WO2017158151A1 - Dérivés de pyrimidone et leur utilisation dans le traitement, le soulagement ou la prévention d'une maladie virale - Google Patents

Dérivés de pyrimidone et leur utilisation dans le traitement, le soulagement ou la prévention d'une maladie virale Download PDF

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WO2017158151A1
WO2017158151A1 PCT/EP2017/056361 EP2017056361W WO2017158151A1 WO 2017158151 A1 WO2017158151 A1 WO 2017158151A1 EP 2017056361 W EP2017056361 W EP 2017056361W WO 2017158151 A1 WO2017158151 A1 WO 2017158151A1
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optionally substituted
methyl
title compound
alkyl
mmol
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Christian Lerner
Lukas KREIS
Hans Hilpert
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Savira Pharmaceuticals GmbH
Europaisches Laboratorium fuer Molekularbiologie EMBL
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Savira Pharmaceuticals GmbH
Europaisches Laboratorium fuer Molekularbiologie EMBL
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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 genera! 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 (Ta ilf!u) and zanamivir (Re!enza)
  • 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).
  • This has already happenend in the case of some seasonal H1 N1 strains which have recently been identified (Dharan et al., The Journal of the American Medical Association, 2009, 301(10), 1034-1041 ; Moscona et al., The New England Journal of Medicine 2009, 360(10), 953-956).
  • the unavoidable delay in generating and deploying a vaccine could in such cases be catastrophically costly in human lives and societal disruption.
  • 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, 1 13-122). 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, 1 189-1 193).
  • 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. It is an object of the present invention to identify further compounds which are effective against viral diseases and which have improved pharmacological properties.
  • 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.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (lUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kolb!, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.
  • the word “comprise”, and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
  • each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary.
  • any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
  • 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.
  • heterocycloalkyl represents a version of "cycloalkyl” in which one or more CH 2 g roups are independently replaced by O, NH, N(C 1-6 -alkyl) or S. Unless specified otherwise, the heterocycloalkyl group can have 3 to 12 carbon atoms and 1 to 3 atoms selected from O, N and S.
  • “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, 3, or 4 (for the five-membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) and 1 , 2, 3, 4, 5 or 6 (for the seven-membered ring) of the same or different heteroatoms, whereby the 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.
  • hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring refers to any group having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and 2 as long as the group contains at least one ring.
  • the term is also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one ring is present, they can be separate from each other or be annelated.
  • the ring(s) can be either carbocyclic or heterocyclic and can be saturated, unsaturated or aromatic.
  • these groups include -(optionally substituted C 3 _ 7 cycloalkyl), -(optionally substituted aryl) wherein the aryl group can be, for example, phenyl, -(optionally substituted biphenyl), adamantyl, -(C 3 . 7 cycloalkyl)-aryl as well as the corresponding compounds with a linker.
  • 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.
  • 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.
  • 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 C M 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 1 ° 9 , or lower alkenyl optionally substituted with one or more R 1 ° 9
  • R 10b is a carbocyclic group optionally substituted with one or more R 1 ° 9 , a heterocyclic group optionally substituted with one or more R 1 ° 9 , lower alkyi amino optionally substituted with one or more R 109 , or lower alkylthio optionally substituted with one or more R 1 ° 9 ,
  • R 10c is lower alkyi optionally substituted with one or more R 10g , a carbocyclic group optionally substituted with one or more R 1 ° 9 , or a heterocyclic group optionally substituted with one or more R ° 9 ,
  • R 10d is lower alkyi optionally substituted with one or more R 1 ° 9 , a carbocyclic group optionally substituted with one or more R 10s , a heterocyclic group optionally substituted with one or more R 0g , lower alkyi amino optionally substituted with one or more R 1 ° 9 , carbocycle lower alkyi optionally substituted with one or more R 1 ° 9 , heterocycle lower alkyi optionally substituted with one or more R 1 ° 9 , or lower alkylsilyl,
  • R 10e is carbocyclic group optionally substituted with one or more R 10g , or heterocyclic group optionally substituted with one or more R 1 ° 9 , and
  • R 0f is lower alkyi optionally substituted with one or more R 1 ° 9 ,
  • R 1 ° 9 is selected from oxo, lower alkyi, hydroxy lower alkyi, amino, lower alkylamino, carbocycle lower a!ky!, lower a!kylcarbony!, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower aikylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro.
  • R 10a to R 10s refers to C-, . ⁇ , except for lower alkenyl and alkenylene, where it refers to C 2 .7-
  • the "R 0 " 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) in which the following definitions apply.
  • R 0 is -H, -(optionally substituted Ci_6 alkyl group) or -C(0)-(optionally substituted d_e alkyl group).
  • R 10 is preferably -H, -C(0)-dminister 6 alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -d-6 alkyl group which may optionally be substituted by one or more halogen atoms. More preferably, R 10 is -H, -Ci_6 alkyl group or -C(0)-Ci_6 alkyl group. Even more preferably R 10 is -H.
