WO2011000566A2 - Compounds and pharmaceutical compositions for the treatment of negative-sense ssrna virus infections - Google Patents

Compounds and pharmaceutical compositions for the treatment of negative-sense ssrna virus infections Download PDF

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WO2011000566A2
WO2011000566A2 PCT/EP2010/003967 EP2010003967W WO2011000566A2 WO 2011000566 A2 WO2011000566 A2 WO 2011000566A2 EP 2010003967 W EP2010003967 W EP 2010003967W WO 2011000566 A2 WO2011000566 A2 WO 2011000566A2
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optionally substituted
alkyl
group
alkenyl
alkynyl
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PCT/EP2010/003967
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French (fr)
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WO2011000566A3 (en
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Dirk Classen-Houben
Oliver Szolar
Peter Sehr
Bernd Wendt
Delphine Gulligay
Stephen Cusack
Joe Lewis
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Savira Pharmaceuticals Gmbh
European Molecular Biology Laboratory (Embl)
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Publication of WO2011000566A2 publication Critical patent/WO2011000566A2/en
Publication of WO2011000566A3 publication Critical patent/WO2011000566A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel compounds and pharmaceutical compositions and the use thereof for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection with negative-sense ssRNA viruses.
  • Influenza and other negative-sense ssRNA virus infections are responsible for much morbidity and mortality in the world.
  • annual epidemics swipe the globe and occasional new virulent strains cause pandemics of great destructive power.
  • the primary means of controlling Influenza virus epidemics is vaccination.
  • mutant Influenza viruses are rapidly generated which escape the effects of vaccination.
  • alternative therapeutic means i.e., antiviral medication, are required especially as the first line of defense against a rapidly spreading pandemic.
  • anti-Influenza compounds such as amantadine and rimantadine target an ion channel protein, i.e., the M2 protein, in the viral membrane interfering with the uncoating of the virus inside the cell.
  • an ion channel protein i.e., the M2 protein
  • they have not been extensively used due to their side effects and the rapid development of resistant virus mutants (Magden et al., 2005).
  • more unspecific viral drugs such as ribavirin, have been shown to work for treatment of Influenza and other negative-sense ssRNA virus infections (Eriksson et al., 1977).
  • ribavirin is only approved in a few countries, probably due to severe side effects (Furuta et al., 2005).
  • Influenza virus as well as Thogotovirus belong to the family of Orthomyxoviridae which, as well as the family of the Bunyaviridae, including the Hantavirus, Nairovirus, Orthobunya- virus, and Phlebovirus, are negative stranded RNA viruses. Their genome is segmented and comes in ribonucleoprotein particles that include the RNA dependent RNA polymerase which carries out (i) the initial copying of the single-stranded virion RNA (vRNA) into viral mRNAs and (ii) the vRNA replication.
  • vRNA single-stranded virion RNA
  • a 5' cap (also termed an RNA cap, RNA 7-methylguanosine cap or an RNA m 7 G cap) is a modified guanine nucleotide that has been added to the 5' end of a messenger RNA.
  • the 5' cap consists of a terminal 7-methylguanosine residue which is linked through a 5 '-5 '-triphosphate bond to the first transcribed nucleotide.
  • the viral polymerase binds to the 5' RNA cap of cellular mRNA molecules and cleaves the RNA cap together with a stretch of nucleotides. The capped RNA fragments then serve as primers for the synthesis of viral mRNA.
  • the viral polymerase is composed of three subunits: PBl (polymerase basic protein), PB2, and PA. While PBl harbours the endonuclease and polymerase activities, PB2 contains the RNA cap binding domain.
  • the polymerase complex seems to be an appropriate antiviral drug target since it is essential for synthesis of viral mRNA and viral replication and contains several functional active sites likely to be significantly different from those found in host cell proteins (Magden et al., 2005). Thus, for example, there have been attempts to interfere with the assembly of polymerase subunits by a 25-amino-acid peptide resembling the PA-binding domain within PBl (Ghanem et al., 2007).
  • the present invention provides novel anti-viral compounds against negative-sense ssRNA viruses that use the above outlined cap snatching mechanism for synthesis of viral mRNA. Specifically, the present invention provides in a first aspect a compound having a structure according to formula (I):
  • X is NH, NR 9 , O or S
  • R 1 and R 2 are each individually selected from the group consisting of Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -C(O)NH 2 , -C(O)NHR 7 , -C(O)NR 7 R 8 , -NHC(O)NH 2 , -NHC(O)NHR 7 , -NHC(O)NR 7 R 8 , halogen, -C(O)OR 7 , -OR 7 and -NR 7 R 8 ; optionally substituted;
  • R 3 through R 6 are each individually selected from the group consisting of hydrogen, CpC ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -C(O)NH 2 , -C(O)NHR 7 , -C(O)NR 7 R 8 , -NHC(O)NH 2 ,
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl and -C(O)R 9 ; optionally substituted; and
  • R is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • Y and Z is -XR 12 and the other is R 10' ;
  • R 10 , R 10 and R 10 are each individually selected from the group consisting of hydrogen, Ci-C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, -(CH 2 ) n C(O)OH, -(CHj) n C(O)OR 16 , -(CH 2 ) n OH,
  • -(CHz) n S(O) 2 R 16 halogen, -CN, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 ) n NH 2 , -(CH 2 ) n NHR 16 , and -(CHz) n NR 16 R 17 ; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, Ci.C ⁇ -alkyl, -CF 3 , C 2- C6-alkenyl, C 2- Cg- alkynyl, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocycloalkyl and -(CH 2 ),,- heteroaryl; optionally substituted;
  • R 12 is selected from the group consisting of Ci-C 6 -alkyl, -CF 3 , C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl,
  • R 16 and R 17 are independently selected from the group consisting of Q-C ⁇ -alkyl, C 2 -C 6 -alkenyl,
  • R 18 is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, -(CH 2 ) ⁇ -cycloalkyl and -CF 3 ; optionally substituted;
  • n is in each instance selected from O, 1 and 2.
  • the invention further provides a compound having a structure according to formula (X):
  • X is O or S
  • R 27 is selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C6-alkynyl, -
  • R 29 is selected from the group consisting of hydrogen, Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, -C(O)OR 33 , -OR 33 and -NR 33 R 34 ; optionally substituted;
  • R 28 and R 30 are each individually selected from the group consisting of hydrogen, halogen,
  • R 31 and R 32 are each individually selected from the group consisting of hydrogen, halogen,
  • R 33 and R 34 are independently selected from the group consisting of hydrogen, aryl, heteroaryl,
  • a and B is each individually selected from S and O;
  • R 40 and R 41 are each individually selected from the group consisting of halogen, -CF 3 , -CN, -
  • R 37 and R 39 are each individually selected from the group consisting of hydrogen, Q-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -C(O)OR 44 , -OR 44 and -NR 44 R 45 ; optionally substituted;
  • R 36 , R 38 , R 42 and R 43 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R 44 , -C(O)OR 44 , -CF 3 , -CN, -SO 3 -, -NO 2 , -N(R 4 V, C,-C 6 -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -OR 44 and -NR 44 R 45 ; optionally substituted;
  • R 44 and R 45 are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, C 2 - C 6 -alkenyl, C 2 -C 6 -alkynyl and -C(O)R 46 ; optionally substituted; and R 46 is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • X is S and O
  • R 47 through R 49 are each individually selected from the group consisting of hydrogen, Ci-C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -C(O)OR 53 , -OR 53 and -NR 53 R 54 ; optionally substituted;
  • R 50 through R 52 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R 53 , -C(O)OR 53 , -CF 3 , -CN, -SO 3 " , -NO 2 , -N(R 53 ) 3 + , Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -OR 53 and -NR 53 R 54 ; optionally substituted;
  • R 53 and R 54 are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, C 2 -
  • R 55 is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl; optionally substituted. Also provided is a compound having a structure according to formula (XVII):
  • R 56 is C 3 -C 6 -alkyl; optionally substituted.
  • R 57 and R 58 is each individually an C 2 -C 6 -alkyl; optionally substituted.
  • R 62 , R 63 and R 64 is each individually aryl or heteroaryl; optionally substituted.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the compounds according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • a further aspect of the invention is the use of any one of the compounds according to the invention or the pharmaceutical composition according to the invention for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection with a negative-sense ssRNA virus.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • alkyl "heteroalkyl”, “cycloalkyl”, “heterocycloalkyl”, “alicyclic system”, “aryl”, “aralkyl”, “heteroaryl”, “heteroaralkyl”, "alkenyl”, “cycloalkenyl”, “alkynyl” and “optionally substituted” are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl, heptyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso-propy ⁇ , butyl, wo-butyl, sec-butyl, tert-butyl, pentyl or hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-mo ⁇ holinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl,
  • alicyclic system refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond.
  • an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs.
  • the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds.
  • the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system.
  • Alicyclic systems are optionally substituted.
  • 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, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, w ⁇ -propyl, butyl, /so-butyl, sec-butenyl, tert-butyl, pentyl or hexyl, pentyl, octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are 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, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • Examples are oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1,2-benzisothi
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and cycloalkenyl refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • R 5 and R' ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -OE, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl; optionally substituted;
  • R 555 and R" 55 is each independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 5 R";
  • E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.
  • RNA cap or “Cap” refers to a cap structure found on the 5' end of an mRNA molecule and consists of a guanine nucleotide connected to the mRNA via a 5' to 5' triphosphate linkage. The guanosine is methylated on the 7 position. Further modifications include the possible methylation of the 2' hydroxy-groups of the first 3 ribose sugars of the 5' end of the mRNA. "RNA cap analogs" refer to structures that resemble the RNA cap structure.
  • RNA cap analogs include 7-methyl-guanosine (m 7 G), 7-methyl-guanosine monophosphate (m 7 GMP), 7-methyl-guanosine triphosphate (m 7 GTP), 7-methyl-guanosine linked via a 5 5 to 5 5 triphosphate bridge to guanosine (m 7 GpppG), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to guanosine methylated at the 2' OH position of the ribose (m 7 GpppGm), 7- methyl-guanosine linked via a 5' to 5' triphosphate bridge to adenosine (m 7 GpppA), 7-methyl- guanosine linked via a 5' to 5' triphosphate bridge to adenosine methylated at the 2 5 OH position of the ribose (m 7 GpppAm), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to
  • the cap analog is selected from the group consisting of m 7 G, m 7 GMP, m 7 GTP, m 7 GpppN, m 7 GpppNm, where N is a nucleotide, preferably G, A, U, or C.
  • the RNA cap analogs may comprise additional, e.g., 1 to 15 nucleotides, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the nucleotides are preferably independently selected from the group consisting of A, C, G, U, and/or T.
  • nucleotides are, preferably linked via a phosphoester, phophodiester or phosphotrieester bond or a non- hydrolyzable analog thereof to the first nucleotide N in m 7 GpppN or m 7 GpppNm.
  • 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
  • a compound according to the invention refers to a compound according to any of formulas I through XX including all preferred respective embodiments of such a compound and physiological acceptable salts thereof.
  • drug and pharmaceutically active compound(s) are used interchangeably.
  • the present invention provides novel anti-viral compounds effective against negative- sense ssRNA viruses that use a cap snatching mechanism for synthesis of viral mRNA.
  • the invention provides a compound having a structure according to formula (I)
  • X is NH, NR 9 , O or S; preferably O or S;
  • R 1 and R 2 are each individually selected from the group consisting of Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl, C 2 -
  • NHC(O)NR 7 R 8 halogen, in particular F, Cl, Br or I; -C(O)OR 7 , -OR 7 and -NR 7 R 8 ; optionally substituted;
  • R 1 and R 2 are Ci-C 6 -alkyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C 2 -C ⁇ -alkenyl
  • Ci preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl
  • C 2 -C 6 -alkynyl preferably Cj, C 2 , C 3 , C 4 , C 5 or Ce-alkynyl
  • halogen in particular F, Cl, Br or I
  • -C(O)OR 7 , -OR 7 and -NR 7 R 8 optionally substituted; most preferably -OR 7 ; optionally substituted;
  • R 3 through R 6 are each individually selected from the group consisting of hydrogen, Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -C(O)NH 2 , -C(O)NHR 7 , -C(O)NR 7 R 8 , -NHC(O)NH 2 ,
  • Ci-C 6 -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 3 through R 6 are each individually selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C ⁇ -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C ⁇ -Q-alkenyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl), C 2 -C 6 -alkynyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkynyl), halogen (in particular F, Cl, Br or I), -C(O)OR 7 , -OR 7 and -NR 7 R 8 ; optionally substituted;
  • Ci-C ⁇ -alkyl preferably Ci, C 2 , C 3 , C
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl and -C(O)R 9 ; optionally substituted;
  • Ci-C ⁇ -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl and -C(O)R 9 optionally substituted;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, CpC 6 - alkyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C 2 -C 6 -alkenyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl), C 2 -C 6 -alkynyl (preferably d, C 2 , C 3 , C 4 , C 5 or C 6 -alkynyl) and -C(O)R 9 ; optionally substituted;
  • CpC 6 - alkyl preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g. methyl, e
  • R 9 is independently selected from the group consisting of Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl; optionally substituted; and preferably R 9 is independently selected from the group consisting of Ci-C 6 -alkyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g.
  • C 2 -C 6 -alkenyl preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl
  • C 2 -C 6 -alkynyl preferably C, C 2 , C 3 , C 4 , C 5 or C 6 - alkynyl
  • the compound has the structure (II), (III) or (IV):
  • X is O
  • R 1 and R 2 are each selected from the group consisting of -OH and -OC r C 3 -alkyl, i.e. -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 and -O- isopropyl.
  • R 1 and R 2 are -OH and R 3 , R 4 and R 5 are -OR 7 .
  • the compound of the first aspect of the invention is selected from the group consisting of compounds No. 6-9 of table 1.
  • Y and Z is -XR 12 and the other is R 10' ;
  • R 10 , R 10 and R 10 are each individually selected from the group consisting of hydrogen, Ci-C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, -(CH 2 ) n C(O)OH, -(CH 2 ) n C(O)OR 16 , -(CH 2 ) n OH, -(CH 2 ) n OR 16 , -CF 3 , -(CH 2 ) n -cycloalkyl, -(CH 2 ) ⁇ C(O)NH 2 , -(CHz) n C(O)NHR 16 , -(CH 2 ) n C(O)NR 16 R 17 , -(CH 2 ) n S(O) 2 NH 2 , -(CH 2 ) n S(O) 2 NHR 16 , -(CH 2 ) n S(O) 2 NR 16 R 17 , -(CH
  • X is selected from the group consisting of CH 2 , -C(O)-, -C(S)-, -C(O)-N(H)- and -N(H)-C(O)-; most preferably X is selected from the group consisting of -C(O)-, -C(O)-N(H)- and -N(H)-C(O)-;
  • R 12 is selected from the group consisting of Ci-C ⁇ -alkyl, -CF 3 , C 2 -Ce-alkenyl, C 2 -C 8 -alkynyl, -(CH 2 ) n -cycloalkyl, -(CH ⁇ n -heterocycloalkyl, -(CH 2 ) n -aryl (e.g. -(CH 2 ) n -phenyl),
  • R 12 is selected from the group consisting of -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -heterocycloalkyl (e.g. piperidinyl, imidazolidinyl, pyrrolidinyl or pyrazolidinyl), -(CH 2 ) n -aryl (e.g. -(CH 2 ) n -phenyl),
  • R 12 is selected from the group consisting of -(CH 2 ) n -heterocycloalkyl, -(CH 2 ) n -aryl (e.g. -(CH 2 ) n - phenyl), -NR 16 R 17 and -(CH 2 ) n -heteroaryl; optionally substituted;
  • R 16 and R 17 are independently selected from the group consisting of C
  • R 18 is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, -(CH 2 ) n -cycloalkyl and -CF 3 ; optionally substituted;
  • n is in each instance selected from O, 1 and 2.
