WO2023152709A1 - Rna polymerase inhibitors and methods using same - Google Patents

Rna polymerase inhibitors and methods using same Download PDF

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Publication number
WO2023152709A1
WO2023152709A1 PCT/IB2023/051227 IB2023051227W WO2023152709A1 WO 2023152709 A1 WO2023152709 A1 WO 2023152709A1 IB 2023051227 W IB2023051227 W IB 2023051227W WO 2023152709 A1 WO2023152709 A1 WO 2023152709A1
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optionally substituted
group
alkyl
certain embodiments
compound
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PCT/IB2023/051227
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French (fr)
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Andrew G. Cole
Benjamin J. Dugan
Eugen F. Mesaros
Michael J. Sofia
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Arbutus Biopharma Corporation
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Publication of WO2023152709A1 publication Critical patent/WO2023152709A1/en

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    • 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
    • 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
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • 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
    • C07H19/16—Purine radicals
    • 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
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical

Definitions

  • non- structural protein 12 is a multidomain, 932 amino acid enzyme, which contains RNA-dependent RNA polymerase (RdRp) catalytic activity and is commonly identified as the viral RdRp.
  • RdRp RNA-dependent RNA polymerase
  • the C-terminal polymerase domain of nsp12 is responsible for the synthesis of viral RNA.
  • nsp12 is a critical element of the viral lifecycle (i.e., replication and transcription) and represents a key therapeutic target for viral life cycle disruption.
  • the betacoronavirus is selected from the group consisting of Severe acute respiratory syndrome- related coronavirus 2 (SARS-CoV-2), Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1).
  • a coronavirus RNA polymerase is inhibited.
  • the RNA polymerase comprises nonstructural protein 12 (nsp12).
  • the carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning herein.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C (CH 3 ), and -CH 2 C ⁇ C (CH 2 CH 3 ) among others.
  • amine also includes ammonium ions as used herein.
  • amino group refers to a substituent of the form -NH2, - NHR, -NR2, -NR3 + , wherein each R is independently selected, and protonated forms of each, except for -NR 3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
  • alkylamino includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • aralkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized ⁇ (pi) electrons, where 'n' is an integer.
  • aryl employed alone or in combination with other terms means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl.
  • aryl-CH 2 - and aryl-CH(CH 3 )- are aryl-CH 2 - and aryl-CH(CH 3 )-.
  • substituted aryl-(C 1 -C 6 )alkyl refers to an aryl-(C 1 -C 6 )alkyl functional group in which the aryl group is substituted.
  • substituted aryl(CH 2 )- is substituted.
  • heteroaryl-(C 1 -C 6 )alkyl refers to a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH 2 CH 2 -pyridyl.
  • a specific example is heteroaryl-(CH 2 )-.
  • co-administered and “co-administration” as relating to a subject refer to administering to the subject a compound and/or composition of the disclosure along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein.
  • the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach.
  • the co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.
  • COVID or “COVID-19” as used herein refers to the Coronavirus disease 2019, a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • cycloalkyl by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C 3 -C 6 refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups.
  • cycloalkyl also includes bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1] heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • a "disease” is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate.
  • a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder.
  • epoxy-functional or "epoxy-substituted” as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system.
  • epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- epoxyhexyl.
  • halide refers to a halogen atom bearing a negative charge.
  • the halide anions are fluoride (F ⁇ ), chloride (C1 ⁇ ), bromide (Br ⁇ ), and iodide (I ⁇ ).
  • haloalkyl group includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • heteroalkenyl by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively.
  • heteroalkyl by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 NH-OCH 3 , or -CH 2 CH 2 SSCH 3 .
  • heteroaryl refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolin
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydry
  • heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.
  • heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein.
  • heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • heterocyclyl refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • heterocyclyl group includes fused ring species including those that include fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.
  • hydrocarbon or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.
  • hydrocarbyl refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- C b )hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms.
  • (C 1 -C 4 )hydrocarbyl means the hydrocarbyl group can be methyl (C 1 ), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.
  • the term "independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.
  • X 1 , X 2 , and X 3 are independently selected from noble gases” would include the scenario where, for example, X 1 , X 2 , and X 3 are all the same, where X 1 , X 2 , and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other analogous permutations.
  • the term "monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or C1, it is bonded to the atom it is substituting by a single bond.
  • organic group as used herein refers to any carbon-containing functional group.
  • Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.
  • an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group
  • a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester such as an alkyl and aryl sulfide group
  • sulfur-containing group such as an alkyl and aryl sulfide group
  • Non-limiting examples of organic groups include OR, OOR, OC(O)N(R) 2 , CN, CF 3 , OCF 3 , R, C(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH 2 )0- 2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2
  • the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a subject.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the disclosure, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term "pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the subject.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
  • the "pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates thereof.
  • a “pharmaceutically effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • the term “prevent,” “preventing,” or “prevention” as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.
  • room temperature refers to a temperature of about 15 °C to 28 °C.
  • solvent refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
  • specifically bind or “specifically binds” as used herein is meant that a first molecule preferentially binds to a second molecule (e.g., a particular receptor or enzyme), but does not necessarily bind only to that second molecule.
  • the terms “subject” and “individual” and “patient” can be used interchangeably and may refer to a human or non-human mammal or a bird.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the subject is human.
  • the term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.
  • substantially free of can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less.
  • substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.
  • substituted as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms.
  • functional group or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group.
  • substituents or functional groups include, but are not limited to, a halogen (e.g., F, C1, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
  • a halogen e.g., F, C1, Br, and I
  • an oxygen atom in groups such as hydroxy groups, al
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, C1, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH 2 )0- 2N(R)C(O)R, (CH 2 )0-2N(R)N(R)2, N(R)N(R)C(
  • substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl.
  • substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl.
  • substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl.
  • substituted as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three.
  • the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of C 1 -C 6 alkyl, -OH, C 1 -C 6 alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.
  • each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 - C 6 alkyl, halo, -OR, phenyl (thus yielding, in non-limiting examples, optionally substituted phenyl-(C1-C3 alkyl), such as, but not limited to, benzyl or substituted benzyl) and -N(R)(R), wherein each occurrence of R is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
  • each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 - C6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, -CN, -OR, -N(R)(R), and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
  • the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the ring can be saturated or partially saturated, and can be optionally substituted. Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein.
  • substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • C1-6 alkyl is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C 1 -C 6 , C1-C5, C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • treat means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.
  • ACN acetonitrile
  • DCE 1,2- dichloroethane
  • DCM dichloromethane
  • DIEA or DIPEA diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DIAD diisopropyl azodicarboxylate
  • DMAP 4-dimethylaminopyridine
  • DMSO dimethylsulfoxide
  • d.r. diastereomeric ratio
  • EtOAc ethyl acetate
  • HPLC high pressure liquid chromatography
  • IPA isopropanol (2-propanol
  • LCMS liquid chromatography mass spect
  • a 1 is selected from the group consisting o
  • X is selected from the group consisting of CR b1 and N
  • Y is selected from the group consisting of O and NR 7c
  • R 1 is selected from the group consisting of: wherein: R c1 is selected from the group consisting of optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C 2 -C 8 heterocyclyl; R d1 and R d2 are each independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein one or more of R d1 and R e1 , and R d2 and R e3 , may combine with atoms to which they are bound to
  • the phenyl, naphthyl, or C 2 -C 8 heterocyclyl in R c1 is optionally substituted with at least one substituent.
  • R c1 is benzyl.
  • R c1 is benzyl substituted with one substituent.
  • R c1 is benzyl substituted with two substituents.
  • R c1 is benzyl substituted with three substituents.
  • R c1 is benzyl substituted with four substituents.
  • R c1 is benzyl substituted with five substituents.
  • the benzyl in R c1 is substituted with at least one substituent selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, CF3, CF2H, OH, OMe, OCF3, OCF2H, OPh, NH2, NMe2, NO2, CN, F, C1, Br, and I.
  • R c1 is phenyl.
  • R c1 is phenyl substituted with one substituent.
  • R c1 is phenyl substituted with two substituents.
  • R c1 is substituted with three substituents.
  • R c1 is phenyl substituted with four substituents. In certain embodiments R c1 is phenyl substituted with 5 substituents. In certain embodiments, the phenyl in R c1 is substituted with at least one substituent selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, CF3, CF2H, OH, OMe, OCF3, OCF2H, OPh, NH2, NMe2, NO2, CN, F, C1, Br, and I. In certain embodiments, R 1 is . In certain embodiments, R 1 is .
  • R 1 is In certain embodiments 1 , R is In certain embodiments, R 1 is In certain embodiments, R 1 is . In certain embodiments, R 1 is In certain embodiments, R 1 is . In certain embodiments, R d1 is H. In certain embodiments, R d1 is methyl. In certain embodiments, R d1 is isopropyl. In certain embodiments, R d1 is isobutyl. In certain embodiments, R d1 is sec-butyl. In certain embodiments, R d1 is methanethioethyl. In certain embodiments, R d1 is benzyl. In certain embodiments, R d1 is 3-indolyl. In certain embodiments, R d1 is hydroxymethyl.
  • R d2 is H. In certain embodiments, R d2 is methyl. In certain embodiments, R d2 is isopropyl. In certain embodiments, R d2 is isobutyl. In certain embodiments, R d2 is sec-butyl. In certain embodiments, R d2 is methanethioethyl. In certain embodiments, R d2 is benzyl. In certain embodiments, R d2 is 3-indolyl. In certain embodiments, R d2 is hydroxymethyl. In certain embodiments, R d2 is 1-hydroxyethy. In certain embodiments, R d2 is, thiomethyl. In certain embodiments, R d2 is 4-hydroxybenzyl.
  • R 1 is In certain embodiments, R 1 is n certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain e 1 mbodiments, R is In c ertain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is 1 In certain embodiments, R is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is .
  • R 1 is In certain e mbodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodi 1 ments, the R substituent has a (S)-configuration. In certain embodiments, the R 1 has a (R)-configuration. In certain embodiments, R e1 is H. In certain embodiments, R e1 is methyl. In certain embodiments, R e1 is ethyl. In certain embodiments, R e1 is propyl. In certain embodiments, R e1 is is isobutyl. In certain embodiments, R e1 is butyl. In certain embodiments, R e1 is neopentyl.
  • R e1 is 3,3-dimethylbutyl. In certain embodiments, R e1 is 2-methylbutyl. In certain embodiments, R e1 is pentyl. In certain embodiments, R e1 is 2- methylpentyl. In certain embodiments, R e1 is 3-methylpentyl. In certain embodiments, R e1 is 4-methylpentyl. In certain embodiments, R e1 is hexyl. In certain embodiments, R e1 is 2- propylpentyl. In certain embodiments, R e1 is benzyl. In certain embodiments, R e1 is phenyl. In certain embodiments, R e2 is H.
  • R e2 is methyl. In certain embodiments, R e2 is ethyl. In certain embodiments, R e2 is propyl. In certain embodiments, R e2 is isobutyl. In certain embodiments, R e2 is butyl. In certain embodiments, R e2 is neopentyl. In certain embodiments, R e2 is 3,3-dimethylbutyl. In certain embodiments, R e2 is 2-methylbutyl. In certain embodiments, R e2 is pentyl. In certain embodiments, R e2 is 2- methylpentyl. In certain embodiments, R e2 is 3-methylpentyl.
  • R e2 is 4-methylpentyl. In certain embodiments, R e2 is hexyl. In certain embodiments, R e2 is 2- propylpentyl. In certain embodiments, R e2 is benzyl. In certain embodiments, R e2 is phenyl. In certain embodiments, R e3 is H. In certain embodiments, R e3 is methyl. In certain embodiments, R e3 is ethyl. In certain embodiments, R e3 is propyl. In certain embodiments, R e3 is isobutyl. In certain embodiments, R e3 is butyl. In certain embodiments, R e3 is neopentyl.
  • R e3 is 3,3-dimethylbutyl. In certain embodiments, R e3 is 2-methylbutyl. In certain embodiments, R e3 is pentyl. In certain embodiments, R e3 is 2- methylpentyl. In certain embodiments, R e3 is 3-methylpentyl. In certain embodiments, R e3 is 4-methylpentyl. In certain embodiments, R e3 is hexyl. In certain embodiments, R e3 is 2- propylpentyl. In certain embodiments, R e3 is benzyl. In certain embodiments, R e3 is phenyl. In certain embodiments, R e4 is H.
  • R e4 is methyl. In certain embodiments, R e4 is ethyl. In certain embodiments, R e4 is propyl. In certain embodiments, R e4 is isobutyl. In certain embodiments, R e4 is butyl. In certain embodiments, R e4 is neopentyl. In certain embodiments, R e4 is 3,3-dimethylbutyl. In certain embodiments, R e4 is 2-methylbutyl. In certain embodiments, R e4 is pentyl. In certain embodiments, R e4 is 2- methylpentyl. In certain embodiments, R e4 is 3-methylpentyl.
  • R e4 is 4-methylpentyl. In certain embodiments, R e4 is hexyl. In certain embodiments, R e4 is 2- propylpentyl. In certain embodiments, R e4 is benzyl. In certain embodiments, R e4 is phenyl. In certain embodiments, R f1 is methyl. In certain embodiments, R f1 is ethyl. In certain embodiments, R f1 is propyl. In certain embodiments, R f1 is is isobutyl. In certain embodiments, R f1 is butyl. In certain embodiments, R f1 is neopentyl.
  • R f1 is 3,3-dimethylbutyl. In certain embodiments, R f1 is 2-methylbutyl. In certain embodiments, R f1 is pentyl. In certain embodiments, R f1 is 2-methylpentyl. In certain embodiments, R f1 is 3-methylpentyl. In certain embodiments, R f1 is 4-methylpentyl. In certain embodiments, R f1 is hexyl. In certain embodiments, R f1 is 2-propylpentyl. In certain embodiments, R f1 is propargyl. In certain embodiments, R f1 is benzyl. In certain embodiments, R f1 is phenyl.
  • R f1 is methoxy. In certain embodiments, R f1 is ethoxy. In certain embodiments, R f1 is propoxy. In certain embodiments, R f1 is isobutyloxy. In certain embodiments, R f1 is butoxy. In certain embodiments, R f1 is neopentoxy. In certain embodiments, R f1 is 3,3-dimethylbutoxy. In certain embodiments, R f1 is 2-methylbutoxy. In certain embodiments, R f1 is pentoxy. In certain embodiments, R f1 is 2-methylpentoxy. In certain embodiments, R f1 is 3- methylpentoxy. In certain embodiments, R f1 is 4-methylpentoxy.
  • R f1 is hexoxy. In certain embodiments, R f1 is 2-propylpentoxy. In certain embodiments, R f1 is propargyloxy. In certain embodiments, R f1 is benzyloxy. In certain embodiments, R f1 is phenoxy. In certain embodiments, R f2 is methyl. In certain embodiments, R f2 is ethyl. In certain embodiments, R f2 is propyl. In certain embodiments, R f2 is isobutyl. In certain embodiments, R f2 is butyl. In certain embodiments, R f2 is neopentyl. In certain embodiments, R f2 is 3,3-dimethylbutyl.
  • R f2 is 2-methylbutyl. In certain embodiments, R f2 is pentyl. In certain embodiments, R f2 is 2-methylpentyl. In certain embodiments, R f2 is 3-methylpentyl. In certain embodiments, R f2 is 4-methylpentyl. In certain embodiments, R f2 is hexyl. In certain embodiments, R f2 is 2-propylpentyl. In certain embodiments, R f2 is propargyl. In certain embodiments, R f2 is benzyl. In certain embodiments, R f2 is phenyl. In certain embodiments, R f2 is methoxy. In certain embodiments, R f2 is ethoxy.
  • R f2 is propoxy. In certain embodiments, R f2 is isobutyloxy. In certain embodiments, R f2 is butoxy. In certain embodiments, R f2 is neopentoxy. In certain embodiments, R f2 is 3,3-dimethylbutoxy. In certain embodiments, R f2 is 2-methylbutoxy. In certain embodiments, R f2 is pentoxy. In certain embodiments, R f2 is 2-methylpentoxy. In certain embodiments, R f2 is 3- methylpentoxy. In certain embodiments, R f2 is 4-methylpentoxy. In certain embodiments, R f2 is hexoxy. In certain embodiments, R f2 is 2-propylpentoxy.
  • R f2 is propargyloxy. In certain embodiments, R f2 is benzyloxy. In certain embodiments, R f2 is phenoxy. In certain embodiments, R g1 is methyl. In certain embodiments, R g1 is ethyl. In certain embodiments, R g1 is propyl. In certain embodiments, R g1 is isobutyl. In certain embodiments, R g1 is butyl. In certain embodiments, R g1 is neopentyl. In certain embodiments, R g1 is 3,3-dimethylbutyl. In certain embodiments, R g1 is 2-methylbutyl. In certain embodiments, R g1 is pentyl.
  • R g1 is 2-methylpentyl. In certain embodiments, R g1 is 3-methylpentyl. In certain embodiments, R g1 is 4-methylpentyl. In certain embodiments, R g1 is hexyl. In certain embodiments, R g1 is 2-propylpentyl. In certain embodiments, R g1 is benzyl. In certain embodiments, R g1 is and phenyl. In certain embodiments, R g2 is methyl. In certain embodiments, R g2 is ethyl. In certain embodiments, R g2 is propyl. In certain embodiments, R g2 is is isobutyl. In certain embodiments, R g2 is butyl.
  • R g2 is neopentyl. In certain embodiments, R g2 is 3,3-dimethylbutyl. In certain embodiments, R g2 is 2-methylbutyl. In certain embodiments, R g2 is pentyl. In certain embodiments, R g2 is 2-methylpentyl. In certain embodiments, R g2 is 3-methylpentyl. In certain embodiments, R g2 is 4-methylpentyl. In certain embodiments, R g2 is hexyl. In certain embodiments, R g2 is 2-propylpentyl. In certain embodiments, R g2 is benzyl. In certain embodiments, R g2 is and phenyl.
  • R h1 is: -(CH 2 )r-O-(CH 2 )sCH 3 , wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH 2 - and -CH 3 is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(C 1 - C 6 alkyl)O(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)O(benzyl), and -(C 1 -C 6 alkyl)O(C 6 -C 10 aryl).
  • R h1 is O(CH 2 ) 2 O(CH 2 ) 17 CH 3 , octadecyloxyethyl (ODE). In certain embodiments, R h1 is O(CH 2 ) 3 O(CH 2 ) 15 CH 3 , hexadecyloxypropyl (HDP). In certain embodiments, R j1 is H. In certain embodiments, R j1 is CN. In certain embodiments, R j1 is CH 2 F . In certain embodiments, R j1 is CHF 2 . In certain embodiments, R j1 is CF 3 . In certain embodiments, R j1 is OCF 3 . In certain embodiments, R j1 is F.
  • R j1 is C1. In certain embodiments, R j1 is I. In certain embodiments, R j2 is H. In certain embodiments, R j2 is CN. In certain embodiments, R j2 is CH 2 F . In certain embodiments, R j2 is CHF 2 . In certain embodiments, R j2 is CF3. In certain embodiments, R j2 is OCF3. In certain embodiments, R j2 is F. In certain embodiments, R j2 is C1. In certain embodiments, R j2 is I. In certain embodiments, R j3 is H. In certain embodiments, R j3 is CN. In certain embodiments, R j3 is CH 2 F.
  • R j3 is CHF2. In certain embodiments, R j3 is CF3. In certain embodiments, R j3 is OCF3. In certain embodiments, R j3 is F. In certain embodiments, R j3 is C1. In certain embodiments, R j3 is I. In certain embodiments, R j4 is H. In certain embodiments, R j4 is CN. In certain embodiments, R j4 is CH 2 F. In certain embodiments, R j4 is CHF2. In certain embodiments, R j4 is CF 3 . In certain embodiments, R j4 is OCF 3 . In certain embodiments, R j4 is F. In certain embodiments, R j4 is C1.
  • R j4 is I.
  • R j5 is H.
  • R j5 is CN.
  • R j5 is CH 2 F.
  • R j5 is CHF2.
  • R j5 is CF3.
  • R j5 is OCF3.
  • R j5 is F.
  • R j5 is C1.
  • R j5 is I.
  • the compound is Ia-1).
  • the compound is Ia-2).
  • the compound is a-1’).
  • the compound is Ia-1’’).
  • the compound is Ia-2’).
  • the compound is (Ia-2’’).
  • R A is selected from the group consisting of: wherein: R f1 is selected from the group consisting of optionally substituted C 1 -C 24 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 6 allyl, optionally substituted C 3 -C 6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C 2 -C 8 heterocyclyl, optionally substituted C 1 -C 24 alkoxy, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted C 3 -C 6 allyloxy, optionally substituted C 3 -C 6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; R g1 is selected from the group consisting of optionally substituted benzy
  • R B is: wherein: R d1 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein R d1 and R C may combine with atoms to which they are bound to form an optionally substituted C 2 -C 5 heterocyclyl; and R e1 is selected from the group consisting of H, optionally substituted C 1 -C 24 alkyl, C 3 -C 8 cycloalkyl, and optionally substituted benzyl.
  • R B is In certain embodiments, R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is .
  • R B is n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is R n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is .
  • R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is In Certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is .
  • R B is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is . In certain embodiments, the compound of formula (Ia-2) is . In certain embodiments, the compound of formula (Ia-2’) is . In certain embodiments, the compound of formula (Ia-2’’) is . In certain embodiments, the R B substituent in any one of (Ia-2), (Ia-2’), and (Ia-2’’) has a (S)- configuration.
  • the R B substituent in any one of (Ia-2), (Ia-2’), and (Ia-2’’) has a (R)-configuration.
  • R 1 is .
  • R 1 is .
  • R 1 is .
  • R 1 is .
  • R 1 is .
  • R 1 is ethanoyl.
  • R 1 is propanoyl.
  • R 1 is isobutanoyl.
  • R 1 is butanoyl.
  • R 1 is neopentanoyl.
  • R 1 is 3,3-dimethyl-butanoyl. In certain embodiments, R 1 is 2-methyl-butanoyl. In certain embodiments, R 1 is pentanoyl. In certain embodiments, R 1 is 2-methyl-pentanoyl. In certain embodiments, R 1 is 3-methyl-pentanoyl. In certain embodiments, R 1 is 4-methyl- pentanoyl. In certain embodiments, R 1 is hexanoyl. In certain embodiments, R 2 is H. In certain embodiments, R 2 is F. In certain embodiments, R 2 is CH 3 . In certain embodiments, R 2 is CH 2 CH 3 . In certain embodiments, R 2 is C ⁇ CH.