  • R 11 is -H, -OH, -CH2-OH, a -d-6 alkyl group, or a -C ⁇ alkyl group which is substituted by one or more halogen atoms; preferably R 1 is -H, or -OH, -CH 2 -OH. R is -H, -OH, -CH2-OH, a -d-e alkyl group, or a -Ci_ 6 alkyl group which Is substituted by one or more halogen atoms; preferably R 12 is -H.
  • R 11 and R 12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring.
  • R 13 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring).
  • the at least one ring is aromatic such as an aryl or heteroaryl ring.
  • R 13 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms and which contains at least two rings, wherein the hydrocarbon group can be optionally substituted.
  • at least one of the at least two rings is aromatic such as an aryl or heteroaryl ring.
  • Preferred examples of R 13 can be selected from the group consisting of
  • R is selected from
  • X is absent, CH 2 , NH, C(0)NH, S or O.
  • Y is CH 2 .
  • X and Y can be joined together to form an annulated, carbo- or heterocvlic 3- to 8-membered ring which can be saturated or unsaturated.
  • Specific examples of X-Y include -CH 2 -, -CH 2 -CH 2 -, -0-, and -NH-.
  • Z is O or S.
  • R is independently selected from -C ⁇ alkyl, -C, 6 alkenyl, , -Ci_ 6 alkinyl, -CF 3 , - halogen, -CN, -OH, -CH 2 C(0)OH, -CH 2 C(0)OCi_6 alkyl, -O-d 6 alkyl, -C 3 7 cycloalkyl, -(CH 2 ) 1 . 4 -0-C ⁇ 6 alkyl, -(CH 2 ) 1-4 -CN, -(CH 2 ) 1-4 -OH, -(CHz ⁇ -O-iC ⁇ alkyl), alkyl, -aryl, -heterocycloalkyi or -heteroaryl.
  • R e is independently selected from -H, -d_ 6 alkyl, -C $ alkenyl, , -C t _6 alkinyl, -CF 3 , -halogen, -CN, -OH, -CH 2 C(0)OH, -CH 2 C(0)OC ⁇ alkyl, -O-d 6 alkyl, -C 3 _ 7 cycloalkyl, -(CH ⁇ -O-C, ⁇ alkyl, -(CH 2 ) 1 .4-CN, -(CH 2 ) 1-4 -OH, - ⁇ CH 2 ) r 4 -0-(C, 6 alkyl), alkyl, -aryl, -heterocycloalkyi or -heteroaryl.
  • t is 0 to 5, preferably 0 to 3.
  • R is preferably -(optionally substituted Ci_6 alkyl).
  • R 14 is more preferably selected from -CH 3 , CH(CH 3 ) 2 and CH(CH 3 )(CF 3 ).
  • R is -R or -d_4 alkyl-R, wherein R is selected from -XH, -COOH, -COO-(optionally substituted Ci_ 6 alkyl), -(optionally substituted d-e alkyl), -(optionally substituted C 3 _ 7 cycloalkyl), -(optionally substituted aryl), -(optionally substituted heteroaryl), -(optionally substituted heterocycloalkyl), -X-(optionally substituted Ci_e alkyl), -X-(optionally substituted C 3 ⁇ 7 cycloalkyl), -X-(optionally substituted aryl), -X-(optionally substituted heterocycloalkyl), or -X-(optionally substituted heteroaryl), wherein X is O or S.
  • R 14 and R 7 can be joined together to form an optionally substituted 3- to 7-membered (e.g., 5 or 6-membered) heterocyclic ring which can include one or more additional heteroatoms selected from N, O and S in addition to the nitrogen atom to which R 14 is attached.
  • This optionally substituted 3- to 7-membered heterocyclic ring may optionally be benzannulated, wherein benzannulated preferably indicates that a benzene ring is attached in such a manner that two neighboring carbon atoms in the 3- to 7-membered heterocyclic ring are at the same time two neighboring carbon atoms in the benzene ring.
  • 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)-Ci_e alkyl, -Hal, -CF 3 , -CN, - COOR**, -(CH 2 ) q -OR * *, -S(0)R ** , -S(0) 2 R ** , -(CH 2 ) q NR ** R *** , -C(0)-NR ** R *** and - NR**-C(0)-Ci_6 alkyl;
  • the optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted hydrocarbon group and/or an optionally substituted 3- to 7- membered heterocyclic ring is one or more substituents R b , wherein each R b is independently selected from -d_ 6 alkyl, -C(0)-d_6 alkyl, -Hal, -CF 3 , -CN, -COOR ** , -(CH 2 ) q -OR ** , - S(0)R* * , -S(0) 2 R**, -(CH 2 ) q NR ** R* ** , -C(0)-NR ** R *** and -NR ** -C(0)-d_ 6 alkyl;
  • the optional substituent(s) of the optionally substituted hydrocarbon group is one or more substituents R d , wherein each R d is independently selected from -d-e alkyl, -C 1 -6 alkenyl, - d_e alkinyl, -C(0)-C, 6 alkyl, -Hal, -CF 3 , -CN, -OH, -CH 2 C(0)OH, -CH 2 C(0)Od_6 alkyl, - G-d- € alkyl, -C 3 _ 7 cycloalkyl, -COOR ** , -(CH 2 ) q -OR ** , -(CH 2 ) q -CN, -S(0)R ** , -S(0) 2 R ** , - (CH 2 ) P NR**R***, -C(0)-NR**R***, -NR**-C(0)-C 1 _ 6 alkyl, alkyi, -aryl, - heterocyclo
  • R*** is selected from -H, and -Ci_ 6 alkyl
  • R** is selected from -H, -C ⁇ alkyl which is optionally substituted with one or more halogen atoms, and - ⁇ CH 2 CH 2 0) r H;
  • q 0 to 4.
