WO2023102472A1 - Antiviral prodrugs and formulations thereof - Google Patents

Antiviral prodrugs and formulations thereof Download PDF

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Publication number
WO2023102472A1
WO2023102472A1 PCT/US2022/080740 US2022080740W WO2023102472A1 WO 2023102472 A1 WO2023102472 A1 WO 2023102472A1 US 2022080740 W US2022080740 W US 2022080740W WO 2023102472 A1 WO2023102472 A1 WO 2023102472A1
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alkyl
group
additional therapeutic
therapeutic agent
virus
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PCT/US2022/080740
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French (fr)
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Arnab Kumar CHATTERJEE
Anil Kumar Gupta
Jian Jeffrey Chen
Katy WILSON
Gennadii GRABOBYI
Hank Michael James PETRASSI
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The Scripps Research Institute
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Publication of WO2023102472A1 publication Critical patent/WO2023102472A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • RNA viruses such compounds target the RNA-dependent RNA polymerase (RDRP) which carries out the key viral RNA synthesis reactions.
  • RDRPs are attractive drug targets because they are essential for virus growth, are not encoded by the mammalian host cell and are well-conserved among viral families 2 .
  • SARS-CoV-2 the RDRP is non-structural protein (nsp) 12.
  • Nsp12 associates with nsp7 and nsp8 in order to replicate the SARS-COV-2 genome.
  • nucleoside analogs that selectively target the RDRP have been the most promising approach to SARS-CoV-2 inhibition.
  • Remdesivir functions as a non-obligate or delayed RNA chain terminator. Delayed chain termination occurs when a nucleotide analogue has a free 3-OH group required for the addition of natural nucleotides. The incorporation of the delayed chain terminator, however, perturbs the RNA structure, and RNA synthesis is halted.
  • WO 2012/050961 and WO 2012/050956 refer to antiviral prodrugs and pharmaceutical compositions thereof.
  • WO 2021/154687 refers to methods for treating SARS COV-2 infections. References: 1. Geraghty, R. J.; Aliota, M. T.; Bonnac, L. F., Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 2021, 13 (4). 2.
  • Some embodiments described herein also provide a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Some embodiments described herein also provide a method of inhibiting an RNA- dependent RNA polymerase in a patient infected with a virus, or a method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof.
  • FIGURES Figure 1 shows in graphic form the Cyano/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, and GS-621763 following PO (oral) administration at 2.3-10 mg/kg equivalent dose of GS-441524.
  • DETAILED DESCRIPTION OF THE DISCLOSURE Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • “Patient” includes both human and animals. “Patient” and “subject” are used interchangeably herein. When a range of values is listed, it is intended to encompass each value and sub– range within the range.
  • C 1–6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”).
  • an alkyl group has 1 to 15 carbon atoms (“C 1–15 alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C 1–14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C 1–13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C 1–11 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”).
  • an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2–6 alkyl”). Examples of C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n– pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n– octyl (C 8 ) and the like.
  • Alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1– butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3–14 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3–10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3–8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3–7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5–10 carbocyclyl”).
  • Exemplary C 3–6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3–8 carbocyclyl groups include, without limitation, the aforementioned C 3–6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3–10 carbocyclyl groups include, without limitation, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon–carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3–14 cycloalkyl”).
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”).
  • C 5–6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • Examples of C 3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • Heterocyclyl refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl ( ⁇ -naphthyl) and 2–naphthyl ( ⁇ -naphthyl)).
  • C 10 aryl e.g., naphthyl such as 1–naphthyl ( ⁇ -naphthyl) and 2–naphthyl ( ⁇ -naphthyl)).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Heteroaryl refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
  • Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted.
  • substituted means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I). It should be noted that in hetero-atom containing ring systems described herein, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: are considered equivalent unless otherwise specified.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition described herein that is effective in inhibiting the above-noted enzyme, diseases or conditions, and thus producing the desired therapeutic, ameliorative, inhibitory and/or preventative effect.
  • Salt includes any and all salts.
  • “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19.
  • Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, replacement of a carbon by a 13 C- or 14 C- enriched carbon, and/or replacement of an oxygen atom with 18 O are within the scope of the disclosure.
  • isotopes include 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I.
  • Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.
  • Certain isotopically-labelled compounds of Formula (I), are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single Photon Emission Computed Tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances.
  • isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • Isotopically labeled compounds of Formula (I) in particular those containing isotopes with longer half-lives (t 1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds described herein can also be used in combination with one or more additional therapeutic and/or prophylactic agents.
  • the methods comprise administering to a subject in need thereof a compound of the disclosure and a therapeutically effective amount of one or more additional therapeutic and/or prophylactic agents (“therapeutic agent” is interchangeable with “prophylactic agent” as used herein).
  • therapeutic agent is interchangeable with “prophylactic agent” as used herein.
  • the compounds of the present invention and the additional therapeutic agents can be utilized for pre-exposure and post-exposure prophylaxis.
  • the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.
  • the antiviral agent is selected from the group consisting of 5-substituted 2' -deoxyuridine analogues, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A inhibitors, NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulators, oligonucleotides, antimitotic inhibitors, and combinations thereof.
  • the additional therapeutic agent is a 5-substituted 2' - deoxyuridine analogue.
  • the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine (bromo vinyl deoxyuridine or “BVDU”), and combinations thereof.
  • the additional therapeutic agent is a nucleoside analogue.
  • the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF) and combinations thereof.
  • the additional therapeutic agent is favipiravir, ribavirin, galidesivir, or a combination thereof. In some embodiments, the additional therapeutic agent is ⁇ -D-N4-hydroxycytidine. In some embodiments, the additional therapeutic agent is a pyrophosphate analogue. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet. In some embodiments, the additional therapeutic agent is nucleoside reverse transcriptase inhibitor.
  • the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.
  • the additional therapeutic agent is sangivamycin, ⁇ -d-N4-Hydroxycytidine (NHC), EIDD-2801, EIDD-1931, or a combination thereof.
  • the antiviral agent is MK-4482 (EIDD-2801).
  • the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor.
  • the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.
  • the additional therapeutic agent is a protease inhibitor.
  • the protease inhibitor is a HIV protease inhibitor.
  • the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof.
  • the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof.
  • the protease inhibitor is a HCV NS3/4A protease inhibitor.
  • the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.
  • the protease inhibitor is PF-07321332, having the structure
  • PF-07321332 acts an orally active 3CL protease inhibitor, and the combination of PF- 07321332 with ritonavir is in phase III trials for the treatment of COVID-19.
  • the protease inhibitor is lenacapavir (GS-6207) that is being developed by Gilead Sciences for the treatment of HIV. It has the structure: .
  • the additional therapeutic agent is an integrase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is an entry inhibitor.
  • the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella- zoster immune globulin [VZIG]), and combinations thereof.
  • the additional therapeutic agent is an acyclic guanosine analogue.
  • the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.
  • the additional therapeutic agent is an acyclic nucleoside phosphonate analogues.
  • the additional therapeutic agent is selected from a group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is a HCV NS5A or NS5B inhibitor. In some embodiments, the additional therapeutic agent is a NS3/4A protease inhibitor. In some embodiments, the additional therapeutic agent is a NS5A protein inhibitor.
  • the additional therapeutic agent is a NS5B polymerase inhibitor of the nucleoside/nucleotide type. In some embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the nonnucleoside type. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.
  • the additional therapeutic agent is an influenza virus inhibitor.
  • the additional therapeutic agents is a matrix 2 inhibitor.
  • the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof.
  • the additional therapeutic agent is a neuraminidase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof.
  • the additional therapeutic agent is a polymerase inhibitor distinct from the compounds of the present invention.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.
  • the additional therapeutic agent is DAS-181 or XC-221. In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFN ⁇ -2a), and PegIFNa-2b.
  • the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNa-2a), PegIFNa-2b, and ribavirin.
  • the additional therapeutic agent is pegylated interferon alfa- 2a, pegylated interferon alfa-2b, or a combination thereof.
  • the additional therapeutic agent is interferon-beta.
  • the additional therapeutic agent ls interfernn- beta-1 a, such as SNG-001.
  • the additional therapeutic agent is an inteferon--inducing agent, such as tilorone hydrochloride.
  • the additional therapeutic agent is IL-17 antagonist such as ixekizumab.
  • the additional therapeutic agent is interferon alfa 2 ligand, secukinumab, IMU-838, or vidofludimus.
  • the additional therapeutic agent is an immunostimulatory agent.
  • the additional therapeutic agent is an oligonucleotide.
  • the additional therapeutic agent is an antimitotic inhibitor.
  • the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechins, and combinations thereof.
  • the additional therapeutic agent is azoximer bromide or IMM-101.
  • the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FVl00, and letermovir, and combinations thereof.
  • the additional therapeutic agent is an agent for treatment of RSV.
  • the antiviral agent is ribavirin, ALS-8112 or presatovir.
  • the antiviral agent is ALS-8112 or presatovir.
  • the antiviral agent is DFV890.
  • the antiviral agent is MAS825.
  • the antiviral agent is emetine. In some embodiments, the antiviral agent is protoporphyrin IX, SnPP protoporphyrin and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivermectin. In some embodiments, the additional therapeutic agent is an agent for treatment of picomavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, L-buthionine sulfoximine, Py-11, and combinations thereof.
  • the additional therapeutic agent is a picomavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir. In some embodiments, the additional therapeutic agent is an agent for treatment of malaria. For example, the additional therapeutic agent is dihydroartemisinin piperaquine. In some embodiments, the additional therapeutic agent is pyramax.
  • the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinations thereof.
  • the additional therapeutic agent is an agent for treatment of coronavirus.
  • the additional therapeutic agent is selected from a group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporins, and combinations thereof.
  • the additional therapeutic agent is an agent for treatment of ebola virus.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI- 557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino- 5Hpyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (l-N,7-N-bis[3-( dimethylamino )propyl]-3,9-dimethylquinolino[8, 7-h]quinolone
  • the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.
  • the additional therapeutic agent is an agent for treatment of HCV.
  • the additional therapeutic agent is a HCV polymerase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938 , ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof.
  • the additional therapeutic agent is a HCV protease inhibitor.
