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WO2017158147A1 - Dérivés de pyrimidone et leur utilisation pour le traitement, la prévention ou l'atténuation des symptômes d'une maladie virale - Google Patents

Dérivés de pyrimidone et leur utilisation pour le traitement, la prévention ou l'atténuation des symptômes d'une maladie virale Download PDF

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WO2017158147A1
WO2017158147A1 PCT/EP2017/056354 EP2017056354W WO2017158147A1 WO 2017158147 A1 WO2017158147 A1 WO 2017158147A1 EP 2017056354 W EP2017056354 W EP 2017056354W WO 2017158147 A1 WO2017158147 A1 WO 2017158147A1
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Prior art keywords
optionally substituted
group
alkyl
methyl
compound
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PCT/EP2017/056354
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English (en)
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Christian Lerner
Lukas KREIS
Robert James Weikert
Werner Neidhart
Hans Hilpert
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Savira Pharmaceuticals Gmbh
European Molecular Biology Laboratory
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Publication of WO2017158147A1 publication Critical patent/WO2017158147A1/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

Definitions

  • the present invention relates to a compound having the general formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
  • Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins, influenza viruses are further divided into three types named influenza A, B, and C viruses. All influenza viruses have an envelope, and their genomes are composed of eight or seven single-stranded, negative-sensed RNA segments. These viruses cause respiratory diseases in humans and animals with a significant morbidity and mortality.
  • the influenza pandemic of 1918, Spanish flu is thought to have killed up to 100 million people.
  • the reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemics in 1957 H2N2 "Asian influenza" and 1968 H3N2 "Hong Kong influenza".
  • the prophylaxis is an effective method, at least in some populations, for preventing influenza virus infection and its potentially severe complications.
  • continuous viral antigenicity shifting and drafting makes future circulating flu strains unpredictable.
  • other anti-flu approaches such as anti-flu drugs are highly desirable.
  • neuraminidase inhibitors such as oseltamivir phosphate (Tamilflu) and zanamivir (Relenza)
  • M2 ion channel blockers such as amantadine and rimantadine.
  • H5N1 and related highly pathogenic avian influenza viruses could acquire mutations rendering them more easily transmissible between humans.
  • the new A/H1 N1 could become more virulent and only a single point mutation would be enough to confer resistance to oseltamivir (Neumann et al., Nature 2009, 18, 459(7249), 931-939).
  • Adamantane-containing compounds such as amantadine and rimantadine are another example of active compounds which have been used in order to treat influenza. However, they often lead to side effects and have been found to be ineffective in a growing number of cases (Magden et al., Appl. Microbiol. Biotechnol. 2005, 66, 612-621 ).
  • Influenza viruses being Orthomyxoviridae are negative-sense ssRNA viruses.
  • viruses of this group include Arenaviridae, Bunyaviridae, Ophioviridae, Deltavirus, Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae and Nyamiviridae. These viruses use negative-sense RNA as their genetic material. Single- stranded RNA viruses are classified as positive or negative depending on the sense or polarity of the RNA. Before transcription, the action of an RNA polymerase is necessary to produce positive RNA from the negative viral RNA. The RNA of a negative-sense virus alone is therefore considered non-infectious.
  • the trimeric viral RNA-dependent RNA polymerase consisting of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2) and polymerase acidic protein (PA) subunits, is responsible for the transcription and replication of the viral RNA genome segments.
  • the ribonucleoprotein represents the minimal transcriptional and replicative machinery of an influenza virus.
  • the viral RNA polymerase synthesizes capped and polyadenylated mRNA using 5 ' capped RNA primers.
  • the viral RNA polymerase generates a complementary RNA (cRNA) replication intermediate, a full-length complement of the vRNA that serves as a template for the synthesis of new copies of vRNA.
  • the nucleoprotein is also an essential component of the viral transcriptional machinery.
  • the polymerase complex which is responsible for transcribing the single-stranded negative-sense viral RNA into viral mRNAs and for replicating the viral mRNAs, is thus a promising starting points for developing new classes of compounds which may be used in order to treat influenza (Fodor, Acta virologica 2013, 57, 113-122). This finding is augmented by the fact that the polymerase complex contains a number of functional active sites which are expected to differ to a considerable degree from functional sites present in proteins of cells functioning as hosts for the virus (Magden et al., Appl. Microbiol. Biotechnol. 2005, 66, 612-621 ).
  • a substituted 2,6-diketopiperazine has been identified which selectively inhibits the cap- dependent transcriptase of influenza A and B viruses without having an effect on the activities of other polymerases (Tomassini et al., Antimicrob. Agents Chemother. 1996, 40, 1 89-1 93).