  • 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 cycloalkyl group, optionally Rnhstiti ited heterocvc!oa!kv! 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 alkyi 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.
  • 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, containinn fnr e amnie water-buffered aaueous solutions, e.a. biocomoatible buffers, ethanol, po!yol, 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, phenoi, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride, may be incorporated in infusion or injection solutions.
  • preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenoi, 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 propeilant 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. In general, 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.
  • examples of the various viruses are given in the following table.
  • 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 (inciuding 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 endonuciease 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. md 5 g01 s3) 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.
  • 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.
  • 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 (DME , 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.
  • DME 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. md 5 g01 s3), and stocks frozen at -80°C.
  • Viral infections were carried out using DMEM Glutamax supplemented with 0.3% BSA (Sigma), 25mM Hepes (Sigma), and 1 X penicillin/streptomycin (Invitrogen). ICmg of viral replication inhibition in a cell-based Luciferase Reporter Assay (LRA)
  • HATU (1-[Bis(dimethylamino)methyiene]-1 H-1 ,2,3-triazoio[4,5- bjpyridinium 3-oxid hexafluorophosphate)
  • 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.
  • Compounds of general structure I can be prepared starting from unsaturated cyano esters of general formula 1 and Grignard reagents of general formula 2 which are reacted in the presence of metal salts such as CuCN or Cul in THF to give cyano esters of general formula 3.
  • Grignard reagents of general structure 2 can be purchased from commercial vendors or prepared from compounds of general structure 2a by using Mg in solvents such as THF or Et 2 0.
  • the nitrile building blocks of general formula 4 may then be obtained via Krapcho decarboxylation preferentially with NaCI in DMSO at 120 °C or higher temperatures.
  • Imino ether hydrochlorides of general formula 5 can then be prepared via common Pinner reaction conditions - namely saturated HCI in MeOH.
  • Amidine intermediates of general formula 7 can be obtained by coupling of immino ether hydrochloride salt of general formula 5 with a suitable piperazinone of general formula 6 in the presence of AcOH and a tertiary amine such as DIPEA in a solvent such as THF.
  • Compounds of general structure la can finally be obtained via cyclization of amidine of general formula 7 in the presence of reagents such as diethyl oxalate and LHMDS in solvents such as THF.
  • compounds of general formula la can be obtained in a one-pot amidine formation / cyclization procedure in analogy to the above described two-step procedure.
  • Piperazinones of general structure 6 can be prepared starting from 2,2'-((tert- butoxycarbonyl)azanediyl)diacetic acid 9 by formation of the corresponding Weinreb amide of structe 10 using any of the commen peptide coupling reagents such as DCC preferentially in DMF.
  • Intermediates of general structure 11 can then be obtained via addition of suitable Grignard reagents in solvents such as THF.
  • Boc-protected intermediates of general formula 12 can then be obtained by reaction with a suitable primary amine in a one-pot reductive amination/piperazinone formation step using reagents such as BH(OAc) 3 and AcOH in solvents such as THF followed by piperazinone formation via the use of coupling agents such as EDC in solvents such as DMF.
  • Piperazinones of general structure 6 can then be obtained by using conditions such as TFA in DCM or HCI in dioxane.
  • piperazinones of general structure 6 can be prepared starting from enantiomerically pure amino acid derivatives of general structure 13. After reduction, preferentially using BH 3 in solvents such as THF, oxidation, preferably using sodium hypochlorite in combination with TEMPO in solvent mixtures such as DCM/water, generates aldehydes of general structure 14. Amino esters of general structure 15 can then be obtained via reductive amination using reagents such as NaHB(OAc) 3 in solvents such as DCM. Piperazinones of general structure 6 can then be obtained via deprotection under hydrogenation using catalysts such as 10% Pd/C in solvents such as MeOH which is followed by in-situ cyclization.
  • catalysts such as 10% Pd/C in solvents such as MeOH which is followed by in-situ cyclization.
  • compounds of general structure 6a can be obtained via deprotection, preferentially by using HCI in dioxane, followed by in-situ cyclization and protection, preferentially by using di-tert-butyl dicarbonate in THF and NaOH as base.