  • the additional therapeutic agent is selected from the group consisting of such as GS-9256, vedroprevir, voxilaprevir, and combinations thereof.
  • the additional therapeutic agent is a NS5A inhibitor.
  • the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.
  • the additional therapeutic agent is an anti HBV agent.
  • the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof.
  • additional anti HBV agents include but are not limited to alpha-hydroxytropolones, amdoxovir, antroquinonol, beta- hydroxycytosine nucleosides,, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN- co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP
  • the additional therapeutic agent is a HBV polymerase inhibitor.
  • HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clev
  • the additional therapeutic agent is a HBV capsid inhibitor. In some embodiments, the additional therapeutic agent is an agent for treatment of HIV. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogues, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non- nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies).
  • HIV protease inhibitors HIV non- nucleoside or non-nucleotide inhibitors of reverse transcriptase
  • HIV integrase inhibitors HIV non-cata
  • the additional therapeutic agent is an immunotherapeutic peptides such as tertomotide.
  • the additional therapeutic agent is a CCL26 gene inhibitor, such as mosedipimod.
  • the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.
  • the additional therapeutic agent is a PI3K inhibitor, for example idelalisib or duvelisib.
  • the additional therapeutic agent is a HIV combination drug.
  • the HIV combination drugs include, but are not limited to ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine ); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafen
  • the additional therapeutic agent is a HIV protease inhibitor.
  • the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS- 1156, and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat.
  • the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.
  • the additional therapeutic agent is a HIV integrase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir and combinations thereof.
  • the additional therapeutic agent is bictegravir.
  • the additional therapeutic agent is selected from a group consisting of bictegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS- 986197, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives, integrase- LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217,
  • the additional therapeutic agent is a HIV entry inhibitor.
  • the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof.
  • HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.
  • CCR5 inhibitors examples include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).
  • CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).
  • the additional therapeutic agent is a HIV nucleoside reverse transcriptase inhibitors.
  • the additional therapeutic agent is a HIV non- nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogue. In some embodiments, the additional therapeutic agent is a HIV capsid inhibitor. In some embodiments, the additional therapeutic agent is a HIV nucleoside or nucleotide inhibitor of reverse transcriptase.
  • the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753
  • the additional therapeutic agent is a HIV non-nucleoside or nonnucleotide inhibitor of reverse transcriptase.
  • the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM- 023, PC-1005, elsulfavirine rilp (VM-1500), combinations thereof.
  • the additional therapeutic agents are selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adef
  • the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.
  • the additional therapeutic agent is an inhibitor of Bruton tyrosine kinase (BTK, AGMXI, AT, ATK, BPK, IGHD3, IMDl, PSCTKl, XLA; NCBI Gene ID: 695).
  • BTK Bruton tyrosine kinase
  • the additional therapeutic agent is selected from the group consisting of (S )-6-amino-9-( l -(but-2-ynoy l)pyrrolidin-3-y 1)-7-( 4-phenoxypheny l)-7H- purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatirsen, and combinations thereof.
  • the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a receptor tyrosine kinase inhibitor (RTKI). In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9). In some embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor. In some embodiments, the additional therapeutic agent is abivertinib maleate (STI-5656).
  • the additional therapeutic agent is a tyrosine kinase inhibitor, such as masitinib.
  • the additional therapeutic agent is a sphingosine kinase-2 (sk2)inhibitor, such as opaganib.
  • the additional therapeutic agent is a kinase inhibitor such as pacritinib.
  • the additional therapeutic agent is an Axl tyrosine kinase receptor inhibitor, such as bemcentinib.
  • the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor.
  • the additional therapeutic agent is a checkpoint kinase inhibitor, such as prexasertib.
  • the additional therapeutic agent is a MAP kinase inhibitor, such as KTH-222, ATI-450.
  • the additional therapeutic agent is a mTOR inhibitor, such as sirolimus.
  • the additional therapeutic agent is a pi3k/ mTOR inhibitor such as dactolisib.
  • the additional therapeutic agent is a Hsp90 inhibitor, such as ganetespib, ADX-1612.
  • the additional therapeutic agent is an MEK inhibitor such as ATR-002.
  • the additional therapeutic agent is a topoisomerase II inhibitor, such as etoposide.
  • the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor, verdinexor.
  • the additional therapeutic agent is a dual inhibitor of PARPl/2 and Tankyrase 1/2, such as 2X-121.
  • the additional therapeutic agent is a cyclin dependent kinase inhibitor, such as CYC-065, CYC-202.
  • the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine.
  • the additional therapeutic agent is a DHFR inhibitor, such as methotrexate.
  • the additional therapeutic agent is a small ubiquitin related modifier inhibitor, such as TAK- 981.
  • the additional therapeutic agent is an integrin agonist such as 7HP- 349.
  • the additional therapeutic agent is a BET inhibitor, such as apabetalone.
  • the additional therapeutic agent is a BRD4 inhibitor, such as CPI-0610, ABBV-744.
  • the additional therapeutic agent is a ERl inhibitor, such as toremifene.
  • the additional therapeutic agent is a KRAS inhibitor.
  • the additional therapeutic agent is selected from the group consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (Gl2C), SML-8-73-1 (Gl2C), Compound 3144 (Gl2D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (Gl2C) and K-Ras(Gl2D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPL YISYDPVCRRRR-NH2), and combinations thereof.
  • KRpep-2 Ac-RRCPLYISYDPVCRR-NH2
  • KRpep-2d Ac-RRRRCPL YISYDPVCRRRR-NH2
  • the additional therapeutic agent is an alkylating agent, such as melphalan.
  • the additional therapeutic agent is a proteasome inhibitor.
  • the additional therapeutic agent is selected from a group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof.
  • the additional therapeutic agent is carfilzomib.
  • the additional therapeutic agent is a vaccine.
  • the additional therapeutic agent is a DNA vaccine, RNA vaccine, live attenuated vaccine, therapeutic vaccine, prophylactic vaccine, protein based vaccine, or a combination thereof.
  • the additional therapeutic agent is mRNA-1273.
  • the additional therapeutic agent is INO-4800 or INO-4700.
  • the additional therapeutic agent is live-attenuated RSV vaccine MEDI-559, human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof.
  • the additional therapeutic agent is a HBV vaccine, for example pediarix, engerix-B, and recombivax HB.
  • the additional therapeutic agent is a VZV vaccine, for example zostavax and varivax.
  • the additional therapeutic agent is a HPV vaccine, for example cervarix, gardasil 9, and gardasil.
  • the additional therapeutic agent is an influenza virus vaccine.
  • a (i) monovalent vaccine for influenza A e.g. influenza A (H5Nl) virus monovalent vaccine and influenza A (HlNl) 2009 virus monovalent vaccines
  • (ii) trivalent vaccine for influenza A and B viruses e.g. Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone
  • quadrivalent vaccine for influenza A and B viruses FrluMist, Fluarix, Fluzone, and FluLaval.
  • the additional therapeutic agent is a human adenovirus vaccine (e.g. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral).
  • the additional therapeutic agent is a rotavirus vaccine (e.g. Rotarix for rotavirus serotype G 1, G3, G4, or G9 and RotaTeq for rotavirus serotype Gl, G2, G3, or G4).
  • the additional therapeutic agent is a hepatitis A virus vaccine (e.g. Havrix and Vaqta).
  • the additional therapeutic agent is poliovirus vaccines (e.g. Kinrix, Quadracel, and Ipol).
  • the additional therapeutic agent is a yellow fever virus vaccine (e.g. YFVax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccines ( e.g. Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g. ProQuad).
  • YFVax yellow fever virus vaccine
  • the additional therapeutic agent is a Japanese encephalitis virus vaccines (e.g. Ixiaro and JE-Vax).
  • the additional therapeutic agent is a measles vaccine (e.g. M-M
  • the additional therapeutic agent is a rabies vaccine (e.g. Imovax and RabAvert).
  • the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000).
  • the additional therapeutic agent is a and hepatitis E virus (HEV) vaccine (e.g. HEV239).
  • the additional therapeutic agent is a 2019-nCov vaccine.
  • the additional therapeutic agent is Ad5-nCoV.
  • the additional therapeutic agent is a BCG vaccine.
  • the additional therapeutic agent is Pfizer-BioNTech COVID-19 vaccine.
  • the additional therapeutic agent is Moderna Covid-19 vaccine.
  • the additional therapeutic agent is AZD1222 (astrazeneca Covid-19 vaccine).
  • the additional therapeutic agent is a poliovirus vaccine, e.g. OPV.
  • the additional therapeutic agent is BNT162al, BNT162bl, BNT162b2, or BNT162c2 (prime/boost, single or multiple doses).
  • the additional agent is AZD1222 (ChAdOxl nCov-19) vaccine.
  • the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 Prime-boost), Covax-19, or Naso VAX.
  • the additional therapeutic agents is LUNAR-COV19 (ARCT-021).
  • the additional agent is TerraCoV2.
  • the additional agent is COVID-19 S-Trimer.
  • the additional agent is TNX-1810, TNX-1820, or TNX-1830.
  • the additional agent is VaxiPatch COVID-19 vaccine.
  • the additional agent is VBI-2901.
  • the additional agent is VLA-2001.
  • the additional agent is exoVACC-SARS-CoV2CoV-2. In some embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-Mor NVX-CoV2373. In some embodiments, the additional agent is BBV152A, B, C, PicoVacc, KBP-COVID-19, MF59 adjuvanted SARS-CoV-2 Sclamp, MVC-COV1901, SCB-2019 (COVID-19 S-Trimer + CpG1018+AS03), TMV-083, V-591, VPM1002, or V-SARS.
  • the additional therapeutic agent is an antibody, for example a monoclonal antibody.
  • the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of the Regeneron antibodies, the Wuxi Antibodies, the Vir Biotechnology Antibodies, antibodies that target the SARS-CoV-2 spike protein, antibodies that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations thereof.
  • the additional therapeutic agent is anti-SARS CoV antibody CR- 3022.
  • the additional therapeutic agent is aPD-1 antibody.
  • the additional therapeutic agent is anti-IL-6R mAb.
  • the additional therapeutic agent is TZLS-501 or siltuximab.
