替代方法
WO2022052923A1 (fr) * 2020-09-08 2022-03-17 和博医药有限公司 Composé dihydropyrimidine et son utilisation
WO2022166923A1 (fr) * 2021-02-05 2022-08-11 和博医药有限公司 Composé phényldihydropyrimidine et son utilisation
EP3898632A4 (fr) * 2018-12-20 2023-02-22 Janssen Pharmaceutica NV Dérivés d'hétéroaryldihydropyrimidine et procédés de traitement d'infections par le virus de l'hépatite b
US11639350B2 (en) 2017-06-27 2023-05-02 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
KR102667040B1 (ko) 2017-10-18 2024-05-20 선샤인 레이크 파르마 컴퍼니 리미티드 디하이드로피리미딘 화합물 및 약제에서의 이의 용도

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WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US11142527B2 (en) 2017-06-26 2021-10-12 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and uses thereof in medicine
JP2020525453A (ja) * 2017-06-26 2020-08-27 ノース・アンド・サウス・ブラザー・ファーマシー・インベストメント・カンパニー・リミテッド ジヒドロピリミジン化合物、及び医薬におけるその使用
JP7260488B2 (ja) 2017-06-26 2023-04-18 サンシャイン・レイク・ファーマ・カンパニー・リミテッド ジヒドロピリミジン化合物、及び医薬におけるその使用
US11639350B2 (en) 2017-06-27 2023-05-02 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
CN109678859A (zh) * 2017-10-18 2019-04-26 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
US11261190B2 (en) 2017-10-18 2022-03-01 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and uses thereof in medicine
EP3697792A4 (fr) * 2017-10-18 2021-10-13 Sunshine Lake Pharma Co., Ltd. Composés dihydropyrimidine et utilisations de ceux-ci en médecine
JP7202373B2 (ja) 2017-10-18 2023-01-11 サンシャイン・レイク・ファーマ・カンパニー・リミテッド ジヒドロピリミジン化合物、及び医薬におけるその使用
AU2018351400B2 (en) * 2017-10-18 2022-12-15 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and uses thereof in medicine
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WO2019076310A1 (fr) * 2017-10-18 2019-04-25 Sunshine Lake Pharma Co., Ltd. Composés dihydropyrimidine et utilisations de ceux-ci en médecine
JP2020537677A (ja) * 2017-10-18 2020-12-24 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン化合物、及び医薬におけるその使用
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US11447489B2 (en) 2017-12-28 2022-09-20 Hoffmann-La Roche Inc. Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis B virus infection
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JP7256810B2 (ja) 2017-12-28 2023-04-12 エフ． ホフマン－ラ ロシュ アーゲー Ｂ型肝炎ウイルス感染の治療及び予防のためのジヒドロピリミジニルチアゾール
WO2019129681A1 (fr) * 2017-12-28 2019-07-04 F. Hoffmann-La Roche Ag Dihydropyrimidinylthiazole pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
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JP2021508712A (ja) * 2017-12-28 2021-03-11 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｂ型肝炎ウイルス感染の治療及び予防のためのジヒドロピリミジニルチアゾール
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WO2021078221A1 (fr) * 2019-10-24 2021-04-29 广东东阳光药业有限公司 Composé dihydropyrimidine et son utilisation en tant que médicament
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