  • Compounds of general structure 6 can then be obtained via alkylation, preferentially using alkyl halides in presence of bases such as NaH in DMF, or, alternatively via Buchwald couplings using methods well-known to people trained in the art, followed by deprotection using preferentially HCI in dioxane.
  • nitrile building blocks of general formula 4 can be prepared by alternative synthetic routes as outlined in Scheme L4.
  • Aldehydes of general formula 18 can then be obtained by treatment with DIBAL preferentially in DCM.
  • Nitrile building blocks of general formula 4 can then be obtained by treatment with TosMIC in the presence of a base such as KO'Bu in a solvent such as THF followed by refluxing in presence of MeOH.
  • aldehydes of general structure 18 can be transformed into the corresponding nitrile of general structure 4 by reduction preferentially with NaBH 4 in MeOH followed by mesylation preferentially with MsCI in presence of a base such as NEt 3 in DCM and nucleophilic substitution preferentially with KCN in the presence of Kl in DMSO at 140 °C.
  • intermediates of general structure 17 can be obtained via decarboxylative coupling of compounds of general formula 21 with potassium cyano carboxylate 22 catalyzed preferentially by Pd 2 (allyl) 2 Cl 2 and Xantphos in mesitylene at 140 °C.
  • Scheme 5
  • Compounds of general structure 26 can be obtained from aryl halide building blocks such as general structure 23 by carbonyiation preferentially with Mo(CO) 6 catalyzed by Pd(OAc) 2 in solvents such as DMF in presence of EtOH. After hydrolysis preferentially with NaOH, reduction preferentially with BH 3 in THF, oxidation preferentially with Mn0 2 and transformation with DAST in DCM, compounds of general formula 26 can be obtained.
  • Benzylic fluorides of general structure 28 can be obtained by coupling of 23 with 30 catalyzed by Pd(PPh 3 ) 4 followed by reduction preferentially with NaBH 4 in DCM/water followed by transformation with DAST preferentially in DCM.
  • Ethyl benzene derivatives of general formula 33 can be prepared from bromo- benzaldehydes of general structure 31 by Wittig reaction using preferentially PPh 3 Mel in presence of KO'Bu in THF followed by hydrogenation using preferentially 10% Pd/C in EtOAc/AcOH as solvent mixture.
  • R 3 7 alkyl, cycloalkyl
  • benzylic nitriles By using boronic acid 34 catalyzed by Pd(dppf)CI 2 in solvent mixtures such as dioxane/water benzylic nitriles can be introduced.
  • the benzylic nitriles can be transformed into the corresponding carboxilic acids by HCI at 80 °C or into the corresponding amides by HCI at room temperature.
  • Compounds of general formula 35a can be obtained via alkylation by using preferentially NaH as base in DMF and Mel as alkylation agent.
  • compounds of general formula 36 can be obtained starting from compounds of general formula 35b.
  • compounds of general formula 37 can be obtained by nucleophilic substitution by a suitable nucleophile, as for example alcohols or amines, preferentially in solvents such as MeOH or THF in presence of a base such as NaOH or NaOMe.
  • Compounds of general structure 39 can be obtained via Suzuki reactions starting from compounds of general structure 38.
  • Compounds of general structure 40 can be obtained via Negishi reactions catalyzed by Pd(dppf)CI 2 in dioxane using Et 2 Zn or by Suzuki reaction followed by hydrogenation starting from 38.
  • Compounds of general structure 45 can be obtained by lithiation of compounds of general structure 2a, preferentially by using "BuLi in THF followed by addition of DMF.
  • Compounds of general structure 46 can be obtained starting from compounds of general structure 45 by reduction, preferentially using NaBH,, in MeOH, followed by mesylation, preferentially by using MsCI in DCM and bases such as NEt 3 .
  • Compounds of general structure 16 can then be obtained by substitution using KCN in solvents such as DMF.
  • Compounds of general structure 48 can be obtained via Negishi reactions catalyzed by Pd(dppf)CI 2 in dioxane using Et 2 Zn or by Suzuki reaction followed by hydrogenation starting from 17.
  • Compounds of general structure 53 (Scheme 15) can be obtained by condensation of aldehyde 51 with an amino alcohol of general structure 52 preferably in presence of AcOH in DCM under microwave irradiation.
  • Compounds of general structure 54 can then be obtained by deprotection, preferably by hydrogenation using 10% Pd/C in MeOH.
  • Compounds of genera! structure 57 can be prepared by condensing cyano ethyl acetate 55 with ketones of general structure 56, preferentially by refluxing in toluene in presence of ammonium acetate and AcOH using a Dean-Stark apparatus.
  • Compounds of general structure 57 can then be further transformed by using Grignard reagents of general formula 2 in the presence of metal salts such as CuCN or Cul in THF to give cyano esters of general formula 58.