  • phosphorylated 2'-deoxy-2'-fluoroguanosine reversibly inhibits influenza virus replication in chick embryo cells. While primary and secondary transcription of influenza virus RNA were blocked even at low concentrations of the compound, no inhibition of cell protein synthesis was observed even at high compound concentrations (Tisdale et al., Antimicrob. Agents Chemother. 1995, 39, 2454-2458).
  • WO 2005/087766 discloses certain pyridopyrazine- and pyrimidopyrazine-dione compounds which are stated to be inhibitors of HIV integrase and inhibitors of HIV replication. The compounds are described as being useful in the prevention and treatment of infection caused by HIV and in the prevention, delay in the onset, and treatment of AIDS.
  • WO 2010/147068 also discloses compounds which allegedly have antiviral activities, especially inhibiting activity for influenza viruses.
  • WO 2012/039414 relates to compounds which are described as having antiviral effects, particularly having growth inhibitory activity on influenza viruses.
  • WO 2014/108406 discloses certain pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease.
  • the present invention provides a compound having the general formula (I).
  • a compound having the general formula (I) encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, codrugs, cocrystals, tautomers, racemates, enantiomers, or diastereomers or mixtures thereof unless mentioned otherwise.
  • a further embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the general formula (I) and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • the compounds having the general formula (I) are useful for treating, ameliorating or preventing viral diseases.
  • alkyl refers to a saturated straight or branched carbon chain.
  • cycloalkyl represents a cyclic version of “alkyl”.
  • cycloalkyl is also meant to include bicyclic, tricyclic and polycyclic versions thereof. Unless specified otherwise, the cycloalkyl group can have 3 to 12 carbon atoms.
  • “Hal” or “halogen” represents F, CI, Br and I.
  • "3- to 7-membered carbo- or heterocyclic ring” refers to a three-, four-, five-, six- or seven- membered ring wherein none, one or more of the carbon atoms in the ring have been replaced by 1 or 2 (for the three-membered ring), 1 , 2 or 3 (for the four-membered ring), 1 , 2,
  • heteroatoms are selected from O, N and S.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthyl or anthracenyl, preferably phenyl.
  • heteroaryl preferably refers to a five-or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2, 3, or 4 (for the five- membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S.
  • heteroaryl group examples include pyrrole, pyrrolidine, oxolane, furan, imidazolidine, imidazole, pyrazole, oxazolidine, oxazole, thiazole, piperidine, pyridine, morpholine, piperazine, and dioxolane. If a compound or moiety is referred to as being "optionally substituted", it can in each instance include 1 or more of the indicated substituents, whereby the substituents can be the same or different.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention.
  • Suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • compositions include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the structure can contain solvent molecules.
  • the solvents are typically pharmaceutically acceptable solvents and include, among others, water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates.
  • codrug refers to two or more therapeutic compounds bonded via a covalent chemical bond.
  • a detailed definition can be found, e.g., in N. Das et al., European Journal of Pharmaceutical Sciences, 41 , 2010, 571-588.
  • cocrystal refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoichometric ratio of a target molecule or ion (i.e., compound of the present invention) and one or more neutral molecular cocrystal formers.
  • the compounds of the present invention can also be provided in the form of a prodrug, namely a compound which is metabolized in vivo to the active metabolite.
  • Suitable prodrugs are, for instance, esters.
  • Specific examples of suitable groups are given, among others, in US 2007/0072831 in paragraphs [0082] to [01 18] under the headings prodrugs and protecting groups as well as the groups disclosed in Prog. Med. 5: 2157-2161 (1985) and provided by The British Library - "The world's Knowledge".
  • the group R is H or d_6 alkyl.
  • the "R 10 " group in -OR 10 may be a group converted into an -OH group in vivo.
  • the groups selected from various substituted carbonyl groups, substituted lower alkyl oxy groups (e.g., substituted oxymethyl), optionally substituted cyclic group lower alkyl (e.g., optionally substituted cyclic methyl group), and optionally substituted imino lower alkyl (e.g., optionally substituted imino methyl) are exemplified, and examples preferably include a group selected from the following formulae a) to y).