  • the additional therapeutic agent is an antibody that targets specific sites on ACE2.
  • the additional therapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein (S-protein).
  • the additional therapeutic agent is a virus suppressing factor (VSF, HzVSFv13).
  • the additional therapeutic agent is an anti-CD147 antibody.
  • the additional therapeutic agent is meplazumab.
  • the additional therapeutic agent is a phosphodiesterase type 4 (PDE4) or phosphodiesterase type 5 (PDE5) inhibitor.
  • the additional therapeutic agent is a PDE5 inhibitor, for example, the additional therapeutic agent is sildenafil.
  • the additional therapeutic agent is a PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin. In some embodiments, the additional therapeutic agent is an agent targeting NKGA2. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is NKG2 A B activating NK receptor antagonist, such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor, such as BPI-002. In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as CPI-006. In some embodiments, the additional therapeutic agent is recombinant cytokine gene derived protein injection. In some embodiments, the additional therapeutic agent is a polymerase inhibitor.
  • the additional therapeutic agent is a DNA polymerase inhibitor.
  • the additional therapeutic agent is cidofovir.
  • the additional therapeutic agent is lamivudine.
  • the additional therapeutic agent is a RNA polymerase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir and combination thereof.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, pimodivir and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.
  • the additional therapeutic agent is a beta-catenin inhibitor.
  • the additional therapeutic agent is tetrandrine.
  • the additional therapeutic agent is a trypsin inhibitor, for example the additional therapeutic agent is ulinastatin.
  • the additional therapeutic agent is TAK-671.
  • the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZl, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat, N afamostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof.
  • the additional therapeutic agent is selected form the group consisting of JQ-1, RVX-208,silmitasertib, TMCB, apicidin, valproic acid, Bafilomycin Al, E- 52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, Metformin, Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623, Midostaurin, Ruxolitinib, ZINC I 775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, Daunorubicin, GB llO, S-verapamil, AZ3451, and combinations thereof.
  • the additional therapeutic agent is selected form a group consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, chiliedoxifene, niclosamide, eltrombopag, and combinations thereof.
  • the additional therapeutic agent is a drug targeting the coronavirus main protease 3CLpro (e.g. lopinavir). In some embodiments the additional therapeutic agent is a drug targeting the papain-like protease PLpro (e.g., lopinavir). In some examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells (e.g. arbidol). In some embodiments, the additional therapeutic agent is a TMPRSS2 inhibitor (e.g. camostat mesylate).
  • the additional therapeutic agent is a serine protease inhibitor, such as LB ll 48, upamostat, RHB-107, or alpha- I antitrypsin.
  • the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonodelestat.
  • the additional therapeutic agent is an a-ketoamide.
  • the additional therapeutic agent is a poly-ADP-ribose polymerase 1 (PARPl) inhibitor, for example, the additional therapeutic agent is CVL218.
  • PARPl poly-ADP-ribose polymerase 1
  • the additional therapeutic agent is selected from the group consisting of 6' -fluorinated aristeromycin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives, SSYAl0-001, griffithsin, HR2P-Ml, HR2P-M2, P21S10, Dihydrotanshinone E-64-C and E-64- D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, l-thia-4- azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferons,
  • the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a of 2019-nCoV virus antibody. In some embodiments, the additional therapeutic agent is LY-CoV555. In some embodiments, the additional therapeutic agent is S309. In some embodiments, the additional therapeutic agent is SAB-185. In some embodiments, the additional therapeutic agent is CB6. In some embodiments, the additional therapeutic agent is STI-1499. In some embodiments, the additional therapeutic agent is JS016. In some embodiments, the additional therapeutic agent is VNAR.
  • the additional therapeutic agent is VIR-7832 and/or VIR- 7831.
  • the additional therapeutic agent is REGN-COV2 (REGN10933 + RGN10987)
  • the additional therapeutic agent is BAT2020, BAT2019.
  • the additional therapeutic agent is 47D 11.
  • the additional therapeutic agent is COVI-SHIELD.
  • the additional therapeutic agent is BRII-196, BRII-198.
  • the additional therapeutic agent is INM-005, SCTA0l, TY-027, XAV-19. Compositions of the invention are also used in combination with other active ingredients.
  • the other active therapeutic agent is active against coronavirus infections, for example 2019-nCoV virus infections.
  • the compounds and compositions of the present invention are also intended for use with general care provided patients with 2019-nCoV viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin Kand zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immonumodulatory medications (eg interferon), other small molecule or biologics antiviral agents targeting 2019-nCoV (such as but not limited to lop
  • the additional therapeutic agent is dihydroartemisinin/piperaquine. In some embodiments, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide.
  • the compounds disclosed herein are used in combination with amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, cholecalciferol, vitamin C, prednisone, mometasone, or budenoside. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as Panaphix (PAX-1), which inhibit production of pro-inflammatory cytokines.
  • PAX-1 Panaphix
  • the compounds disclosed herein are used in combination with inhibitors such as NCP-112 which inhibit excessive immune response such as cytokine storm.
  • the additional therapeutic agent is an antifungal agent, for example itraconazole or 17-0H- itraconazole.
  • the additional therapeutic agent is an immunomodulator.
  • immune-based therapies include toll-like receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrll, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-Ll) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PE
  • the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide. In some embodiments, the additional therapeutic agent is CD24Fc. In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonists, such as anakinra. In some embodiments, the additional therapeutic agent is a TLR4 antagonist, such as EB-05. In some embodiments, the additional therapeutic agent is nivolumab, efineptakin alfa, lactoferrin, ozanimod, astegolimab (MSTT1041A, RG-6149), or UTTR1147 A. In some embodiments, the additional therapeutic agent is Ampligen.
  • the additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor such as MEDI3506. In some embodiments, the additional therapeutic agent is an IL-5 receptor antagonist, such as mepolizumab. In some embodiments, the additional therapeutic agent is an IL-12 inhibitor, such as apilimod. In some embodiments, the additional therapeutic agent is a IL-15 receptor agonist, such as N-803. In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.
  • the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, or a combination thereof. In some embodiments, the additional therapeutic agent is tocilizumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, olokizumab, sirukumab, clazakizumab, levilimab or a combination thereof. In some embodiments, the additional therapeutic agent is a nicotinamide phosphoribosyltransferase inhibitors. For example, the additional therapeutic agent is enamptcumab.
  • the additional therapeutic agent is a di peptidase 1 (DPEP-1) inhibitor.
  • the additional therapeutic agent is Metablok (LSALT peptide).
  • the additional therapeutic agent is an anti-TNF inhibitor.
  • the additional therapeutic agent is adalimumab, etanercept, golirnurnab, infliximab, or a combination thereof.
  • the additional therapeutic agent is a TNF alpha ligand inhibitor, such as XPro1595.
  • the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, olumiant, or a combination thereof.
  • the additional therapeutic agent is jaktinib. In some embodiments, the additional therapeutic agent is tofacitinib or TD-0903. In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone. In some embodiments, the additional therapeutic agent is L YT-100. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as dociparstat sodium. In some embodiments, the additional agent is used in the treatment of septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a CCRl antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent targets IKK ⁇ and NFK ⁇ , such as OP-101.
  • the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone or dexamethasone.
  • the additional therapeutic agent is an immunosuppressant, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, M-5049.
  • the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758.
  • the additional therapeutic agent is a IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8).
  • the additional therapeutic agent is a CD 14 inhibitor, such as IC-14.
  • the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299.
  • the additional therapeutic is anti-fibrotic, such as RT- 1840,nintedanib, GB-0139, nintedanib, pamrevlumab.
  • the additional therapeutic is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777).
  • the additional therapeutic agent is an A3 adenosine receptor (A3AR) antagonist, for example the additional therapeutic agent is piclidenoson.
  • the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia.
  • the additional therapeutic agent is macrolide antibiotics (e.g. azithromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g. ciprofloxacin and levofloxacin), tetracyclines (e.g. doxycycline and tetracycline), or a combination thereof.
  • the additional therapeutic agent is XEL 1004.
  • the additional therapeutic agent is eravacycline.
  • the compounds disclosed herein are used in combination with pneumonia standard of care (see e.g. Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)).
  • Treatment for pneumonia generally involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of pneumonia, age and overall health of the individuals. The options include: (i) antibiotics, (ii) cough medicine, and (iii) fever reducers/pain relievers (for e.g. aspirin, ibuprofen (Advil, Motrin IB, others) and acetaminophen (Tylenol, others)).
  • the additional therapeutic agent is bromhexine anti-cough.
  • the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion.
  • the compounds disclosed herein are used in combination with TAK-888 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)). In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immunoglobulin. In some embodiments, the compounds described herein are used in combination with COVID- EIG or COVID-HIG. In some embodiments, the compounds disclosed herein are used in combination with stem cells. For example, in some embodiments, the compounds disclosed herein are used in combination with MultiStem or Remestemcel-L (mesenchymal stem cells).
  • the compounds described herein are used in combination with allogenic mesenchymal-like cells, for example in combination with PLX cells. In some embodiments, the compounds described herein are used in combination with allogenic cell therapy, for example in combination with CK-0802. In some embodiments, the compounds described herein are used in combination with Pluristem or ACT-20. In some examples, the additional therapeutic agent is an TLR agonist.
  • TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531.
  • the additional therapeutic agent is PUL-042.
  • the additional therapeutic agent is polyinosinic-polycytidylic acid (poly I:C).
  • the additional therapeutic agent is selected from the group consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.
  • the additional therapeutic agent is simvastatin or rosuvastatin.
  • the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor, or a-ketoamine.
  • the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2).
  • the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).
  • the additional therapeutic agent is a recombinant human angiotensin-converting enzyme 2 (rhACE2), for example APN-01.
  • the additional therapeutic agent is an angiotensin II receptor agonist.
  • the additional therapeutic agent is a partial agonist of A T2 or a partial antagonist of AT 1.
  • the additional therapeutic agent is L-163491.
  • the additional therapeutic agent is ACE2-Fc fusion protein, for example the additional therapeutic agent is STI-4398.
  • the additional therapeutic agent is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan.
  • the additional therapeutic agent is VP-01, TXA-127.