  • the compound according to formula (XXI) as outlined above has a structure according to formula (V) or (XXII):
  • a compound having a structure according to formula (V) as shown above or a pharmaceutically effective salt, a solvate, a prodrug, a tautomer, a racemate, an enantiomer or a diastereomer thereof; wherein
  • R 10 , R 10 and R 10 are each individually selected from the group consisting of hydrogen, Ci-C 6 - alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, -(CH 2 ) n C(O)OH, -(CHz) n C(O)OR 16 , -(CH 2 ) n OH,
  • -(CH 2 ) n OR 16 , -CF 3 , -(CH 2 ) ⁇ -cycloalkyl, -(CH 2 ) n C(O)NH 2 , -(CH 2 ) n C(O)NHR 16 , -(CH 2 ) n C(O)NR 16 R 17 , -(CH 2 ) n S(O) 2 NH 2 , -(CH 2 ) n S(O) 2 NHR 16 , -(CH 2 ) n S(O) 2 NR 16 R 17 ,
  • -(CH 2 ) n S(O) 2 R 16 halogen (in particular F, Cl, Br or I), -CN, -(CH 2 ) n -aryl, -(CH 2 ),,- heteroaryl, -(CH 2 ) n NH 2 , -(CH 2 ) n NHR 16 , and -(CH 2 ) n NR 16 R 17 ; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, Ci.C ⁇ -alkyl, -CF 3 , C 2- C 6 -alkenyl, C 2- C 8 - alkynyl, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -aryl, and -(CH 2 ) n -heteroaryl; optionally substituted;
  • R 12 is selected from the group consisting of Cj-C ⁇ -alkyl, -CF 3 , C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, - (CH 2 ) n -cycloalkyl, -(CH 2 ) n -aryl, and -(CH 2 ) n -heteroaryl; optionally substituted;
  • R 16 and R 17 are independently selected from the group consisting of Ci-C 6 -alkyl, C 2 -C 6 -alkenyl,
  • R 18 is independently selected from the group consisting of C t -C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, -(CH 2 ) n -cycloalkyl and -CF 3 ; optionally substituted;
  • n is in each instance selected from O, 1 and 2.
  • R 10 is selected from the group consisting of hydrogen, Ci-C 6 -alkyl (preferably Cj, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C 2 -C 6 -alkenyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl), C 2 -C f i-alkynyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkynyl) -(CH 2 ) n -cycloalkyl, -O-Ci-C 6 -alkyl, - (CH 2 ) n NH 2 , -(CHz) n NHR 16 , -(CH 2 )
  • R 10 is selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl (preferably Ci, C 2 , C 3 , C 4 , C5 or C ⁇ -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C 2 -C 6 -alkenyl (preferably C,, C 2 , C 3 , C 4 , C 5 or C 6 - alkenyl), C 2 -C 6 -alkynyl
  • Ci-C ⁇ -alkyl preferably Ci, C 2 , C 3 , C 4 , C5 or C ⁇ -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 10 is hydrogen
  • R 10 is selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl (preferably Ci, C 2 , C 3 , C 4 , C 5 or C 6 -alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), -CF 3 , -(CHz) n C(O)OH, -(CH 2 ) n C(O)OR 16 , -(CH 2 ) n OH, -(CHs) n OR 16 ,
  • R 10' and/or R 10" is hydrogen.
  • X is CH 2 , C(O), C(S), -N(-R 16 )-C(0)- or -C(0)-N(- R 16 )- and in a more preferred embodiment X is C(O) or C(S).
  • X is selected from CH 2 , C(O), CH(OH), -S(O) 2 -N(H)-, - N(H)S(O) 2 -, -C(O)-N(H)-, -N(H)-C(O)-, N(H), and O.
  • R 11 is hydrogen.
  • R 10 , R 10 and R 1 1 are hydrogen.
  • R 10 is preferably selected from -OH, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, phenyl, hydroxymethyl, 2-hydroxyethyl, methoxy, -C(O)NH 2 , - C(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2, -CH 2 NHC(O)CH 3 , and -
  • R 10 is selected from ethyl, isopropyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxy, and -CF 3
  • R 10 is selected from the group consisting of
  • R 10 is hydrogen and R 10 is selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyl, (CHz) n - cycloalkyl, -CF 3 , -(CH 2 ) n C(O)OH, -(CH 2 ) n C(O)OR 16 , -(CH 2 ) n OH, -(CH 2 ) n OR 16 , -(CH 2 ) n NH 2 , -(CH 2 ) n NHR 16 , -(CH 2 ) n NR 16 R 17 , -(CH 2 ) n C(O)NH 2 , -(CH 2 ) n C(O)NHR 16 , -(CH 2 ) n C(O)NR 16 R 17 , -(CH 2 ) n S(O) 2 R 16 ,
  • R 10 is more preferably selected from the group consisting of -CF 3 , - (CH 2 ) n C(O)OH, -(CH 2 ) n C(O)OR 16 , -(CH 2 ) n OH, -(CH 2 ) n OR 16 , -(CH 2 ) n NH 2 , -(CH 2 ) n NHR 16 , - (CH 2 ) n NR 16 R 17 , -(CH 2 ) n C(O)NH 2 , -(CHz) n C(O)NHR 16 , -(CH 2 ) n C(O)NR 16 R 17 , -(CH 2 ) n S(O) 2 NH 2 , -(CHz) n S(O) 2 NHR 16 and -(CHz) n S(O) 2 NR 16 R 17 .
  • R 10 is hydrogen and R 10 is selected from the group consisting of Ci-C 6 -alkyl, Cz-C ⁇ -alkenyl, Cz-Cg-alkynyl, (CH 2 ) n -cycloalkyl, -CF 3 , -(CHz) n C(O)OH, -(CHz) n C(O)OR 16 , -(CHz) n NHC(O)R 18 , -(CHz) n NR 16 C(O)R 18 ,
  • R 10 is more selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C6-alkenyl, C 2 -C 8 -alkynyl, -(CH 2 ) n -cycloalkyl, -CF 3 , (CH 2 ) n -aryl, and (CH 2 ) n -heteroaryl; optionally substituted.
  • R 12 is preferably selected from the group consisting of -(CH 2 ) n -aryl, -(CH 2 ) n -heterocycloalkyl (preferably heterocycloalkyl), -NR 16 R 17 and -(CH 2 ) n -heteroaryl; optionally substituted; and more preferably R 12 is selected from the group consisting of -(CH 2 ) n -aryl, -(CH 2 ) n -heterocycloalkyl and -(CH 2 ) n -heteroaryl; optionally substituted; and most preferably selected from aryl, heteroaryl and heterocycloalkyl.
  • R 12 is selected from phenyl, naphthyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and purinyl; optionally substituted.
  • R 12 is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl and benzimidazolyl; optionally substituted.
  • R 12 is selected from the group consisting of:
  • each R 12 substituent may be optionally substituted
  • R 12 is substituted with a substituent selected from the group consisting of:
  • R 12 is C
  • m is in each instance selected from O, 1 and 2 and is most preferably O;
  • substituent may optionally be substituted as defined herein on p. 1 1.
  • the compound has a structure according to formula (VI) or (VIb):
  • X is C(O) or C(S);
  • A is O or S
  • R 10 and R 15 are each individually selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -CF 3 , -C(O)OR 16 , -OH, -OR 16 , -NHR 16 , -NH 2 and -NR 16 R 17 ; optionally substituted; and
  • R 10 , R 10 " , R 13 and R 14 are each individually selected from the group consisting of hydrogen, C 1 -
  • X is C(O) or C(S);
  • R 10 and R 15 are each individually selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -CF 3 , -C(O)OR 16 , -OH, -OR 16 , -NHR 16 , -NH 2 and -NR 16 R 17 ; optionally substituted; and
  • R 10 , R 10 , R 13 and R 14 are each individually selected from the group consisting of hydrogen, Ci- C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halogen, -CF 3 , -COOH, -CN, -C(O)OR 16 , -OH, -
  • R 10 and R 15 are each individually selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 - alkenyl, Cz-Ce-alkynyl, -C(O)OR 16 , -OH, -OR 16 , -NHR 16 , -NH 2 and -NR 16 R 17 ; optionally substituted; most preferably, R 15 is -OH;
  • R 10 , R 10 , R 13 and R 14 are each individually selected from the group consisting of hydrogen, Q-
  • R 16 and R 17 are independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl,
  • R » 18 is independently selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C ⁇ -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • R 10 and R 10 are preferably hydrogen or R 10' , R 10" , R 13 and R 14 are hydrogen. Most preferably, R 10> , R 10" , R 13 and R 14 are hydrogen and X is -C(O)-.
  • the compound has the structure (VIIA), (VIIB) or (VIIC):
  • R 10 and R 15 are each individually selected from the group consisting of Ci-C ⁇ -alkyl, C 2 -C O - alkenyl, C 2 -C 6 -alkynyl, -CF 3 , -C(O)OR 16 , -OH, -OR 16 , -NHR 16 , -NH 2 and -NR 16 R 17 ; optionally substituted; and
  • R 13 and R 14 are each individually selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl,
  • the compound has the structure according to formula (VIII):
  • X is -C(O)- or -C(S)- and most preferably wherein X is -C(O)-.
  • R 15 of the compound is -OH.
  • R 15 is -OH and R 10 is -OH or Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl).
  • R 13 and R 14 is the same substituent, preferably halogen, e.g. F, I, Cl or Br.
  • R 10 is methyl or ethyl.
  • R 13 and R 14 is hydrogen.
  • the compound is selected from compounds No. 1-5 as listed in table 1 and from the compounds as listed in Tables 2A-J below. Also the following compound effectively inhibits the interaction between a Cap analogue and viral PB2 with an EC 50 of 22.3 ⁇ M:
  • this compound is a preferred embodiment of the compound of the invention.
  • the compound has the following structure: wherein R 65 is selected from the group consisting of -OH or Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), -(CH 2 ) m -cycloalkyl, halogen,
  • R 12 is Ci-C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 8 -alkynyl;
  • m is in each instance selected from O, 1 and 2 and is most preferably O.
  • X is O or S
  • R 27 is selected from the group consisting of Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -C(O)OR 33 ,
  • R 29 is selected from the group consisting of hydrogen, Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl,
  • R 28 and R 30 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R 33 , -C(O)OR 33 , -CF 3 , -CN, -SO 3 " , -NO 2 , -N(R 33 ) 3 + , C r C 6 - alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
  • R 31 and R 32 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R 33 , -C(O)OR 33 , -CF 3 , -CN, -S0 3 ⁇ -NO 2 , -N(R 33 ) 3 + , C 1 -C 6 - alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
  • R 33 and R 34 are independently selected from the group consisting of hydrogen, aryl, heteroaryl, Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and -C(O)R 35 ; optionally substituted; and
  • R 35 is independently selected from the group consisting of Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C ⁇ -C ⁇ -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • Ci-C 6 -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C ⁇ -C ⁇ -alkenyl and C 2 -C 6 - alkynyl optionally substituted.
  • R 27 and R 29 of the compound are the same substituents and also R 28 and R 30 are the same substituents and X is O.
  • the compound has the structure according to formula (XI) or (XII):
  • R 27 is -OH.
  • R 31 and R 32 are hydrogen.
  • the compound is selected from compounds No. 10 or 11 as listed in table 1 below.
  • a and B is each individually selected from S and O;
  • R 40 and R 41 are each individually selected from the group consisting of halogen, in particular F, Cl, Br or I; -CF 3 , -CN, -SO 3 ' , -NO 2 , -N(R 44 ) 3 + , C,-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -OR 44 and -NR 44 R 45 ;
  • halogen in particular F, Cl, Br or I
  • C,-C 6 -alkyl e.g. methyl, ethyl, propyl, iso- propy
  • R 37 and R 39 are each individually selected from the group consisting of hydrogen, Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -C(O)OR 44 , -OR 44 and -NR 44 R 45 ; optionally substituted;
  • Ci-C 6 -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, -C(O)OR 44 , -OR 44 and -NR 44 R 45 optionally substitute
  • R 36 , R 38 , R 42 and R 43 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R 44 , -C(O)OR 44 , -CF 3 , -CN, -SO 3 " , -NO 2 , -
  • Ci-C ⁇ -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, -OR 44 and -NR 44 R 45 optionally substituted;
  • R 44 and R 45 are independently selected from the group consisting of hydrogen, Ci-C ⁇ -alkyi (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl and -C(O)R 46 ; optionally substituted; and
  • R 46 is independently selected from the group consisting of Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • Ci-C 6 -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl optionally substituted.
  • the R 40 and R 41 of the compound are the same; preferably halogen; most preferably Cl.
  • R 37 and R 39 are the same, preferably -NR 44 R 45 , and most preferably -NH 2 .
  • R 36 and R 38 are the same, preferably -SO 3 " .
  • R 40 and R 41 are the same.
  • the compound is compound No. 12 from table 1 below.
  • X is S and O
  • R 47 through R 49 are each individually selected from the group consisting of hydrogen, Ci-C 6 - alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
  • Ci-C 6 - alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 50 through R 52 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R 53 , -C(O)OR 53 , -CF 3 , -CN, -SO 3 ' , -NO 2 , -N(R 5 V, C 1 - C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
  • R 53 and R 54 are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl and -C(O)R 55 ; optionally substituted; and
  • R 55 is independently selected from the group consisting of Ci-C ⁇ -alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl; optionally substituted.
  • Ci-C ⁇ -alkyl e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • C 2 -C 6 -alkenyl and C 2 -C 6 - alkynyl optionally substituted.
  • the compound has the structure according to formula (XVI):
  • X is S and R 51 is halogen.
  • R 47 and R 48 is -OH.
  • R 51 is halogen and R 49 is -OR 53 in particular -OCH 3 .
  • the compound is compound 13 of table 1 below.
  • Within the ambit of the invention is also a compound having a structure according to formula (XVII):
  • R 56 is C 3 -C 6 -alkyl (e.g. propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 57 and R 58 is each individually an C 2 -C 6 -alkyl (e.g. ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), preferably ethyl; optionally substituted.
  • C 2 -C 6 -alkyl e.g. ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 56 is unbranched and/or that R 56 is propyl; optionally substituted;
  • R 57 has the structure according to formula (XVIII):
  • R 58 has the structure (IXX):
  • R 59 and R 6C are each individually selected from the group consisting of aryl, in particular phenyl, heteroaryl and -OR 61 ; optionally substituted;
  • R 61 is Ci-C ⁇ -alkyl, preferably methyl; optionally substituted;
  • the compound is compound 14 of table 1 below.
  • R 62 , R 63 and R 64 is each individually aryl or heteroaryl; optionally substituted.
  • R 62 and R 63 are mono- or polysubstituted phenyl residues and R 64 is unsubstituted phenyl.
  • R 64 is phenyl; optionally substituted
  • R 65 is in each instance individually selected from the group consisting of halogen, in particular F, Cl, Br or I, -CN and -CF 3 and wherein
  • the compound is compound 15 of table 1 below.
  • these compounds have an EC 50 value of less than 60 ⁇ M for the inhibition of the interaction between a protein according to SEQ ID NO: 1 and a m 7 G cap comprising molecule, preferably measured as outlined below in examples 1 and 2. It is further preferred that a molecule according to the invention shows no inhibition (e.g. EC 50 greater than 200 ⁇ M) of the binding of a m 7 G cap comprising molecule and the nuclear cap binding complex (CBC), preferably as determined using the method described below in the examples.
  • m 7 G cap comprising molecule can be any molecule or also solid phase to which a 7-methylguanosine residue is covalently linked.
  • the molecule is a polynucleotide, then it is preferred that said 7- methylguanosine residue is linked through a 5'-5'-triphosphate bond to the first nucleotide of said polynucleotide.
  • the compounds of the invention described above have an EC50 of less than 60 ⁇ M determined for the inhibition of viral PB2 and a m 7 G cap comprising molecule and furthermore have an EC 50 of greater or equal than 200 ⁇ M determined for the inhibition of the interaction between a m 7 G cap and the nuclear cap binding complex (CBC), preferably human CBC.
