WO2023111683A1 - N4-hydroxycytidine derivatives and use thereof as antiviral agent - Google Patents

N4-hydroxycytidine derivatives and use thereof as antiviral agent Download PDF

Info

Publication number
WO2023111683A1
WO2023111683A1 PCT/IB2022/000749 IB2022000749W WO2023111683A1 WO 2023111683 A1 WO2023111683 A1 WO 2023111683A1 IB 2022000749 W IB2022000749 W IB 2022000749W WO 2023111683 A1 WO2023111683 A1 WO 2023111683A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
heteroaryl
group
compound
Prior art date
Application number
PCT/IB2022/000749
Other languages
French (fr)
Inventor
Bin Liang
Bailing YANG
Yang Lai
Jinzi Jason Wu
Original Assignee
Ascletis Bioscience Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US17/664,304 external-priority patent/US11541071B1/en
Application filed by Ascletis Bioscience Co., Ltd. filed Critical Ascletis Bioscience Co., Ltd.
Priority to JP2023519586A priority Critical patent/JP2023553243A/en
Priority to EP22856980.2A priority patent/EP4222158A1/en
Publication of WO2023111683A1 publication Critical patent/WO2023111683A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • 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

Definitions

  • RNA-dependent RNA polymerase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. Viral RdRPs play essential roles in viral genome replication and transcription.
  • R 1 or R 2 is independently H, heteroaryl, -(CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl, - (CO)C 5 -C 10 aryl, -(CO)C 5 -C 10 heteroaryl, -(CO)OC 5 -C 10 aryl, -(CO)OC 5 -C 10 heteroaryl, - (CO)NHC 1 -C 6 alkyl, (CO)NHC 5 -C 10 aryl, or (CO)NHC 5 -C 10 heteroaryl, wherein the heteroaryl
  • R 5 or R 6 is independently H, OH, C 1 -C 6 alkyl, -(CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, -(CO)C 5 -C 10 heteroaryl, C 5 -C 10 aryl or C 5 -C 10 heteroaryl, wherein the link is independently selected from wherein each R 7 and R 8 is independently selected from H and C 1 -C 6 alkyl and wherein R 7 and R 8 can fuse to each other to form a ring.
  • R 1 or R 2 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R1 or R2 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 1 or R 2 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH.
  • R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1- C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 -C 6 alkyl, or -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 3 or R 4 is independently H, D, F, Cl, Br, CH 3 , or CF 3 .
  • R 5 or R 6 is independently H, OH, C 1 -C 6 alkyl, -(CO)C 1 -C 6 alkyl, or -(CO)OC 1 -C 6 alkyl.
  • Another aspect of the present application relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the present application.
  • Another aspect of the present application relates to a method treating or preventing a virus infection in a patient. The method comprises the step of administering to the patient an effective amount of a compound of the present application.
  • the virus infection is an infection of a coronavirus.
  • the virus infection is an infection of SARS-CoV2 virus.
  • a pharmaceutical agent which may be in the form of a salt or prodrug, is administered in methods disclosed herein that is specified by a weight.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b-camphorsulfonic acid.
  • optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b-camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, TV-methylephedrine, cyclohexylethylamine, 1,2- diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • each of the chiral centers in the compound may be independently ( R ) or (S), unless otherwise indicated.
  • Compounds of the application also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine -imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 H- and 3/f-imidazole, 1 H-, 2H- and 4 H- 1,2, 4-triazole, ⁇ H- and 211-isoindole and 1 H- and 2//-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the application can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the application can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the term, "compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the applications, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the application, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the application.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the application, or salt thereof.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g. , a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C.
  • present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the non-toxic salts of the parent compound formed, e.g., from non toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p.1418, Berge et al., J. Pharm.
  • the compounds described herein include the N-oxide forms.
  • subject and “patient,” are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the term "treating" or “treatment” refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • solvate refers to the compound formed by the interaction of a solvent and an effective pharmaceutical ingredient, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • substituted or optionally substituted as used in the present invention means that one or more hydrogen atoms of the group to which the term “substitute” or “optionally substituted” refers are replaced with one or more substituents.
  • each of the one or more substitutents is independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower- carboxamidoalkylaryl, lower-carboxamidoaryl, lower hydroxyalkyl, lower lower hydroxyalky
  • alkyl refers to a straight or branched or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted.
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms.
  • Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium.
  • Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • biasing represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
  • substituted aryl and substituted heteroaryl refers to aryl and heteroaryl groups substituted with 1-3 substituents. In some embodiments, the 1-3 substituents are each independently selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
  • -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • alkylaryl- refers to an aryl group substituted with an alkyl group. “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl.
  • the carbon atom designations may have the indicated integer and any intervening integer.
  • the number of carbon atoms in a (C 1 -C 4 )-alkyl group is 1, 2, 3, or 4. It should be understood that these designation refer to the total number of atoms in the corresponding hetero group, including carbon atoms and heteroatoms.
  • the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
  • cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms. Suitable cyclic groups include fused cyclic group, spiro cyclic group, norbornyl and cyclopropyl. Such groups may be substituted.
  • heterocyclic refers to cyclic groups of 3 to 10 atoms, and in one aspect cyclic groups of 3 to 6 atoms, that contain at least one heteroatom, in a further aspect 1 to 3 heteroatoms.
  • Suitable heteroatoms include oxygen, sulfur, and nitrogen.
  • Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring.
  • the heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups.
  • Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
  • arylamino (a), and “aralkylamino” (b), respectively, refer to the group— NRR', wherein respectively, (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.
  • acyl refers to— C(O)-R, where R is alkyl, heterocycloalkyl, or aryl.
  • carboxy esters refers to— C(O)-OR, where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.
  • carboxyl refers to— C(O)-OH.
  • amino refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R' can form a cyclic ring system.
  • -carboxylamido refers to –C(O)NR 2 , where each R is independently hydrogen or alkyl.
  • the term “halogen” or“halo” refers to -F, -Cl, -Br and -I.
  • alkylaminoalkylcarboxy refers to the group alkyl-NR-alk- C(O)- O- where “alk” is an alkylene group, and R is a H or lower alkyl.
  • sulphonyl or “sulfonyl” refers to -SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • sulphonate or “sulfonate” refers to— SO 2 -OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched- chain and cyclic groups. Alkenyl groups may be optionally substituted.
  • Suitable alkenyl groups include allyl.“1-Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon. [0070]
  • alkynyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched- chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.
  • alkynyl refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1 -alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene group contains up to and including 6 atoms. In a further aspect the alkylene group contains up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic.
  • acyloxy refers to the ester group –O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • aminoalkyl- refers to the group NR 2 -alk- wherein “alk” is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alkylaminoalkyl- refers to the group alkyl-NR-alk- wherein each“alk” is an independently selected alkylene, and R is H or lower alkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively.
  • arylaminoalkyl- refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkylene group is lower alkylene.
  • alkylaminoaryl- refers to the group alkyl-NR-aryl- wherein “aryl” is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylaminoaryl-,” the alkyl group is lower alkyl.
  • alkoxyaryl- refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-,” the alkyl group is lower alkyl.
  • aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • aralkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • alkoxy- or alkyloxy- refers to the group alkyl-O- .
  • alkoxyalkyl- or“alkyloxyalkyl-” refers to the group alkyl-O-alk- wherein“alk” is an alkylene group. In “lower alkoxyalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkylthio- refers to the group alkyl-S-.
  • alkylthioalkyl- refers to the group alkyl-S-alk- wherein “alk” is an alkylene group. In “lower alkylthioalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkoxycarbonyloxy- refers to alkyl-O-C(O)-O-
  • aryloxycarbonyloxy- refers to aryl-O-C(O)-O- .
  • alkylthiocarbonyloxy- refers to alkyl-S-C(O)-O-
  • carboxy refers to NR 2 -C(O)- and RC(O)-NR 1 - , where R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • urea does not include urea, -NR- C(O)-NR-.
  • R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • carboxyalkylaryl or “carboxamidoaryl” refers to an aryl-alk- NR 1 -C(O), and aryl-NR 1 -C(O)-alk-, respectively, where “alk” is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • hydroxyalkyl refers to an alkyl group substituted with one -OH.
  • haloalkyl refers to an alkyl group substituted with halo.
  • cyano refers to -CN.
  • acylalkyl refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
  • aminocarboxamidoalkyl- refers to the group NR 2- C(O)-N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups, wherein “alk” is lower alkylen
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced. [0100] As used herein, the term “combination with” when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof. II.
  • R 1 or R 2 is independently H, heteroaryl, -(CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl, - (CO)C 5 -C 10 aryl, -(CO)C 5 -C 10 heteroaryl, -(CO)OC 5 -C 10 aryl, -(CO)OC 5 -C 10 heteroaryl, - (CO)NHC 1 -C 6 alkyl, (CO)NHC 5 -C 10 aryl, or (CO)NHC 5 -C 10 heteroaryl, wherein the heteroaryl, - (CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, -(CO)C 5 -C 5 -C
  • R 5 or R 6 is independently H, OH, C 1 -C 6 alkyl, -(CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, -(CO)C 5 -C 10 heteroaryl, C 5 -C 10 aryl or C 5 -C 10 heteroaryl, wherein the link is independently selected from wherein each R 7 and R 8 is independently selected from H and C 1 -C 6 alkyl and wherein R 7 and R 8 can fuse to each other to form a ring.
  • R 1 or R 2 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 - C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 1 or R 2 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 1 or R 2 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the -(CO)C 1 - C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
  • R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
  • R 1 is independently H, -(CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, wherein the - (CO)C 1 -C 6 alkyl, -(CO)C 5 -C 10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
  • R 3 or R 4 is independently H, D, F, Cl, Br, CH 3 , CF 3 .
  • R 5 or R 6 is independently H, OH, C 1 -C 6 alkyl, -(CO)C 1 -C 6 alkyl, -(CO)OC 1 -C 6 alkyl.
  • the compound of the present application is selected from the group consisting of the following compounds:
  • Another aspect of the present application relates to a method for preventing, treating, or ameliorating the symptoms of a viral infection in a subject with a compound of the present application.
  • the method comprises the step of administering an effective amount of the compound of the present application to a subject in need thereof.
  • the viral infection is a coronavirus infection.
  • the viral infection is SARS-CoV-2 infection.
  • the viral infection is caused by alphavirus, flavivirus, coronavirus, RSV, influenza virus, Powassan virus, ebola virus, or viruses of filoviridae, orthomyxoviridae or paramyxoviridae.
  • the viral infection caused by a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis viruses, Ross River virus, Barmah Forest virus, Powassan virus, Zika virus, and Chikungunya virus.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with, infection of influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV- 1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), Dengue virus, Zika virus, chikungunya, Eastern equine ence
  • influenza A virus including subtype
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with a Zika virus infection.
  • influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus,
  • influenza A virus including subtypes H1N1, H3N
  • the subject is diagnosed with a Zika virus infection.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with, infection of subgroup 1a or 1b alphacoronaviruses, subgroup 2a, 2b, 2c or 2d betacoronaviruses, or subgroup 3 gammscoronaviruses.
  • subgroup 1a alphacoronaviruses and their GenBank Accession Nos.
  • FCov.FIPV.79.1146.VR.2202 (NV_007025), transmissible gastroenteritis virus (TGEV) (NC_002306; Q811789.2; DQ811786.2; DQ811788.1; DQ811785.1; X52157.1; AJ011482.1; KC962433.1; AJ271965.2; JQ693060.1; KC609371.1; JQ693060.1; JQ693059.1; JQ693058.1; JQ693057.1; JQ693052.1; JQ693051.1; JQ693050.1); porcine reproductive and respiratory syndrome virus (PRRSV) (NC_001961.1; DQ811787), as well as any subtype, clade or sub-clade thereof, including any other subgroup 1a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • TGEV transmissible gastroenteritis virus
  • Nonlimiting examples of a subgroup 1b alphacoronaviruses and their GenBank Accession Nos. include HCoV.NL63.Amsterdam.I (NC_005831), BtCoV.HKU2.HK.298.2006 (EF203066), BtCoV.HKU2.HK.33.2006 (EF203067), BtCoV.HKU2.HK.46.2006 (EF203065), BtCoV.HKU2.GD.430.2006 (EF203064), BtCoV.1A.AFCD62 (NC_010437), BtCoV.1B.AFCD307 (NC_010436), BtCov.HKU8.AFCD77 (NC_010438), BtCoV.512.2005 (DQ648858); porcine epidemic diarrhea viruses (NC_003436, DQ355224.1, DQ355223.1, DQ355221.1, JN601062.1, JN601061.1, JN601060.1, JN60105