  • R a1 is 3- methylpentyl. In certain embodiments, R a1 is 4-methylpentyl. In certain embodiments, R a1 is hexyl. In certain embodiments, R a1 is ethanoyl. In certain embodiments, R a1 is propanoyl. In certain embodiments, R a1 is isobutanoyl. In certain embodiments, R a1 is butanoyl. In certain embodiments, R a1 is neopentanoyl. In certain embodiments, R a1 is 3,3-dimethyl-butanoyl. In certain embodiments, R a1 is 2-methyl-butanoyl.
  • R a1 is pentanoyl. In certain embodiments, R a1 is 2-methyl-pentanoyl. In certain embodiments, R a1 is 3-methyl- pentanoyl. In certain embodiments, R a1 is 4-methyl-pentanoyl. In certain embodiments, R a1 is hexanoyl. In certain embodiments, R 3b is F. In certain embodiments, R 3b is C1. In certain embodiments, R 3b is OR a2 . In certain embodiments, OR a2 is OH. In certain embodiments, OR a2 is OMe. In certain embodiments, R a2 is methyl. In certain embodiments, R a2 is ethyl.
  • R a2 is propyl. In certain embodiments, R a2 is isobutyl. In certain embodiments, R a2 is butyl. In certain embodiments, R a2 is neopentyl. In certain embodiments, R a2 is 3,3- dimethylbutyl. In certain embodiments, R a2 is 2-methylbutyl. In certain embodiments, R a2 is pentyl. In certain embodiments, R a2 is 2-methylpentyl. In certain embodiments, R a2 is 3- methylpentyl. In certain embodiments, R a2 is 4-methylpentyl. In certain embodiments, R a2 is hexyl.
  • R a2 is ethanoyl. In certain embodiments, R a2 is propanoyl. In certain embodiments, R a2 is isobutanoyl. In certain embodiments, R a2 is butanoyl. In certain embodiments, R a2 is neopentanoyl. In certain embodiments, R a2 is 3,3-dimethyl-butanoyl. In certain embodiments, R a2 is 2-methyl-butanoyl. In certain embodiments, R a2 is pentanoyl. In certain embodiments, R a2 is 2-methyl-pentanoyl. In certain embodiments, R a2 is 3-methyl- pentanoyl.
  • R a2 is 4-methyl-pentanoyl. In certain embodiments, R a2 is hexanoyl. In certain embodiments, R 4b is H. In certain embodiments, R 4b is F. In certain embodiments, R 4b is C1. In certain embodiments, R 5 is H. In certain embodiments, R 6 is H. In certain embodiments, R 7a is H. In certain embodiments, R 7b is H. In certain embodiments, R 7c is H. In certain embodiments, R 8 is H. In certain embodiments, R 8 is NH 2 In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, X is CF. In certain embodiments, Y is N.
  • Y is O.
  • a 1 is certain embodiments, A 1 is . In certain embodim ents, A 1 is . In certain embodiments, A 1 is . In certain embodiments, A 1 is In certain embodiments, A 1 is .
  • each occurrence of alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, and aryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 24 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 allyl, C 3 -C 6 propargyl, C 1 -C 6 hydroxyalkyl, halogen, NO 2 , CN, OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)2, NH(C6-C10 aryl), N(C6-C10 aryl)2, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, C1-C3 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 halocycloalkoxy, benzy
  • the compound is selected from the group consisting of: (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-(hydroxya
  • the compounds of the disclosure may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms.
  • the compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a compound illustrated herein by the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof.
  • the compounds of the disclosure exist as tautomers. All tautomers are included within the scope of the compounds recited herein.
  • Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • suitable optional substituents are not intended to limit the scope of the claimed disclosure.
  • the compounds of the disclosure may contain any of the substituents, or combinations of substituents, provided herein.
  • Salts The compounds described herein may form salts with acids or bases, and such salts are included in the present disclosure.
  • salts embraces addition salts of free acids or bases that are useful within the methods of the disclosure.
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • the salts are pharmaceutically acceptable salts.
  • Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present disclosure, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the disclosure.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, 2-hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric, sal
  • Reported RdRp inhibitors further include, but are not limited to (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((isobutyryloxy)methyl)tetrahydrofuran- 3,4-diyl bis(2-methylpropanoate) (i.e., GS-621763) as described in Nat. Commun.2021, 12:6415, which is incorporated herein by reference in its entirety.
  • RdRp inhibitors further include, but are not limited to prodrugs of the above- mentioned RdRp inhibitors, for example as described in Int’l Patent Appl. Pub. No. WO2021262826, which is incorporated herein by reference in its entirety.
  • the protease inhibitor inhibits the 3-chymotrypsin-like cysteine protease (3CL pro ), main protease (M pro ), and/or nonstructural protein 5 (nsp5).
  • Reported protease inhibitors include, but are not limited to, paxlovid (i.e.
  • the present disclosure further provides methods of preparing the compounds of the present disclosure.
  • Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It is appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, and so forth) are given, other process conditions can also be used unless otherwise stated.
  • Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein. The processes described herein can be monitored according to any suitable method known in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • the reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • Intermediate IV can be converted to a compound of formula (I) by employing, in any suitable order, any of the general transformations illustrated as examples, but not as limitations, in Scheme 1 as deprotection, acylation, displacement of a suitable leaving group LG 2 with an appropriate nucleophile (i.e., R 7b -NH-Y-R 7a or H 2 N-Y-R 7a ), followed by reaction of the resulting intermediate with a suitable electrophile reagent (e.g., R 7b -LG 3 , wherein LG 3 is a suitable leaving group), and separation of isomers as needed.
  • a suitable electrophile reagent e.g., R 7b -LG 3 , wherein LG 3 is a suitable leaving group
  • Analogous compounds can be synthesized in a similar fashion to those exemplified using the appropriately substituted intermediates and reagents.
  • Methods The compounds described herein are effective for the treatment, prevention, and/or amelioration of an infection caused by one or more coronaviruses, non-limiting examples including an alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus.
  • the present disclosure provides a method of treating, ameliorating, and/or preventing a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure.
  • the alphacoronavirus is Human coronavirus 229E (HCoV- 229E). In certain embodiments, the alphacoronavirus is Human coronavirus NL63 (HCoV- NL63). In certain embodiments, the betacoronavirus is Severe acute respiratory syndrome- related coronavirus 2 (SARS-CoV-2). In certain embodiments, the betacoronavirus is Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1). In certain embodiments, the betacoronavirus is Middle East respiratory syndrome-related coronavirus (MERS-CoV). In certain embodiments, the betacoronavirus is Human coronavirus OC43 (HCoV-OC43).
  • the betacoronavirus is Human coronavirus HKU1 (HCoV-HKU1). In certain embodiments, the betacoronavirus is SARS-CoV-2. In certain embodiments, a coronavirus RNA polymerase is inhibited. In certain embodiments, the RNA polymerase comprises nonstructural protein 12 (nsp12). In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.
  • Pharmaceutical Compositions and Formulations In certain embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection.
  • compositions comprising at least one compound of the disclosure or a salt or solvate thereof, which are useful to practice methods of the disclosure.
  • a pharmaceutical composition may consist of at least one compound of the disclosure or a salt or solvate thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the disclosure or a salt or solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
  • At least one compound of the disclosure may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
  • the pharmaceutical compositions useful for practicing the method of the disclosure may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In other embodiments, the pharmaceutical compositions useful for practicing the disclosure may be administered to deliver a dose of between 1 ng/kg/day and 1,000 mg/kg/day.
  • the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions of the disclosure are part of a pharmaceutical matrix, which allows for manipulation of insoluble materials and improvement of the bioavailability thereof, development of controlled or sustained release products, and generation of homogeneous compositions.
  • a pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction technologies, molecular complexes (e.g., cyclodextrins, and others), microparticulate, and particle and formulation coating processes. Amorphous or crystalline phases may be used in such processes.
  • the route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology and pharmaceutics.
  • preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-dose or multi-dose unit.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
  • compositions of the disclosure include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
  • the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of at least one compound of the disclosure and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g., RECOMBUMIN®), solubilized gelatins (e.g., GELOFUSINE®), and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or fragrance-conferring substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic, anxiolytics or hypnotic agents.
  • additional ingredients include, but are not limited to, one or more ingredients that may be used as a pharmaceutical carrier.
  • the composition of the disclosure may comprise a preservative from about 0.005% to 2.0% by total weight of the composition.
  • emulsifying agents include, but are not limited to, lecithin, acacia, and ionic or non-ionic surfactants.
  • Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid.
  • Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
  • Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
  • an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
  • Liquid solutions of the pharmaceutical composition of the disclosure may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.
  • Aqueous solvents include, for example, water, and isotonic saline.
  • Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Powdered and granular formulations of a pharmaceutical preparation of the disclosure may be prepared using known methods.
  • Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto.
  • Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, ionic and non-ionic surfactants, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • a pharmaceutical composition of the disclosure may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
  • the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
  • Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
  • Methods for impregnating or coating a material with a chemical composition include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
  • Methods for mixing components include physical milling, the use of pellets in solid and suspension formulations and mixing in a transdermal patch, as known to those skilled in the art.
  • Administration/Dosing The regimen of administration may affect what constitutes an effective amount.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the frequency of the dose is readily apparent to the skilled artisan and depends upon a number of factors, such as, but not limited to, type and severity of the disease being treated, and type and age of the animal.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • Compounds of the disclosure for administration may be in the range of from about 1 ⁇ g to about 7,500 mg, about 20 ⁇ g to about 7,000 mg, about 40 ⁇ g to about 6,500 mg, about 80 ⁇ g to about 6,000 mg, about 100 ⁇ g to about 5,500 mg, about 200 ⁇ g to about 5,000 mg, about 400 ⁇ g to about 4,000 mg, about 800 ⁇ g to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments there-in- between.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present disclosure is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.
  • the term "container" includes any receptacle for holding the pharmaceutical composition or for managing stability or water uptake.
  • the container is the packaging that contains the pharmaceutical composition, such as liquid (solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized formulation present in dual chambers.
  • the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
  • packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound's ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a patient.
  • compositions of the disclosure include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • inhalational e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular
  • compositions of the invention include nasal, inhalational, intratracheal, intrapulmonary, and intrabronchial.
  • Suitable compositions and dosage forms include, for example, dispersions, suspensions, solutions, syrups, granules, beads, powders, pellets, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein. Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods.
  • Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension.
  • Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 micrometers.
  • the pharmaceutical composition of the invention may be delivered using an inhalator such as those recited in U.S. Patent No.
  • formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
  • a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
  • tablets may be coated using methods described in U.S. Patents Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets.
  • Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
  • the capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
  • Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin from animal-derived collagen or from a hypromellose, a modified form of cellulose, and manufactured using optional mixtures of gelatin, water and plasticizers such as sorbitol or glycerol.
  • Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • the compounds of the disclosure may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents; fillers; lubricants; disintegrates; or wetting agents.
  • Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate.
  • Known surface-active agents include, but are not limited to, sodium lauryl sulphate.
  • Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate.
  • Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
  • Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
  • Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation.”
  • solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents.
  • the low melting solids when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.
  • the liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together.
  • the resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.
  • melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.
  • U.S. Patent No.5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt.
  • the present disclosure also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds useful within the methods of the disclosure, and a further layer providing for the immediate release of one or more compounds useful within the methods of the disclosure.
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non- aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non- aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl para-hydroxy benzoates or sorbic acid
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
  • Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.
  • a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline.
  • Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration.
  • Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Injectable formulations may also be prepared, packaged, or sold in devices such as patient-controlled analgesia (PCA) devices.
  • PCA patient-controlled analgesia
  • Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non- toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example.
  • a non- toxic parenterally acceptable diluent or solvent such as water or 1,3-butanediol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • the stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells.
  • One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin.
  • Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone.
  • One acceptable vehicle for topical delivery of some of the compositions of the disclosure may contain liposomes.
  • the composition of the liposomes and their use are known in the art (i.e., U.S. Patent No.6,323,219).
  • the topically active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, preservatives, and the like.
  • a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer.
  • compositions may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum.
  • hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.
  • the topically active pharmaceutical composition should be applied in an amount effective to affect desired changes.
  • a pharmaceutical composition of the disclosure may be prepared, packaged, or sold in a formulation suitable for buccal administration.
  • formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient.
  • Such powdered, aerosolized, or aerosolized formulations, when dispersed may have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • compositions and/or formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • the compounds useful within the disclosure are administered to a subject, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, include a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • LCMS Method B Waters Acquity UPLC system employing a Waters Acquity UPLC BEH C18, 1.7 ⁇ m, 50 x 2.1 mm column with an aqueous acetonitrile based solvent gradient of 2-98% CH 3 CN/H2O (0.05 % TFA) over 1.0 mins.
  • Flow rate 0.8 mL/min.
  • the vial was capped, and the reaction mixture was heated at 60 °C in reaction block behind a blast shield overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated to give a tan resin. The resin was triturated with a mixture of MeOH/p- dioxane/Et 2 O (1:2:2 v/v/v). Additional p-dioxane/Et 2 O (1:2) was added and the resulting suspension was stirred vigorously at room temperature.
  • (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diyl dibenzoate (900.0 mg, 1.46 mmol) was treated dropwise at 0-5 °C with ammonia (7N in MeOH, 10.0 mL, 70.0 mmol).
  • the pale- yellow mixture was stirred and allowed to slowly warm to room temperature. Reaction was monitored by TLC (9:1 v/v CH 2 C1 2 -MeOH, with KMnO 4 staining). The mixture was stirred at room temperature overnight, then cooled and neutralized by slow addition of solid NaOMe (5.0 g, 92.5 mmol). The suspension was stirred for 1 hour, then filtered through a plug of Celite ® , rinsed with MeOH and the solvent was evaporated.
  • Step (2) (2R,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5- methoxytetrahydrofuran
  • Sodium hydride 60 wt% in mineral oil, 23.9 g, 597 mmol
  • 3R,4S,5R 4-(benzyloxy)-5-((benzyloxy)methyl)-2- methoxytetrahydrofuran-3-ol
  • cesium carbonate 4.75 g, 14.6 mmol
  • iodomethane 907 ⁇ L, 14.6 mmol
  • crude (3R,4R,5R)-4-(benzyloxy)-5- ((benzyloxy)methyl)-3-methoxytetrahydrofuran-2-ol IIIb, 630 mg, 1.83 mmol
  • triphenylphosphine 720 mg, 2.74 mmol
  • 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine IIa, 314 mg, 1.83 mmol
  • Step (8) (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol
  • (2R,3R,4R,5R)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol (IVd, 50.0 mg, 0.16 mmol) in p-dioxane (0.5 mL) was added hydroxylamine (50 wt% in water, 0.50 mL, 7.6 mmol).
  • the vial was sealed and heated at 60 °C behind a blast shield for 36 hours. The mixture was evaporated to dryness.
  • the product was purified by column chromatography (Silica gel, 0-20% MeOH/CH 2 C12). The desired fractions were collected, and the solvent was evaporated to give a clear resin.
  • the recovered material was further purified by preparative TLC [20 cm x 20 cm, 1.5 mm, 20% MeOH/CH 2 C1 2 ].
  • Example 5 ((2R,3S,4R,5R)-5-(2-Amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 5) Step (1): ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVf) To a solution of (2R,3R,4S,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVe, 1.00 g, 3.31 mmol) and 2,2- dimethoxypropane (2.10 mL, 16.6 mmol) in dry DMF (10
  • Step (2) ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate
  • a solution of ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl isobutyrate 50 mg, 0.12 mmol
  • IPA mL
  • hydroxylamine 50 wt% in water, 26 ⁇ L, 0.39 mmol
  • Example 6 and 7 Isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Compound 6 and 7) Step (1): isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate
  • the product was purified by column chromatography (Silica gel, 50% Acetone/Hexanes, isocratic). The desired fractions were evaporated to a clear resin. The resin was further purified by preparative TLC (20 cm x 20 cm, 1.5 mm, 50% Acetone/Hexanes).
  • a microwave vial equipped with a stir bar was charged with isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (72 mg, 0.12 mmol) (mixture of phosphorous
  • Example 8 ((2R,3S,4R,5R)-3,4-Dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 8) Step (1): ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVh) To a solution of (2R,3R,4S,5R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVg, 1.00 g, 3.50 mmol) and 2,2- dimethoxypropan
  • Step (2) ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate
  • a solution of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (106 mg, 0.27 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 57 ⁇ L, 0.86 mmol).
  • Example 9 Isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Compound 9) Step (1): isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)- L-alaninate
  • the mixture was stirred at room temperature for 45 minutes.
  • the mixture was diluted with EtOAc (50 mL) and sat. aq. NH 4 C1 solution.
  • the layers were separated.
  • the aqueous phase was extracted with EtOAc (2 x 10 mL).
  • the combined organic layer was washed with water (10 mL) and sat. aq. NaC1 solution (10 mL).
  • the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated.
  • a microwave vial equipped with a stir bar was charged with isopropyl ((S)- (((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (163 mg, 0.27 mmol), IPA (1 mL) and hydroxylamine (50 wt% in water, 91.0 ⁇ L, 1.37
  • Example 10 (2R,3R,4S,5R)-2-(4-(Hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 10)
  • a microwave vial equipped with a stir bar was charged with (2R,3R,4S,5R)-2-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVg, 50.0 mg, 0.18 mmol), IPA (1 mL) and hydroxylamine (50 wt% in water, 37 ⁇ L, 0.56 mmol).
  • TBAF
  • the vial was sealed, and the mixture was heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the residue was subjected to high vacuum for 1 hour. The recovered material was taken directly into the next step. The residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to a brown resin. The residue was neutralized with ammonia in MeOH (7N, 3 mL). The mixture was stirred for 15 minutes, and the volatiles were evaporated. The product was purified by column chromatography (Silica gel, 0-25% MeOH/CH 2 C1 2 ).
  • Example 12 ((2R,3S,4R,5R)-5-(2-Amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 12) Step (1): ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate To a solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxo
  • a solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (112 mg, 0.27 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 57 ⁇ L, 0.87 mmol).
  • Example 13 Isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 13) Step (1): isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
  • a microwave vial equipped with a stir bar was charged with isopropyl ((S)- (((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (167 mg, 0.27 mmol), IPA (1 m
  • the mixture was stirred at -78 °C for 0.5 h.
  • the reaction mixture was diluted with MeOH (80 mL) and the pH was adjusted to 7 with triethylamine (25 mL) at -78 °C.
  • the reaction mixture was concentrated under reduced pressure and the residue was suspended in H 2 O (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduce pressure.
  • Example 16 SARS-CoV-2 Assay Test compounds were serially diluted using eight half-log dilutions in test medium (MEM supplemented with 2% FBS and 50 ⁇ g/mL gentamicin). Each dilution was added to 5 wells of a 96-well plate with 80-100% confluent Vero E6 cells.
  • Viruses were prepared to achieve the lowest possible multiplicity of infection (MOI) that would yield >80% cytopathic effect (CPE) at 3 days. Plates were incubated at 37 ⁇ 2°C, 5% CO2. On day 3 post-infection, once untreated virus control wells reached maximum CPE, plates were stained with neutral red dye for approximately 2 hours ( ⁇ 15 minutes).
  • MOI multiplicity of infection
  • CPE cytopathic effect
  • Embodiment 2 provides the compound of Embodiment 1, wherein R 1 is selected from the group consisting of: wherein: R c1 is selected from the group consisting of optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R d1 and R d2 are each independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein one or more of R d1 and R e1 , and R d2 and R e3 , may combine
  • Embodiment 3 provides the compound of Embodiment 2, wherein the benzyl, phenyl, naphthyl, or C 2 -C 8 heterocyclyl in R c1 is optionally substituted with at least one substituent.
  • Embodiment 4 provides the compound of Embodiment 2 or 3, wherein R 1 is selected from the group consisting of: , , , and .
  • Embodiment 5 provides the compound of Embodiment 2 or 3, wherein R 1 is selected from the group consisting of: , , , and .
  • R d1 and R d2 is selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, methanethioethyl, benzyl, 3-indolyl, hydroxymethyl, 1- hydroxyethyl
  • Embodiment 7 provides the compound of any one of Embodiments 2-4 and 6, wherein R 1 is .
  • Embodiment 8 provides the compound of any one of Embodiments 2-6, wherein R 1 is selected from the group consisting of and
  • Embodiment 9 provides the compound of Embodiment 1, wherein R 1 is selected from the group consisting of: an d .
  • Embodiment 10 provides the compound of any one of Embodiments 2-6, wherein R e1 , R e2 , R e3 , and R e4 , if present, are each independently selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • R e1 , R e2 , R e3 , and R e4 are each independently selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methyl
  • Embodiment 11 provides the compound of Embodiment 2, wherein R f1 and R f2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3-dimethylbutoxy, 2-methylbutoxy, pentoxy, 2- methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, hexoxy, 2-propylpentoxy, propargyloxy, benzyloxy, and phenoxy.
  • Embodiment 12 provides the compound of Embodiment 2, wherein R g1 and R g2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • R g1 and R g2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • Embodiment 13 provides the compound of Embodiment 2, wherein R h1 is: -(CH 2 )r-O-(CH 2 )sCH 3 , wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH 2 - and -CH 3 is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)O(benzyl), and -(C 1 -C 6 alkyl)O(C6-C10 aryl).
  • Embodiment 14 provides the compound of Embodiment 2, wherein R h1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP).
  • Embodiment 15 provides the compound of Embodiment 2, wherein R j1 , R j2 , R j3 , R j4 , and R j5 , if present, are each independently selected from the group consisting of H, CN, CH 2 F , CHF 2 , CF 3 , OCF 3 , F, and C1.
  • Embodiment 17 provides the compound of Embodiment 1 or 16, which is selected from the group consisting of: ( ) nd Embodiment 18 provides the compound of Embodiment 17, which is selected from the group consisting of: Embodiment 19 provides the compound of Embodiment 17 or 18, wherein R A is selected from the group consisting of: wherein: R f1 is selected from the group consisting of optionally substituted C 1 -C 24 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C 2 -C 8 heterocyclyl, optionally substituted C 1 -C 24 alkoxy, optionally substituted C 3 -C 8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6
  • Embodiment 20 provides the compound of Embodiment 19, wherein R f1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3-dimethylbutoxy, 2-methylbutoxy, pentoxy, 2-methylpentoxy, 3- methylpentoxy, 4-methylpentoxy, hexoxy, 2-propylpentoxy, propargyloxy, benzyloxy, and phenoxy.
