WO2014023691A1 - Dihydroxypyrimidine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease - Google Patents

Dihydroxypyrimidine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease Download PDF

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Publication number
WO2014023691A1
WO2014023691A1 PCT/EP2013/066388 EP2013066388W WO2014023691A1 WO 2014023691 A1 WO2014023691 A1 WO 2014023691A1 EP 2013066388 W EP2013066388 W EP 2013066388W WO 2014023691 A1 WO2014023691 A1 WO 2014023691A1
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Prior art keywords
optionally substituted
alkyl
aryl
group
optionally
Prior art date
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PCT/EP2013/066388
Other languages
French (fr)
Inventor
Helmut Buschmann
Andrea Wolkerstorfer
Oliver Szolar
Norbert Handler
Stephen Cusack
Mark Smith
Sung-Sau So
Original Assignee
Savira Pharmaceuticals Gmbh
F. Hoffmann-La Roche Ag
European Molecular Biology Laboratory
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Filing date
Publication date
Application filed by Savira Pharmaceuticals Gmbh, F. Hoffmann-La Roche Ag, European Molecular Biology Laboratory filed Critical Savira Pharmaceuticals Gmbh
Priority to CN201380041462.1A priority Critical patent/CN104619699A/en
Priority to MX2015001478A priority patent/MX2015001478A/en
Priority to KR20157005600A priority patent/KR20150039832A/en
Priority to EP13759141.8A priority patent/EP2885289A1/en
Priority to JP2015525852A priority patent/JP2015524457A/en
Priority to CA2879245A priority patent/CA2879245A1/en
Priority to BR112015002516A priority patent/BR112015002516A2/en
Priority to RU2015107803A priority patent/RU2015107803A/en
Publication of WO2014023691A1 publication Critical patent/WO2014023691A1/en
Priority to HK15111131.0A priority patent/HK1210177A1/en
Priority to HK15112102.3A priority patent/HK1211289A1/en

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a compound having the general formula (Di), (Dii), or (Diii) optionally in the form of a pharmaceuticaliy acceptable salt, solvate, polymorph, codrug cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
  • H5N1 could have been more easily transmissible between humans or the new A/H1N1 could have been more virulent and could have carried the single point mutation that confers Tamiflu resistance (Neumann et al., Nature, 2009 (18; 459(7249) 931-939)); as many seasonal H1 N1 strains have recently done (Dharan et al., The Journal of the American Medical Association, 2009 Mar 1 1 ; 301 (10), 1034-1041 ; Moscona et al., The New England Journal of Medicine, 2009 (Mar 5;360(10) pp 953-956)).
  • ribavirin is only approved in a few countries, probably due to severe side effects (Furuta et a!., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, p. 981-986). Cleariy, new antiviral compounds are needed, preferably directed against different targets. influenza virus as well as Thogotovirus beiong to the family of Orthomyxoviridae which, as we!l as the family of the Bunyaviridae, including the Hantavirus, Nairovirus, Orthobunyavirus, and Phlebovirus, are negative stranded RNA viruses.
  • RNA dependent RNA polymerase which carries out (i) the initial copying of the single-stranded virion RNA (vRNA) into virai mRNAs and (ii) the vRNA replication.
  • This enzyme a trimeric complex composed of subunits PA, PB1 and PB2, is central to the life cycle of the virus since it is responsible for the repiication and transcription of viral RNA.
  • 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 10 to 15 nucleotides. The capped RNA fragments then serve as primers for the synthesis of viral mRNA.
  • 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, J. et al., (2005), Appl. Microbiol.
  • WO 2011/046920 refers to DXR inhibitors which are stated to be suitable for antimicrobial therapy.
  • the present invention provides a compound having the general formula (Di), (Dii), or (Diii).
  • a compound having the general formula (Di), (Dii), or (Diii) encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, codrugs, cocrystals, tautomers, racemates, enantiomers, or diastereomers or mixtures thereof unless mentioned otherwise.
  • a further embodiment of the present invention relates to a pharmaceutical composition comprising a compound having the general formula (Dt), (Dii), or (Diii) and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • the compounds having the general formula (Di), (Dii), or (Diii) are useful for treating, ameliorating or preventing viral diseases.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (SUPAC Recommendations)", Leuenberger, H.G.W, Nage!, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.
  • alkyl refers to a saturated straight or branched carbon chain.
  • cycloalkyl represents a cyclic version of "aikyl".
  • cycloalkyl is also meant to include bicycitc, tricyclic and polycyciic versions thereof. Unless specified otherwise, the cycSoalky! group can have 3 to 12 carbon atoms.
  • cyclic heteroaikyl includes monocyclic, bicyclic, tricyclic and polycyciic heteroalky! groups. Unless specified otherwise, the cyclic heteroaikyl group can have 3 to 12 atoms and can include one or more heteroatoms selected from N, O or S.
  • Hal or "halogen” represents F, CI, Br and I.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing in carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthyl or anthracenyl, preferably phenyl.
  • heteroaryl preferably refers to a five-or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2, 3, or 4 (for the five- membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S.
  • heteroaryl group examples include pyrrole, pyrrolidine, oxo!ane, iuran, imidazolidine, imidazole, pyrazoie, oxazolidine, oxazole, thiazole, piperidine, pyridine, morpholine, piperazine, and dioxo!ane.
  • hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring refers to any group having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and 2 as long as the group contains at least one ring.
  • the ring(s) can be either carbocycfic or heterocyclic and can be saturated, unsaturated or aromatic.
  • linker group such as - ⁇ CH 2
  • these groups include -(optionally substituted C 3 _ 7 cycioalkyi), -(optionally substituted aryl) wherein the aryl group can be, for example, phenyl, -(optionally substituted biphenyl), adamantyl, -(C 3 _ 7 cycloalkyl)-aryl as well as the corresponding compounds with a linker.
  • Further examples of these groups include -(optionally substituted 3 to 7 membered. cyclic heteroalkyl) or -(optionally substituted heteroaryl) containing, for instance, 1 to 3 N atoms.
  • the term "(optionally substituted mono- or poiycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S)" refers to any mono- or poiycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S. This term includes monocyclic, bicyclic, tricyclic and poiycyclic versions thereof. If more than one ring is present, they can be separate from each other or be an nuisanceated.
  • the ring(s) can be either carbocyclic or heterocyclic and can be saturated, unsaturated or aromatic.
  • these groups include -(optionally substituted C " r.vnlnaikvl ' S and— nntinnallv Si ihetifi itaH arw wharain tha nrni in nan ha fnr evannnle phenyl or anthracenyl as well as the corresponding compounds with a linker.
  • a compound or moiety is referred to as being "optionally substituted", it can in each instance include 1 or more of the indicated substituents, whereby the substituents can be the same or different.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention.
  • suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts ⁇ ; alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as haltde, 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 haltde, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl
  • compositions include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesuifonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesuifonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexySresorcinate
  • the structure can contain solvent molecules.
  • the solvents are typically pharmaceutically acceptable solvents and include, among others, water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates.
  • codrug refers to two or more therapeutic compounds bonded via a covalent chemical bond. A detailed definition can be found, e.g., in N. Das et a!., European Journal of Pharmaceutical Sciences, 41 , 2010, 571-588.
  • cocrysta refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoichometric ratio of a target molecule or ion (i.e., compound of the present invention) and one or more neutral molecular cocrysta! formers.
  • the compounds of the present invention can also be provided in the form of a prodrug, namely a compound which is metabolized in vivo to the active metabolite.
  • a prodrug namely a compound which is metabolized in vivo to the active metabolite.
  • Suitabie prodrugs are, for instance, esters. Specific examples of suitable groups are given, among others, in US 2007/0072831 in paragraphs [0082] to [01 18] under the headings prodrugs and protecting groups. If X 1 is O or S, preferred examples of the prodrug include compounds in which R 1 is replaced by one of the following groups:
  • R 7 can be the same or different.
  • R 9 is a cyclic group such as an aryl group or a C cycloaikyl group, p is 2 to 8.
  • X 1 is NR *
  • preferred examples of the prodrug include compounds in which R and R * are not both H.
  • Compounds having the general formula (Di), (Dii), or (Diii) The present invention provides a compound having the generai formula (Di), (Dii), or (Diii).
  • the present invention provides a compound having the generai formula (Di), (Dii), or (Diii) which the following definitions apply,
  • X 1 is O, S or NR * ; preferably O, or NR*.
  • ⁇ S preferably O.
  • X 3 is O or S; preferably O.
  • X 4 is O or S; preferably O.
  • X 5 is O or S; preferably O.
  • L is -(CH 2 ) m - -NR*-S0 2 - or -S0 2 -NR*-; preferably -(CH 2 ) M - or -NR*-S0 2 -.
  • m is 1 to 4; preferably m is 1 or 2; more preferably m is 1 .
  • R 1 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted C 3 _ 7 cycloalkyl), -(optionally substituted aryl), -C 1 aikyl— (optionally substituted aryl), -C(0)-0-R** or TMP(0)(OR**) 2 .
  • X 1 is NR* then R and R* can optionally be bound together to form a 5- to 7-membered ring.
  • R is -H or -(optionally substituted C-HS alkyl).
  • R 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroaioms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted.
  • R 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C 5 - 7 cycloalkyl, more preferably R 2 is selected from
  • heterocyclic group, phenyl group, cyclohexyl group or cycSopentyl group can be optionally substituted in any available position by a subsiituent which is independently selected from -Ci_6 alkyl, halogen, -CF 3 , -CN, -OH, and -G-C ⁇ . alkyl.
  • R 4 is -H, -(optionally substituted C -6 alkyl), -(optionally substituted C3-.7 cycloalkyl), -(optionally substituted aryl), or -C-M alkyl-(optionally substituted aryl).
  • R s isTMH, -C(OWoptionaliy substituted Ci_ 6 alkyl), or -(optionally substituted C-i_e alkyl).
  • R 6 is -H, -C(0)-(optionally substituted alkyl), or -(optionally substituted Ci_ 6 alkyl).
  • R* is -H, or -(C e alkyl); preferably -H.
  • alkyf group is selected from the group consisting of halogen, -CN, -NR*R*, -OH, and -O-Cf-e alkyl:
  • the optional substituent of the cycloalkyl group, the aryi group or the hydrocarbon group is selected from the group consisting of ⁇ C ⁇ 6 alkyl, -halogen, -CF 3) -CN, -X 1 ⁇ R * , -aryl and -C A alkyl-ar l.
  • the present inventors have surprisingly found that the compounds of the present invention which have a bulky, hydrophobic group represented by -L-R 2 have improved pharmacological properties compared to corresponding compounds which have a less space demanding group in this position. Without wishing to be bound by theory, it is assumed that the viral polymerase protein has a pocket for binding and that this hydrophobic group of the compounds of the present invention has improved binding compared to other groups. This could not have been predicted or expected based on the art.
  • the compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient(s) and/or carriers).
  • the compounds of the present invention can be administered by various well known, routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Oral, intranasal and parenteral administration are particulariy preferred.
  • 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 caps!et, 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 injectionabie use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half-life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. 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: binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethy! 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, croscarmel!ose, sodium methyl cellulose, agar, bentonite, aiginic 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, croscarmeilose 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 prope!lant, e.g., dichlorodifluoromethane, trichiorof!uoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 ,1 ,1 ,2-tetrafiuoroethane (HFA 134ATM) or 1 ,1 ,1 ,2,3,3,3-heptafiuoropropane (HFA 227EATM), carbon dioxide, or another suitable gas.
  • a suitable prope!lant e.g., dichlorodifluoromethane, trichiorof!uoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 ,1 ,1 ,2-tetrafiu
  • 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 propeliant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.
  • a lubricant e.g., sorbitan trioleate.
  • the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g of the active ingredient (i.e. compound of the invention) per kg body weight.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 1 to 200 mg/kg body weight.
  • the duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • from 10 mg to 200 mg of the compound are orally administered to an adu!t per day, depending on the severity of the disease and/or the degree of exposure to disease carriers.
  • the pharmaceutically effective amount of a given composition will also depend on the administration route, in general, the required amount will be higher if the administration is through the gastrointestinal tract, e.g., by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g., intravenous.
  • a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 10 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 1 to 100 mg/kg body weight if parenteral administration is used. For intranasal administration, 1 to 100 mg/kg body weight are envisaged.
  • a person is known to be at risk of developing a disease treatable with a compound of the invention, prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible.
  • the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, from 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective viral disorder has lessened. In most instances, however, a compound of the Invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily.
  • the compounds of the present invention are particularly useful for treating, ameliorating, or preventing viral diseases.
  • the type of viral disease is not particularly limited.
  • examples of possible viral diseases include, but are not limited to, viral diseases which are caused by Poxvirldae, Herpesviridae, Adenoviridae, Papillomaviridae, Poiyomaviridae, Parvoviridae, Hepadnaviridae, Retroviridae, Reoviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae, Caiiciviridae, Astroviridae, Togaviridae, Flaviviridae, Deitavirus, Bornaviridae, and prions.
  • viral diseases which are caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, more preferably viral diseases which are caused by orthomyxoviridae. Examples of the various viruses are given in the fo!iowing tabie.
  • Herpesviridae Herpes simplex virus
  • Picornaviridae Human enterovirus types A-D (Poliovirus, Echovirus,
  • the compounds of the present invention are employed to treat influenza.
  • influenza includes influenza A, B, C, isavirus and thogotovirus and also covers bird flu and swine flu.
  • the subject to be treated is not particularly restricted and can be any vertebrate, such as birds and mammals ⁇ including humans).
  • the compounds of the present invention are capable of inhibiting endonuciease activity, particularly of the influenza virus. More specifically it is assumed that they directly interfere with the N-terminal part of the influenza PA protein, which harbours endonuciease activity.
  • delivery of a compound into a cell may represent a problem depending on, e.g., the solubility of the compound or its capabilities to cross the cell membrane.
  • the present invention not only shows that the claimed compounds have in vitro polymerase inhibitory activity but also in vivo antiviral activity.
  • a possible measure of the in vitro polymerase inhibitory activity of the compounds having the formula (Di), (Dii), (Diii), (A) and/or (C) is the FRET endonuciease activity assay disclosed herein.
  • the compounds exhibit a % reduction of at least about 50 % at 25 ⁇ in the FRET assay.
  • the % reduction is the % reduction of the initial reaction velocity (vO) of substrate cleavage of compound-treated samples compared to untreated samples.
  • the compounds exhibit an IC 50 of at least about 40 ⁇ , more preferably at least about 20 ⁇ , in the FRET assay.
  • the half maximal inhibitory concentration (iC S0 ) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the initial reaction velocities (vO) in a given concentration series ranging from maximum 100 ⁇ to at least 2 n .
  • a possible measure of the in vivo antiviral activity of the compounds having the formula (Di), (Dii), (Diii), (A) and/or (C) is the CPE assay disclosed herein.
  • the compounds exhibit a % reduction of at least about 30 % at 50 ⁇ .
  • the reduction in the virus-mediated cytopathic effect (CPE) upon treatment with the compounds was calculated as follows:
  • the cell viability of infected-treated and uninfected-treated cells was determined using an ATP-based cell viability assay (Promega).
  • the response in relative luminescent units (RLU) of infected-u treated 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.
  • the compounds exhibit an IC 50 of at least about 45 ⁇ , more preferably at least about 10 ⁇ , in the CPE assay.
  • the half maximal inhibitory concentration (SC 50 ) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the RLU response in a given concentration series ranging from maximum 100 ⁇ to at least 100 nM.
  • the compounds having the general formula (Di), (Dii), or (Diii) can be used in combination with one or more other medicaments.
  • the type of the other medicaments is not particularly Simited and will depend on the disorder to be treated.
  • the other medicament will be a further medicament which is useful in treating, ameioriating or preventing a viral disease, more preferably a further medicament which is useful in treating, ameioriating or preventing influenza.
  • endonuclease and cap-binding inhibitors particularly targeting influenza.
  • the endonuclease inhibitors are not particularly limited and can be any endonuclease inhibitor, particularly any virai endonuclease inhibitor.
  • Preferred endonuclease inhibitors are those having the general formula (I) as defined in the US application with the serial number 61/550,045, filed on October 21 , 201 , the complete disclosure of which is incorporated by reference. In particular, all descriptions with respect to the general formula of the compounds according to US 61/550,045, the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference.
  • the compounds having the general formula (l) of this reference can optionally be in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined as follows (wherein the definitions of the various moieties given in this earlier application apply):
  • R 1 is selected from -H, -C,_ 6 alkyl, -(C 3 _ 7 cycloalkyl) and ⁇ CH 2 -(C 3 _ 7 cycloalkyf);
  • R 2 is selected from -H, aikyl, -Hai, -(C3-7 cycloalkyl), -CH 2 -(C 3 _ 7 cycloalkyl), -(CH 2 ) m -(optiona!ly substituted aryl), -(optionally substituted 5- or 6- membered heterocyclic ring which contains at least one heteroatom selected from N, O and S, wherein the substituent is selected from -C ⁇ aikyl, -halogen, -CN, -CHal 3 , -aryl, -NR 6 R 7 , and -CONR 6 R 7 ;
  • R 3 is selected from -H, -C-i_5 alkyl
  • R 4 is -H
  • R 5 is selected from the group consisting of ⁇ H or ⁇ (CH 2 ) n --(optionally substituted aryl), wherein the substituent is selected from -Hal and -C ⁇ 4 alkyl; or wherein R 4 and R 5 together form a methylene group ⁇ CH 2 TM ethylene group -CH 2 CH 2 - or ethyne group -CHCH-, which can be optionally substituted by -C-, ⁇ alkyl, -halogen, -CHal 3 , -R 6 R 7 , -OR 6 , ⁇ CONR 6 R 7 , ⁇ S0 2 R 6 R 7 , aryl or heteroaryl;
  • R 6 is selected from -H and -d_4 a!kyl
  • R 7 is selected from -H and -C ⁇ alkyl
  • R 8 is selected from -H, -C- ⁇ e aikyl, -(CH 2 ) n -(optionaliy substituted aryl), -S0 2 -(CH 2 ) n - (optional!y substituted aryl), -S0 2 -(CH 2 ) n -(optionally substituted 5- to 10-membered mono- or bicyclic heteroring which contains at least one heteroatom selected from N, O and S), -(CH 2 ) n -(optionally substituted 5- or 6-membered heterocyclic ring which contains at least one heteroatom selected from N, O and S), wherein the substituent is selected from -Hal, -CF 3 , -C 1- alkyl, and -(CH 2 ) n -aryl;
  • R 9 is selected from -H, -C M alkyl, and ⁇ C H alkylene--NR 1 3 ⁇ 4 R 11 ;
  • R 10 is selected from -H, -C M alkyl, and -C ⁇ alky!ene-NR 11 R 11 ;
  • R 11 is selected from -H, -CF 3 , and -C-i_4 alkyl; each m is 0 or 1 ; and each n is independently 0, 1 , 2, or 3.
  • Further preferred endonuclease inhibitors are those having the general formula (A) as defined in the copending application with attorney's docket number T3448 US, the complete disclosure of which is incorporated by reference, !n particular, all descriptions with respect to the general formula of the compounds having the general formula (A), the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference.