  • the additional therapeutic agent is telmisartan.
  • the additional therapeutic agent is an ACE inhibitor, such as ramipril, captopril, enalapril, or lisonopril.
  • the additional therapeutic agent is an aldose reductase inhibitor, such as AT-001.
  • the additional therapeutic agent is a platelet inhibitor.
  • the additional therapeutic agent is dipyridamole.
  • the additional therapeutic agent is an anti-coagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, fondaparinux.
  • the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.
  • the additional therapeutic is a Factor Xlla antagonist, such as garadacimab.
  • the additional therapeutic agent is a VE-PTP inhibitor, such as razuprotafib.
  • the additional therapeutic agent is a VIP 2 receptor agonist, such as PB-1046.
  • the additional therapeutic agent is an anti-thrombotic, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, tranexamic acid.
  • the additional therapeutic agent is a vasodilator, such as iloprost, ventaprost, vazegepant, angiotensin 1-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301, sodium nitrite, TRV-027.
  • the additional therapeutic agent is a blood clotting modulator, such as lanadelumab.
  • the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.
  • the additional therapeutic agent is antihypoxic, such as trans-sodium crocetinate.
  • the additional therapeutic agent is MK-5475.
  • the additional therapeutic agent is a hypoxia-inducible factor (HF) prolyl hydroxylase-2 (PHD-2) inhibitor such as desidustat or vadadustat.
  • the additional therapeutic agent is a renin inhibitor, such as aliskiren.
  • the additional therapeutic agent is a calcium channel inhibitor such as nifedipine.
  • the additional therapeutic agent is a chelating agent, such as desferal, deferiprone, deferoxamine.
  • the additional therapeutic agent is a retinoic acid receptor agonist, such as isotretinoin or fenretinide.
  • the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.
  • the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i.
  • the additional therapeutic agent is a microbiome modulator, such as EDP-1815, KB-109.
  • the additional therapeutic agent is an estrogen receptor antagonist, such as tamoxifen.
  • the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide.
  • the additional therapeutic agent is a GNRH receptor antagonist, such as degarelix.
  • the additional therapeutic agent is a sex hormone modulator, such as dutasteride.
  • the additional therapeutic agent is a calpain inhibitor, such as BLD-2660.
  • the additional therapeutic agent is a GM-CSF ligand inhibitor such as gimsilumab, lenzilumab, namilumab, TJM2 or otilimab.
  • the additional therapeutic agent is a GM-CSF receptor antagonist, such as mavrilimumab.
  • the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.
  • the additional therapeutic agent is an alpha 1 adrenoreceptor antagonist such as prazosin.
  • the additional therapeutic agent is a neuropilin 2 inhibitor, such as ATYR-1923.
  • the additional therapeutic agent is an activated calcium (CRAC) channel inhibitor, such as CM- 4620.
  • the additional therapeutic agent is a proto-oncogene Mas agonist, such as BIO101.
  • the additional therapeutic agent is a DPP4 inhibitor, such as saxagliptin, sitagliptin, alogliptin, linagliptin.
  • the additional therapeutic agent is a sodium glucose cotransporter type 2 (SGLT-2) inhibitor such as dapagliflozin propanediol.
  • the additional therapeutic agent is a fractalkine receptor inhibitor such as KAND-567.
  • the additional therapeutic agent is an alpha2-receptor agonist.
  • the additional therapeutic agent is dexmedetomidine.
  • the additional therapeutic agent is a mCBM40 (multivalent carbohydrate-binding module Family 40 domain) product, for example the additional therapeutic agent is neumifil.
  • the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine.
  • the additional therapeutic agent is tranilast.
  • the additional therapeutic agent is a histamine H2 receptor antagonist.
  • the additional therapeutic agent is famotidine.
  • the additional therapeutic agent is anti-histamine.
  • the additional therapeutic agent is cloroperastine or clemastine.
  • the additional therapeutic agent is a vasoactive intestinal peptide receptor 1 agonists, such as aviptadil.
  • the additional therapeutic agent is a drug that treats acute respiratory distress syndrome (ARDS).
  • the additional therapeutic agent is a peptide, for example the additional therapeutic agent is BIO-11006.
  • the additional therapeutic agent is aliposomal formulation, for example the additional therapeutic agent is LEAF-4L6715, LEAF-4L7520.
  • the additional therapeutic agent is a respiratory stimulant, such as almitrine.
  • the additional therapeutic agent is a bronchodilator, such as brensocatib or formoterol.
  • the additional therapeutic agent is an anti-LIGHT antibody, such as CERC-002.
  • the additional therapeutic agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE.
  • the compounds described herein are used in combination with respiratory-specific small interfering RNA therapies. In some embodiments, these therapies are delivered by a nebulizer.
  • the additional therapeutic agent is a vimentin modulators.
  • the additional therapeutic agent is pritumumab.
  • the additional therapeutic agent is hzVSF-v13.
  • the additional therapeutic agent is a modulator of Nspl5 (nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, NSC-306711 and N-65828.
  • the additional therapeutic agent is a xanthine dehydrogenase inhibitor, such as oxypurinol (XRx-101).
  • the additional therapeutic agent is a cathepsin L-inhibitor.
  • the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825 or ONO-5334.
  • the additional therapeutic agent is a Transforming growth factor beta (TGF- ⁇ ) inhibitor.
  • the additional therapeutic agent is OT-101.
  • the additional therapeutic agent is a N-methyl-D-aspartate (NMDA) receptor antagonist.
  • the additional therapeutic agent is ifenprodil.
  • the additional therapeutic agent is a glycolysis inhibitor.
  • the additional therapeutic agent is WP-1122.
  • the additional therapeutic is a Leukotriene D4 antagonist, such as montelukast.
  • the additional therapeutic is a Leukotriene BLT receptor antagonist, such as ebselen.
  • the additional therapeutic is a tubulin inhibitor, such as VERU-111 or colchicine.
  • the additional therapeutic agent is a glucosylceramide synthase inhibitor such as miglustat.
  • the additional therapeutic agent is a Nrf2 activator, such as PB 125.
  • the additional therapeutic agent is a Rev protein modulator, such as ABX464.
  • the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV-15).
  • the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as PPP003.
  • the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide.
  • the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, aspirin/dipyridamole.
  • the additional therapeutic agent is an antitoxin such as CAL02.
  • the additional therapeutic agent is a nitric oxide stimulant, such as GLS-1200.
  • the additional therapeutic agent is an apelin receptor agonist, such as CB-5064.
  • the additional therapeutic agent is a complement inhibitor, such as ravulizumab.
  • the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSFlR) inhibitor, such as avdoralimab.
  • CSFlR colony-stimulating factor 1 receptor
  • the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, zilucoplan, and C5a such as BDB-001, IFX-1, advoralimab, In some embodiments, the additional therapeutic agent is a complement C 1 s inhibitor, such as cone stat alpha. In some embodiments, the additional therapeutic agent is a C3 inhibitor, such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor 1 alpha 2 inhibitor, such as plitidepsin.
  • the additional therapeutic agent is an angiopoietin ligand-2 inhibitor, such as L Y-3127804.
  • the additional therapeutic agent is a lysine specific histone demethylase 1 inhibitor, such as vafidemstat.
  • the additional therapeutic agent is a hyaluronan inhibitor.
  • the additional therapeutic agent is a proton pump inhibitor, such as omeprazole.
  • the additional therapeutic agent is an anti-viroporin therapeutic.
  • the additional therapeutic agent is BIT-314 or BIT-225.
  • the additional therapeutic agent is coronavirus E protein inhibitor.
  • the additional therapeutic agent is BIT-009.
  • additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.
  • the compounds disclosed herein are used in combination with cell therapy, such as allogeneic natural killer cells, BM-Allo.MSC, CAStem, IL-15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, partially HLA-matched Virus Specific T cells (VSTs), RAPA-501, or SARS-CoV-2 Specific T Cells.
  • cell therapy such as allogeneic natural killer cells, BM-Allo.MSC, CAStem, IL-15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, partially HLA-matched Virus Specific T cells (VSTs), RAPA-501, or SARS-CoV-2 Specific T Cells.
  • VSTs partially HLA-matched Virus Specific T cells
  • RAPA-501 RAPA-501
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • the combination therapy may provide "synergy" and "synergistic", i.e.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • Embodiment 5 The compound of any one of Embodiments 1-4
  • Embodiment 6 The compound of any one of Embodiments 1-5, having the Formula: pharmaceutically acceptable salt thereof.
  • Embodiment 7 A pharmaceutical composition comprising at least one compound of any one of Embodiments 1-6, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 8 A method of inhibiting an RNA-dependent RNA polymerase in a patient infected with a virus, comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 9 A method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 10 The method of Embodiment 8 or 9, wherein the virus of Embodiment 8 comprises, or the viral infection of Embodiment 9 is caused by at least one virus selected from the table below listing the virus families and the respective viruses thereunder:
  • Embodiment 11 The method of Embodiment 9, wherein the viral infection is caused by at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus.
  • Ebola Mala
  • Ebola (Kikwit) virus Bundibugyo virus
  • Sudan virus Marburg virus
  • RSV respiratory syncytial virus
  • Nipah virus measles virus
  • parainfluenza virus Middle Eastern Respiratory Syndrome (MERS) virus
  • SARS-CoV South Asian
  • Embodiment 12 The method of Embodiment 11, wherein the viral infection is caused by SARS-COV- 2 and its variants selected from the group consisting of delta, epsilon, kappa, zeta, UK SARS- COV-2 variant B.1.1.7 and South Africa SARS-CoV-2501.V2.
  • Embodiment 13 The method of any one of claims 8-12, further comprising administering at least one additional antiviral agent selected from the group consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, an integrase inhibitor and/or an entry inhibitor.
  • Embodiment 14 The method of Embodiment 13, wherein the protease inhibitor comprises at least one selected from the group consisting of PF-07321332, islatravir and lenacapavir.
  • Embodiment 15 The method of Embodiment 14, wherein the protease inhibitor is PF-07321332.
  • Embodiment 16 The method of any one of Embodiment s 8-15, wherein the compound is administered via a route selected from the group consisting of oral, inhalation, parenteral and implants.