  • Nonlimiting examples of subgroup 2a betacoronaviruses and their GenBank Accession Nos. include HCoV.HKU1.C.N5 (DQ339101), MHV.A59 (NC_001846), PHEV.VW572 (NC_007732), HCoV.OC43.ATCC.VR.759 (NC_005147), bovine enteric coronavirus (BCoV.ENT) (NC_003045), as well as any subtype, clade or sub-clade thereof, including any other subgroup 2a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • HCoV.HKU1.C.N5 DQ339101
  • MHV.A59 NC_001846)
  • PHEV.VW572 NC_007732
  • HCoV.OC43.ATCC.VR.759 NC_005147
  • bovine enteric coronavirus BCo
  • Nonlimiting examples of subgroup 2b betacoronaviruses and their GenBank Accession Nos. include human SARS CoV-2 isolates, such as Wuhan-Hu-1 (NC_045512.2) and any CoV-2 isolates comprising a genomic sequence set forth in GenBank Accession Nos., such as MT079851.1, MT470137.1, MT121215.1, MT438728.1, MT470115.1, MT358641.1, MT449678.1, MT438742.1, LC529905.1, MT438756.1, MT438751.1, MT460090.1, MT449643.1, MT385425.1, MT019529.1, MT449638.1, MT374105.1, MT449644.1, MT385421.1, MT365031.1, MT385424.1, MT334529.1, MT466071.1, MT461669.1, MT449639.1, MT415321.1, MT38
  • Nonlimiting examples of subgroup 2c betacoronaviruses and their GenBank Accession Nos. include Middle East respiratory syndrome coronavirus (MERS) isolates, such as Riyadh 22012 (KF600652.1), Al-Hasa_18_2013 (KF600651.1), Al-Hasa_17_2013 (KF600647.1), Al-Hasa_152013 (KF600645.1), Al-Hasa_16_2013 (KF600644.1), Al- Hasa_21_2013 (KF600634), Al-Hasa 19_2013 (KF600632), Buraidah_1_2013 (KF600630.1), Hafr-Al-Batin_1_2013 (KF600628.1), Al-Hasa_122013 (KF600627.1), Bisha.ltoreq.1_2012 (KF600620.1), Riyadh_3_2013 (KF600613.1), Riyadh_1_2012 (KF60065
  • Nonlimiting examples of subgroup 2d betacoronaviruses and their GenBank Accession Nos. include BtCoV.HKU9.2 (EF065514), BtCoV.HKU9.1 (NC_009021), BtCoV.HkU9.3 (EF065515), BtCoV.HKU9.4 (EF065516), as well as any subtype, clade or sub- clade thereof, including any other subgroup 2d coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • Nonlimiting examples of subgroup 3 gammacoronaviruses include IBV.Beaudette.IBV.p65 (DQ001339) or any other subgroup 3 coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • a coronavirus defined by any of the isolates or genomic sequences in the aforementioned subgroups 1a, 1b, 2a, 2b, 2c, 2d and 3 can be targeted for decontamination in accordance with the methods and compositions of the present application.
  • the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis.
  • the compound of the present application is administered orally or by inhalation. In certain embodiments, the compound is administered by inhalation through the lungs.
  • the compound of the present application is administered at a daily dosage in the range of 10-8000 mg,, 20-400 mg, 20-200 mg, 20-100 mg, 20-80 mg, 20-40 mg, 40-8000 mg, 40-4000 mg, 40-2000 mg, 40-1000 mg, 40-800 mg, 40-400 mg, 40-200 mg, 40-100 mg, 40-80 mg, 80-8000 mg, 80-4000 mg, 80-2000 mg, 80-1000 mg, 80-800 mg, 80-400 mg, 80-200 mg, 80-100 mg, 100-8000 mg, 100-4000 mg, 100-2000 mg, 100-1000 mg, 100-800 mg, 100-400 mg, 100-200 mg, 200-8000 mg, 200-4000 mg, 200-2000 mg, 200-1000 mg, 200- 800 mg, 200-400 mg, 400-8000 mg, 400-4000 mg, 400-2000 mg, 400-1000 mg, 400-800 mg, 800-8000 mg, 800-4000 mg, 800-2000 mg, 800-1000 mg, 1000-8000 mg, 1000-4000
  • the compound of the present application is administered at a daily dosage in the range of 50-1000 mg, 100-800 mg, 200-600 mg or 300-500 mg. IV.
  • Pharmaceutical compositions [0135] Another aspect of the present application relates to a pharmaceutical composition comprising a compound of the present application.
  • the pharmaceutical composition comprises a compound of the present application and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises, or is in the form of, a pharmaceutically acceptable salt of the compound of the present application, as generally described below.
  • Suitable pharmaceutically acceptable organic and/or inorganic acids that may form a salt with a compound of the present application include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).
  • a compound of the present application contains an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein.
  • salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of the compounds of the present application include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosy
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.
  • Physiologically acceptable salts of the compounds of the present application are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.
  • the compounds of the present application can be administered in the form of prodrugs.
  • a prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a subject, cleaves to form a free hydroxyl group.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds. Methods of structuring a compound as prodrugs can be found in the book of Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006).
  • Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids.
  • the pharmaceutical composition of the present application comprises an effective amount of a compound of the present application and a pharmaceutically acceptable carrier.
  • the compound of the present application can be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the preparations can be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to U.S. Pat.
  • compositions can be in a unit dosage form, and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which can be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • such unit dosages will contain from 1 and 1000 mg, and usually from 5 and 500 mg, of the at least one compound of the disclosure, e.g., about 50, 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 or 800 mg per unit dosage.
  • the compound or pharmaceutical composition of the present application can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used.
  • the compound or pharmaceutical composition will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.
  • an effective amount will usually be from 0.01 to 1000 mg per kilogram body weight of the patient per day, more often from 0.1 and 500 mg, such as from 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which can be administered as a single daily dose, divided over one or more daily doses.
  • the amount(s) to be administered, the route of administration and the further treatment regimen can be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • the pharmaceutical composotion described herein can be formulated in a variety of ways.
  • Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols and the like.
  • the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages.
  • Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets.
  • liquid dosage forms such as solutions, syrups, suspension, shakes, etc. can also be utilized.
  • the formulation is administered topically.
  • Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels. In a preferred embodiment, the topical formulation is a gel. In another embodiment, the formulation is administered intranasally. [0144] Formulations containing one or more of the compounds described herein can be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions. [0145] Carrier also includes all components of the coating composition, which can include plasticizers, pigments, colorants, stabilizing agents, and glidants. Delayed release, extended release, and/or pulsatile release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage form tablets", eds. Liberman et al.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT TM (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • the coating material can contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as "fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross-linked polymers, such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants can be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER TM 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads, granules, or particles can also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • the concentration of the compound of the present application can vary from about 0.5 to about 100 wt. % (weight percent) of the final pharmaceutical composition.
  • the pharmaceutical composition can generally contain from about 5 to about 100% by weight of the active material.
  • the pharmaceutical composition can generally have from about 0.5 to about 50 wt. % of the active material.
  • the compositions described herein can be formulated for modified or controlled release. Examples of controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.
  • the extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington--The science and practice of pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000).
  • a diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOL TM 934, polyethylene oxides and mixtures thereof.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the trade name EUDRAGIT.
  • the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names EUDRAGIT RL30D and EUDRAGIT RS30D, respectively.
  • EUDRAGIT RL30D and EUDRAGIT RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL30D and 1:40 in EUDRAGIT RS30D.
  • the mean molecular weight is about 150,000.
  • EUDRAGIT S-100 and EUDRAGIT L-100 are also preferred.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • EUDRAGIT RL/RS mixtures are insoluble in water and in digestive fluids.
  • multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the polymers described above such as EUDRAGIT RL/RS can be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems can be obtained, for instance, from 100% EUDRAGIT RL, 50% EUDRAGIT RL and 50% EUDRAGIT RS, and 10% EUDRAGIT RL and 90% EUDRAGITRS.
  • acrylic polymers can also be used, such as, for example, EUDRAGIT L.
  • Extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose.
  • Natural and synthetic gums including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used.
  • Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition can be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and can be conventional "enteric" polymers.
  • Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastro-intestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the trade name EUDRAGIT TM (Rohm Pharma; Westerstadt, Germany), including EUDRAGIT TM L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT TM L
  • the coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • plasticizers examples include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt.
  • the formulation can provide pulsatile delivery of the one or more compounds.
  • pulsatile is meant that a plurality of drug doses are released at spaced apart intervals of time. Generally, upon ingestion of the dosage form, release of the initial dose is substantially immediate, i.e., the first drug release "pulse" occurs within about one hour of ingestion.
  • This initial pulse is followed by a first time interval (lag time) during which very little or no drug is released from the dosage form, after which a second dose is then released.
  • a second nearly drug release-free interval between the second and third drug release pulses can be designed.
  • the duration of the nearly drug release-free time interval will vary depending upon the dosage form design e.g., a twice daily dosing profile, a three times daily dosing profile, etc.
  • the nearly drug release-free interval has a duration of approximately 3 hours to 14 hours between the first and second dose.
  • the nearly drug release-free interval has a duration of approximately 2 hours to 8 hours between each of the three doses.
  • the pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug-containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile.
  • Control of the delayed release dosage unit(s) is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix.
  • Each dosage unit can comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug approximately 3 hours to less than 14 hours following ingestion of the dosage form.
  • each dosage unit in the capsule can comprise a plurality of drug- containing beads, granules or particles.
  • drug-containing "beads" refer to beads made with drug and one or more excipients or polymers.
  • Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core" comprising both drug and one or more excipients.
  • drug- containing "granules” and “particles” comprise drug particles that can or cannot include one or more additional excipients or polymers.
  • granules and particles do not contain an inert support.
  • Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed.
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units.
  • multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • the compound of the present application is formulated for topical administration. Suitable topical dosage forms include lotions, creams, ointments, and gels.
  • a "gel” is a semisolid system containing a dispersion of the active agent, i.e., compound, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid can include a lipophilic component, an aqueous component or both.
  • Some emulsions can be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.
  • Methods for preparing lotions, creams, ointments, and gels are well known in the art. V. Combination Therapies [0175]
  • the compound described herein can be administered adjunctively with other active compounds.
  • These compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents.
  • antiviral agents include, but are not limited to, RNA-dependent RNA polymerase (RdRp) inhibitors, protease drugs, anti-viral neutralizing antibodies and other antiviral drugs.
  • the antiviral agent is a non-CNS targeting antiviral compound.
  • Adjunctive administration means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • the additional active agent(s) can be formulated for immediate release, controlled release, or combinations thereof.
  • compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine,
  • the exemplary compounds and pharmaceutical compositions can be administered in combination with another antiviral agent(s) such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod
  • another antiviral agent such
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable [0187] protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well- known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0190] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), N, N-dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
  • the present invention provides a method for preparing a compound of the formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, the method comprising five general routes (Route A, Route B, Route C, Route D and Route E): Route A: Route C:
  • Example 2 Permeability of Compounds in Caco-2 Assay
  • Caco-2 Culture Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96-well Corning Insert plates at 1 x 105 cells/ cm2, and refreshed medium every 4 ⁇ 5 days until to the 21st to 28th day for confluent cell monolayer formation.
  • Transport Methods [0226] The transport buffer in the study was HBSS with 10.0 mM HEPES at pH 7.40 ⁇ 0.05. Test compound was tested at 2.00 ⁇ M bi-directionally in duplicate.
  • Digoxin was tested at 10.0 ⁇ M bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 ⁇ M in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1%. The plate was incubated for 2 hours in CO 2 incubator at 37 ⁇ 1°C, with 5% CO 2 at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3200 xg for 10 min. For nadolol and metoprolol, 200 ⁇ L supernatant solution was diluted with 600 ⁇ L ultra-pure water for LC-MS/MS analysis.
  • lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.