  • R f1 is selected from the group consisting of methyl, ethyl, propyl, is
  • Embodiment 21 provides the compound of Embodiment 19, wherein R g1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • R g1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • Embodiment 22 provides the compound of Embodiment 19, wherein R h1 is: -(CH 2 )r-O-(CH 2 )sCH 3 , wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH 2 - and -CH 3 is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), -(C 1 -C 6 alkyl)O(benzyl), and -(C 1 -C 6 alkyl)O(C 6 -C 10 aryl).
  • Embodiment 23 provides the compound of Embodiment 19, wherein R h1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP).
  • Embodiment 24 provides the compound of Embodiment 17 or 18, wherein R B is: wherein: R d1 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein R d1 and R C may combine with atoms to which they are bound to form an optionally substituted C2-C5 hetero
  • Embodiment 25 provides the compound of Embodiment 24, wherein R B is selected from the group consisting of:
  • Embodiment 27 provides the compound of any one of Embodiments 24-26, wherein R e1 is selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • R e1 is selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl.
  • Embodiment 28 provides the compound of Embodiment 1, wherein R 1 is selected from the group consisting of ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3- dimethyl-butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl-pentanoyl, and hexanoyl.
  • Embodiment 30 provides the compound of any one of Embodiments 1-15 and 29, wherein R a1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl- butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl- pentanoyl, and hexanoyl.
  • R a1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, buty
  • Embodiment 31 provides the compound of any one of Embodiments 1-30, wherein R 3b is F.
  • Embodiment 32 provides the compound of any one of Embodiments 1-30, wherein R 3b is OR a2 .
  • Embodiment 33 provides the compound of Embodiment 32, wherein R a2 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl-butanoyl, 2-methyl- butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl
  • Embodiment 34 provides the compound of any one of Embodiments 1-33, wherein R 4b is H.
  • Embodiment 35 provides the compound of any one of Embodiments 1-34, wherein R 5 is H.
  • Embodiment 36 provides the compound of any one of Embodiments 1-35, wherein R 8 is H or NH2.
  • Embodiment 37 provides the compound of any one of Embodiments 1-36, wherein X is selected from the group consisting of N, CH, and CF.
  • Embodiment 38 provides the compound of any one of Embodiments 1-37, wherein A 1 is selected from the group consisting of Embodiment 39 provides the compound of any one of Embodiments 1-38, wherein each occurrence of alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, and aryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 24 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 allyl, C 3 -C 6 propargyl, C 1 -C 6 hydroxyalkyl, halogen, NO2, CN, OH, NH2, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)2, NH(C6-C10 aryl), N(C6-C10 aryl)2, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy
  • Embodiment 41 provides the compound of any one of Embodiments 1-40, which is selected from the group consisting of: (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyr
  • Embodiment 42 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-41 and a pharmaceutically acceptable carrier.
  • Embodiment 43 provides the pharmaceutical composition of Embodiment 42, further comprising at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection.
  • Embodiment 44 provides a method of treating, ameliorating, and/or preventing a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of Embodiments 1-41 and/or at least one pharmaceutical composition of any one of Embodiments 42-43.
  • Embodiment 45 provides the method of Embodiment 44, wherein the subject is further administered at least one additional agent useful for treating, ameliorating, and/or preventing the coronavirus infection.
  • Embodiment 46 provides the method of Embodiment 45, wherein the subject is co- administered the at least one additional agent and the at least one compound and/or composition.
  • Embodiment 47 provides the method of Embodiment 46, wherein the at least one additional agent and the at least one compound and/or composition are coformulated.
  • Embodiment 48 provides the method of any one of Embodiments 45-47, wherein the additional agent is selected from the group consisting of a RNA-dependent RNA polymerase (RdRp) inhibitor and a protease inhibitor.
  • RdRp RNA-dependent RNA polymerase
  • Embodiment 49 provides the method of any one of Embodiments 44-48, wherein the coronavirus is selected from the group consisting of an alphacoronavirus and a betacoronavirus.
  • Embodiment 50 provides the method of Embodiment 49, wherein the alphacoronavirus is selected from the group consisting of Human coronavirus 229E (HCoV- 229E) and Human coronavirus NL63 (HCoV-NL63).
  • Embodiment 51 provides the method of Embodiment 49, wherein the betacoronavirus is selected from the group consisting of Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1).
  • Embodiment 52 provides the method of Embodiment 51, wherein the betacoronavirus is SARS-CoV-2.
  • Embodiment 53 provides the method of any one of Embodiments 44-52, wherein a coronavirus RNA polymerase is inhibited.
  • Embodiment 54 provides the method of Embodiment 53, wherein the RNA polymerase comprises nonstructural protein 12 (nsp12).
  • Embodiment 55 provides the method of any one of Embodiments 44-54, wherein the subject is a mammal.
  • Embodiment 56 provides the method of Embodiment 55, wherein the mammal is a human.

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Abstract

The present disclosure relates to compounds of formula (I) and compositions thereof, which are useful for the treatment, amelioration, or prevention of coronavirus infections. A1 is selected from the group consisting of (II), (III) and (IV).

Description

TITLE OF THE INVENTION RNA Polymerase Inhibitors and Methods Using Same CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63/309,965, filed February 14, 2022, which is hereby incorporated by reference herein in its entirety. BACKGROUND SARS-CoV-2, one of a family of human coronaviruses, is the pathogen responsible for coronavirus disease 2019 (COVID-19). Initially identified in Wuhan in December 2019, the virus has subsequently spread throughout the world and was declared a pandemic by the World Health Organization on March 11, 2020. Although several vaccines are available for the prevention of COVID-19, there is an urgent need for effective new drug treatments to reduce the morbidity and/or mortality for patients who have already contracted COVID-19, have not yet received a vaccine, and/or have been infected with a more resistant SARS-CoV- 2 variant. Further, these treatments may prove indispensable for future coronavirus pandemics. SARS-CoV-2 is a positive-stranded, enveloped RNA virus. Like many coronaviruses, its genome comprises six major open-reading frames (ORFs), in addition to other accessory genes. After extensive proteolytic processing, the polyproteins encoded by ORF 1a and ORF 1ab are implicated in a number of essential tasks pertaining to viral replication, transcription, viral assembly, and immune response modulation. One of several functional proteins released by ORF 1a proteolytic processing, non- structural protein 12 (nsp12), is a multidomain, 932 amino acid enzyme, which contains RNA-dependent RNA polymerase (RdRp) catalytic activity and is commonly identified as the viral RdRp. The C-terminal polymerase domain of nsp12 is responsible for the synthesis of viral RNA. Thus, nsp12 is a critical element of the viral lifecycle (i.e., replication and transcription) and represents a key therapeutic target for viral life cycle disruption. There is thus a need in the art for compounds useful for the treatment, amelioration, and/or prevention of a coronavirus infection in a subject and methods of using the same. The present disclosure addresses this need. BRIEF SUMMARY The present disclosure provides certain compounds of formula (I), or a salt, solvate, geometric isomer, stereoisomer, or tautomer thereof, or any mixtures thereof, wherein the substituents in (I) are defined elsewhere herein:
Figure imgf000003_0001
The present disclosure further provides pharmaceutical compositions comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection. The present disclosure further provides methods of treating, ameliorating, and/or preventing a coronavirus infection. In certain embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the coronavirus is selected from the group consisting of an alphacoronavirus and a betacoronavirus. In certain embodiments, the alphacoronavirus is selected from the group consisting of Human coronavirus 229E (HCoV- 229E) and Human coronavirus NL63 (HCoV-NL63). In certain embodiments, the betacoronavirus is selected from the group consisting of Severe acute respiratory syndrome- related coronavirus 2 (SARS-CoV-2), Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1). In certain embodiments, a coronavirus RNA polymerase is inhibited. In certain embodiments, the RNA polymerase comprises nonstructural protein 12 (nsp12). DETAILED DESCRIPTION OF THE INVENTION The present invention provides, in one aspect, compounds and compositions that can be used to treat, ameliorate, and/or prevent coronavirus infections, such as but not limited to SARS-CoV-2 infection. In certain embodiments, the compounds inhibit a coronavirus RNA polymerase. In certain embodiments, the coronavirus RNA polymerase comprises nonstructural protein 12 (nsp12). Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Definitions As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously or not. The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "acyl" as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group. The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C CH, -C ^C(CH3), -C ^
Figure imgf000006_0001
C(CH2CH3), -CH2C ^
Figure imgf000006_0002
CH, -CH2C ^C
Figure imgf000006_0003
(CH3), and -CH2C ^C
Figure imgf000006_0004
(CH2CH3) among others. The term "amine" as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein. The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term "aralkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. As used herein, the term "aromatic" refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where 'n' is an integer. As used herein, the term "aryl" employed alone or in combination with other terms means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5- trienyl, or indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings. As used herein, the term "aryl-(C1-C6)alkyl" or “aralkyl” refers to a functional group wherein a one to six carbon alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl (or benzyl). Specific examples are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C6)alkyl" refers to an aryl-(C1-C6)alkyl functional group in which the aryl group is substituted. A specific example is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C6)alkyl" refers to a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. A specific example is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C6)alkyl" refers to a heteroaryl-(C1- C6)alkyl functional group in which the heteroaryl group is substituted. A specific example is substituted heteroaryl-(CH2)-. The term "atm" as used herein refers to a pressure in atmospheres under standard conditions. Thus, 1 atm is a pressure of 101 kPa, 2 atm is a pressure of 202 kPa, and so on. In one aspect, the terms "co-administered" and "co-administration" as relating to a subject refer to administering to the subject a compound and/or composition of the disclosure along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution. The term “COVID” or “COVID-19” as used herein refers to the Coronavirus disease 2019, a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As used herein, the term "cycloalkyl" by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5- dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H- fluorenyl. The term "cycloalkyl" also includes bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1] heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. The term “degree(s) of unsaturation” as used herein refers to the presence of one or more carbon-carbon double bonds (i.e. C=C) in a hydrocarbon, wherein the presence of a carbon-carbon double bond indicates one degree of unsaturation. For example, 1-butene, cis 2-butene, and trans 2-butene each correspond to n-butane having one degree of unsaturation. Further, butadiene corresponds to n-butane having two degrees of unsaturation. As used herein, a "disease" is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate. As used herein, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject's state of health. The terms "epoxy-functional" or "epoxy-substituted" as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- epoxyhexyl. As used herein, the term "halide" refers to a halogen atom bearing a negative charge. The halide anions are fluoride (F−), chloride (C1−), bromide (Br−), and iodide (I−). The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. As used herein, the term "heteroalkenyl" by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include - CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2- CH=CH-CH2-SH. As used herein, the term "heteroalkyl" by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -OCH2CH2CH3, - CH2CH2CH2OH, -CH2CH2NHCH3, -CH2SCH2CH3, and -CH2CH2S(=O)CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2NH-OCH3, or -CH2CH2SSCH3. The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term "heteroarylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term "heterocyclylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term "hydrocarbon" or "hydrocarbyl" as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X1, X2, and X3 are independently selected from noble gases" would include the scenario where, for example, X1, X2, and X3 are all the same, where X1, X2, and X3 are all different, where X1 and X2 are the same but X3 is different, and other analogous permutations. The term "monovalent" as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or C1, it is bonded to the atom it is substituting by a single bond. The term "organic group" as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the disclosure, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates thereof. As used herein, a "pharmaceutically effective amount," "therapeutically effective amount," or "effective amount" of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered. The term "prevent," "preventing," or "prevention" as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. Disease, condition and disorder are used interchangeably herein. The term "room temperature" as used herein refers to a temperature of about 15 °C to 28 °C. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. By the term "specifically bind" or "specifically binds" as used herein is meant that a first molecule preferentially binds to a second molecule (e.g., a particular receptor or enzyme), but does not necessarily bind only to that second molecule. As used herein, the terms "subject" and "individual" and "patient" can be used interchangeably and may refer to a human or non-human mammal or a bird. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term "substituted" as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, C1, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, C1, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. As used herein, the term "substituted alkyl," "substituted cycloalkyl," "substituted alkenyl," or "substituted alkynyl" refers to alkyl, cycloalkyl, alkenyl or alkynyl, as defined elsewhere herein, substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 1-methyl-imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, - C(=O)OH, -C(=O)O(C1-C6)alkyl, trifluoromethyl, -C≡N, -C(=O)NH2, -C(=O)NH(C1- C6)alkyl, -C(=O)N((C1-C6)alkyl)2, -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, - C(=NH)NH2, and -NO2, in certain embodiments containing one or two substituents independently selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and - C(=O)OH, in certain embodiments independently selected from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl. For aryl, aryl-(C1-C3)alkyl and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of C1-C6 alkyl, -OH, C1-C6 alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic. In certain embodiments, each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C1- C6 alkyl, halo, -OR, phenyl (thus yielding, in non-limiting examples, optionally substituted phenyl-(C1-C3 alkyl), such as, but not limited to, benzyl or substituted benzyl) and -N(R)(R), wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl. In other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, -CN, -OR, -N(R)(R), -NO2, -S(=O)2N(R)(R), acyl, and C1- C6 alkoxycarbonyl, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl. In yet other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, -CN, -OR, -N(R)(R), and C1-C6 alkoxycarbonyl, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl. Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2 and R3 taken together with the nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring can be saturated or partially saturated, and can be optionally substituted. Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given elsewhere herein for "alkyl" and "aryl" respectively. In certain embodiments, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. The terms "treat," "treating," and "treatment," as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. Certain abbreviations used herein follow: ACN, acetonitrile; DCE, 1,2- dichloroethane; DCM, dichloromethane; DIEA or DIPEA, diisopropylethylamine; DMF, N,N-dimethylformamide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DIAD, diisopropyl azodicarboxylate; DMAP, 4-dimethylaminopyridine; DMSO, dimethylsulfoxide; d.r., diastereomeric ratio; EtOAc, ethyl acetate; HPLC, high pressure liquid chromatography; IPA, isopropanol (2-propanol); LCMS, liquid chromatography mass spectrometry; NMR, Nuclear Magnetic Resonance; RdRp, RNA-dependent RNA polymerase; RT, retention time; sAg, surface antigen; SFC, supercritical fluid chromatography; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TLC, thin layer chromatography. Compounds The present disclosure provides a compound of formula (I), or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof:
Figure imgf000018_0003
wherein: A1 is selected from the group consisting o
Figure imgf000018_0001
Figure imgf000018_0002
X is selected from the group consisting of CRb1 and N; Y is selected from the group consisting of O and NR7c; R1 is selected from the group consisting of H, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); R2 is selected from the group consisting of H, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N3, and F; R3a is ORa1, wherein R1 and Ra1 may combine with the atoms to which they are bound to form a C3-C5 heterocyclyl; R3b is selected from the group consisting of H, C1, F, and ORa2, wherein Ra1 and Ra2 may combine with the atoms to which they are bound to form a C2-C5 heterocyclyl, and wherein if R3b is C1, then R4b is H; R4a is H; R4b is selected from the group consisting of H, C1, and F, wherein if R4b is C1, then R3b is H; R5 is selected from the group consisting of H, CN, halogen, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB, wherein R5 and R3b may combine with the atoms to which they are bound to form a C2-C6 heterocyclyl; R6 is selected from the group consisting of H, halogen, and C1-C3 haloalkyl; R7a, R7b, and R7c are each independently selected from the group consisting of H, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB; R8 is selected from the group consisting of H, halogen, and N(RA)(RB); RA, RB, RC, and RD are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, optionally substituted C6-C24 alkanoyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted benzyl, optionally substituted C6-C10 aryl, C(=O)(optionally substituted C1-C6 alkyl), C(=O)(optionally substituted C2-C8 heterocyclyl), and C(=O)(optionally substituted C6-C10 aryl, wherein any two selected from the group consisting of RA, RB, RC, and RD may combine with the atoms to which they are bound to form an optionally substituted C2- C6 heterocyclyl, wherein any two vicinal substituents in the optionally substituted C2-C6 heterocyclyl may combine with the atoms to which they are bound to form an optionally substituted C6-C10 aryl; Ra1 and Ra2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)-NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2-NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); Rb1 is selected from the group consisting of H, halogen, C1-C3 haloalkyl, and C(=O)NRANRB; and m is an integer selected from the group consisting of 0, 1, and 2. In certain embodiments, R1 is selected from the group consisting of:
Figure imgf000020_0001
wherein: Rc1 is selected from the group consisting of optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rd1 and Rd2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein one or more of Rd1 and Re1 , and Rd2 and Re3, may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; Re1, Re2, Re3, and Re4 are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl; Rf1 and Rf2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 and Rg2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation; Ri1, Ri2, Ri3, and Ri4, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted phenyl, wherein any two selected from the group consisting of Ri1, Ri2, Ri3, and Ri4 may combine with the atoms to which they are bound to form an optionally substituted C3-C8 cycloalkyl; and Rj1, Rj2, Rj3, Rj4, and Rj5, if present, are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, N(RA)(RB), C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, phenyl, C2-C8 heterocyclyl, C(=O)RA, C(=O)ORA, OC(=O)RA, OC(=O)ORA, SRA, S(=O)RA, S(=O)2RA, S(=O)2NRARB, S(=O)2N(RA)C(=O)NHRB, N(RB)- S(=O)2RC, N(RB)-C(=O)RC, and C(=O)-NRARB. In certain embodiments, the phenyl, naphthyl, or C2-C8 heterocyclyl in Rc1 is optionally substituted with at least one substituent. In certain embodiments, Rc1 is benzyl. In certain embodiments, Rc1 is benzyl substituted with one substituent. In certain embodiments, Rc1 is benzyl substituted with two substituents. In certain embodiments, Rc1 is benzyl substituted with three substituents. In certain embodiments, Rc1 is benzyl substituted with four substituents. In certain embodiments, Rc1 is benzyl substituted with five substituents. In certain embodiments, the benzyl in Rc1 is substituted with at least one substituent selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, CF3, CF2H, OH, OMe, OCF3, OCF2H, OPh, NH2, NMe2, NO2, CN, F, C1, Br, and I. In certain embodiments, Rc1 is phenyl. In certain embodiments, Rc1 is phenyl substituted with one substituent. In certain embodiments, Rc1 is phenyl substituted with two substituents. In certain embodiments, Rc1 is substituted with three substituents. In certain embodiments, Rc1 is phenyl substituted with four substituents. In certain embodiments Rc1 is phenyl substituted with 5 substituents. In certain embodiments, the phenyl in Rc1 is substituted with at least one substituent selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl, CF3, CF2H, OH, OMe, OCF3, OCF2H, OPh, NH2, NMe2, NO2, CN, F, C1, Br, and I. In certain embodiments, R1 is
Figure imgf000022_0001
. In certain embodiments, R1 is . In certain embodiments, R1 is In certain embodiments 1
Figure imgf000022_0003
, R
Figure imgf000022_0002
is In certain embodiments, R1 is In certain embodiments, R1 is
Figure imgf000022_0006
. In certain embodiments, R1 is In certain embodiments,
Figure imgf000022_0004
R1 is
Figure imgf000022_0005