  • L' is straight or branched lower alkylene
  • K is hydrogen, or straight or branched lower alkylene, or straight or branched lower alkenylene
  • R 10a is lower alkyl optionally substituted with one or more R 10g , or lower alkenyl optionally substituted with one or more R 10g ,
  • R 10b is a carbocyclic group optionally substituted with one or more R 10g , a heterocyclic group optionally substituted with one or more R 1 ° 9 , lower alkyl amino optionally substituted with one or more R 10g , or lower alkylthio optionally substituted with one or more R 10g ,
  • R 10c is lower alkyl optionally substituted with one or more R 10g , a carbocyclic group optionally substituted with one or more R 10g , or a heterocyclic group optionally substituted with one or more R 10g
  • R 10d is lower alkyl optionally substituted with one or more R 1 ° 9
  • a carbocyclic group optionally substituted with one or more R 10g a heterocyclic group optionally substituted with one or more R 10g
  • lower alkyl amino optionally substituted with one or more R 1 ° 9
  • carbocycle lower alkyl optionally substituted with one or more R 10g , heterocycle lower alkyl optionally substituted with one or more R 109 , or lower alkylsilyl
  • R 10e is carbocyclic group optionally substituted with one or more R 1 ° 9 , or heterocyclic group optionally substituted with one or more R 10g , and
  • R 10f is lower alkyl optionally substituted with one or more R 10g ,
  • R 10g is selected from oxo, lower alkyl, hydroxy lower alkyl, amino, lower alkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro.
  • lower refers to d.7, except for lower alkenyl and alkenylene, where it refers to C2-7.
  • the "R 10 " group in -OR 10 group in the formula (I) is preferably a group selected from the following b), I), m), and n).
  • the present invention provides a compound having the general formula (I).
  • the present invention provides a compound having the general formula (I)
  • R 10 is preferably -H, -(optionally substituted alkyl group) or -C(0)-(optionally substituted Ci_e alkyl group).
  • R 10 is preferably -H, -C(0)-C-i_6 alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -Ci_e alkyl group which may optionally be substituted by one or more halogen atoms. More preferably, R 10 is -H, -Ci_6 alkyl group or -CCOy-C ⁇ alkyl group. Even more preferably R 10 is -H.
  • R 1 is -H. is independently a -C ⁇ alkyl group, a -C ⁇ alkenyl group or a C 3 _ 7 cycloalkyi group; or wherein two R 12 can be joined together to form a 3- to 7-membered cycloalkyi ring.
  • R 12 is independently a -Ci_6 alkyl group, a -Ci_6 alkenyl group or a
  • R 12 is independently a -C ⁇ alkyl group.
  • two R 12 are joined together to form a 3- to 7-membered cycloalkyi ring, preferably a 5- or 6-membered cycloalkyi ring.
  • R 13 is independently -H, -halogen, -CN, -OH, -0-(Ci_e alkyl group, wherein the alkyl group is optionally substituted by halogen) or -(C ⁇ alkyl group, wherein the alkyl group is optionally substituted by halogen).
  • R 14 is -H, -(optionally substituted d-s alkyl), -(optionally substituted C 3 _ 7 cycloalkyi), - (optionally substituted aryl), -(optionally substituted heterocycloalkyl), -(optionally substituted heteroaryl), -Ci_ 4 alkyl— (optionally substituted C 3 _ 7 cycloalkyi), - _4 alkyl— (optionally substituted aryl), -C -4 alkyl— (optionally substituted heterocycloalkyl), or -d-4 alkyl— (optionally substituted heteroaryl).
  • R 14 is preferably -(optionally substituted Ci_e alkyl).
  • R 14 is more preferably selected from -CH 3 , CH(CH 3 ) 2 and CH(CH 3 )(CF 3 ).
  • R 5 is selected from -H, -C1-6 alkyl, -OH and -O-C ⁇ alkyl; preferably R 1S is -H.
  • m is 1 , 2 or 3, preferably 1 or 2.
  • n is 1 , 2 or 3, preferably 1 or 2.
  • o is 0, 1 , 2, 3 or 4, preferably 0.
  • the optional substituent(s) of the optionally substituted alkyl group is one or more substituents R a , wherein each R a is independently selected from -C(0)-d_6 alkyl, -Hal, -CF 3 , -CN, -COOR**, -OR**, -S(0)R**, -S(0) 2 R**, -(CH 2 ) q NR**R***, -C(0)-NR**R*** and -NR**- C(0)-d_6 alkyl; wherein the optional substituent(s) of the optionally substituted cycloalkyi group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is one or more substituents R b , wherein each R b is independently selected from -Ci_e alkyl, - ⁇ OJ-d ⁇ alkyl, -Hal, -CF 3 , -CN,
  • R*** is selected from -H, and -Ci_ 6 alkyl
  • R** is selected from -H, -d-e alkyl which is optionally substituted with one or more halogen atoms, and -(CH 2 CH 2 0) r H;
  • the optional substituent(s) of any group which is indicated as being “optionally substituted” in the present specification may be one or more substituents R a as defined above, unless other substituents are defined for this group.