  • the compounds having the general formula (A) can be optionally in the form of a pharmaceuttcaily acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined below.
  • Further preferred endonuclease inhibitors are those having the general formula (C) as defined in the copending application with attorney's docket number T3450 US, the complete disclosure of which is incorporated by reference.
  • the compounds having the general formula (C) can be optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined below.
  • cap-binding inhibitors are not particularly limited either and can be any cap-binding inhibitor, particularly any viral cap-binding inhibitor.
  • Preferred cap-binding inhibitors are those having the general formula (II) as defined in US application 61/550,057 and/or the compounds disclosed in WO2011/000566, the complete disclosure of which is incorporated by reference.
  • all descriptions with respect to the general formula of the compounds according to US 61/550,057 or WO2011/000566, the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference.
  • the compound having the general formula (SI) can be optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. It is defined as follows:
  • R Z is selected from -H, -C h alky!, -(CH 2 ) q -aryl, -(CH 2 ) q -heterocyclyl, -(CH 2 ) q -cycloa!kyl, -(CH 2 ) p -OR 25 , and -(CH 2 ) P -NR 25 R 26 ;
  • R 22 is selected from -H, -C ⁇ alkyl, -(CH 2 ) q -cycioalkyi ! -Hal, -CF 3 and -CN;
  • R 23 is selected from -aryl, -heterocyclyl, -cycloalkyl, -C(-R 28 )(-R 29 )-aryl, -C(-R 28 )(-R 29 )-heferocyclyl, and -C(-R 28 )(-R 29 )-cycloaikyl;
  • R 25 is selected from -H, -C ⁇ alkyl, and -(CH 2 CH 2 0),H;
  • R 26 is selected from -H, and -Cikos 6 alkyl; 27 is independently selected from -C-i_6 alkyl, -C(0)-Ci_s alkyl, -Hal, ⁇ CF 3 , -CN, -COOR 25 , -OR 25 , - ⁇ C ⁇ R ⁇ R 26 , -C(0)-NR 25 R 26 , and - R 25 -C(0)-C ⁇ 6 alkyl; 2 8 and R 29 are independently selected from -H, -C ⁇ aikyl, - ⁇ CH 2 ) q -aryl, - ⁇ CH 2 ) q - heierocyclyl, -(CH 2 ) (r cycloalkyl 1 -OH, -0-d_ 6 alkyl, -0-(CH 2 ) q -aryI, -0-(CH 2 ) q - heterocyclyl, and -0-(CH 2 ) -cycloalkyl; or R 28
  • XXI 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 -XR 12 and the other is R 10' ; R 10 , R 10' and R 10" are each individua!ly selected from the group consisting of hydrogen, d-Ce-alkyl, C 2 -C 6 -alkenyl, C 2 -C 3 -alkynyl, -(CH 2 ) n C(0)OH,
  • R 1 is selected from the group consisting of hydrogen, Ci-C 6 -alkyi, -CF 3 , C 2 -C 6 -alkenyl, C 2 -C 8 -alkynyi, -(CH 2 ) n -cycioalkyl, -(CH 2 ) suddenly-aryl, - ⁇ CH 2 ),-heterocycloalkyl and -(CH 2 ) n - heteroaryl; optionally substituted;
  • R 12 is selected from the group consisting of C-i-Cg-alkyl, -CF 3 , C 2 -C 6 -alkenyS, C 2 -C 6 - alkynyl, -(CH z ) n -cycloaikyl, -(CH 2 ) n -heterocycloa!kyl, -(CH 2 ) n -aryl ! ⁇ NR 16 R 17 , 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, C 2 ⁇ C 6 -alkynyi, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -aryl, -CF 3 , -C ⁇ 0)R 18 and -S(0) 2 R 1S ; optionally substituted;
  • R 18 is independently selected from the group consisting of d-Cg-alkyl, C 2 -C 6 -alkenyL C 2 -C 6 -alkynyi, - ⁇ CH 2 ) n -cycloalkyl and -CF 3 ; optionally substituted; and n is in each instance selected from 0, 1 and 2.
  • R' and R" are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -OE, cycloalkyi, heterocycloalkyl, aryi, heteroaryl, and ara!kyi or together form a heteroaryl, or heterocycloalkyl; optionally substituted;
  • R'" and R"" are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";
  • E is selected from the group consisting of alkyl, alkenyl, cycloalkyi, alkoxy, alkoxyaikyi, heterocycloalkyl, an aiicyclic system, aryl and heteroaryl; optionally substituted.
  • M2 ion channel inhibitors adamantanes
  • Oseltamivir neuraminidase inhibitors
  • Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. These two targets are located within distinct subunits of the polymerase complex and thus represent unique drug targets. Due to the fact that both functions are required for the so-called "cap-snatching" mechanism mandatory for viral transcription, concurrent inhibition of both functions is expected to act highly synergistica!ly. This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles.
  • Both of these active sites are composed of identical residues in all influenza A strains (e.g., avian and human) and hence this high degree of sequence conservation underpins the perception that these targets are not likely to trigger rapid resistant virus generation.
  • endonuclease and cap-binding inhibitors individually and in combination are ideal drug candidates to combat both seasonal and pandemic influenza, irrespectively of the virus strain.
  • an endonuclease inhibitor and a cap-binding inhibitor or a dual specific polymerase inhibitor targeting both the endonuclease active site and the cap- binding domain would be effective against virus strains resistant against adamantanes and neuraminidase inhibitors and moreover combine the advantage of low susceptibility to resistance generation with activity against a broad range of virus strains.
  • influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap- binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle.
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different antiviral target is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetics properties which act advantageously and synergisticaSly on the antivirai efficacy of the combination.
  • At least one compound selected from the first group of polymerase inhibitors is combined with at least one compound selected from the second group of polymerase inhibitors.
  • the first group of polymerase inhibitors which can be used in this type of combination therapy includes, but is not limited to, the compounds having the formula (A) and/or (C).
  • the second group of polymerase inhibitors which can be used in this type of combination therapy inciudes is not limited to, the compounds having the general formula (I), the compounds having the general formula (II), the compounds disclosed in WO 2011/000566, WO 2010/1 10231 , WO 2010/1 10409, WO 2006/030807 or US 5,475,109 as well as flutimide and analogues, favipiravir and analogues, epigallocatechin gailate and analogues, as well as nucleoside analogs such as ribavirine.
  • Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle.
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different extracellular antiviral target, especially the (e.g., viral) neuraminidase is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
  • At least one compound selected from the above mentioned first group of polymerase inhibitors is combined with at least one neuramidase inhibitor.
  • the neuraminidase inhibitor (particularly influenza neuramidase inhibitor) is not specifically limited. Examples include zanamivir, oseltamivir, peramivir, KDN DANA, FANA, and cyclopentane derivatives.
  • Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuc!ease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle.
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different extracellular and cytoplasmic antiviral target, especially the viral M2 ion channel, is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
  • the M2 channel inhibitor (particularly influenza M2 channel inhibitor) is not specifically limited. Examples include amantadine and rimantadine.
  • the combination of polymerase inhibitors with alpha giucosidase inhibitors influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle.
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target, with an inhibitor of a different extracellular target, especially alpha giucosidase is expected to act highly synergistical!y. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
  • At Ieast one compound selected from the above-mentioned first group of polymerase inhibitors is combined with at Ieast one alpha giucosidase inhibitor.
  • the alpha giucosidase inhibitor (particularly influenza alpha giucosidase inhibitor) is not specifically limited. Examples include the compounds described in Chang et a!., Antiviral Research 2011 , 89, 26-34. The combination of polymerase inhibitors with ligands of other influenza targets
  • Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle,
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of different extracellular, cytoplasmic or nucleic antiviral targets is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
  • At least one compound selected from the above mentioned first group of polymerase inhibitors is combined with at least one ligand of another influenza target.
  • the ligand of another influenza target is not specifically limited.
  • examples include compounds acting on the sialidase fusion protein, e.g. Fiudase (DAS181 ), si NAs and phosphorothioate oligonucleotides, signal transduction inhibitors (ErbB tyrosine kinase, Abi kinase family, MAP kinases, PKCa-mediated activation of ERK signaling as well as interferon (inducers).
  • influenza polymerase inhibitors preferably influenza polymerase inhibitors with a compound used as an adjuvance to minimize the symptoms of the disease
  • antibiotics anti-inflammatory agents like COX inhibitors (e.g., COX-1/COX-2 inhibitors, selective COX-2 inhibitors), lipoxygenase inhibitors, EP ligands (particularly EP4 ligands), bradykinin ligands, and/or cannabinoid ligands (e.g., CB2 agonists).
  • Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle.
  • the combination of a polymerase inhibitor specifically addressing a viral intracellular target with an compound used as an adjuvance to minimize the symptoms of the disease address the causative and symptomatic pathological consequences of viral infection.
  • This combination is expected to act synergistically because these different types of drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
  • R ' is -H, -Hal, - ⁇ optionally substituted alkyl), -(optionally substituted C 3 consult 7 cycloalkyl), -(optionally substituted aryl), -C H aikyl-(optiona!ly substituted C 3 _ 7 cycloalkyl), -C H a!kyl— (opiionally substituted aryl) or -X 1 -R 1 .
  • R * is -Hal, -(optionally substituted alkyl) (wherein the optional substituent of the alkyl group is preferably Hal, more preferably F); -C- alkyl— (optionally substituted aryl) (wherein the optional substituent of the aryl group is preferably halogen) or -X -R 1 .
  • R* is X 1 -R 1 .
  • X 1 is O, C(O), C ⁇ 0)0, OC(O); S, SO, S0 2 , NR 4 , N(R 5 )C(0), C(0)NR 5 , preferably X 1 is O, or NR 4 , more preferably X 1 is NR 4 .
  • X 1 is NR 4 and R and R 4 are joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N.
  • X 1 is NR 4 and R 1 is -S0 2 -R 4 .
  • X 2 is O, S, NR 4 , preferably X 2 is O.
  • X 3 is O or S, preferably X 3 is O.
  • X 4 is 0 or S, preferably X 4 is O.
  • 1 is -H, -(optionally substituted alkyl), -(optionally substituted C 3 _ 7 cycloalkyl), (optionally substituted aryl), -C -4 alkyl-(optionaily substituted C 3 potentially 7 cycloalkyl), -C ⁇ alkyl— (optiona!ly substituted aryl).
  • R 1 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted benzyl), more preferably R 1 is -H or -(optionally substituted benzyl).
  • 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted.
  • the at least one ring is aromatic such as an aryl or heteroaryl ring.
  • R z is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms and which contains at least two rings, wherein the hydrocarbon group can be optionally substituted.
  • At least one of the at least two rings is aromatic such as an aryl or heteroaryl ring.
  • Preferred examples of R 2 can be selected from the group consisting of
  • X is absent, CH 2 , NH, C(0)NH, S or O.
  • Y is CH 2 .
  • X and Y can be joined together to form an annulated, carbo- or heterocylic 3- to 8-membered ring which can be saturated or unsaturated.
  • Specific examples of X-Y include -CH 2 -, -CH 2 -CH 2 -, -0-, and -NH-.
  • R is independently selected from H, -C ⁇ alkyl, halogen, -CN, -OH, and -O-C ⁇ alkyl. is -H, -(optionally substituted Ci_e alkyi), -(optionally substituted C 3 _ 7 cycloalkyi), -(optionally substituted aryl), or -d_4 alkyi— (optionally substituted aryl) or if X 2 is NR 4 , then R 3 can aiso be -OH, preferably R 3 is -H, -C ⁇ alkyl or Bz.
  • R 4 and R 1 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N or if X 2 is NR 4 , then R 4 and R 3 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N.
  • R 4 is -H, -(optionally substituted aryl), or -(optionally substituted C ⁇ a alky!), more preferably, R 4 is -H or -(optionally substituted benzyl). is arriving H, -(optionaliy substituted alkyi), -(optionally substituted C3-.7 cycloalkyi), -(optionally substituted aryl), -C -4 aikyl-(optionally substituted C 3 _ 7 cycloalkyi), or -C1-4 alkyl ⁇ (optionally substituted aryl).
  • R 5 is -H.
  • R 6 is -H, or -C,..e alkyl.
  • the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN , -NR 6 R 6 , -O H , and -O-Ci-e aikyl.
  • the substituent is -halogen, more preferably F.
  • the optional substituent of the cycloalkyi group, the aryl group or the hydrocarbon group is selected from the group consisting of -C ⁇ alkyl, halogen, -CF 3 , -CN, -X 1 -R 5 and -C 1-4 alkyi— aryl.
  • the substituent is -halogen (preferably F), -OCH 3 or -CN.
  • a compound having the general formula (C) encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, tautomers, racemates, enantiomers, or dtastereomers or mixtures thereof unless mentioned otherwise.
  • V is N, or CR 6 .
  • X 1 is O, S, or NR 8 , preferably X 1 is O,
  • X 2 is R 5 , N(R 5 )C(0), C(0)NR 5 , O, C(O), C(0)0, OC(O); S, SO, S0 2 , S0 2 N(R 5 ) or
  • N(R 5 )S0 2 is N(R 5 )S0 2 .
  • X 2 is NR 6 or N(R s )S0 2 .
  • R * is -H, -Hal, -(optionally substituted d_6 alkyi), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heiercatcms selected from O, N and S), ⁇ Ci_4 alky!— ⁇ optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), or -X 2 -R 1 .
  • R * is H, - (optionally substituted aikyl), -(optionally substituted C 3 _ 7 cyc!oalkyl) or - X 2 -R 1 .
  • R 1 is -H, -(optionally substituted C H alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), -C 1-4 alkyl— (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S).
  • R 1 is -C M alkyl— (optionaHy substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S).
  • R 2 is -H, -(optionally substituted Ci assign 6 alkyl), -(optionally substituted C 3 _ 7 cycloalkyl), -(optionally substituted aryl), -Ci_ aikyl-(optiona!ly substituted C 3 _ 7 cycloalkyl), or -C ⁇ alkyl— (optionally substituted aryl) or if X 1 is NR' then R 2 can also be -OH.
  • R 2 is -H or -C ⁇ alkyl.
  • R 3 is -H, ⁇ R 7 , or -X 2 -R 7 .
  • R 3 is -H, ⁇ C M aikyl-(optional!y substituted aryl) or -S0 2 -R 6 .
  • R 3 is -H.
  • R 4 is -H, -(optionally substituted alkyl), -(optionally substituted C 3 _ 7 cycloalkyl), - ⁇ optionally substituted aryl), -Ci.. 4 alkyl— (optionally substituted C 3 potentially 7 cycloalkyl), or -C ⁇ alkyl— (optionally substituted aryl).
  • R 4 is -H, or -(optionally substituted C-i_ 6 alkyl).
  • R 5 is -H, -(optionally substituted C ⁇ 6 alkyl), - ⁇ optionally substituted C 3 _ 7 cycloalkyl), - ⁇ optionally substituted aryl), -C H alkyl— (optionally substituted C 3 _ 7 cycloalkyl), or -C-M alkyl— (optionally substituted aryl).
  • R 5 is -C-M aikyl— (optionally substituted aryl) or -(optionally substituted C 3 _ 7 cycloalkyl).
  • R 6 H, ⁇ Ci_ 6 alkyl, -aryl, halogen or CN.
  • R 6 is H or -aryl.
  • R 7 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring).
  • R 7 is -C-M aiky!-(optiona!iy substituted aryl).
  • R s is -H, -C ⁇ alkyl or ⁇ Ci_ 4 alkyl— (optionally substituted aryl).
  • R 8 is
  • n is 0 to 4, preferably 0 or 1.
  • the optional substituent of the alkyl group can be selected from the group consisting of halogen, -CN, -NR 5 R 5 , -OH, and -0-Ci_e alkyl.
  • the optional substituent of the cycloalkyl group, the aryl group, the mono- or polycyclic group or the hydrocarbon group can be selected from the group consisting of -C ⁇ e alkyl, halogen, -CF 3 , -CN, -X 2 -d_ 6 alkyl and -Ci_e alkyl— aryl.
  • influenza A virus PA-Nter fragment (amino acids 1 - 209) harbouring the influenza endonuclease activity was generated and purified as described in Dias et al., Nature 2009; Apr 16; 458(7240), 914-918.
  • the protein was dissolved in buffer containing 20mM Tris pH 8.0, I QOm!vl NaCI and l Om ⁇ -mercaptoethanol and aliquots were stored at -20 °C.
  • RNA oligo with 5 ' -FAM fluorophore and 3 ' -BHQ1 quencher was used as a substrate to be cleaved by the endonuclease activity of the PA-Nter. Cleavage of the RNA substrate frees the fluorophore from the quencher resulting in an increase of the fluorescent signal.
  • All assay components were diluted in assay buffer containing 20mM Tris-HC! pH 8.0, 100mM NaCi, 1 miv1 MnC! 2 , 1 QmM MgCI 2 and 10m ⁇ -mercaptoethano!.
  • the final concentration of PA- Nter was 0.5 ⁇ and 1.6 ⁇ RNA substrate.
  • the test compounds were dissolved in DMSO and generally tested at two concentrations or a concentration series resulting in a final plate well DMSO concentration of 0.5 %. In those cases where the compounds were not soluble at that concentration, they were tested at the highest soluble concentration.
  • SAV-6004 was used as a reference in the assay at a concentration of 0.1 ⁇ .
  • ⁇ IC 50 The half maximal inhibitory concentration ⁇ IC 50 ) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the initial reaction velocities (vO) ina given concentration series ranging from maximum 100 ⁇ to at least 2 nM.
  • 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 ardin- Darby canine kidney ( DCK; ATCC CCL-34) cells and infectious titres of virus stocks were determined by the 50 % tissue culture infective dose (TCtDso) analysis as described in Reed, L. J., and H. Muench. 1938, Am. J. Hyg. 27:493-497.
  • TCDso tissue culture infective dose
  • MDCK cells were seeded in 96-weil plates at 2> ⁇ 10 4 cells/well using DMEM/Ham's F-12 (1 :1 ) medium containing 10 % foetal bovine serum (FBS), 2 mM L-glutamine and 1 % antibiotics (ail from PAA). Until infection the cells were incubated for 5 hrs at 37 °C, 5.0 % C0 2 to form a -80 % confluent monolayer on the bottom of the well. Each test compound was dissolved in DMSO and generally tested at 25 ⁇ and 250 ⁇ . In those cases where the compounds were not soluble at that concentration they were tested at the highest soluble concentration.
  • the compounds were diluted in infection medium (DMEM/Ham's F-12 (1 :1 ) containing 5 pg/mi trypsin, and 1 % antibiotics) for a final plate well DMSO concentration of 1 %.
  • the virus stock was diluted in infection medium (DMEM/Ham's F-12 (1 :1 ) containing 5 pg/ml Trypsin, 1 % DMSO, and 1 % antibiotics) to a theoretical multiplicity of infection (MOi) of 0.05.
  • virus and compound were added together to the ceils.
  • no virus suspension was added. Instead, infection medium was added.
  • Each treatment was conducted in two replicates. After incubation at 37 °C, 5 % C0 2 for 48 hrs, each well was observed microscopicaliy for apparent cytotoxicity, precipitate formation, or other notable abnormalities. Then, cell viability was determined using CeilTiter- Glo luminescent cell viabiiity assay (Promega). The supernatant was removed carefully and 65 ⁇ of the reconstituted reagent were added to each well and incubated with gentle shaking for 15 min at room temperature.