Abstract

Certain anti-viral compounds, pharmaceutical compositions, and methods related thereto are disclosed.

Description

N4-HYDROXYCYTIDINE DERIVATIVES AND USE THEREOF AS ANTIVIRAL AGENT RELATED APPLICATIONS [0001] This application claims priority of U.S. Provisional Application No.63/265,577, filed on December 16, 2021, U.S. Provisional Application No.63/267,434, filed on February 2, 2022 and U.S. Application No.17/664,304, filed on May 20, 2022. The entirety of the aforementioned applications is incorporated herein by reference. FIELD [0002] This application generally relates to nucleoside derivatives, as well as compositions and methods of use related thereto. BACKGROUND [0003] Nucleoside analogues mimic endogenous nucleosides, exploiting cellular metabolism and becoming incorporated into both DNA and RNA. This property makes nucleoside analogues effective at inhibiting viral replication and stopping cancer cell proliferation. RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. Viral RdRPs play essential roles in viral genome replication and transcription. While a number of nucleoside analogues have been developed for the treatment of viral infections, including HBV, HCV and SARS-CoV2 infections, there still exists a need for nucleoside analogues that are more effective in treating viral infections. SUMMARY [0004] One aspect of the present application relates to compounds having a structure as shown in Formula I:
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H, heteroaryl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, - (CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, - (CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl, or (CO)NHC5-C10 heteroaryl, wherein the heteroaryl, - (CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, -(CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl or (CO)NHC5-C10 heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, OH, -O-C1-C6 alkyl, NR6R5, C1-C6 alkyl, C5-C10 aryl and heteroaryl, wherein R3 or R4 is independently H, D, halo or C1-C3 alkyl, wherein alkyl is optionally substituted with one or more halo. wherein R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, C5-C10 aryl or C5-C10 heteroaryl, wherein the link is independently selected from
Figure imgf000003_0001
wherein each R7 and R8 is independently selected from H and C1-C6 alkyl and wherein R7 and R8 can fuse to each other to form a ring. [0005] Another aspect of the present application relates to compounds having a structure as shown in Formula II:
Figure imgf000003_0002
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH. [0006] Another aspect of the present application relates to compounds having a structure as shown in Formula III:
Figure imgf000004_0001
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0007] Another aspect of the present application relates to compounds having a structure as shown in Formula IV:
Figure imgf000004_0002
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH. [0008] Another aspect of the present application relates to compounds having a structure as shown in Formula V:
Figure imgf000004_0003
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0009] Another aspect of the present application relates to compounds having a structure as shown in Formula VI:
Figure imgf000005_0001
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH. [0010] Another aspect of the present application relates to compounds having a structure as shown in Formula VII:
Figure imgf000005_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0011] Another aspect of the present application relates to compounds having a structure as shown in Formula VIII:
Figure imgf000006_0001
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH. [0012] Another aspect of the present application relates to compounds having a structure as shown in Formula IX:
Figure imgf000006_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1- C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0013] Another aspect of the present application relates to compounds having a structure as shown in Formula X:
Figure imgf000006_0003
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo, and OH. [0014] Another aspect of the present application relates to compounds having a structure as shown in Formula XI:
Figure imgf000007_0001
[0015] wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0016] In some embodiments, R3 or R4 is independently H, D, F, Cl, Br, CH3, or CF3. [0017] In some embodiments, R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, or -(CO)OC1-C6 alkyl. [0018] Another aspect of the present application relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the present application. [0019] Another aspect of the present application relates to a method treating or preventing a virus infection in a patient. The method comprises the step of administering to the patient an effective amount of a compound of the present application. In some embodiments, the virus infection is an infection of a coronavirus. In some embodiments, the virus infection is an infection of SARS-CoV2 virus. DETAILED DESCRIPTION [0020] Reference will be made in detail to certain aspects and exemplary embodiments of the application, illustrating examples in the accompanying structures and figures. The aspects of the application will be described in conjunction with the exemplary embodiments, including methods, materials and examples, such description is non-limiting and the scope of the application is intended to encompass all equivalents, alternatives, and modifications, either generally known, or incorporated here. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. One of skill in the art will recognize many techniques and materials similar or equivalent to those described here, which could be used in the practice of the aspects and embodiments of the present application. The described aspects and embodiments of the application are not limited to the methods and materials described. [0021] As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. [0022] Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value is disclosed that "less than or equal to "the value," greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "10" is disclosed the "less than or equal to 10" as well as "greater than or equal to 10" is also disclosed. [0023] In certain embodiments, a pharmaceutical agent, which may be in the form of a salt or prodrug, is administered in methods disclosed herein that is specified by a weight. This refers to the weight of the recited compound. If in the form of a salt or prodrug, then the weight is the molar equivalent of the corresponding salt or prodrug [0024] At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure includes each and every individual subcombination of the members of such groups and ranges. [0025] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present application that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present application. Cis and trans geometric isomers of the compounds of the present application are described and may be isolated as a mixture of isomers or as separated isomeric forms. [0026] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, TV-methylephedrine, cyclohexylethylamine, 1,2- diaminocyclohexane and the like. [0027] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. [0028] In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently ( R ) or (S), unless otherwise indicated. [0029] Compounds of the application also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine -imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 H- and 3/f-imidazole, 1 H-, 2H- and 4 H- 1,2, 4-triazole, \H- and 211-isoindole and 1 H- and 2//-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. [0030] Compounds of the application can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the application can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. I. Definitions [0031] The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the applications, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. [0032] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound. [0033] In some embodiments, the compounds of the application, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the application. [0034] Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the application, or salt thereof. [0035] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0036] The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. , a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C. [0037] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include the non-toxic salts of the parent compound formed, e.g., from non toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p.1418, Berge et al., J. Pharm. Sci, 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms. [0038] The terms “subject,” "individual," and "patient," are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. [0039] The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. [0040] As used herein, the term "treating" or "treatment" refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. [0041] The term “solvate” refers to the compound formed by the interaction of a solvent and an effective pharmaceutical ingredient, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates. [0042] The term "substituted" or “optionally substituted” as used in the present invention means that one or more hydrogen atoms of the group to which the term "substitute" or “optionally substituted” refers are replaced with one or more substituents. In some embodiments, each of the one or more substitutents is independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower- carboxamidoalkylaryl, lower-carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, lower aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkyloxyalkyl, provided that the normal valency of the atom on which the substitution is considered is not exceeded and that the substitution results in a stable chemical compound, that is to say a compound that is sufficiently robust to be isolated from a reaction mixture. [0043] The term “alkyl” refers to a straight or branched or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted. [0044] The term “aryl” refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. [0045] Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups. [0046] Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted. [0047] The term “biaryl” represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl. [0048] The term “substituted aryl” and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-3 substituents. In some embodiments, the 1-3 substituents are each independently selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. [0049] The term “-aralkyl” refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. [0050] The term “heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group. [0051] The term “alkylaryl-” refers to an aryl group substituted with an alkyl group. “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl. [0052] As used herein, the carbon atom designations may have the indicated integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designation refer to the total number of atoms in the corresponding hetero group, including carbon atoms and heteroatoms. For example, in a (C3- C10)-heterocyclyl the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10. [0053] The term “lower” referred to herein in connection with organic radicals or compounds respectively refers to 6 carbon atoms or less. Such groups may be straight chain, branched, or cyclic. [0054] The term “higher” referred to herein in connection with organic radicals or compounds respectively refers to 7 or more carbon atoms. Such groups may be straight chain, branched, or cyclic. [0055] The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms. Suitable cyclic groups include fused cyclic group, spiro cyclic group, norbornyl and cyclopropyl. Such groups may be substituted. [0056] The term “heterocyclic,” “heterocyclic alkyl” or “heterocycloalkyl” refer to cyclic groups of 3 to 10 atoms, and in one aspect cyclic groups of 3 to 6 atoms, that contain at least one heteroatom, in a further aspect 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. The heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. [0057] The terms “arylamino” (a), and “aralkylamino” (b), respectively, refer to the group— NRR', wherein respectively, (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl. [0058] The term “acyl” refers to— C(O)-R, where R is alkyl, heterocycloalkyl, or aryl. [0059] The term “carboxy esters” refers to— C(O)-OR, where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted. [0060] The term “carboxyl” refers to— C(O)-OH. [0061] The term “oxo” refers to =O in an alkyl or heterocycloalkyl group. [0062] The term “amino” refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R' can form a cyclic ring system. [0063] The term “-carboxylamido” refers to –C(O)NR2, where each R is independently hydrogen or alkyl. [0064] The term“-sulphonylamido” or“-sulfonylamido” refers to -S(=O)2NR2 where each R is independently hydrogen or alkyl. [0065] The term “halogen” or“halo” refers to -F, -Cl, -Br and -I. [0066] The term “alkylaminoalkylcarboxy” refers to the group alkyl-NR-alk- C(O)- O- where “alk” is an alkylene group, and R is a H or lower alkyl. [0067] The term “sulphonyl” or “sulfonyl” refers to -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl. [0068] The term “sulphonate” or “sulfonate” refers to— SO2-OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. [0069] The term “alkenyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched- chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl.“1-Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon. [0070] The term “alkynyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched- chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. “1-Alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1 -alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon. [0071] The term “alkylene” refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene group contains up to and including 6 atoms. In a further aspect the alkylene group contains up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic. [0072] The term “acyloxy” refers to the ester group –O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl. [0073] The term “aminoalkyl-” refers to the group NR2-alk- wherein “alk” is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl. [0074] The term “alkylaminoalkyl-” refers to the group alkyl-NR-alk- wherein each“alk” is an independently selected alkylene, and R is H or lower alkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively. [0075] The term “arylaminoalkyl-” refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In “lower arylaminoalkyl-,” the alkylene group is lower alkylene. [0076] The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl- wherein “aryl” is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylaminoaryl-,” the alkyl group is lower alkyl. [0077] The term “alkoxyaryl-” refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-,” the alkyl group is lower alkyl. [0078] The term “aryloxyalkyl-” refers to an alkyl group substituted with an aryloxy group. [0079] The term “aralkyloxyalkyl-” refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene. [0080] The term “alkoxy-” or “alkyloxy-” refers to the group alkyl-O- . [0081] The term “alkoxyalkyl-” or“alkyloxyalkyl-” refers to the group alkyl-O-alk- wherein“alk” is an alkylene group. In “lower alkoxyalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively [0082] The term “alkylthio-” refers to the group alkyl-S-. [0083] The term “alkylthioalkyl-” refers to the group alkyl-S-alk- wherein “alk” is an alkylene group. In “lower alkylthioalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively. [0084] The term “alkoxycarbonyloxy-” refers to alkyl-O-C(O)-O- [0085] The term “aryloxycarbonyloxy-” refers to aryl-O-C(O)-O- . [0086] The term “alkylthiocarbonyloxy-” refers to alkyl-S-C(O)-O- [0087] The term “amido” refers to the NR2 group next to an acyl or sulfonyl group as in NR2-C(O)-, RC(O)-NR1— , NR2-S(=O)2- and RS(=O)2-NR1- , where R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl [0088] The term “carboxamido” refers to NR2-C(O)- and RC(O)-NR1- , where R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR- C(O)-NR-. [0089] The term “sulphonamido” or “sulfonamido” refers to NR2-S(=O)2- and RS(=O)2- NR1-, where R and R1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include sulfonylurea, -NR-S(=O)2-NR-. [0090] The term “carboxamidoalkylaryl” or “carboxamidoaryl” refers to an aryl-alk- NR1-C(O), and aryl-NR1-C(O)-alk-, respectively, where “alk” is alkylene, R1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl. [0091] The term “sulfonamidoalkylaryl” or “sulfonamidoaryl” refers to an aryl- alk-NR1- S(=O)2-, and aryl-NR1-S(=O)2-, respectively, where “alk” is alkylene, R1 and R include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. [0092] The term “hydroxyalkyl” refers to an alkyl group substituted with one -OH. [0093] The term “haloalkyl” refers to an alkyl group substituted with halo. [0094] The term “cyano” refers to -CN. [0095] The term “nitro” refers to -NO2. [0096] The term “acylalkyl” refers to an alkyl-C(O)-alk-, where “alk” is alkylene. [0097] The term “aminocarboxamidoalkyl-” refers to the group NR2-C(O)-N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups, wherein “alk” is lower alkylen [0098] The term “heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group. [0099] As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced. [0100] As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof. II. Compounds and compositions of the present application [0101] One aspect of the present application relates to compounds having a structure as shown in Formula I:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H, heteroaryl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, - (CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, - (CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl, or (CO)NHC5-C10 heteroaryl, wherein the heteroaryl, - (CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, -(CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl or (CO)NHC5-C10 heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, OH, -O-C1-C6 alkyl, NR6R5, C1-C6 alkyl, C5-C10 aryl and heteroaryl, wherein R3 or R4 is independently H, D, halo or C1-C3 alkyl, wherein alkyl is optionally substituted with one or more halo. wherein R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, C5-C10 aryl or C5-C10 heteroaryl, wherein the link is independently selected from
Figure imgf000017_0002
wherein each R7 and R8 is independently selected from H and C1-C6 alkyl and wherein R7 and R8 can fuse to each other to form a ring. [0102] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula II:
Figure imgf000017_0003
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH. [0103] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula III:
Figure imgf000018_0001
wherein R1 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the -(CO)C1- C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0104] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula IV:
Figure imgf000018_0002
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH. [0105] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula V:
Figure imgf000019_0001
wherein R1 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0106] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula VI:
Figure imgf000019_0002
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH. [0107] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula VII:
Figure imgf000019_0003
wherein R1 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0108] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula VIII:
Figure imgf000020_0001
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the -(CO)C1- C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH. [0109] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula IX:
Figure imgf000020_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0110] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula X:
Figure imgf000020_0003
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH. [0111] Another group of preferred compounds, or a pharmaceutically acceptable salt thereof, having the structure of Formula XI:
Figure imgf000021_0001
wherein R1 is independently H, -(CO)C1-C6 alkyl, -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo. [0112] In some embodiments, R3 or R4 is independently H, D, F, Cl, Br, CH3, CF3. [0113] In some embodiments, R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl. [0114] In some embodiments, the compound of the present application is selected from the group consisting of the following compounds:
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
III. Methods of Use [0115] Another aspect of the present application relates to a method for preventing, treating, or ameliorating the symptoms of a viral infection in a subject with a compound of the present application. [0116] In some embodiments, the method comprises the step of administering an effective amount of the compound of the present application to a subject in need thereof. [0117] In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is SARS-CoV-2 infection. [0118] In certain embodiments, the viral infection is caused by alphavirus, flavivirus, coronavirus, RSV, influenza virus, Powassan virus, ebola virus, or viruses of filoviridae, orthomyxoviridae or paramyxoviridae. [0119] In certain embodiments, the viral infection caused by a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis viruses, Ross River virus, Barmah Forest virus, Powassan virus, Zika virus, and Chikungunya virus. [0120] In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with, infection of influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV- 1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), Dengue virus, Zika virus, chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, Barmah Forest virus, yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, ebola virus, marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV), The Human T-lymphotropic virus Type I (HTLV-1), Friend spleen focus-forming virus (SFFV) or Xenotropic MuLVRelated Virus (XMRV). In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with a Zika virus infection. [0121] In certain embodiments, the subject is diagnosed with influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza viruses 1 and 3, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV), hantavirus, Dengue virus serotypes 1, 2, 3 and 4, Zika virus, West Nile virus, Tacaribe virus, Junin, rabies virus, ebola virus, marburg virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E or human immunodeficiency virus (HIV). In certain embodiments, the subject is diagnosed with a Zika virus infection. [0122] In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with, infection of subgroup 1a or 1b alphacoronaviruses, subgroup 2a, 2b, 2c or 2d betacoronaviruses, or subgroup 3 gammscoronaviruses. [0123] Nonlimiting examples of subgroup 1a alphacoronaviruses and their GenBank Accession Nos. include FCov.FIPV.79.1146.VR.2202 (NV_007025), transmissible gastroenteritis virus (TGEV) (NC_002306; Q811789.2; DQ811786.2; DQ811788.1; DQ811785.1; X52157.1; AJ011482.1; KC962433.1; AJ271965.2; JQ693060.1; KC609371.1; JQ693060.1; JQ693059.1; JQ693058.1; JQ693057.1; JQ693052.1; JQ693051.1; JQ693050.1); porcine reproductive and respiratory syndrome virus (PRRSV) (NC_001961.1; DQ811787), as well as any subtype, clade or sub-clade thereof, including any other subgroup 1a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0124] Nonlimiting examples of a subgroup 1b alphacoronaviruses and their GenBank Accession Nos. include HCoV.NL63.Amsterdam.I (NC_005831), BtCoV.HKU2.HK.298.2006 (EF203066), BtCoV.HKU2.HK.33.2006 (EF203067), BtCoV.HKU2.HK.46.2006 (EF203065), BtCoV.HKU2.GD.430.2006 (EF203064), BtCoV.1A.AFCD62 (NC_010437), BtCoV.1B.AFCD307 (NC_010436), BtCov.HKU8.AFCD77 (NC_010438), BtCoV.512.2005 (DQ648858); porcine epidemic diarrhea viruses (NC_003436, DQ355224.1, DQ355223.1, DQ355221.1, JN601062.1, JN601061.1, JN601060.1, JN601059.1, JN601058.1, JN601057.1, JN601056.1, JN601055.1, JN601054.1, JN601053.1, JN601052.1, JN400902.1, JN547395.1, FJ687473.1, FJ687472.1, FJ687471.1, FJ687470.1, FJ687469.1, FJ687468.1, FJ687467.1, FJ687466.1, FJ687465.1, FJ687464.1, FJ687463.1, FJ687462.1, FJ687461.1, FJ687460.1, FJ687459.1, FJ687458.1, FJ687457.1, FJ687456.1, FJ687455.1, FJ687454.1, FJ687453 FJ687452.1, FJ687451.1, FJ687450.1, FJ687449.1, AF500215.1, KF476061.1, KF476060.1, KF476059.1, KF476058.1, KF476057.1, KF476056.1, KF476055.1, KF476054.1, KF476053.1, KF476052.1, KF476051.1, KF476050.1, KF476049.1, KF476048.1, KF177258.1, KF177257.1, KF177256.1, KF177255.1), HCoV.229E (NC_002645), as well as any subtype, clade or sub- clade thereof, including any other subgroup 1b coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0125] Nonlimiting examples of subgroup 2a betacoronaviruses and their GenBank Accession Nos. include HCoV.HKU1.C.N5 (DQ339101), MHV.A59 (NC_001846), PHEV.VW572 (NC_007732), HCoV.OC43.ATCC.VR.759 (NC_005147), bovine enteric coronavirus (BCoV.ENT) (NC_003045), as well as any subtype, clade or sub-clade thereof, including any other subgroup 2a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0126] Nonlimiting examples of subgroup 2b betacoronaviruses and their GenBank Accession Nos. include human SARS CoV-2 isolates, such as Wuhan-Hu-1 (NC_045512.2) and any CoV-2 isolates comprising a genomic sequence set forth in GenBank Accession Nos., such as MT079851.1, MT470137.1, MT121215.1, MT438728.1, MT470115.1, MT358641.1, MT449678.1, MT438742.1, LC529905.1, MT438756.1, MT438751.1, MT460090.1, MT449643.1, MT385425.1, MT019529.1, MT449638.1, MT374105.1, MT449644.1, MT385421.1, MT365031.1, MT385424.1, MT334529.1, MT466071.1, MT461669.1, MT449639.1, MT415321.1, MT385430.1, MT135041.1, MT470179.1, MT470167.1, MT470143.1, MT365029.1, MT114413.1, MT192772.1, MT135043.1, MT049951.1; human SARS CoV-1 isolates, such as SARS CoV.A022 (AY686863), SARSCoV.CUHK-W1 (AY278554), SARSCoV.GD01 (AY278489), SARSCoV.HC.SZ.61.03 (AY515512), SARSCoV.SZ16 (AY304488), SARSCoV.Urbani (AY278741), SARSCoV.civet010 (AY572035), SARSCoV.MA.15 (DQ497008); bat SARS CoV isolates, such as BtSARS.HKU3.1 (DQ022305), BtSARS.HKU3.2 (DQ084199), BtSARS.HKU3.3 (DQ084200), BtSARS.Rm1 (DQ412043), BtCoV.279.2005 (DQ648857), BtSARS.Rf1 (DQ412042), BtCoV.273.2005 (DQ648856), BtSARS.Rp3 (DQ071615), ), SARS-CoV-2 Delta variants (B.1.617.2 and AY lineages), SARS-CoV-2 omicron variants (B.1.1.529), SARS-CoV-2 Alpha variants (B.1.1.7 and Q lineages) SARS-CoV-2 Beta variants (B.1.351 and descendent lineages), SARS-CoV-2 Gamma vairants (P.1 and descendent lineages), SARS-CoV-2 Epsilon variants (B.1.427 and B.1.429), SARS-CoV-2 Eta vairants (B.1.525), SARS-CoV-2 Iota variants (B.1.526), SARS-CoV-2 Kappa variants (B.1.617.1), SARS-CoV-2 variants 1.617.3, SARS- CoV-2 Mu variants (B.1.621, B.1.621.1) and SARS-CoV-2 Zeta variants (P.2), as well as any subtype, clade or sub-clade thereof, including any other subgroup 2b coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0127] Nonlimiting examples of subgroup 2c betacoronaviruses and their GenBank Accession Nos. include Middle East respiratory syndrome coronavirus (MERS) isolates, such as Riyadh 22012 (KF600652.1), Al-Hasa_18_2013 (KF600651.1), Al-Hasa_17_2013 (KF600647.1), Al-Hasa_152013 (KF600645.1), Al-Hasa_16_2013 (KF600644.1), Al- Hasa_21_2013 (KF600634), Al-Hasa 19_2013 (KF600632), Buraidah_1_2013 (KF600630.1), Hafr-Al-Batin_1_2013 (KF600628.1), Al-Hasa_122013 (KF600627.1), Bisha.ltoreq.1_2012 (KF600620.1), Riyadh_3_2013 (KF600613.1), Riyadh_1_2012 (KF600612.1), Al-Hasa_3_2013 (KF186565.1), Al-Hasa_1_2013 (KF186567.1), Al-Hasa_2_2013 (KF186566.1), Al- Hasa_4_2013 (KF186564.1); Betacoronavirus England 1-N1 (NC_019843), SA-N1 (KC667074); human betacoronavirus 2c Jordan-N3/2012 (KC776174.1); human betacoronavirus 2c EMC/2012, (JX869059.2); any bat coronavirus subgroup 2c isolate, such as bat coronavirus Taper/CII_KSA_287/Bisha/Saudi Arabia (KF493885.1), bat coronavirus Rhhar/CII_KSA 003/Bisha/Saudi Arabia/2013 (KF493888.1), bat coronavirus Pikuh/CII_KSA_001/Riyadh/Saudi Arabia/2013 (KF493887.1), bat coronavirus Rhhar/CII_KSA 002/Bisha/Saudi Arabia/2013 (KF493886.1), bat coronavirus Rhhar/CII_KSA_004/Bisha/Saudi Arabia/2013 (KF493884.1), bat coronavirus BtCoV.HKU4.2 (EF065506), bat coronavirus BtCoV.HKU4.1 (NC_009019), bat coronavirus BtCoV.HKU4.3 (EF065507), bat coronavirus BtCoV.HKU4.4 (EF065508), bat coronavirus BtCoV133.2005 (NC_008315), bat coronavirus BtCoV.HKU5.5 (EF065512), bat coronavirus BtCoV.HKU5.1 (NC_009020), bat coronavirus BtCoV.HKU5.2 (EF065510), bat coronavirus BtCoV.HKU5.3 (EF065511), and bat coronavirus HKU5 isolate (KC522089.1); any additional subgroup 2c, such as KF192507.1, KF600656.1, KF600655.1, KF600654.1, KF600649.1, KF600648.1, KF600646.1, KF600643.1, KF600642.1, KF600640.1, KF600639.1, KF600638.1, KF600637.1, KF600636.1, KF600635.1, KF600631.1, KF600626.1, KF600625.1, KF600624.1, KF600623.1, KF600622.1, KF600621.1, KF600619.1, KF600618.1, KF600616.1, KF600615.1, KF600614.1, KF600641.1, KF600633.1, KF600629.1, KF600617.1, KC869678.2; KC522088.1, KC522087.1, KC522086.1, KC522085.1, KC522084.1, KC522083.1, KC522082.1, KC522081.1, KC522080.1, KC522079.1, KC522078.1, KC522077.1, KC522076.1, KC522075.1, KC522104.1, KC522104.1, KC522103.1, KC522102.1, KC522101.1, KC522100.1, KC522099.1, KC522098.1, KC522097.1, KC522096.1, KC522095.1, KC522094.1, KC522093.1, KC522092.1, KC522091.1, KC522090.1, KC522119.1, KC522118.1, KC522117.1, KC522116.1, KC522115.1, KC522114.1, KC522113.1, KC522112.1, KC522111.1, KC522110.1, KC522109.1, KC522108.1,, KC522107.1, KC522106.1, KC522105.1); Pipistrellus bat coronavirus HKU4 isolates (KC522048.1, KC522047.1, KC522046, 1, KC522045.1, KC522044.1, KC522043.1, KC522042.1, KC522041.1, KC522040.1, KC522039.1,, KC522038.1,, KC522037.1,, KC522036.1,, KC522048.1, KC522047.1, KC522046.1, KC522045.1, KC522044.1, KC522043.1, KC522042.1, KC522041.1, KC522040, 1, KC522039.1, KC522038.1, KC522037.1, KC522036.1, KC522061.1, KC522060.1, KC522059.1, KC522058.1, KC522057.1, KC522056.1, KC522055.1, KC522054.1, KC522053.1, KC522052.1, KC522051.1, KC522050.1, KC522049.1, KC522074.1, KC522073.1, KC522072.1, KC522071.1, KC522070.1, KC522069.1, KC522068.1, KC522067.1, KC522066.1, KC522065.1, KC522064.1, KC522063.1, KC522062.1 ), as well as any subtype, clade or sub- clade thereof, including any other subgroup 2c coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0128] Nonlimiting examples of subgroup 2d betacoronaviruses and their GenBank Accession Nos. include BtCoV.HKU9.2 (EF065514), BtCoV.HKU9.1 (NC_009021), BtCoV.HkU9.3 (EF065515), BtCoV.HKU9.4 (EF065516), as well as any subtype, clade or sub- clade thereof, including any other subgroup 2d coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0129] Nonlimiting examples of subgroup 3 gammacoronaviruses include IBV.Beaudette.IBV.p65 (DQ001339) or any other subgroup 3 coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database. [0130] A coronavirus defined by any of the isolates or genomic sequences in the aforementioned subgroups 1a, 1b, 2a, 2b, 2c, 2d and 3 can be targeted for decontamination in accordance with the methods and compositions of the present application. [0131] In certain embodiments, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fevers, acquired immunodeficiency syndrome or hepatitis. [0132] In some embodiments, the compound of the present application is administered orally or by inhalation. In certain embodiments, the compound is administered by inhalation through the lungs. [0133] In some embodiments, the compound of the present application is administered at a daily dosage in the range of 10-8000 mg,, 20-400 mg, 20-200 mg, 20-100 mg, 20-80 mg, 20-40 mg, 40-8000 mg, 40-4000 mg, 40-2000 mg, 40-1000 mg, 40-800 mg, 40-400 mg, 40-200 mg, 40-100 mg, 40-80 mg, 80-8000 mg, 80-4000 mg, 80-2000 mg, 80-1000 mg, 80-800 mg, 80-400 mg, 80-200 mg, 80-100 mg, 100-8000 mg, 100-4000 mg, 100-2000 mg, 100-1000 mg, 100-800 mg, 100-400 mg, 100-200 mg, 200-8000 mg, 200-4000 mg, 200-2000 mg, 200-1000 mg, 200- 800 mg, 200-400 mg, 400-8000 mg, 400-4000 mg, 400-2000 mg, 400-1000 mg, 400-800 mg, 800-8000 mg, 800-4000 mg, 800-2000 mg, 800-1000 mg, 1000-8000 mg, 1000-4000 mg, 1000- 2000 mg, 2000-8000 mg, 2000-4000 mg, or 4000-8000 mg. [0134] In some embodiments, the compound of the present application is administered at a daily dosage in the range of 50-1000 mg, 100-800 mg, 200-600 mg or 300-500 mg. IV. Pharmaceutical compositions [0135] Another aspect of the present application relates to a pharmaceutical composition comprising a compound of the present application. In some embodiments, the pharmaceutical composition comprises a compound of the present application and a pharmaceutically acceptable carrier. [0136] In some embodiments, the pharmaceutical composition comprises, or is in the form of, a pharmaceutically acceptable salt of the compound of the present application, as generally described below. Examples of suitable pharmaceutically acceptable organic and/or inorganic acids that may form a salt with a compound of the present application include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below). [0137] When a compound of the present application contains an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein. When a compound of the present application contains a hydrogen- donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. [0138] Pharmaceutically acceptable salts of the compounds of the present application include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference. [0139] Physiologically acceptable salts of the compounds of the present application are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts. [0140] The compounds of the present application can be administered in the form of prodrugs. A prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a subject, cleaves to form a free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds. Methods of structuring a compound as prodrugs can be found in the book of Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids. [0141] In some embodiments, the pharmaceutical composition of the present application comprises an effective amount of a compound of the present application and a pharmaceutically acceptable carrier. Generally, for pharmaceutical use, the compound of the present application can be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. The preparations can be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to U.S. Pat. Nos.6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. The disclosed pharmaceutical compositions can be in a unit dosage form, and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which can be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain from 1 and 1000 mg, and usually from 5 and 500 mg, of the at least one compound of the disclosure, e.g., about 50, 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 or 800 mg per unit dosage. [0142] The compound or pharmaceutical composition of the present application can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used. The compound or pharmaceutical composition will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be from 0.01 to 1000 mg per kilogram body weight of the patient per day, more often from 0.1 and 500 mg, such as from 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which can be administered as a single daily dose, divided over one or more daily doses. The amount(s) to be administered, the route of administration and the further treatment regimen can be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to U.S. Pat. Nos.6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. [0143] Depending upon the manner of introduction, the pharmaceutical composotion described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension, shakes, etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels. In a preferred embodiment, the topical formulation is a gel. In another embodiment, the formulation is administered intranasally. [0144] Formulations containing one or more of the compounds described herein can be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions. [0145] Carrier also includes all components of the coating composition, which can include plasticizers, pigments, colorants, stabilizing agents, and glidants. Delayed release, extended release, and/or pulsatile release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage form tablets", eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington--The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al., (Media, Pa.: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules. [0146] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGITTM (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides. [0147] Additionally, the coating material can contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. [0148] Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. [0149] Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. [0150] Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. [0151] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. [0152] Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross-linked polymers, such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp). [0153] Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. [0154] Surfactants can be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMERTM 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. [0155] If desired, the tablets, beads, granules, or particles can also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives. [0156] The concentration of the compound of the present application can vary from about 0.5 to about 100 wt. % (weight percent) of the final pharmaceutical composition. For oral use, the pharmaceutical composition can generally contain from about 5 to about 100% by weight of the active material. For other uses, the pharmaceutical composition can generally have from about 0.5 to about 50 wt. % of the active material. [0157] The compositions described herein can be formulated for modified or controlled release. Examples of controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof. [0158] The extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington--The science and practice of pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOLTM 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof. [0159] In certain embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. [0160] In certain embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. [0161] In some embodiments, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the trade name EUDRAGIT. In further preferred embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names EUDRAGIT RL30D and EUDRAGIT RS30D, respectively. EUDRAGIT RL30D and EUDRAGIT RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL30D and 1:40 in EUDRAGIT RS30D. The mean molecular weight is about 150,000. EUDRAGIT S-100 and EUDRAGIT L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. [0162] The polymers described above such as EUDRAGIT RL/RS can be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems can be obtained, for instance, from 100% EUDRAGIT RL, 50% EUDRAGIT RL and 50% EUDRAGIT RS, and 10% EUDRAGIT RL and 90% EUDRAGITRS. One skilled in the art will recognize that other acrylic polymers can also be used, such as, for example, EUDRAGIT L. [0163] Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. [0164] Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. [0165] Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spraycongealed