  • the optional substituent(s) of the optionally substituted cycloalkyi group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is -halogen (preferably F), -OCH 3 or -CN.
  • the optional substituent of the optionally substituted alkyl group is selected from the group consisting of halogen, -CN, -NR * *R* * (wherein each R** is chosen independently of each other), -OH, and -O-C ⁇ alkyl.
  • the substituent of the optionally substituted alkyl group is -halogen, more preferably F.
  • t is 1 to 5, preferably 1 to 3.
  • Non-limiting examples of the compounds are given in the examples section and further include the following compound:
  • the present inventors have surprisingly found that the compounds according to the present invention which have this type of bulky substituent at the pyrimidone ring exhibit improved pharmacological properties. Without wishing to be bound by theory it is assumed that these compounds provide improved cellular activity.
  • the compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • the compounds of the present invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Oral, intranasal and parenteral administration are particularly preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.
  • a compound of the invention is formulated as a syrup, an infusion or injection solution, a spray, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from cocoa butter and vitebesole.
  • Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound of the invention can also be formulated into liposomes, in particular for parenteral administration.
  • Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chloride, may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like;
  • lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates
  • disintegrants such as starches, croscarmellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • the formulation is for oral administration and the formulation comprises one or more or all of the following ingredients: pregelatinized starch, talc, povidone K 30, croscarmellose sodium, sodium stearyl fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring, sodium benzoate and saccharin sodium.
  • a compound of the invention may be administered in the form of a dry powder inhaler or an aerosol spray from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134ATM) or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EATM), carbon dioxide, or another suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA
  • the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the compound of the invention, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.
  • a lubricant e.g., sorbitan trioleate.
  • the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g of the active ingredient (i.e. compound of the invention) per kg body weight.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 1 to 200 mg/kg body weight.
  • the duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • from 10 mg to 200 mg of the compound are orally administered to an adult per day, depending on the severity of the disease and/or the degree of exposure to disease carriers.
  • the pharmaceutically effective amount of a given composition will also depend on the administration route.
  • the required amount will be higher if the administration is through the gastrointestinal tract, e.g., by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g., intravenous.
  • a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 10 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 1 to 100 mg/kg body weight if parenteral administration is used. For intranasal administration, 1 to 100 mg/kg body weight are envisaged.
  • a person is known to be at risk of developing a disease treatable with a compound of the invention, prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible.
  • the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, from 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective viral disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily.
  • the compounds of the present invention are particularly useful for treating, ameliorating, or preventing viral diseases.
  • the type of viral disease is not particularly limited.
  • examples of possible viral diseases include, but are not limited to, viral diseases which are caused by Poxviridae, Herpesviridae, Adenoviridae, Papillomaviridae, Polyomaviridae, Parvoviridae, Hepadnaviridae, Reoviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae, Caliciviridae, Astroviridae, Togaviridae, Flaviviridae, Deltavirus, Bornaviridae, and prions.
  • viral diseases which are caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, more preferably viral diseases which are caused by orthomyxoviridae.
  • Herpesviridae Herpes simplex virus
  • Picornaviridae Human enterovirus types A-D (Poliovirus, Echovirus,
  • the compounds of the present invention are employed to treat influenza.
  • the present invention covers all virus genera belonging to the family of orthomyxoviridae, specifically influenza virus type A, B, and C, isavirus, and thogotovirus.
  • influenza virus includes influenza caused by any influenza virus such as influenza virus type A, B, and C including their various stains and isolates, and also covers influenza A virus strains commonly referred to as bird flu and swine flu.
  • the subject to be treated is not particularly restricted and can be any vertebrate, such as birds and mammals (including humans).
  • the compounds of the present invention are capable of inhibiting endonuclease activity, particularly that of influenza virus.
  • a possible measure of the in vitro endonuclease inhibitory activity of the compounds having the formula (I) is the FRET (fluorescence-resonance energy transfer)-based endonuclease activity assay disclosed herein.
  • the % reduction is the % reduction of the initial reaction velocity (vO) measured as fluorescence increase of a dual-labelled RNA substrate cleaved by the influenza virus endonuclease subunit (PA-Nter) upon compound treatment compared to untreated samples.
  • the compounds having the general formula (I) can be used in combination with one or more other medicaments.
  • the type of the other medicaments is not particularly limited and will depend on the disorder to be treated.
  • the other medicament will be a further medicament which is useful in treating, ameliorating or preventing a viral disease, more preferably a further medicament which is useful in treating, ameliorating or preventing influenza that has been caused by influenza virus infection and conditions associated with this viral infection such as viral pneumonia or secondary bacterial pneumonia and medicaments to treat symptoms such as chills, fever, sore throat, muscle pains, severe headache, coughing, weakness and fatigue.