. In certain embodiments, Rd1 is H. In certain embodiments, Rd1 is methyl. In certain embodiments, Rd1 is isopropyl. In certain embodiments, Rd1 is isobutyl. In certain embodiments, Rd1 is sec-butyl. In certain embodiments, Rd1 is methanethioethyl. In certain embodiments, Rd1 is benzyl. In certain embodiments, Rd1 is 3-indolyl. In certain embodiments, Rd1 is hydroxymethyl. In certain embodiments, Rd1 is 1-hydroxyethy. In certain embodiments, Rd1 is, thiomethyl. In certain embodiments, Rd1 is 4-hydroxybenzyl. In certain embodiments, Rd1 is CH2C(=O)NH2. In certain embodiments, Rd1 is CH2CH2C(=O)NH2. In certain embodiments, Rd1 is CH2C(=O)OH. In certain embodiments, Rd1 is CH2CH2C(=O)OH. In certain embodiments, Rd1 is guanidinylpropyl. In certain embodiments, Rd1 is 4-imidazolyl. In certain embodiments, Rd1 is aminobutyl. In certain embodiments, Rd2 is H. In certain embodiments, Rd2 is methyl. In certain embodiments, Rd2 is isopropyl. In certain embodiments, Rd2 is isobutyl. In certain embodiments, Rd2 is sec-butyl. In certain embodiments, Rd2 is methanethioethyl. In certain embodiments, Rd2 is benzyl. In certain embodiments, Rd2 is 3-indolyl. In certain embodiments, Rd2 is hydroxymethyl. In certain embodiments, Rd2 is 1-hydroxyethy. In certain embodiments, Rd2 is, thiomethyl. In certain embodiments, Rd2 is 4-hydroxybenzyl. In certain embodiments, Rd2 is CH2C(=O)NH2. In certain embodiments, Rd2 is CH2CH2C(=O)NH2. In certain embodiments, Rd2 is CH2C(=O)OH. In certain embodiments, Rd2 is CH2CH2C(=O)OH. In certain embodiments, Rd2 is guanidinylpropyl. In certain embodiments, Rd2 is 4-imidazolyl. In certain embodiments, Rd2 is aminobutyl. In certain embodiments, R1 is
Figure imgf000023_0001
. In certain embodiments, R1 is
Figure imgf000023_0007
In certain embodiments, R1 is n certain embodiments, R1 is In certain embodiments, R1 is In certain embodiments, R1 is In certain e 1
Figure imgf000023_0008
mbodiments, R is In certain
Figure imgf000023_0006
embodiments, R 1 is . In certain embodiments, R1 is
Figure imgf000023_0002
. In certain embodiments, R1 is 1
Figure imgf000023_0005
In certain embodiments, R is In certain embodiments, R1 is In certain embodiments,
Figure imgf000023_0003
Figure imgf000023_0004
Figure imgf000024_0001
In certain embodiments, R1 is
Figure imgf000024_0002
In certain embodiments, R1 is . In certain embodiments, R1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In
Figure imgf000024_0003
certain embodiments, R1 is In certain embodiments, R1 is In certain embodi 1
Figure imgf000024_0004
ments, the R substituent has a (S)-configuration. In certain embodiments, the R1 has a (R)-configuration. In certain embodiments, Re1 is H. In certain embodiments, Re1 is methyl. In certain embodiments, Re1 is ethyl. In certain embodiments, Re1 is propyl. In certain embodiments, Re1 is isobutyl. In certain embodiments, Re1 is butyl. In certain embodiments, Re1 is neopentyl. In certain embodiments, Re1 is 3,3-dimethylbutyl. In certain embodiments, Re1 is 2-methylbutyl. In certain embodiments, Re1 is pentyl. In certain embodiments, Re1 is 2- methylpentyl. In certain embodiments, Re1 is 3-methylpentyl. In certain embodiments, Re1 is 4-methylpentyl. In certain embodiments, Re1 is hexyl. In certain embodiments, Re1 is 2- propylpentyl. In certain embodiments, Re1 is benzyl. In certain embodiments, Re1 is phenyl. In certain embodiments, Re2 is H. In certain embodiments, Re2 is methyl. In certain embodiments, Re2 is ethyl. In certain embodiments, Re2 is propyl. In certain embodiments, Re2 is isobutyl. In certain embodiments, Re2 is butyl. In certain embodiments, Re2 is neopentyl. In certain embodiments, Re2 is 3,3-dimethylbutyl. In certain embodiments, Re2 is 2-methylbutyl. In certain embodiments, Re2 is pentyl. In certain embodiments, Re2 is 2- methylpentyl. In certain embodiments, Re2 is 3-methylpentyl. In certain embodiments, Re2 is 4-methylpentyl. In certain embodiments, Re2 is hexyl. In certain embodiments, Re2 is 2- propylpentyl. In certain embodiments, Re2 is benzyl. In certain embodiments, Re2 is phenyl. In certain embodiments, Re3 is H. In certain embodiments, Re3 is methyl. In certain embodiments, Re3 is ethyl. In certain embodiments, Re3 is propyl. In certain embodiments, Re3 is isobutyl. In certain embodiments, Re3 is butyl. In certain embodiments, Re3 is neopentyl. In certain embodiments, Re3 is 3,3-dimethylbutyl. In certain embodiments, Re3 is 2-methylbutyl. In certain embodiments, Re3 is pentyl. In certain embodiments, Re3 is 2- methylpentyl. In certain embodiments, Re3 is 3-methylpentyl. In certain embodiments, Re3 is 4-methylpentyl. In certain embodiments, Re3 is hexyl. In certain embodiments, Re3 is 2- propylpentyl. In certain embodiments, Re3 is benzyl. In certain embodiments, Re3 is phenyl. In certain embodiments, Re4 is H. In certain embodiments, Re4 is methyl. In certain embodiments, Re4 is ethyl. In certain embodiments, Re4 is propyl. In certain embodiments, Re4 is isobutyl. In certain embodiments, Re4 is butyl. In certain embodiments, Re4 is neopentyl. In certain embodiments, Re4 is 3,3-dimethylbutyl. In certain embodiments, Re4 is 2-methylbutyl. In certain embodiments, Re4 is pentyl. In certain embodiments, Re4 is 2- methylpentyl. In certain embodiments, Re4 is 3-methylpentyl. In certain embodiments, Re4 is 4-methylpentyl. In certain embodiments, Re4 is hexyl. In certain embodiments, Re4 is 2- propylpentyl. In certain embodiments, Re4 is benzyl. In certain embodiments, Re4 is phenyl. In certain embodiments, Rf1 is methyl. In certain embodiments, Rf1 is ethyl. In certain embodiments, Rf1 is propyl. In certain embodiments, Rf1 is isobutyl. In certain embodiments, Rf1 is butyl. In certain embodiments, Rf1 is neopentyl. In certain embodiments, Rf1 is 3,3-dimethylbutyl. In certain embodiments, Rf1 is 2-methylbutyl. In certain embodiments, Rf1 is pentyl. In certain embodiments, Rf1 is 2-methylpentyl. In certain embodiments, Rf1 is 3-methylpentyl. In certain embodiments, Rf1 is 4-methylpentyl. In certain embodiments, Rf1 is hexyl. In certain embodiments, Rf1 is 2-propylpentyl. In certain embodiments, Rf1 is propargyl. In certain embodiments, Rf1 is benzyl. In certain embodiments, Rf1 is phenyl. In certain embodiments, Rf1 is methoxy. In certain embodiments, Rf1 is ethoxy. In certain embodiments, Rf1 is propoxy. In certain embodiments, Rf1 is isobutyloxy. In certain embodiments, Rf1 is butoxy. In certain embodiments, Rf1 is neopentoxy. In certain embodiments, Rf1 is 3,3-dimethylbutoxy. In certain embodiments, Rf1 is 2-methylbutoxy. In certain embodiments, Rf1 is pentoxy. In certain embodiments, Rf1 is 2-methylpentoxy. In certain embodiments, Rf1 is 3- methylpentoxy. In certain embodiments, Rf1 is 4-methylpentoxy. In certain embodiments, Rf1 is hexoxy. In certain embodiments, Rf1 is 2-propylpentoxy. In certain embodiments, Rf1 is propargyloxy. In certain embodiments, Rf1 is benzyloxy. In certain embodiments, Rf1 is phenoxy. In certain embodiments, Rf2 is methyl. In certain embodiments, Rf2 is ethyl. In certain embodiments, Rf2 is propyl. In certain embodiments, Rf2 is isobutyl. In certain embodiments, Rf2 is butyl. In certain embodiments, Rf2 is neopentyl. In certain embodiments, Rf2 is 3,3-dimethylbutyl. In certain embodiments, Rf2 is 2-methylbutyl. In certain embodiments, Rf2 is pentyl. In certain embodiments, Rf2 is 2-methylpentyl. In certain embodiments, Rf2 is 3-methylpentyl. In certain embodiments, Rf2 is 4-methylpentyl. In certain embodiments, Rf2 is hexyl. In certain embodiments, Rf2 is 2-propylpentyl. In certain embodiments, Rf2 is propargyl. In certain embodiments, Rf2 is benzyl. In certain embodiments, Rf2 is phenyl. In certain embodiments, Rf2 is methoxy. In certain embodiments, Rf2 is ethoxy. In certain embodiments, Rf2 is propoxy. In certain embodiments, Rf2 is isobutyloxy. In certain embodiments, Rf2 is butoxy. In certain embodiments, Rf2 is neopentoxy. In certain embodiments, Rf2 is 3,3-dimethylbutoxy. In certain embodiments, Rf2 is 2-methylbutoxy. In certain embodiments, Rf2 is pentoxy. In certain embodiments, Rf2 is 2-methylpentoxy. In certain embodiments, Rf2 is 3- methylpentoxy. In certain embodiments, Rf2 is 4-methylpentoxy. In certain embodiments, Rf2 is hexoxy. In certain embodiments, Rf2 is 2-propylpentoxy. In certain embodiments, Rf2 is propargyloxy. In certain embodiments, Rf2 is benzyloxy. In certain embodiments, Rf2 is phenoxy. In certain embodiments, Rg1 is methyl. In certain embodiments, Rg1 is ethyl. In certain embodiments, Rg1 is propyl. In certain embodiments, Rg1 is isobutyl. In certain embodiments, Rg1 is butyl. In certain embodiments, Rg1 is neopentyl. In certain embodiments, Rg1 is 3,3-dimethylbutyl. In certain embodiments, Rg1 is 2-methylbutyl. In certain embodiments, Rg1 is pentyl. In certain embodiments, Rg1 is 2-methylpentyl. In certain embodiments, Rg1 is 3-methylpentyl. In certain embodiments, Rg1 is 4-methylpentyl. In certain embodiments, Rg1 is hexyl. In certain embodiments, Rg1 is 2-propylpentyl. In certain embodiments, Rg1 is benzyl. In certain embodiments, Rg1 is and phenyl. In certain embodiments, Rg2 is methyl. In certain embodiments, Rg2 is ethyl. In certain embodiments, Rg2 is propyl. In certain embodiments, Rg2 is isobutyl. In certain embodiments, Rg2 is butyl. In certain embodiments, Rg2 is neopentyl. In certain embodiments, Rg2 is 3,3-dimethylbutyl. In certain embodiments, Rg2 is 2-methylbutyl. In certain embodiments, Rg2 is pentyl. In certain embodiments, Rg2 is 2-methylpentyl. In certain embodiments, Rg2 is 3-methylpentyl. In certain embodiments, Rg2 is 4-methylpentyl. In certain embodiments, Rg2 is hexyl. In certain embodiments, Rg2 is 2-propylpentyl. In certain embodiments, Rg2 is benzyl. In certain embodiments, Rg2 is and phenyl. In certain embodiments, Rh1 is: -(CH2)r-O-(CH2)sCH3, wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH2- and -CH3 is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(C1- C6 alkyl)O(C1-C6 alkyl), -(C1-C6 alkyl)O(benzyl), and -(C1-C6 alkyl)O(C6-C10 aryl). In certain embodiments, Rh1 is O(CH2)2O(CH2)17CH3, octadecyloxyethyl (ODE). In certain embodiments, Rh1 is O(CH2)3O(CH2)15CH3, hexadecyloxypropyl (HDP). In certain embodiments, Rj1 is H. In certain embodiments, Rj1 is CN. In certain embodiments, Rj1 is CH2F. In certain embodiments, Rj1 is CHF2. In certain embodiments, Rj1 is CF3. In certain embodiments, Rj1 is OCF3. In certain embodiments, Rj1 is F. In certain embodiments, Rj1 is C1. In certain embodiments, Rj1 is I. In certain embodiments, Rj2 is H. In certain embodiments, Rj2 is CN. In certain embodiments, Rj2 is CH2F. In certain embodiments, Rj2 is CHF2. In certain embodiments, Rj2 is CF3. In certain embodiments, Rj2 is OCF3. In certain embodiments, Rj2 is F. In certain embodiments, Rj2 is C1. In certain embodiments, Rj2 is I. In certain embodiments, Rj3 is H. In certain embodiments, Rj3 is CN. In certain embodiments, Rj3 is CH2F. In certain embodiments, Rj3 is CHF2. In certain embodiments, Rj3 is CF3. In certain embodiments, Rj3 is OCF3. In certain embodiments, Rj3 is F. In certain embodiments, Rj3 is C1. In certain embodiments, Rj3 is I. In certain embodiments, Rj4 is H. In certain embodiments, Rj4 is CN. In certain embodiments, Rj4 is CH2F. In certain embodiments, Rj4 is CHF2. In certain embodiments, Rj4 is CF3. In certain embodiments, Rj4 is OCF3. In certain embodiments, Rj4 is F. In certain embodiments, Rj4 is C1. In certain embodiments, Rj4 is I. In certain embodiments, Rj5 is H. In certain embodiments, Rj5 is CN. In certain embodiments, Rj5 is CH2F. In certain embodiments, Rj5 is CHF2. In certain embodiments, Rj5 is CF3. In certain embodiments, Rj5 is OCF3. In certain embodiments, Rj5 is F. In certain embodiments, Rj5 is C1. In certain embodiments, Rj5 is I. In certain embodiments, the compound is a compound of formula (Ia):
Figure imgf000028_0001
wherein: G is selected from the group consisting of -P(=O)(ORA)-, -P(=O)(NRBRC)-, -C(=O)-, - S(=O)2-, -S(=O)-, and -C(RA)(RB)-. In certain embodiments, the compound is Ia-1). In certain embodiments, the compound is Ia-2). In certain embodiments, the compound is a-1’). In certain embodiments, the compound is Ia-1’’). In certain embodiments, the compound is Ia-2’). In certain embodiments, the compound is
Figure imgf000028_0002
(Ia-2’’). In certain embodiments, RA is selected from the group consisting of:
Figure imgf000029_0001
wherein: Rf1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation. In certain embodiments, RB is:
Figure imgf000029_0002
wherein: Rd1 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein Rd1 and RC may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; and Re1 is selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl. In certain embodiments, RB is In certain embodiments, RB is
Figure imgf000030_0001
In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is
Figure imgf000030_0002
In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), R B is R
Figure imgf000030_0003
n certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is
Figure imgf000030_0004
In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is
Figure imgf000031_0001
. In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In certain
Figure imgf000031_0003
embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is In Certain
Figure imgf000031_0002
embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is . In certain embodiments, in any one of (Ia-2), (Ia-2’), and (Ia-2’’), RB is . In certain embodiments, the compound of formula (Ia-2) is . In certain embodiments, the compound of formula (Ia-2’) is . In certain embodiments, the compound of formula (Ia-2’’) is . In certain embodiments, the RB substituent in any one of (Ia-2), (Ia-2’), and (Ia-2’’) has a (S)- configuration. In certain embodiments, the RB substituent in any one of (Ia-2), (Ia-2’), and (Ia-2’’) has a (R)-configuration. In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is . In certain embodiments, R1 is ethanoyl. In certain embodiments, R1 is propanoyl. In certain embodiments, R1 is isobutanoyl. In certain embodiments, R1 is butanoyl. In certain embodiments, R1 is neopentanoyl. In certain embodiments, R1 is 3,3-dimethyl-butanoyl. In certain embodiments, R1 is 2-methyl-butanoyl. In certain embodiments, R1 is pentanoyl. In certain embodiments, R1 is 2-methyl-pentanoyl. In certain embodiments, R1 is 3-methyl-pentanoyl. In certain embodiments, R1 is 4-methyl- pentanoyl. In certain embodiments, R1 is hexanoyl. In certain embodiments, R2 is H. In certain embodiments, R2 is F. In certain embodiments, R2 is CH3. In certain embodiments, R2 is CH2CH3. In certain embodiments, R2 is C≡CH. In certain embodiments, R2 is C=CH2. In certain embodiments, R2 is CH2OH. In certain embodiments, Ra1 is methyl. In certain embodiments, Ra1 is ethyl. In certain embodiments, Ra1 is propyl. In certain embodiments, Ra1 is isobutyl. In certain embodiments, Ra1 is butyl. In certain embodiments, Ra1 is neopentyl. In certain embodiments, Ra1 is 3,3- dimethylbutyl. In certain embodiments, Ra1 is 2-methylbutyl. In certain embodiments, Ra1 is pentyl. In certain embodiments, Ra1 is 2-methylpentyl. In certain embodiments, Ra1 is 3- methylpentyl. In certain embodiments, Ra1 is 4-methylpentyl. In certain embodiments, Ra1 is hexyl. In certain embodiments, Ra1 is ethanoyl. In certain embodiments, Ra1 is propanoyl. In certain embodiments, Ra1 is isobutanoyl. In certain embodiments, Ra1 is butanoyl. In certain embodiments, Ra1 is neopentanoyl. In certain embodiments, Ra1 is 3,3-dimethyl-butanoyl. In certain embodiments, Ra1 is 2-methyl-butanoyl. In certain embodiments, Ra1 is pentanoyl. In certain embodiments, Ra1 is 2-methyl-pentanoyl. In certain embodiments, Ra1 is 3-methyl- pentanoyl. In certain embodiments, Ra1 is 4-methyl-pentanoyl. In certain embodiments, Ra1 is hexanoyl. In certain embodiments, R3b is F. In certain embodiments, R3b is C1. In certain embodiments, R3b is ORa2. In certain embodiments, ORa2 is OH. In certain embodiments, ORa2 is OMe. In certain embodiments, Ra2 is methyl. In certain embodiments, Ra2 is ethyl. In certain embodiments, Ra2 is propyl. In certain embodiments, Ra2 is isobutyl. In certain embodiments, Ra2 is butyl. In certain embodiments, Ra2 is neopentyl. In certain embodiments, Ra2 is 3,3- dimethylbutyl. In certain embodiments, Ra2 is 2-methylbutyl. In certain embodiments, Ra2 is pentyl. In certain embodiments, Ra2 is 2-methylpentyl. In certain embodiments, Ra2 is 3- methylpentyl. In certain embodiments, Ra2 is 4-methylpentyl. In certain embodiments, Ra2 is hexyl. In certain embodiments, Ra2 is ethanoyl. In certain embodiments, Ra2 is propanoyl. In certain embodiments, Ra2 is isobutanoyl. In certain embodiments, Ra2 is butanoyl. In certain embodiments, Ra2 is neopentanoyl. In certain embodiments, Ra2 is 3,3-dimethyl-butanoyl. In certain embodiments, Ra2 is 2-methyl-butanoyl. In certain embodiments, Ra2 is pentanoyl. In certain embodiments, Ra2 is 2-methyl-pentanoyl. In certain embodiments, Ra2 is 3-methyl- pentanoyl. In certain embodiments, Ra2 is 4-methyl-pentanoyl. In certain embodiments, Ra2 is hexanoyl. In certain embodiments, R4b is H. In certain embodiments, R4b is F. In certain embodiments, R4b is C1. In certain embodiments, R5 is H. In certain embodiments, R6 is H. In certain embodiments, R7a is H. In certain embodiments, R7b is H. In certain embodiments, R7c is H. In certain embodiments, R8 is H. In certain embodiments, R8 is NH2 In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, X is CF. In certain embodiments, Y is N. In certain embodiments, Y is O. In certain embodiments, A1 is certain embodiments, A1 is
Figure imgf000034_0001
. In certain embodim
Figure imgf000034_0004
ents, A1 is . In certain embodiments, A1 is . In certain embodiments, A1 is In certain embodiments, A1 is
Figure imgf000034_0003
Figure imgf000034_0002
. In certain embodiments, each occurrence of alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, and aryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C24 alkyl, C3-C8 cycloalkyl, C3-C6 allyl, C3-C6 propargyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C6-C10 aryl), N(C6-C10 aryl)2, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, benzyl, phenyl, naphthyl, C2-C8 heterocyclyl, C(=O)H, C(=O)(C1-C6 alkyl), C(=O)(C6-C10 aryl), C(=O)O(benzyl), C(=O)(C3-C8 cycloalkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)O(C6-C10 aryl), OC(=O)H, OC(=O)(C1- C6 alkyl), OC(=O)(C6-C10 aryl), OC(=O)OH, OC(=O)O(C1-C6 alkyl), OC(=O)O(C6-C10 aryl), SH, S(C1-C6 alkyl), S(C6-C10 aryl), S(=O)(C1-C6 alkyl), S(=O)(C6-C10 aryl), S(=O)2OH, S(=O)2O(C1-C6 alkyl), S(=O)2O(C6-C10 aryl), S(=O)2(C1-C6 alkyl), S(=O)2(C6-C10 aryl), S(=O)2NH2, S(=O)2NH(C1-C6 alkyl), S(=O)2N(C1-C6 alkyl)2, S(=O)2NH(C6-C10 aryl), S(=O)2N(C6-C10 aryl)2, S(=O)2NHC(=O)NH2, S(=O)2N(C1-C6 alkyl)C(=O)NH2, S(=O)2NHC(=O)NH(C1-C6 alkyl), S(=O)2N(C1-C6 alkyl)C(=O)NH(C1-C6 alkyl), S(=O)2NHC(=O)NH(C6-C10 aryl), NHS(=O)2(C1-C6 alkyl), N(C1-C6 alkyl)S(=O)2(C1-C6 alkyl), NHS(=O)2(C6-C10 aryl), N(C1-C6 alkyl)S(=O)2(C6-C10 aryl), NHC(=O)H, NHC(=O)(C1-C6 alkyl), N(C1-C6 alkyl)C(=O)(C1-C6 alkyl), NHC(=O)(C6-C10 aryl), N(C1-C6 alkyl)C(=O)(C6-C10 aryl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, C(=O)NH(C6-C10 aryl), C(=O)N(C1-C6 alkyl)(C6-C10 aryl), and C(=O)N(C6-C10 aryl)2. In certain embodiments, the optional substituent in the optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted benzyl, or optionally substituted aryl is further optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 heteroalkyl, halogen, CN, NO2, OH, O(C1-C6 alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, NH(C=NH)NH2, and imidazolyl. In certain embodiments, the compound is selected from the group consisting of: (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-methoxytetrahydrofuran-3-ol; ((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4S,5R)-2-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; ((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4R,5R)-4-fluoro-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol; and (2R,3R,4R,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate); or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof. The compounds of the disclosure may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. The compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. A compound illustrated herein by the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof. In certain embodiments, the compounds of the disclosure exist as tautomers. All tautomers are included within the scope of the compounds recited herein. Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36C1, 18F, 123I, 125I, 13N, 15N, 15O, 17O, 18O, 32P, and 35S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed disclosure. The compounds of the disclosure may contain any of the substituents, or combinations of substituents, provided herein. Salts The compounds described herein may form salts with acids or bases, and such salts are included in the present disclosure. The term "salts" embraces addition salts of free acids or bases that are useful within the methods of the disclosure. The term "pharmaceutically acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. In certain embodiments, the salts are pharmaceutically acceptable salts. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present disclosure, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the disclosure. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, 2-hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric, galacturonic acid, glycerophosphonic acids and saccharin (e.g., saccharinate, saccharate). Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with respect to any compound of the disclosure. Suitable pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N- methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. Combination Therapies In one aspect, the compounds of the disclosure are useful within the methods of the disclosure in combination with one or more additional agents useful for treating a coronavirus infection. These additional agents may comprise compounds or compositions identified herein, or compounds (e.g., commercially available compounds) known to treat, prevent, or reduce the symptoms of a coronavirus infection. Non-limiting examples of one or more additional agents useful for treating coronavirus infection include: (a) RNA-dependent RNA polymerase (RdRp) inhibitors; and (b) protease inhibitors. (a) RNA-dependent RNA polymerase (RdRp) inhibitors In certain embodiments, the RdRp inhibitor prevents or reduces formation and/or function of the nsp12-nsp8-nsp7 complex. In certain embodiments, the RdRp inhibitor is a nsp12 inhibitor. Reported RdRp inhibitors include, but are not limited to remdesivir, molnupiravir, 4’- fluorouridine, and sangivamycin. Reported RdRp inhibitors further include, but are not limited to (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((isobutyryloxy)methyl)tetrahydrofuran- 3,4-diyl bis(2-methylpropanoate) (i.e., GS-621763) as described in Nat. Commun.2021, 12:6415, which is incorporated herein by reference in its entirety. Reported RdRp inhibitors further include, but are not limited to isopropyl ((S)- (((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4- methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (i.e., AT-511), as described in U.S. Patent No.10,874,687, which is incorporated herein by reference in its entirety, and/or a sulfuric acid salt thereof (i.e., AT-527). Reported RdRp inhibitors further include ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((S)-3-(benzyloxy)- 2-((octadecyloxy)methyl)propyl) hydrogen phosphate (i.e., ODBG-P-RVn), as described in Antimicrob. Agents Chemother.2021, 65(10):e01155-21, which is incorporated herein by reference in its entirety. RdRp inhibitors further include, but are not limited to prodrugs of the above- mentioned RdRp inhibitors, for example as described in Int’l Patent Appl. Pub. No. WO2021262826, which is incorporated herein by reference in its entirety. (b) Protease inhibitors In certain embodiments, the protease inhibitor inhibits the 3-chymotrypsin-like cysteine protease (3CLpro), main protease (Mpro), and/or nonstructural protein 5 (nsp5). Reported protease inhibitors include, but are not limited to, paxlovid (i.e. nirmatrelvir and ritonavir), lufotrelvir (i.e., PF07304814), S-217622, PBI-0451, EDP-235, ALG-097431, and other Mpro inhibitors, as described in U.S. Patent Nos.11,174,231 and 11,124,497; Int’l Patent Appl. Pub. Nos. WO2021250648, WO2021205298, WO2021252491, WO2021212039, WO2021252644, and WO2022020242; and doi: https://doi dot org/10 dot 1101/2022 dot 01 dot 26 dot 477782; all of which are incorporated herein by reference in their entireties. Synthesis The present disclosure further provides methods of preparing the compounds of the present disclosure. Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It is appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, and so forth) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC). Preparation of the compounds can involve protection/deprotection of various chemical groups. Need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes. The reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. A compound of formula (I) can be prepared from commercially available or previously documented starting materials, for example, according to the synthetic methods outlined in Scheme 1, wherein R1, R2, R3a, R3b, R4a, R4b, R5, R6, R7a, R7b, R7c, R8, X, Y, LG1, LG2, and LG3 are defined within the scope of the present disclosure.