  • Reduction in the virus-mediated cytopathic effect (CPE) upon treatment with the compounds 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 viabiiity of the corresponding uninfected sample resulting in % CPE reduction.
  • the half maximal inhibitory concentration (IC 50 ) is a measure of the effectiveness of a compound in inhibiting bioiogical or biochemical function and was calculated from the RLU response in a given concentration series ranging from maximum 100 ⁇ to at least 100 nM.
  • NaBH 4 (3.2 g, 86.2 mmol) was added portion wise to a cooled (ice bath) solution of 1-phenyi- cyclopentanecarbaidehyde (7.5 g, 43.1 mmol) in methanol (100 mi) and then stirred for 16 h at RT. After completion of the reaction, it was quenched with saturated ammonium chioride solution and the methanol under reduced pressure. The mixture was diluted with water, extracted with EtOAc, washed with water, brine, dried (Na 2 S0 ) and evaporated to dryness under reduced pressure.
  • Example 7 Preparation of 5-hydroxy-6-oxo-2-(1 -phenyl-cyclopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxylic acid.
  • Example 36 Preparation of 5 ⁇ ydroxy-2-(3'-meihyi-biphenyi-2-ylmethyi)-6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid amide
  • the compound was prepared using the same general procedure as Example 33 using 2,5- dimethylphenylboronic acid (4.21 g, 28.1 mmol. Eq: 1.1 ).
  • the titie compound was prepared as a colourless oil (4.7 g; 83%).
  • the compound was prepared using the same generai procedure as Example 32 using 2-(2',5'- dimeihylbiphenyl-2-yl)acetonitriie (4.7 g, 21.2 mmol) and diethyi but-2-ynedioate (3.61 g, 21.2 mmol).
  • the title product was isolated as a white solid (0.84 g; 10%).
  • LCMS: m/z 379 ( H+).
  • the compound was prepared according to the same procedure as in Example 21 using 2-(2- bromo-benzyi)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxyiic acid methyl ester (0.08 g; 0.236 mmol) and 4-chlorobenzylamine (0.5 ml; 4.1 mmol).
  • the title compound was prepared as a white solid (0.042 g; 39%).
  • LCMS: m/z 449 (MH+).
  • thiocyanatomethane (17.5 g, 239 mmoi) and N- methy!hydroxyiamine hydrochloride (20 g, 239 rnrnol) were combined with EtOH (100 mi) to give a light yellow solution.
  • Example 60 Preparation of 2-(4-chioro-phenylmethanesulfonyiamino)-5-hydroxy-1 - methyl-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxylic acid methy!amide and 5-hydroxy-1 - meihyl-6-oxo-2-phenylmeihanesuifony[arnino-1 ,6-dihydro-pynmidine-4-carboxyHc acid methyl amide
  • Cyciohexylmethyimagnesium bromide solution (1.77 ml; 885 ⁇ of 0.5M solution in THF) was added dropwise to a solution of 5-benzyloxy-2-methanesu!fonyl-1 -methyl-6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid methyl ester (0.26 g; 738 ⁇ ) in THF (10 ml). After stirring at room temperature for 1 h, the reaction mixture was quenched by the addition of saturated ammonium chloride solution.

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Abstract

The present invention relates to a compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, formula (Di), (Dii), (Diii) which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.

Description

Dihydroxypyrimidine carbonic acid derivatives
and their use in the treatment, amelioration or prevention of a viral disease
Field of the invention
The present invention relates to a compound having the general formula (Di), (Dii), or (Diii) optionally in the form of a pharmaceuticaliy acceptable salt, solvate, polymorph, codrug cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000003_0001
(Di) (Dii) (Diii) which is useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.
Background of the invention
In recent years the serious threat posed by influenza virus to worldwide public health has been highiighted by, firstly, the ongoing low level transmission to humans of the highly pathogenic avian H5N1 strain (63% mortality in infected humans, http;//www.who.int/ csr/disease/avian_influenza/en/) and secondly, the unexpected emergence in 2009 of a novel pandemic strain A H1N1 that has rapidly spread around the entire world (http://www.who.int/csr/disease/swineflu/en/). Whiist the new strain is highly contagious but currently only generally gives mild illness, the future evolution of this virus is unpredictable, in a much more serious, but highly plausible scenario, H5N1 could have been more easily transmissible between humans or the new A/H1N1 could have been more virulent and could have carried the single point mutation that confers Tamiflu resistance (Neumann et al., Nature, 2009 (18; 459(7249) 931-939)); as many seasonal H1 N1 strains have recently done (Dharan et al., The Journal of the American Medical Association, 2009 Mar 1 1 ; 301 (10), 1034-1041 ; Moscona et al., The New England Journal of Medicine, 2009 (Mar 5;360(10) pp 953-956)). In this case, the delay in generating and deploying a vaccine (-6 months in the relatively favourable case of A H1 N1 and still not a solved problem for H5N1 ) could have been catastrophically costly in human lives and societal disruption. It is widely acknowledged that to bridge the period before a new vaccine becomes available and to treat severe cases, as well as to counter the problem of viral resistance, a wider choice of anti-influenza drugs is required. Development of new anti-influenza drugs has therefore again become a high priority, having been largely abandoned by the major pharmaceutical companies once the anti-neuraminidase drugs became available.
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, M. et a!., (1993), Nature, 363, pp. 418-423) 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, J. et al., (2005), Appl. Microbiol. Biotechnol., 66, pp. 61.2-621). In addition, more unspecific viral drugs, such as ribavirin, have been shown to work for treatment of influenza and other virus infections (Eriksson, B. et al., (1977), Antimicrob. Agents Chemother., 11 , pp. 946-951 ). However, ribavirin is only approved in a few countries, probably due to severe side effects (Furuta et a!., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, p. 981-986). Cleariy, new antiviral compounds are needed, preferably directed against different targets. influenza virus as well as Thogotovirus beiong to the family of Orthomyxoviridae which, as we!l as the family of the Bunyaviridae, including the Hantavirus, Nairovirus, Orthobunyavirus, 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 virai mRNAs and (ii) the vRNA replication. This enzyme, a trimeric complex composed of subunits PA, PB1 and PB2, is central to the life cycle of the virus since it is responsible for the repiication and transcription of viral RNA. in previous work the atomic structure of two key domains of the polymerase, the mRNA cap-binding domain in the PB2 subunit (Guiiligay et al., Nature Structural & Molecular Biology 2008; May; 15(5): 500-506) and the endonuciease-active site in the PA subunit (Dias et al., Nature 2009, 458, 914-918) have been identified and determined. These two sites are critical for the unique cap-snatching mode of transcription that is used by influenza virus to generate viral mRNAs. For the generation of virai mRNA the polymerase makes use of the so called "cap-snatching" mechanism (Plotch, S. J. et al., (1981 ), Cell, 23, pp. 847-858; Kukkonen, S. K. et a! (2005), Arch. Virol., 150, pp. 533-556; Leahy, M. B. et al, (2005), J. Virol., 71 , pp. 8347-8351 ; Noah, D. L. et al., (2005), Adv. Virus Res., 65, pp. 121-145). 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 10 to 15 nucleotides. The capped RNA fragments then serve as primers for the synthesis of viral mRNA. 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, J. et al., (2005), Appl. Microbiol. Biotechnol., 66, pp. 612-621 ). 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 PB1 (Ghanem, A. ei al., (2007), J. Virol., 81 , pp. 7801 -7804). Furthermore, the endonuciease 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, J. et al., (1994), Antimicrob. Agents Chemother., 38, pp. 2827-2837). in addition, flutimide, a substituted 2,6-diketopiperazine, identified in extracts of Deiitschia confertaspora, a fungal species, has been shown to inhibit the endonuciease of influenza virus (Tomassini, J. et al., (1996), Antimicrob. Agents Chemother., 40, pp. 1 189-1 193), Moreover, there have been attempts to interfere with viral transcription by nucleoside analogs, such as 2'-deoxy-2'-fiuoroguanosine (Tisdaie, M. et al., (1995), Antimicrob. Agents Chemother., 39, pp. 2454-2458).
Certain heterocyclic carboxamides which are stated to be useful in preventing or treating atherosclerosis or restenosis are disclosed in WO 2004/019933. The compounds are stated to be useful in these applications due to their activity against herpes viruses because atherosclerosis is related to a number of herpes virus infections.
WO 2011/046920 refers to DXR inhibitors which are stated to be suitable for antimicrobial therapy.
B. M. Baughman et al. identify influenza endonuciease inhibitors using a fluorescence polarization assay (ACS Chem. Biol. 2012, 7, 526-534). it is an object of the present invention to identify further compounds which are effective against viral diseases and which have improved pharmacological properties.
Summary of the invention
Accordingly, in a first embodiment, the present invention provides a compound having the general formula (Di), (Dii), or (Diii).
It is understood that throughout the present specification the term "a compound having the general formula (Di), (Dii), or (Diii)" encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, codrugs, cocrystals, tautomers, racemates, enantiomers, or diastereomers or mixtures thereof unless mentioned otherwise. A further embodiment of the present invention relates to a pharmaceutical composition comprising a compound having the general formula (Dt), (Dii), or (Diii) and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s). The compounds having the general formula (Di), (Dii), or (Diii) are useful for treating, ameliorating or preventing viral diseases.
Detailed description of the invention
Before the present invention is described in detail beiow, 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, at! 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: (SUPAC Recommendations)", Leuenberger, H.G.W, Nage!, B. and Kolbl, 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, !n 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 D 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.
Definitions
The term "alkyl" refers to a saturated straight or branched carbon chain.
The term "cycloalkyl" represents a cyclic version of "aikyl". The term "cycloalkyl" is also meant to include bicycitc, tricyclic and polycyciic versions thereof. Unless specified otherwise, the cycSoalky! group can have 3 to 12 carbon atoms.
The term "cyclic heteroaikyl" includes monocyclic, bicyclic, tricyclic and polycyciic heteroalky! groups. Unless specified otherwise, the cyclic heteroaikyl group can have 3 to 12 atoms and can include one or more heteroatoms selected from N, O or S.
"Hal" or "halogen" represents F, CI, Br and I.
The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing in carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthyl or anthracenyl, preferably phenyl.
The term "heteroaryl" preferably refers to a five-or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2, 3, or 4 (for the five- membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S. Examples of the heteroaryl group include pyrrole, pyrrolidine, oxo!ane, iuran, imidazolidine, imidazole, pyrazoie, oxazolidine, oxazole, thiazole, piperidine, pyridine, morpholine, piperazine, and dioxo!ane.
The term "hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring" refers to any group having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and 2 as long as the group contains at least one ring. The term Is also meant to include bicyclic, tricyclic and polycyciic versions thereof. If more than one ring is present, they can be separate from each other or be annuiated. The ring(s) can be either carbocycfic or heterocyclic and can be saturated, unsaturated or aromatic. The carbon atoms and heteroatoms can either ail be present in the one or more rings or some of the carbon atoms and/or heteroatoms can be present outside of the ring, e.g., in a linker group {such as -{CH2)P- with p = 1 to 6). Examples of these groups include -(optionally substituted C3_7 cycioalkyi), -(optionally substituted aryl) wherein the aryl group can be, for example, phenyl, -(optionally substituted biphenyl), adamantyl, -(C3_7 cycloalkyl)-aryl as well as the corresponding compounds with a linker. Further examples of these groups include -(optionally substituted 3 to 7 membered. cyclic heteroalkyl) or -(optionally substituted heteroaryl) containing, for instance, 1 to 3 N atoms.
The term "(optionally substituted mono- or poiycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S)" refers to any mono- or poiycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S. This term includes monocyclic, bicyclic, tricyclic and poiycyclic versions thereof. If more than one ring is present, they can be separate from each other or be annuiated. The ring(s) can be either carbocyclic or heterocyclic and can be saturated, unsaturated or aromatic. The carbon atoms and heteroatoms can either ail be present in the one or more rings or some of the carbon atoms and/or heteroatoms can be present outside of the ring, e.g., in a linker group (such as -(CH2)P- with p = 1 to 6). Examples of these groups include -(optionally substituted C" r.vnlnaikvl'S and— nntinnallv Si ihetifi itaH arw wharain tha
Figure imgf000009_0001
nrni in nan ha fnr evannnle phenyl or anthracenyl as well as the corresponding compounds with a linker.
If a compound or moiety is referred to as being "optionally substituted", it can in each instance include 1 or more of the indicated substituents, whereby the substituents can be the same or different.
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 haltde, 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, benzenesuifonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesuifonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexySresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesuifonate, hydroxynaphthoate, iodide, isoihionate, lactate, lactobionate, laurate, lauryl sulfate, ma!ate, ma!eate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methy!g!ucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, po!ygalaciuronate, propionate, salicylate, stearate, sulfate, subacetaie, succinate, tannate, tartrate, teoclate, tosylate, t ethiodide, undecanoate, valerate, and the like (see, for example, S. . Berge et a!., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977)). When the compounds of the present Invention are provided in crystalline form, the structure can contain solvent molecules. The solvents are typically pharmaceutically acceptable solvents and include, among others, water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates. The term "codrug" refers to two or more therapeutic compounds bonded via a covalent chemical bond. A detailed definition can be found, e.g., in N. Das et a!., European Journal of Pharmaceutical Sciences, 41 , 2010, 571-588.
The term "cocrysta!" refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoichometric ratio of a target molecule or ion (i.e., compound of the present invention) and one or more neutral molecular cocrysta! formers. A detailed discussion can be found, for example, in Ning Shan et a!., Drug Discovery Today, 13(9/10), 2008, 440-446 and in D. J. Good et a!., Cryst. Growth Des., 9(5), 2009, 2252-2264. The compounds of the present invention can also be provided in the form of a prodrug, namely a compound which is metabolized in vivo to the active metabolite. Suitabie prodrugs are, for instance, esters. Specific examples of suitable groups are given, among others, in US 2007/0072831 in paragraphs [0082] to [01 18] under the headings prodrugs and protecting groups. If X1 is O or S, preferred examples of the prodrug include compounds in which R1 is replaced by one of the following groups:
Figure imgf000011_0001
In these formulae, R7 can be the same or different. R9 is a cyclic group such as an aryl group or a C cycloaikyl group, p is 2 to 8.
If X1 is NR*, preferred examples of the prodrug include compounds in which R and R* are not both H. Compounds having the general formula (Di), (Dii), or (Diii) The present invention provides a compound having the generai formula (Di), (Dii), or (Diii).
Figure imgf000012_0001
(Di) (Dii) (Diii)
The present invention provides a compound having the generai formula (Di), (Dii), or (Diii) which the following definitions apply,
X1 is O, S or NR*; preferably O, or NR*. ■ S; preferably O.
X3 is O or S; preferably O.
X4 is O or S; preferably O. X5 is O or S; preferably O.
L is -(CH2)m- -NR*-S02- or -S02-NR*-; preferably -(CH2)M- or -NR*-S02-. m is 1 to 4; preferably m is 1 or 2; more preferably m is 1 .
R1 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted C3_7 cycloalkyl), -(optionally substituted aryl), -C1 aikyl— (optionally substituted aryl), -C(0)-0-R** or ™P(0)(OR**)2. If X1 is NR* then R and R* can optionally be bound together to form a 5- to 7-membered ring. Preferably R is -H or -(optionally substituted C-HS alkyl). R2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroaioms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted. Preferably R2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C5-7 cycloalkyl, more preferably R2 is selected from
Figure imgf000013_0001
wherein the heterocyclic group, phenyl group, cyclohexyl group or cycSopentyl group can be optionally substituted in any available position by a subsiituent which is independently selected from -Ci_6 alkyl, halogen, -CF3, -CN, -OH, and -G-C^. alkyl.
R3 ic „!-! —/nntionallv cnhcfitntoH .. „
Figure imgf000013_0002
—Ynntinnalk/ ci ihctiti (tArj Π„ ,
-(optionally substituted aryl), or -C^ alkyl— (optionally substituted aryl).
R4 is -H, -(optionally substituted C -6 alkyl), -(optionally substituted C3-.7 cycloalkyl), -(optionally substituted aryl), or -C-M alkyl-(optionally substituted aryl). Rs is™H, -C(OWoptionaliy substituted Ci_6 alkyl), or -(optionally substituted C-i_e alkyl). R6 is -H, -C(0)-(optionally substituted alkyl), or -(optionally substituted Ci_6 alkyl). R* is -H, or -(C e alkyl); preferably -H. is -H, ™(Ci_6 alkyl), -(C^ cycloalkyl), -(aryl), or -C^ alkyl— (aryl); preferably -(C^ alkyl) or -(aryl). The optional substituent of the alkyf group is selected from the group consisting of halogen, -CN, -NR*R*, -OH, and -O-Cf-e alkyl:
The optional substituent of the cycloalkyl group, the aryi group or the hydrocarbon group is selected from the group consisting of ~C^6 alkyl, -halogen, -CF3) -CN, -X1~R*, -aryl and -C A alkyl-ar l.
The present inventors have surprisingly found that the compounds of the present invention which have a bulky, hydrophobic group represented by -L-R2 have improved pharmacological properties compared to corresponding compounds which have a less space demanding group in this position. Without wishing to be bound by theory, it is assumed that the viral polymerase protein has a pocket for binding and that this hydrophobic group of the compounds of the present invention has improved binding compared to other groups. This could not have been predicted or expected based on the art.
The compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient(s) and/or carriers). The compounds of the present invention can be administered by various well known, routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Oral, intranasal and parenteral administration are particulariy 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 caps!et, 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 injectionabie use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the final solution or dispersion form must be sterile and fluid. 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: binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethy! 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, croscarmel!ose, sodium methyl cellulose, agar, bentonite, aiginic 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, croscarmeilose 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 intranasaily 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 prope!lant, e.g., dichlorodifluoromethane, trichiorof!uoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 ,1 ,1 ,2-tetrafiuoroethane (HFA 134A™) or 1 ,1 ,1 ,2,3,3,3-heptafiuoropropane (HFA 227EA™), 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 propeliant 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, from 10 mg to 200 mg of the compound are orally administered to an adu!t 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 10 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 1 to 100 mg/kg body weight if parenteral administration is used. For intranasal administration, 1 to 100 mg/kg body weight are envisaged.
If a person is known to be at risk of developing a disease treatable with a compound of the invention, prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. 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, from 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective viral disorder has lessened. In most instances, however, a compound of the Invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily.
The compounds of the present invention are particularly useful for treating, ameliorating, or preventing viral diseases. The type of viral disease is not particularly limited. Examples of possible viral diseases include, but are not limited to, viral diseases which are caused by Poxvirldae, Herpesviridae, Adenoviridae, Papillomaviridae, Poiyomaviridae, Parvoviridae, Hepadnaviridae, Retroviridae, Reoviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae, Caiiciviridae, Astroviridae, Togaviridae, Flaviviridae, Deitavirus, Bornaviridae, and prions. Preferably viral diseases which are caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, more preferably viral diseases which are caused by orthomyxoviridae. Examples of the various viruses are given in the fo!iowing tabie.