  • the compounds having the general formula (I) can be used in combination with anti-inflammatories.
  • This in vitro, cell-based assay is used to identify small molecule inhibitors of influenza A virus and relies upon a replication competent influenza reporter virus.
  • This virus was generated in a A/WSN background (Szretter KJ, Balish AL, Katz JM. Curr Protoc Microbiol. Influenza: propagation, quantification, and storage. 2006 Dec;Chapter 15:Unit 15G.1. doi: 10.1002/0471729256. mc15g01s3) and contains the extremely bright luciferase variant, NanoLuc (Promega), which has been appended to the C-terminus of the polymerase subunit, PA.
  • the reporter virus replicates with near native properties both in cell culture and in vivo. Thus, NanoLuc luciferase activity can be used as a readout of viral infection.
  • A549 human non-small cell lung cancer cells are infected with the reporter virus and following infection, the cells are treated with serially diluted compounds.
  • the inhibitory effect of the small molecules tested is a direct measure of viral levels and can be rapidly obtained by measuring a reduction in luciferase activity.
  • LRA Luciferase Reporter Assay
  • A549 cells were plated in 384-well plates at a density of 10,000 cells per well in Dulbecco's modified Eagle's medium with Glutamax (DMEM, Invitrogen) supplemented 10% fetal bovine serum (FBS, Invitrogen) and 1X penicillin/streptomycin (Invitrogen), herein referred to as complete DMEM, and incubated at 37°C, 5% C0 2 overnight. The following day, cells were washed once with 1X PBS and then infected with virus, MOI 0.1 in 10 ⁇ of infection media for 60 min.
  • DMEM Dulbecco's modified Eagle's medium with Glutamax
  • FBS fetal bovine serum
  • Invitrogen 1X penicillin/streptomycin
  • A/WSN/33 influenza virus containing the NanoLuc reporter construct was obtained from the laboratory of Andrew Mehle (University of Wisconsin).
  • A549 human lung carcinoma cells were purchased (ATCC). All studies were performed with A549 cells cultured in complete DMEM.
  • Influenza virus stocks were propagated in MDBK cells (ATCC) using standard methods (Szretter KJ, Balish AL, Katz JM. Curr Protoc Microbiol. Influenza: propagation, quantification, and storage. 2006 Dec;Chapter 15:Unit 15G.1. doi: 10.1002/0471729256.mc15g01s3), and stocks frozen at -80°C.
  • Viral infections were carried out using DMEM Glutamax supplemented with 0.3% BSA (Sigma), 25mM Hepes (Sigma), and 1X penicillin/streptomycin (Invitrogen).
  • silica gel chromatography was either performed using cartridges packed with silica gel (ISOLUTE® Columns, TELOSTM Flash Columns) on ISCO Combi Flash Companion or on glass columns on silica gel 60 (32-60 mesh, 60 A).
  • MS Mass spectra (MS) were measured with electrospray ionization (ESI) on a Perkin-Elmer SCIEX API 300.
  • ethers e.g. diethyl ether or preferably tetrahydrofuran
  • Conversion of the nitriles 3 to the methylimidates 4 can be accomplished in methanol saturated with hydrogen chloride gas at temperatures between -20 to 0°C, preferably at 0°C.
  • Amidines of formula 6 are prepared by the reaction of methylimidates 4 with piperazinones 5 in the presence of a base such as e.g. diisopropylethylamine and an acid, e.g. acetic acid in a solvent such as ethers, preferably tetrahydrofuran, at room temperature.
  • a base such as e.g. diisopropylethylamine
  • an acid e.g. acetic acid
  • a solvent such as ethers, preferably tetrahydrofuran
  • Compounds of formula I are prepared from amidines 6 by reaction with an alkyl oxalate, preferably diethyl oxalate, and a base, preferably lithium hexamethyldisilazide, in a solvent, e.g. tetrahydrofuran, at -30 to 0°C.
  • an alkyl oxalate preferably diethyl oxalate
  • a base preferably lithium hexamethyldisilazide
  • Piperazinones 5 can be prepared by various methods (Scheme 2).
  • a coupling reagent preferably S-(1-oxido-2-pyridinyl)-1 ,1 ,3,3-tetramethylthiouronium hexafluoro-phosphate (HOTT), and an amine, e.g. diisopropylamine, in a solvent such as dimethylformamide at room temperature to give the amides 9.