  • Embodiment 17 The method of any one of Embodiment s 8-16, wherein the administration is for pre- exposure or post-exposure prophylaxis.
  • Therapeutically effective amounts of a compound described herein may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous, intrasternal or subcutaneous) topical (e.g., application to skin) administration, or through an implant.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous, intrasternal or subcutaneous) topical (e.g., application to skin) administration, or through an implant.
  • parenteral e.g., intramuscular, intravenous, intrasternal or subcutaneous
  • topical e.g., application to skin
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • No.5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • the compositions are comprised of in general, a compound described herein in combination with at least one pharmaceutically acceptable carrier/excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be chosen from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound described herein in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound described based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • a compound described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which a compound described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein.
  • a pharmaceutical composition in unit dosage form containing such other drugs and a compound described herein is preferred.
  • the combination therapy may also include therapies in which a compound described herein and one or more other drugs are administered on different overlapping schedules.
  • a compound described herein and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, a pharmaceutical composition described herein also can include those that contain one or more other active ingredients, in addition to a compound described herein.
  • reaction mixture was stirred at 60 °C for 45 min. After completion of reaction by TLC, solvent was evaporated and dried under reduced pressure to give a residue. The residue was basified by saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 X 50 mL). Then organic layer was washed with cold water (50 mL) and brine (50 mL).
  • reaction was concentration in vacuo then diluted with EtOAc (50 mL) and H 2 O (50 mL), before adding saturated aqueous NaHCO 3 (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), then the combined organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • Examples 31-37 Compounds 31-37 were prepared by using the procedure followed for the compound 30.
  • Example 38 Compounds 38 was prepared by using the procedure followed for the compound 39.
  • Example 39 and 56 Synthesis of ,4]triazin-7-yl)-2-cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 39) (2R,3R,4S,5R) ⁇ 2 ⁇ (4 ⁇ aminopyrrolo[1,2 ⁇ f][1,2,4]triazin ⁇ 7 ⁇ yl) ⁇ 3,4 ⁇ dihydroxy ⁇ 5 ⁇ (hydroxymethyl)tetrahydrofuran ⁇ 2 ⁇ carbonitrile (1 g, 3.43 mmol), 4- dimethylaminopyridine (127 mg, 1.04 mmol), and phenylacetic acid (1.43 g, 10.5 mmol) were combined with DMF (7.5 mL) and MeCN (34 mL) under argon and chilled to
  • Example 42 Compound 42 was prepared by using the procedure followed for the compound 41.
  • Example 43 Compound 43 was prepared by using the procedure followed for the compound 39.
  • Example 44 Compound 44 was prepared by using the procedure followed for the compound 41.
  • Example 45 Compound 45 was prepared by using the procedure followed for the compound 39.
  • Example 46 Compound 46 was prepared by using the procedure followed for the compound 41.
  • Example 47 Compound 47 was prepared by using the procedure followed for the compound 39.
  • Examples 48-49 Compounds 48-49 were prepared by using the procedure followed for the compound 41.
  • Examples 50-52 Compounds 50-52 were prepared by using the procedure followed for the compound 39.
  • reaction mixture was stirred at 0°C for 3 h. After depletion of starting material, the reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound.
  • Example 54 Compound 54 was prepared by using the procedure followed for the compound 53.
  • Example 55 Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy- 2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 55)
  • Example 56 Compound 56 was prepared as a byproduct during the synthesis of the compound 39.
  • DCC 71 mg, 0.344 mmol
  • DMAP 2 mg, 0.018 mmol
  • phenylacetic acid 43 mg, 0.317 mmol
  • (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (30 mg, 0.091 mmol) in DCM (4 mL)
  • Step 2 (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile
  • Y (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 0.344 mmol) was dissolved in MeCN (10 mL), Cs 2 CO 3 (168 mg, 0.516 mmol) was added, cyclopropanamine in MeCN (2 mL) was added.
  • Step 3 (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1 triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (150 mg, 0.249 mmol) was dissolved in DCM (10 mL) and cooled to -78 o C under N 2 , then boron trichloride (146 mg, 1.245 mmol) was added and the mixture was stirred at -78 o C for 1 hour.
  • DCM 10 mL
  • boron trichloride 146 mg, 1.245 mmol
  • Example 59 Compound 59 was prepared by using the procedure followed for the compound 60.
  • Example 60 Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 60) 4-Dimethylaminopyridine (5.2 mg, 0.043 mmol), EDC-HCl (199 mg, 1.04 mmol), and phenylacetic acid (141 mg, 1.04) were dissolved in DCM (10 mL) under argon at 0° C.
  • Examples 61-64 Compounds 61-64 were prepared by using the procedure followed for the compound 60.
  • Step 2 4-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4- hydroxytetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid (65) A solution of (2R,3S,4R,5R)-5- ⁇ 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl ⁇ -5-cyano-2- ⁇ [( ⁇ [(2S)-1-(2-ethylbutoxy)-1-oxoprop)-7-yl ⁇ [( ⁇ [(2S)-1-(2-ethylbutoxy)-1-oxoprop
  • Example 68 Compound 68 was prepared by using the procedure followed for the compound 69.
  • Example 69 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L- alaninate (Compound 69) Preparation of E: To a solution of naphthalen-1-ol (5.0 g, 34.7 mmol) and phosphoryl trichloride (5.3 g, 34.7 mmol) in Et 2 O (50 mL) under nitrogen at -78 °C was added a solution of TEA (3.5 g, 34.7 mmol) in Et 2 O (10 mL) dropwise.
  • TEA 3.5 g, 34.7 mmol
  • Examples 71-73 Compounds 71-73 were prepared by using the procedure followed for the compound 70.
  • Example 74 Compound 74 was prepared by using the procedure followed for the compound 75.
  • Example 75 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1 triazin-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 75) Preparation of K: A mixture of 2-ethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)
  • Example 76 Compound 76 was prepared by using the procedure followed for the compound 75.
  • Example 77 Compound 77 was prepared by using the procedure followed for the compound 78.
  • Example 78 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-phenylalaninate (Compound 78) Preparation of A1: (tert-butoxycarbonyl)-L-phenylalanine (5.0 g, 24.6 mmol) was added to a stirred solution of 2-ethylbutan-1-ol (3.01 g, 29.5 mmol) in DCM (50 mL) at 0 o C, then EDCI (9.40 g, 49.2 mmol) and
  • Example 79 Compound 79 was prepared by using the procedure followed for the compound 78.
  • Biological Examples Virus generation Vero E6 cells (ATCC CRL-1586) were plated in a T225 flask with complete DMEM (Corning 15-013-CV) containing 10% FBS, 1 ⁇ PenStrep (Corning 20-002- CL), 2 mM L-Glutamine (Corning 25-005-CL) overnight at 37°C 5% CO 2 .
  • the media in the flask was removed and 2 mL of SARS-CoV-2 strain USA-WA1/2020 (BEI Resources NR- 52281) in complete DMEM was added to the flask at an MOI of 0.5 and was allowed to incubate for 30 minutes at 34°C 5% CO 2 . After incubation, 30 mL of complete DMEM was added to the flask. The flask was then placed in a 34°C incubator at 5% CO 2 for 5 days. On day 5 post infection the supernatant was harvested and centrifuged at 1,000 ⁇ g for 5 minutes. The supernatant was filtered through a 0.22 ⁇ M filter and stored at -80°C. HeLa-ACE2 stable cell line.
  • HeLa-ACE2 cells were generated through transduction of human ACE2 lentivirus.
  • the lentivirus was created by co-transfection of HEK293T cells with pBOB-hACE2 construct and lentiviral packaging plasmids pMDL, pREV, and pVSV-G (Addgene) using Lipofectamine 2000 (Thermo Fisher Scientific, 11668019). Supernatant was collected 48 h after transfection then used to transduce pre-seeded HeLa cells.12 h after transduction stable cell lines were collected, scaled up and stored.
  • Plated cells were transported to the BSL3 facility where 13 ⁇ L of SARS-CoV-2 diluted in assay media was added to achieve ⁇ 30 – 50% infected cells. Plates were incubated for 24 h at 34°C 5% CO 2 , and then fixed with final concentration of 4% formaldehyde for 1 h at 34°C 5% CO 2. Plates were washed with 1xPBS 0.05% Tween 20 in between fixation and subsequent primary and secondary antibody staining. Human polyclonal plasma diluted 1:500 in Perm/Wash buffer (BD Biosciences 554723) was added to the plate and incubated at RT for 2 h.
  • Perm/Wash buffer BD Biosciences 554723
  • Calu-3 high-content screening assay The assay is carried out as outlined for the HeLa- ACE2 assay, with the following exceptions. Calu-3 cells (ATCC HTB-55), a kind gift from Dr. Catherine Chen at NCATS/NIH and Dr.
  • HeLa-ACE2 cells were seeded in the assay-ready plates at 400 cells/well in DMEM with 2% FBS and plates were incubated for 24 h at 37°C 5% CO 2 .
  • Calu-3 cells were seeded in MEM with 2% FBS at a density of 600 cells per 5 ⁇ L per well and plates were incubated for 48 h at 37°C 5% CO 2 .
  • 2 ⁇ L of 50% Cell-Titer Glo (Promega No G7573) diluted in water was added to the cells and luminescence measured on an EnVision Plate Reader (Perkin Elmer).
  • Example 80 Results from the assays and characterizing data on exemplary compounds are presented in Table 2 below.
  • Acclimation/Quarantine Following arrival, animals were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animals were acclimated for at least 3 days before being placed on study. Animal Husbandry: Animals were group housed during acclimation and individually housed during the study. The animal room environment will be controlled (target conditions: temperature 18 to 26°C, relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Temperature and relative humidity were monitored daily.
  • Blood/Plasma processing Blood Blood samples were processed for plasma by centrifugation at approximately 4 °C, 3000 g 15 min within half an hour of collection. Plasma samples was stored in polypropylene tubes, quick frozen over dry ice and kept at ⁇ 70 ⁇ 10 °C until LC/MS/MS analysis. 6. Sample Analysis Dose formulation concentration verification ⁇ Aliquots of the formulations were collected in the middle position of each dose formulation in duplicate ⁇ The concentrations of the test compound in dose formulation samples were determined by the LC/UV or LC/MS/MS method Bioanalytical method and sample analysis ⁇ LC-MS/MS methods for the quantitative determination of test compound in corresponded biological matrix was developed under non-GLP compliance.