Figure imgf000042_0001
Scheme 1 Intermediate nucleoside analogs IV can be prepared from heteroaromatic pyrimidine derivatives II and substituted tetrahydrofuran derivatives III by a coupling reaction, wherein LG1 in III is a suitable leaving group, non-limiting examples including, a halogen, hydroxy, alkyloxy, acyloxy, triflate, tosylate, mesylate, and the like, in the presence of a suitable catalyst such as, but not limited to, a Bronsted or Lewis acid, or an activating reagent, such as, but not limited to triphenylphosphine, DEAD, DIAD, TMAD, and the like. The coupling step is optionally followed by a deprotection step. Intermediate IV can be converted to a compound of formula (I) by employing, in any suitable order, any of the general transformations illustrated as examples, but not as limitations, in Scheme 1 as deprotection, acylation, displacement of a suitable leaving group LG2 with an appropriate nucleophile (i.e., R7b-NH-Y-R7a or H2N-Y-R7a), followed by reaction of the resulting intermediate with a suitable electrophile reagent (e.g., R7b-LG3, wherein LG3 is a suitable leaving group), and separation of isomers as needed. The protocols incorporated elsewhere herein exemplify synthesis of representative compounds of the present invention. Analogous compounds can be synthesized in a similar fashion to those exemplified using the appropriately substituted intermediates and reagents. Methods The compounds described herein are effective for the treatment, prevention, and/or amelioration of an infection caused by one or more coronaviruses, non-limiting examples including an alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. In certain embodiments, the present disclosure provides a method of treating, ameliorating, and/or preventing a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure and/or at least one pharmaceutical composition of the present disclosure. In certain embodiments, the subject is further administered at least one additional agent useful for treating, ameliorating, and/or preventing the coronavirus infection. In certain embodiments, the subject is co-administered the at least one additional agent and the at least one compound and/or composition. In certain embodiments, the at least one additional agent and the at least one compound and/or composition are coformulated. In certain embodiments, the additional agent is selected from the group consisting of a RNA-dependent RNA polymerase (RdRp) inhibitor and a protease inhibitor. In certain embodiments, the coronavirus is an alphacoronavirus. In certain embodiments, the coronavirus is a betacoronavirus. In certain embodiments, the alphacoronavirus is Human coronavirus 229E (HCoV- 229E). In certain embodiments, the alphacoronavirus is Human coronavirus NL63 (HCoV- NL63). In certain embodiments, the betacoronavirus is Severe acute respiratory syndrome- related coronavirus 2 (SARS-CoV-2). In certain embodiments, the betacoronavirus is Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1). In certain embodiments, the betacoronavirus is Middle East respiratory syndrome-related coronavirus (MERS-CoV). In certain embodiments, the betacoronavirus is Human coronavirus OC43 (HCoV-OC43). In certain embodiments, the betacoronavirus is Human coronavirus HKU1 (HCoV-HKU1). In certain embodiments, the betacoronavirus is SARS-CoV-2. In certain embodiments, a coronavirus RNA polymerase is inhibited. In certain embodiments, the RNA polymerase comprises nonstructural protein 12 (nsp12). In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. Pharmaceutical Compositions and Formulations In certain embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection. The disclosure provides pharmaceutical compositions comprising at least one compound of the disclosure or a salt or solvate thereof, which are useful to practice methods of the disclosure. Such a pharmaceutical composition may consist of at least one compound of the disclosure or a salt or solvate thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the disclosure or a salt or solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. At least one compound of the disclosure may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. In certain embodiments, the pharmaceutical compositions useful for practicing the method of the disclosure may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In other embodiments, the pharmaceutical compositions useful for practicing the disclosure may be administered to deliver a dose of between 1 ng/kg/day and 1,000 mg/kg/day. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient. Pharmaceutical compositions that are useful in the methods of the disclosure may be suitably developed for nasal, inhalational, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, epidural, intrathecal, intravenous or another route of administration. A composition useful within the methods of the disclosure may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal or bird. Other contemplated formulations include projected nanoparticles, microspheres, liposomal preparations, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunologically- based formulations. In certain embodiments, the compositions of the disclosure are part of a pharmaceutical matrix, which allows for manipulation of insoluble materials and improvement of the bioavailability thereof, development of controlled or sustained release products, and generation of homogeneous compositions. By way of example, a pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction technologies, molecular complexes (e.g., cyclodextrins, and others), microparticulate, and particle and formulation coating processes. Amorphous or crystalline phases may be used in such processes. The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology and pharmaceutics. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-dose or multi-dose unit. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the disclosure is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs. In certain embodiments, the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of at least one compound of the disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g., RECOMBUMIN®), solubilized gelatins (e.g., GELOFUSINE®), and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey). The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, are included in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or fragrance-conferring substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic, anxiolytics or hypnotic agents. As used herein, "additional ingredients" include, but are not limited to, one or more ingredients that may be used as a pharmaceutical carrier. The composition of the disclosure may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the disclosure include but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid. The composition may include an antioxidant and a chelating agent which inhibit the degradation of the compound. Antioxidants for some compounds are BHT, BHA, alpha- tocopherol and ascorbic acid in the exemplary range of about 0.01% to 0.3%, or BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. The chelating agent may be present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Exemplary chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%, or in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are exemplary antioxidant and chelating agent, respectively, for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art. Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, acacia, and ionic or non-ionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the disclosure may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Powdered and granular formulations of a pharmaceutical preparation of the disclosure may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, ionic and non-ionic surfactants, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations. A pharmaceutical composition of the disclosure may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents. Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying. Methods for mixing components include physical milling, the use of pellets in solid and suspension formulations and mixing in a transdermal patch, as known to those skilled in the art. Administration/Dosing The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the patient either prior to or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions of the present disclosure to a patient, such as a mammal, such as a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 0.01 mg/kg to 100 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose is readily apparent to the skilled artisan and depends upon a number of factors, such as, but not limited to, type and severity of the disease being treated, and type and age of the animal. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease or disorder in a patient. In certain embodiments, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking all other factors about the patient into account. Compounds of the disclosure for administration may be in the range of from about 1 ^g to about 7,500 mg, about 20 ^g to about 7,000 mg, about 40 ^g to about 6,500 mg, about 80 ^g to about 6,000 mg, about 100 ^g to about 5,500 mg, about 200 ^g to about 5,000 mg, about 400 ^g to about 4,000 mg, about 800 ^g to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments there-in- between. In some embodiments, the dose of a compound of the disclosure is from about 0.5 ^g and about 5,000 mg. In some embodiments, a dose of a compound of the disclosure used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient. The term "container" includes any receptacle for holding the pharmaceutical composition or for managing stability or water uptake. For example, in certain embodiments, the container is the packaging that contains the pharmaceutical composition, such as liquid (solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized formulation present in dual chambers. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound's ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a patient. Administration Routes of administration of any of the compositions of the disclosure include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, emulsions, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein. Inhalational Administration Routes of administration of any of the compositions of the invention include nasal, inhalational, intratracheal, intrapulmonary, and intrabronchial. Suitable compositions and dosage forms include, for example, dispersions, suspensions, solutions, syrups, granules, beads, powders, pellets, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein. Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form a material that is suitable to administration to a subject. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations. A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles that comprise the active ingredient and have a diameter in the range from about 0.5 to about 7 micrometers, and preferably from about 1 to about 6 micrometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder- dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 micrometers and at least 95% of the particles by number have a diameter less than 7 micrometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 micrometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient). Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 micrometers. The pharmaceutical composition of the invention may be delivered using an inhalator such as those recited in U.S. Patent No. US 8,333,192 B2, which is incorporated herein by reference in its entirety. The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, capsules, caplets and gelcaps. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic, generally recognized as safe (GRAS) pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patents Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. The capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin from animal-derived collagen or from a hypromellose, a modified form of cellulose, and manufactured using optional mixtures of gelatin, water and plasticizers such as sorbitol or glycerol. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. For oral administration, the compounds of the disclosure may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents; fillers; lubricants; disintegrates; or wetting agents. If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY® White, 32K18400). It is understood that similar type of film coating or polymeric products from other companies may be used. A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface-active agents include, but are not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc. Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation." For example, solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated. Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution. U.S. Patent No.5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt. The present disclosure also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds useful within the methods of the disclosure, and a further layer providing for the immediate release of one or more compounds useful within the methods of the disclosure. Using a wax/pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release. Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non- aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a pharmaceutical composition of the disclosure which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use. Parenteral Administration As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Injectable formulations may also be prepared, packaged, or sold in devices such as patient-controlled analgesia (PCA) devices. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non- toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form in a recombinant human albumin, a fluidized gelatin, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. Topical Administration An obstacle for topical administration of pharmaceuticals is the stratum corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells. One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal. Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone. One acceptable vehicle for topical delivery of some of the compositions of the disclosure may contain liposomes. The composition of the liposomes and their use are known in the art (i.e., U.S. Patent No.6,323,219). In alternative embodiments, the topically active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, preservatives, and the like. In other embodiments, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, are known to those of skill in the art. In another aspect, the composition may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art. The topically active pharmaceutical composition should be applied in an amount effective to affect desired changes. As used herein "amount effective" shall mean an amount sufficient to cover the region of skin surface where a change is desired. An active compound should be present in the amount of from about 0.0001% to about 15% by weight volume of the composition. For example, it should be present in an amount from about 0.0005% to about 5% of the composition; for example, it should be present in an amount of from about 0.001% to about 1% of the composition. Such compounds may be synthetically-or naturally derived. Buccal Administration A pharmaceutical composition of the disclosure may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, may have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. The examples of formulations described herein are not exhaustive and it is understood that the disclosure includes additional modifications of these and other formulations not described herein, but which are known to those of skill in the art. Rectal Administration A pharmaceutical composition of the disclosure may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation. Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 20 ^C) and which is liquid at the rectal temperature of the subject (i.e., about 37 ^C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives. Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives. Additional Administration Forms Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos.6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos.20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the compositions and/or formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the disclosure may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In certain embodiments of the disclosure, the compounds useful within the disclosure are administered to a subject, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, include a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. EXAMPLES The disclosure is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the disclosure is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein. As described herein, "Diastereomer I" or “Epimer I” refers to the first diastereomer or epimer eluted from a chiral or achiral column under the specific analytical conditions detailed for examples provided elsewhere herein. As described herein, "Diastereomer II" or “Epimer II” refers to the second diastereomer or epimer eluted from the chiral or achiral column under the specific analytical conditions detailed for examples provided elsewhere herein. Such nomenclature does not imply or impart any particular relative and/or absolute configuration for these compounds. LCMS Methods LCMS Method A: Waters Acquity UPLC system employing a Waters Acquity UPLC BEH C18, 1.7 μm, 50 x 2.1 mm column with an aqueous acetonitrile based solvent gradient of 2-98% CH3CN/H2O (0.05 % TFA) over 9.5 mins. Flow rate = 0.8 mL/min. LCMS Method B: Waters Acquity UPLC system employing a Waters Acquity UPLC BEH C18, 1.7 μm, 50 x 2.1 mm column with an aqueous acetonitrile based solvent gradient of 2-98% CH3CN/H2O (0.05 % TFA) over 1.0 mins. Flow rate = 0.8 mL/min. LCMS Method C: Shimadzu UFLC system employing an ACE UltraCore Super PhenylHexyl, 2.5 μm, 50 x 2.1 mm column with an aqueous acetonitrile based solvent gradient of 5-100% CH3CN/H2O (0.05 % Formic acid) over 5.0 mins. Flow rate = 1.0 mL/min. LCMS Method D: Waters Acquity UPLC system employing a Waters Acquity UPLC BEH C18, 1.7 μm, 50 x 2.1 mm column with an aqueous acetonitrile based solvent gradient of 2-98% CH3CN/H2O (0.05 % TFA) over 5.0 mins. Flow rate = 0.8 mL/min. Example 1: (2R,3R,4S,5R)-2-(6-(Hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 1)
Figure imgf000064_0001
To a microwave vial equipped with a stir bar was added (2R,3R,4S,5R)-2-(6-chloro- 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVa) (250.0 mg, 0.87 mmol) and EtOH-Water (1:1, 3 mL) followed by hydroxylamine (50wt% in water, 0.58 mL, 8.72 mmol). The vial was capped, and the reaction mixture was heated at 60 °C in reaction block behind a blast shield overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated to give a tan resin. The resin was triturated with a mixture of MeOH/p- dioxane/Et2O (1:2:2 v/v/v). Additional p-dioxane/Et2O (1:2) was added and the resulting suspension was stirred vigorously at room temperature. The resulting solid was collected by filtration then dried under high vacuum to give (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H- purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (247 mg, 85% yield). LCMS m/z found 284.1 [M+H]+; RT = 0.33 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.05 (s, 1H), 5.96 (d, 1H), 4.69 – 4.63 (m, 1H), 4.30 (dd, 1H), 4.17 – 4.09 (m, 1H), 3.86 (dd, 1H), 3.74 (dd, 1H). Example 2: (2R,3R,4S,5R)-2-(2-Amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 2)
Figure imgf000064_0002
To a microwave vial equipped with a stir bar was added (2R,3R,4S,5R)-2-(2-amino-6- chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVb, 250 mg, 0.83 mmol) and EtOH-Water (1:1 v/v, 3 mL), followed by hydroxylamine (50 wt% in water, 0.55 mL, 8.3 mmol). The vial was capped, and the reaction mixture was heated at 60 °C in a reaction block behind a blast shield, overnight. The suspension was cooled to room temperature, the solid was filtered, rinsed with cold EtOH and dried under high vacuum to give (2R,3R,4S,5R)-2- (2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (145 mg, 58% yield). LCMS m/z found 299.2 [M+H]+; RT = 0.37 min (Method A).1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 5.81 (d, 1H), 4.63 (t, 1H), 4.28 (dd, 1H), 4.13 – 4.08 (m, 1H), 3.85 (dd, 1H), 3.73 (dd, 1H). Example 3: (2R,3R,4S,5R)-2-(5-Fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 3)
Figure imgf000065_0001
Step (1): (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diyl dibenzoate
Figure imgf000065_0002
To an oven dried round bottom flask equipped with a stir bar and rubber septum with gas inlet was added (2S,3R,4R,5R)-2-acetoxy-5-((benzoyloxy)methyl)tetrahydrofuran-3,4- diyl dibenzoate (IIIa, 6.47 g, 12.8 mmol), 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (IIa, 2.00 g, 11.7 mmol) and dry MeCN (20 mL). Both IIa and IIIa were co-evaporated from dry toluene (3 x 20 mL) and subjected to high vacuum overnight prior to use. To the resulting suspension was added dropwise N,O-bis(trimethylsilyl)acetamide (4.30 mL, 17.5 mmol) and the mixture was stirred for 30 minutes then trimethylsilyl trifluoromethanesulfonate (2.54 mL, 14.0 mmol) was added dropwise. The mixture was stirred for 15 minutes then heated at 80 °C for 1 hour under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and washed with sat. aq. NaHCO3 (25 mL), sat. aq. NaC1 (10 mL), then dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes) to give (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diyl dibenzoate (1.61 g, 22% yield)LCMS m/z found 616.1 [M+H]+; RT = 4.05 min (Method C). Step (2): (2R,3R,4S,5R)-2-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVc)
Figure imgf000066_0001
In a cooled round bottom flask equipped with a stir bar and rubber septum (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diyl dibenzoate (900.0 mg, 1.46 mmol) was treated dropwise at 0-5 °C with ammonia (7N in MeOH, 10.0 mL, 70.0 mmol). The mixture was stirred at 0-5 °C until a solution resulted, then allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure, with water bath at 30 °C. The product was purified by column chromatography (Silica gel, 0-15% MeOH/CH2C12) to give (2R,3R,4S,5R)-2-(4- chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVc, 224.6 mg, 44% yield, 88% purity) as an off-white solid, containing the byproduct (2R,3R,4S,5R)-2-(5-fluoro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol. The recovered material was used without further purification. LCMS m/z found 304.1 [M+H]+; RT = 1.93 min (Method D).1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.79 (d, 1H), 6.36 (d, 1H), 4.45 (t, 1H), 4.30 – 4.24 (m, 1H), 4.08 (q, 1H), 3.83 (dd, 1H), 3.74 (dd, 1H). Step (3): (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol
Figure imgf000066_0002