Family Virus (preferred examples)
Poxviridae Smallpox virus
Moltuscum contagiosum virus
Herpesviridae Herpes simplex virus
Varicella zoster virus
Cytomegaiovirus
Epstein Barr virus
Kaposi's sarcoma-associated herpesvirus
Adenoviridae Human adenovirus A-F
Papillomaviridae Papillomavirus
Polyomaviridae BK-virus
JC-Virsu
Parvoviridae B19 virus
Adeno associated virus 2/3/5
Hepadnaviridae Hepatitis B virus
Retroviridae Human immunodeficiency virus
types 1/2
Human T-cell leukemia virus
Human foamy virus
Reoviridae Reovirus 1/2/3
Rotavirus A/B/C
Colorado tick fever virus
Filoviridae Ebola virus
Marburg virus
Paramyxoviridae Parainfluenza virus 1 -4
Mumps virus
Measles virus
Respiratory syncytial virus
Hendravirus
Rhabdoviridae Vesicular stomatitis virus
Rabies virus
Mokoia virus
European bat virus
Duvenhage virus
Orthomyxoviridae Influenza virus types A-C
Bunyaviridae California encephalitis virus
La Crosse virus
Hantaan virus
Puumala virus
Sin Nombre virus
Seoul virus
Crimean- Congo hemorrhagic fever virus Sakhalin virus
Rift valley virus
Sandfly fever virus
Uukuniemi virus
Arenaviridae Lassa virus
Lymphocytic choriomeningitis virus
Guanarito virus
Junin virus,
Machupo virus
Sabia virus
Coronaviridae Human coronavirus
Picornaviridae Human enterovirus types A-D (Poliovirus, Echovirus,
Coxsackie virus A/B)
Rhinovirus types A/B/C
Hepatitis A virus
Parechovirus
Food and mouth disease virus
Hepeviridae Hepatitis E virus
Caliciviridae Norwalk virus
Sapporo virus
Asiroviridae Human astrovirus 1
Togaviridae Ross River virus
Chikungunya virus
O'nyong-nyong virus
Rubella virus
Flaviviridae Tick-borne encephalitis virus
Dengue virus
Yellow Fever virus
Japanese encephalitis virus
Murray Valley virus
St. Louis encephalitis virus
West Nile virus
Hepatitis C virus
Hepatitis G virus
Hepatitis GB virus
Deltavirus Hepatitis deltavirus
Bornaviridae Bo navirus
Prions
Preferabiy, the compounds of the present invention are employed to treat influenza. Within the present invention, the term "influenza" includes influenza A, B, C, isavirus and thogotovirus and also covers bird flu and swine flu. The subject to be treated is not particularly restricted and can be any vertebrate, such as birds and mammals {including humans). Without wishing to be bound by theory it is assumed that the compounds of the present invention are capable of inhibiting endonuciease activity, particularly of the influenza virus. More specifically it is assumed that they directly interfere with the N-terminal part of the influenza PA protein, which harbours endonuciease activity. However, delivery of a compound into a cell may represent a problem depending on, e.g., the solubility of the compound or its capabilities to cross the cell membrane. The present invention not only shows that the claimed compounds have in vitro polymerase inhibitory activity but also in vivo antiviral activity.
A possible measure of the in vitro polymerase inhibitory activity of the compounds having the formula (Di), (Dii), (Diii), (A) and/or (C) is the FRET endonuciease activity assay disclosed herein. Preferably, the compounds exhibit a % reduction of at least about 50 % at 25 μΜ in the FRET assay. In this context, the % reduction is the % reduction of the initial reaction velocity (vO) of substrate cleavage of compound-treated samples compared to untreated samples. Preferably, the compounds exhibit an IC50 of at least about 40 μ , more preferably at least about 20 μΜ, in the FRET assay. The half maximal inhibitory concentration (iCS0) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the initial reaction velocities (vO) in a given concentration series ranging from maximum 100 μΜ to at least 2 n . A possible measure of the in vivo antiviral activity of the compounds having the formula (Di), (Dii), (Diii), (A) and/or (C) is the CPE assay disclosed herein. Preferably, the compounds exhibit a % reduction of at least about 30 % at 50 μΜ. In this connection, the reduction in the virus-mediated cytopathic effect (CPE) upon treatment with the compounds was calculated as follows: The cell viability of infected-treated and uninfected-treated cells was determined using an ATP-based cell viability assay (Promega). The response in relative luminescent units (RLU) of infected-u treated 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. Preferably, the compounds exhibit an IC50 of at least about 45 μΜ, more preferably at least about 10 μΜ, in the CPE assay. The half maximal inhibitory concentration (SC50) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the RLU response in a given concentration series ranging from maximum 100 μΜ to at least 100 nM.
The compounds having the general formula (Di), (Dii), or (Diii) can be used in combination with one or more other medicaments. The type of the other medicaments is not particularly Simited and will depend on the disorder to be treated. Preferably, the other medicament will be a further medicament which is useful in treating, ameioriating or preventing a viral disease, more preferably a further medicament which is useful in treating, ameioriating or preventing influenza.
The following combinations of medicaments are envisaged as being particularly suitable:
(i) The combination of endonuclease and cap-binding inhibitors (particularly targeting influenza). The endonuclease inhibitors are not particularly limited and can be any endonuclease inhibitor, particularly any virai endonuclease inhibitor. Preferred endonuclease inhibitors are those having the general formula (I) as defined in the US application with the serial number 61/550,045, filed on October 21 , 201 , the complete disclosure of which is incorporated by reference. In particular, all descriptions with respect to the general formula of the compounds according to US 61/550,045, the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference.
The compounds having the general formula (l) of this reference can optionally be in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined as follows (wherein the definitions of the various moieties given in this earlier application apply):
Figure imgf000021_0001
wherein
R1 is selected from -H, -C,_6 alkyl, -(C3_7 cycloalkyl) and ~CH2-(C3_7 cycloalkyf);
R2 is selected from -H,
Figure imgf000021_0002
aikyl, -Hai, -(C3-7 cycloalkyl), -CH2-(C3_7 cycloalkyl), -(CH2)m-(optiona!ly substituted aryl), -(optionally substituted 5- or 6- membered heterocyclic ring which contains at least one heteroatom selected from N, O and S, wherein the substituent is selected from -C^ aikyl, -halogen, -CN, -CHal3, -aryl, -NR6R7, and -CONR6R7;
R3 is selected from -H, -C-i_5 alkyl,
-(CH2) -NR6R8,
-(optionally substituted 5- or 6-membered carbo- or heterocyclic ring wherein the heterocyclic ring contains at least one heteroatom selected from N, O and S), wherein the substituent is selected from -Hal, -CM alkyl, -NR9R10, -(CH2)n-OH, -C(0)-NR9R10, -S02-NR9R10, -NH-C(0)-0-R11, -C(0)-0-R11, and a 5- or 6-membered heterocyclic ring which contains at least one heteroatom selected from N, O and S; or wherein R1 and R2 together form a phenyl ring or wherein R2 and R3 together form a phenyl ring;
R4 is -H;
R5 is selected from the group consisting of ~H or ~(CH2)n--(optionally substituted aryl), wherein the substituent is selected from -Hal and -C^4 alkyl; or wherein R4 and R5 together form a methylene group ~CH2™ ethylene group -CH2CH2- or ethyne group -CHCH-, which can be optionally substituted by -C-,^ alkyl, -halogen, -CHal3, -R6R7, -OR6, ~CONR6R7, ~S02R6R7, aryl or heteroaryl;
R6 is selected from -H and -d_4 a!kyl;
R7 is selected from -H and -C^ alkyl;
R8 is selected from -H, -C-^e aikyl, -(CH2)n-(optionaliy substituted aryl), -S02-(CH2)n- (optional!y substituted aryl), -S02-(CH2)n-(optionally substituted 5- to 10-membered mono- or bicyclic heteroring which contains at least one heteroatom selected from N, O and S), -(CH2)n-(optionally substituted 5- or 6-membered heterocyclic ring which contains at least one heteroatom selected from N, O and S), wherein the substituent is selected from -Hal, -CF3, -C1- alkyl, and -(CH2)n-aryl;
R9 is selected from -H, -CM alkyl, and ~CH alkylene--NR1 ¾R11; R10 is selected from -H, -CM alkyl, and -C^ alky!ene-NR11R11;
R11 is selected from -H, -CF3, and -C-i_4 alkyl; each m is 0 or 1 ; and each n is independently 0, 1 , 2, or 3.
Further preferred endonuclease inhibitors are those having the general formula (A) as defined in the copending application with attorney's docket number T3448 US, the complete disclosure of which is incorporated by reference, !n particular, all descriptions with respect to the general formula of the compounds having the general formula (A), the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference. The compounds having the general formula (A) can be optionally in the form of a pharmaceuttcaily acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined below. Further preferred endonuclease inhibitors are those having the general formula (C) as defined in the copending application with attorney's docket number T3450 US, the complete disclosure of which is incorporated by reference. In particular, all descriptions with respect to the general formula of the compounds having the general formula (C), the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference. The compounds having the general formula (C) can be optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. They are defined below. The cap-binding inhibitors are not particularly limited either and can be any cap-binding inhibitor, particularly any viral cap-binding inhibitor. Preferred cap-binding inhibitors are those having the general formula (II) as defined in US application 61/550,057 and/or the compounds disclosed in WO2011/000566, the complete disclosure of which is incorporated by reference. In particular, all descriptions with respect to the general formula of the compounds according to US 61/550,057 or WO2011/000566, the preferred embodiments of the various substituents as well as the medical utility and advantages of the compounds are incorporated herein by reference.
The compound having the general formula (SI) can be optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. It is defined as follows:
Figure imgf000024_0001
wherein Y is S;
RZ is selected from -H, -Chalky!, -(CH2)q-aryl, -(CH2)q-heterocyclyl, -(CH2)q-cycloa!kyl, -(CH2)p-OR25, and -(CH2)P-NR25R26;
R22 is selected from -H, -C^ alkyl, -(CH2)q-cycioalkyi! -Hal, -CF3 and -CN;
R23 is selected from -aryl, -heterocyclyl, -cycloalkyl, -C(-R28)(-R29)-aryl, -C(-R28)(-R29)-heferocyclyl, and -C(-R28)(-R29)-cycloaikyl;
R25 is selected from -H, -C^ alkyl, and -(CH2CH20),H;
R26 is selected from -H, and -Ci„6 alkyl; 27 is independently selected from -C-i_6 alkyl, -C(0)-Ci_s alkyl, -Hal, ~CF3, -CN, -COOR25, -OR25, -{C^ R^R26, -C(0)-NR25R26, and - R25-C(0)-C^6 alkyl; 28 and R29 are independently selected from -H, -C^ aikyl, -{CH2)q-aryl, -{CH2)q- heierocyclyl, -(CH2)(rcycloalkyl1 -OH, -0-d_6 alkyl, -0-(CH2)q-aryI, -0-(CH2)q- heterocyclyl, and -0-(CH2) -cycloalkyl; or R28 and R29 are together =0, -CH2CH2~,™CH2CH2CH2- or -CH2CH2CH2CH2-; p is 1 to 4; q is 0 to 4; and r is 1 to 3; wherein the aryl group, heterocyclyl group and/or cycioalkyl group can be optionally substituted with one or more substituents R27.
The compounds of WO201 1 /000566 have the general formula (XXi):
Figure imgf000025_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 individua!ly selected from the group consisting of hydrogen, d-Ce-alkyl, C2-C6-alkenyl, C2-C3-alkynyl, -(CH2)nC(0)OH,
-(CH2)nC(0)OR16, -(CH2)nOH, -{CH2)nOR16, -CF3l -(CH2)n-cycloaikyl, -(CH2)nC(0)NH2, -(CH2)nC(0}NHR16, -(CH2)nC(0)NR 6R17, -{CH2)nS(0)2NH2, -(CH2)nS(0)2NHR16, -(CH2)nS(0)2NR16R17, -(CH2)nS<0)2R16, halogen, -CN, -(CH2)n- aryl, -(CH2)n-heteroaryl, -(CH2)nNH2, -{CH2)nNHR16, and -{CH2)nNR16R17; optionally substituted;
R 1 is selected from the group consisting of hydrogen, Ci-C6-alkyi, -CF3, C2-C6-alkenyl, C2-C8-alkynyi, -(CH2)n-cycioalkyl, -(CH2)„-aryl, -{CH2),-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(0)2, -S(0)z-N(H)-, -S(0)2-N(R16)- -N(H)-S(0)2- -N(R 6)-S(0}2-, C(=NH), C<=N~R16), CH(NH2), CH(NHR16), CH(NR16R17), -C(0)-N(H)- -C(0)-N(R16)- -N(H)-C{0)-, -N(R 6)-C(0)- N(H), N(-R16} and O;
R12 is selected from the group consisting of C-i-Cg-alkyl, -CF3, C2-C6-alkenyS, C2-C6- alkynyl, -(CHz)n-cycloaikyl, -(CH2)n-heterocycloa!kyl, -(CH2)n-aryl! ~NR16R17, 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-alkynyi, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -CF3, -C{0)R18 and -S(0)2R1S; optionally substituted;
R18 is independently selected from the group consisting of d-Cg-alkyl, C2-C6-alkenyL C2-C6-alkynyi, -{CH2)n-cycloalkyl and -CF3; optionally substituted; and n is in each instance selected from 0, 1 and 2.
In the context of WO201 1/000566 the term "optionally substituted" in each instance 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, CI, Br or I; -N02) -CN, -OR', -NR'R", -(CO)OR', -(CO)O ™, -(CO)NR'R", -NR'COR"", -NR'COR', -NR"CONR'R", -NR"S02A, -COR'"; -S02NR'R", -OOCR'", -CR"'R"OHS -R'"OH, =0, and -E;
R' and R" are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -OE, cycloalkyi, heterocycloalkyl, aryi, heteroaryl, and ara!kyi or together form a heteroaryl, or heterocycloalkyl; optionally substituted;
R'" and R"" are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R"; and
E is selected from the group consisting of alkyl, alkenyl, cycloalkyi, alkoxy, alkoxyaikyi, heterocycloalkyl, an aiicyclic system, aryl and heteroaryl; optionally substituted.
Widespread resistance to both classes of licensed influenza antivirals (M2 ion channel inhibitors (adamantanes) and neuraminidase inhibitors (Oseltamivir)) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. For M2 ion channel inhibitors, the frequency of viral resistance has been increasing since 2003 and for seasonal influenza A H3N2, adamantanes are now regarded as ineffective. Virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes {rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI). For oseltamivir the WHO reported on significant emergence of influenza A/H1N1 resistance starting in the influenza season 2007/2008; and for the second and third quarters of 2008 in the southern hemisphere. Even more serious numbers were published for the fourth quarter of 2008 (northern hemisphere) where 95% of all tested isolates revealed no Ose!tamivir-susceptibility. Considering the fact that now most national governments have been stockpiling Oseltamivir as part of their influenza pandemic preparedness plan, it is obvious that the demand for new, effective drugs is growing significantly. To address the need for more effective therapy, preliminary studies using double or even triple combinations of antiviral drugs with different mechanisms of action have been undertaken. Adamantanes and neuraminidase inhibitors in combination were analysed in vitro and in vivo and found to act highly synergistically. However, it is known that for both types of antivirals resistant viruses emerge rather rapidly and this issue is not tackled by combining these established antiviral drugs.
Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. These two targets are located within distinct subunits of the polymerase complex and thus represent unique drug targets. Due to the fact that both functions are required for the so-called "cap-snatching" mechanism mandatory for viral transcription, concurrent inhibition of both functions is expected to act highly synergistica!ly. This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles.
Both of these active sites are composed of identical residues in all influenza A strains (e.g., avian and human) and hence this high degree of sequence conservation underpins the perception that these targets are not likely to trigger rapid resistant virus generation. Thus, endonuclease and cap-binding inhibitors individually and in combination are ideal drug candidates to combat both seasonal and pandemic influenza, irrespectively of the virus strain.
The combination of an endonuclease inhibitor and a cap-binding inhibitor or a dual specific polymerase inhibitor targeting both the endonuclease active site and the cap- binding domain would be effective against virus strains resistant against adamantanes and neuraminidase inhibitors and moreover combine the advantage of low susceptibility to resistance generation with activity against a broad range of virus strains.
The combination of inhibitors of different antiviral targets (particularly targeting influenza) focusing on the combination with (preferably influenza) polymerase inhibitors as dual or multiple combination therapy, influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap- binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. The combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different antiviral target is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetics properties which act advantageously and synergisticaSly on the antivirai efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-re!ationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors.
Typically, at least one compound selected from the first group of polymerase inhibitors is combined with at least one compound selected from the second group of polymerase inhibitors.
The first group of polymerase inhibitors which can be used in this type of combination therapy includes, but is not limited to, the compounds having the formula (A) and/or (C).
The second group of polymerase inhibitors which can be used in this type of combination therapy inciudes, but is not limited to, the compounds having the general formula (I), the compounds having the general formula (II), the compounds disclosed in WO 2011/000566, WO 2010/1 10231 , WO 2010/1 10409, WO 2006/030807 or US 5,475,109 as well as flutimide and analogues, favipiravir and analogues, epigallocatechin gailate and analogues, as well as nucleoside analogs such as ribavirine.
The combination of polymerase inhibitors with neuramidase inhibitors
Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuclease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. The combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different extracellular antiviral target, especially the (e.g., viral) neuraminidase is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence . improved dose-response-relationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors.
Typically, at least one compound selected from the above mentioned first group of polymerase inhibitors is combined with at least one neuramidase inhibitor.
The neuraminidase inhibitor (particularly influenza neuramidase inhibitor) is not specifically limited. Examples include zanamivir, oseltamivir, peramivir, KDN DANA, FANA, and cyclopentane derivatives.
The combination of polymerase inhibitors with M2 channel inhibitors
Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuc!ease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. The combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of a different extracellular and cytoplasmic antiviral target, especially the viral M2 ion channel, is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors. Typically, at least one compound selected from the above mentioned first group of polymerase inhibitors is combined with at ieast one M2 channel inhibitor.
The M2 channel inhibitor (particularly influenza M2 channel inhibitor) is not specifically limited. Examples include amantadine and rimantadine.
The combination of polymerase inhibitors with alpha giucosidase inhibitors influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. The combination of a polymerase inhibitor specifically addressing a viral intracellular target, with an inhibitor of a different extracellular target, especially alpha giucosidase, is expected to act highly synergistical!y. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors.
Typically, at Ieast one compound selected from the above-mentioned first group of polymerase inhibitors is combined with at Ieast one alpha giucosidase inhibitor.
The alpha giucosidase inhibitor (particularly influenza alpha giucosidase inhibitor) is not specifically limited. Examples include the compounds described in Chang et a!., Antiviral Research 2011 , 89, 26-34. The combination of polymerase inhibitors with ligands of other influenza targets
Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle, The combination of a polymerase inhibitor specifically addressing a viral intracellular target with an inhibitor of different extracellular, cytoplasmic or nucleic antiviral targets is expected to act highly synergistically. This is based on the fact that these different types of antiviral drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors.
Typically at least one compound selected from the above mentioned first group of polymerase inhibitors is combined with at least one ligand of another influenza target.