or congealed and screened and processed. [0166] Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine. [0167] The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition can be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and can be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastro-intestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the trade name EUDRAGITTM (Rohm Pharma; Westerstadt, Germany), including EUDRAGITTM L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGITTM L-100 (soluble at pH 6.0 and above), EUDRAGITTM S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and EUDRAGITTM NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials can also be used. Multi-layer coatings using different polymers can also be applied. [0168] The preferred coating weights for particular coating materials can be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies. [0169] The coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates can also be used. Pigments such as titanium dioxide can also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), can also be added to the coating composition. [0170] The formulation can provide pulsatile delivery of the one or more compounds. By "pulsatile" is meant that a plurality of drug doses are released at spaced apart intervals of time. Generally, upon ingestion of the dosage form, release of the initial dose is substantially immediate, i.e., the first drug release "pulse" occurs within about one hour of ingestion. This initial pulse is followed by a first time interval (lag time) during which very little or no drug is released from the dosage form, after which a second dose is then released. Similarly, a second nearly drug release-free interval between the second and third drug release pulses can be designed. The duration of the nearly drug release-free time interval will vary depending upon the dosage form design e.g., a twice daily dosing profile, a three times daily dosing profile, etc. For dosage forms providing a twice daily dosage profile, the nearly drug release-free interval has a duration of approximately 3 hours to 14 hours between the first and second dose. For dosage forms providing a three times daily profile, the nearly drug release-free interval has a duration of approximately 2 hours to 8 hours between each of the three doses. [0171] In one embodiment, the pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug-containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile. Control of the delayed release dosage unit(s) is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix. Each dosage unit can comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug approximately 3 hours to less than 14 hours following ingestion of the dosage form. For dosage forms mimicking a three times daily dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, a second tablet releases drug approximately 3 hours to less than 10 hours following ingestion of the dosage form, and the third tablet releases drug at least 5 hours to approximately 18 hours following ingestion of the dosage form. It is possible that the dosage form includes more than three tablets. While the dosage form will not generally include more than a third tablet, dosage forms housing more than three tablets can be utilized. [0172] Alternatively, each dosage unit in the capsule can comprise a plurality of drug- containing beads, granules or particles. As is known in the art, drug-containing "beads" refer to beads made with drug and one or more excipients or polymers. Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core" comprising both drug and one or more excipients. As is also known, drug- containing "granules" and "particles" comprise drug particles that can or cannot include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed. Although beads, granules and particles can be formulated to provide immediate release, beads and granules are generally employed to provide delayed release. [0173] The devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads. [0174] In one embodiment, the compound of the present application is formulated for topical administration. Suitable topical dosage forms include lotions, creams, ointments, and gels. A "gel" is a semisolid system containing a dispersion of the active agent, i.e., compound, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid can include a lipophilic component, an aqueous component or both. Some emulsions can be gels or otherwise include a gel component. Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components. Methods for preparing lotions, creams, ointments, and gels are well known in the art. V. Combination Therapies [0175] The compound described herein can be administered adjunctively with other active compounds. These compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents. [0176] Examples of antiviral agents include, but are not limited to, RNA-dependent RNA polymerase (RdRp) inhibitors, protease drugs, anti-viral neutralizing antibodies and other antiviral drugs. In a particular embodiment, the antiviral agent is a non-CNS targeting antiviral compound. "Adjunctive administration", as used herein, means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents. The additional active agent(s) can be formulated for immediate release, controlled release, or combinations thereof. [0177] Specific examples of compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproxex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, ginko bilboa, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketaserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalicylate, methysergid(e), metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (an anti-narcoleptic), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprazin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propanolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxitine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenozine, thiazides, thioridazine, thiothixene, tiapride, tiasipirone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone and isomers, salts, and combinations thereof. [0178] In certain embodiments, the exemplary compounds and pharmaceutical compositions can be administered in combination with another antiviral agent(s) such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, Tenofovir Exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof. [0179] Although a particular embodiment of the invention has been described in detail for purposes of illustration, various modifications and enhancements may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not to be limited except as by the appended claims. EXAMPLES Example 1: Synthesis [0180] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. [0181] The synthesis of typical compounds of formula (I), or a pharmaceutically acceptable salt thereof, e.g., compounds having structures described by one or more of formula (I), or other formulas or compounds disclosed herein, may be accomplished as described in the following examples. [0182] General Syntheses [0183] Typical embodiments of compounds in accordance with the present disclosure may be synthesized using the general reaction schemes and/or examples described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. Group labels (e.g., R1, R2) used in the reaction schemes herein are for illustrative purposes only and unless otherwise specified do not necessarily match by name or function the labels used elsewhere to describe compounds of formula (I) or aspects or fragments thereof. [0184] Synthetic Reaction Parameters [0185] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0186] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable [0187] protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein. [0188] Furthermore, the compounds of this disclosure may contain one or more chiral centers. [0189] Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well- known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0190] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5thEdition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0191] The terms “solvent,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), N, N-dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen. [0192] The term “q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%). [0193] Compounds as provided herein may be synthesized according to the general schemes provided below. In the Schemes below, it should be appreciated that each of the compounds shown therein may have protecting groups as required present at any step. Standard protecting groups are well within the pervue of one skilled in the art. [0194] In another aspect, the present invention provides a method for preparing a compound of the formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, the method comprising five general routes (Route A, Route B, Route C, Route D and Route E): Route A:
Figure imgf000051_0001
Route C:
Figure imgf000052_0001
PROCEDURE [0195] Procedure 1 Preparation of ((3aR,4R,6R,6aR)-6-((Z)-4-(hydroxyimino)-2-oxo- 3,4-dihydropyrimidin-1(2H)-yl)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate(1)
Figure imgf000053_0001
[0196] To a solution of molnupiravir (4 g, 1.0 eq.) in dichloromethane (DCM) (15 mL), 1,1'-Carbonyldiimidazole (CDI) (2.16 g, 1.1 eq.) was added at room temperature, and stirred overnight. H2O (15 mL) was added and extracted to get an organic layer. The organic layer was concentrated and crystallized by ethyl acetate to obtain Compound 1，3.04g, yield: 70.5%. [0197] Procedure 2 Preparation of ((3aR,4R,6R,6aR)-6-(4-((benzoyloxy)amino)-2- oxopyrimidin-1(2H)-yl)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate(2)
Figure imgf000053_0002
[0198] To a solution of Compound 1 (10 g, 1.0 eq.) and trimethylamine (4.27g, 1.5eq.) in dichloromethane (100 mL), benzoyl chloride (4.35 g, 1.1 eq.) was added dropwise at room temperature, and stirred 1 hour. H2O (100 mL) was added and extracted to get an organic layer. The organic layer was concentrated and crystallized by ethyl acetate to obtain Compound 2, 6.5g, yield: 50.3%. [0199] Procedure 3 Preparation of ((3aR,4R,6R,6aR)-6-(4-(hydroxyamino)-2- oxopyrimidin-1(2H)-yl)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl benzoate (3)
Figure imgf000054_0001
[0200] To a solution of Compound NHC (50 g, 1.0 eq.) and trimethylamine (48.7g, 2.5eq.) in dichloromethane (300 mL), benzoyl chloride (59.4g, 2.2 eq.) was added dropwise at room temperature, and stirred 1 hour. H2O (300 mL) was added and extracted to get an organic layer. The organic layer was concentrated and crystallized by ethyl acetate to obtain Compound 3-1, 30.0g, yield: 33.3%. LCMS: [M+H]+: 468.13.1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.16-8.18(m, 2H), 7.93-7.97(m, 4H), 7.61-7.68(m, 2H), 7.47-7.52(m, 3H), 7.198-7.22(d, 1H, J=8.4Hz) , 5.74- 5.76 (m, 2H), 5.65-5.67 (m, 2H), 5.46-5.50 (m, 1H), 5.31- 5.32 (d, 1H, J=5.2Hz), 4.54-4.50 (m, 1H), 4.39-4.44 (m, 1H). [0201] To a solution of Compound 3-1 (15g, 1.0 eq.) in dichloromethane (100 mL), 1,1'- Carbonyldiimidazole (6.76 g, 1.3 eq.) was added at room temperature, and stirred overnight. H2O (40 mL) was added and extracted to get an organic layer. The organic layer was concentrated and crystallized by ethyl acetate/PE(v/v:20%) to obtain Compound 3-2，15g, yield: 94.5%. LCMS: [M+H]+: 494.11.1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.16-8.18(m, 2H), 7.93- 7.97(m, 4H), 7.61-7.68(m, 2H), 7.47-7.52(m, 3H), 7.198-7.22(d, 1H, J=8.4Hz) , 5.74- 5.76 (m, 1H), 5.61 - 5.56 (m, 1H), 5.55-5.50 (m, 1H), 5.40-5.35 (m, 1H), 4.57 -4.50 (m, 1H), 4.49 - 4.43 (m, 1H). [0202] To a solution of Compound 3-2(30.0g, 1.0 eq.) in Methanol (90 mL) and N, N- Dimethylacetamide (90mL), 37% aqueous HCl (37.5mL) was added. And the mixture was stirred 8 hours at 55℃. After cooling, H2O (400 mL) was added and adjust pH to 8 by NaHCO3 solution, then extract to get an organic layer. The organic layer was concentrated and crystallized by ethyl acetate to obtain Compound 3 (4.8g, 40.5%). [0203] Procedure 4 Preparation of ((3aR,4R,6R,6aR)-6-((Z)-4-(hydroxyimino)-2- oxo-3,4-dihydropyrimidin-1(2H)-yl-5,6-d2)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate (4)
Figure imgf000055_0001
[0204] Following procedure 1, the title Compound 4 was obtained by substituting 1, 5, 6- D2-molnupiravir for molnupiravir. LCMS: [M+H]+: 358.10.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.84 (d, J = 2.1 Hz, 1H), 5.58-5.50 (m, 2H), 5.29-5.19 (m, 1H), 4.42-4.32 (m, 1H), 4.32-4.23 (m, 1H), 4.22-4.13 (m, 1H), 2.56-2.48 (m, 1H), 1.06 (d, J = 1.3 Hz, 3H), 1.04 (d, J = 1.3 Hz, 3H). [0205] Procedure 5 Preparation of ((7R,9R,9aS,Z)-9-((E)-4-(hydroxyimino)-2-oxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dioxo-2,5,6a,7,9,9a-hexahydrofuro[3,4-b][1,4]dioxocin- 7-yl)methyl isobutyrate (5)
Figure imgf000055_0002
[0206] To a solution of molnupiravir (4.0g, 1.0 eq.) and Et3N(3.07g, 2.5eq. ) in dichloromethane (20 mL), maleoyl dichloride (21.23g, 1.20 eq.) was added at 0℃, and stirred 4 hours. H2O (20 mL) was added and extracted to get an organic layer. The organic layer was concentrated and purified by column chromatography to give Compound 5，450mg, yield: 9%. [0207] Procedure 6 Preparation of ((7R,9R,9aS,Z)-9-((E)-4-(hydroxyimino)-2-oxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dioxo-2,5,6a,7,9,9a-hexahydrofuro[3,4-b][1,4]dioxocin- 7-yl)methyl isobutyrate (6)