  • the nitriie building blocks of general formula 59 may then be obtained via Krapcho decarboxylation preferentially with NaCI in DMSO at 120 X or higher temperatures.
  • Imino ether hydrochlorides of general formula 60 can then be prepared via common Pinner reaction conditions - namely saturated HCI in MeOH.
  • Amidine intermediates of general formula 61 can be obtained by coupling of imino ether hydrochloride salt of general formula 60 with a suitable piperazinone of general formula 6 in the presence of AcOH and a tertiary amine such as DIPEA in a solvent such as THF.
  • Compounds of general structure If can be finally obtained via cyclization of amidine of general formula 61 in the presence of reagents such as diethyl oxalate and LHMDS in solvents such as THF.
  • compounds of general formula If can be obtained in a one-pot amidine formation / cyclization procedure in analogy to the above described two-step procedure.
  • Compounds of general structure Ih can be prepared from compounds of general structure Ig by de-methylation, preferentially by using BBr 3 in presence of Nal and 15-crown-5 in DCM.
  • Compounds of general structure li can be prepared starting from compounds of general structure 66 via allylalion, preferentially by using LHMDS and ally! bromide in THF, to give compounds of general structure 67.
  • Compounds of general structure 68 can then be obtained by Horner-Wadsworth-Emmons reactions by using conditions well aware to people trained in the art.
  • Compounds of general structure 69 can then be obtained by hydroboration, preferentially by using 9-BBN in THF followed by oxidation with NaBO,,, followed by Appel reaction by using conditions well aware to people trained in the art.
  • Compounds of general structure 70 can then be obtained via radical cyclization, preferentially using Bu 3 SnH and AIBN in solvents such as benzene.
  • Compounds of general structure li can then be obtained following the corresponding steps of Scheme 1.
  • Compounds of general structure Ij (Scheme 21 ) can be prepared starting from compounds of general structure 72 via a nucleophilic substitution reaction using electrophile 71.
  • Compounds of general structure 74 can be obtained via Horner-Wadsworth-Emmons reactions by using conditions well aware to people trained in the art.
  • Compounds of general structure 75 can then be obtained via radical cyclization, preferentially using Bu 3 SnH and A!BN in solvents such as benzene.
  • Compounds of general structure Ij can then be obtained following the corresponding steps of Scheme 1.
  • One phenolic OH of 76 is protected with a suitable protective group such as benzyl.
  • Amides 78 can be then cyclized to intermediates 79 using Mitsunobu conditions such as DEAD/PPh 3 /DCM, preferentially at room temperature or higher reaction temperatures.
  • Deprotection for example cleavage of a benzyl protective group using hydrogenation with a suitable solvent such as MeOH and catalyst such as Pd/C gives compounds Ik.
  • the benzyl protective group can be cleaved with other methods, for example by treatment with cone, aq HCI in MeOH at temperatures from 5 °C to room temperature.
  • Chiral compounds can be obtained starting from chiral starting materials such as chiral, optionally protected amino alcohols 77 or by separation of racemic mixtures to the chiral components using suitable methods such as chromatography with a chiral stationary phase, preferentially with intermediates 79.
  • Alkenes 80 can then be deprotected as described above to derivatives II or reduced to alkyl substituted derivatives 81 , for example by hydrogenation in presence of Pd/C and a solvent such as EtOAc at room temperature.
  • Derivatives 81 can then be deprotected as described above.
  • Methyl groups can be introduced in analogy using a suitable reagent such as 2,4,6-trimethyl- 1 ,3,5,2,4,6-tn ' oxatriborinane without the hydrogenation step.
  • Isopropyl groups can be introduced in analogy using a suitable reagent such as prop-1 -en-2- ylboronic acid with the hydrogenation step.
  • Protected and unprotected amino alcohols 77 can be prepared by various routes. For example, as illustrated in Scheme 23, an amine 82 can be reacted with ketones 83 under reductive amination conditions such as NaBH(AcO) 3 , AcOK in DCE, at temperatures ranging from 0°C to room temperature.
  • reductive amination conditions such as NaBH(AcO) 3 , AcOK in DCE, at temperatures ranging from 0°C to room temperature.
  • N-Me substituted amino alcohols 77b can be prepared from suitable, N protected, for example Boc protected, amino acids 84, which are converted to esters 85 (Scheme 24).
  • acids 84 can be treated with an alkylating agent like methyl iodide, a base such as potassium carbonate in a solvent such as acetone, preferentially at a iemperature above room temperature such as 60 °C.
  • an amino acid 86 can be esterified, for example using SOCI 2 in MeOH to give 87, preferentially at temperatures between 0 °C and 70 °C, followed by protection to give 85, for example using Boc 2 0 and TEA in MeOH at temperatures preferentially between 0 °C and room temperature.
  • Amino alcohols 88 can be selectively O protected to give intermediates 89 (Scheme 25), for example by reaction with TBS-CI in presence of a base such as DIPEA and solvent such as DCM at temperatures preferentially between 5 °C and room temperature.