  • Sensitivity the LLOQ will be tried to target 1 ⁇ 3 ng/mL.
  • Carryover the mean calculated carry-over concentration in the single blank matrix immediately after the highest standard injection should be £ LLOQ. If the carryover could’t meet the criteria, then the percent of carryover should be estimated following in-house bioanalytical SOP. 7.
  • Data Analysis Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. C max , T max , T 1 ⁇ 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) , %F and graphs of plasma concentration versus time profile were reported.
  • Example 81 Compounds 19, 25, 39, 59, GS-441524, GS-5734 and GS-621763 were subjected to a single dose Cyno/rhesus macaque PK studies via oral route of administration with equivalent doses of 2.3-10 mg/kg of GS-441524.
  • Oral administration of comp 39 shows ⁇ 9x increase in dose-normalized (DN) area under curve (AUC) exposure vs. GS-441524 in Rhesus; ⁇ 5.2x better DN AUC and 4x better MRT than GS-621763.
  • DN dose-normalized
  • AUC area under curve
  • Comp 39 is 3-fold more stable in a human primary hep assay than GS-5734 (t1/2: 21.5 vs 7.5 min) and has improved permeability Caco-2 Papp A-B/B-A than GS-5734 (2.2 vs 0.1).
  • compounds 19, 25, 59 have shown improved DN AUC by 1.8x, 3.8x and 2.2x fold respectively when compared to GS-441524 in Cyno PK studies.
  • Compounds 19 and 25 have higher Cmax than compound 39, but faster elimination and lower AUC.
  • Table 3 shows the Cyno/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, GS- 5734 and GS-621763 (structure shown below) following PO administration at 2.3-10 mg/kg equivalent dose of GS-441524.
  • the data are shown in graphic form in Figure 1.
  • the present invention provides an approach to improve oral exposure by modifying RDV or its parent nucleoside (GS-441524) to increase absorption.
  • This patent application discloses various molecules that are ester prodrugs of GS-441524 that show increased absorption and exposure.

Abstract

Provided herein are compounds of Formula (I) as disclosed herein, pharmaceutical compositions comprising said compounds, and methods of using said compounds for the treatment and/or prevention of various viral infections, such as SARS-CoV-2 infections.

Description

ANTIVIRAL PRODRUGS AND FORMULATIONS THEREOF CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. provisional patent application No.63/284,952, which was filed on December 1, 2021, and which is hereby incorporated by reference in its entirety. FIELD OF INVENTION This invention relates to antiviral compounds and compositions useful for the treatment of various viral infections, such as SARS-CoV-2 infections. BACKGROUND OF THE DISCLOSURE Nucleoside analogs have been utilized as small-molecule, broad-spectrum, direct- acting antivirals for the prevention and treatment of viral infections1. For RNA viruses, such compounds target the RNA-dependent RNA polymerase (RDRP) which carries out the key viral RNA synthesis reactions. RDRPs are attractive drug targets because they are essential for virus growth, are not encoded by the mammalian host cell and are well-conserved among viral families2. For SARS-CoV-2 the RDRP is non-structural protein (nsp) 12. Nsp12 associates with nsp7 and nsp8 in order to replicate the SARS-COV-2 genome. To date, nucleoside analogs that selectively target the RDRP have been the most promising approach to SARS-CoV-2 inhibition. Currently, there are ribonucleoside analogs that are approved by a stringent regulatory authority; such as Remdesivir (RDV; GS-5734, registered by Gilead Sciences as VEKLURY) (whose structure is show below) and are undergoing mid-stage clinical development3-4, for the treatment of SARS-CoV-2 infections.
Figure imgf000003_0001
Remdesivir functions as a non-obligate or delayed RNA chain terminator. Delayed chain termination occurs when a nucleotide analogue has a free 3-OH group required for the addition of natural nucleotides. The incorporation of the delayed chain terminator, however, perturbs the RNA structure, and RNA synthesis is halted. In SARS-CoV-1, SARS-CoV-2, and MERS-CoV, remdesivir-TP incorporation consistently results in chain termination. Remdesivir (RDV, GS-5374), a nucleotide analog prodrug and an RNA-dependent RNA polymerase (RdRp) inhibitor with broad antiviral activity, demonstrated positive clinical endpoints in a Phase III Adaptive COVID-19 Treatment Trial (median time to recovery shortened from 15 to 11 days)5 that justified its emergency use authorization by the US Food & Drug Administration for treatment of hospitalized COVID-19 patients6. However, its intravenous delivery makes the discovery of new or supplemental therapies that produce greater clinical improvements and can be administered outside of a hospital setting (i.e. orally) highly desirable. As mentioned, RDV is administered intravenously due to the drug’s poor hepatic stability and low plasma/serum stability, with each infusion taking up to two hours and requiring daily administration for either 5 or 10 days. Accordingly, alternative therapies that improve oral exposure is desirable. The present invention provides such alternatives. WO 2012/050961 and WO 2012/050956 refer to antiviral prodrugs and pharmaceutical compositions thereof. WO 2021/154687 refers to methods for treating SARS COV-2 infections. References: 1. Geraghty, R. J.; Aliota, M. T.; Bonnac, L. F., Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 2021, 13 (4). 2. Cannalire, R.; Cerchia, C.; Beccari, A. R.; Di Leva, F. S.; Summa, V., Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities. J Med Chem 2020. 3. Study of MK-4482 for Prevention of Coronavirus Disease 2019 (COVID-19) in Adults (MK-4482-013) (MOVe-AHEAD). https://clinicaltrials.gov/ct2/show/NCT04939428. 4. Study to Evaluate the Effects of RO7496998 (AT-527) in Non-Hospitalized Adult and Adolescent Participants With Mild or Moderate COVID-19 (MORNINGSKY). https://clinicaltrials.gov/ct2/show/NCT04889040. 5. Health, N. I. o., NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19.2020. 6. Administration, U. S. F. D., Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. Administration, U. S. F. D., Ed. U.S. Food & Drug Administration: 2020. SUMMARY OF THE DISCLOSURE Some embodiments described herein relate to a compound of Formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-CH(CH3)2; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; and (e) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen. The application further provides a compound of Formula (I)
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-(C1-C6)alkyl; when R4 = hydrogen, then R1, R2, and R3 cannot all be -C(=O)-CH(CH3)2 -C(=O)-CH3 - C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-(C1-C6)alkyl(C3-C7)cycloalkyl or -C(=O)- cyclopropyl; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; (e) when R2 = R3 and is selected from hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)- cyclopropyl, and R4 is hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)-cyclopropyl, then R1 cannot be -C(=O)-CH(CH3)2 , -C(=O)-hetero(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, - C(=O)((C1-C6)alkylPh((NHC=OO(C1-C6)alkyl, -C(=O)((C1-C6)alkyl((NHC=OO(C1- C6)alkyl, -C(=O)-hetero(C1-C6)alkyl-C(=O)O-hetero(C1-C6)alkyl, -C(=O)-hetero(C1- C6)alkyl-C(=O)OH, or -C(=O)-hetero(C1-C6)alkyl; (f) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen; and (g) when R2 = R3= R4= hydrogen, R1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C1-C10)alkyl, -C(=O)-(C1-C10)alkyl-C(=O)-(C1-C6)alkyl, -C(=O)-(C1- C6)alkenyl, -C(=O)-(C1-C6)alkynyl, -C(=O)-halo(C1-C6)alkyl, -C(=O)-halo(C1-C6)alkenyl, - C(=O)-hetero(C1-C6)alkyl, -C(=O)-hetero(C1-C6)alkenyl, -C(=O)-(C3-C7)cycloalkyl, -C(=O)- (C1-C6)alkyl-(C3-C7)cycloalkyl, -C(=O)-(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3- C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3-C7)heterocycloalkyl-(C1-C6)alkyl, -C(=O)- halo(C3-C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)cycloalkyl, -C(=O)-hydroxy(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)cycloalkyl, -C(=O)-amino(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)cycloalkyl, -C(=O)-(C1-C6)heteroalkyl(C3- C7)cycloalkyl, and -C(=O)-(C1-C6)alkyl-(C1-C6)heteroalkyl(C3-C7)cycloalkyl, -C(=O)- halo(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)heterocycloalkyl, -C(=O)- hydroxy(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)heterocycloalkyl, - C(=O)-amino(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)heterocycloalkyl, - C(=O)-(C1-C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C1- C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)heteroalkyl-C(=O)-(C1-C6)alkyl, - C(=O)-(C1-C6)heteroalkyl-phenyl, and -C(=O)-(C1-C6)heteroalkyl-(C5-C8)heteroaryl. Some embodiments described herein also provide a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Some embodiments described herein also provide a method of inhibiting an RNA- dependent RNA polymerase in a patient infected with a virus, or a method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows in graphic form the Cyano/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, and GS-621763 following PO (oral) administration at 2.3-10 mg/kg equivalent dose of GS-441524. DETAILED DESCRIPTION OF THE DISCLOSURE Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein. “Patient” includes both human and animals. “Patient” and “subject” are used interchangeably herein. When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl. “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C1–15 alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C1–14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C1–13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C1–11 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n– pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n– octyl (C8) and the like. “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3–14 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3–10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3–7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10 carbocyclyl”). Exemplary C3–6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8 carbocyclyl groups include, without limitation, the aforementioned C3–6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3–10 carbocyclyl groups include, without limitation, the aforementioned C3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon–carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3–14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5–10 cycloalkyl”). Examples of C5–6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3–6 cycloalkyl groups include the aforementioned C5–6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8 cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][1,4]diazepinyl, 1,4,5,7–tetrahydropyrano[3,4–b]pyrrolyl, 5,6–dihydro–4H–furo[3,2–b]pyrrolyl, 6,7–dihydro– 5H–furo[3,2–b]pyranyl, 5,7–dihydro–4H–thieno[2,3–c]pyranyl, 2,3–dihydro–1H– pyrrolo[2,3–b]pyridinyl, 2,3–dihydrofuro[2,3–b]pyridinyl, 4,5,6,7–tetrahydro–1H–pyrrolo- [2,3–b]pyridinyl, 4,5,6,7–tetrahydrofuro[3,2–c]pyridinyl, 4,5,6,7–tetrahydrothieno[3,2– b]pyridinyl, 1,2,3,4–tetrahydro–1,6–naphthyridinyl, and the like. “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl (α-naphthyl) and 2–naphthyl (β-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. “Heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds. Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound. Exemplary non-hydrogen substituents may be selected from the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –N(Rbb)2, –N(ORcc)Rbb, –SH, – SRaa, –C(=O)Raa, –CO2H, –CHO, –CO2Raa, –OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, – OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, –NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, – C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, –C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, –NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, – S(=O)Raa, –OS(=O)Raa, -B(ORcc)2, C1–10 alkyl, C2–10 alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, or two geminal hydrogens on a carbon atom are replaced with the group =O; each instance of Raa is, independently, selected from the group consisting of C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, or two Raa groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from the group consisting of hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, – SO2N(Rcc)2, –SORaa, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, or two Rbb groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rcc is, independently, selected from the group consisting of hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, or two Rcc groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; and each instance of Rdd is, independently, selected from the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC1–6 alkyl, –ON(C1–6 alkyl)2, –N(C1–6 alkyl)2, – N(OC1–6 alkyl)(C1–6 alkyl), –N(OH)(C1–6 alkyl), –NH(OH), –SH, –SC1–6 alkyl, –C(=O)(C1–6 alkyl), –CO2H, –CO2(C1–6 alkyl), –OC(=O)(C1–6 alkyl), –OCO2(C1–6 alkyl), –C(=O)NH2, – C(=O)N(C1–6 alkyl)2, –OC(=O)NH(C1–6 alkyl), –NHC(=O)( C1–6 alkyl), –N(C1–6 alkyl)C(=O)( C1–6 alkyl), –NHCO2(C1–6 alkyl), –NHC(=O)N(C1–6 alkyl)2, –NHC(=O)NH(C1– 6 alkyl), –NHC(=O)NH2, –C(=NH)O(C1–6 alkyl),–OC(=NH)(C1–6 alkyl), –OC(=NH)OC1–6 alkyl, –C(=NH)N(C1–6 alkyl)2, –C(=NH)NH(C1–6 alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6 alkyl)2, –OC(NH)NH(C1–6 alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6 alkyl)2, – NHC(=NH)NH2, –NHSO2(C1–6 alkyl), –SO2N(C1–6 alkyl)2, –SO2NH(C1–6 alkyl), –SO2NH2,– SO2C1–6 alkyl, -B(OH)2, -B(OC1–6 alkyl)2,C1–6 alkyl, C1–6 perhaloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclyl, C6–10 aryl, 3–to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rdd substituents on a carbon atom may be joined to form =O. “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I). It should be noted that in hetero-atom containing ring systems described herein, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000017_0001