Figure imgf000055_0003
[0208] To a solution of 3-1 (5.0g, 1.0 eq.) and Et3N(2.71g, 2.5eq. ) in dichloromethane (20 mL), phthaloyl dichloride (21.23g, 1.20 eq.) was added at 0℃, and stirred 4 hours. H2O (20 mL) was added and extracted to get an organic layer. The organic layer was concentrated and purified by column chromatography to give Compound 6，900mg, yield: 14%. [0209] Procedure 7 Preparation of ((3aR,4R,6R,6aR)-6-((Z)-4-(hydroxyimino)-2- oxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate (7)
Figure imgf000056_0001
[0210] To a solution of molnupiravir (10 g, 1.0 eq.) and 2, 2-dimethoxypropane(3.48g, 1.1eq.) in MeOH (100 mL), H2SO4 (98%, 0.5ml.) was added at room temperature, and stirred overnight. H2O (100 mL) was added, and precipitated solid. After filtering, the solid was obtained which is the compound 7, 8.50g, yield: 75.8%. [0211] Procedure 8 Preparation of 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2- oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-((isobutyryloxy)amino)pyrimidin-2(1H)-one(8)
Figure imgf000056_0002
[0212] To a solution of NHC (1.0g, 1.0 eq.) and Et3N(0.43g, 1.1eq. ) in dichloromethane (10 mL), isobutyryl chloride(0.37, 0.9eq.) was added at -25~-20℃, and stirred 4 hours. H2O (20 mL) was added and extracted to get an organic layer. The organic layer was concentrated and purified by column chromatography to give Compound 8-1, 0.45g, Yield: 35.42%. LCMS: [M+H]+: 330.1. [0213] To a solution of Compound 8-1 (0.45g, 1.0 eq.) in dichloromethane (10 mL), 1,1'- Carbonyldiimidazole (0.29 g, 1.3 eq.) was added at room temperature, and stirred overnight. H2O (10 mL) was added and extracted to get an organic layer. The organic layer was concentrated and purified by column chromatography to give Compound 8，0.32g, yield: 65.9%. [0214] Procedure 9 Preparation of ((3aR,4R,6R,6aR)-6-(4-(hydroxyamino)-2- oxopyrimidin-1(2H)-yl)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl L-alaninate (9)
Figure imgf000057_0001
[0215] To a solution of cytidine (5.0g, 20.5mmol) and pyridine(10ml) in DCM (50ml), DMF-DMA (9.8mg, 82mmol) was added at 0℃. The reaction was stirred overnight at room temperature under N2 atmosphere. H2O (50 mL) was added and extracted to get an organic layer and evaporated under reduced pressure to give the crude 9-1 that was used to the next step without purification. [0216] To a solution of compound 9-1 in DCM (50ml), (tert-butoxycarbonyl)-L-alanine (7.78g, 2eq), HATU(23.45g, 3eq), DIPEA(13.3g,5eq) and DMAP (100mg)were added, and stirred 3hours at room temperature. Then EtOH (100mL) was added and heated to reflux and maintain 1hour. After cooling, the mixture was evaporated under reduced pressure to get the crude 9-2. The crude product was subjected to column chromatography on silica gel using dichloromethane and MeOH to get the product 9-2, 4.3g. LCMS: [M+H]+: 470.2. [0217] To a solution of compound 9-2 (1.0g, 1eq) in water (5ml), Hydroxyamine sulfate (1.4g, 4eq) was added and stirred at 78℃ for 18h. After cooling, the solid was precipitated and filtrated, The solid was added into the HCl in EA (1mol/L, 10ml),and stirred 2hours at room temperature. The compound 9-3 was precipitated and filtrated, 0.5g, yield: 71.07%. [0218] Following the Procedure 1, the title Compound 9 was obtained by cyclization using 1,1'-Carbonyldiimidazole . [0219] Procedure 10 Preparation ((3aR,4R,6R,6aR)-6-(4-(hydroxyamino)-2- oxopyrimidin-1(2H)-yl)-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl L-serinate (10)
Figure imgf000058_0001
[0220] Following procedure 9, the compound 10-3 was was obtained by substituting O- benzyl-N-(tert-butoxycarbonyl)-L-serine for (tert-butoxycarbonyl)-L-alanine. [0221] Under H2, to a solution of compound 10-3 (120mg, 1eq) in MeOH (5mL), Pd/C (12mg, wt 10%) was added and was stirred overnight. After filtering, the filtrate was concentrated and purified by Preparative HPLC (0.1% trifluoroacetic acid in water/acetonitrile) to obtain compound 10, 35mg, yield: 36.23%. [0222] The following compounds were prepared according to the procedures described herein (and indicated in Table 1 under Procedure) using the appropriate starting material(s) and appropriate protecting group chemistry as needed. And the key reaction is the cyclization reaction：five-membered ring formation was used by CDI or 2,2-dimethoxypropane; six- membered ring formation was used by oxalyl chloride; eight- membered ring formation was used by maleoyl dichloride or phthaloyl dichloride. Table 1
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Example 2. Permeability of Compounds in Caco-2 Assay [0223] Caco-2 Culture [0224] Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96-well Corning Insert plates at 1 x 105 cells/ cm2, and refreshed medium every 4~5 days until to the 21st to 28th day for confluent cell monolayer formation. [0225] Transport Methods [0226] The transport buffer in the study was HBSS with 10.0 mM HEPES at pH 7.40±0.05. Test compound was tested at 2.00 μM bi-directionally in duplicate. Digoxin was tested at 10.0 μM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 μM in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1%. The plate was incubated for 2 hours in CO2 incubator at 37±1°C, with 5% CO2 at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3200 xg for 10 min. For nadolol and metoprolol, 200 µL supernatant solution was diluted with 600 µL ultra-pure water for LC-MS/MS analysis. For digoxin and test compounds, 200 µL supernatant solution was diluted with 200 µL ultra-pure water for LC-MS/MS analysis. Concentrations of test and control compounds in starting solution, donor solution, and receiver solution were quantified by LC-MS/MS methodologies, using peak area ratio of analyte/internal standard. [0227] After transport assay, lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity. [0228] Data Analysis [0229] The apparent permeability coefficient Papp (cm/s) was calculated using the equation: [0230] Papp = (dCr/dt) x Vr / (A x C0) [0231] Where dCr/dt is the cumulative concentration of compound in the receiver chamber as a function of time (µM/s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e.0.0804 cm2 for the area of the monolayer; C0 is the initial concentration in the donor chamber (µM). [0232] The efflux ratio was calculated using the equation: [0233] Efflux Ratio = Papp (BA) / Papp (AB) [0234] Percent recovery was calculated using the equation: [0235] %Solution Recovery = 100 ×[(Vr × Cr) + (Vd ×Cd)] / (Vd ×C0) [0236] Where Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side); Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively. [0237] Result： Table 2. Permeability of Compounds in Caco-2 Assay
Figure imgf000125_0001
Figure imgf000126_0002
Binning Criteria*: Low permeability: Papp ≤ 2×10-6cm/s；Moderate permeability: 2 < Papp < 20 (× 10-6 cm/s)；High permeability: Papp ≥ 20 (×10-6 cm/s); [0238] Example 3. Pharmacokinetics studies
Figure imgf000126_0001
[0239] Individual plasma concentrations of compound NHC after a single oral administration of Compounds and molnupiravir to monkeys (100 mg/kg) were used to calculate the mean pharmacokinetic parameters summarized in Table 3. [0240] Table 3. Summaries of pharmacokinetic parameters in Male Cynomolgus monkeys
Figure imgf000126_0003
Figure imgf000127_0001
[0241] The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention, and it is not intended to detail all those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. The claims are intended to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates the contrary.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000128_0001
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
2. A compound of Formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000128_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
3. A compound of Formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000128_0003
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, having the structure of Formula VII:
Figure imgf000129_0001
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
5. A compound of Formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000129_0003
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
6. A compound of Formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000129_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
7. A compound of Formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000130_0001
wherein R1 or R2 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the - (CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo and OH.
8. A compound of Formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000130_0002
wherein R1 is independently H, -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, wherein the -(CO)C1-C6 alkyl, or -(CO)C5-C10 aryl, is optionally substituted with one or more substituents each independently selected from the group consisting of halo.
9. A compound of Formula I
Figure imgf000130_0003
or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H, heteroaryl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, - (CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, - (CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl, or (CO)NHC5-C10 heteroaryl, wherein the heteroaryl, - (CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, -(CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl or (CO)NHC5-C10 heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, OH, -O-C1-C6 alkyl, NR6R5, C1-C6 alkyl, C5-C10 aryl and heteroaryl, wherein R3 or R4 is independently H, D, F, Cl, Br, CH3, or CF3, wherein R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, C5-C10 aryl or C5-C10 heteroaryl, wherein each R7 and R8 is independently selected from H and C1-C6 alkyl and wheren R7 and R8 can fuse to each other to form a ring, and wherein the link is independently selected from the group consisting of
Figure imgf000131_0001
10. A compound of Formula I
Figure imgf000131_0002
or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H, heteroaryl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, - (CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, - (CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl, or (CO)NHC5-C10 heteroaryl, wherein the heteroaryl, - (CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, -(CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl or (CO)NHC5-C10 heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, OH, -O-C1-C6 alkyl, NR6R5, C1-C6 alkyl, C5-C10 aryl and heteroaryl, wherein R3 or R4 is independently H, D, halo or C1-C3 alkyl, wherein alkyl is optionally substituted with one or more halo, wherein R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, or -(CO)OC1-C6 alkyl, wherein each R7 and R8 is independently selected from H and C1-C6 alkyl and wherein R7 and R8 can fuse to each other to form a ring, and wherein the link is independently selected from the group consisting of
Figure imgf000132_0001
11. A compound of Formula I
Figure imgf000132_0002
or a pharmaceutically acceptable salt thereof, wherein R1 or R2 is independently H, heteroaryl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, - (CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, - (CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl, or (CO)NHC5-C10 heteroaryl, wherein the heteroaryl, - (CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, -(CO)OC5-C10 aryl, -(CO)OC5-C10 heteroaryl, -(CO)NHC1-C6 alkyl, (CO)NHC5-C10 aryl or (CO)NHC5-C10 heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, OH, -O-C1-C6 alkyl, NR6R5, C1-C6 alkyl, C5-C10 aryl and heteroaryl, wherein R3 or R4 is independently H, D, halo or C1-C3 alkyl, wherein alkyl is optionally substituted with one or more halo, wherein R5 or R6 is independently H, OH, C1-C6 alkyl, -(CO)C1-C6 alkyl, -(CO)OC1-C6 alkyl, -(CO)C5-C10 aryl, -(CO)C5-C10 heteroaryl, C5-C10 aryl or C5-C10 heteroaryl, wherein each R7 and R8 is independently selected from H and C1-C6 alkyl and wherein R7 and R8 can fuse to each other to form a ring, and wherein the link is independently selected from the group consisting of
Figure imgf000132_0003
12. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient and the compound of any one of claims 1 to 11.
13. A method of treating or preventing a virus infection in a patient, comprising: administering to the patient an effective amount of the compound of any one of claims 1 to 11.
14. The method of Claim 13, wherein the virus infection is a coronavirus infection.
15. The method of Claim 14, wherein the virus infection is COVID-19.
16. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient and a compound selected from the group consisting of:
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
PCT/IB2022/000749 2021-12-16 2022-12-09 N4-hydroxycytidine derivatives and use thereof as antiviral agent WO2023111683A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2023519586A JP2023553243A (en) 2021-12-16 2022-12-09 Nucleoside derivatives and their use
EP22856980.2A EP4222158A1 (en) 2021-12-16 2022-12-09 N4-hydroxycytidine derivatives and use thereof as antiviral agent