  • Amines 89 can be converted to intermediates 77c by reductive amination with acetone, a reducing agent such as NaBH(OAc) 3 at temperatures preferentially between 5 °C and room temperature.
  • Amino alcohols 88 can be converted to N-benzyl derivatives 90 by treatment with PhCHO and a suitable reducing agent such as NaBH(OAc) 3 at temperatures preferentially between 5 °C and room temperature (Scheme 26).
  • a methyl group can be introduced by treating derivatives 90 with CH 2 0 and a suitable reducing agent such as NaBH(OAc) 3 at temperatures
  • an N-benzyl protected ester 92 can be reacted with CH 2 0 and a suitable reducing agent such as NaBH(OAc) 3 at temperatures preferentially between 5 °C and room temperature to give derivatives 93.
  • the ester group of 93 is then reduced to aicohols 91 with a reducing agent such as NaBH 4 in the presence of LiCi and a solvent such as THF/EtOH, preferentially between 5 °C and room temperature.
  • ester 94 Treatment of ester 94 with a strong base such as LDA in a solvent such as THF at low temperature, e.g. -78 °C, followed by addition of a brominating agent such as NBS gives bromide 95 (Scheme 27).
  • a strong base such as LDA
  • a brominating agent such as NBS
  • Substitution with MeNHBn in a solvent like MeCN preferentially at temperatures between 5 °C and room temperature gives intermediate 96, which is then reduced with a suitable reducing agent like LAH in a solvent like THF, preferentially at temperatures close to 0 °C to an alcohol.
  • the benzyl group of can then be cleaved for example by hydrogenation in the presence of Pd(OH) 2 /C in MeOH, preferentially at a pressure of 50 psi and room temperature to give 77e.
  • a nitrile of general formula 103 can be converted to amidinium salts 104, for example by treatment with NH 4 CI in a solvent such as toluene and trimethyl aluminum at temperatures ranging preferentially from 0 °C to 80 °C.
  • Amidinium salts 104 can be reacted with intermediate 105, in a solvent such as methanol and a suitable base such as sodium methoxide, preferentially at room temperature to give terf-butyl esters 106, which can then be cleaved to acids 76, for example by hydrolysis with aqueous LiOH in THF at reflux temperature.
  • a compound of general formula Ip (Scheme 30) can be prepared from intermediate 107, which can be prepared by the methods outlined above, by treatment with MeOH and cone. aq. HCI at temperatures between 5 °C and room temperature.
  • esters 107 can be hydrolyzed with a mineral base such as LiOH in a mixture of water and a solvent such as methanol, preferentially at room temperature.
  • Acids Iq can be converted to amides Ir by treatment with NH 4 CI and a suitable coupling reagent such as HATU in a solvent such as DMF in presence of a base such as DIPEA, preferentially at a temperature between 10 °C and room temperature.
  • Amides Ir can be converted to nitriles Is by treatment with Burgess reagent in a solvent such as THF, preferentially a temperature between 15 °C and room temperature.
  • Thioethers of general formula 79b (Scheme 32) can be oxidized with m-CPBA in a solvent such as DCM, preferentially at a temperature close to 0 °C to sulfoxides 79c and sulfones 79d which can be deprotected to compounds It and compounds lu.
  • Alcohols of general structure Iv obtained with the methods described above can be oxidized to acids Iw with an oxidizing agent such as Phl(OAc) 2 in the presence of catalytic amounts of TEMPO in a solvent mixture such as DCM/water, preferentially at temperatures between 15 °C and 30 °C.
  • Acids Iw can be converted to amides Ix by treatment with an amine or ammonium salt and a suitable coupling reagent such as HATU in a solvent such as DMF in presence of a base such as DIPEA, preferentially at a temperature between 10°C and room temperature.
  • intermediates 79 can be chlorinated selectively to intermediates 79e by treatment with a suitable chlorinating agent such as 1 ,3,5-trichloro-l ,3,5-triazinane-2,4,6- trione in a solvent such as chloroform, preferentially at temperatures ranging from 5 °C to 75 "C.
  • a suitable chlorinating agent such as 1 ,3,5-trichloro-l ,3,5-triazinane-2,4,6- trione in a solvent such as chloroform, preferentially at temperatures ranging from 5 °C to 75 "C.
  • a suitable chlorinating agent such as 1 ,3,5-trichloro-l ,3,5-triazinane-2,4,6- trione in a solvent such as chloroform, preferentially at temperatures ranging from 5 °C to 75 "C.
  • the chlorine group can be substituted with acetate to give Iz, for example by treatment with NaOAc, Nal in a solvent such as
  • the acetate group of Iz can be hydrolyzed to give alcohols laa, by standard ester hydrolysis methods well known in the art such as treatment with NaOH in a solvent such as MeOH, preferentially at temperatures between 0°C and room temperature.
  • Example 1
  • the reaction mixture was allowed to cool down to room temperature and water was added.