The ligand of another influenza target is not specifically limited. Examples include compounds acting on the sialidase fusion protein, e.g. Fiudase (DAS181 ), si NAs and phosphorothioate oligonucleotides, signal transduction inhibitors (ErbB tyrosine kinase, Abi kinase family, MAP kinases, PKCa-mediated activation of ERK signaling as well as interferon (inducers).
(vii) The combination of (preferably influenza) polymerase inhibitors with a compound used as an adjuvance to minimize the symptoms of the disease (antibiotics, anti-inflammatory agents like COX inhibitors (e.g., COX-1/COX-2 inhibitors, selective COX-2 inhibitors), lipoxygenase inhibitors, EP ligands (particularly EP4 ligands), bradykinin ligands, and/or cannabinoid ligands (e.g., CB2 agonists). Influenza virus polymerase inhibitors are novel drugs targeting the transcription activity of the polymerase. Selective inhibitors against the cap-binding and endonuciease active sites of the viral polymerase severely attenuate virus infection by stopping the viral reproductive cycle. The combination of a polymerase inhibitor specifically addressing a viral intracellular target with an compound used as an adjuvance to minimize the symptoms of the disease address the causative and symptomatic pathological consequences of viral infection. This combination is expected to act synergistically because these different types of drugs exhibit completely different mechanisms of action and pharmacokinetic properties which act advantageously and synergistically on the antiviral efficacy of the combination.
This highly efficient drug combination would result in lower substance concentrations and hence improved dose-response-relationships and better side effect profiles. Moreover, advantages described under (i) for polymerase inhibitors would prevail for combinations of inhibitors of different antiviral targets with polymerase inhibitors.
Compounds having the general formu!a (A)
The compounds having the general formula (A) are identified in the following.
Figure imgf000033_0001
(A)
The present invention provides a compound having the general formula (A) in which the following definitions apply. R' is -H, -Hal, -{optionally substituted alkyl), -(optionally substituted C3„7 cycloalkyl), -(optionally substituted aryl), -CH aikyl-(optiona!ly substituted C3_7 cycloalkyl), -CH a!kyl— (opiionally substituted aryl) or -X1-R1. In a preferred embodiment, R* is -Hal, -(optionally substituted alkyl) (wherein the optional substituent of the alkyl group is preferably Hal, more preferably F); -C- alkyl— (optionally substituted aryl) (wherein the optional substituent of the aryl group is preferably halogen) or -X -R1. In a more preferred embodiment R* is X1-R1. X1 is O, C(O), C{0)0, OC(O); S, SO, S02, NR4, N(R5)C(0), C(0)NR5, preferably X1 is O, or NR4, more preferably X1 is NR4. in one preferred embodiment, X1 is NR4 and R and R4 are joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N. In another preferred embodiment, X1 is NR4 and R1 is -S02-R4.
X2 is O, S, NR4, preferably X2 is O.
X3 is O or S, preferably X3 is O.
X4 is 0 or S, preferably X4 is O. 1 is -H, -(optionally substituted alkyl), -(optionally substituted C3_7 cycloalkyl), (optionally substituted aryl), -C -4 alkyl-(optionaily substituted C3„7 cycloalkyl), -C^ alkyl— (optiona!ly substituted aryl). Preferably R1 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted benzyl), more preferably R1 is -H or -(optionally substituted benzyl). Throughout the present specification, it is understood that the definitions of the substituents of the aryl group apply analogously to the benzyl group. 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted. Preferably, the at least one ring is aromatic such as an aryl or heteroaryl ring. More preferably, Rz is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms and which contains at least two rings, wherein the hydrocarbon group can be optionally substituted.
Even more preferably, at least one of the at least two rings is aromatic such as an aryl or heteroaryl ring. Preferred examples of R2 can be selected from the group consisting of
Figure imgf000034_0001
wherein X is absent, CH2, NH, C(0)NH, S or O. Furthermore,
Y is CH2.
in an alternative embodiment, X and Y can be joined together to form an annulated, carbo- or heterocylic 3- to 8-membered ring which can be saturated or unsaturated. Specific examples of X-Y include -CH2-, -CH2-CH2-, -0-, and -NH-.
R is independently selected from H, -C^ alkyl, halogen, -CN, -OH, and -O-C^ alkyl. is -H, -(optionally substituted Ci_e alkyi), -(optionally substituted C3_7 cycloalkyi), -(optionally substituted aryl), or -d_4 alkyi— (optionally substituted aryl) or if X2 is NR4, then R3 can aiso be -OH, preferably R3 is -H, -C^ alkyl or Bz. is -H, -(optionally substituted C-i_6 alkyl), -(optionally substituted C3_7 cycloalkyi), - (optionally substituted aryl), -C1-4 alkyl— (optionaliy substituted C^7 cycloalkyi), or -C^ alkyi— (optionally substituted aryl) or if X1 is NR4, then R4 and R1 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N or if X2 is NR4, then R4 and R3 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N. Preferably, R4 is -H, -(optionally substituted aryl), or -(optionally substituted C^a alky!), more preferably, R4 is -H or -(optionally substituted benzyl). is „H, -(optionaliy substituted alkyi), -(optionally substituted C3-.7 cycloalkyi), -(optionally substituted aryl), -C -4 aikyl-(optionally substituted C3_7 cycloalkyi), or -C1-4 alkyl~~(optionally substituted aryl). Preferably, R5 is -H.
R6 is -H, or -C,..e alkyl.
The optional substituent of the alkyl group is selected from the group consisting of halogen, -CN , -NR6R6, -O H , and -O-Ci-e aikyl. Preferably the substituent is -halogen, more preferably F.
The optional substituent of the cycloalkyi group, the aryl group or the hydrocarbon group is selected from the group consisting of -C^ alkyl, halogen, -CF3, -CN, -X1-R5 and -C1-4 alkyi— aryl. Preferably, the substituent is -halogen (preferably F), -OCH3 or -CN. Compounds having the general formula (C)
The compounds having the genera! formula (C) are identified in the following.
Figure imgf000036_0001
(C)
It is understood that throughout the present specification the term "a compound having the general formula (C)" encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, tautomers, racemates, enantiomers, or dtastereomers or mixtures thereof unless mentioned otherwise.
In the present invention the following definitions apply with respect to the compounds having the genera! formula (C).
V is N, or CR6.
X1 is O, S, or NR8, preferably X1 is O,
X2 is R5, N(R5)C(0), C(0)NR5, O, C(O), C(0)0, OC(O); S, SO, S02, S02N(R5) or
N(R5)S02. Preferably, X2 is NR6 or N(Rs)S02.
R* is -H, -Hal, -(optionally substituted d_6 alkyi), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heiercatcms selected from O, N and S), ~Ci_4 alky!— {optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), or -X2-R1. Preferably R* is H, - (optionally substituted aikyl), -(optionally substituted C3_7 cyc!oalkyl) or - X2-R1.
R1 is -H, -(optionally substituted CH alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), -C1-4 alkyl— (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S). Preferably R1 is -CM alkyl— (optionaHy substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S).
R2 is -H, -(optionally substituted Ci„6 alkyl), -(optionally substituted C3_7 cycloalkyl), -(optionally substituted aryl), -Ci_ aikyl-(optiona!ly substituted C3_7 cycloalkyl), or -C^ alkyl— (optionally substituted aryl) or if X1 is NR' then R2 can also be -OH. Preferably, R2 is -H or -C^ alkyl.
R3 is -H, ~R7, or -X2-R7. Preferably R3 is -H, ~CM aikyl-(optional!y substituted aryl) or -S02-R6. Preferably R3 is -H.
R4 is -H, -(optionally substituted alkyl), -(optionally substituted C3_7 cycloalkyl), -{optionally substituted aryl), -Ci..4 alkyl— (optionally substituted C3„7 cycloalkyl), or -C^ alkyl— (optionally substituted aryl). Preferably, R4 is -H, or -(optionally substituted C-i_6 alkyl).
R5 is -H, -(optionally substituted C^6 alkyl), -{optionally substituted C3_7 cycloalkyl), -{optionally substituted aryl), -CH alkyl— (optionally substituted C3_7 cycloalkyl), or -C-M alkyl— (optionally substituted aryl). Preferably R5 is -C-M aikyl— (optionally substituted aryl) or -(optionally substituted C3_7 cycloalkyl).
R6 H, ~Ci_6 alkyl, -aryl, halogen or CN. Preferably, R6 is H or -aryl.
R7 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring). Preferably, R7 is -C-M aiky!-(optiona!iy substituted aryl).
Rs is -H, -C^ alkyl or ~Ci_4 alkyl— (optionally substituted aryl). Preferably, R8 is
-Ci_6 alkyl or -CM alkyl— (optionally substituted aryl).
n is 0 to 4, preferably 0 or 1.
The optional substituent of the alkyl group can be selected from the group consisting of halogen, -CN, -NR5R5, -OH, and -0-Ci_e alkyl.
The optional substituent of the cycloalkyl group, the aryl group, the mono- or polycyclic group or the hydrocarbon group can be selected from the group consisting of -C^e alkyl, halogen, -CF3, -CN, -X2-d_6 alkyl and -Ci_e alkyl— aryl. 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 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.
EXAMPLES
FRET endonuclease activity assay
The influenza A virus (IAV) PA-Nter fragment (amino acids 1 - 209) harbouring the influenza endonuclease activity was generated and purified as described in Dias et al., Nature 2009; Apr 16; 458(7240), 914-918. The protein was dissolved in buffer containing 20mM Tris pH 8.0, I QOm!vl NaCI and l Om β-mercaptoethanol and aliquots were stored at -20 °C.
A 20 bases dual-labelled RNA oligo with 5'-FAM fluorophore and 3'-BHQ1 quencher was used as a substrate to be cleaved by the endonuclease activity of the PA-Nter. Cleavage of the RNA substrate frees the fluorophore from the quencher resulting in an increase of the fluorescent signal.
All assay components were diluted in assay buffer containing 20mM Tris-HC! pH 8.0, 100mM NaCi, 1 miv1 MnC!2, 1 QmM MgCI2 and 10m β-mercaptoethano!. The final concentration of PA- Nter was 0.5μ and 1.6μΜ RNA substrate. The test compounds were dissolved in DMSO and generally tested at two concentrations or a concentration series resulting in a final plate well DMSO concentration of 0.5 %. In those cases where the compounds were not soluble at that concentration, they were tested at the highest soluble concentration. SAV-6004 was used as a reference in the assay at a concentration of 0.1 μΜ. 5μ[ of each compound dilution was provided in the wells of white 384-weli microliter plates (Perkin Elmer) in eight replicates. After addition of PA-Nter dilution, the plates were sealed and incubated for 30min at room temperature prior to the addition of 1 ,6μΜ RNA substrate diluted in assay buffer. Subsequently, the increasing fluorescence signal of cleaved RNA was measured in a microplate reader (Synergy HT, Biotek) at 485nm excitation and 535nm emission wavelength. The kinetic read interval was 35sec at a sensitivity of 35. Fluorescence signal data over a period of 20min were used to calculate the initial velocity (vO) of substrate cleavage. Final readout was the % reduction of vO of compound-treated samples compared to untreated. The half maximal inhibitory concentration {IC50) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function and was calculated from the initial reaction velocities (vO) ina given concentration series ranging from maximum 100 μΜ to at least 2 nM.
Cytopathic effect (CPE) assay
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 ardin- Darby canine kidney ( DCK; ATCC CCL-34) cells and infectious titres of virus stocks were determined by the 50 % tissue culture infective dose (TCtDso) analysis as described in Reed, L. J., and H. Muench. 1938, Am. J. Hyg. 27:493-497.
MDCK cells were seeded in 96-weil plates at 2><104 cells/well using DMEM/Ham's F-12 (1 :1 ) medium containing 10 % foetal bovine serum (FBS), 2 mM L-glutamine and 1 % antibiotics (ail from PAA). Until infection the cells were incubated for 5 hrs at 37 °C, 5.0 % C02 to form a -80 % confluent monolayer on the bottom of the well. Each test compound was dissolved in DMSO and generally tested at 25 μ and 250 μ . In those cases where the compounds were not soluble at that concentration they were tested at the highest soluble concentration. The compounds were diluted in infection medium (DMEM/Ham's F-12 (1 :1 ) containing 5 pg/mi trypsin, and 1 % antibiotics) for a final plate well DMSO concentration of 1 %. The virus stock was diluted in infection medium (DMEM/Ham's F-12 (1 :1 ) containing 5 pg/ml Trypsin, 1 % DMSO, and 1 % antibiotics) to a theoretical multiplicity of infection (MOi) of 0.05.
After removal of the culture medium and one washing step with PBS, virus and compound were added together to the ceils. In the weils used for cytotoxicity determination (i.e. in the absence of viral infection), no virus suspension was added. Instead, infection medium was added. Each treatment was conducted in two replicates. After incubation at 37 °C, 5 % C02 for 48 hrs, each well was observed microscopicaliy for apparent cytotoxicity, precipitate formation, or other notable abnormalities. Then, cell viability was determined using CeilTiter- Glo luminescent cell viabiiity assay (Promega). The supernatant was removed carefully and 65 μΙ of the reconstituted reagent were added to each well and incubated with gentle shaking for 15 min at room temperature. Then, 60 μΙ of the solution was transferred to an opaque piate and luminescence (RLU) was measured using Synergy HT plate reader (Biotek). Relative cell viabiiity vaiues of uninfected-treated versus uninfected-untreated cells were used to evaluate cytotoxicity of the compounds. Substances with a relative viabiiity below 80 % at the tested concentration were regarded as cytotoxic and retested at lower concentrations.
Reduction in the virus-mediated cytopathic effect (CPE) upon treatment with the compounds 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 viabiiity of the corresponding uninfected sample resulting in % CPE reduction. The half maximal inhibitory concentration (IC50) is a measure of the effectiveness of a compound in inhibiting bioiogical or biochemical function and was calculated from the RLU response in a given concentration series ranging from maximum 100 μΜ to at least 100 nM.
Example 1 : Preparation of 1 -phenyl-cyclo entanecarbonitriie
Figure imgf000040_0001
To a suspension of NaH (1 1.3 g, 28 .7 mmol, 60 %) in DMSO (75 mi) were added dropwise a mixture of phenyl-acetonitrile (15 g, 128.0 mmol) and 1 ,4-dibromo-butane (18 ml, 128.0 mmol) dissolved in DMSO: Ether (150 ml, 1 :1 ) at 0 °C and the reaction mixture was stirred at room temperature (RT) for 2 to 3 h. After completion of the reaction, water and 10% HCi solution were added to the crude mass. It was extracted with EtOAc. The organic layer was dried over Na2S04l concentrated and purified by column chromatography (10% EtOAc-hexane) to get 1 - phenyi-cyciopentanecarbonitrile (2) {19 g, 86.64 %) as a yellow solid. MS: m/z = 171 (MH÷). Example 2; Preparation of 1 -phenyl-cyclopentanecarbaldehyde
Figure imgf000041_0001
To a solution of 1 ~phenyi-cyclopentanecarbonitrile (17 g, 99.4 mmol) in DCM (200 ml) was added diisobutylaluminium hydride (DIBAL) (140 ml, 25% in toiuene, 248.5 mmol) very slowly. The mixture was stirred at -70 °C for 2 h. After completion of the reaction, it was slowly quenched by the addition of aqueous potassium sodium tartrate solution and then the mixture was stirred at RT for 16 h. It was then extracted with dichloromethane (DCM), washed with water, brine and dried with Na2S04. The organic phase was concentrated to provide 1-phenyl- cyciopentanecarbaidehyde as a colorless liquid (15.5 g, crude).
ExmapSe 3: Preparation of (1 -phenyl-cyclopentyl)-methanol
Figure imgf000041_0002
NaBH4 (3.2 g, 86.2 mmol) was added portion wise to a cooled (ice bath) solution of 1-phenyi- cyclopentanecarbaidehyde (7.5 g, 43.1 mmol) in methanol (100 mi) and then stirred for 16 h at RT. After completion of the reaction, it was quenched with saturated ammonium chioride solution and the methanol under reduced pressure. The mixture was diluted with water, extracted with EtOAc, washed with water, brine, dried (Na2S0 ) and evaporated to dryness under reduced pressure. Chromatography (15% EtOAc in hexanes) provided (1 -phenyi- cyclopenty!)-methanol as a white solid (6 g, 79.8%). Example 4: Preparation of methanesulfonic acid 1 -phenyl -eye! opentyl methyl ester
Figure imgf000042_0001
To a solution of (l -phenyl-cyclopeniyl)-methano! (1 1.5 g, 64.34 mmol) in DCM (100 mi) was added TEA (17.5 ml, 130.68 mmol) and followed by methanesuifonyl chloride (MsCI) (8.9 g, 78.4 mmoi) was added drop wise at 0 °C and the reaction mixture was stirred at RT for 16 h. After completion of the reaction, it was quenched with water and concentrated. Then the crude product was dissolved in DCM, extracted with DCM and the organic layer was washed with water, and brine and then dried over Na2S0 . The combined organic layer was concentrated to get crude methanesulfonic acid 1-phenyl-cyclopentylrrtethy! ester (10 g, crude) as a white solid.
Example 5: Preparation of (1 -phenyl-cyciopentyl)-acetonitrile
Figure imgf000042_0002
To a stirred solution of methanesulfonic acid 1 -phenyi-cyciopentylmethyi ester (10 g, 39.37 mmol) in DMSO (30 mi) were added Kl (0.6 g, 3.9 mmol) and NaCN (2.89 g, 59.05 mmol). It was then stirred at 140 °C for 16 h. After completion of the reaction, it was diluted with water, extracted with EtOAc and the organic layer was washed with water and brine, it was then dried over Na2S04, concentrated and purified by normal column chromatography (15% EtOAc in hexanes) to afford the title compound as a colorless liquid {2.5 g, 34%). Example 6: Preparation of 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxyiic acid methyl ester
Figure imgf000043_0001
A solution of potassium hydroxide ( 0.8 ml, 10.8 mmol) in methanol and hydroxylamine hydrochloride (10.8 ml, 10.8 mmol) in methanol were mixed, filtered and added to 2-(1- phenylcyclopentyl)acetonitrile (1 g, 5.4 mmol) in methanol (MeOH) and stirred at 60 °C for 24 h. it was then evaporated to dryness. The residue was dissolved in chloroform (30 ml) and to this was added dimethyl but-2-ynedioate {844 mg, 5.94 mmol). The reaction mixture was The mixture was stirred at 60 °C for 24 h, cooled and evaporated to dryness. The residue was dissolved in xylene (10 ml) and heated at 140 °C in a microwave oven for 1 h. The cooled residue was evaporated to dryness. Chromatography was conducted (40 g Si02; 10 to 70% EtOAc in hexanes). The residue was triturated with EtOAc, filtered and washed with Et20 and dried under vacuum to give the title product as an off-white solid (0.110 g; 6%). LCMS: m/z = 329 (MH+).
Example 7: Preparation of 5-hydroxy-6-oxo-2-(1 -phenyl-cyclopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxylic acid.