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163265577P 2021-12-16 2021-12-16
US63/265,577 2021-12-16
US202263267434P 2022-02-02 2022-02-02
US63/267,434 2022-02-02
US17/664,304 US11541071B1 (en) 2021-12-16 2022-05-20 Nucleoside derivatives and methods of use thereof
US17/664,304 2022-05-20

Publications (1)

Publication Number Publication Date
WO2023111683A1 true WO2023111683A1 (en) 2023-06-22

Family

ID=85382958

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/000749 WO2023111683A1 (en) 2021-12-16 2022-12-09 N4-hydroxycytidine derivatives and use thereof as antiviral agent

Country Status (1)

Country Link
WO (1) WO2023111683A1 (en)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
WO2006033709A2 (en) * 2004-07-29 2006-03-30 Metabasis Therapeutics, Inc. Novel nucleoside derivatives
WO2019113462A1 (en) * 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN112608357A (en) * 2020-12-21 2021-04-06 杭州科巢生物科技有限公司 Preparation method of antiviral drug Molnbupiravir
CN113735928A (en) * 2021-10-21 2021-12-03 药康众拓(江苏)医药科技有限公司 N4-hydroxycytidine derivative and preparation method and application thereof
CN113929724A (en) * 2021-11-02 2022-01-14 周雨恬 Nucleoside compound and pharmaceutical composition and application thereof
WO2022218274A1 (en) * 2021-04-15 2022-10-20 中国科学院上海药物研究所 Nucleoside analog and use thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
WO2006033709A2 (en) * 2004-07-29 2006-03-30 Metabasis Therapeutics, Inc. Novel nucleoside derivatives
WO2019113462A1 (en) * 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN112608357A (en) * 2020-12-21 2021-04-06 杭州科巢生物科技有限公司 Preparation method of antiviral drug Molnbupiravir
WO2022218274A1 (en) * 2021-04-15 2022-10-20 中国科学院上海药物研究所 Nucleoside analog and use thereof
CN113735928A (en) * 2021-10-21 2021-12-03 药康众拓(江苏)医药科技有限公司 N4-hydroxycytidine derivative and preparation method and application thereof
CN113929724A (en) * 2021-11-02 2022-01-14 周雨恬 Nucleoside compound and pharmaceutical composition and application thereof

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Fieser and Fieser's Reagents for Organic Synthesis", vol. 1-40, 1991, JOHN WILEY, AND SONS
"GenBank", Database accession no. KF60064 1. 1
"Larock's Comprehensive Organic Transformations", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
"March's Advanced Organic Chemistry", 2001, JOHN WILEY, AND SONS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
"Remington--The science and practice of pharmacy", 2000, LIPPINCOTT WILLIAMS & WILKINS
ANSEL ET AL.: "Pharmaceutical dosage forms and drug delivery systems", 1995, WILLIAMS AND WILKINS
BERGE ET AL., J. PHARM. SCI, vol. 66, no. 1, 1977, pages 1 - 19
FIER PATRICK S. ET AL: "Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 25, no. 12, 10 December 2021 (2021-12-10), US, pages 2806 - 2815, XP093049389, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.1c00400 *
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
T. W. GREENEG. M. WUTS: "Protecting Groups in Organic Synthesis", 1999, WILEY
TESTAMAYER: "Hydrolysis in Drug and Prodrug Metabolism", 2006, WILEY

Similar Documents

Publication Publication Date Title
EP4222158A1 (en) N4-hydroxycytidine derivatives and use thereof as antiviral agent
AU2021206866B2 (en) N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11628181B2 (en) N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US10874683B2 (en) N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11702406B1 (en) Triazine derivatives and methods of use thereof
EP4017501A1 (en) N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11760722B2 (en) Inhibitors of cysteine proteases and methods of use thereof
WO2023111683A1 (en) N4-hydroxycytidine derivatives and use thereof as antiviral agent
WO2024009120A1 (en) Triazine derivatives and methods of use thereof
WO2023139402A1 (en) Inhibitors of cysteine proteases and methods of use thereof

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2023519586

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 2022856980

Country of ref document: EP

Effective date: 20230327

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22856980

Country of ref document: EP

Kind code of ref document: A1