To a microwave vial equipped with a stir bar was added (2R,3R,4S,5R)-2-(4-chloro- 5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVc, 50.0 mg, 0.16 mmol) and p-dioxane (1 mL) followed by hydroxylamine (50 wt% in water, 0.11 mL, 1.7 mmol). The vial was capped, and the reaction mixture was heated at 60 °C in a reaction block behind a blast shield overnight. The reaction mixture was cooled to room temperature and evaporated to dryness to give a resin. The resin was triturated with MeOH and CH2C12 to give (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (29.3 mg, 59% yield) . LCMS m/z found 301.1 [M+H]+; RT = 0.42 min (Method A).1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.07 (s, 1H), 6.01 (d, 1H), 4.41 (t, 1H), 4.21 (dd, 3.3 Hz, 1H), 4.03 (q, 1H), 3.80 (dd, 1H), 3.70 (dd, 1H). Example 4: (2R,3R,4R,5R)-5-(5-Fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol (Compound 4)
Figure imgf000067_0001
Step (1): (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3,4-diol
Figure imgf000067_0002
To a stirred, cooled solution of D-(-)-ribose (25.0 g, 166.5 mmol) in dry methanol (350 mL) at 0 °C was added dropwise con. sulfuric acid (2.5 mL, 46.9 mmol). The pale- yellow mixture was stirred and allowed to slowly warm to room temperature. Reaction was monitored by TLC (9:1 v/v CH2C12-MeOH, with KMnO4 staining). The mixture was stirred at room temperature overnight, then cooled and neutralized by slow addition of solid NaOMe (5.0 g, 92.5 mmol). The suspension was stirred for 1 hour, then filtered through a plug of Celite®, rinsed with MeOH and the solvent was evaporated. The residue was co-evaporated with toluene (2 x 100 mL) and subjected to high vacuum for 16 hours to give crude (2R,3S,4R)-2-(hydroxymethyl)-5-methoxy-tetrahydrofuran-3,4-diol (28.0 g) as a clear yellow syrup, as a mixture of anomers (~2.9:1). The recovered material was used without further purification. Step (2): (2R,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5- methoxytetrahydrofuran
Figure imgf000068_0001
Sodium hydride (60 wt% in mineral oil, 23.9 g, 597 mmol) was added portionwise (~1g x 24) to a cooled mixture of crude (2R,3S,4R)-2-(hydroxymethyl)-5-methoxy- tetrahydrofuran-3,4-diol (28.0 g, 170.6 mmol) and benzyl bromide (67.0 mL, 562.9 mmol) in dry DMF (500 mL) at 0-5 °C. The mixture was stirred and slowly warmed to room temperature under nitrogen, overnight. The mixture was concentrated (water bath at 67 °C and vacuum at 25-30 mbar). The residue was cooled to room temperature then to 0-5 °C and carefully quenched with aq. HC1 solution (1.0 M, 200 mL) while stirring, then mixed with Et2O (300 mL). The layers were separated. The aqueous phase was extracted with Et2O (2 x 100 mL). The combined Et2O layers were washed with water (3 x 50 mL), sat. aq. NaHCO3 (3 x 50 mL) and sat. aq. NaC1 solution (50 mL), dried over MgSO4, filtered, and the solvent was evaporated. The recovered cloudy, yellow oil was diluted with MeCN (300 mL) and washed with Hexanes (2 x 100 mL). The MeCN layer was evaporated to give a crude, amber oil (73 g). Purification was performed by column chromatography (Silica gel, 15% EtOAc/Hexanes) to give (2R,3R,4R)-3,4-dibenzyloxy-2-(benzyloxymethyl)-5-methoxy- tetrahydrofuran (44.6 g, 48% yield) . The recovered material was used without further purification. LCMS m/z found 457.2 [M+Na]+; RT = 3.83 min (Method C). Step (3): (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxytetrahydrofuran-3- ol
Figure imgf000068_0002
To a cooled solution of crude (2R,3R,4R)-3,4-dibenzyloxy-2-(benzyloxymethyl)-5- methoxy-tetrahydrofuran (6.20 g, 14.27 mmol) in dry CH2C12 (100 mL) at 0-5 °C was added dropwise tin(IV) chloride (1.0 M in CH2C12, 15.7 mL, 15.7 mmol) by syringe. The mixture was stirred at 0-5 °C overnight under nitrogen, then cooled to 0-5 °C and water (10 mL) was added dropwise. The mixture was stirred for 15 minutes then diluted further with water (150 mL) and the layers were separated. The organic layer was washed with water (150 mL), aq. HC1 solution (0.05N, 100 mL), sat. aq. NaHCO3 solution, sat. aq. NaC1 solution, then dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 25% EtOAc/Hexanes) to give (3R,4S,5R)-4-(benzyloxy)-5- ((benzyloxy)methyl)-2-methoxytetrahydrofuran-3-ol (2.96 g, 60% yield) as a yellow oil. LCMS m/z found 367.1 [M+Na]+; RT = 3.08 min (Method C).1H NMR (400 MHz, CDC13) δ 7.41 –7.19 (m, 10H), 4.89 (d, 1H), 4.72 (d, 1H), 4.57 (d, 1H), 4.51 (d, 1H), 4.45 (d, 1H), 4.19 –4.07 (m, 2H), 3.78 (dd, 1H), 3.48 (s, 3H), 3.43 (dd, 1H), 3.35 (dd, 1H), 2.94 (d, 1H). Step (4): (2R,3R,4R)-3-(benzyloxy)-2-((benzyloxy)methyl)-4,5- dimethoxytetrahydrofuran
Figure imgf000069_0001
To a suspension of (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2- methoxytetrahydrofuran-3-ol (0.50 g, 1.46 mmol) and cesium carbonate (4.75 g, 14.6 mmol) in dry DMF (5 mL) was added iodomethane (907 ^L, 14.6 mmol). The mixture was stirred at room temperature overnight. The mixture was cooled, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (2 x 25 mL), sat. aq. NaC1 (15 mL), dried over Na2SO4, filtered, and the solvent was evaporated to give crude (2R,3R,4R)-3-(benzyloxy)-2-((benzyloxy)methyl)-4,5- dimethoxytetrahydrofuran (0.49 g, 93% yield) as a yellow oil. The recovered material was used without further purification. LCMS m/z found 381.1 [M+Na]+; RT = 3.17 min (Method C). Step (5): (3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-methoxytetrahydrofuran-2- ol (IIIb)
Figure imgf000069_0002
To a mixture of crude (2R,3R,4R)-3-(benzyloxy)-2-((benzyloxy)methyl)-4,5- dimethoxytetrahydrofuran (670 mg, 1.87 mmol) in TFA (9 mL) at 0-5 °C was added dropwise water (1 mL). The mixture was stirred and slowly warmed to room temperature over 2 hours. The reaction mixture was evaporated to dryness. The residue was co-evaporated with toluene (3 x 10 mL) and the residue was subjected to high vacuum overnight to give crude (3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-methoxytetrahydrofuran-2-ol (IIIb, 630 mg, 97% yield) as a clear oil (mixture of anomers). The recovered material was used without further purification. LCMS m/z found 367.1 [M+Na]+; RT = 3.01 min (Method C). Step (6): 7-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3- methoxytetrahydrofuran-2-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
Figure imgf000070_0001
To a cooled, stirred solution of crude (3R,4R,5R)-4-(benzyloxy)-5- ((benzyloxy)methyl)-3-methoxytetrahydrofuran-2-ol (IIIb, 630 mg, 1.83 mmol), triphenylphosphine (720 mg, 2.74 mmol) and 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (IIa, 314 mg, 1.83 mmol) in dry THF (10 mL) at 0-5 °C was added dropwise DIAD (0.54 mL, 2.7 mmol). The reaction mixture was stirred at room temperature for 1 hour. The orange- brown reaction mixture was evaporated to dryness. The product was purified by column chromatography (Silica gel, 20% EtOAc/Hexanes). The first eluting epimer was consistent for desired 7-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3- methoxytetrahydrofuran-2-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine: pale-yellow resin (330 mg, 36% yield). LCMS m/z found 498.2 [M+H]+; RT = 3.94 min (Method C).1H NMR (400 MHz, CDC13) δ 8.60 (s, 1H), 7.45 (d, 1H), 7.43 – 7.28 (m, 10H), 6.56 – 6.50 (m, 1H), 4.72 – 4.50 (m, 4H), 4.36 – 4.29 (m, 1H), 4.27 – 4.20 (m, 1H), 3.99 – 3.93 (m, 1H), 3.85 (dd, 2.6 Hz, 1H), 3.63 (dd, 1H), 3.45 (s, 3H). Step (7): (2R,3R,4R,5R)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-methoxytetrahydrofuran-3-ol (IVd)
Figure imgf000071_0001
7-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-methoxytetrahydrofuran- 2-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (first eluting epimer, 330 mg) was dissolved in dry CH2C12 (5 mL) and cooled to 0-5 °C followed by dropwise addition of BC13 (1.0 M in CH2C12, 1.5 mL). The mixture was stirred at 0-5 °C for 30 minutes, then the reaction was quenched by dropwise addition of MeOH (3 mL) at 0-5 °C, followed by stirring for additional 15 minutes. The mixture was evaporated to give crude (2R,3R,4R,5R)-5-(4- chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)-4- methoxytetrahydrofuran-3-ol (IVd) (198 mg, 34% yield) as a yellow resin. The recovered material was used in the next step without further purification. LCMS m/z found 318.0 [M+H]+; RT = 2.21 min (Method C). Step (8): (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol
Figure imgf000071_0002
To a mixture of crude (2R,3R,4R,5R)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol (IVd, 50.0 mg, 0.16 mmol) in p-dioxane (0.5 mL) was added hydroxylamine (50 wt% in water, 0.50 mL, 7.6 mmol). The vial was sealed and heated at 60 °C behind a blast shield for 36 hours. The mixture was evaporated to dryness. The product was purified by column chromatography (Silica gel, 0-20% MeOH/CH2C12). The desired fractions were collected, and the solvent was evaporated to give a clear resin. The recovered material was further purified by preparative TLC [20 cm x 20 cm, 1.5 mm, 20% MeOH/CH2C12]. The desired band was collected by extraction with 20% MeOH/CH2C12 to give, after drying in high vacuum overnight, (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-methoxytetrahydrofuran-3-ol (17.5 mg, 35% yield),. LCMS m/z found 315.1 [M+H]+; RT = 0.57 min (Method A).1H NMR (400 MHz, CD3OD) δ 7.51 (s, 1H), 6.99 (s, 1H), 6.10 (s, 1H), 4.38 – 4.33 (m, 1H), 4.15 – 4.04 (m, 1H), 4.04 – 4.00 (m, 1H), 3.83 – 3.75 (m, 1H), 3.70 (dd, 1H), 3.39 (s, 3H). Example 5: ((2R,3S,4R,5R)-5-(2-Amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 5)
Figure imgf000072_0001
Step (1): ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVf)
Figure imgf000072_0002
To a solution of (2R,3R,4S,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVe, 1.00 g, 3.31 mmol) and 2,2- dimethoxypropane (2.10 mL, 16.6 mmol) in dry DMF (10 mL) was added p-toluenesulfonic acid monohydrate (1.89 g, 9.94 mmol). The mixture was stirred at room temperature overnight, then diluted with EtOAc (100 mL), washed with water (3 x 50 mL) and a sat. aq. NaC1 solution. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The material was purified by column chromatography (Silica gel, 1:1 Hexanes/Acetone) to give ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVf, 463 mg, 40% yield) . LCMS m/z found 341.9 [M+H]+; RT = 2.04 min (Method C).1H NMR (400 MHz, CDC13) δ 7.81 (s, 1H), 5.78 (d, 1H), 5.74 (d, 1H), 5.20 – 5.13 (m, 3H), 5.07 (d, 1H), 4.51 (s, 1H), 3.97 (d, 1H), 3.83 – 3.73 (m, 1H), 1.64 (s, 3H), 1.38 (s, 3H). Step (2): ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate
Figure imgf000073_0001
To a solution of ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVf, 100 mg, 0.29 mmol) and DMAP (3.6 mg, 0.03 mmol) in dry acetone (1 mL) was added dropwise DBU (48 ^L, 0.32 mmol). The mixture was stirred under nitrogen for 5 minutes then 2-methylpropanoyl 2- methylpropanoate (53 ^L, 0.32 mmol) was added dropwise. The mixture was stirred at room temperature under nitrogen for 2 hours. The volatiles were evaporated, and the residue was diluted with EtOAc (50 mL) and washed with sat. aq. NH4C1 solution (10 mL), water (10 mL), and sat. aq. NaC1 solution (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes) to give ((3aR,4R,6R,6aR)-6-(2-Amino-6-chloro-9H-purin-9- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (103 mg, 85% yield), as a clear resin. LCMS m/z found 412.2 [M+H]+; RT = 2.16 min (Method D).1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 6.13 (d, 1H), 5.48 (dd, 1H), 5.14 (dd, 1H), 4.47 – 4.38 (m, 1H), 4.34 (dd, 1H), 4.22 (dd, 1H), 2.52 – 2.40 (m, 1H), 1.58 (s, 3H), 1.39 (s, 3H), 1.11 – 1.03 (m, 6H). Step (3): ((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate
Figure imgf000073_0002
To a microwave vial equipped with a stir bar was added a solution of ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl isobutyrate (50 mg, 0.12 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 26 ^L, 0.39 mmol). The vial was sealed, and the mixture was heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the residue was subjected to high vacuum for 2 hours. The recovered material was taken directly into the next step. LCMS m/z found 409.3 [M+H]+; RT = 1.54 min (Method D).1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 6.09 (d, 1H), 5.40 (dd, 1H), 5.10 (dd, 1H), 4.42 (td, 1H), 4.29 – 4.25 (m, 2H), 2.49 (p, 1H), 1.57 (s, 3H), 1.38 (s, 3H), 1.11 – 1.06 (m, 6H). The crude residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The volatiles were evaporated. The product was purified by reverse phase HPLC (C18, 5-45% acetonitrile/water with 0.05% formic acid modifier) and lyophilized to give ((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (23 mg, 51% yield) as a white solid (formic acid salt). LCMS m/z found 369.3 [M+H]+; RT = 0.91 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.76 (s, 1H), 5.82 (d, 1H), 4.61 (t, 1H), 4.43 – 4.28 (m, 3H), 4.24 – 4.16 (m, 1H), 2.64 – 2.52 (m, 1H), 1.17 – 1.09 (m, 6H). Example 6 and 7: Isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Compound 6 and 7)
Figure imgf000074_0001
Step (1): isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate
Figure imgf000075_0001
To a stirred solution of ((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVf, 100.0 mg, 0.29 mmol) and isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (159 mg, 0.35 mmol) in dry THF (1 mL) and dry MeCN (0.1 mL) under nitrogen at room temperature was added dropwise 1-methylimidazole (70.0 ^L, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. Anhydrous MgC12 (27 mg, ~1 eq.) and DIPEA (100 ^L, ~2 eq.) were added. The reaction was stirred at room temperature under nitrogen for 2 days. The mixture was diluted with EtOAc (50 mL) and sat. aq. NH4C1 solution (10 mL). The layers were separated. The aqueous was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and sat. aq. NaC1 solution (10 mL), dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 50% Acetone/Hexanes, isocratic). The desired fractions were evaporated to a clear resin. The resin was further purified by preparative TLC (20 cm x 20 cm, 1.5 mm, 50% Acetone/Hexanes). The desired band was collected, extracted with 25% MeOH/CH2C12, the solvent was evaporated, and the residue subjected to high vacuum for 2 hours to give isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (72 mg, 40% yield) as a clear resin ( mixture of two diastereomers). The recovered material was used without further purification. LCMS m/z found 611.3 [M+H]+; RT = 2.50 min (minor) and 2.58 min (major) (Method D). Step (2): isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
Figure imgf000076_0001
A microwave vial equipped with a stir bar was charged with isopropyl ((((3aR,4R,6R,6aR)-6-(2-amino-6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (72 mg, 0.12 mmol) (mixture of phosphorous epimers ~3.7:1), IPA (1 mL), and hydroxylamine (50 wt% in water, 39 ^L, 0.59 mmol). The vial was sealed and heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the residue was subjected to high vacuum for 2 hours. LCMS m/z found 608.3 [M+H]+; RT = 1.95 min (minor) and 2.05 min (major) (Method D). The recovered material was used without further purification. The residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to give a tan resin. The product was purified and epimers were separated by reverse phase HPLC (10-50% acetonitrile:water w/ 0.05% formic acid as modifier) to give isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (first eluting, Epimer I, 6.1 mg, 9% yield) as a white solid (formic acid salt) and isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (second eluting, Epimer II, 17.2 mg, 25% yield) as white solid (formic acid salt). Epimer I (Compound 6): LCMS m/z found 568.2 [M+H]+; RT = 2.31 min (Method A); 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.76 (s, 1H), 7.36 – 7.27 (m, 2H), 7.24 – 7.12 (m, 3H), 5.82 (d, 1H), 4.56 (t, 1H), 4.47 – 4.30 (m, 3H), 4.25 – 4.19 (m, 1H), 3.91 – 3.79 (m, 1H), 1.27 (dd, 3H), 1.20 (dd, 6H); 31P NMR (162 MHz, CD3OD) δ 4.06. Epimer II (Compound 7): LCMS m/z found 568.2 [M+H]+; RT = 2.38 min (Method A); 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.76 (s, 1H), 7.37 – 7.28 (m, 2H), 7.26 – 7.13 (m, 3H), 5.81 (d, 1H), 4.59 (t, 1H), 4.44 – 4.24 (m, 3H), 4.22 – 4.16 (m, 1H), 3.94 – 3.82 (m, 1H), 1.29 (dd, 3H), 1.18 (dd, 6H); 31P NMR (162 MHz, CD3OD) δ 3.88. Example 8: ((2R,3S,4R,5R)-3,4-Dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Compound 8)
Figure imgf000077_0001
Step (1): ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVh)
Figure imgf000077_0002
To a solution of (2R,3R,4S,5R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVg, 1.00 g, 3.50 mmol) and 2,2- dimethoxypropane (2.20 mL, 17.5 mmol) in dry DMF (10 mL) was added p-toluenesulfonic acid monohydrate (2.00 g, 10.5 mmol). The mixture was stirred at room temperature overnight, then diluted with EtOAc (100 mL), washed with water (3 x 50 mL) and sat. aq. NaC1 solution (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The resulting residue was dried on high vacuum for 1 hour to give ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVh, 979 mg, 85% yield) . LCMS m/z found 325.9 [M+H]+; RT = 2.55 min (Method C).1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.85 (d, 1H), 6.72 (d, 1H), 6.38 (d, 1H), 5.20 (dd, 1H), 5.01 (dd, 1H), 4.29 (td, 1H), 3.76 (dd, 1H), 3.70 (dd, 1H), 1.61 (s, 3H), 1.37 (s, 3H). Step (2): ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate
Figure imgf000078_0001
To a solution of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVh, 100.0 mg, 0.31 mmol) and DMAP (3.8 mg, 0.03 mmol) in dry acetone (1 mL) was added dropwise DBU (51 ^L, 0.34 mmol). The mixture was stirred under nitrogen for 5 minutes then 2-methylpropanoyl 2- methylpropanoate (56 ^L, 0.34 mmol) was added dropwise. The mixture was stirred at room temperature under nitrogen overnight. The volatiles were evaporated, and the residue was diluted with EtOAc (50 mL) and washed with sat. aq. NH4C1 solution (10 mL), water (10 mL) and sat. aq. NaC1 solution (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes) to give ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (106 mg, 87% yield),. LCMS m/z found 396.2 [M+H]+; RT = 3.11 min (Method D).1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 7.71 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 5.39 (dd, 1H), 5.05 (dd, 1H), 4.44 – 4.36 (m, 1H), 4.31 – 4.18 (m, 2H), 2.52 (hept, 1H), 1.60 (s, 3H), 1.38 (s, 3H), 1.12 – 1.08 (m, 6H). Step (3): ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate
Figure imgf000078_0002
To a microwave vial equipped with a stir bar was added a solution of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (106 mg, 0.27 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 57 ^L, 0.86 mmol). The vial was sealed, and the mixture was heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the residue was subjected to high vacuum for 2 hours. The recovered material was taken directly into the next step. LCMS m/z found 377.2 [M+H]+; RT = 2.22 min (Method D). The residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated, and the product was purified by reverse phase HPLC (C18, 10-60% acetonitrile:water w/ 0.05% formic acid as modifier). The desired fractions were collected, frozen and lyophilized to give ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4- (hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate (36.4 mg, 34% yield) as an off-white solid. LCMS m/z found 353.1 [M+H]+; RT = 1.42 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.25 – 7.91 (m, 1H), 7.23 (d, 1H), 6.63 (d, 1H), 6.15 (d, 1H), 4.50 – 4.42 (m, 1H), 4.40 – 4.24 (m, 3H), 4.24 – 4.15 (m, 1H), 2.68 – 2.53 (m, 1H), 1.21 – 1.11 (m, 6H). Example 9: Isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Compound 9)
Figure imgf000079_0001
Step (1): isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)- L-alaninate
Figure imgf000080_0001
To a stirred solution of ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVh, 100 mg, 0.31 mmol), MgC12 (29 mg, 0.31 mmol), isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L- alaninate (167 mg, 0.37 mmol) in dry THF (1 mL), and dry MeCN (0.1 mL) under nitrogen at room temperature was added dropwise DIPEA (160 ^L, 0.92 mmol). The mixture was stirred at room temperature for 45 minutes. The mixture was diluted with EtOAc (50 mL) and sat. aq. NH4C1 solution. The layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL) and sat. aq. NaC1 solution (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes), to give isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (163 mg, 89% yield) as clear resin (single diastereomer). LCMS m/z found 595.1 [M+H]+; RT = 3.34 min (Method C).1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.67 (d, 1H), 7.36 – 7.28 (m, 2H), 7.22 – 7.13 (m, 3H), 6.68 (d, 1H), 6.37 (d, 1H), 5.25 (dd, 1H), 5.08 (dd, 1H), 4.43 – 4.37 (m, 1H), 4.33 – 4.18 (m, 2H), 3.89 – 3.77 (m, 1H), 1.61 (s, 3H), 1.37 (s, 3H), 1.26 (dd, 3H), 1.18 (dd, 6H).31P NMR (162 MHz, CD3OD) δ 3.57. Step (2): isopropyl ((S)-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate
Figure imgf000081_0001
A microwave vial equipped with a stir bar was charged with isopropyl ((S)- (((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (163 mg, 0.27 mmol), IPA (1 mL) and hydroxylamine (50 wt% in water, 91.0 ^L, 1.37 mmol). The vial was sealed and heated at 80 °C in a reaction block behind a blast shield overnight. The reaction mixture was evaporated to dryness. The recovered material was taken directly into the next step without further purification. LCMS m/z found 592.3 [M+H]+; RT = 2.60 min (Method D). The residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated, and the product was purified by reverse phase HPLC (C18, 10-50% acetonitrile:water w/ 0.05% formic acid as modifier) to give isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (68 mg, 40% yield). LCMS m/z found 552.2 [M+H]+; RT = 2.50 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.20 – 7.94 (m, 1H), 7.39 – 7.30 (m, 2H), 7.30 – 7.17 (m, 5H), 6.60 (d, 1H), 6.18 (d, 1H), 4.39 (t, 1H), 4.37 – 4.25 (m, 3H), 4.23 – 4.14 (m, 1H), 3.88 (dq, 1H), 1.29 (d, 3H), 1.21 – 1.16 (m, 6H).31P NMR (162 MHz, CD3OD) δ 3.70. Example 10: (2R,3R,4S,5R)-2-(4-(Hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 10)
Figure imgf000081_0002
A microwave vial equipped with a stir bar was charged with (2R,3R,4S,5R)-2-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (IVg, 50.0 mg, 0.18 mmol), IPA (1 mL) and hydroxylamine (50 wt% in water, 37 ^L, 0.56 mmol). The vial was sealed and heated at 80 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated and the product was purified by reverse phase HPLC (C18, 0- 25% acetonitrile/water w/ 0.05% formic acid modifier) to give (2R,3R,4S,5R)-2-(4- (hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4- diol (23 mg, 43% yield) as an off-white lyophilate. LCMS m/z found 283.1 [M+H]+; RT = 0.39 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.23 – 7.93 (m, 1H), 7.31 (d, 1H), 6.61 (d, 1H), 6.02 (d, 1H), 4.58 (dd, 1H), 4.26 (dd, 1H), 4.09 (q, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H). Example 11: (2R,3R,4S,5R)-2-(2-Amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 11)
Figure imgf000082_0001
Step (1): 7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2- amine
Figure imgf000082_0002