Figure imgf000043_0002
A solution of iithium hydroxide (7.66 mg, 320 Mmol) in water (1.00 ml) was added to a stirred mixture of methyl 5,6-dihydroxy-2~((1~phenyicyclopentyl)methyl)pyrimidine-4-carboxy!ate (0.035 g, 107 pmol) in tetrahydrofuran (THF) (4 ml). The mixture was stirred at RT for 72 h and then quenched with amber!yst (H+) IE resin, filtered and evaporated to dryness. The residue was triturated with EtOAc and dried under vacuum to give the title product as a white solid (0.012 g; 32%). LCMS: m/z = 315 (MH+).
Example 8; Preparation of 5-hydroxy-6-oxo-2-(1 -phenyl-cyclopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxylic acid amide
Figure imgf000044_0001
A solution of methyl 5,6-dihydroxy-2-((1-phenylcyciopentyl)methyl)pyrimidine-4-carboxylate (0.020 g, 60.9 pmoi) in ammonia in MeOH (435 μΙ, 3.05 mmoi) was heated at 100 °C for 20 min. The cooled solution was evaporated to dryness. The residue was diluted with MeOH and heated in the presence of Amberlyst resin (H+) until in solution. The material was filtered to remove the resin and evaporated to dryness. Trituration with MeOH followed by washing with Et20 provided the desired product as a white solid (0.01 g; 49%). LCMS: m/z = 314 (MH+).
Example 9: Preparation of 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxylic acid methylamide
Figure imgf000044_0002
To a solution of 5,6-dihydroxy-2-(1-phenyl-cyclopentylmethyI)-pyrimidine-4~carboxylic acid methyl ester (55 mg, 0.167 mmoi) in THF (2 ml) was added 2M solution of methyl amine in THF (0.419 mL, 0.838 mmoi) under nitrogen atmosphere in a microwave vessel. The reaction mixture was heated in a microwave oven at 1 10 °C for 10 min, then cooled and evaporated to dryness. The residue was washed with water and 30% ethyl acetate in hexane to get the title compound as an off-white solid (0.020 g, 36%). LCMS: m/z = 327.8 (MH+).
Example 10: Preparation of 5-hydroxy-6-oxo-2-(1 -phenyl-cyclopentylmethyl)-1 ,6- dihydro-pyrimidine-4-carboxylic acid benzylamide
Figure imgf000045_0001
5,6-Dihydroxy-2-(1-phenyl-cyciopentylmethyl)-pyrimidine-4-carboxylic acid benzylamide was synthesized as an off-white solid (20 mg, 30%) from 55 mg of 5,6-dihydroxy-2-(1-phenyl- cyclopentylmethyl)-pyrimidine-4-carboxylic acid methyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyciopentyimethy!)-1 ,6-dihydro-pyrimidine-4- carboxyiic acid methySamide (Example 9). LCMS: m/z = 403.8 ( H+).
Example 11 : Preparation of 5-hydroxy-1 -methyl -6 -oxo-2 -(1 -phenyl-cyclopentylmethyl)- 1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester
Figure imgf000045_0002
5-Hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopentyimethyl)-1 ,6-dihydro-pyrimidine-4-carboxyiic acid ethyl ester was synthesized as a brown solid (35 mg, 20%) from 200 mg of 5- ethoxycarbonylmethyl-2-methyl-3-(1-phenyl-cyclopentylmethyl)-2,5-dihydro-[1 ,2,4]oxadiazole- 5-carboxyiic acid ethyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1- phenyl-cyclopentylmethyi)-1 ,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (Example 6). LCMS: m/z = 357.0 (MH+). Example 12: Preparation of 5-hydroxy-1 -methyl-6-oxo-2-(1 -phenyi-cyclopentylmethyl) 1 ,6-dihydro-pyrimidine-4-carboxylic acid
Figure imgf000046_0001
5-Hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopen†ylm^
acid ethyi acid was synthesized as a white solid (30 mg, 23.2%) from 140 mg of 5-hydroxy-1- meihyl-6-oxo-2-(1-phenyi-cyclopentylmethyl)- ,6-dihydro-pyrirnidine-4-carboxylic acid ethyi ester foliowing the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyciopentylmethyi)- 1 ,6-dihydro-pyrtmidine-4-carboxylic acid (Example 7). LCMS: m/z 327,0 (M-H).
Example 13: Preparation of 5-hydroxy-1 -methyl-6-oxo-2-(1 -phenyl-cyclopentylmethyl)- 1 ,6-dihydro-pyrimidine-4-carboxylic acid methylamide
Figure imgf000046_0002
To a mixture of 5-hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyciopentylmethyl)-1 ,6-dihydro- pyrimidine-4-carboxy!ic acid ethyl ester (175 mg, 0.491 mmol) and methyl amine (0.98 mi, 1.96 mmol, 2M in THF) was added a catalytic amount of e3AI under argon atmosphere in a sealed tube and it was heated at 60°C for 16 h. After completion of the reaction, it was quenched with ice slowly and then extracted with EtOAc. The combined organic iayer was then washed with water and brine, it was then dried over Na2S04 and concentrated under vacuum. Purification by preparative HPLC provided the title compound as an off-white solid (40 mg, 24%). LCMS: m/z = 342.0 ( H+), Example 14: Preparation of 2»biphenyS-2-yimethyl-5-hydroxy-1 -methy!-6- dihydro-pyrimidine-
4-carboxylic acid methyl ester
Figure imgf000047_0001
A mixture containing 2-(biphenyi-2-yl)acetonitriSe (2 g, 10.3 mmol), sodium carbonate (329 mg, 3.1 mmol) and N-methylhydroxylamine hydrochloride (432 mg, 5.17 mmol) in ethanoi (5 ml) and water (5 ml) was heated at 80°C for 2 h, cooled and treated with dimethyl but-2-ynedioate (809 mg, 5.69 mmol). The mixture was stirred at room temperature for 5 h and then diluted with EtOAc, washed with water and brine, dried ( gS04) and evaporated to dryness. Chromatography (40 g Si02, 10 to 60% EtOAc in hexanes) provided the 1 ,2,4-oxadiazoiine intermediate as an orange oil. The oil was diluted in xylene (5.00 ml) and heated at 130 °C in a microwave oven for 3.5 h. The cooled mixture was diluted with EtOAc, washed with brine, dried (MgS04) and evaporated to dryness. Chromatography (24 g Si02; 20 to 60% EtOAc in hexanes) gave the title compound as a light brown foam (0.43 g; 81 %). LCMS: m/z = 351 (MH+).
Example 15: Preparation of 2-biphenyl-2-ylmethyl-5-hydroxy-1 -methyl -6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid
Figure imgf000047_0002
A solution of lithium hydroxide (8.2 mg, 342 μιτηοΙ) in water was added to a stirred solution of methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μηιο!) in THF. After 24 h, the reaction was quenched by addition of 1 HCi, extracted into EtOAc, washed with brine, dried (MgS04) and evaporated. Purification by preparative HPLC gave the desired product as a white solid (0.010 g; 10%). LC S: m/z = 337 (MH+).
Example 16: Preparation of 2-biphenyl-2-ylmethyl-5-hydroxy-1 -methyl-6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid diethylamide
Figure imgf000048_0001
A sealed tube containing 2M solution of methy!amine {1.71 ml, 3.42 mmol) in THF and methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1 -methyl-6-oxo-1 ,6-dihydropyrimidine-4-carbox.yiate (0.1 g, 285 pmol) was heated at 100 °C in a microwave oven for 20 min, cooled and filtered. The solid was stirred in MeOH, in the presence of Amberlyst 15 IE resin, at 60 °C for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et20 to give the title compound as a white solid (0.040 g; 40%). LCMS: m/z = 351 (MH+).
Example 17: Preparation of 2-bip ersyl-2-ylrrseihy!-5- ydroxy-1 -rrietrsyl=6=oxo-1,6= di hydro-py ri m i d i ne-4-carboxyl i c acid isopropylamide
Figure imgf000048_0002
A sealed tube containing propan-2-amine (202 mg, 292 μΙ, 3.42 mmol), methyl 2-(biphenyl-2- yimethyl)-5-hydroxy-1 -methyl-6-oxo-1 ,6-dihydropyrimidine~4-carboxylate (0.1 g, 285 pmol) and THF (1.7 ml} was heated at 110 DC in a microwave oven for 20 minutes. The crude reaction mixture was cooled and evaporated to dryness. Purification by preparative HPLC provided the desired product as a light pink solid (0.015 g; 14%). LCMS: m/z - 379 (MH+). ExampSe 18: Preparation of 2-bi phenyl -2-yi methyl -5-hydroxy-6-oxo-1 , 6-di hydro- pyrimidine-4-carboxylic acid methyl ester
Figure imgf000049_0001
A 1 M solution of hydroxylamine hydrochloride in MeOH (15 ml) and 1 M KOH solution in MeOH (15 ml) was combined at 0 °C. After 10 minutes, the salt was removed by filtration and the filtrate was directly added to a flask containing 2-(biphenyl-2-yl)acetonitriie (0.50 g, 2.58 mrnoi) and was heated at 60 °C overnight. The cooled mixture was evaporated to dryness under reduced pressure and the residue was dissolve in EtOAc, washed with water, and brine, dried (MgS04) and evaporated to dryness. The residue was dissolved in chloroform (10 mi) and treated with dimethyl but-2-ynedioate (0.403 g, 2.84 mmol). The mixture was stirred at 60 °C for 1 h and then evaporated to dryness. The residue was diluted with xylenes (10 mi) and heated at 130 °C for 90 min. The cooled filtrate was filtered, triturated with EtOAc and dried under vacuum to give the title product as an off-white solid (0.161 g; 18%). LCMS: m/z = 337 ( H+).
Example 19: Preparation of 2-biphenyi-2-ylmethyl-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxyiic acid
Figure imgf000049_0002
The title product was prepared according to Example 15 using 2-biphenyl-2-yimethyl-5- hydroxy-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.050 g; 0.148 mmol). The title compound was produced as an off-white solid (0.020 g; 41%). LCMS: m/z = 321 (M- H).
Example 20: Preparation of 2-bip enyl-2-yimethyf-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid methylamide
Figure imgf000050_0001
A sealed tube containing 2M solution of methyiamine (2 ml, 4 mmol) in THF and methyl 2- (biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.05 g, 163 pmol, Eq: 1.00) was heated at 150 °C in a microwave oven for 15 min, cooied and filtered. The solid was stirred in MeOH, in the presence of Amberiyst 15 IE resin, at 60°C for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et20 to give the title compound as a white solid (0.015 g; 27%). LCMS: m/z = 336 (MH+).
Example 21: Preparation of 2-biphenyl-2-ylmeihyl-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid isopropylamide
Figure imgf000050_0002
A seaied tube containing propan-2-amine (347 mg, 500 μΙ, 5.87 mmol), methyl 2-(biphenyl-2- ylmethyl)-5-hydroxy-6-oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.50 g, 148 pmol) was heated at 150 °C in a microwave oven for 10 minutes. The crude reaction mixture was coo!ed and evaporated to dryness. The solid residue was stirred in MeOH, in the presence of ArnberSyst 15 IE resin, at 60 °C for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et20 to give the title compound as a white soiid (0.012 g; 22%). LCMS: m/z = 364 (MH+).
Example 22: Preparation of 2-biphenyi-2-ylmethyl-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid benzylamide
Figure imgf000051_0001
The synthesis was performed as in Example 21 using methyl 2-(biphenyt-2-ylmethyi)-5- hydroxy-6-oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.070 g, 208 pmol) and benzyiamine (0.5 ml; 4.58 mmol) to provide the title compound as an off-white soiid (0.055 g; 64%). LCMS: m/z = 412 (MH+).
Example 23: Preparation of 2-biphenyl-2-ylmethyl-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid-4-fluorobenzylamide
Figure imgf000051_0002
The synthesis performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6- oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.070 g, 208 pmol) and 4-fluorobenzylamine (0.5 mi; 4.38 mmol) to provide the title compound as an off-white solid (0.016 g; 18%). LCMS: m/z = 430 (MH+). Example 24: Preparation of 2-biphenyl-2-yImeihyi-5-h droxy-6-oxo-1,6-dihyciro- pyri mid i ne-4-carboxyl i c acid pheneth lamide
Figure imgf000052_0001
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5- hydroxy-6-oxo-1 ,6-dihydropyrimidine-4-carboxylaie (0.10 g, 298 μηιο!) and pheneihyiamtne (0.5 ml; 3.98 mmol) to provide the title compound as an off-white solid (0.054 g; 42%). LCMS: m/z = 425 ( H+).
Example 25: Preparation of 2-biphenyl-2-ylmethyf-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid isopropylamide
Figure imgf000052_0002
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5- hydroxy-6-oxo-1 ,6-dihydropyrimidine-4-carboxylate (0.10 g, 298 pmol) and isopropylamine (0.5 ml; 6.10 mmoi) to provide the title compound as an off-white soiid (0.059 g; 54%). LCMS: m/z = 412 (MH+). Example 26: Preparation of 2-biphenyl-2-ylmethyl-5-hydroxy-6-(pyrrolidine-1-carbonyl)- 3H-pyrimidin-4-one
Figure imgf000053_0001
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5- hyd roxy-6-oxo- 1 , 6-dihyd ropyri m idi ne-4-carboxyi ate (0.10 g, 298 pmol) and pyrrolidine (0.5 ml; 6.06 mmoi) to provide the title compound as an off-white solid (0.059 g; 54%). LC S: m/z = 412 (MH+). LCMS: m/z = 375 (MH+).
Example 27: Preparation of 2-(2,2-diphenyl-ethyl)-5-hydroxy-6-oxo-1,6-dihydro- py r i m i d i ne-4-car boxy I i c acid methyl ester
Figure imgf000053_0002
A solution of hydroxylamine hydrochloride (38.6 ml, 38.6 mmol) in MeOH was added to a solution θ! pOiasSiUm riyui uxlue ( o.o 11 II, o.o n in tui, cq. in iviewn eu u 1 1 its i iSuuii i mixture was filtered and the filtrate was added to a 150 mL round-bottomed flask containing 3,3-diphenylpropanenitrile (2 g, 9.65 mmol). The mixture was heated at reflux for 16 h, cooled and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine, dried (MgS04) and evaporated to dryness. The crude product was dissolved in CHC!3 (50 ml), treated with dimethyl but-2-ynedioaie (1.65 g, 11.6 mmol, Eq: 1.2) and heated at reflux for 1 h and then evaporated to dryness. The residue was dissolved in xylene (10 ml), heated at 120 °C in a microwave oven for 4 h and evaporated to dryness. Chromatography (80 g Si02; 20 to 100% EtOAc in hexanes) gave the title product as an off-white solid (0.42; 12%). LCMS: m/z = 348.9 (MH+). Example 28: Preparation of 2-(2f2-diphenyi-ethyl)-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid
Figure imgf000054_0001
A solution of lithium hydroxide (21.9 mg, 913 μιτποΙ) in water (2 ml) was added to a flask containing a stirred solution of 2-(2,2-diphenyl-ethyl)-5~hydroxy-6-oxo-1 ,6-dihydro-pyrimidsne- 4-carboxylic acid methyl ester (0.160 g, 457 pmol) in THF (8 ml). The mixture was stirred at room temperature for 8 h, quenched with 1 HCi, extracted into EfOAc, washed with brine, dried (MgS04) and evaporated to dryness. Purification by preparative HPLC provided the desired product as a white solid (0.024 g; 15%). LC S: m/z = 337 (MH+).
Example 29: Preparation of 2-(2-bromo-4-fluoro-benzyl)-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid methyl ester
Figure imgf000054_0002
A solution of potassium hydroxide (18.7 ml, 18.7 mmol) in methanol and hydroxylamine hydrochloride (18.7 ml, 18.7 mmol) in methanol were mixed, filtered and added to 2-(2-bromo- 4-fluoropheny[)acetonitrile (1 g, 4.67 mmol) in eOH and stirred at 60°C for 24 h, evaporated to dryness. The residue was dissolved in chloroform (30.0 ml) and to this was added dimethyl but-2-ynedioate (730 mg, 5.14 mmol). The mixture was stirred at 60°C for 24 h, cooled and evaporated to dryness. The residue was dissolved in xylene (10 ml) and heated at 120°C for 2 h in microwave oven. The cooled residue was evaporated to dryness and then triturated with EtOAc, filtered and washed with Et20 to give the title compound as a brown solid (0.21 g; 12%). LCMS: m/z = 358 (MH+). Example 30: Preparation of 2-{2-bromo-4-fSuoro-ben∑y!)-5-hydroxy-6-oxo-1 ,6-di ydrO' pyrimidine-4-carboxy!ic acid
Figure imgf000055_0001
A solution of lithium hydroxide monohydrate (23.5 mg, 560 pmol) in water (1 mi) was added to a stirred solution of methyl 2-(2-bromo-4-fiuorobenzyl)-5!6-dihydroxypyrimidine-4-carboxyiate (50 mg, 140 pmol) in THF (4 ml). The resulting mixture was stirred at room temperature for 24 h. The mixture was then acidified by the addition of Amber!yst resin, filtered and evaporated to dryness. The residue was triturated with Et20 to give the title compound as a white solid (0.02 g; 41 %). LC S: m/z = 344 (MH+).
Example 31 : Preparation of 2-(2-bromo-4-fIuoro-benzyl)-5-hydroxy-6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid amide
Figure imgf000055_0002
A solution of ammonia in MeOH (1 mL, 7.00 mmol) was added to a flask containing methyl 2- (2-bromo-4-fiuorobenzyS)-5,6-dihydroxypynmidine-4-carboxylate (50 mg, 140 μιηοί). The mixture was heated at 120°C for 15 minutes in a microwave oven. The resulting product was collected by filtration, suspended in MeOH with Amberlyst resin and heated. The warm mixture was filtered and evaporated to dryness. The residue was triturated with Ei20 and dried under vacuum to give the title compound as a white solid (0.032 g; 67%). LCMS: m/z = 343 (MH+). Examp!e 32: Preparation of (2*-rneth l-biphenyl-2-yi)-acetonitrHe
Figure imgf000056_0001
In a vial, 2-bromophenylacetonitriie {2 g, 10.2 mmol), 2-methylphenylboronic acid (1 .53 g, 1 1.2 mmoi) and potassium carbonate (2.82 g, 20.4 mmol, Eq: 2) were combined with toluene (15.0 ml), ethanol (15 ml) and water (5 mi) to give a light brown suspension. The mixture was degassed with argon and then tetrakis(triphenylphosphine)pa!ladium(0) (354 mg, 306 pmol) was added. The reaction mixture was heated at 90°C for 12 h, cooled and poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2S0 ) and evaporated to dryness under reduced pressure. Chromatography (silica gel, 0% to 5% EtOAc in hexanes) provided the title product as a colourless oil (1.57 g; 74%).
1H N R (300 MHz; CDCI3) δ ppm 2.06 (s, 3 H), 3.43 (s, 2 H), 7.07-7.61 (m, 8 H).