  • HOTT S
  • Cyclization of amides 9 can be accomplished with 1 ,2-dibromoethane and a base, preferably potassium carbonate, in a solvent such as acetonitrile at elevated temperature, e.g. at 110°C, yielding protected piperazinones 10.
  • Deprotection of 10 can be effected with thiophenol and a base, preferably potassium carbonate, in a solvent such as acetonitrile at room temperature to give piperazinones 5.
  • X iodo substituted aromatic residues 12
  • R 1 2,6- dichlorophenyl, 1-methylpyrazol-3-yl, 4-pyridyl and 1-methylimidazol-4-yl
  • copper (I) iodide, potassium phosphate tribasic and a base e.g. ⁇ , ⁇ '-dimethylethylenediamine in an ether,
  • Deprotection of 13 can be accomplished with trifluoroacetic acid or hydrochloric acid in dioxane and dichloromethane at room temperature to give the piperazinones 5.
  • a hydride preferably sodium hydride
  • compounds of formula I can be prepared from nitriles 14 and 1 ,4-dibromobutane or 1 ,5-dibromopentane in the presence of a hydride, e.g. sodium hydride, in a solvent mixture of dimethylsulfoxide and diethylether at room temperature to give the alkylated nitriles 15.
  • a hydride e.g. sodium hydride
  • Nitriles 15 are reduced to aldehyds 16 using an aluminium hydride reagents, preferably diisobutylaluminium hydride, in a solvent such as dichloromethane at low temperature, preferably at -70°C.
  • R 3 or R 4 or R 5 alkyl, alkenyl or cycloalkyl
  • the reaction of amidines 19 with 4-methyl (2E)-3-(benzyloxy)-2-hydroxybut-2-enedioate in the presence of a base such as sodium methoxide in a solvent like methanol at room temperature yields the pyrimidine derivatives 20.
  • Pyrimidine derivatives 20 can be converted to the acids 21 with a base such as lithium hydroxide in a solvent mixture of water and tetrahydrofuran at elevated temperature, e.g. at 70°C.
  • Coupling of the acids 21 to the amides 22 can be accomplished with a O-silyl protected hydroxyethylamine, e.g.
  • the silyl protecting group of amides 22 can be cleaved by reaction with an acid, e.g. hydrochloric acid, in a solvent such as dioxane at room temperature to give the alcohols 23.
  • an acid e.g. hydrochloric acid
  • Alcohols 23 can be cyclized by the Mitsunobu reaction using diethylazodicarboxylate and triphenylphosphine in a solvent such as dichloromethane at room temperature affording the pyrazino-pyrimidines 24.
  • the mixture can be further processed as described below or the intermediate 4-[2-[1-(3- ethylphenyl)cyclopentyl]ethanimidoyl]-1-methyl-piperazin-2-one hydrochloride can be isolated by dilution with ethyl ether followed by filtration and drying of the residue.
  • Example 2 was prepared in analogy to example 1 starting with 4-bromo-2-methoxy-1 -methyl- benzene in step a to give the product as an off-white solid. MS (ESI, m/z): 398.3 [(M+H) + ]. Example 3
  • Example 3 was prepared in analogy to example 1 starting with 4-bromo-1 ,2-dimethyl-benzene in step a to give the product as an off-white solid. MS (ESI, m/z): 382.3 [(M+H) + ].
  • Example 4 was prepared in analogy to example 1 starting with 6-bromotetralin in step a to give the product as an off-white powder.
  • Example 5 was prepared in analogy to example 1 starting with 5-bromoindane in step a to give the product as an off-white powder. MS (ESI, m/z): 394.3 [(M+H) + ].
  • Example 9 was prepared in analogy to example 7h but using cyclopropylboronic acid to give the compound as an off-white solid. MS (ESI, m/z): 394.2 [(M+H) + ].
  • Example 11 prepared from example 10 in analogy to example 8b, was obtained as an off- white solid.
  • Example 12 prepared in analogy to example 10, was obtained as an off-white solid. MS (ESI, m/z): 394.0 [(M+H) + ]. Example 13
  • Example 13 prepared in analogy to example 7, was obtained as an off-white solid. MS (ESI, m/z): 368.2 [(M+H) + 3. Example 14
  • Example 14 prepared in analogy to example 7, was obtained as an off-white solid. MS (ESI, m/z): 368.0 [(M+H) + ]. Example 15
  • Example 15 prepared in analogy to example 6, was obtained as an off-white solid.
  • Example 16 prepared in analogy to example 6 starting with 2-(4-tert-butylphenyl)acetonitrile, was obtained as a white solid. MS (ESI, m/z): 410.3 [(M+H) + ]. Example 17
  • Example 17 prepared in analogy to example 6 starting with 2-(2,4-dimethylphenyl)acetonitrile, was obtained as a colorless powder.