To a cooled solution of (3aR,4R,6R,6aR)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]- 2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (IIIc, 3.00 g, 9.85 mmol) and carbon tetrachloride (1.14 mL, 11.8 mmol) in dry THF (30 mL) at -78 °C was added dropwise tris(dimethylamino)phosphine (HMPT, 2.15 mL, 11.8 mmol). The solution was stirred at -78 °C until a gel formed then the mixture was slowly warmed to room temperature for 1 hour. The resulting yellow suspension was added to a previously prepared solution of sodium hydride (60wt% in mineral oil, 0.79 g, 20.7 mmol) and 4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-amine (IIb, 3.32 g, 19.7 mmol) in dry MeCN (200 mL) under nitrogen. The mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), aq. sat. NaC1 solution (2 x 50 mL) and dried over MgSO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 20% EtOAc/Hexanes) to give 7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2- amine (2.04 g, 45% yield) . LCMS m/z found 455.3 [M+H]+; RT = 3.83 min (Method D).1H NMR (400 MHz, DMSO) δ 7.29 (d, 1H), 6.80 (s, 2H), 6.36 (d, 1H), 6.10 (d, 1H), 5.15 (dd, 1H), 4.94 (dd, 1H), 4.10 – 4.04 (m, 1H), 3.71 – 3.63 (m, 2H), 1.50 (s, 3H), 1.30 (s, 3H), 0.80 (s, 9H), -0.04 – -0.08 (m, 6H). Step (2): ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVi)
Figure imgf000083_0001
To a stirred solution of 7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2- amine (2.04 g, 4.48 mmol) in dry THF (5 mL) was added dropwise TBAF (1.0 M in THF, 4.90 mL, 4.90 mmol) at room temperature for 20 minutes. The reaction mixture was evaporated to an oil and the product was purified by column chromatography (Silica gel, 125g, 40% EtOAc/Hexanes for 7 minutes then 50%EtOAc/Hexanes until product eluted completely) to give ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVi, 1.24 g, 81% yield). LCMS m/z found 341.1 [M+H]+; RT = 1.87 min (Method D).1H NMR (400 MHz, DMSO) δ 7.37 (d, 1H), 6.78 (s, 2H), 6.37 (d, 1H), 6.09 (d, 1H), 5.10 (dd, 1H), 5.02 (t, 1H), 4.92 (dd, 1H), 4.05 (td, 1H), 3.57 – 3.43 (m, 2H), 1.50 (s, 3H), 1.29 (s, 3H). Step (3): (2R,3R,4S,5R)-2-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol
Figure imgf000084_0001
In a microwave vial equipped with a stir bar was added a solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVi, 100 mg, 0.29 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 62 ^L, 0.94 mmol). The vial was sealed, and the mixture was heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the residue was subjected to high vacuum for 1 hour. The recovered material was taken directly into the next step. The residue was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to a brown resin. The residue was neutralized with ammonia in MeOH (7N, 3 mL). The mixture was stirred for 15 minutes, and the volatiles were evaporated. The product was purified by column chromatography (Silica gel, 0-25% MeOH/CH2C12). The recovered resin was lyophilized from ACN-Water (1:1, 1 mL) to give (2R,3R,4S,5R)-2-(2-amino-4- (hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4- diol (50 mg, 50% yield) (formic acid salt). LCMS m/z found 298.1 [M+H]+; RT = 0.46 min (Method A).1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.28 (s, 1H), 7.22 – 6.95 (m, 4H), 6.64 – 6.29 (m, 1H), 5.89 – 5.82 (m, 1H), 5.32 – 5.19 (m, 1H), 5.16 – 4.98 (m, 2H), 4.28 – 4.20 (m, 1H), 4.05 – 3.97 (m, 1H), 3.84 – 3.76 (m, 1H), 3.59 – 3.42 (m, 2H). Example 12: ((2R,3S,4R,5R)-5-(2-Amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 12)
Figure imgf000084_0002
Step (1): ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate
Figure imgf000085_0001
To a solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVi, 100 mg, 0.29 mmol) and DMAP (3.6 mg, 0.03 mmol) in dry acetone (1 mL) was added dropwise DBU (48 ^L, 0.32 mmol). The mixture was stirred under nitrogen atmosphere for 5 minutes then 2- methylpropanoyl 2-methylpropanoate (54 ^L, 0.32 mmol) was added dropwise. The mixture was stirred at room temperature under nitrogen for 2 hours, the volatiles were evaporated, and the residue was diluted with EtOAc (50 mL) and washed with sat. aq. NH4C1 solution (10 mL), water (10 mL) and sat. aq. NaC1 solution (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes) to give ((3aR,4R,6R,6aR)-6-(2-amino- 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate (112 mg, 92% yield) as a clear resin. LCMS m/z found 411.2 [M+H]+; RT = 2.81 min (Method D).1H NMR (400 MHz, DMSO) δ 7.30 (d, 1H), 6.83 (s, 2H), 6.37 (d, 1H), 6.10 (d, 1H), 5.21 (dd, 1H), 5.08 (dd, 1H), 4.28 – 4.16 (m, 2H), 4.07 (dd, 1H), 2.57 – 2.43 (m, 1H), 1.50 (s, 3H), 1.30 (s, 3H), 1.03 (d, 6H). Step (2): ((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate
Figure imgf000085_0002
To a microwave vial equipped with a stir bar was added a solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (112 mg, 0.27 mmol) in IPA (1 mL) followed by hydroxylamine (50 wt% in water, 57 ^L, 0.87 mmol). The vial was sealed, and the mixture was heated at 70 °C in a reaction block behind a blast shield overnight. The reaction mixture was evaporated and the product was purified by column chromatography (Silica gel, 0-20% MeOH/CH2C12). LCMS m/z found 407.9 [M+H]+; RT = 2.15 min (Method C). The resulting intermediate was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated and the product was purified by reverse phase HPLC (C18, 10-50% acetonitrile:water w/ 0.05% formic acid as modifier) to give ((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (9.1 mg, 8% yield) as an off-white solid (formic acid salt). LCMS m/z found 368.2 [M+H]+; RT = 1.51 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 6.89 – 6.82 (m, 1H), 6.49 – 6.39 (m, 1H), 6.04 – 5.96 (m, 1H), 4.41 – 4.33 (m, 2H), 4.30 – 4.21 (m, 2H), 4.18 – 4.10 (m, 1H), 2.66 – 2.54 (m, 1H), 1.18 – 1.14 (m, 6H). Example 13: Isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 13)
Figure imgf000086_0001
Step (1): isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
Figure imgf000087_0001
To a stirred solution of ((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (IVi, 100.0 mg, 0.29 mmol), MgC12 (28 mg, 0.29 mmol) and isopropyl ((S)- (perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (160 mg, 0.35 mmol) in dry THF (1 mL) under nitrogen at room temperature was added dropwise DIPEA (153 ^L, 0.88 mmol). The mixture was stirred at room temperature for 45 minutes, then diluted with EtOAc (50 mL) and sat. aq. NH4C1 solution (10 mL). The layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and sat. aq. NaC1 solution (10 mL), dried over Na2SO4, filtered, and the solvent was evaporated. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/Hexanes) to give isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (167 mg, 93% yield) as clear resin (single diastereomer). LCMS m/z found 610.3 [M+H]+; RT = 3.06 min (Method D).1H NMR (400 MHz, DMSO) δ 7.38 – 7.29 (m, 2H), 7.25 (d, 1H), 7.17 (d, 3H), 6.84 (s, 2H), 6.33 (d, 1H), 6.11 (d, 1H), 6.02 (dd, 1H), 5.13 (dd, 1H), 5.08 (dd, 1H), 4.85 – 4.74 (m, 1H), 4.26 – 4.18 (m, 2H), 4.07 – 3.96 (m, 1H), 3.80 – 3.67 (m, 1H), 1.50 (s, 3H), 1.29 (s, 3H), 1.15 (d, 3H), 1.12 – 1.07 (m, 6H).31P NMR (162 MHz, DMSO) δ 3.84. Step (2): isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)- L-alaninate
Figure imgf000088_0001
A microwave vial equipped with a stir bar was charged with isopropyl ((S)- (((3aR,4R,6R,6aR)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (167 mg, 0.27 mmol), IPA (1 mL) and hydroxylamine (50 wt% in water, 90.0 ^L, 1.37 mmol). The vial was sealed and heated at 70 °C in a reaction block behind a blast shield overnight. The volatiles were evaporated, and the product was purified by column chromatography (Silica gel, 0-20% MeOH/CH2C12). LCMS m/z found 607.0 [M+H]+; RT = 2.46 min (Method C). The resulting intermediate was dissolved in formic acid (1 mL) and stirred at room temperature overnight. The volatiles were evaporated and the product was purified by reverse phase HPLC (C18, 10-60% acetonitrile:water w/ 0.05% formic acid as modifier) to give isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (17 mg, 10% yield) as a white lyophilate (formic acid salt). LCMS m/z found 567.3 [M+H]+; RT = 2.56 min (Method A).1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 7.39 – 7.29 (m, 2H), 7.26 – 7.14 (m, 3H), 6.90 – 6.79 (m, 1H), 6.44 – 6.34 (m, 1H), 6.00 (t, 1H), 4.99 – 4.87 (m, 1H), 4.40 – 4.21 (m, 4H), 4.18 – 4.09 (m, 1H), 3.94 – 3.82 (m, 1H), 1.32 – 1.25 (m, 3H), 1.22 – 1.16 (m, 6H).31P NMR (162 MHz, CD3OD) δ 3.73. Example 14: (2R,3R,4R,5R)-4-Fluoro-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (Compound 14)
Figure imgf000088_0002
Step (1): 7-((2R,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3- fluorotetrahydrofuran-2-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (IVj)
Figure imgf000089_0001
To a solution of (3R,4R,5R)-4-benzyloxy-5-(benzyloxymethyl)-3-fluoro- tetrahydrofuran-2-ol (Larsen, C. et al. J. Am. Chem. Soc.2005, 127, 10879-10884; IIId, 1.0 g, 3 mmol) in THF (10 mL) was added 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (IIc, 0.5 g, 3 mmol), triphenylphosphine (2.4 g, 9 mmol) and (3E)-3-(dimethylcarbamoylimino)- 1,1-dimethyl-urea (TMAD; 0.8 g, 4.5 mmol). The mixture was stirred at room temperature for 12 h under a nitrogen. The reaction mixture was combined with another five batches at the same scale, and the combined mixture was filtered to give a residue. The residue was diluted with H2O (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduce pressure. The product was purified by column chromatography (Silica gel, 0-100% EtOAc/petroleum ether) to afford 7- [(2R,3R,4R,5R)-4-benzyloxy-5-(benzyloxymethyl)-3-fluoro-tetrahydrofuran-2-yl]-4-chloro- 5-fluoro-pyrrolo[2,3-d]pyrimidine (3.6 g, 39% yield).1H NMR (400 MHz, CDC13): δ.8.61 (s, 1H), 7.41 - 7.27 (m, 11H), 6.65 - 6.60 (m, 1H), 5.27 - 5.13 (m, 1H), 4.79 - 4.76 (m, 1H), 4.62 - 4.58 (m, 2H), 4.55 - 4.52 (m, 1H), 4.42 - 4.35 (m, 2H), 3.89 (dd, 1H), 3.67 (dd, 1H). Step (2): (2R,3R,4R,5R)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4- fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol (IVk)
Figure imgf000089_0002
To a solution of 7-[(2R,3R,4R,5R)-4-benzyloxy-5-(benzyloxymethyl)-3-fluoro- tetrahydrofuran-2-yl]-4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (IVj, 3.6 g, 7.4 mmol) in DCM (36 mL) was added boron trichloride (74 mL, 74 mmol, 1 M in DCM). The mixture was stirred at -78 °C for 0.5 h. The reaction mixture was diluted with MeOH (80 mL) and the pH was adjusted to 7 with triethylamine (25 mL) at -78 °C. The reaction mixture was concentrated under reduced pressure and the residue was suspended in H2O (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduce pressure. The product was purified by normal phase column chromatography (Silica gel, 0-100% EtOAc/petroleum ether) to afford (2R,3R,4R,5R)-5-(4- chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3- ol as a white solid (1.9 g, 82% yield).1H NMR (400 MHz, DMSO-d6): δ.8.73 (s, 1H), 8.02 (d, 1H), 6.52 (d, 1H), 5.74 (d, 1H), 5.34 - 5.19 (m, 2H), 4.42 - 4.33 (m, 1H), 4.05 - 3.97 (m, 1H), 3.79 - 3.59 (m, 2H). Step (3): (2R,3R,4R,5R)-4-fluoro-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol
Figure imgf000090_0001
A solution of (2R,3R,4R,5R)-5-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol (IVk, 25 mg, 0.08 mmol) in isopropanol (0.25 mL) was treated with hydroxylamine (50% wt. in water) (18 µL, 0.26 mmol) in a capped vial. The mixture was stirred at 70 ºC behind a blast shield for 16 h. The reaction was cooled, the volatiles were evaporated under reduce pressure, and the product was purified by preparative reverse-phase HPLC (C18, 0.1% FA, ACN/water 0-60%), followed by lyophilization to afford (2R,3R,4R,5R)-4-fluoro-5-(5-fluoro-4-(hydroxyamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol as a white solid (5.6 mg, 22.7% yield). LCMS: m/z found 303.1 [M+H]+, RT = 3.58 min, (Method A); 1H NMR (400 MHz, CD3OD): δ 8.32 (s, 1H), 7.70 (s, 1H), 7.07 (d, 1H), 6.30 (m, 1H), 5.12 (m, 1H), 4.44 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1H), 3.72 (m, 1H). Example 15: (2R,3R,4R,5R)-2-(2-Amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) (Compound 15)
Figure imgf000091_0001
Step (1): (2R,3R,4R,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)
Figure imgf000091_0002
To a cooled suspension of (2R,3R,4S,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (IVe, 1.00 g, 3.31 mmol), triethylamine (2.80 mL, 19.9 mmol) and DMAP (41 mg, 0.33 mmol) in dry MeCN (15 mL) at 0-5 °C was added dropwise isobutyric anhydride (1.65 mL, 9.94 mmol). The mixture was stirred and slowly warmed to room temperature over 2 hours. The mixture was evaporated to give an oil. The product was crystallized from IPA (10 mL) then stirred at room temperature for 1 hour. The solid was filtered and rinsed with cold IPA then dried under high vacuum to give (2R,3R,4R,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) (1.20 g, 70% yield) as a white solid. LCMS m/z found 512.3 [M+H]+; RT = 2.90 min (Method D).1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 6.13 (d, 1H), 6.01 (dd, 1H), 5.78 – 5.71 (m, 1H), 4.49 – 4.35 (m, 3H), 2.71 – 2.49 (m, 3H), 1.25 – 1.07 (m, 18H). Step (2): (2R,3R,4R,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate)
Figure imgf000092_0001
A microwave vial equipped with a stir bar was charged with (2R,3R,4R,5R)-2-(2- amino-6-chloro-9H-purin-9-yl)-5-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2- methylpropanoate) (200.00 mg, 0.39 mmol) and IPA (1 mL) followed by hydroxylamine (50 wt% in water, 83 ^L, 1.25 mmol). The vial was sealed and heated at 70 °C in a reaction block behind a blast shield for 4 hours. The reaction mixture was evaporated, and the product was purified by reverse phase HPLC (C18, 15-60% acetonitrile/water w/ 0.05% formic acid modifier) to give (2R,3R,4R,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) (26.4 mg, 13% yield) as a tan lyophilate (formic acid salt). LCMS m/z found 509.2 [M+H]+; RT = 3.68 min (Method A).1H NMR (400 MHz, CD3OD) δ 7.75 (br s, 1H), 6.14 (br s, 1H), 6.02 (br s, 1H), 5.81 (br s, 1H), 4.47-4.34 (m, 3H), 2.69 – 2.54 (m, 3H), 1.26 – 1.08 (m, 18H). Example 16: SARS-CoV-2 Assay Test compounds were serially diluted using eight half-log dilutions in test medium (MEM supplemented with 2% FBS and 50 μg/mL gentamicin). Each dilution was added to 5 wells of a 96-well plate with 80-100% confluent Vero E6 cells. Three wells of each dilution were infected with the SARS-CoV-2 virus, and two wells remained uninfected as toxicity controls. Six wells were infected and untreated as virus controls, and six wells were uninfected and untreated as cell controls. Viruses were prepared to achieve the lowest possible multiplicity of infection (MOI) that would yield >80% cytopathic effect (CPE) at 3 days. Plates were incubated at 37±2°C, 5% CO2. On day 3 post-infection, once untreated virus control wells reached maximum CPE, plates were stained with neutral red dye for approximately 2 hours (±15 minutes). Supernatant dye was removed, and wells rinsed with PBS, and the incorporated dye was extracted in 50:50 Sorensen citrate buffer/ethanol for >30 minutes and the optical density was read on a spectrophotometer at 540 nm. Optical densities were converted to percent of cell controls and normalized to the virus control, then the concentration of test compound required to inhibit CPE by 50% (EC50) was calculated by regression analysis. To exemplify, Compound 2 showed an inhibition of SARS-CoV-2 CPE in Vero E6 cells with EC50 = 19.4 µM. Table 1.
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0003
Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a compound of formula (I), or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof:
Figure imgf000095_0001
wherein: A1 is selected from the group consisting of nd 
Figure imgf000095_0002
Figure imgf000096_0001
X is selected from the group consisting of CRb1 and N; Y is selected from the group consisting of O and NR7c; R1 is selected from the group consisting of H, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); R2 is selected from the group consisting of H, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N3, and F; R3a is ORa1, wherein R1 and Ra1 may combine with the atoms to which they are bound to form a C3-C5 heterocyclyl; R3b is selected from the group consisting of H, C1, F, and ORa2, wherein Ra1 and Ra2 may combine with the atoms to which they are bound to form a C2-C5 heterocyclyl, and wherein if R3b is C1, then R4b is H; R4a is H; R4b is selected from the group consisting of H, C1, and F, wherein if R4b is C1, then R3b is H; R5 is selected from the group consisting of H, CN, halogen, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB, wherein R5 and R3b may combine with the atoms to which they are bound to form a C2-C6 heterocyclyl; R6 is selected from the group consisting of H, halogen, and C1-C3 haloalkyl; R7a, R7b, and R7c are each independently selected from the group consisting of H, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB; R8 is selected from the group consisting of H, halogen, and N(RA)(RB); RA, RB, RC, and RD are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, optionally substituted C1-C24 alkanoyl, optionally substituted C1-C23 heteroalkyl, optionally substituted C1-C23 heteroalkanoyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted benzyl, optionally substituted C6-C10 aryl, C(=O)(optionally substituted C1-C6 alkyl), C(=O)(optionally substituted C2-C8 heterocyclyl), and C(=O)(optionally substituted C6-C10 aryl, wherein any two selected from the group consisting of RA, RB, RC, and RD may combine with the atoms to which they are bound to form an optionally substituted C2- C6 heterocyclyl, wherein any two vicinal substituents in the optionally substituted C2-C6 heterocyclyl may combine with the atoms to which they are bound to form an optionally substituted C6-C10 aryl; Ra1 and Ra2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)-NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2-NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); Rb1 is selected from the group consisting of H, halogen, C1-C3 haloalkyl, and C(=O)NRANRB; and m is an integer selected from the group consisting of 0, 1, and 2. Embodiment 2 provides the compound of Embodiment 1, wherein R1 is selected from the group consisting of:
Figure imgf000097_0001
wherein: Rc1 is selected from the group consisting of optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rd1 and Rd2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein one or more of Rd1 and Re1, and Rd2 and Re3, may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; Re1, Re2, Re3, and Re4 are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl; Rf1 and Rf2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 and Rg2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation; Ri1, Ri2, Ri3, and Ri4, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted phenyl, wherein any two selected from the group consisting of Ri1, Ri2, Ri3, and Ri4 may combine with the atoms to which they are bound to form an optionally substituted C3- C8 cycloalkyl; and Rj1, Rj2, Rj3, Rj4, and Rj5, if present, are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, N(RA)(RB), C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, phenyl, C2-C8 heterocyclyl, C(=O)RA, C(=O)ORA, OC(=O)RA, OC(=O)ORA, SRA, S(=O)RA, S(=O)2RA, S(=O)2NRARB, S(=O)2N(RA)C(=O)NHRB, N(RB)- S(=O)2RC, N(RB)-C(=O)RC, and C(=O)-NRARB. Embodiment 3 provides the compound of Embodiment 2, wherein the benzyl, phenyl, naphthyl, or C2-C8 heterocyclyl in Rc1 is optionally substituted with at least one substituent. Embodiment 4 provides the compound of Embodiment 2 or 3, wherein R1 is selected from the group consisting of: , , , and . Embodiment 5 provides the compound of Embodiment 2 or 3, wherein R1 is selected from the group consisting of: , , , and . Embodiment 6 provides the compound of any one of Embodiments 2-5, wherein at least one of Rd1 and Rd2, if present, is selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, methanethioethyl, benzyl, 3-indolyl, hydroxymethyl, 1- hydroxyethyl, thiomethyl, 4-hydroxybenzyl, CH2C(=O)NH2, CH2CH2C(=O)NH2, CH2C(=O)OH, CH2CH2C(=O)OH, guanidinylpropyl, 4-imidazolyl, and aminobutyl. Embodiment 7 provides the compound of any one of Embodiments 2-4 and 6, wherein R1 is
Figure imgf000099_0001
. Embodiment 8 provides the compound of any one of Embodiments 2-6, wherein R1 is
Figure imgf000099_0002
selected from the group consisting of
Figure imgf000099_0003
and
Figure imgf000099_0004
Embodiment 9 provides the compound of Embodiment 1, wherein R1 is selected from the group consisting of: an
Figure imgf000100_0002
Figure imgf000100_0001
d . Embodiment 10 provides the compound of any one of Embodiments 2-6, wherein Re1, Re2, Re3, and Re4, if present, are each independently selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. Embodiment 11 provides the compound of Embodiment 2, wherein Rf1 and Rf2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3-dimethylbutoxy, 2-methylbutoxy, pentoxy, 2- methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, hexoxy, 2-propylpentoxy, propargyloxy, benzyloxy, and phenoxy. Embodiment 12 provides the compound of Embodiment 2, wherein Rg1 and Rg2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. Embodiment 13 provides the compound of Embodiment 2, wherein Rh1 is: -(CH2)r-O-(CH2)sCH3, wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH2- and -CH3 is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(C1-C6 alkyl)O(C1-C6 alkyl), -(C1-C6 alkyl)O(benzyl), and -(C1-C6 alkyl)O(C6-C10 aryl). Embodiment 14 provides the compound of Embodiment 2, wherein Rh1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP). Embodiment 15 provides the compound of Embodiment 2, wherein Rj1, Rj2, Rj3, Rj4, and Rj5, if present, are each independently selected from the group consisting of H, CN, CH2F, CHF2, CF3, OCF3, F, and C1. Embodiment 16 provides the compound of Embodiment 1, which is a compound of formula (Ia):
Figure imgf000101_0001
wherein: G is selected from the group consisting of -P(=O)(ORA)-, -P(=O)(NRBRC)-, -C(=O)-, - S(=O)2-, -S(=O)-, and -C(RA)(RB)-. Embodiment 17 provides the compound of Embodiment 1 or 16, which is selected from the group consisting of:
Figure imgf000101_0005
( ) nd
Figure imgf000101_0002
Embodiment 18 provides the compound of Embodiment 17, which is selected from the group consisting of:
Figure imgf000101_0003
Embodiment 19 provides the compound of Embodiment 17 or 18, wherein RA is selected from the group consisting of:
Figure imgf000101_0004
wherein: Rf1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation. Embodiment 20 provides the compound of Embodiment 19, wherein Rf1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3-dimethylbutoxy, 2-methylbutoxy, pentoxy, 2-methylpentoxy, 3- methylpentoxy, 4-methylpentoxy, hexoxy, 2-propylpentoxy, propargyloxy, benzyloxy, and phenoxy. Embodiment 21 provides the compound of Embodiment 19, wherein Rg1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. Embodiment 22 provides the compound of Embodiment 19, wherein Rh1 is: -(CH2)r-O-(CH2)sCH3, wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH2- and -CH3 is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(C1-C6 alkyl)O(C1-C6 alkyl), -(C1-C6 alkyl)O(benzyl), and -(C1-C6 alkyl)O(C6-C10 aryl). Embodiment 23 provides the compound of Embodiment 19, wherein Rh1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP). Embodiment 24 provides the compound of Embodiment 17 or 18, wherein RB is:
Figure imgf000103_0001
wherein: Rd1 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein Rd1 and RC may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; and Re1 is selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl. Embodiment 25 provides the compound of Embodiment 24, wherein RB is selected from the group consisting of:
Figure imgf000103_0002