Example 33: Preparation of 5-hydroxy-2-(2'-methyl-biphenyl-2-ylmethy!)-6-oxo-1 ,6- d i hydro-pyri m i d i ne-4-ca rboxyl ic acid methyl ester
Figure imgf000056_0002
A solution of hydroxylamine hydrochloride (979 mg, 14.1 mmoi) in methanol (15 mi) and a solution of potassium hydroxide (790 mg, 14.1 mmol) in methanol (15 mi) were combined at 0°C. Solid (KCi) was removed by filtration. The filtrate was added to 2-(2'-methylbiphenyl-2- yl)acetonitrile (1.46 g, 7.04 mmoi) and heated at 60°C overnight. An extra equivalent of NH2OH in eOH solution was added and heating was continued for 5 h. The mixture was cooled and then concentrated in vacuo. The residue was taken up into CHCI3 (30 ml) and to this was added dimethyl acetylenedicarboxylate (1.00 g, 7.04 mmol). The mixture was heated at 60°C overnight, cooled and evaporated. The residue was transferred to a microwave vial and xylene (8 ml) was added. The vial was capped and heated in the microwave oven at OO
140°C for 3 h, cooled. Chromatography (silica gel; 10% to 00% EtOAc in hexanes) provided the desired product as an off-white solid (0.003 g; 0.12%). LCMS: m/z - 351 ( H+).
Example 34: Preparation (3'-methyl-biphenyl-2-yl)-acetonitrile
Figure imgf000057_0001
In a via!, 2-bromophenyiacetonitirle (2 g, 10.2 mmol), m-tolylboronic acid (1.66 g, 12.2 rnmol) and potassium carbonate (2.82 g, 20.4 mmoi) were combined with toluene (15 ml), ethanol (15 ml) and water (5 ml) to give a light brown suspension. The mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium(0) (354 mg, 306 μιηοΙ) was added. The reaction mixture was heated to 90°C and stirred overnight. The resulting cooled mixture was diluted with water and extracted into EtOAc. The organic phase was separated and washed with brine, dried (Na2S04) and concentrated under reduced pressure. Chromatography (silica gel; 0% to 5% EtOAc in hexanes) provided the title product as a colourless oil (1.82 g; 80%). 1H NMR (300 MHz; CDC ) δ ppm 2.42 (s, 3 H), 3.65 (s. 2 H), 7.03-7.62 (m, 8 H).
Example 35: Preparation of 5-hydroxy-2-(3'-methyl-biphenyl-2-ylmethyl)-6-oxo-1,6- dihydro-pyrimidine-4-carboxylic acid methyl ester
Figure imgf000057_0002
The compound was prepared using the same general procedure as Example 32 using 2-(3'- methylbiphenyl-2-yl)acetonitrile (1.81 g, 8.73 mmol). The title product was isolated as a white solid (0.07 g; 2%). LCMS: m/z = 351 (MH+). [Example 36: Preparation of 5^ydroxy-2-(3'-meihyi-biphenyi-2-ylmethyi)-6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid amide
Figure imgf000058_0001
A mixture containing methyl 5-hydroxy-2-((3,-methy!biphenyl-2-y!)methyi)-6-oxo--1 ,6-- dihydropyrimidine-4-carboxylate (55 mg, 157 pmol) and ammonia (7M in MeOH) (4 mi, 28.0 mmol) in MeOH (2 ml) was heated at 100°C overnight. The cooled reaction mixture was concentrated in vacuo and then triturated from methanol to give the title product as an off- white solid (0.025 g; 47%). LCMS: m/z = 336 ( H+).
Example 37: Preparation of 5-hydroxy-2-(3'-methyl-biphenyl-2-ylmethyl)-6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid
Figure imgf000058_0002
In a round-bottomed flask, methyl 5-hydroxy-2-((3'-methylbipheny!-2-yi)methyl)-6-oxo-1 ,6- dihydropyrimidine-4-carboxyiate (30 mg, 85.6 pmol) and lithium hydroxide hydrate (6.5 mg, 155 mol) were combined with THF (2 ml) and water (1 ml) to give a colorless solution. The mixture was stirred at 50°C for one day. Amberiyst (15, ion exchange resin) was added, the mixture was stirred for 10 min, filtered and evaporated to dryness. Trituration with EtOAc and hexanes provided the title compound as a white solid {0.011 g; 34%). LCMS: m/z = 337 (MH+) 90%) pure. Example 38: Preparation of (2',5'-dimeth l-biphenyl-2-yi)-acetonitrile
Figure imgf000059_0001
The compound was prepared using the same general procedure as Example 33 using 2,5- dimethylphenylboronic acid (4.21 g, 28.1 mmol. Eq: 1.1 ). The titie compound was prepared as a colourless oil (4.7 g; 83%).
1H NMR (300 MHz; CDCI3) δ ppm 2.01 (s, 3 H), 2.35 (s, 3 H), 3.44 (s, 2 H), 6.96 (s, 1 H), 7.08- 7.24 (m, 3 H), 7.34-7.47 (m, 2 H), 7.53-7.62 (mm 1 H).
Example 39: Preparation of 2-(2',5'"dimethyl-biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1 ,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester
Figure imgf000059_0002
The compound was prepared using the same generai procedure as Example 32 using 2-(2',5'- dimeihylbiphenyl-2-yl)acetonitriie (4.7 g, 21.2 mmol) and diethyi but-2-ynedioate (3.61 g, 21.2 mmol). The title product was isolated as a white solid (0.84 g; 10%). LCMS: m/z = 379 ( H+).
Example 40: Preparation of 2-{2 5,-d!meth i-blphenyi-2-yϊmeth ί}-5-hydrox -6-oxo-1Iδ- dihydro-pyrimidine-4-carboxylic acid
Figure imgf000060_0001
The compound was prepared according to the same procedure as in Example 29 using 2- (2,,5'-dimethyi-biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1 I6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (22 mg, 58.1 rnol) to provide the title compound as an off-white solid (0.018 g; 95% pure, 84% yield). LCMS: m/z = 349 ( -H).
Example 41 : Preparation of 2-cyclohexylmethyi-5-hydroxy-6-oxo-1 ,6-dihydro- pyrimidine-4-carboxyiic acid methyl ester
Figure imgf000060_0002
The compound was prepared according to the same procedure as in Example 32 using 2- cyclohexylaceionitrile (2,5 g, 20.3 mmoi). The title product was Isolated as a white solid (0.060 g; 1%). LCMS: m/z = 280 (MH+).
Example 42: Preparation of 2-cyciohexyirnethyi-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine-4-carboxylic acid methylamide
Figure imgf000061_0001
A mixture of meihyi 2-(cyclohexylmethyi)-5-hydroxy-6-oxo-1 ,6-dihydropyrimiciine-4-carboxylate (30 mg, 113 pmol), methylamine (2 in THF) (1.5 ml, 3.00 mmol) and eOH (10 ml) was heated in a microwave oven at 140°C for 40 min. The cooled reaction mixture was concentrated in vacuo. The residue was heated in a mixture of MeOH and Amberiyst until all the product had dissolved. The resin was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.011 g; 35% with 95% purity). LC S: m/z = 266 (MH+).
Example 43: Preparation of 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidine- 4-carboxyiic acid methyl ester
Figure imgf000061_0002
The compound was prepared according to the same procedure as in Example 18 using 2-(2- bromopheny!)acetonltrile (0.50 g, 2.5 mmol) and dimethy!acetyienedicarboxyiate (0.40g, 2.81 mmol). This provided the title product as a white soiid (0.084 g; 9%). LCMS: m/z = 340 (MH+). Example 44: Preparation of 5-acetoxy-2-(2-bromo-benzyl)-6-oxo-1,6-dihydro-pyrirnidine 4-carboxylic acid methyl ester
Figure imgf000062_0001
In a round-bottomed flask, methyl 2-(2-bromobenzyl)-5,6-dihydroxypynmidine-4-carboxylate (300 mg, 885 pmol) was combined with DCM (10 ml) to give a brown suspension. Acetyl chloride (1 M in DCM) (2.21 mi, 2.21 mmoi) was added slowly at room temperature. The mixture was stirred for one hour and then poured onto aqueous saturated NH4CI solution and extracted with DCM. The organic phase was washed with brine solution, dried (Na2S04), and evaporated to dryness under reduced pressure. Chromatography (Si02; DCM) provided the title product as a white solid (0.33 g; 97%). LCMS: rn/z - 381/383 (MH+).
Example 45: Preparation of 2-{2-bromo-benzyf)-5-hydroxy-6oxo-1 ,6-dihydro-pyrimidine- 4-carboxylic acid methylamide
Figure imgf000062_0002
The compound was prepared according to the same procedure as in Example 20 using 2-(2- bromo-benzyl)-5-hydroxy-6-oxo-1 t6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmoi). This gave the title compound as a white solid (0.032 g; 40%). LCMS: m/z = 339 (MH+). Example 46: Preparation of 2-{2»bromo-benzyf)-5-hydroxy-6-oxo-1,6-dihydro-pyrirnidine 4-carboxylic acid isopropylamide
Figure imgf000063_0001
The compound was prepared according to the same procedure as in Example 21 using 2-(2- bromo-benzyl)-5-hydroxy-6-oxo-1!6-dihydro-pyrimidine-4-carboxyIic acid methyl ester (0.08 g; 0.236 mmol) and isopropylamine (0.4 ml; 4.7 mmol). This gave the title compound as a white solid (0.021 g; 24%). LCMS: m/z = 367 (MH+).
Example 47: Preparation of 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidtne- 4-carboxylic acid 4-chloro-benzylamide
Figure imgf000063_0002
The compound was prepared according to the same procedure as in Example 21 using 2-(2- bromo-benzyi)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxyiic acid methyl ester (0.08 g; 0.236 mmol) and 4-chlorobenzylamine (0.5 ml; 4.1 mmol). The title compound was prepared as a white solid (0.042 g; 39%). LCMS: m/z = 449 (MH+).
Example 48: Preparation of 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidine- 4-carboxySic acid 4-fluoro-benzylamide
Figure imgf000063_0003
The compound was prepared according to the same procedure as in Example 21 using 2-(2- bromo-benzyl)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and 4-fluorobenzylamine (0.5 ml; 4.4 mmol). This gave the title compound as a white solid (0.072 g; 70%). LCMS: m/z = 433 ( H+).
Exampie 49: Preparation of 2-(3-benzyl-3H-imida2o!-4-ylmethyl)-5-hydroxy-6-oxo-1 ,6- di hyd ro-pyri mi d i ne-4-carboxyl ic acid ethyl ester
Figure imgf000064_0001
A solution of hydroxylamine hydrochloride (2.85 g, 41.1 mmol) in methanol (25 ml) and a solution of potassium hydroxide (2.3 g, 41.1 mmol) in methanol (25 ml) were combined at 0°C. The resulting salt was removed by filtration and the filtrate was immediately added to 2-(1- benzyl-1 H-imidazoi-5-yi)acetonitrile (1.62 g, 8.21 mmol). The resulting solution was heated at 60°C overnight and then evaporated to dryness. The residue was taken up into CHCI3 (100 mi), and diethyl but-2-ynedioate (1.4 g, 8.21 mmol) was added. The resulting mixture was heated at 60°C overnight. After cooling, the crude reaction mixture was concentrated in vacuo. The residue was treated with water and EtOAc. The organic phase was separated, washed with brine, dried (Na2S04) and concentrated in vacuo. The residue was heated in xylene (2.5ml), at 140°C in a microwave reactor for 40 min. The cooled mixture was evaporated to dryness, dissolved in MeOH, passed through Ce!ite® and then evaporated to dryness under reduced pressure. Purification by preparative HPLC provided the desired product as a yellow solid (0.014 g; 0.36%). LCMS: m/z = 355 (MH+) 75% purity.
Example 50: Preparation of 2-(2-bromo-5-trifluoromethyi-benzyi)-5-hydroxy-6-oxo-1J6- dihydro-pyrimidrne-4-carboxylic acid methyl ester
Figure imgf000065_0001
Preparation was performed following the general procedure used in Example 18 using 2- bromo-5-(trifluoromethyi)phenyiacetonitrile (1 g; 3.78 mmoi) and dimethyl but-2-ynedioate (1 .09 g, 7.67 mmoi) to provide the desired product as an off-white solid (0.29 g; 16%). LCMS: m/z = 408 (MH+).
Example 51 : Preparation of 2-(2-bromo-5-trifluoromethyl-benzyl)-5-hydroxy-6-oxo-1,6- dihydro-pyrimidine-4-carboxylic acid methylamide
Figure imgf000065_0002
The compound was prepared according to the same procedure as in Example 21 using 2-(2- bromo-5-trifluoromethyl-benzy!)-5-hydroxy-6-oxo-1 ,6-dihydro-pyrimidSne-4-carboxylic acid methyl ester {0.080 g; 0.197 mmoi) and 2M methylamine solution in THF {1 mi). This provided the title product as an off-white solid (0.043 g; 53%). LCMS: m/z≡ 427 (MH+).
Example 52: Preparation of 5-hydroxy-1 -methyl-2-methyisulfanyl-6-oxo-1 ,6-dihyd pyrimidine-4-carboxylic acid methyl ester
Figure imgf000065_0003
in a round-bottomed flask, thiocyanatomethane (17.5 g, 239 mmoi) and N- methy!hydroxyiamine hydrochloride (20 g, 239 rnrnol) were combined with EtOH (100 mi) to give a light yellow solution. A solution of sodium carbonate (12.7 g, 120 mmoi) in water (50 ml) was added slowly over 8 min at RT. The resulting mixture was stirred at RT for 2.5 days and then cooled in an ice bath. Dimethyl but-2-ynedioate (34.0 g, 239 mmo ) was added slowly over 10 min and the resulting mixture was stirred for 2 hours, keeping the interna! temperature below 22°C. Ice water and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting methyl 5-(2-methoxy-2- oxoethyi)-2-methyl-3-(rriethylthio)-2,5-dihydro-1 ,2,4-oxadiazo!e-5-carboxylate (62.7 g, 239 mmol) was placed in a round-bottomed flask, dissolved in xylene (1 10 mi), then heated at 140°C for 48 hours, cooled and then evaporated to dryness to give the crude title product as a brown solid. LCMS: m/z = 231 ( H+).
Example 53: Preparation 5-benzyloxy-1 -methyl-2-methylsulfanyl-6-oxo-1 ,6-dihydro- pyri mid i ne-4-carboxyl i c acid methyl ester
Figure imgf000066_0001
In a round-bottomed flask, methyl 5-hydroxy-1 -methyl-2-(methylthio)-6-oxo-1 ,6- dihydropyrimidine-4-carboxyiaie (55.0 g, 239 mmol) and potassium carbonate (33.0 g, 239 mmol) were combined with D F (200 ml) to give a black suspension. Benzyl bromide (40.9 g, 239 mmol) was added and the resulting mixture was stirred at room temperature for 3.5 days. The reaction was quenched by the addition of cold water. The mixture was filtered to provide a brown solid. Chromatography (Si02; 10% to 50% EtOAc in hexanes) provided the desired product as an off-white solid (14.3 g; 18%). LCMS: m/z = 321 (MH+). Example 54: Preparation 5-benzyloxy-2-methanesulfonyl-1 -methyl-6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid methyl ester
Figure imgf000067_0001
In a 1 L round-bottomed flask, methyl 5-(benzy xy)-1 -methy!-2-(methyithio)-6-oxo-1 ,6- dihydropyrimidine-4-carboxylate (5.57 g, 17.4 mmoi) was combined with MeOH (400 mi) and DC (50 ml), A solution of oxone (21.4 g, 34.8 mmoi) in water (100 mi) was added. The mixture was stirred at room temperature for 5 hours and then evaporated to dryness. The residue was taken up into EtOAc, washed with 3N NaOH aqueous solution, water, and brine, dried over Na2S04 and concentrated under reduced pressure to give the title compound as a white solid (3.7 g; 60%). LCMS: m/z = 353 (MH+).
Example 55: Preparation of 2-amino-5-benzyloxy-1 -methyl -6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid methyl ester
Figure imgf000067_0002
In a round-bottomed flask, methyl 5-(benzyloxy)-1-methyl-2-(methyisulfonyi)-6-oxo-1 ,6- dihydropyrimidine-4-carboxylate (3.65 g, 10.4 mmoi) was combined with CH3CN (50 mi) to give a colorless soiution. Gaseous ammonia was bubbled at 25°C for 20 min. The crude material was purified by flash chromatography (siiica ge!, 30% to 50% EtOAc in hexanes) and then through a second column (5% MeOH/DCM) to give the title product as a white solid. LCMS: m/z = 290 (MH+). Example 56: Preparation of 2-amino-5-benzyloxy-1 -methyl -6-oxo-1 ,6-dihydro- pyrimidine-4-carbQxyIic acid methylamide
Figure imgf000068_0001
To a mixture of methyl 2-amino-5-(benzyloxy)-1-methyl-6-oxo-1 ,6-dihydropyrimidine-4- carboxylate (0.907 g, 3.14 mmoi, Eq: 1.00), methylamine 2 in THF (12 ml, 24.0 mmoi) was added. The mixture was heated in a microwave oven at 140°C for 2 h. The crude reaction mixture was concentrated in vacuo to give the title product as an off-white soiid (0.90g; 100%). LCMS: m/2 = 289 ( H+).
Example 57: Preparation of 5-benzyloxy-1 «methyl-6-oxo-2-m- tolylmethanesulfonylamino-1 ,6-dihydro- rimidine-4-carboxylic acid methylamide
Figure imgf000068_0002
Potassium tert-butoxide (75.9 mg, 676 μπιοΙ) was added to a solution of 2-amino-5- {benzyloxy)-N,1 -dimethyl-6-oxo-1 ,6-dihydropyrimidine-4-carboxamide (150 mg, 520 mol) in THF (15.0 ml) and DMF (3 ml). The resulting mixture was stirred for 10 min and then cooled with an ice-bath. To this mixture was slowly added a solution of (3- methylphenyl)methanesulfonyl chloride (140 mg, 684 pmo!) in THF (1 ml). The reaction mixture was stirred at room temperature overnight. A further solution of (3- methylphenyl)methanesulfonyl chloride (140 mg, 684 mol) in THF (1 ml) was added and then the mixture was stirred at room temperature for 48 hours. The resulting mixture was diluted with EtOAc, washed with saturated NaHC03 aqueous solution and brine. The organic layers were dried over NazS04 and concentrated in vacuo. Flash chromatography (silica gel, 0% to 2% eOH in DCM) provided the desired product as a light yellow solid (0.070g; 29%). LC S: m/z = 457 (MH+).
Example 58: Preparation of 5-hydroxy-1 -meihy!-6-oxo-2-m-toiyimethanesuifonyiamino- 1,6-dihydro-pyrimidine^-carboxylic acid methylamide
Figure imgf000069_0001
Palladium on carbon 10% (20 mg, 18.8 μιηοΙ) was added to a round-bottomed flask containing a solution of 5-(benzyloxy)-N, 1-dimethyl-6-oxo-2-(m-totylmethylsulfonarnido)-1 ,6-dihydro- pyrirnidine-4-carboxamide (0.07 g, 153 μηιοΐ) in ethyl acetate (5 ml) and MeOH (5 ml). The resulting mixture was degassed by nitrogen, evacuated and purged with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for one hour, filtered and evaporated to dryness under reduced pressure. The residue was washed with hexane and DCM, and crystallized from MeOH/Et20 to give the title compound as an off-white solid (0.03 g; 53%). LCMS m/z = 367 (MH+).