  • the mixture was extracted three times with ethyl acetate and the combined organic layers were washed once with H 2 0 and once with saturated aq. NaCI, dried over MgS0 4 and concentrated in vacuo.
  • the residue was filtered over a plug of silica gel eluting with ethyl acetate. After evaporation and drying on high vacuum the title compound was obtained as a brown oil (270 mg, 74 % yield) and used as such in the next step.
  • the mixture was cooled to 0°C, treated drop wise with a premixed solution of ⁇ , ⁇ -Dimethy!hydroxylamine hydrochloride (4.5 g, 45.2 mmol, Eq: 1 .22) and N,N- diisopropylethylamine (5.92 g, 8 ml, 45.8 mmol, Eq: 1.24) in dimethylformamide (20 ml) and stirred for 18 h at room temperature.
  • the reaction mixture was poured on ice (100 g) mixed with 2M HCI (120 mL) and extracted with ethyl acetate (2 x 100 mL).
  • methyl 2-(1-phenylcyclopentyl)acetimidate hydrochloride (287 mg, 1.13 mmol, Eq: 1 .34) and 6-ethyl-1 -methylpiperazin-2-one (120 mg, 844 ⁇ , Eq: 1 ) were combined with THF (17.5 ml) and N,N-diisopropylethylamine (293 mg, 396 ⁇ , 2.27 mmol, Eq: 2.69) to give a light yellow solution.
  • acetic acid (67.9 mg, 64.7 ⁇ , 1 .13 mmol, Eq: 1 .34) was added and the mixture was stirred at room temperature for 2 days.
  • the thick suspension was diluted with THF (3 ml) and was cooled to -30°C, then first lithium bis(trimethylsilyl)amide 1 M in THF (6.33 ml, 6.33 mmol, Eq: 7.5) was added at -30°C followed by diethyl oxalate (555 mg, 519 ⁇ , 3.8 mmol, Eq: 4.5).
  • the cooling bath was removed and the reaction was stirred for 3 h at room temperature.
  • the reaction mixture was taken up in 1 M HCI and extracted four times with DCM.
  • the combined organic layers were evaporated and the residue purified by reversed phase preparative HPLC to give the title compound as white powder (74 mg, 23 % yield).
  • the title compound was prepared in analogy to Example 1 by using (3- ethylphenyi)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a white powder.
  • Example 6 MS (ESI, m/z): 410.3 [(M+H) + ]. The absolute configuration was tentatively assigned in analogy to Example 1 1 based on biological activity.
  • the title compound was prepared in analogy to Example 1 by using (3,5- dimethy!phenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and isopropylamine instead of methylamine in step f) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3,5- dimethylpheny!)magnesium bromide instead of phenylmagnesium bromide in step a) and cyclopropylamine instead of methylamine in step f) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3- trifiuoromethylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a white powder.
  • Example 1 19 (19 mg) was submitted to chiral separation on the column Reprosil 100 AILIC-A (5 pm) eiuting with 80% MeOH in water to to give the title compounds as white powders (6 mg for Example 1 1 and 6 mg for Example 12).
  • the absolute stereochemistry was determined via X-ray co-crystallography.
  • the title compound was prepared in analogy to Example 1 by using (3-trifluoromethyl-5- methylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyi-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3.5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and octahydro-4h-pyrido[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1-methyl-piperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and octahydro-4h-pyriuo[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1 -methyl-piperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 17 by using 1 ,2,3,6,7,1 1 B- Hexahydro-4h-pyrazino(2, 1 -a)isoquinoline-4-one instead of (S)-1 ,6-dimethylpiperazin-2-one in step a) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and 1 ,2,3,6,7,1 1 B-hexahydro-4h-pyrazino(2,1-a)isoquinoline-4-one instead of 6-ethyl-1 -methyl- piperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3-chloro-5- methy!phenyl)magnesium bromide (prepared in analogy to 3-trifluoromethyl-5- methyipenyl)magnesium bromide, see Example 14, by starting from 1-bromo-3-chloro-5- methylbenzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3,5-dimethyl-4- fluorophenyl)magnesium bromide (prepared in analogy to 3-trifluoromethyl-5- methylpenyl)magnesium bromide, see Example 14, by starting from 1 -bromo-3,5-dimethyl-4- fluorobenzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using 2-[1-[3- (difluoromethyl)phenyl]cyclopentyl]acetonitrile instead of 2-(1-phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using methyl 2-[1 -[3-(1 - chloroethyl)phenyl]cyclopentyl]ethanimidate hydrochloride instead of methyl 2-(1- phenylcyclopentyl)ethanimidate hydrochloride and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using (3-ethyl-4- fluorophenyi)magnesium bromide (prepared in analogy to 3-trifluoromethy!-5- methylpenyl)magnesium bromide, see Example 14, by starting from 4-bromo-2-ethyl-1 -f!uoro- benzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2- one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • This reaction mixture was stirred in a pre-heated plate at 140 °C for 15h.