  • Example 18 prepared in analogy to example 6 starting with 2-(2,5-dimethylphenyl)acetonitrile, was obtained as a colorless powder.
  • Example 19 prepared in analogy to example 6 starting with 2-(2,3-dimethylphenyl)acetonitrile, was obtained as a colorless powder. MS (ESI, m/z): 382.3 [(M+H) + ].
  • Example 20 prepared in analogy to example 6 starting with 2-(3,5-dimethylphenyl)acetonitrile, was obtained as a colorless powder.
  • Example 21 prepared in analogy to example 1 , was obtained as a light red powder.
  • Example 22 prepared in analogy to example 11 , was obtained as an off-white powder. MS (ESI, m/z): 396.4 [(M+H) + ]. Example 23
  • Example 24 prepared in analogy to example 1 but using bromo-(3-fluoro-5-methyl- phenyl)magnesium in step a, was obtained as a brown solid.
  • Example 25 prepared in analogy to example 6a - d but using 2-(3-bromophenyl)acetonitrile in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one) and example 7h, was obtained as a colorless powder.
  • Example 26 prepared in analogy to example 18 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.
  • Example 27 prepared in analogy to example 1 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder. MS (ESI, m/z): 410.3 [(M+H) + ].
  • Example 28 prepared in analogy to example 22 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.
  • Example 29 prepared in analogy to example 4 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder.
  • Example 30 prepared in analogy to example 5 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a white powder. MS (ESI, m/z): 422.4 [(M+H) + ].
  • Example 31 prepared in analogy to example 6 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white solid.
  • Example 32 prepared in analogy to example 3 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white solid. MS (ESI, m/z): 410.3 [(M+H) + ].
  • Example 33 prepared in analogy to example 24 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder.
  • Example 34 prepared in analogy to example 10 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a light red powder. MS (ESI, m/z): 422.3 [(M+H) + ].
  • Example 35 prepared in analogy to example 11 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.
  • Example 36 prepared in analogy to example 6 but using 2-(3-bromo-5-methyl- phenyl)acetonitrile in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2- one), was obtained as a white solid.
  • Example 37 prepared in analogy to example 1 starting with 1-bromo-3-chloro-5- methylbenzene in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless solid.
  • Example 38 prepared from example 36 by reaction with 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2- dioxaborolane (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a light brown solid.
  • Example 39 prepared from example 38 by hydrogenation (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a light brown solid.
  • Example 41 prepared in analogy to example 1 but using (4-fluoro-3,5- dimethylphenyl)magnesium bromide in step a (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a white solid.
  • Example 42 prepared in analogy to example 1 but using 4-bromo-2-ethyl-1-fluoro-benzene (preparation: Chu, X. et al., patent WO 2003097048) in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a white powder.
  • Example 44 prepared in analogy to example 1 but using 1-bromo-3-methyl-5- (trifluoromethyl)benzene in step a (1-methylpiperazin-2-one replaced by -isopropylpiperazin- 2-one), was obtained as a white powder.
  • Example 45 prepared in analogy to example 1 but using 2-bromo-4-ethyl-1-fluoro-benzene (preparation: Zhang, X. et al., patent WO 2006076246) in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless powder.
  • Example 46 prepared in analogy to example 1 but using 1-bromo-3,5-dimethyl-benzene in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless powder.
  • Example 47 prepared in analogy to example 1d from methyl 2-[1-(m- tolyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2,2,2-trifluoroethyl)piperazin-2-one (preparation: Bayrakdarian, M. et al., patent WO 2008136756), was obtained as a solid.
  • Example 48 prepared in analogy to example 1d from methyl 2-[1-(m- tolyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-phenylethyl)piperazin-2-one (preparation: Chambers, M. S. et al., Journal of Medicinal Chemistry (1999), 42(4), 691-705)), was obtained as a solid.
  • Example 49 prepared in analogy to example 1d from methyl 2-(1-tetralin-5- ylcyclopentyl)ethanimidate-hydrochloride and 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]piperazin-2- one, was obtained as an off-white solid.
  • Example 50 prepared in analogy to example 1d from methyl 2-(1-tetralin-5- ylcyclopentyl)ethanimidate-hydrochloride and 1-[(1 R)-2,2,2-trifluoro-1-methyl-ethyl]piperazin- 2-one (prepared according to example 49a - c but using (2R)-1,1 ,1-trifluoropropan-2-amine hydrochloride in step a), was obtained as an off-white solid.