Example 59: Preparation of 5-benzyioxy-2-{4-chloro-phenyimeihanesuifonyiariiino}-1 - methyl-6-oxo-1,6-dihydro-pyrimidine-4-carbox lic acid methyiamide
Figure imgf000070_0001
In a round-bottomed flask, 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1 ,6-dihydropyrimidine-4- carboxamide (250 mg, 867 pmol, Eq; 1.00) was combined with THF (20 mi) to give a white suspension. D F (4 mi) was added followed by potassium tert-butoxide (1 17 mg, 1.04 mmol, Eq: 1.2). The resulting mixture was stirred at room temperature for 10 min, then cooied with an ice bath. To this was slowly added a solution of (4-chlorophenyl)methanesulfonyi chloride (240 mg, 1.07 mmol, Eq: 1.23) in THF (1ml). After stirring at room temperature for 14 h, further t- BuOK (234 mgs) was added. The mixture was stirred for 5 min, cooled in the ice bath and then further (4-chlorophenyl)methanesulfonyl chloride (240 mg, 1 ,07 mmol) was added. The reaction mixture was stirred for 72 hours at RT and then diluted with EtOAc, washed with saturated aqueous NaHC03 solution and brine. Some solid precipitated in the EtOAc solution and was collected by filtration. The remaining filtrate was evaporated to dryness, purified by flash chromatography (silica gel, 2% to 6% MeOH in DCM) and then triturated by EtOAc/Hex. The solids were combined to give the desired product as a white solid (0.210 g; 51%). LC S rn/z = 477 (MH+).
Example 60: Preparation of 2-(4-chioro-phenylmethanesulfonyiamino)-5-hydroxy-1 - methyl-6-oxo-1 ,6-dihydro-pyrimidine-4-carboxylic acid methy!amide and 5-hydroxy-1 - meihyl-6-oxo-2-phenylmeihanesuifony[arnino-1 ,6-dihydro-pynmidine-4-carboxyHc acid methyl amide
Figure imgf000071_0001
In a round-boitomed flask, 5~(benzyloxy)-2~((4-chlorophenyl)rnethylsulfonarnido)-N,1~dirnethyl- 6-OXO-1 ,6-dihydropyrimidine-4-carboxamide (0.16 g, 335 μιηοΐ) was combined with ethyl acetate (40 ml) and MeOH (40.0 ml) to give a white suspension. Palladium on carbon 5% (50 mg, 470 pmol) was added and the solution was degassed by nitrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen (balloon) for one hour and then the catalyst was removed by filtration and the filtrate was evaporated to dryness. Purification by preparative HPLC yielded:
2-(4-Chloro-phenylmethanesulfonylamino)-5-hydroxy-1-methy!-6-oxo-1 ,6-dihydro-pyrirnidine- 4-carboxylic acid methylamide as a white amorphous solid (0.026 g; 20%). LCMS: m/z = 387 (MH+).
5-Hydroxy-1-methyi-6-oxo~2-phenylmethanesulfonyiamino-1 ,6-dihydro-pyrimidine-4-carboxylic acid methylamide as a white amorphous solid (0.022 g; 17%). LCMS: m/z = 353 (MH+)-
Example 61 : Preparation of 5-benzyloxy-1 -methyl -6-oxo-2-p-toiylmethanesulfonyl- amino-1 ,6-dihydro-pyrimidine-4-carbox lic acid methylamide
Figure imgf000072_0001
Potassium tert-butoxide (93.8 mg, 836 pmol) was added to a solution of 2-amino-5- (benzyloxy)-N,1-dimethyl-6-oxo-1 ,6-dihydropyrimidine-4-carboxamide (1 10 mg, 380 pmol) in THF (10 mi) in DMF (2 ml) [Comment: please check]. After 10 min., the reaction mixture was cooled by an ice bath and then a solution of (4-methylphenyl)methanesulfonyi chloride (33.7 mg, 458 pmol) in THF (2 mi) was added. After 70 min., EtOAc and 1 N NaOH aqueous solution were added. The organic phase was extracted with EtOAc and then with DCM. The combined organic phases were washed with water, and brine, dried over Na2S04 and evaporated to dryness. Chromatography (silica gel, 0 to 2% MeOH in DCM) provided the title compound as a pale yellow solid (0.080 g; 46%). LCMS: m/z = 457 (MH+).
Example 62: Preparation of 5-hydroxy-1 -methyl -6-oxo-2-p-tolylmethanesulfonylamino- 1,6-dihydro-pyrimidine-4-carboxylic acid methylamide
Figure imgf000072_0002
A mixture of 5-(benzyloxy)-N,1 -dimethyi-6-oxo-2-(p-toiylmethylsuifonamido)-1 ,6-dthydro- pyrimidine-4-carboxamide (80 mg, 175 pmol), palladium on carbon (186 mg, 87.6 pmol), MeOH (5 mi) and ethyl acetate (5 ml) was placed under an atmosphere of hydrogen. After stirring for 1.5 hour, the reaction mixture was filtered and evaporated to dryness. Crystal iization from eOH provided the title product as an off-white solid (0.045 g; 70%). LC S: m/z = 367 (MH+).
Example 63: Preparation of 5-benzyloxy-2-cyclohexylmethy1-1 -methyl-6-oxo-1 ,6- dihydropyrimidine-4-carboxylic acid meth l ester
Figure imgf000073_0001
Cyciohexylmethyimagnesium bromide solution (1.77 ml; 885 μ of 0.5M solution in THF) was added dropwise to a solution of 5-benzyloxy-2-methanesu!fonyl-1 -methyl-6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid methyl ester (0.26 g; 738 μΜ) in THF (10 ml). After stirring at room temperature for 1 h, the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The product was extracted into EtOAc, washed with brine, dried (Na2S04) and evaporated to dryness under reduced pressure to give the title product as a colourless oil (0.040 g; 70%). LCMS: m/z = 367 (MH+).
Example 64: Preparation of 2-cyclohexylmethyl-5-hydroxy-1 -methyl -6-oxo-1 ,6-dihydro- pyrimidine-4-carboxylic acid methyl ester
Figure imgf000073_0002
A mixture of methyl 5-(benzyloxy}-2-(cyclohexyimethyl)-1-methyl-6-oxo-1 ,6-dihydropyrimidine- 4-carboxylate (60 mg, 162 prnol) and 20% palladium hydroxide on carbon (1 1.4 mg, 16.2 μηποΙ) in EtOAc (10 mi) was placed under an atmosphere of hydrogen and stirred at room temperature overnight. The mixture was filtered and then evaporated to dryness. Chromatography (Si02;. 0 to 20% EtOAc in hexanes) gave the title product as a white solid (0,032 g; 70%). LCMS: m/z = 281 (MH+).
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
not determ. = not determined

Claims

1. A compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000080_0001
(Di) (Dii) (Diii) wherein
X1 is O, S or NR*;
X2 is O or S;
X3 is O or S;
X4 is O or S;
Xs is O or S;
L is -(CH2)m- -NR*-S02- or -S02-NR*-;
m is 1 to 4;
R1 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted C3.7 cycloalkyl), -(optionally substituted aryl), -C1-4 alkyl— (optionally substituted aryl), -C(0)-0- R** or -P(0)(OR**)2, if X1 is NR* then R1 and R* can optionally be bound together to form a 5- to 7-membered ring; R2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R3 is -H, -(optionally substituted d_6 alkyl), -(optionally substituted C3_7 cycloalkyi), -(optionally substituted aryl), or -C1-4 alkyl— (optionally substituted aryl);
R4 is -H, -(optionally substituted C1-6 alkyl), -(optionally substituted Cw cycloalkyi), -(optionally substituted aryl), or -C^ alkyl-(optionally substituted aryl);
R5 is -H, -C(0)-(optionally substituted d-e alkyl), or -(optionally substituted alkyl);
RB is -H, -C(0)-(optionally substituted C1-6 alkyl), or -(optionally substituted alkyl);
R* is -H, or -(C-,-6 alkyl); and
R** is -H, -(C.,-6 alkyl), -(C3-7 cycloalkyi), -(aryl), or -C^ alkyl-(aryl); wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN, -NR*R*, -OH, and -O-C^ alkyl; and
wherein the optional substituent of the cycloalkyi group, the aryl group or the hydrocarbon group is selected from the group consisting of -C^ alkyl, -halogen, - CF3, -CN, -X1-R*. -aryl and -C-,_4 alkyl-aryl,
with the proviso that the followin compound
Figure imgf000081_0001
is disclaimed.
2. A pharmaceutical composition comprising a compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000082_0001
(Di) (Dii) (Diii) wherein
X1 is O, S or NR*;
X2 is O or S;
X3 is O or S;
X4 is O or S;
Xs is O or S;
L is -(CH2)m-, -NR*-S02- or -S02-NR*-;
m is 1 to 4;
R1 is -H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl), -(optionally substituted aryl), -d- alkyl-(optionally substituted aryl), -C(0)-0- R** or -P(0)(OR**)2, if X1 is NR* then R1 and R* can optionally be bound together to form a 5- to 7-membered ring;
R2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R3 is -H, -(optionally substituted d-e alkyl), -(optionally substituted C3-7 cycloalkyl), -(optionally substituted aryl), or -d-4 alkyl— (optionally substituted aryl);
R4 is -H, -(optionally substituted d-e alkyl), -(optionally substituted C3-7 cycloalkyl), -(optionally substituted aryl), or -d-4 alkyJ— (optionally substituted aryl);
R5 is -H, -C(0)-(optionally substituted d-e alkyl), or -(optionally substituted d-e alkyl);
R6 is -H, -C(0)-(optionally substituted d-e alkyl), or -(optionally substituted d_6 alkyl);
R* is -H, or -( -« alkyl); and
R** is -H, -(d-e alkyl), -(C^7 cycloalkyl), -(aryl), or -d-4 alkyl-(aryl); wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN, -NR*R*. -OH, and -O-C^ alkyl; and
wherein the optional substituent of the cycloalkyi group, the aryl group or the hydrocarbon group is selected from the group consisting of -Ci_e alkyl, -halogen, - CF3, -CN, -X1-R*, -aryl and -C^ alkyl-aryl, and optionally a pharmaceutically acceptable excipient.
3. A compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000083_0001
(Di) (Dii) (Dili) wherein
X1 s O, S or NR*;
X2 s O or S;
X3 s O or S;
X4 s O or S;
X5 s O or S;
L s -(CH2)m- -NR*-S02- or -S02-NR*-;
m s 1 to 4;
R1 s -H, -(optionally substituted d_6 alkyl), -(optionally substituted cycloalkyi), -(optionally substituted aryl), -C^ alkyl— (optionally substituted aryl), -C(0)-0- R** or -P(0)(OR**)2, if X1 is NR* then R1 and R* can optionally be bound together to form a 5- to 7-membered ring; R2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R3 is -H, -(optionally substituted alkyl), -(optionally substituted C3_7 cycioalkyi), -(optionally substituted aryl), or -C^ alkyf— (optionally substituted aryl);
R4 is -H, -(optionally substituted alkyl), -(optionally substituted C3_7 cycioalkyi), -(optionally substituted aryl), or -C^ alkyl— (optionally substituted aryl);
R5 is -H, -C(0)-(optionally substituted alkyl), or -(optionally substituted alkyl);
R6 is -H, -C(0)-(optionally substituted Ci_e alkyl), or -(optionally substituted Ci_6 alkyl);
R* is -H, or -(d_6 alkyl); and
R** is -H, -(C,^ alkyl), -(C^ cycioalkyi), -(aryl), or -C^ alkyl-(aryl); wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN, - R*R*, -OH, and -0-C1-J3 alkyl; and
wherein the optional substituent of the cycioalkyi group, the aryl group or the hydrocarbon group is selected from the group consisting of -C^ alkyl, -halogen, - CF3, -CN, -X1-R*, -aryl and -C^ alkyl-aryl, wherein the compound is for use in the treatment, amelioration or prevention of a viral disease.
4. The compound according to claim 3, wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae.
5. The compound according to claim 4, wherein the viral disease is influenza.
6. A method of treating, ameliorating or preventing a viral disease, the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.
7. The method according to claim 6, wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae.
8. The method according to claim 7, wherein the viral disease is influenza.
9. The compound according to claim 1, 3, 4, or 5, the pharmaceutical composition according to. claim 2, or the method according to claim 6, 7, or 8, wherein m is 1 or 2.
10. The compound according to claim 1 , 3, 4, or 5, the pharmaceutical composition according to claim 2, or the method according to claim 6, 7, or 8, wherein R1 is -H or -(optionally substituted Ci_s alkyl).
11. The compound according to claim 1 , 3, 4, or 5, the pharmaceutical composition according to claim 2, or the method according to claim 6, 7, or 8, wherein R2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted Cs- 7 cycloalkyl.
12. The compound according to claim 1 , 3, 4, or 5, the pharmaceutical composition according to claim 2, or the method according to claim 6, 7, or 8, wherein R2 is
Figure imgf000085_0001
and wherein the heterocyclic group, phenyl group, cyclohexyl group or cyclopentyl group can be optionally substituted in any available position by a substituent which is independently selected from -d_6 alkyl, halogen, -CF3, -CN, -OH, and -0-Ci_6 alkyl.
13. The compound according to claim 1 , 3, 4, or 5, the pharmaceutical composition according to claim 2, or the method according to claim 6, 7, or 8, wherein L is -(CH2)m-. or -NR*-S02-.
14. The compound according to claim 1 , 3, 4, or 5, the pharmaceutical composition according to claim 2, or the method according to claim 6, 7, or 8, wherein X1 is O or NR*.
15. The compound according to claim 3, or the method according to claim 6, wherein a further antiviral agent is to be administered concurrently or sequentially with the compound according to claim 3.
16. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one polymerase inhibitor which is different from the compound having the general formula (Di), (Dii), or (Diii); and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
17. The pharmaceutical composition according to claim 16, wherein the at least one polymerase inhibitor which is different from the compound having the general formula (Di), (Dii), or (Diii) is selected from
(a) a compound having the general formula (A), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000086_0001
(A)
wherein RA* is -H, -Hal, -(optionally substituted alkyl), -(optionally substituted C3_7 cycloalkyl), -(optionally substituted aryl), -C^ alkyl— (optionally substituted C3_ 7 cycloalkyl), -Ci_4 alkyl— (optionally substituted aryl) or -X -R1;
XA1 is O, C(O), C(0)0, OC(O); S, SO, S02l NR , N(RA5)C(0), C(0)NRA5;
XA2 is O, S, NR ;
XA3 is O or S;
XM is O or S;
RA1 is -H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-.7 cycloalkyl), -(optionally substituted aryl), -C^ alkyl— (optionally substituted C3_ 7 cycloalkyl), -C^ alkyl— (optionally substituted aryl);
RA2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
RA3 is -H, -(optionally substituted Ci_e alkyl), -(optionally substituted C3_7 cycloalkyl), -(optionally substituted aryl), or -C^ alkyl-(optionally substituted aryl) if XA2 is NRA4 then RA3 can also be -OH;
RA4 is -H, -(optionally substituted alkyl), -(optionally substituted
cycloalkyl), -(optionally substituted aryl), -C1-4 alkyl-(optionally substituted C3_ 7 cycloalkyl), or -C^ alkyl— (optionally substituted aryl) or if XA1 is NRA4, then RA4 and RA1 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N or if XA2 is NRA4, then R and RA3 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N; and
RA5 is -H, -(optionally substituted alkyl), -(optionally substituted
cycloalkyl), -(optionally substituted aryl), -C^ alkyl— (optionally substituted C3_ 7 cycloalkyl), or -C^ alkyl— (optionally substituted aryl); and
RA6 is -H, or -d-6 alkyl;
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN,— NRA6RA6, -OH, and -O-C^ alkyl;
wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of -C^ alkyl, halogen, -CF3, -CN, -XA1-RA5 and -C^ alkyl-aryl; and a compound having the general formula (C), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof,
Figure imgf000088_0001
is N, or CRC6;
is O, S, or NRC8;
is NRC5, N(RC5)C(0), C(0)NRcs, O, C(O), C(0)0, OC(Q); S, SO, S02, S02N(RC5) or N(RC5)S02;
is -H, -Hal, -(optionally substituted Ci_e alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), -Ci_4 alkyl— (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), or -XC2-Rc1;
is -H, -(optionally substituted Ci_6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), -C^ alkyl— (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S);
is -H, -(optionally substituted C1-j3 alkyl), -(optionally substituted C .7 cycloalkyl), -(optionally substituted aryl), -C^ alkyl— (optionally substituted cycloalkyl), or -C,_4 alkyl— (optionally substituted aryl) or if XC1 is NRC*. then RC2 can also be -OH;
is -H, -RC7, or -XC2-RC7;
is -H, -(optionally substituted d_6 alkyl), -(optionally substituted
Figure imgf000088_0002
cycloalkyl), -(optionally substituted aryl), -d_4 alkyl-(optionally substituted C3-7 cycloalkyl), or -C1-4 alkyl— (optionally substituted aryl); C5
R is -H, -(optionally substituted alkyl), -(optionally substituted cycloalkyl), -(optionally substituted aryl), -C^ afkyl— (optionally substituted C3_7 cycloalkyl), or -C1-4 a!kyl— (optionally substituted aryl);
R iC6 H, -C1-6 alkyl, -aryl, halogen or CN;
C7 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R ,'C8 -H, or -C^ alkyl; and
0 to 4; wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, -CN, -NRC5RCS, -OH, and -O-d-e alkyl;
wherein the optional substituent of the cycloalkyl group, the aryl group, the mono- or polycyclic group or the hydrocarbon group is selected from the group consisting of -Ci_e alkyl, halogen, -CF3, -CN, -XC2-RC8 and -Cw alkyl-aryl; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
18. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one neuramidase inhibitor; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
19. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one M2 channel inhibitor; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
20. A pharmaceutical composition comprising: (i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one alpha glucosidase inhibitor; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
21. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one ligand of another influenza target; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
22. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3; and
(ii) at least one medicament selected from antibiotics, anti-inflammatory agents, lipoxygenase inhibitors, EP ligands, bradykinin ligands, and cannabinoid ligands; and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
23. The pharmaceutical composition as defined in any of claims 16 to 22 for use in the treatment, amelioration or prevention of a viral disease.
24. A method of treating, ameliorating or preventing a viral disease, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition as defined in any of claims 16 to 22.
The pharmaceutical composition according to claim 23 or the method according to claim 24, wherein the viral disease is caused by Herpesviridae, Retroviridae, Fi!oviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae; more specifically wherein the viral disease is influenza.
26. The compound, pharmaceutical composition or method according to any of the preceding claims, wherein the compound having the general formula (Di), (Dii), or (Diii) exhibits a % reduction of at least about 30 % at 50 μ in the CPE assay disclosed herein.
27. The compound, pharmaceutical composition or method according to any of the preceding claims, wherein the compound having the general formula (Di), (Dii), or (Diii) exhibits an IC50 of at least about 40 μΜ in the FRET endonuclease activity assay disclosed herein.
PCT/EP2013/066388 2012-08-06 2013-08-05 Dihydroxypyrimidine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease WO2014023691A1 (en)

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RU2015107803A RU2015107803A (en) 2012-08-06 2013-08-05 DIHYDROXYPYrimidinecarboxylic Acid Derivatives AND THEIR APPLICATION IN TREATMENT, TREATMENT OR PREVENTION OF VIRAL DISEASE
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