  • the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness under reduced pressure.
  • the residue was purified by silica gel column chromatography (100-200 mesh) eluting with 6% EtOAc in hexane to afford the title compound (370 mg, 35%).
  • the title compound was prepared in analogy to Example 29 by using 1 -bromo-2-fluoro-3,5- dimethyl-benzene instead of 1 -bromo-3-ethyl-2-fluoro-benzene in step a) to afford the title compound as a white powder.
  • the title compound was prepared in analogy to 2-[1 -(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26) by using 2-(3-bromo-5-methyl-phenyl)acetonitrile (prepared according to Guo Hongyan et al. PCT patent application WO 2009/005674 instead of 2-(3- bromophenyl)acetonitrile in step a).
  • the title compound was prepared in analogy to Example 1 by using 2-[1-(3-bromo-5-methyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.
  • reaction mixture was stirred at 120°C. After completion of the reaction as judged by LC/MS analysis the reaction mixture was concentrated in vacuo and diluted in DMSO. The solution was filtered using a syringe filter and submitted to reversed phase preparative HPLC purification to afford the title compound (19 mg, 42%) as a red solid.
  • the title compound was prepared in analogy to Example 34 by using hexahydropyrrolo[1 ,2- a]pyrazin-4(1 H)-one instead of octahydro-4h-pyrido[1 ,2-a]pyrazin-4-one in step b) to give the title compound as a white powder.
  • the title compound was prepared in analogy to Example 1 by using 2-[1-(3,5- dibromophenyl)cyclopentyl]acetonitrile instead of 2-( 1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methy!piperazin- 2-one in step h) to give the title compound as a white solid.
  • reaction mixture was heated to 80° overnight.
  • 1 ,1 '-bis(diphenyiposphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 9 pmol) and cyclopropylboronic acid (16 mg, 190 pmol) was added and the reaction mixture was heated to 90 °C overnight.
  • 1 N HCI was added and the reaction mixture was extracted with DCM (3 x). The combined organic layers were dried over Na 2 S0 4 , evaporated and the residue was purified by reversed phase preparative HPLC to give the title compound (2 mg, 2 %) as an off-white solid.
  • the title compound was prepared in analogy to methyl 2-(1-phenylcyclopentyl)ethanimidate hydrochloride (see Example 1 , step c) starting from 2-[1-(3- bromophenyl)cyclopentyl]acetonitrile (see Example 26, steps a-c) instead of 2-(1 - phenylcyclopentyi)acetonitrile to afford the title compound as a light brown solid.
  • the titie compound was prepared in analogy to Example 54 by using 1 -methyl-1 H-pyrazole-5- boronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as off-white solid.
  • the titie compound was prepared in analogy to Example 1 by using 2-[1-(3,5- diethylphenyl)cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin- 2-one in step h) to give the title compound as a white solid.
  • the title compound was prepared in analogy to methyl 2-(1 -phenylcyclopentyl)ethanimidate hydrochloride (see Example 1 , step c) by starting from 2-hydroxy-2-(1- phenylcyclopentyl)acetonitrile to afford the title compound as a white solid.
  • the title compound was prepared in analogy to 2-(1 -phenylcyclopentyl)acetonitrile (see Example 1 ) by using (3,5-dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a brown oil.
  • reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by flash column chromatography (5% EtOAc in hexane) to get the title compound (2 g, 65%) as a colorless oil.
  • the title compound was prepared in anaolgy to Example 1 by using 2-[1 -(3-ethyl-2-methyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1-phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as as a white solid.
  • the title compound was prepared in analogy to 1-bromo-3-ethyl-2-fluoro-benzene (see Example 29, steps a-b) by starting from 3-bromo-4-methylbenzaldehyde instead of 3-bromo-2- fluorobenzaldehyde to give the title compound as a colorless liquid.

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Abstract

La présente invention concerne un composé de formule générale (I), se présentant éventuellement sous la forme d'un sel, d'un solvate, d'un polymorphe, d'un comédicament, d'un cocristal, d'un promédicament, d'un tautomère, d'un racémate, d'un énantiomère ou d'un diastéréomère pharmaceutiquement acceptable, ou bien d'un mélange de ceux-ci, utiles pour traiter, soulager ou prévenir une maladie virale, en particulier la grippe.
PCT/EP2017/056361 2016-03-18 2017-03-17 Dérivés de pyrimidone et leur utilisation dans le traitement, le soulagement ou la prévention d'une maladie virale Ceased WO2017158151A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180118760A1 (en) 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
US10759814B2 (en) 2016-08-10 2020-09-01 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug 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
CN118459369A (zh) * 2023-09-05 2024-08-09 成都师范学院 N-Boc-乙烯基甘氨酸甲酯及其异构化物的合成方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180118760A1 (en) 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
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
CN118459369A (zh) * 2023-09-05 2024-08-09 成都师范学院 N-Boc-乙烯基甘氨酸甲酯及其异构化物的合成方法

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