  • the EC 50 values are preferably determined as described in the respective examples below.
  • a further aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the compounds according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • the compounds of the invention effectively interfere with binding of viral PB2 protein to mRNA cap which inhibits the replication of viral RNA.
  • the compounds of the invention for medical use.
  • a further aspect of the invention relates to the use of any one of the compounds according to the invention or the pharmaceutical composition according to the invention for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection; preferably a viral infection with a negative-sense ssRNA virus.
  • the virus belongs to a viral family selected from the group consisting of Orthomyxoviridae, Arenaviridae and Bunyaviridae, Bornaviridae, Filoviridae, Paramyxoviridae and Rhabdoviridae family.
  • the virus belongs to a viral family selected from the group consisting of Orthomyxoviridae, Paramyxoviridae and Rhabdoviridae.
  • the vial family is Orthomyxoviridae.
  • said disease condition is caused by a virus selected from the group consisting of Borna disease virus, Marburg virus, Ebola virus, Sendai virus, Mumps virus, Measles virus, Human respiratory syncytial virus, Turkey rhinotracheitis virus, Vesicular stomatitis Indiana virus, Nipah virus, Henda virus, Rabies virus, Bovine ephemeral fever virus, Infectious hematopoietic necrosis virus, Thogoto virus, Influenza A virus, Influenza B virus, Influenza C virus, Hantaan virus, Crimean-congo hemorrhagic fever virus, Rift Valley fever virus, La Crosse virus, Thogoto virus, Isavirus, Lassa virus and Hanta virus.
  • the virus is of the Mononegavirales order.
  • the compounds of the invention having a structure according to (I) to (XXII) and preferred embodiments of these compounds described herein are further characterized in that they are
  • (ii) capable of reducing the binding affinity between the PB2 protein of a negative-sense ssRNA virus such as SEQ ID NO: 1 and the mRNA Cap of a host mRNA. It is further preferred that in (ii) the binding affinity of PB2 to Cap measured in the absence of any of said compounds is reduced to at least 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 0% of the affinity when said compound of the invention is present.
  • a viral PB2 protein interacts with a mRNA Cap.
  • assays as described in the examples below may be used.
  • the PB2 polypeptide or a fragment such as the cap binding domain thereof may be purified and immobilized on beads.
  • the PB2 immobilized on beads may be contacted with Cap, washed and probed with a Cap-specific antibody, available in the state of the art.
  • binding assays well known in the art and suitable to determine binding affinities between two binding partners can be used such as e.g.
  • ELISA-based assays fluorescence resonance energy transfer (FRET)-based assays, co- immunoprecipitation assays and plasmon-resonance assays.
  • the binding can be detected by fluorescence means, e.g. using a fluorescent cap, e.g. fluorescein-labeled 7-methyl-guanosine monophosphate (m 7 GMP) as described by Natarajan et al. (2004), or a ribose diol-modified fluorescent cap analog, anthraniloyl-m 7 GTP as set forth by Ren et al. (1996).
  • radioactive assays may be used that are well known in the art to assess binding.
  • any of the aforementioned exemplary methods can be used to determine if a compound is capable of inhibiting binding affinity between Cap and PB2.
  • the compound is capable of inhibiting virus, preferably Influenza virus, most preferably Influenza virus A, replication.
  • virus replication can be detected using e.g. an in vitro plaque forming assay.
  • a cell line that is susceptible for a negative-sense ssRNA virus infection such as 293T human embryonic kidney cells, Madin-Darby canine kidney cells, or chicken embryo fibroblasts may be infected with the respective virus in presence or absence of the compound.
  • the compound may be added to the culture medium of the cells in various concentrations. Viral plaque formation (i.e.
  • lysis of host cells may be used as a visual read out for the infectious capacity of the virus and may be compared between cells that have been contacted with the test compound and cells that have not been treated. If the compound inhibits virus replication, the plaque formation will be reduced, e.g. the number and/or size of plaques will be reduced.
  • a compound inhibits negative- sense ssRNA virus replication, if it is capable of reducing the number of plaques per unit area by at least 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4-fold or even more and most preferably by at least 2- fold.
  • a compound according to the 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 the group consisting of cocoa butter and vitebesole.
  • Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for i ⁇ jectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. 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. 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, 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, croscaramellose, 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 hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A.TM.) or 1,1,1,2,3, 3,3-heptafluoropropane (HFA)
  • HFA 134A.TM. 1,1,1,2,3, 3,3-heptafluoropropane
  • 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.
  • between 100 mg to 200 mg of the compound is 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 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
  • a 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, between 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. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
  • Table 1 lists the results obtained from the AlphaScreen assay and the CBC assay as described in the examples.
  • the inhibitory activity of exemplary compounds is shown, wherein the half maximal effective concentration (EC 50 ) is indicated in ⁇ M.
  • biotin-GSTHis control refers to the specificity control, which examines unspecific binding inhibition of the GSTHis control to AlphaScreen beads as outlined in example 2.
  • CBC stands for the second specificity control using a nuclear cap-binding protein complex (CBC) as outlined in example 4.
  • CPE Cytopathic effect as is well known in the art of virology.
  • N.D. stands for "not determined”
  • biotinylated Cap-analogue a biotinylated-21-UTP RNA capped with a m 7 G cap as described in Ptushkina, et al., EMBO Journal Vol.18 No.14 pp.4068-4075, 1999 can be used, for example.
  • concentrations of His-PB2 and Biotin-Cap or His-CBC and Biotin-Cap that give maximum signal in the AlphaScreen assay were determined in a checkerboard cross titration. Equal concentrations of 7.5 ⁇ g/ml Acceptor and Donor beads were always used.
  • PB2 refers to the RNA-dependent RNA polymerase subunit PB2 protein of Influenza as also further mentioned in the introduction and description above. Specifically, this assay was carried out using a His-tagged PB2 cap-binding domain protein of a H3N2 strain of Influenza A (SEQ ID NO: 1). However, also any derivative thereof or other polymerase subunit PB2 variants, e.g.
  • Example 2 EC 5 o-determination of small molecule inhibitors using Alphascreen
  • 11-fold l:2-serial dilution of compounds in 20% DMSO starting from 2 mM were prepared from 10 mM stocks in pure DMSO in 384-well storage plates (Greiner, Frickenhausen, Germany) using an EP3 pipetting robot (PerkinElmer). One ⁇ l of this 1Ox intermediate dilution was transferred with the pipetting robot to 384-well ProxiPlates. These assay plates were then sealed with aluminum cover foil and stored at -2O 0 C until usage. After equilibration to RT and centrifugation the assay plates were unsealed and 4.5 ⁇ l of His-PB2/Biotin-Cap analogue mix added.
  • Nuclear cap-binding protein complex which is composed of Cbcl/Cbc2 in yeast and a CBC20/CBC80 heteromer in metazoans, is a RNA-binding protein which binds to the 5' cap inside the nucleus. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. As a specificity control, it was tested, if compounds of the invention would also inhibit the binding of the nuclear cap binding complex (CBC) to a biotinylated Cap analogue. To determine the respective EC 50 values, the assay was carried out as described above.
  • CBC nuclear cap binding complex
  • the Biacore system is based on an optical phenomenon known as surface plasmon resonance (SPR). This technique is the basis for measuring adsorption of material onto planar metal surfaces such as gold or silver.
  • SPR surface plasmon resonance
  • the PB2 cap binding domain (CBD) of an avian H5N1 influenza virus was immobilized on the surface of a CM7 sensor chip by amine coupling according to the manufacturer's protocol.
  • the protein was diluted in a 1OmM phosphate buffer pH 6.5 and as running buffer for immobilization HBS-EP buffer (1 OmM HEPES, 15OmM NaCl, 3mM EDTA, 0,005 % Surfactant p20) was used.
  • HBS-EP buffer 1 OmM HEPES, 15OmM NaCl, 3mM EDTA, 0,005 % Surfactant p20
  • a running buffer containing 1OmM TRIS, 3mM EDTA, 15OmM NaCl, 0.005% Surfactant p20 (GE Healthcare/Biacore), ImM DTT, 0.5 % DMSO was used.
  • Two mM DMSO stock solutions of each compound were diluted in 1.005X sample buffer without DMSO (1.005X TRIS/EDTA/NaCl/p20/DTT; diluted from a 1OX stock) to a final compound concentration of lO ⁇ M and 0.5 % DMSO.
  • m 7 GTP Sigma Aldrich
  • a preferred compound of the invention were used as references and chip stability controls at a concentration of 4 mM and 10 ⁇ M, respectively.
  • Stock solutions of each reference compound were made and aliquots stored at -20°C.
  • Buffer bulk effects were accounted for by reducing the response obtained for the reference flow cell FcI from the active flow cell Fc2 resulting in relative response units (RU), reflecting binding of the compounds to the ligand.
  • Organic solvents such as DMSO in the buffer cause high bulk effects which differ in the reference flow cell and the active flow cell due to ligand immobilization.
  • a calibration curve was established. Eight DMSO concentrations ranging from 0.1 % - 1.5 % in buffer were measured and a linear calibration curve was calculated by plotting Fc2-Fcl vs. FcI. The relative response of each sample was then corrected by the solvent factor given by the respective FcI signal on the calibration curve and the corresponding Fc2-Fcl difference. To account for the different size of the compounds, the buffer and solvent corrected response units were normalized to the molecular weight.
  • Example 5 Antiviral screening - CPE reduction
  • influenza A virus was obtained from American Tissue Culture Collection (A/Aichi/2/68 (H3N2); VR-547). Virus stocks were prepared by propagation of virus on Mardin- Darby canine kidney (MDCK; ATCC CCL-34) cells and infectious titres of virus stocks were determined by the 50 % tissue culture infective dose (TCID50) analysis.
  • MDCK cells were seeded in 96-well plates at 2 ⁇ lOE4 cells/well using DMEM/Ham's F-12 (1:1) medium containing 10 % foetal bovine serum (FBS), 2 mM L-Glutamine and 1 % antibiotics (all from PAA). Until infection the cells were incubated for 5 hrs at 37°C/5.0 % CO2 to form a -80 % confluent monolayer on the bottom of the well. Each test compound was dissolved in DMSO and generally tested at 5 ⁇ M and 50 ⁇ M. In case the compounds were not soluble at that concentration they were tested at the highest soluble concentration. Ribavirin is used as a reference in the assay at a concentration of 12,5 ⁇ M.
  • the compounds were diluted in infection medium (DMEM/Ham's F-12 (1 : 1) containing 5 ⁇ g/ml trypsin, and 1 % antibiotics) for a final plate well DMSO concentration of 1 %.
  • the virus stock was generally diluted in infection medium (DMEM/Ham's F-12 (1 :1) containing 5 ⁇ g/ml Trypsin, 1 % DMSO, and 1 % antibiotics) to a theoretical multiplicity of infection (MOI) of 0,05. In certain cases the infection efficiency was too high and therefore the MOI was reduced to 0,01 to result in a residual cell viability between 5 and 16,8 % as determined during assay qualification.
  • virus and compound were added together to the cells.
  • the virus suspension was replaced by infection medium.
  • Each treatment was conducted in two replicates. After incubation at 37 0 C, 5 % CO 2 for 48 hrs, each well was observed in the microscope for apparent cytotoxicity, precipitate formation, or other notable abnormalities. Then, cell viability was determined using CellTiter-Glo luminescent cell viability assay (Promega). The supernatant was removed carefully and 65 ⁇ l of the reconstituted reagent were added to each well and incubated for 15 min at room temperature gently shaking. Then, 60 ⁇ l of the solution was transferred to an opaque plate and luminescence (RLU) was measured using Synergy HT plate reader (Biotek).
  • CPE cytopathic effect
  • 172 candidate compounds were screened using the Alpha screening assay described above for their ability to inhibit binding of PB2 protein to Cap.
  • a control, biotinylated GSTHis fusion protein was included in the screen to identify unspecific binding inhibition.
  • Effective inhibitory compounds were identified showing a specific inhibitory activity with low EC 5 0 values for binding inhibition of Cap to PB2.
  • Exemplary inhibitory compounds were further characterized using the CBC assay as described above. Compounds that showed effective inhibiting activity and specificity are summarized in Table 1. Additional compounds which are structurally related to the compounds listed in Table 1 can be synthesized and further improved e.g. with respect to their EC 50 values or with respect to their pharmacology. Guidance and methods for optimizing the pharmacology of the molecules can be found, for example, in "Goodman and Gilman's The Pharmacological Basis of Therapeutics", 8 th Edition.
  • Binding (RU) The binding affinities as measured by surface plasmon resonance (cf. example 4 above), between the PB2 cap binding domain (CBD) of H5N1 influenza virus and the respective inhibitory substances are indicated ("Binding (RU)") for exemplary inhibitory compounds that have been analyzed. A larger RU value indicates a stronger binding. Also indicated is the reduction in cytopathic effect (CPE reduction; cf. example 5 above) for several compounds.
  • the initial acid 1 can be prepared using methods of the prior art as e.g. documented in Mityuk, Audrey P.; Volochnyuk, Dmitriy M.; Ryabukhin, Sergey V.; Plaskon, Andrey S.; Shivanyuk, Alexander; Tolmachev, Andrey A. Synthesis, 2009, 11, 1858 - 1864.
  • the carbaldehyde 4 was synthesized from corresponding N-protected 3- and 5-aminopyrazoles 2 and a synthone of triformylmethane 3 (Scheme 1).
  • the isomeric acid 7 was obtained using ethyl acetylpyruvate 6 and a mixture of N-protected 3- and 5-aminopyrazoles 5 with a following hydrolysis (Scheme 2).
  • Preparation of the carbaldehyde 4.
  • 2-dimethylaminomethylene-l,3-bis(dimethylimmonio)propane diperchlorate 3 (36 g) was added to a mixture of 8.6 g MeONa in 400 mL of methanol and stirred for 20 minutes.
  • N- protected aminopyrazole 2 was added and a reaction mixture was refluxed for 12 hours.
  • a precipitate was filtered and washed with a solvent.
  • Combined portions of MeOH solutions were evaporated and a residue was diluted with water.
  • An aqueous solution was extacted with dichloromethane (4X50 mL). The extract was dried over MgSO 4 and evaporated. After. column chromatography H g of the desired carbalde
  • Ethyl acetylpyruvate 6 (17.2 g) and aminopyrazoles 5 (1O g ) were refluxed in 150 mL of AcOH for 6 hours. A solvent was evaporated under reduced pressure and a residue was taken up into 150 mL of CH 2 Cl 2 . A solvent was removed under reduced pressure after drying over sodium sulfate. A concentrated hydrochloric acid (100 mL) was added and a heterogeneous reaction mixture was refluxed for 4 hours. The precipitate was filtered and characterized. It was a desired acid 7 (15 g) with an appropriate purity.
  • amines 9 reductive amination can be used.
  • sodium triacetoxyborohydride (generated in situ) can be used.
  • sodium tris- (trifluoroacetoxy)-borohydride (generated in situ) in the reaction of aldehyde 3 with diphenylamine can be used.
  • the desired compounds 8 were obtained in the same conditions and into the same procedure as amides 6.

Abstract

The present invention relates to novel compounds and pharmaceutical compositions and the use thereof for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection with negative-sense ssRNA viruses.

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF NEGATIVE-SENSE ssRNA VIRUS INFECTIONS
The present invention relates to novel compounds and pharmaceutical compositions and the use thereof for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection with negative-sense ssRNA viruses.
BACKGROUND OF THE INVENTION Influenza and other negative-sense ssRNA virus infections are responsible for much morbidity and mortality in the world. In the case of Influenza, annual epidemics swipe the globe and occasional new virulent strains cause pandemics of great destructive power. At present the primary means of controlling Influenza virus epidemics is vaccination. However, mutant Influenza viruses are rapidly generated which escape the effects of vaccination. In the light of the fact that it takes approximately 6 months to generate a new Influenza or other negative-sense ssRNA virus vaccine, alternative therapeutic means, i.e., antiviral medication, are required especially as the first line of defense against a rapidly spreading pandemic.