Embodiment 26 provides the compound of Embodiment 24 or 25, wherein Rd1 is selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, methanethioethyl, benzyl, 3-indolyl, hydroxymethyl, 1-hydroxyethyl, thiomethyl, 4- hydroxybenzyl, CH2C(=O)NH2, CH2CH2C(=O)NH2, CH2C(=O)OH, CH2CH2C(=O)OH, guanidinylpropyl, 4-imidazolyl, and aminobutyl. Embodiment 27 provides the compound of any one of Embodiments 24-26, wherein Re1 is selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. Embodiment 28 provides the compound of Embodiment 1, wherein R1 is selected from the group consisting of ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3- dimethyl-butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl-pentanoyl, and hexanoyl. Embodiment 29 provides the compound of any one of Embodiments 1-28, wherein R2 is selected from the group consisting of H, F, CH3, CH2 CH3, C≡CH, C=CH2, and CH2OH. Embodiment 30 provides the compound of any one of Embodiments 1-15 and 29, wherein Ra1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl- butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl- pentanoyl, and hexanoyl. Embodiment 31 provides the compound of any one of Embodiments 1-30, wherein R3b is F. Embodiment 32 provides the compound of any one of Embodiments 1-30, wherein R3b is ORa2. Embodiment 33 provides the compound of Embodiment 32, wherein Ra2 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3- dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl-butanoyl, 2-methyl- butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl-pentanoyl, and hexanoyl. Embodiment 34 provides the compound of any one of Embodiments 1-33, wherein R4b is H. Embodiment 35 provides the compound of any one of Embodiments 1-34, wherein R5 is H. Embodiment 36 provides the compound of any one of Embodiments 1-35, wherein R8 is H or NH2. Embodiment 37 provides the compound of any one of Embodiments 1-36, wherein X is selected from the group consisting of N, CH, and CF. Embodiment 38 provides the compound of any one of Embodiments 1-37, wherein A1 is selected from the group consisting of
Figure imgf000104_0001
Embodiment 39 provides the compound of any one of Embodiments 1-38, wherein each occurrence of alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, and aryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C24 alkyl, C3-C8 cycloalkyl, C3-C6 allyl, C3-C6 propargyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C6-C10 aryl), N(C6-C10 aryl)2, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, benzyl, phenyl, naphthyl, C2-C8 heterocyclyl, C(=O)H, C(=O)(C1-C6 alkyl), C(=O)(C6-C10 aryl), C(=O)O(benzyl), C(=O)(C3-C8 cycloalkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)O(C6-C10 aryl), OC(=O)H, OC(=O)(C1-C6 alkyl), OC(=O)(C6- C10 aryl), OC(=O)OH, OC(=O)O(C1-C6 alkyl), OC(=O)O(C6-C10 aryl), SH, S(C1-C6 alkyl), S(C6-C10 aryl), S(=O)(C1-C6 alkyl), S(=O)(C6-C10 aryl), S(=O)2OH, S(=O)2O(C1-C6 alkyl), S(=O)2O(C6-C10 aryl), S(=O)2(C1-C6 alkyl), S(=O)2(C6-C10 aryl), S(=O)2NH2, S(=O)2NH(C1- C6 alkyl), S(=O)2N(C1-C6 alkyl)2, S(=O)2NH(C6-C10 aryl), S(=O)2N(C6-C10 aryl)2, S(=O)2NHC(=O)NH2, S(=O)2N(C1-C6 alkyl)C(=O)NH2, S(=O)2NHC(=O)NH(C1-C6 alkyl), S(=O)2N(C1-C6 alkyl)C(=O)NH(C1-C6 alkyl), S(=O)2NHC(=O)NH(C6-C10 aryl), NHS(=O)2(C1-C6 alkyl), N(C1-C6 alkyl)S(=O)2(C1-C6 alkyl), NHS(=O)2(C6-C10 aryl), N(C1- C6 alkyl)S(=O)2(C6-C10 aryl), NHC(=O)H, NHC(=O)(C1-C6 alkyl), N(C1-C6 alkyl)C(=O)(C1- C6 alkyl), NHC(=O)(C6-C10 aryl), N(C1-C6 alkyl)C(=O)(C6-C10 aryl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, C(=O)NH(C6-C10 aryl), C(=O)N(C1-C6 alkyl)(C6-C10 aryl), and C(=O)N(C6-C10 aryl)2. Embodiment 40 provides the compound of Embodiment 39, wherein each optional substituent in the alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, or aryl is further optionally substituted with at least one substituent selected from the group consisting of C1- C6 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 heteroalkyl, halogen, CN, NO2, OH, O(C1-C6 alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, NH(C=NH)NH2, and imidazolyl. Embodiment 41 provides the compound of any one of Embodiments 1-40, which is selected from the group consisting of: (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-methoxytetrahydrofuran-3-ol; ((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4S,5R)-2-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; ((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4R,5R)-4-fluoro-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol; and (2R,3R,4R,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate); or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof. Embodiment 42 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-41 and a pharmaceutically acceptable carrier. Embodiment 43 provides the pharmaceutical composition of Embodiment 42, further comprising at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection. Embodiment 44 provides a method of treating, ameliorating, and/or preventing a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of Embodiments 1-41 and/or at least one pharmaceutical composition of any one of Embodiments 42-43. Embodiment 45 provides the method of Embodiment 44, wherein the subject is further administered at least one additional agent useful for treating, ameliorating, and/or preventing the coronavirus infection. Embodiment 46 provides the method of Embodiment 45, wherein the subject is co- administered the at least one additional agent and the at least one compound and/or composition. Embodiment 47 provides the method of Embodiment 46, wherein the at least one additional agent and the at least one compound and/or composition are coformulated. Embodiment 48 provides the method of any one of Embodiments 45-47, wherein the additional agent is selected from the group consisting of a RNA-dependent RNA polymerase (RdRp) inhibitor and a protease inhibitor. Embodiment 49 provides the method of any one of Embodiments 44-48, wherein the coronavirus is selected from the group consisting of an alphacoronavirus and a betacoronavirus. Embodiment 50 provides the method of Embodiment 49, wherein the alphacoronavirus is selected from the group consisting of Human coronavirus 229E (HCoV- 229E) and Human coronavirus NL63 (HCoV-NL63). Embodiment 51 provides the method of Embodiment 49, wherein the betacoronavirus is selected from the group consisting of Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1). Embodiment 52 provides the method of Embodiment 51, wherein the betacoronavirus is SARS-CoV-2. Embodiment 53 provides the method of any one of Embodiments 44-52, wherein a coronavirus RNA polymerase is inhibited. Embodiment 54 provides the method of Embodiment 53, wherein the RNA polymerase comprises nonstructural protein 12 (nsp12). Embodiment 55 provides the method of any one of Embodiments 44-54, wherein the subject is a mammal. Embodiment 56 provides the method of Embodiment 55, wherein the mammal is a human. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

Claims

CLAIMS What is claimed is: 1. A compound of formula (I), or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof: wherein: A1 is selected from the group consisting of and 
Figure imgf000110_0001
Figure imgf000110_0002
; X is selected from the group consisting of CRb1 and N; Y is selected from the group consisting of O and NR7c; R1 is selected from the group consisting of H, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); R2 is selected from the group consisting of H, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N3, and F; R3a is ORa1, wherein R1 and Ra1 may combine with the atoms to which they are bound to form a C3-C5 heterocyclyl; R3b is selected from the group consisting of H, C1, F, and ORa2, wherein Ra1 and Ra2 may combine with the atoms to which they are bound to form a C2-C5 heterocyclyl, and wherein if R3b is C1, then R4b is H; R4a is H; R4b is selected from the group consisting of H, C1, and F, wherein if R4b is C1, then R3b is H; R5 is selected from the group consisting of H, CN, halogen, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB, wherein R5 and R3b may combine with the atoms to which they are bound to form a C2-C6 heterocyclyl; R6 is selected from the group consisting of H, halogen, and C1-C3 haloalkyl; R7a, R7b, and R7c are each independently selected from the group consisting of H, C1-C6 alkyl, CH2ORA, C(=O)RA, C(=O)ORA, and C(=O)NRARB; R8 is selected from the group consisting of H, halogen, and N(RA)(RB); RA, RB, RC, and RD are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, optionally substituted C1-C24 alkanoyl, optionally substituted C1-C23 heteroalkyl, optionally substituted C1-C23 heteroalkanoyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted benzyl, optionally substituted C6-C10 aryl, C(=O)(optionally substituted C1-C6 alkyl), C(=O)(optionally substituted C2-C8 heterocyclyl), and C(=O)(optionally substituted C6-C10 aryl, wherein any two selected from the group consisting of RA, RB, RC, and RD may combine with the atoms to which they are bound to form an optionally substituted C2- C6 heterocyclyl, wherein any two vicinal substituents in the optionally substituted C2-C6 heterocyclyl may combine with the atoms to which they are bound to form an optionally substituted C6-C10 aryl; Ra1 and Ra2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, C(=O)RA, C(=O)ORA, C(=S)SRA, C(=O)-NRARB, C(=NRA)-NRBRC, (P(=O)(ORA)O)mP(=O)(ORB)(ORC), P(=O)(ORA)(NRBRC), P(=O)(NRARB)(NRCRD), S(=O)2RA, S(=O)2ORA, S(=O)2-NRARB, S(=O)(=NRA)(NRBRC), S(=O)RA, and C(RA)(RB)(ORC); Rb1 is selected from the group consisting of H, halogen, C1-C3 haloalkyl, and C(=O)NRANRB; and m is an integer selected from the group consisting of 0, 1, and 2. 2. The compound of claim 1, wherein R1 is selected from the group consisting of:
an
Figure imgf000112_0001
wherein: Rc1 is selected from the group consisting of optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rd1 and Rd2 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein one or more of Rd1 and Re1, and Rd2 and Re3, may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; Re1, Re2, Re3, and Re4 are each independently selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl; Rf1 and Rf2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 and Rg2 are each independently selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation; Ri1, Ri2, Ri3, and Ri4, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted phenyl, wherein any two selected from the group consisting of Ri1, Ri2, Ri3, and Ri4 may combine with the atoms to which they are bound to form an optionally substituted C3- C8 cycloalkyl; and Rj1, Rj2, Rj3, Rj4, and Rj5, if present, are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, N(RA)(RB), C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, phenyl, C2-C8 heterocyclyl, C(=O)RA, C(=O)ORA, OC(=O)RA, OC(=O)ORA, SRA, S(=O)RA, S(=O)2RA, S(=O)2NRARB, S(=O)2N(RA)C(=O)NHRB, N(RB)- S(=O)2RC, N(RB)-C(=O)RC, and C(=O)-NRARB. 3. The compound of claim 2, wherein the benzyl, phenyl, naphthyl, or C2-C8 heterocyclyl in Rc1 is optionally substituted with at least one substituent. 4. The compound of claim 2 or 3, wherein R1 is selected from the group consisting of:
Figure imgf000113_0001
5. The compound of claim 2 or 3, wherein R1 is selected from the group consisting of:
Figure imgf000113_0002
6. The compound of any one of claims 2-5, wherein at least one of Rd1 and Rd2, if present, is selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, methanethioethyl, benzyl, 3-indolyl, hydroxymethyl, 1-hydroxyethyl, thiomethyl, 4- hydroxybenzyl, CH2C(=O)NH2, CH2CH2C(=O)NH2, CH2C(=O)OH, CH2CH2C(=O)OH, guanidinylpropyl, 4-imidazolyl, and aminobutyl. . The compound of any one of claims 2-4 and 6, wherein R
Figure imgf000114_0001
. 8. The compound of any one of claims 2-6, wherein R1 is selected from the group
Figure imgf000114_0002
9. The compound of claim 1, wherein R1 is selected from the group consisting of:
Figure imgf000114_0003
10. The compound of any one of claims 2-6, wherein Re1, Re2, Re3, and Re4, if present, are each independently selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. 11. The compound of claim 2, wherein Rf1 and Rf2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2- methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3- dimethylbutoxy, 2-methylbutoxy, pentoxy, 2-methylpentoxy, 3-methylpentoxy, 4- methylpentoxy, hexoxy, 2-propylpentoxy, propargyloxy, benzyloxy, and phenoxy.
12. The method of claim 2, wherein Rg1 and Rg2 are each independently selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2- methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. 13. The compound of claim 2, wherein Rh1 is: -(CH2)r-O-(CH2)sCH3, wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH2- and -CH3 is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(C1-C6 alkyl)O(C1-C6 alkyl), -(C1-C6 alkyl)O(benzyl), and -(C1-C6 alkyl)O(C6-C10 aryl). 14. The compound of claim 2, wherein Rh1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP). 15. The compound of claim 2, wherein Rj1, Rj2, Rj3, Rj4, and Rj5, if present, are each independently selected from the group consisting of H, CN, CH2F, CHF2, CF3, OCF3, F, and C1. 16. The compound of claim 1, which is a compound of formula (Ia):
Figure imgf000115_0001
wherein: G is selected from the group consisting of -P(=O)(ORA)-, -P(=O)(NRBRC)-, -C(=O)-, - S(=O)2-, -S(=O)-, and -C(RA)(RB)-. 17. The compound of claim 1 or 16, which is selected from the group consisting of:
Figure imgf000116_0001
18. The compound of claim 17, which is selected from the group consisting of:
Figure imgf000116_0002
19. The compound of claim 17 or 18, wherein RA is selected from the group consisting of:
Figure imgf000116_0003
wherein: Rf1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted C2-C8 heterocyclyl, optionally substituted C1-C24 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C3-C6 allyloxy, optionally substituted C3-C6 propargyloxy, optionally substituted benzyloxy, optionally substituted phenoxy, optionally substituted naphthyloxy, and optionally substituted C2-C8 heterocyclyloxy; Rg1 is selected from the group consisting of optionally substituted C1-C24 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C6 allyl, optionally substituted C3-C6 propargyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Rh1 is selected from the group consisting of optionally substituted C6-C24 alkyl, optionally substituted C5-C23 heteroalkyl, C6-C24 alkanoyl and optionally substituted C5-C23 heteroalkanoyl, wherein the C6-C24 alkyl, C5-C23 heteroalkyl, C6-C24 alkanoyl, and C5-C23 heteroalkanoyl optionally comprise one or more degrees of unsaturation. 20. The compound of claim 19, wherein Rf1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, propargyl, benzyl, phenyl, methoxy, ethoxy, propoxy, isobutyloxy, butoxy, neopentoxy, 3,3-dimethylbutoxy, 2- methylbutoxy, pentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, hexoxy, 2- propylpentoxy, propargyloxy, benzyloxy, and phenoxy. 21. The compound of claim 19, wherein Rg1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. 22. The compound of claim 19, wherein Rh1 is: -(CH2)r-O-(CH2)sCH3, wherein: r is an integer selected from the group consisting of 1, 2, 3, and 4; s is an integer selected from the group consisting of 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19; and each occurrence of -CH2- and -CH3 is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(C1-C6 alkyl)O(C1-C6 alkyl), -(C1-C6 alkyl)O(benzyl), and -(C1-C6 alkyl)O(C6-C10 aryl). 23. The compound of claim 19, wherein Rh1 is selected from the group consisting of octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP). 24. The compound of claim 17 or 18, wherein RB is:
Figure imgf000117_0001
, wherein: Rd1 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, C1-C6 heteroalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted indolyl, and optionally substituted imidazolyl, wherein Rd1 and RC may combine with atoms to which they are bound to form an optionally substituted C2-C5 heterocyclyl; and Re1 is selected from the group consisting of H, optionally substituted C1-C24 alkyl, C3-C8 cycloalkyl, and optionally substituted benzyl. 25. The compound of claim 24, wherein RB is selected from the group consisting of:
Figure imgf000118_0001
26. The compound of claim 24 or 25, wherein Rd1 is selected from the group consisting of H, methyl, isopropyl, isobutyl, sec-butyl, methanethioethyl, benzyl, 3-indolyl, hydroxymethyl, 1-hydroxyethyl, thiomethyl, 4-hydroxybenzyl, CH2C(=O)NH2, CH2CH2C(=O)NH2, CH2C(=O)OH, CH2CH2C(=O)OH, guanidinylpropyl, 4-imidazolyl, and aminobutyl. 27. The compound of any one of claims 24-26, wherein Re1 is selected from the group consisting of H, methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2- methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, 2-propylpentyl, benzyl, and phenyl. 28. The compound of any one of claim 1, wherein R1 is selected from the group consisting of ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl- butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl- pentanoyl, and hexanoyl. 29. The compound of any one of claims 1-28, wherein R2 is selected from the group consisting of H, F, CH3, CH2CH3, C≡CH, C=CH2, and CH2OH. 30. The compound of any one of claims 1-15 and 29, wherein Ra1 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2- methylbutyl, pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl-butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl-pentanoyl, 3-methyl-pentanoyl, 4-methyl-pentanoyl, and hexanoyl. 31. The compound of any one of claims 1-30, wherein R3b is F. 32. The compound of any one of claims 1-30, wherein R3b is ORa2. 33. The compound of claim 32, wherein Ra2 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, butyl, neopentyl, 3,3-dimethylbutyl, 2-methylbutyl, pentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, hexyl, ethanoyl, propanoyl, isobutanoyl, butanoyl, neopentanoyl, 3,3-dimethyl-butanoyl, 2-methyl-butanoyl, pentanoyl, 2-methyl- pentanoyl, 3-methyl-pentanoyl, 4-methyl-pentanoyl, and hexanoyl. 34. The compound of any one of claims 1-33, wherein R4b is H. 35. The compound of any one of claims 1-34, wherein R5 is H. 36. The compound of any one of claims 1-35, wherein R8 is H or NH2. 37. The compound of any one of claims 1-36, wherein X is selected from the group consisting of N, CH, and CF. 38. The compound of any one of claims 1-37, wherein A1 is selected from the group ,
Figure imgf000119_0001
39. The compound of any one of claims 1-38, wherein each occurrence of alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, and aryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C24 alkyl, C3-C8 cycloalkyl, C3-C6 allyl, C3-C6 propargyl, C1-C6 hydroxyalkyl, halogen, NO2, CN, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C6-C10 aryl), N(C6-C10 aryl)2, C1-C6 alkoxy, C3- C8 cycloalkoxy, C1-C3 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, benzyl, phenyl, naphthyl, C2-C8 heterocyclyl, C(=O)H, C(=O)(C1-C6 alkyl), C(=O)(C6-C10 aryl), C(=O)O(benzyl), C(=O)(C3-C8 cycloalkyl), C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)O(C6- C10 aryl), OC(=O)H, OC(=O)(C1-C6 alkyl), OC(=O)(C6-C10 aryl), OC(=O)OH, OC(=O)O(C1-C6 alkyl), OC(=O)O(C6-C10 aryl), SH, S(C1-C6 alkyl), S(C6-C10 aryl), S(=O)(C1-C6 alkyl), S(=O)(C6-C10 aryl), S(=O)2OH, S(=O)2O(C1-C6 alkyl), S(=O)2O(C6-C10 aryl), S(=O)2(C1-C6 alkyl), S(=O)2(C6-C10 aryl), S(=O)2NH2, S(=O)2NH(C1-C6 alkyl), S(=O)2N(C1-C6 alkyl)2, S(=O)2NH(C6-C10 aryl), S(=O)2N(C6-C10 aryl)2, S(=O)2NHC(=O)NH2, S(=O)2N(C1-C6 alkyl)C(=O)NH2, S(=O)2NHC(=O)NH(C1-C6 alkyl), S(=O)2N(C1-C6 alkyl)C(=O)NH(C1-C6 alkyl), S(=O)2NHC(=O)NH(C6-C10 aryl), NHS(=O)2(C1-C6 alkyl), N(C1-C6 alkyl)S(=O)2(C1-C6 alkyl), NHS(=O)2(C6-C10 aryl), N(C1- C6 alkyl)S(=O)2(C6-C10 aryl), NHC(=O)H, NHC(=O)(C1-C6 alkyl), N(C1-C6 alkyl)C(=O)(C1- C6 alkyl), NHC(=O)(C6-C10 aryl), N(C1-C6 alkyl)C(=O)(C6-C10 aryl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, C(=O)NH(C6-C10 aryl), C(=O)N(C1-C6 alkyl)(C6-C10 aryl), and C(=O)N(C6-C10 aryl)2. 40. The compound of claim 39, wherein each optional substituent in the alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, benzyl, or aryl is further optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 heteroalkyl, halogen, CN, NO2, OH, O(C1-C6 alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(=O)OH, C(=O)O(C1-C6 alkyl), C(=O)NH2, C(=O)NH(C1-C6 alkyl), C(=O)N(C1-C6 alkyl)2, NH(C=NH)NH2, and imidazolyl. 41. The compound of any one of claims 1-40, which is selected from the group consisting of: (2R,3R,4S,5R)-2-(6-(hydroxyamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4R,5R)-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)-4-methoxytetrahydrofuran-3-ol; ((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4S,5R)-2-(4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol; ((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate; isopropyl ((S)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((R)-(((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D- alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; isopropyl ((((2R,3S,4R,5R)-5-(2-amino-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; (2R,3R,4R,5R)-4-fluoro-5-(5-fluoro-4-(hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol; and (2R,3R,4R,5R)-2-(2-amino-6-(hydroxyamino)-9H-purin-9-yl)-5- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate); or a salt, prodrug, solvate, isotopologue, tautomer, or stereoisomer thereof. 42. A pharmaceutical composition comprising at least one compound of any one of claims 1-41 and a pharmaceutically acceptable carrier. 43. The pharmaceutical composition of claim 42, further comprising at least one additional agent useful for treating, ameliorating, and/or preventing a coronavirus infection. 44. A method of treating, ameliorating, and/or preventing a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of claims 1-41 and/or at least one pharmaceutical composition of any one of claims 42-43. 45. The method of claim 44, wherein the subject is further administered at least one additional agent useful for treating, ameliorating, and/or preventing the coronavirus infection. 46. The method of claim 45, wherein the subject is co-administered the at least one additional agent and the at least one compound and/or composition. 47. The method of claim 46, wherein the at least one additional agent and the at least one compound and/or composition are coformulated. 48. The method of any one of claims 45-47, wherein the additional agent is selected from the group consisting of a RNA-dependent RNA polymerase (RdRp) inhibitor and a protease inhibitor. 49. The method of any one of claims 44-48, wherein the coronavirus is selected from the group consisting of an alphacoronavirus and a betacoronavirus. 50. The method of claim 49, wherein the alphacoronavirus is selected from the group consisting of Human coronavirus 229E (HCoV-229E) and Human coronavirus NL63 (HCoV- NL63). 51. The method of claim 49, wherein the betacoronavirus is selected from the group consisting of Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), Severe acute respiratory syndrome-related coronavirus 1 (SARS-CoV or SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1). 52. The method of claim 51, wherein the betacoronavirus is SARS-CoV-2. 53. The method of any one of claims 44-52, wherein a coronavirus RNA polymerase is inhibited. 54. The method of claim 53, wherein the RNA polymerase comprises nonstructural protein 12 (nsp12). 55. The method of any one of claims 44-54, wherein the subject is a mammal. 56. The method of claim 55, wherein the mammal is a human.
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