  • Example 51 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(2,2,2-trifluoroethyl)piperazin-2- one (preparation: Bayrakdarian, M. et al., patent WO 2008136756), was obtained as an off- white solid.
  • Example 52 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -[( 1 S)-2,2,2-trifluoro-1 -methyl- ethyl]piperazin-2-one, was obtained as a white solid.
  • Example 53 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-[(1 R)-2,2,2-trifluoro-1-methyl- ethyl]piperazin-2-one, was obtained as a white solid.
  • Example 54 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-cyclopropylpiperazin-2-one, was obtained as an off-white solid. MS (ESI, m/z): 408.0 [(M+H) + ].
  • Example 55 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(2,6-dichlorophenyl)piperazin-2- one (prepared in analogy to example 56), was obtained as an off-white solid.
  • Example 56 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylpyrazol-3-yl)piperazin- 2-one, was obtained as an off-white solid. MS (ESI, m/z): 448.3 [(M+H) + ].
  • tert-Butyl 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-oxo-piperazine-1-carboxylate (1.12 g) dissolved in a solution of hydrochloric acid in dioxane (4 M, 8 ml) and dichloromethane (6 ml) was stirred at 22°C for 5 h. The mixture was evaporated and the residue treated with aqueous ammonium hydroxide, which was followed by chromatography (NH 2 -Si0 2 , 5% methanol in dichloromethane) to give the title compound (168 mg) as a yellow solid.
  • Example 57 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2- one, was obtained as an off-white solid
  • Example 58 prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -[(4-fluorophenyl)methyl]- piperazin-2-one (preparation: Kim, H. et al., Bioorganic & Medicinal Chemistry Letters (2011), 21(12), 3809-3812), was obtained as a light brown solid.
  • Example 59 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylpyrazol-3-yl)piperazin-2- one (from example 56b), was obtained as an off-white solid.
  • Example 60 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(4-pyridyl)piperazin-2-one (prepared in analogy to example 56a - b but using 4-iodopyridine in step a, white solid, MS (ESI, m/z): 178.1 [(M+H) + ]), was obtained as a light yellow solid.
  • Example 61 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-methoxyethyl)piperazin-2-one (prepared in analogy to example 57a - b but using 1-bromo-2-methoxyethane in step a, yellow oil, MS (ESI, m/z): 159.1 [(M+H) + ]), was obtained as a white solid.
  • Example 62 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylimidazol-4-yl)piperazin-2- one (prepared in analogy to example 56a - b but using 4-iodo-1-methyl-1 H-imidazole in step a, light yellow solid, MS (ESI, m/z): 181.1 [(M+H) + ]), was obtained as an off-white solid.
  • Example 63 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2-one (from example 57b), was obtained as an off-white solid.
  • Example 64 prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2-one (prepared in analogy to example 57a - b but using 1-[2-(trifluoromethoxy)ethyl]piperazin-2- one in step a, light yellow oil, MS (ESI, m/z): 213.1 [(M+H) + ]), was obtained as an off-white solid.
  • Example 66 prepared in analogy to example 1 but using 1-bromo-3,5-dimethyl-benzene and ethyl 2-cyano-2-cyclohexylideneacetate in step a, was obtained as a light brown solid. MS (ESI, m/z): 424.3 [(M+H) + ].
  • the mixture was quenched by the addition of a saturated solution of Rocheller salt (potassium sodium tartrate heptahydrate, 40 ml) and stirring was continued at 22°C for 16 h.
  • the organic layer was separated, the aqueous layer extracted with dichloromethane, the combined organic layers dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (1.05 g) as a light yellow solid.

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Abstract

La présente invention porte sur un composé de formule générale (I), qui se présente éventuellement sous la forme d'un sel, solvate, polymorphe, comédicament, cocristal, promédicament, tautomère, racémate, énantiomère ou diastéréomère, pharmaceutiquement acceptable, de ce composé, ou un mélange de ceux-ci, qui sont utiles pour traiter, prévenir ou atténuer les symptômes d'une maladie virale, en particulier la grippe.
PCT/EP2017/056354 2016-03-18 2017-03-17 Dérivés de pyrimidone et leur utilisation pour le traitement, la prévention ou l'atténuation des symptômes d'une maladie virale WO2017158147A1 (fr)

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US10392406B2 (en) 2015-04-28 2019-08-27 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
US11040048B2 (en) 2015-12-15 2021-06-22 Shionogi & Co., Ltd. Medicament for treating influenza characterized by combining a Cap-dependent endonuclease inhibitor and an anti-influenza drug
US10759814B2 (en) 2016-08-10 2020-09-01 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
US11306106B2 (en) 2016-08-10 2022-04-19 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof

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