An excellent starting point for the development of antiviral medication is structural data of essential viral proteins. Thus, the crystal structure determination of e.g. the Influenza virus surface antigen neuraminidase (von Itzstein et al., 1993) led directly to the development of neuraminidase inhibitors with anti-viral activity preventing the release of virus from the cells, however, not the virus production. These and their derivatives have subsequently developed into the anti-Influenza drugs, zanamivir (Glaxo) and oseltamivir (Roche), which are currently being stockpiled by many countries as a first line of defence against an eventual pandemic. However, these medicaments provide only a reduction in the duration of the clinical disease. Alternatively, other anti-Influenza compounds such as amantadine and rimantadine target an ion channel protein, i.e., the M2 protein, in the viral membrane interfering with the uncoating of the virus inside the cell. However, they have not been extensively used due to their side effects and the rapid development of resistant virus mutants (Magden et al., 2005). In addition, more unspecific viral drugs, such as ribavirin, have been shown to work for treatment of Influenza and other negative-sense ssRNA virus infections (Eriksson et al., 1977). However, ribavirin is only approved in a few countries, probably due to severe side effects (Furuta et al., 2005). Clearly, new antiviral compounds are needed, preferably directed against different targets. Influenza virus as well as Thogotovirus belong to the family of Orthomyxoviridae which, as well as the family of the Bunyaviridae, including the Hantavirus, Nairovirus, Orthobunya- virus, and Phlebovirus, are negative stranded RNA viruses. Their genome is segmented and comes in ribonucleoprotein particles that include the RNA dependent RNA polymerase which carries out (i) the initial copying of the single-stranded virion RNA (vRNA) into viral mRNAs and (ii) the vRNA replication. For the generation of viral mRNA the polymerase makes use of the so called "cap-snatching" mechanism (Plotch et al., 1981; Kukkonen et al., 2005; Leahy et al., 1997; Noah and Krug, 2005). A 5' cap (also termed an RNA cap, RNA 7-methylguanosine cap or an RNA m7G cap) is a modified guanine nucleotide that has been added to the 5' end of a messenger RNA. The 5' cap consists of a terminal 7-methylguanosine residue which is linked through a 5 '-5 '-triphosphate bond to the first transcribed nucleotide. The viral polymerase binds to the 5' RNA cap of cellular mRNA molecules and cleaves the RNA cap together with a stretch of nucleotides. The capped RNA fragments then serve as primers for the synthesis of viral mRNA. The viral polymerase is composed of three subunits: PBl (polymerase basic protein), PB2, and PA. While PBl harbours the endonuclease and polymerase activities, PB2 contains the RNA cap binding domain.
The polymerase complex seems to be an appropriate antiviral drug target since it is essential for synthesis of viral mRNA and viral replication and contains several functional active sites likely to be significantly different from those found in host cell proteins (Magden et al., 2005). Thus, for example, there have been attempts to interfere with the assembly of polymerase subunits by a 25-amino-acid peptide resembling the PA-binding domain within PBl (Ghanem et al., 2007). Furthermore, the endonuclease activity of the polymerase has been targeted and a series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in Influenza viruses (Tomassini et al., 1994). In addition, flutimide, a substituted 2,6-diketopiperazine, identified in extracts of Delitschia confertaspora, a fungal species, has been shown to inhibit the endonuclease of Influenza virus (Tomassini et al., 1996). Moreover, there have been attempts to interfere with viral transcription by nucleoside analogs, such as 2'-deoxy-2'-fluoroguanosine (Tisdale et al., 1995).
To meet the need for additional compounds that can effectively interfere with the replication cycle of negative-sense ssRNA viruses, the inventors have identified and provide new compounds that can interfere with the binding of the RNA binding pocket of viral PB2 to host RNA cap resulting in interference with viral RNA polymerase activity. These compounds are useful for therapy and prevention of viral infection of viruses that use the above outlined cap snatching mechanism for synthesis of viral mRNA. SUMMARY OF THE INVENTION
The present invention provides novel anti-viral compounds against negative-sense ssRNA viruses that use the above outlined cap snatching mechanism for synthesis of viral mRNA. Specifically, the present invention provides in a first aspect a compound having a structure according to formula (I):
Figure imgf000004_0001
(I)
wherein
X is NH, NR9, O or S;
R1 and R2 are each individually selected from the group consisting of Ci-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2, -NHC(O)NHR7, -NHC(O)NR7R8, halogen, -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
R3 through R6 are each individually selected from the group consisting of hydrogen, CpCβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2,
-NHC(O)NHR7, -NHC(O)NR7R8, halogen, -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
R7 and R8 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl and -C(O)R9; optionally substituted; and
R is independently selected from the group consisting of Ci-Cβ-alkyl, C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted.
Also provided is a compound having a structure according to formula (XXI):
Figure imgf000004_0002
or a pharmaceutically effective salt, a solvate, a prodrug, a tautomer, a racemate, an enantiomer or a diastereomer thereof;
wherein
one of Y and Z is -XR12 and the other is R10';
R10, R10 and R10 are each individually selected from the group consisting of hydrogen, Ci-C6- alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)nC(O)OH, -(CHj)nC(O)OR16, -(CH2)nOH,
-(CH2)nOR16, -CF3, -(CH2)n^ycloalkyl, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16,
-(CH2)nC(O)NR16R17, -(CH2)nS(O)2NH2, -(CH2)nS(O)2NHR16, -(CH2)nS(O)2NR16R17,
-(CHz)nS(O)2R16, halogen, -CN, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nNH2, -(CH2)nNHR16, and -(CHz)nNR16R17; optionally substituted;
R11 is selected from the group consisting of hydrogen, Ci.Cδ-alkyl, -CF3, C2-C6-alkenyl, C2-Cg- alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heterocycloalkyl and -(CH2),,- heteroaryl; optionally substituted;
X is selected from the group consisting of CH2, C(O), C(S), CH(OH), CH(OR16), S(O)2, -S(O)2- N(H)-, -S(O)2-N(R16)-, -N(H)-S(O)2-, -N(R16)-S(O)2-, C(=NH), C(=N-R16), CH(NH2),
CH(NHR16), CH(NR16R17), -C(O)-N(H)-, -C(O)-N(R16)-, -N(H)-C(O)-, -N(R16)-C(0)-,
N(H), N(-R16) and O;
R12 is selected from the group consisting of Ci-C6-alkyl, -CF3, C2-C6-alkenyl, C2-C8-alkynyl,
-(CH2)n-cycloalkyl, -(CHOn-heterocycloalkyl, -(CH2)n-aryl, -NR16R17 and -(CH2)n- heteroaryl; optionally substituted;
R16 and R17 are independently selected from the group consisting of Q-Cό-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -CF3, -C(O)R18 and -S(O)2R18; optionally substituted;
R18 is independently selected from the group consisting of Ci-Cό-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, -(CH2)π-cycloalkyl and -CF3; optionally substituted;
and
n is in each instance selected from O, 1 and 2.
The invention further provides a compound having a structure according to formula (X):
Figure imgf000005_0001
wherein X is O or S;
R27 is selected from the group consisting of Ci-Cδ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -
C(O)OR33, -OR33 and -NR33R34; optionally substituted;
R29 is selected from the group consisting of hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, -C(O)OR33, -OR33 and -NR33R34; optionally substituted;
R28 and R30 are each individually selected from the group consisting of hydrogen, halogen,
-C(O)R33, -C(O)OR33, -CF3, -CN, -SO3-, -NO2, -N(R3V, CrC6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, -OR15 and -NR33R34; optionally substituted;
R31 and R32 are each individually selected from the group consisting of hydrogen, halogen,
-C(O)R33, -C(O)OR33, -CF3, -CN, -SO3-, -NO2, -N(R3V, C,-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, -OR33 and -NR33R34; optionally substituted;
R33 and R34 are independently selected from the group consisting of hydrogen, aryl, heteroaryl,
Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R35; optionally substituted; and R35 is independently selected from the group consisting of Ci-Cδ-alkyl, C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted.
Also provided is a compound having a structure according to formula (XIII):
Figure imgf000006_0001
(XIII)
wherein
A and B is each individually selected from S and O;
R40 and R41 are each individually selected from the group consisting of halogen, -CF3, -CN, -
SO3-, -NO2, -N(R44)3 +, C,-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45; R37 and R39 are each individually selected from the group consisting of hydrogen, Q-Cδ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR44, -OR44 and -NR44R45 ; optionally substituted;
R36, R38, R42 and R43 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R44, -C(O)OR44, -CF3, -CN, -SO3-, -NO2, -N(R4V, C,-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45; optionally substituted;
R44 and R45 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl and -C(O)R46; optionally substituted; and R46 is independently selected from the group consisting of Ci-Cδ-alkyl, C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted.
In a further aspect a compound is provided that has a structure according to formula (XV):
Figure imgf000007_0001
(XV)
wherein
X is S and O;
R47 through R49 are each individually selected from the group consisting of hydrogen, Ci-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR53, -OR53 and -NR53R54; optionally substituted;
R50 through R52 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R53, -C(O)OR53, -CF3, -CN, -SO3 ", -NO2, -N(R53)3 +, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OR53 and -NR53R54; optionally substituted;
R53 and R54 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, C2-
C6-alkenyl, C2-C6-alkynyl and -C(O)R55; optionally substituted; and
R55 is independently selected from the group consisting of Ci-Cδ-alkyl, C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted. Also provided is a compound having a structure according to formula (XVII):
Figure imgf000007_0002
(XVII)
wherein
R56 is C3-C6-alkyl; optionally substituted; and
R57 and R58 is each individually an C2-C6-alkyl; optionally substituted.
In a further aspect the invention provides a compound having a structure according to formula (XX):
Figure imgf000008_0001
(XX)
wherein
R62, R63 and R64 is each individually aryl or heteroaryl; optionally substituted.
In a further aspect the invention provides a pharmaceutical composition comprising any one of the compounds according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
Also provided is the compound according to the invention for medical use.
A further aspect of the invention is the use of any one of the compounds according to the invention or the pharmaceutical composition according to the invention for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection with a negative-sense ssRNA virus. DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Throughout this specification and the claims which follow, unless the context requires otherwise, 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. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In the following definitions of the chemical terms: "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "alicyclic system", "aryl", "aralkyl", "heteroaryl", "heteroaralkyl", "alkenyl", "cycloalkenyl", "alkynyl" and "optionally substituted" are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings.
The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl, heptyl, or octyl. Alkyl groups are optionally substituted.
The term "heteroalkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso-propy\, butyl, wo-butyl, sec-butyl, tert-butyl, pentyl or hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. -0-CH3, -S-CH3, -CH2-O-CH3, - CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S- C2H5 etc. Heteroalkyl groups are optionally substituted.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one cyclic ring is present such as in bicyclic, tricyclic and polycyclic versions, then these rings may also comprise one or more aryl- or heteroaryl ring. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, or decahydro-naphthalenyl. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-moφholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond. However, an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs. Thus, the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus, the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system. Alicyclic systems are optionally substituted.
The term "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, naphtyl or anthracenyl. The aryl group is optionally substituted.
The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wø-propyl, butyl, /so-butyl, sec-butenyl, tert-butyl, pentyl or hexyl, pentyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
The term "heteroaryl" preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are 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, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl, 1 ,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl.
The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wø-propyl, butyl, /sø-butyl, sec-butenyl, tert-butyl, pentyl or hexyl, pentyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1 -propenyl, 2-propenyl, wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. The term also comprises CH2, i.e. methenyl, if the substituent is directly bonded via the double bond. Preferably the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl.
The term "alkynyl" refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
The term "optionally substituted" in each instance if not further specified refers to between 1 and 10 substituents, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents which are in each instance preferably independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -NO2, -CN, -OR', -NR'R", -(CO)OR', -(CO)OR'", -(CO)NR5R", -NR'COR"", -NR'COR', -NR"C0NR'R", -NR"SO2A, -COR'"; -SO2NR5R", -OOCR"5, -CR'"R""0H, -R"OH, =0, and -E;
R5 and R' ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -OE, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl; optionally substituted;
R555 and R"55 is each independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR5R";
E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.
The term "RNA cap" or "Cap" refers to a cap structure found on the 5' end of an mRNA molecule and consists of a guanine nucleotide connected to the mRNA via a 5' to 5' triphosphate linkage. The guanosine is methylated on the 7 position. Further modifications include the possible methylation of the 2' hydroxy-groups of the first 3 ribose sugars of the 5' end of the mRNA. "RNA cap analogs" refer to structures that resemble the RNA cap structure. Examples of RNA cap analogs include 7-methyl-guanosine (m7G), 7-methyl-guanosine monophosphate (m7GMP), 7-methyl-guanosine triphosphate (m7GTP), 7-methyl-guanosine linked via a 55 to 55 triphosphate bridge to guanosine (m7GpppG), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to guanosine methylated at the 2' OH position of the ribose (m7GpppGm), 7- methyl-guanosine linked via a 5' to 5' triphosphate bridge to adenosine (m7GpppA), 7-methyl- guanosine linked via a 5' to 5' triphosphate bridge to adenosine methylated at the 25 OH position of the ribose (m7GpppAm), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to cytidine (m7GpppC), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to cytidine methylated at the 2' OH position of the ribose (m7GpppCm), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to uridine (m7GpppU), 7-methyl-guanosine linked via a 5' to 5' triphosphate bridge to uridine methylated at the 2' OH position of the ribose (m7GpppUm). Thus, preferably the cap analog is selected from the group consisting of m7G, m7GMP, m7GTP, m7GpppN, m7GpppNm, where N is a nucleotide, preferably G, A, U, or C. In another preferred embodiment, the RNA cap analogs may comprise additional, e.g., 1 to 15 nucleotides, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the nucleotides are preferably independently selected from the group consisting of A, C, G, U, and/or T. These further nucleotides are, preferably linked via a phosphoester, phophodiester or phosphotrieester bond or a non- hydrolyzable analog thereof to the first nucleotide N in m7GpppN or m7GpppNm.
The term "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. Furthermore, where the compound carries an acidic moiety, 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). Illustrative examples of pharmaceutically acceptable salts 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, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977)).
As used throughout the specification, the term "a compound according to the invention" refers to a compound according to any of formulas I through XX including all preferred respective embodiments of such a compound and physiological acceptable salts thereof. As used herein, the terms "drug" and pharmaceutically active compound(s) are used interchangeably.
The present invention provides novel anti-viral compounds effective against negative- sense ssRNA viruses that use a cap snatching mechanism for synthesis of viral mRNA. In a first aspect the invention provides a compound having a structure according to formula (I)
Figure imgf000014_0001
(I)
wherein
X is NH, NR9, O or S; preferably O or S;
R1 and R2 are each individually selected from the group consisting of Ci-Cβ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-
Cβ-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2, -NHC(O)NHR7, -
NHC(O)NR7R8, halogen, in particular F, Cl, Br or I; -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
and preferably R1 and R2 are Ci-C6-alkyl (preferably Ci, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-Cβ-alkenyl
(preferably Ci, C2, C3, C4, C5 or C6- alkenyl), C2-C6-alkynyl (preferably Cj, C2, C3, C4, C5 or Ce-alkynyl), halogen (in particular F, Cl, Br or I), -C(O)OR7, -OR7 and -NR7R8; optionally substituted; most preferably -OR7; optionally substituted;
R3 through R6 are each individually selected from the group consisting of hydrogen, Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6- alkenyl, C2-C6-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2,
-NHC(O)NHR7, -NHC(O)NR7R8, halogen, in particular F, Cl, Br or I; -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
and preferably R3 through R6 are each individually selected from the group consisting of hydrogen, Ci-Cδ-alkyl (preferably Ci, C2, C3, C4, C5 or Cβ-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C∑-Q-alkenyl (preferably Ci, C2, C3, C4, C5 or C6- alkenyl), C2-C6-alkynyl (preferably Ci, C2, C3, C4, C5 or C6-alkynyl), halogen (in particular F, Cl, Br or I), -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
R7 and R8 are independently selected from the group consisting of hydrogen, Ci-Cδ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6- alkenyl, C2-C6-alkynyl and -C(O)R9; optionally substituted;
preferably, R7 and R8 are independently selected from the group consisting of hydrogen, CpC6- alkyl (preferably Ci, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-C6-alkenyl (preferably Ci, C2, C3, C4, C5 or C6- alkenyl), C2-C6-alkynyl (preferably d, C2, C3, C4, C5 or C6-alkynyl) and -C(O)R9; optionally substituted;
and
R9 is independently selected from the group consisting of Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl and C2-C6-alkynyl; optionally substituted; and preferably R9 is independently selected from the group consisting of Ci-C6-alkyl (preferably Ci, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-C6-alkenyl (preferably Ci, C2, C3, C4, C5 or C6- alkenyl) and C2-C6-alkynyl (preferably C, C2, C3, C4, C5 or C6- alkynyl); optionally substituted.
In a preferred embodiment of the first aspect of the invention and the above-outlined preferred embodiment thereof, the compound has the structure (II), (III) or (IV):
Figure imgf000015_0001
Figure imgf000016_0001
Further preferred are the above outlined compounds (I)-(IV) of the invention, wherein X is O and wherein R1 and R2 are -OR7, and, more preferably, wherein R1 and R2 are -OH.
In another preferred embodiment, X is O, and R1 and R2 are each selected from the group consisting of -OH and -OCrC3-alkyl, i.e. -OCH3, -OCH2CH3, -OCH2CH2CH3 and -O- isopropyl.
In a further preferred embodiment of compounds (I)-(IV) above, R1 and R2 are -OH and R3, R4 and R5 are -OR7.
In a particularly preferred embodiment, the compound of the first aspect of the invention is selected from the group consisting of compounds No. 6-9 of table 1.
In a second aspect the invention provides a compound having a structure according to formula (XXI):
Figure imgf000016_0002
Z
(XXI)
or a pharmaceutically effective salt, a solvate, a prodrug, a tautomer, a racemate, an enantiomer or a diastereomer thereof;
wherein
one of Y and Z is -XR12 and the other is R10';
R10, R10 and R10 are each individually selected from the group consisting of hydrogen, Ci-C6- alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH, -(CH2)nOR16, -CF3, -(CH2)n-cycloalkyl, -(CH2)πC(O)NH2, -(CHz)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2NH2, -(CH2)nS(O)2NHR16, -(CH2)nS(O)2NR16R17, -(CH2)nS(O)2R16, halogen (in particular F, Cl, Br or I), -CN, -(CH2)n-aryl, -(CH2V- heteroaryl, -(CH2)nNH2, -(CH2)nNHR16, and -(CH2)nNRl6R17; optionally substituted; R11 is selected from the group consisting of hydrogen, Ci.C6-alkyl, -CF3, C2-C6-alkenyl, C2-C8- alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heterocycloalkyl (preferably heterocycloalkyl), and -(CH2)n-heteroaryl; optionally substituted; R1 1 is most preferably selected hydrogen, aryl and Ci-Cδ-alkyl; optionally substituted;
X is selected from the group consisting of -CH2-, -C(O)-, -C(S)-, CH(OH), CH(OR16), S(O)2, -S(O)2-N(H)-, -S(O)2-N(R16)-, -N(H)-S(O)2-, -N(R16)-S(O)2-, C(=NH), C(=N-R16), CH(NH2), CH(NHR16), CH(NR16R17), -C(O)-N(H)-, -C(O)-N(R16)-, -N(H)-C(O)-,
-N(R16)-C(0)-, N(H), N(-R16) and O; preferably X is selected from the group consisting of CH2, -C(O)-, -C(S)-, -C(O)-N(H)- and -N(H)-C(O)-; most preferably X is selected from the group consisting of -C(O)-, -C(O)-N(H)- and -N(H)-C(O)-;
R12 is selected from the group consisting of Ci-Cβ-alkyl, -CF3, C2-Ce-alkenyl, C2-C8-alkynyl, -(CH2)n-cycloalkyl, -(CH^n-heterocycloalkyl, -(CH2)n-aryl (e.g. -(CH2)n-phenyl),
-NR16R17 and -(CH2)n-heteroaryl; optionally substituted; preferably R12 is selected from the group consisting of -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl (e.g. piperidinyl, imidazolidinyl, pyrrolidinyl or pyrazolidinyl), -(CH2)n-aryl (e.g. -(CH2)n-phenyl),
-NR16R17 and -(CH2)n-heteroaryl; optionally substituted; most preferably R12 is selected from the group consisting of -(CH2)n-heterocycloalkyl, -(CH2)n-aryl (e.g. -(CH2)n- phenyl), -NR16R17 and -(CH2)n-heteroaryl; optionally substituted;
R16 and R17 are independently selected from the group consisting of C|-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -CF3, -C(O)R18 and -S(O)2R18; optionally substituted;
R18 is independently selected from the group consisting of Ci-Cό-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, -(CH2)n-cycloalkyl and -CF3; optionally substituted;
and
n is in each instance selected from O, 1 and 2.
In a preferred embodiment of the compound according to formula (XXI) as outlined above, the compound has a structure according to formula (V) or (XXII):
Figure imgf000018_0001
(V) (XXII) wherein R10 is preferably hydrogen.
Also preferred is a compound having a structure according to formula (V) as shown above, or a pharmaceutically effective salt, a solvate, a prodrug, a tautomer, a racemate, an enantiomer or a diastereomer thereof; wherein
R10, R10 and R10 are each individually selected from the group consisting of hydrogen, Ci-C6- alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)nC(O)OH, -(CHz)nC(O)OR16, -(CH2)nOH,
-(CH2)nOR16, -CF3, -(CH2)π-cycloalkyl, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2NH2, -(CH2)nS(O)2NHR16, -(CH2)nS(O)2NR16R17,
-(CH2)nS(O)2R16, halogen (in particular F, Cl, Br or I), -CN, -(CH2)n-aryl, -(CH2),,- heteroaryl, -(CH2)nNH2, -(CH2)nNHR16, and -(CH2)nNR16R17; optionally substituted;
R11 is selected from the group consisting of hydrogen, Ci.Cδ-alkyl, -CF3, C2-C6-alkenyl, C2-C8- alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; optionally substituted; X is selected from the group consisting of CH2, C(O), C(S), CH(OH), CH(OR16), S(O)2, -S(O)2- N(H)-, -S(O)2-N(R16)-, -N(H)-S(O)2-, -N(R16)-S(O)2-, C(=NH), C(=N-R16), CH(NH2), CH(NHR16), CH(NR16R17), -C(O)-N(H)-, -C(O)-N(R16)-, -N(H)-C(O)-, -N(R16)-C(0>, N(H), N(-R16) and O;
R12 is selected from the group consisting of Cj-Cό-alkyl, -CF3, C2-C6-alkenyl, C2-C8-alkynyl, - (CH2)n-cycloalkyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; optionally substituted;
R16 and R17 are independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, -(CH2)n-cycloalkyl, -CF3, -C(O)R18 and -S(O)2R18; optionally substituted; R18 is independently selected from the group consisting of Ct-Cό-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, -(CH2)n-cycloalkyl and -CF3; optionally substituted;
and
n is in each instance selected from O, 1 and 2.
In a preferred embodiment of the compound according to formulas (V), (XXI) and (XXII) as outlined above
R10 is selected from the group consisting of hydrogen, Ci-C6-alkyl (preferably Cj, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-C6-alkenyl (preferably Ci, C2, C3, C4, C5 or C6- alkenyl), C2-Cfi-alkynyl (preferably Ci, C2, C3, C4, C5 or C6-alkynyl) -(CH2)n-cycloalkyl, -O-Ci-C6-alkyl, - (CH2)nNH2, -(CHz)nNHR16, -(CH2)nNRI6R17, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16, - (CH2)nC(O)NR16R17, -(CH2)n-aryl, (CH2)n-heteroaryl, -(CH2)nOH, and -CF3; optionally substituted; preferably Ci-Cή-alkyl (preferably Ci, C2, C3, C4, C5 or Cδ-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-C6-alkenyl (preferably d, C2, C3, C4, C5 or C6- alkenyl), aryl, -OH;
R10 is selected from the group consisting of hydrogen, Ci-Cό-alkyl (preferably Ci, C2, C3, C4, C5 or Cό-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), C2-C6-alkenyl (preferably C,, C2, C3, C4, C5 or C6- alkenyl), C2-C6-alkynyl
(preferably Ci, C2, C3, C4, C5 or C6-alkynyl), -(CH2)n-cycloalkyl, -CF3, -<CH2)n-aryl, and -(CH2)n-heteroaryl; optionally substituted; preferably R10 is hydrogen; and
R10 is selected from the group consisting of hydrogen, Ci-Cέ-alkyl (preferably Ci, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), -CF3, -(CHz)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH, -(CHs)nOR16,
-(CH2)nNH2, -(CH2)nNHR16, -(CH2)nNR16R17, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16,
-(CHz)nC(O)NR16R17, -(CHz)nS(O)2NR16R17, and -(CH2)nS(O)2R16, optionally substituted; preferably H, -CF3 or C,-C6-alkyl (preferably C,, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
Preferably, R10' and/or R10" is hydrogen.
In a further preferred embodiment, X is CH2, C(O), C(S), -N(-R16)-C(0)- or -C(0)-N(- R16)- and in a more preferred embodiment X is C(O) or C(S). In another preferred embodiment of the compound of the invention, X is selected from CH2, C(O), CH(OH), -S(O)2-N(H)-, - N(H)S(O)2-, -C(O)-N(H)-, -N(H)-C(O)-, N(H), and O.
It is also preferred that in preferred embodiments of the compound, R11 is hydrogen. In particularly preferred embodiments, R10 , R10 and R1 1 are hydrogen. In the above outlined compounds R10 is preferably selected from -OH, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, phenyl, hydroxymethyl, 2-hydroxyethyl, methoxy, -C(O)NH2, - C(O)NHCH3, -C(O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2NHC(O)CH3, and -
CF3; most preferably from -OH, methyl, ethyl. In a more preferred embodiment, R10 is selected from ethyl, isopropyl, cyclopropyl, hydroxymethyl, 2-hydroxyethyl, methoxy, and -CF3
Alternatively, in another preferred embodiment, R10 is selected from the group consisting of
-C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2NHC(O)CH3, and -CF3. Also preferred are compounds of the invention, wherein R10 is hydrogen and R10 is selected from the group consisting of Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, (CHz)n- cycloalkyl, -CF3, -(CH2)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH, -(CH2)nOR16, -(CH2)nNH2, -(CH2)nNHR16, -(CH2)nNR16R17, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2R16, -(CHz)nS(O)2NH2, -(CH2)nS(O)2NHR16, -(CH2)nS(O)2NR16R17, halogen (in particular F, Cl, Br or I), -CN, (CH2)n-aryl, and (CH2)n-heteroaryl; optionally substituted. In these compounds, R10 is more preferably selected from the group consisting of -CF3, - (CH2)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH, -(CH2)nOR16, -(CH2)nNH2, -(CH2)nNHR16, - (CH2)nNR16R17, -(CH2)nC(O)NH2, -(CHz)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2NH2, -(CHz)nS(O)2NHR16 and -(CHz)nS(O)2NR16R17.
In a different preferred embodiment of the compound, R10 is hydrogen and R10 is selected from the group consisting of Ci-C6-alkyl, Cz-Cβ-alkenyl, Cz-Cg-alkynyl, (CH2)n-cycloalkyl, -CF3, -(CHz)nC(O)OH, -(CHz)nC(O)OR16, -(CHz)nNHC(O)R18, -(CHz)nNR16C(O)R18,
-(CH2)nNHS(O)2R18, -(CHz)nNR16S(O)2R18, -(CHz)nC(O)NH2, -(CH2)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CHz)nS(O)2NH2, -(CHz)nS(O)2NHR16, -(CHz)nS(O)2NR16R17, halogen (in particular F, Cl, Br or I), -CN, (CH2)n-aryl, and (CH2)n-heteroaryl; optionally substituted. In these compounds, R10 is more selected from the group consisting of Ci-Cό-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)n-cycloalkyl, -CF3, (CH2)n-aryl, and (CH2)n-heteroaryl; optionally substituted.
In one embodiment of the compound according to formulas (V), XXI) and (XXII), R12 is preferably selected from the group consisting of -(CH2)n-aryl, -(CH2)n-heterocycloalkyl (preferably heterocycloalkyl), -NR16R17 and -(CH2)n-heteroaryl; optionally substituted; and more preferably R12 is selected from the group consisting of -(CH2)n-aryl, -(CH2)n-heterocycloalkyl and -(CH2)n-heteroaryl; optionally substituted; and most preferably selected from aryl, heteroaryl and heterocycloalkyl.
In one preferred embodiment, R12 is selected from phenyl, naphthyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1 ,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and purinyl; optionally substituted. Most preferably, R12 is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl and benzimidazolyl; optionally substituted.
In another embodiment, R12 is selected from the group consisting of:
Figure imgf000021_0001
and alkyl;
wherein each R12 substituent may be optionally substituted; and
wherein * indicates where the respective R12 substituent is bound to X. In this context it is preferred that X is -C(O)-, -C(S)-, -NHC(O)- or -C(O)NH-. Most preferably, in all above outlined embodiments of the compounds according to formulas (V), (XXI) and (XXII) as outlined above, R12 is substituted with a substituent selected from the group consisting of:
hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH∑V-cycloalkyl, halogen (in particular F, Cl, Br or I), -OH, -OR12', -C(O)NHR12', -R12 C(O)NH2, -NHC(O)R12', -NR16R17, -(CH2V- heterocycloalkyl, -(CH2)m-aryl, -(CH2)m-heteroaryl, -CF3, =0, -C(O)NR16R17, -C(O)OR16,
Figure imgf000022_0001
and
wherein R12 is C|-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl;
wherein m is in each instance selected from O, 1 and 2 and is most preferably O; and
wherein the substituent may optionally be substituted as defined herein on p. 1 1.
In a further preferred embodiment the compound has a structure according to formula (VI) or (VIb):
Figure imgf000022_0002
(VI) (VIb)
wherein
X is C(O) or C(S);
A is O or S;
R10 and R15 are each individually selected from the group consisting of Ci-Cό-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, -CF3, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted; and
R10 , R10 ", R13 and R14 are each individually selected from the group consisting of hydrogen, C1-
Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, heteroaryl, -(CH2)n-heterocycloalkyl
(preferably heterocycloalkyl), -CF3, -COOH, -CN, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted.
In a more preferred embodiment of the compound of the invention, wherein the compound has a structure according to formula (VI), wherein
X is C(O) or C(S); R10 and R15 are each individually selected from the group consisting of Ci-Cβ-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, -CF3, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted; and
R10 , R10 , R13 and R14 are each individually selected from the group consisting of hydrogen, Ci- Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, -CF3, -COOH, -CN, -C(O)OR16, -OH, -
OR16, -NHR16, -NH2 and -NR16R17; optionally substituted.
Also preferred is a compound according to formula (IVb) as shown above, wherein A is O or S;
R10 and R15 are each individually selected from the group consisting of Ci-Cό-alkyl, C2-C6- alkenyl, Cz-Ce-alkynyl, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted; most preferably, R15 is -OH;
R10 , R10 , R13 and R14 are each individually selected from the group consisting of hydrogen, Q-
Cδ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, -CF3, -COOH, -CN, -C(O)OR16, -OH, -
OR16, -NHR16, -NH2 and -NR16R17; optionally substituted;
R16 and R17 are independently selected from the group consisting of Ci-Cδ-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl and -C(O)R , 18 °; optionally substituted; and
R » 18 is independently selected from the group consisting of Ci-Cβ-alkyl, C2-Cδ-alkenyl and C2-C6- alkynyl; optionally substituted.
In the above outlined embodiments of the second aspect of the invention, R10 and R10 are preferably hydrogen or R10', R10", R13 and R14 are hydrogen. Most preferably, R10>, R10", R13 and R14 are hydrogen and X is -C(O)-.
In a further preferred embodiment, the compound has the structure (VIIA), (VIIB) or (VIIC):
Figure imgf000023_0001
(VIIA) (VIIB)
Figure imgf000023_0002
and preferably wherein
R10 and R15 are each individually selected from the group consisting of Ci-Cβ-alkyl, C2-CO- alkenyl, C2-C6-alkynyl, -CF3, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted; and
R13 and R14 are each individually selected from the group consisting of hydrogen, Ci-Cβ-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, halogen, -CF3, -COOH, -CN, -C(O)OR16, -OH, heteroaryl,
-(CH2)n-heterocycloalkyl (preferably heterocycloalkyl), -OR16, -NHR16, -NH2 and -
NR16R17; optionally substituted.
In a further preferred embodiment, the compound has the structure according to formula (VIII):
Figure imgf000024_0001
(VIII),
wherein X is -C(O)- or -C(S)- and most preferably wherein X is -C(O)-.
In the compounds according to formulas (V) through (VIII), (XXI) and (XXII) as outlined above the following preferred embodiments are also within the ambit of the invention: In one embodiment, R15 of the compound is -OH. In another preferred embodiment, R15 is -OH and R10 is -OH or Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl). Also preferred is a compound having a structure according to (VIII), wherein R13 and R14 is the same substituent, preferably halogen, e.g. F, I, Cl or Br. In another embodiment of the structures (XXI), (XXII), (V), (VI), (VIIA), (VIIB) (VIIC) and (VIII) as outlined above, R10 is methyl or ethyl. In another preferred embodiment, R13 and R14 is hydrogen. In a particularly preferred embodiment, the compound is selected from compounds No. 1-5 as listed in table 1 and from the compounds as listed in Tables 2A-J below. Also the following compound effectively inhibits the interaction between a Cap analogue and viral PB2 with an EC50 of 22.3 μM:
Figure imgf000024_0002
Thus, also this compound is a preferred embodiment of the compound of the invention. In another preferred embodiment the compound has the following structure:
Figure imgf000025_0001
wherein R65 is selected from the group consisting of -OH or Ci-Cβ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), -(CH2)m-cycloalkyl, halogen,
-OH, -OR12', -C(O)NHR12', -R12'C(O)NH2, -NHC(O)R12', -NR16R17, -(CH2)m-heterocycloalkyl,
-(CH2)m-aryl, -(CH2)m-heteroaryl, -CF3, -C(O)NR16R17 and -C(O)OR16;
wherein R12 is Ci-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl;
wherein m is in each instance selected from O, 1 and 2 and is most preferably O.
In a further aspect the invention related to a compound having a structure according to formula (X):
Figure imgf000025_0002
(X)
wherein
X is O or S;
R27 is selected from the group consisting of Ci-Cβ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR33,
-OR33 and -NR33R34; optionally substituted;
R29 is selected from the group consisting of hydrogen, Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-C6-alkynyl,
-C(O)OR33, -OR33 and -NR33R34; optionally substituted;
R28 and R30 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R33, -C(O)OR33, -CF3, -CN, -SO3 ", -NO2, -N(R33)3 +, CrC6- alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
C2-C6-alkenyl, C2-C6-alkynyl, -OR15 and -NR33R34; optionally substituted;
R31 and R32 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R33, -C(O)OR33, -CF3, -CN, -S03\ -NO2, -N(R33)3 +, C1-C6- alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
C2-C6-alkenyl, C2-C6-alkynyl, -OR33 and -NR33R34; optionally substituted; R33 and R34 are independently selected from the group consisting of hydrogen, aryl, heteroaryl, Ci-Cό-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R35; optionally substituted; and
R35 is independently selected from the group consisting of Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C∑-Cβ-alkenyl and C2-C6- alkynyl; optionally substituted.
In a further preferred embodiment, R27 and R29 of the compound are the same substituents and also R28 and R30 are the same substituents and X is O.
Preferably, the compound has the structure according to formula (XI) or (XII):
Figure imgf000026_0001
(XII).
In a preferred embodiment of compounds (XII) and (X), R27 is -OH. In another preferred embodiment of the compound (X), (XI) and (XII) of the invention, R31 and R32 are hydrogen. In a particularly preferred embodiment, the compound is selected from compounds No. 10 or 11 as listed in table 1 below.
In a further aspect the invention provides a compound having a structure according to formula (XIII):
Figure imgf000026_0002
wherein A and B is each individually selected from S and O;
R40 and R41 are each individually selected from the group consisting of halogen, in particular F, Cl, Br or I; -CF3, -CN, -SO3 ', -NO2, -N(R44)3 +, C,-C6-alkyl (e.g. methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45;
R37 and R39 are each individually selected from the group consisting of hydrogen, Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6- alkenyl, C2-C6-alkynyl, -C(O)OR44, -OR44 and -NR44R45; optionally substituted;
R36, R38, R42 and R43 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R44, -C(O)OR44, -CF3, -CN, -SO3 ", -NO2, -
N(R44)3 +, Ci-Cβ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45; optionally substituted;
R44 and R45 are independently selected from the group consisting of hydrogen, Ci-Cδ-alkyi (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6- alkenyl, C2-C6-alkynyl and -C(O)R46; optionally substituted; and
R46 is independently selected from the group consisting of Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted.
It is preferred that the compound has the structure (XIV):
Figure imgf000027_0001
In a further preferred embodiment, the R40 and R41 of the compound are the same; preferably halogen; most preferably Cl. In a further preferred embodiment, R37 and R39 are the same, preferably -NR44R45, and most preferably -NH2. In another preferred embodiment, R36 and R38 are the same, preferably -SO3 ". In another preferred embodiment, R40 and R41 are the same. In a particularly preferred embodiment, the compound is compound No. 12 from table 1 below.
Also provided is a compound having a structure according to formula (XV):
Figure imgf000028_0001
(XV)
wherein
X is S and O;
R47 through R49 are each individually selected from the group consisting of hydrogen, Ci-C6- alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR53, -OR53 and -NR53R54; optionally substituted;
R50 through R52 are each individually selected from the group consisting of hydrogen, halogen, in particular F, Cl, Br or I; -C(O)R53, -C(O)OR53, -CF3, -CN, -SO3 ', -NO2, -N(R5V, C1- Cδ-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl);
C2-C6-alkenyl, C2-C6-alkynyl, -OR53 and -NR53R54; optionally substituted;
R53 and R54 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6- alkenyl, C2-C6-alkynyl and -C(O)R55; optionally substituted; and
R55 is independently selected from the group consisting of Ci-Cό-alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); C2-C6-alkenyl and C2-C6- alkynyl; optionally substituted.
In a preferred embodiment, the compound has the structure according to formula (XVI):
Figure imgf000028_0002
(XVI).
In a further preferred embodiment of the above-outlined compounds (XV) and (XVI), X is S and R51 is halogen. In a further preferred embodiment of the compound, R47 and R48 is -OH. In a further preferred embodiment, R51 is halogen and R49 is -OR53 in particular -OCH3. In a particularly preferred embodiment, the compound is compound 13 of table 1 below. Within the ambit of the invention is also a compound having a structure according to formula (XVII):
Figure imgf000029_0001
(XVII)
wherein
R56 is C3-C6-alkyl (e.g. propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
R57 and R58 is each individually an C2-C6-alkyl (e.g. ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), preferably ethyl; optionally substituted.
It is preferred that R56 is unbranched and/or that R56 is propyl; optionally substituted;
Also preferred is a compound as outlined above, wherein R57 has the structure according to formula (XVIII):
Figure imgf000029_0002
(XVIII)
and/or R58 has the structure (IXX):
Figure imgf000029_0003
(IXX)
wherein R59 and R6C are each individually selected from the group consisting of aryl, in particular phenyl, heteroaryl and -OR61; optionally substituted;
R61 is Ci-Cδ-alkyl, preferably methyl; optionally substituted; and
* indicates where the structures according to formulas (XVIII) and (IXX), respectively, are bound to the structure (XVII).
In a particularly preferred embodiment, the compound is compound 14 of table 1 below.
In a further aspect the invention provides a compound having a structure according to formula (XX):
Figure imgf000030_0001
(XX)
wherein
R62, R63 and R64 is each individually aryl or heteroaryl; optionally substituted.
Preferably, R62 and R63 are mono- or polysubstituted phenyl residues and R64 is unsubstituted phenyl.
Also preferred is a compound having a structure according to formula (XX), wherein
Figure imgf000030_0002
R65 R65
R63 is
Figure imgf000030_0003
R64 is phenyl; optionally substituted;
and wherein
R65 is in each instance individually selected from the group consisting of halogen, in particular F, Cl, Br or I, -CN and -CF3 and wherein
* indicates where the structures are bound to the structure according to formula (XX).
In a particularly preferred embodiment, the compound is compound 15 of table 1 below.
In further preferred embodiments of the compounds of the invention as outlined above, these compounds have an EC50 value of less than 60 μM for the inhibition of the interaction between a protein according to SEQ ID NO: 1 and a m7G cap comprising molecule, preferably measured as outlined below in examples 1 and 2. It is further preferred that a molecule according to the invention shows no inhibition (e.g. EC50 greater than 200 μM) of the binding of a m7G cap comprising molecule and the nuclear cap binding complex (CBC), preferably as determined using the method described below in the examples. As used herein "m7G cap comprising molecule" can be any molecule or also solid phase to which a 7-methylguanosine residue is covalently linked. If the molecule is a polynucleotide, then it is preferred that said 7- methylguanosine residue is linked through a 5'-5'-triphosphate bond to the first nucleotide of said polynucleotide. In a particularly preferred embodiment the compounds of the invention described above have an EC50 of less than 60 μM determined for the inhibition of viral PB2 and a m7G cap comprising molecule and furthermore have an EC50 of greater or equal than 200 μM determined for the inhibition of the interaction between a m7G cap and the nuclear cap binding complex (CBC), preferably human CBC. Also for this embodiment, the EC50 values are preferably determined as described in the respective examples below.
A further aspect relates to a pharmaceutical composition comprising any one of the compounds according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
The compounds of the invention effectively interfere with binding of viral PB2 protein to mRNA cap which inhibits the replication of viral RNA. Thus, also provided are the compounds of the invention for medical use.
A further aspect of the invention relates to the use of any one of the compounds according to the invention or the pharmaceutical composition according to the invention for the manufacture of a medicament for treating, ameliorating, or preventing disease conditions caused by a viral infection; preferably a viral infection with a negative-sense ssRNA virus.
In a preferred embodiment of the use the virus belongs to a viral family selected from the group consisting of Orthomyxoviridae, Arenaviridae and Bunyaviridae, Bornaviridae, Filoviridae, Paramyxoviridae and Rhabdoviridae family. In a more preferred embodiment of the use according to the invention the virus belongs to a viral family selected from the group consisting of Orthomyxoviridae, Paramyxoviridae and Rhabdoviridae. In a most preferred embodiment of the use the vial family is Orthomyxoviridae. In a further preferred embodiment of the use, said disease condition is caused by a virus selected from the group consisting of Borna disease virus, Marburg virus, Ebola virus, Sendai virus, Mumps virus, Measles virus, Human respiratory syncytial virus, Turkey rhinotracheitis virus, Vesicular stomatitis Indiana virus, Nipah virus, Henda virus, Rabies virus, Bovine ephemeral fever virus, Infectious hematopoietic necrosis virus, Thogoto virus, Influenza A virus, Influenza B virus, Influenza C virus, Hantaan virus, Crimean-congo hemorrhagic fever virus, Rift Valley fever virus, La Crosse virus, Thogoto virus, Isavirus, Lassa virus and Hanta virus. Preferably, the virus is of the Mononegavirales order.
In preferred embodiments, the compounds of the invention having a structure according to (I) to (XXII) and preferred embodiments of these compounds described herein are further characterized in that they are
(i) capable of interfering with viral replication in a host of negative-sense ssRNA viruses that employ a cap snatching mechanism for synthesis of their viral mRNA; and/or
(ii) capable of reducing the binding affinity between the PB2 protein of a negative-sense ssRNA virus such as SEQ ID NO: 1 and the mRNA Cap of a host mRNA. It is further preferred that in (ii) the binding affinity of PB2 to Cap measured in the absence of any of said compounds is reduced to at least 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 0% of the affinity when said compound of the invention is present.
It is within the skill of the artisan to experimentally determine, if a viral PB2 protein interacts with a mRNA Cap. For example, assays as described in the examples below may be used. Alternatively, it is possible to analyze the interaction between the PB2 polypeptide and Cap using a pull down assay. For example, the PB2 polypeptide or a fragment such as the cap binding domain thereof may be purified and immobilized on beads. In one embodiment, the PB2 immobilized on beads may be contacted with Cap, washed and probed with a Cap-specific antibody, available in the state of the art. Also other binding assays well known in the art and suitable to determine binding affinities between two binding partners can be used such as e.g. ELISA-based assays, fluorescence resonance energy transfer (FRET)-based assays, co- immunoprecipitation assays and plasmon-resonance assays. The binding can be detected by fluorescence means, e.g. using a fluorescent cap, e.g. fluorescein-labeled 7-methyl-guanosine monophosphate (m7GMP) as described by Natarajan et al. (2004), or a ribose diol-modified fluorescent cap analog, anthraniloyl-m7GTP as set forth by Ren et al. (1996). Also radioactive assays may be used that are well known in the art to assess binding. Thus, any of the aforementioned exemplary methods can be used to determine if a compound is capable of inhibiting binding affinity between Cap and PB2.
As mentioned above under (i), it is preferred that the compound is capable of inhibiting virus, preferably Influenza virus, most preferably Influenza virus A, replication. Virus replication can be detected using e.g. an in vitro plaque forming assay. For example, a cell line that is susceptible for a negative-sense ssRNA virus infection such as 293T human embryonic kidney cells, Madin-Darby canine kidney cells, or chicken embryo fibroblasts may be infected with the respective virus in presence or absence of the compound. The compound may be added to the culture medium of the cells in various concentrations. Viral plaque formation (i.e. lysis of host cells) may be used as a visual read out for the infectious capacity of the virus and may be compared between cells that have been contacted with the test compound and cells that have not been treated. If the compound inhibits virus replication, the plaque formation will be reduced, e.g. the number and/or size of plaques will be reduced. Preferably, a compound inhibits negative- sense ssRNA virus replication, if it is capable of reducing the number of plaques per unit area by at least 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4-fold or even more and most preferably by at least 2- fold.
For treating, ameliorating, or preventing disease conditions caused by a viral infection with a negative-sense ssRNA virus, a compound according to the 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.
Thus, preferably, 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. Preferably the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for iηjectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid. Typically, such 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. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
Production of 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;
b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates,
c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
In one embodiment 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.
If a compound of the invention is administered intranasaly in a preferred embodiment, it 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 hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A.TM.) or 1,1,1, 2,3, 3,3-heptafluoropropane (HFA
227EA.TM), carbon dioxide, or another suitable gas. 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.
Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.
It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that 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. However, in a preferred use of the present invention 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. In one preferred embodiment of a prophylactic or therapeutic use, between 100 mg to 200 mg of the compound is orally administered to an adult per day, depending on the severity of the disease and/or the degree of exposure to disease carriers.
As is known in the art, 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. Typically, a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
If a person is known to be at risk of developing a disease treatable with a compound of the invention, a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. In these cases the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 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. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.
The following figures and examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
BRIEF DESCRIPTION OF THE FIGURES Table 1 Table 1 lists the results obtained from the AlphaScreen assay and the CBC assay as described in the examples. The inhibitory activity of exemplary compounds is shown, wherein the half maximal effective concentration (EC50) is indicated in μM. "biotin-GSTHis control" refers to the specificity control, which examines unspecific binding inhibition of the GSTHis control to AlphaScreen beads as outlined in example 2.
"CBC" stands for the second specificity control using a nuclear cap-binding protein complex (CBC) as outlined in example 4.
"N. D." stands for "not determined" and "No." for the compound number. Table 2 Table 2A-J lists results obtained for inhibitory compounds of the invention.
CPE stands for "cytopathic effect" as is well known in the art of virology. "N.D." stands for "not determined"
EXAMPLES
Example 1: AlphaScreen assay
All AlphaScreen experiments were performed in white 384- well ProxiPlates (PerkinElmer, Boston, MA) using 25 mM Hepes pH 6.8, 100 mM NaCl, 1 mM DTT and 0.05% Tween as buffer. For the detection of His6-tagged PB2 fusion protein and biotinylated Cap-analogue, the 6- Histidine detection kit (PerkinElmer, Cat No. 6760619) containing Nickel Chelate coated Acceptor beads and Streptavidin coated Donor beads was used. As a biotinylated Cap-analogue a biotinylated-21-UTP RNA capped with a m7G cap as described in Ptushkina, et al., EMBO Journal Vol.18 No.14 pp.4068-4075, 1999 can be used, for example. In preceding experiments the concentrations of His-PB2 and Biotin-Cap or His-CBC and Biotin-Cap that give maximum signal in the AlphaScreen assay were determined in a checkerboard cross titration. Equal concentrations of 7.5 μg/ml Acceptor and Donor beads were always used. All incubation steps with AlphaScreen beads were performed under subdued lighting conditions and finally the assay plates were read in an EnVision™ plate reader (PerkinElmer). As used herein the term "PB2" refers to the RNA-dependent RNA polymerase subunit PB2 protein of Influenza as also further mentioned in the introduction and description above. Specifically, this assay was carried out using a His-tagged PB2 cap-binding domain protein of a H3N2 strain of Influenza A (SEQ ID NO: 1). However, also any derivative thereof or other polymerase subunit PB2 variants, e.g. from other Influenza strains such as from the H2N2 strain or also from any other negative-sense ssRNA virus may be used to determine the binding of PB2 to Cap or a variant thereof. Example 2: EC5o-determination of small molecule inhibitors using Alphascreen
11-fold l:2-serial dilution of compounds in 20% DMSO starting from 2 mM were prepared from 10 mM stocks in pure DMSO in 384-well storage plates (Greiner, Frickenhausen, Germany) using an EP3 pipetting robot (PerkinElmer). One μl of this 1Ox intermediate dilution was transferred with the pipetting robot to 384-well ProxiPlates. These assay plates were then sealed with aluminum cover foil and stored at -2O0C until usage. After equilibration to RT and centrifugation the assay plates were unsealed and 4.5 μl of His-PB2/Biotin-Cap analogue mix added. After 25 min incubation at room temperature 4.5 μl of Nickel Chelate Acceptor/Streptavidin Donor beads were added, resulting in final concentrations of 300 nM His- PB2, 75 nM Biotin-Cap analogue, 7.5 μg/ml AlphaScreen beads and a serial dilution of compounds starting at 200 μM. His-CBC was prepared as described in detail in Mazza C, et al., Molecular Cell, Vol. 8, 383-396, August, 2001 , p. 383-396. In the CBC AlphaScreen screen (see also below example 3), all conditions and concentrations were identical except that 60 nM His- CBC and 10 nM Biotin-Cap analogue were used. The plates were incubated for further 90 min at room temperature before reading in an En Vision™ plate reader. As specificity control for the AlphaScreen a biotinylated GSTHis fusion protein was incubated with the serial dilution of the compounds instead the His-tagged cap-binding protein (i.e. His-PB2 or His-CBC, respectively) / Biotin-Cap analogue mix. Within the ActivityBase software package from IDBS the curve fit and EC50 calculation was performed.
Example 3: Specificity control using the nuclear cap binding complex (CBC)
Nuclear cap-binding protein complex, which is composed of Cbcl/Cbc2 in yeast and a CBC20/CBC80 heteromer in metazoans, is a RNA-binding protein which binds to the 5' cap inside the nucleus. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. As a specificity control, it was tested, if compounds of the invention would also inhibit the binding of the nuclear cap binding complex (CBC) to a biotinylated Cap analogue. To determine the respective EC50 values, the assay was carried out as described above. The experimental results which are shown in column "CBC" of Table 1 below indicate that the compounds of the invention specifically inhibit the binding of Cap to viral PB2 but that these compounds do not significantly interfere with the binding of Cap to endogenous host factors such as the CBC. As shown in Table 1 below, the measured EC50 numerical values of the compounds of the invention for the inhibition of the interaction between CBC and Cap are very large, demonstrating that there is no significant inhibition of this interaction via the inhibitory compounds. Example 4: Biacore Screening
The Biacore system is based on an optical phenomenon known as surface plasmon resonance (SPR). This technique is the basis for measuring adsorption of material onto planar metal surfaces such as gold or silver.
The PB2 cap binding domain (CBD) of an avian H5N1 influenza virus was immobilized on the surface of a CM7 sensor chip by amine coupling according to the manufacturer's protocol. The protein was diluted in a 1OmM phosphate buffer pH 6.5 and as running buffer for immobilization HBS-EP buffer (1 OmM HEPES, 15OmM NaCl, 3mM EDTA, 0,005 % Surfactant p20) was used. Using a protein concentration of 30 μg/ml and a contact time of 12 min an immobilization level of 29282 RU was achieved resulting in a theoretical RUmax of 850 RU for m7GTP.
For the screening of the compounds a running buffer containing 1OmM TRIS, 3mM EDTA, 15OmM NaCl, 0.005% Surfactant p20 (GE Healthcare/Biacore), ImM DTT, 0.5 % DMSO was used. Two mM DMSO stock solutions of each compound were diluted in 1.005X sample buffer without DMSO (1.005X TRIS/EDTA/NaCl/p20/DTT; diluted from a 1OX stock) to a final compound concentration of lOμM and 0.5 % DMSO. m7GTP (Sigma Aldrich) and a preferred compound of the invention were used as references and chip stability controls at a concentration of 4 mM and 10 μM, respectively. Stock solutions of each reference compound were made and aliquots stored at -20°C.
Buffer bulk effects (matrix) were accounted for by reducing the response obtained for the reference flow cell FcI from the active flow cell Fc2 resulting in relative response units (RU), reflecting binding of the compounds to the ligand. Organic solvents such as DMSO in the buffer cause high bulk effects which differ in the reference flow cell and the active flow cell due to ligand immobilization. To account for these differences, a calibration curve was established. Eight DMSO concentrations ranging from 0.1 % - 1.5 % in buffer were measured and a linear calibration curve was calculated by plotting Fc2-Fcl vs. FcI. The relative response of each sample was then corrected by the solvent factor given by the respective FcI signal on the calibration curve and the corresponding Fc2-Fcl difference. To account for the different size of the compounds, the buffer and solvent corrected response units were normalized to the molecular weight. Example 5: Antiviral screening - CPE reduction
The influenza A virus (IAV) was obtained from American Tissue Culture Collection (A/Aichi/2/68 (H3N2); VR-547). Virus stocks were prepared by propagation of virus on Mardin- Darby canine kidney (MDCK; ATCC CCL-34) cells and infectious titres of virus stocks were determined by the 50 % tissue culture infective dose (TCID50) analysis.
MDCK cells were seeded in 96-well plates at 2χ lOE4 cells/well using DMEM/Ham's F-12 (1:1) medium containing 10 % foetal bovine serum (FBS), 2 mM L-Glutamine and 1 % antibiotics (all from PAA). Until infection the cells were incubated for 5 hrs at 37°C/5.0 % CO2 to form a -80 % confluent monolayer on the bottom of the well. Each test compound was dissolved in DMSO and generally tested at 5 μM and 50 μM. In case the compounds were not soluble at that concentration they were tested at the highest soluble concentration. Ribavirin is used as a reference in the assay at a concentration of 12,5 μM. The compounds were diluted in infection medium (DMEM/Ham's F-12 (1 : 1) containing 5 μg/ml trypsin, and 1 % antibiotics) for a final plate well DMSO concentration of 1 %. The virus stock was generally diluted in infection medium (DMEM/Ham's F-12 (1 :1) containing 5 μg/ml Trypsin, 1 % DMSO, and 1 % antibiotics) to a theoretical multiplicity of infection (MOI) of 0,05. In certain cases the infection efficiency was too high and therefore the MOI was reduced to 0,01 to result in a residual cell viability between 5 and 16,8 % as determined during assay qualification.
After removal of the culture medium and one washing step with PBS, virus and compound were added together to the cells. In the wells used for cytotoxicity determination (uninfected cells), the virus suspension was replaced by infection medium. Each treatment was conducted in two replicates. After incubation at 37 0C, 5 % CO2 for 48 hrs, each well was observed in the microscope for apparent cytotoxicity, precipitate formation, or other notable abnormalities. Then, cell viability was determined using CellTiter-Glo luminescent cell viability assay (Promega). The supernatant was removed carefully and 65 μl of the reconstituted reagent were added to each well and incubated for 15 min at room temperature gently shaking. Then, 60 μl of the solution was transferred to an opaque plate and luminescence (RLU) was measured using Synergy HT plate reader (Biotek).
Relative cell viability values of uninfected treated versus uninfected untreated cells were used to evaluate cytotoxicity of the compounds. Substances with a relative viability below 80 % at the tested concentration were regarded as cytotoxic and retested at lower concentrations. The cytopathic effect (abbreviated CPE) refers to degenerative changes in cells upon viral infection. The CPE reduction e.g. caused by the addition of a compound of the invention was calculated as follows: The response (RLU) of infected untreated samples was subtracted from the response (RLU) of the infected treated samples and then normalized to the viability of the corresponding uninfected sample resulting in % CPE reduction.
To account for variation between the plates, a quality control (QC) compound is included on each plate. Using a qualification procedure certain limits were determined which must be met by the QC sample to assume that the plate was within controlled conditions. Example 6: Screening results
172 candidate compounds were screened using the Alpha screening assay described above for their ability to inhibit binding of PB2 protein to Cap. A control, biotinylated GSTHis fusion protein was included in the screen to identify unspecific binding inhibition. Effective inhibitory compounds were identified showing a specific inhibitory activity with low EC50 values for binding inhibition of Cap to PB2. Exemplary inhibitory compounds were further characterized using the CBC assay as described above. Compounds that showed effective inhibiting activity and specificity are summarized in Table 1. Additional compounds which are structurally related to the compounds listed in Table 1 can be synthesized and further improved e.g. with respect to their EC50 values or with respect to their pharmacology. Guidance and methods for optimizing the pharmacology of the molecules can be found, for example, in "Goodman and Gilman's The Pharmacological Basis of Therapeutics", 8th Edition.
TABLE 1
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Further compounds were synthesized and tested for their ability to inhibit binding of PB2 protein to Cap. Additional effective inhibitory compounds related to the compounds shown in Table 1, Nr. 1-5 were identified and are listed in Table 2A-J below.
The binding affinities as measured by surface plasmon resonance (cf. example 4 above), between the PB2 cap binding domain (CBD) of H5N1 influenza virus and the respective inhibitory substances are indicated ("Binding (RU)") for exemplary inhibitory compounds that have been analyzed. A larger RU value indicates a stronger binding. Also indicated is the reduction in cytopathic effect (CPE reduction; cf. example 5 above) for several compounds.
Figure imgf000043_0001
Figure imgf000044_0002
Figure imgf000044_0001
Figure imgf000044_0003
Figure imgf000045_0001
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000046_0003
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000047_0001
Figure imgf000048_0002
Figure imgf000048_0001
128 cyclopropyl OH H Cl 6.25 21,9
Figure imgf000049_0001
Example 7: Synthesis of Exemplary Compounds of the Invention
7.1 Preparation of key intermediates
The following intermediates may be used for the final synthesis of compounds of the present invention. Many different methods well known in the art can be used by the average skilled person to synthesize the compounds of the present invention. In the following, exemplary synthesis methods are outlined. Also compounds of the invention not shown in the following examples can be synthesized by carrying out the outlined steps using analogous starting materials and intermediates.
Figure imgf000050_0001
The initial acid 1 can be prepared using methods of the prior art as e.g. documented in Mityuk, Audrey P.; Volochnyuk, Dmitriy M.; Ryabukhin, Sergey V.; Plaskon, Andrey S.; Shivanyuk, Alexander; Tolmachev, Andrey A. Synthesis, 2009, 11, 1858 - 1864.
Figure imgf000050_0002
EN stock 034-414
Scheme 1 4
The carbaldehyde 4 was synthesized from corresponding N-protected 3- and 5-aminopyrazoles 2 and a synthone of triformylmethane 3 (Scheme 1).
Figure imgf000050_0003
5 EN 112-220
7
Scheme 2
The isomeric acid 7 was obtained using ethyl acetylpyruvate 6 and a mixture of N-protected 3- and 5-aminopyrazoles 5 with a following hydrolysis (Scheme 2). Preparation of the carbaldehyde 4. 2-dimethylaminomethylene-l,3-bis(dimethylimmonio)propane diperchlorate 3 (36 g) was added to a mixture of 8.6 g MeONa in 400 mL of methanol and stirred for 20 minutes. After N- protected aminopyrazole 2 was added and a reaction mixture was refluxed for 12 hours. A precipitate was filtered and washed with a solvent. Combined portions of MeOH solutions were evaporated and a residue was diluted with water. An aqueous solution was extacted with dichloromethane (4X50 mL). The extract was dried over MgSO4 and evaporated. After. column chromatography H g of the desired carbaldehyde 4 were obtained.
Preparation of the acid 7.
Ethyl acetylpyruvate 6 (17.2 g) and aminopyrazoles 5 (1O g ) were refluxed in 150 mL of AcOH for 6 hours. A solvent was evaporated under reduced pressure and a residue was taken up into 150 mL of CH2Cl2. A solvent was removed under reduced pressure after drying over sodium sulfate. A concentrated hydrochloric acid (100 mL) was added and a heterogeneous reaction mixture was refluxed for 4 hours. The precipitate was filtered and characterized. It was a desired acid 7 (15 g) with an appropriate purity.
7.2. Preparation of final products
The final products were synthesized according to the schemes below. R1 (COCI)2 / DIPEA
Figure imgf000051_0001
Figure imgf000051_0002
8
Scheme 3
Different condensation agents were used such as chloroanhydride, CDI and oxalyldichloride. Only with a last agent a formation of amides was observed (Table 3). General procedure for preparation of amides 8.
To 0.5 g of acid 1 in 30 mL of CHCl3 oxalyldichloride (1.1 eq.) was added at 0 0C with magnetical stirring. After 30 minutes chloroform with traces of oxalyldichloride was evaporated under reduced pressure carefully. A new portion Of CHCl3 was added, DIPEA (1.1 eq) and 1.05 eq. of amine were added to a stirred solution at 0 0C. After an overnight stirring at room temperature a reaction mixture was washed with water. Organic layer was dried over sodium sulfate and evaporated. A residue was purified by column chromatography.
The yields of exemplary compounds 8 are described in the Table 3.
Figure imgf000052_0001
Figure imgf000053_0001
*A11 desired compounds were purified by column chromatography. Yields are given only for the fraction with the best purity. Therefore yields are not optimized.
Figure imgf000053_0002
For aliphatic amines: X= Ac
For anilines: X= TFA
Scheme 4
For the synthesis of amines 9 reductive amination can be used. For example, with all aliphatic amines sodium triacetoxyborohydride (generated in situ) can be used. Also sodium tris- (trifluoroacetoxy)-borohydride (generated in situ) in the reaction of aldehyde 3 with diphenylamine can be used.
General procedure for preparation of amines 9.
To a stirred suspension of 1.1 eq. of sodium boro hydride in 30 mL (CH2)2C12 3.1 eq. of acetic or trifluoroacetic acid were added at 0 0C. After 1.5 hour aldehyde 4 (0.5 g) and 1.0 eq of amine were added and a reaction mixture stirred overnight. After it was washed with water, organic layer was dried over sodium sulfate and evaporated under reduced pressure. A crude product was purified by column chromatography.
The yields of exemplary compounds 9 are described in the Table 4.
52
Figure imgf000054_0001
for the fraction with the best purity. Therefore yields are not optimized.
R1 (COCI)2 / DIPEA
Figure imgf000054_0002
Figure imgf000054_0003
Scheme 5 10
The desired compounds 8 were obtained in the same conditions and into the same procedure as amides 6.
The yields of exemplary compounds 10 are described in the Table 5.
Figure imgf000055_0001
Figure imgf000056_0001
for the fraction with the best purity. Therefore yields are not optimized.
REFERENCES CITED
Berge, S. M. et al., (1977), "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19
Eriksson, B. et al., (1977), Inhibition of Influenza virus ribonucleic acid polymerase by ribavirin triphosphate. Antimicrob. Agents Chemother., 11, pp. 946-951
Fechter, P. et al., (2003), "Two aromatic residues in the PB2 subunit of influenza A RNA polymerase are crucial for cap binding", J. Biol. Chem., 278, pp. 20381-20388 Ghanem, A. et al., (2007), "Peptide-mediated interference with influenza A virus polymerase". J. Virol., 81, pp. 7801-7804
Goodman, L. S. et al., Eds., (1985), "Goodman and Gilman's The Pharmacological Basis of Therapeutics", 8th Edition, Pergamon Press
Honda, A. et al., (1999), "Two separate sequences of PB2 subunit constitute the RNA cap- binding site of influenza virus RNA polymerase", Genes to Cells, 4, pp. 475-485 Kukkonen, S. K. et al (2005), "L protein, the RNA-dependent RNA polymerase of hantaviruses", Arch. Virol., 150, pp. 533-556
Leahy, M. B. et al, (2005), "In Vitro Polymerase Activity of Thogoto Virus: Evidence for a Unique Cap-Snatching Mechanism in a Tick-Borne Orthomyxovirus", J. Virol., 71, pp. 8347- 8351
Leuenberger, H.G.W. et al., Eds., (1995), "A Multilingual Glossary of Biotechnological Terms: IUPAC Recommendations", Helvetica Chimica Acta, CH-4010 Basel, Switzerland,
Li, M.-L. et al., (2001), "The active site of the influenza cap-dependent endonuclease are on different polymerase subunits", EMBO J., 20, pp. 2078-2086
Magden, J. et al., (2005), "Inhibitors of virus replication: recent developments and prospects", Appl. Microbiol. Biotechnol., 66, pp. 612-621
Natarajan, A. et al., (2004), Synthesis of fluorescein labeled 7-methylguanosinemonophosphate. Bioorg. Med. Chem. Lett., 14, pp. 2657-2660 Noah, D. L. and Krug, R. M., (2005), "Influenza virus virulence and its molecular determinants", Adv. Virus Res., 65, pp. 121-145
Plotch, S. J. et al., (1981), "A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription", Cell, 23, pp. 847-858
Ren, J. et al., (1996), "Synthesis of a fluorescent 7-methylguanosine analog and a fluorescence spectroscopic study of its reaction with wheat germ cap binding proteins", Nucleic Acids Res., 15, pp. 3629-3634
Tisdale, M. et al., (1995), "Inhibition of influenza virus transcription by 2'-deoxy-2'- fluoroguanosine", Antimicrob. Agents Chemother., 39, pp. 2454-2458 Tomassini, J. et al., (1994), "Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-diocobutanic acid compounds", Antimicrob. Agents Chemother., 38, pp. 2827-2837 Tomassini, J. et al., (1996), "A novel antiviral agent which inhibits the endonuclease of influenza viruses", Antimicrob. Agents Chemother., 40, pp. 1189-1193
Von Itzstein, M. et al., (1993), "Rational design of potent sialidase-based inhibitors of influenza virus replication", Nature, 363, pp. 418-423

Claims

Claims
A compound having a structure according to formula (XXI):
Figure imgf000059_0001
(XXI)
or a pharmaceutically effective salt, a solvate, a prodrug, a tautomer, a racemate, an enantiomer or a diastereomer thereof;
wherein
one of Y and Z is -XR12 and the other is R10';
R10, R10 and R10 are each individually selected from the group consisting of hydrogen, d-Cβ-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH, -(CH2)nOR16, -CF3, -(CH2)n-cycloalkyl, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2NH2,
-(CH2)nS(O)2NHR16, -(CH2)HS(O)2NR16R1 \ -(CH2)nS(O)2R16, halogen, -CN, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nNH2, -(CH2)nNHR16, and
-(CH2)nNR16R17; optionally substituted;
R1 1 is selected from the group consisting of hydrogen, Ci.Cδ-alkyl, -CF3, C2-C6- alkenyl, C2.C8-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n- heterocycloalkyl and -(CH2)n-heteroaryl; optionally substituted;
X is selected from the group consisting of CH2, C(O), C(S), CH(OH), CH(OR16), S(O)2, -S(O)2-N(H)-, -S(O)2-N(R16)-, -N(H)-S(O)2-, -N(R16)-S(O)2-, C(=NH), C(=N-R16), CH(NH2), CH(NHR16), CH(NR16R17), -C(O)-N(H)-, -C(O)-N(R16)-, -N(H)-C(O)-, -N(R16)-C(0)-, N(H), N(-R16) and O;
R12 is selected from the group consisting of Ci-Cδ-alkyl, -CF3, C2-C6-alkenyl, C2-C8- alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, -(CH2)n-aryl, -NR16R17, and -(CH2)n-heteroaryl; optionally substituted; R16 and R17 are independently selected from the group consisting of Ci-Cβ-alkyl, C2- Cβ-alkenyl, C2-C6-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -CF3, -C(O)R18 and -S(O)2R18; optionally substituted;
R18 is independently selected from the group consisting of Ci-Cό-alkyl, C2-Cδ-alkenyl, C2-C6-alkynyl, -(CH2)n-cycloalkyl and -CF3; optionally substituted; and
n is in each instance selected from 0, 1 and 2.
2. The compound according to claim 1 , wherein R10 is hydrogen.
3. The compound according to claim 1 or 2, wherein R1 1 is hydrogen.
4. The compound according to any of claims 1 to 3, wherein R10 is selected from ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, hydroxymethyl, 2-hydroxyethyl, methoxy, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CH2NH2, -CH2NHCH3,
-CH2N(CHj)2, -CH2NHC(O)CH3, and -CF3.
5. The compound according to any of claims 1-4, wherein R10 is hydrogen; and
R10 selected from the group consisting of Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, -(CH2)n-cycloalkyl, -CF3, -(CH2)nC(O)OH, -(CH2)nC(O)OR16, -(CH2)nOH,
-(CH2)nOR16, -(CH2)nNH2, -(CH2)nNHR16, -(CH2)nNRl6R17, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16, -(CH2)nC(O)NR16R17, -(CH2)nS(O)2R16, -(CH2)nS(O)2NH2, -(CH2)nS(O)2NHR16, -(CH2)HS(O)2NR16R1 \ halogen, -CN, -(CH2)n-aryl, and -(CH2)n-heteroaryl; optionally substituted.
6. The compound according to any of claims 1-4, wherein R10 is hydrogen; and
R10 selected from the group consisting of Cj-Cό-alkyl, C2-C6-alkenyl, C2-C8-alkynyl,
-(CH2)n-cycloalkyl, -CF3, -(CH2)nC(O)OH, -(CH2)nC(O)OR16,
-(CH2)nNHC(O)R18, -(CH2)nNR' 6C(O)R18, -(CHz)nNHS(O)2R18, -(CH2)nNR16S(O)2R18, -(CH2)nC(O)NH2, -(CH2)nC(O)NHR16,
-(CH2)nC(O)NR16R17, -(CHz)nS(O)2NH2, -(CH2)nS(O)2NHR16,
-(CH2)nS(O)2NR16R17, halogen, -CN, (CH2)n-aryl, and (CH2)n-heteroaryl; optionally substituted.
7. The compound according to any of claims 1-6, wherein X is selected from the group consisting of CH2, C(O), CH(OH), -S(O)2N(H)-, -N(H)-S(O)2-, -C(O)-N(H)-, -N(H)- C(O)-, N(H), and O.
8. The compound according to any of claims 1-7, wherein R12 is selected from the group consisting of -(CH2)n-aryl, -(CH2)n-heteroary, -NR16R17, and
-(CH2)n-heterocycloalkyl; optionally substituted;
9. The compound according to claim 8, wherein R12 is selected from phenyl, naphthyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and purinyl; optionally substituted.
10. The compound according to any of claims 1-7, wherein R12 is selected from the group consisting of:
Figure imgf000061_0001
Figure imgf000062_0001
and alkyl;
wherein the R12 substituent is optionally substituted; and
wherein * indicates where the respective R12 substituent is bound to X.
11. The compound according to claim 1 , wherein the compound has a structure according to formula (VI)
Figure imgf000062_0002
(VI),
wherein
X is C(O) or C(S);
R10 and R15 are each individually selected from the group consisting of Ci-Ce-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, -CF3, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and
-NR16R17; optionally substituted; and R10 , R10 , R13 and R14 are each individually selected from the group consisting of hydrogen, d-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, -CF3, -COOH, -CN, -C(O)OR16, -OH, heteroaryl, -(CH2)n-heterocycloalkyl, -OR16, -NHR16, - NH2 and -NR16R17; optionally substituted.
12. The compound according to claims 1, wherein the compound has the structure according to formula (VIIA) or (VIIB):
Figure imgf000063_0001
(VIIA) (VIIB);
and wherein
R10 and R13 are each individually selected from the group consisting of Ci-Cδ-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, -CF3, -C(O)OR16, -OH, -OR16, -NHR16, -NH2 and
-NR16R17; optionally substituted; and
R13 and R14 are each individually selected from the group consisting of hydrogen, Ci-
C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, -CF3, -COOH, -CN,
-C(O)OR16, -OH, heteroaryl, -(CH2)n-heterocycloalkyl, -OR16, -NHR16, -NH2 and -NR16R17; optionally substituted.
13. The compound according to claim 11 or 12, wherein R15 is -OH.
14. A compound having a structure according to formula (I)
Figure imgf000063_0002
(I)
wherein
X is NH, NR9, O or S; R1 and R2 are each individually selected from the group consisting of Ci-Cό-alkyl, C2- Cβ-alkenyl, C2-C6-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2, -NHC(O)NHR7, -NHC(O)NR7R8, halogen, -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
R3 through R6 are each individually selected from the group consisting of hydrogen, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)NH2, -C(O)NHR7, -C(O)NR7R8, -NHC(O)NH2, -NHC(O)NHR7, -NHC(O)NR7R8, halogen, -C(O)OR7, -OR7 and -NR7R8; optionally substituted;
R7 and R8 are independently selected from the group consisting of hydrogen, Ci-Ce- alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R9; optionally substituted; and
R9 is independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl; optionally substituted.
15. The compound according to claim 14, wherein the compound has the structure according to formula (II), (III) or (IV):
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
16. The compound according to claims 14 or 15, wherein X is O and wherein R1 and R2 are -OR7, and preferably -OH.
17. A compound having a structure according to formula (X):
Figure imgf000065_0001
(X)
wherein
X is O or S;
R27 is selected from the group consisting of Ci-Cό-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR33, -OR33 and -NR33R34; optionally substituted;
R29 is selected from the group consisting of hydrogen, Ci-Cδ-alkyl, C2-C6-alkenyl, C2-
Cβ-alkynyl, -C(O)OR33, -OR33 and -NR33R34; optionally substituted; R2S and R30 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R33, -C(O)OR33, -CF3, -CN, -SO3-, -NO2, -N(R3V, C,-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OR15 and -NR33R34; optionally substituted;
R31 and R32 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R33, -C(O)OR33, -CF3, -CN, -SO3 ', -NO2, -N(R33)3 +, CrC6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, -OR33 and -NR33R34; optionally substituted; R33 and R34 are independently selected from the group consisting of hydrogen, aryl, heteroaryl, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R35; optionally substituted; and
R35 is independently selected from the group consisting of Ci-Cό-alkyl, C2-C6-alkenyl and C2-Cό-alkynyl; optionally substituted.
18. The compound according to claim 17, wherein R27 and R29 are the same substituents and wherein R28 and R30 are the same substituents and wherein X is O.
19. The compound according to claim 17, wherein the compound has the structure according to formula (XI) or (XII):
Figure imgf000066_0001
(XII).
20. A compound having a structure according to formula (XIII):
Figure imgf000066_0002
(XIII)
wherein
A and B is each individually selected from S and O;
R40 and R41 are each individually selected from the group consisting of halogen, -CF3,
-CN, -SO3-, -NO2, -N(R44)3 +, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45;
R37 and R39 are each individually selected from the group consisting of hydrogen, Ci-
Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR44, -OR44 and -NR44R45; optionally substituted;
R36, R38, R42 and R43 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R44, -C(O)OR44, -CF3, -CN, -SO3 ", -NO2, -N(R4V,
Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -OR44 and -NR44R45; optionally substituted;
R44 and R45 are independently selected from the group consisting of hydrogen, Ci-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R46; optionally substituted; and R ,46 is independently selected from the group consisting of Ci-C6-alkyl, C2-C6-alkenyl and C∑-Cό-alkynyl; optionally substituted.
21. The compound according to claim 20, wherein the compound has the structure according to formula (XIV):
Figure imgf000067_0001
22. The compound according to claim 20 or 21, wherein R40 and R41 are halogen, preferably Cl.
23. A compound having a structure according to formula (XV):
Figure imgf000067_0002
(XV)
wherein
X is S and O;
R47 through R49 are each individually selected from the group consisting of hydrogen,
Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -C(O)OR53, -OR53 and -NR53R54; optionally substituted;
R50 through R52 are each individually selected from the group consisting of hydrogen, halogen, -C(O)R53, -C(O)OR53, -CF3, -CN, -SO3 ", -NO2, -N(R5V, C,-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, -OR53 and -NR53R54; optionally substituted; R53 and R54 are independently selected from the group consisting of hydrogen, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -C(O)R55; optionally substituted; and R55 is independently selected from the group consisting of Ci-Cδ-alkyl, C2-Cδ-alkenyl and C2-C6-alkynyl; optionally substituted.
24. The compound according to claim 23, wherein the compound has the structure according to formula (XVI):
(XVI).
25. A compound having a structure according to formula (XVII):
Figure imgf000068_0002
(XVII)
wherein
R is C3-C6-alkyl; optionally substituted; and
R57 and R58 is each individually an C2-Cό-alkyl; optionally substituted.
26. The compound according to claim 25, wherein
R57 has the structure (XVIII):
R59
O
(XVIII)
and/or R58 has the structure (IXX):
.N
R60'
O
(IXX)
wherein R59 and R60 are each individually selected from the group consisting of aryl, heteroaryl and -OR61; optionally substituted; R61 is Ci-C6-alkyl; optionally substituted; and
* indicates where the structure (XVIII) and (IXX), respectively, is bound to the structure (XVII).
27. A compound having a structure according to formula (XX):
Figure imgf000069_0001
(XX)
wherein
R62, R63 and R64 is each individually aryl or heteroaryl; optionally substituted.
28. The compound according to claim 27, wherein
Figure imgf000069_0002
R64 is phenyl; optionally substituted;
and wherein
R65 is in each instance individually selected from the group consisting of halogen, -CN and -CF3 and wherein
* indicates where the structures are bound to the structure (XX).
29. A pharmaceutical composition comprising any one of the compounds according to claims 1 to 28 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
30. The compound according to any of claims 1 to 28 for medical use.
31. The compound according to any of claims 1 to 28 or the pharmaceutical composition according to claim 29 for use in treating, ameliorating, or preventing disease conditions caused by a viral infection.
32. The compound or pharmaceutical composition of claim 31, wherein said virus belongs to a viral family selected from the group consisting of Orthomyxoviridae, Arenaviridae and Bunyaviridae, Bornaviridae, Filoviridae, Paramyxoviridae and Rhabdoviridae family.
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