there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000018_0001
are considered equivalent unless otherwise specified. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. “Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition described herein that is effective in inhibiting the above-noted enzyme, diseases or conditions, and thus producing the desired therapeutic, ameliorative, inhibitory and/or preventative effect. “Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, replacement of a carbon by a 13C- or 14C- enriched carbon, and/or replacement of an oxygen atom with 18O, are within the scope of the disclosure. Other examples of isotopes include 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl and 123I. Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays. Certain isotopically-labelled compounds of Formula (I), (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like 11C or 18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half-lives (t1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The compounds described herein can also be used in combination with one or more additional therapeutic and/or prophylactic agents. As such, also provided herein are methods of treatment or prevention of the various viral infections provided herein, wherein the methods comprise administering to a subject in need thereof a compound of the disclosure and a therapeutically effective amount of one or more additional therapeutic and/or prophylactic agents (“therapeutic agent” is interchangeable with “prophylactic agent” as used herein). Accordingly, the compounds of the present invention and the additional therapeutic agents can be utilized for pre-exposure and post-exposure prophylaxis. In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2' -deoxyuridine analogues, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A inhibitors, NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulators, oligonucleotides, antimitotic inhibitors, and combinations thereof. In some embodiments, the additional therapeutic agent is a 5-substituted 2' - deoxyuridine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine (bromo vinyl deoxyuridine or “BVDU”), and combinations thereof. In some embodiments, the additional therapeutic agent is a nucleoside analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF) and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, or a combination thereof. In some embodiments, the additional therapeutic agent is ~-D-N4-hydroxycytidine. In some embodiments, the additional therapeutic agent is a pyrophosphate analogue. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet. In some embodiments, the additional therapeutic agent is nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof. In some embodiments, the additional therapeutic agent is sangivamycin, β-d-N4-Hydroxycytidine (NHC), EIDD-2801, EIDD-1931, or a combination thereof. In some embodiments, the antiviral agent is MK-4482 (EIDD-2801). In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof. In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is a HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is a HCV NS3/4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof. In some embodiments, the protease inhibitor is PF-07321332, having the structure
Figure imgf000022_0001
PF-07321332 acts an orally active 3CL protease inhibitor, and the combination of PF- 07321332 with ritonavir is in phase III trials for the treatment of COVID-19. In some embodiments, the protease inhibitor is lenacapavir (GS-6207) that is being developed by Gilead Sciences for the treatment of HIV. It has the structure:
Figure imgf000022_0002
. In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella- zoster immune globulin [VZIG]), and combinations thereof. In some embodiments, the additional therapeutic agent is an acyclic guanosine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogues. For example, in some embodiments, the additional therapeutic agent is selected from a group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is a HCV NS5A or NS5B inhibitor. In some embodiments, the additional therapeutic agent is a NS3/4A protease inhibitor. In some embodiments, the additional therapeutic agent is a NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the nucleoside/nucleotide type. In some embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the nonnucleoside type. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof. In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agents is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor distinct from the compounds of the present invention. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is DAS-181 or XC-221. In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNa-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNa-2a), PegIFNa-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alfa- 2a, pegylated interferon alfa-2b, or a combination thereof. In some examples, the additional therapeutic agent is interferon-beta. For example, the additional therapeutic agent ls interfernn- beta-1 a, such as SNG-001. In some embodiments, the additional therapeutic agent is an inteferon--inducing agent, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent is IL-17 antagonist such as ixekizumab. In some embodiments, the additional therapeutic agent is interferon alfa 2 ligand, secukinumab, IMU-838, or vidofludimus. In some embodiments, the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechins, and combinations thereof. In some embodiments, the additional therapeutic agent is azoximer bromide or IMM-101. In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FVl00, and letermovir, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112 or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir. In some embodiments, the antiviral agent is DFV890. In some embodiments, the antiviral agent is MAS825. In some embodiments, the antiviral agent is emetine. In some embodiments, the antiviral agent is protoporphyrin IX, SnPP protoporphyrin and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivermectin. In some embodiments, the additional therapeutic agent is an agent for treatment of picomavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, L-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picomavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir. In some embodiments, the additional therapeutic agent is an agent for treatment of malaria. For example, the additional therapeutic agent is dihydroartemisinin piperaquine. In some embodiments, the additional therapeutic agent is pyramax. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of coronavirus. In some embodiments, the additional therapeutic agent is selected from a group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporins, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI- 557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino- 5Hpyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (l-N,7-N-bis[3-( dimethylamino )propyl]-3,9-dimethylquinolino[8, 7-h]quinolone- l,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, Filo Vax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPCl inhibitors), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of HCV. In some embodiments, the additional therapeutic agent is a HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938 , ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is a HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of such as GS-9256, vedroprevir, voxilaprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is a NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof. In some embodiments, the additional therapeutic agent is an anti HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti HBV agents include but are not limited to alpha-hydroxytropolones, amdoxovir, antroquinonol, beta- hydroxycytosine nucleosides,, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN- co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-11- 2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL- 007sofosbuvir, ledipasvir, UB-551, and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US 2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335Al (Roche), WO16120186Al (Roche), US2016237090A (Roche), WO16107833Al (Roche), WO16107832Al (Roche), US2016176899A (Roche), WO16102438Al (Roche), WO16012470Al (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is a HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIRHBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-11-04- 26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, the additional therapeutic agent is a HBV capsid inhibitor. In some embodiments, the additional therapeutic agent is an agent for treatment of HIV. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogues, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non- nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies). In some embodiments, the additional therapeutic agent is an immunotherapeutic peptides such as tertomotide. In some embodiments, the additional therapeutic agent is a CCL26 gene inhibitor, such as mosedipimod. In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. In some embodiments, the additional therapeutic agent is a PI3K inhibitor, for example idelalisib or duvelisib. In some examples, the additional therapeutic agent is a HIV combination drug. Examples of the HIV combination drugs include, but are not limited to ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine ); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT +3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA ®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT +3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir , ritonavir, zidovudine and lamivudine. In some embodiments, the additional therapeutic agent is a HIV protease inhibitor. For example, in some embodiments the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS- 1156, and combinations thereof. For example, in some embodiments the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some examples, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof. In some embodiments, the additional therapeutic agent is a HIV integrase inhibitor. For example, in some embodiment, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir and combinations thereof. In some embodiment, the additional therapeutic agent is bictegravir. In some examples, the additional therapeutic agent is selected from a group consisting of bictegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS- 986197, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives, integrase- LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC- 642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T- 169, VM-3500, cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is a HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). In some embodiments, the additional therapeutic agent is a HIV nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is a HIV non- nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogue. In some embodiments, the additional therapeutic agent is a HIV capsid inhibitor. In some embodiments, the additional therapeutic agent is a HIV nucleoside or nucleotide inhibitor of reverse transcriptase. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP- 1461, and combinations thereof. In some examples, the additional therapeutic agent is a HIV non-nucleoside or nonnucleotide inhibitor of reverse transcriptase. For example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM- 023, PC-1005, elsulfavirine rilp (VM-1500), combinations thereof. In some embodiments, the additional therapeutic agents are selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT +3TC); EPZICOM® (LIVEXA ®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT +3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate. In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone. In some embodiments, the additional therapeutic agent is an inhibitor of Bruton tyrosine kinase (BTK, AGMXI, AT, ATK, BPK, IGHD3, IMDl, PSCTKl, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S )-6-amino-9-( l -(but-2-ynoy l)pyrrolidin-3-y 1)-7-( 4-phenoxypheny l)-7H- purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatirsen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a receptor tyrosine kinase inhibitor (RTKI). In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9). In some embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor. In some embodiments, the additional therapeutic agent is abivertinib maleate (STI-5656). In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor, such as masitinib. In some embodiments, the additional therapeutic agent is a sphingosine kinase-2 (sk2)inhibitor, such as opaganib. In some embodiments, the additional therapeutic agent is a kinase inhibitor such as pacritinib. In some embodiments, the additional therapeutic agent is an Axl tyrosine kinase receptor inhibitor, such as bemcentinib. In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor. In some embodiments, the additional therapeutic agent is a checkpoint kinase inhibitor, such as prexasertib. In some embodiments, the additional therapeutic agent is a MAP kinase inhibitor, such as KTH-222, ATI-450. In some embodiments, the additional therapeutic agent is a mTOR inhibitor, such as sirolimus. In some embodiments, the additional therapeutic agent is a pi3k/ mTOR inhibitor such as dactolisib. In some embodiments, the additional therapeutic agent is a Hsp90 inhibitor, such as ganetespib, ADX-1612. In some embodiments, the additional therapeutic agent is an MEK inhibitor such as ATR-002. In some embodiments, the additional therapeutic agent is a topoisomerase II inhibitor, such as etoposide. In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor, verdinexor. In some embodiments, the additional therapeutic agent is a dual inhibitor of PARPl/2 and Tankyrase 1/2, such as 2X-121. In some embodiments, the additional therapeutic agent is a cyclin dependent kinase inhibitor, such as CYC-065, CYC-202. In some embodiments, the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine. In some embodiments, the additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments, the additional therapeutic agent is a small ubiquitin related modifier inhibitor, such as TAK- 981. In some embodiments, the additional therapeutic agent is an integrin agonist such as 7HP- 349. In some embodiments, the additional therapeutic agent is a BET inhibitor, such as apabetalone. In some embodiments, the additional therapeutic agent is a BRD4 inhibitor, such as CPI-0610, ABBV-744. In some embodiments, the additional therapeutic agent is a ERl inhibitor, such as toremifene. In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (Gl2C), SML-8-73-1 (Gl2C), Compound 3144 (Gl2D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (Gl2C) and K-Ras(Gl2D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPL YISYDPVCRRRR-NH2), and combinations thereof. In some embodiments, the additional therapeutic agent is an alkylating agent, such as melphalan. In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from a group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib. In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, RNA vaccine, live attenuated vaccine, therapeutic vaccine, prophylactic vaccine, protein based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is live-attenuated RSV vaccine MEDI-559, human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof. In some embodiments, the additional therapeutic agent is a HBV vaccine, for example pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, for example zostavax and varivax. In some embodiments, the additional therapeutic agent is a HPV vaccine, for example cervarix, gardasil 9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, a (i) monovalent vaccine for influenza A (e.g. influenza A (H5Nl) virus monovalent vaccine and influenza A (HlNl) 2009 virus monovalent vaccines), (ii) trivalent vaccine for influenza A and B viruses (e.g. Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) quadrivalent vaccine for influenza A and B viruses (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g. Rotarix for rotavirus serotype G 1, G3, G4, or G9 and RotaTeq for rotavirus serotype Gl, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g. Havrix and Vaqta). In some embodiments, the additional therapeutic agent is poliovirus vaccines (e.g. Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g. YFVax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccines ( e.g. Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g. ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g. Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a and hepatitis E virus (HEV) vaccine (e.g. HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine. In some embodiments, the additional therapeutic agent is Ad5-nCoV. In some embodiments, the additional therapeutic agents in the mRNA vaccine BNT-162. In some embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the additional therapeutic agent is Pfizer-BioNTech COVID-19 vaccine. In some embodiments, the additional therapeutic agent is Moderna Covid-19 vaccine. In some embodiments, the additional therapeutic agent is AZD1222 (astrazeneca Covid-19 vaccine). In some embodiments, the additional therapeutic agent is a poliovirus vaccine, e.g. OPV. In some embodiments, the additional therapeutic agent is BNT162al, BNT162bl, BNT162b2, or BNT162c2 (prime/boost, single or multiple doses). In some embodiments, the additional agent is AZD1222 (ChAdOxl nCov-19) vaccine. In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 Prime-boost), Covax-19, or Naso VAX. In some embodiments, the additional therapeutic agents is LUNAR-COV19 (ARCT-021). In some embodiments, the additional agent is TerraCoV2. In some embodiments, the additional agent is COVID-19 S-Trimer. In some embodiments, the additional agent is TNX-1810, TNX-1820, or TNX-1830. In some embodiments, the additional agent is VaxiPatch COVID-19 vaccine. In some embodiments, the additional agent is VBI-2901. In some embodiments, the additional agent is VLA-2001. In some embodiments, the additional agent is exoVACC-SARS-CoV2CoV-2. In some embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-Mor NVX-CoV2373. In some embodiments, the additional agent is BBV152A, B, C, PicoVacc, KBP-COVID-19, MF59 adjuvanted SARS-CoV-2 Sclamp, MVC-COV1901, SCB-2019 (COVID-19 S-Trimer + CpG1018+AS03), TMV-083, V-591, VPM1002, or V-SARS. In some embodiments, the additional therapeutic agent is an antibody, for example a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of the Regeneron antibodies, the Wuxi Antibodies, the Vir Biotechnology Antibodies, antibodies that target the SARS-CoV-2 spike protein, antibodies that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations thereof. In some embodiments, the additional therapeutic agent is anti-SARS CoV antibody CR- 3022. In some embodiments, the additional therapeutic agent is aPD-1 antibody. In some embodiments, the additional therapeutic agent is anti-IL-6R mAb. For example, the additional therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic agent is an antibody that targets specific sites on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein (S-protein). In some embodiments, the additional therapeutic agent is a virus suppressing factor (VSF, HzVSFv13). In some embodiments, the additional therapeutic agent is an anti-CD147 antibody. For example, the additional therapeutic agent is meplazumab. In some embodiments, the additional therapeutic agent is a phosphodiesterase type 4 (PDE4) or phosphodiesterase type 5 (PDE5) inhibitor. In some embodiments, the additional therapeutic agent is a PDE5 inhibitor, for example, the additional therapeutic agent is sildenafil. In some embodiments, the additional therapeutic agent is a PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin. In some embodiments, the additional therapeutic agent is an agent targeting NKGA2. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is NKG2 A B activating NK receptor antagonist, such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor, such as BPI-002. In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as CPI-006. In some embodiments, the additional therapeutic agent is recombinant cytokine gene derived protein injection. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is lamivudine. In some embodiments, the additional therapeutic agent is a RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir and combination thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, pimodivir and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a beta-catenin inhibitor. For example, the additional therapeutic agent is tetrandrine. In some embodiments, the additional therapeutic agent is a trypsin inhibitor, for example the additional therapeutic agent is ulinastatin. In some embodiments, the additional therapeutic agent is TAK-671. In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZl, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat, N afamostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof. In some embodiments, the additional therapeutic agent is selected form the group consisting of JQ-1, RVX-208,silmitasertib, TMCB, apicidin, valproic acid, Bafilomycin Al, E- 52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, Metformin, Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623, Midostaurin, Ruxolitinib, ZINC I 775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, Daunorubicin, GB llO, S-verapamil, AZ3451, and combinations thereof. In some embodiments, the additional therapeutic agent is selected form a group consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof. In some embodiments, the additional therapeutic agent is a drug targeting the coronavirus main protease 3CLpro (e.g. lopinavir). In some embodiments the additional therapeutic agent is a drug targeting the papain-like protease PLpro (e.g., lopinavir). In some examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells (e.g. arbidol). In some embodiments, the additional therapeutic agent is a TMPRSS2 inhibitor (e.g. camostat mesylate). In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as LB ll 48, upamostat, RHB-107, or alpha- I antitrypsin. In some embodiments, the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonodelestat. In some embodiments, the additional therapeutic agent is an a-ketoamide. In some examples, the additional therapeutic agent is a poly-ADP-ribose polymerase 1 (PARPl) inhibitor, for example, the additional therapeutic agent is CVL218. In some embodiments, the additional therapeutic agent is selected from the group consisting of 6' -fluorinated aristeromycin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives, SSYAl0-001, griffithsin, HR2P-Ml, HR2P-M2, P21S10, Dihydrotanshinone E-64-C and E-64- D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, l-thia-4- azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferons, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, Kll 777, camostat, k22, teicoplanin derivatives, benzo- heterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof. In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a of 2019-nCoV virus antibody. In some embodiments, the additional therapeutic agent is LY-CoV555. In some embodiments, the additional therapeutic agent is S309. In some embodiments, the additional therapeutic agent is SAB-185. In some embodiments, the additional therapeutic agent is CB6. In some embodiments, the additional therapeutic agent is STI-1499. In some embodiments, the additional therapeutic agent is JS016. In some embodiments, the additional therapeutic agent is VNAR. In some embodiments, the additional therapeutic agent is VIR-7832 and/or VIR- 7831. In some embodiments, the additional therapeutic agent is REGN-COV2 (REGN10933 + RGN10987) In some embodiments, the additional therapeutic agent is BAT2020, BAT2019. In some embodiments, the additional therapeutic agent is 47D 11. In some embodiments, the additional therapeutic agent is COVI-SHIELD. In some embodiments, the additional therapeutic agent is BRII-196, BRII-198. In some embodiments, the additional therapeutic agent is INM-005, SCTA0l, TY-027, XAV-19. Compositions of the invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infections, preferably, the other active therapeutic agent is active against coronavirus infections, for example 2019-nCoV virus infections. The compounds and compositions of the present invention are also intended for use with general care provided patients with 2019-nCoV viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin Kand zinc sulfate), anti-inflammatory agents ( such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immonumodulatory medications (eg interferon), other small molecule or biologics antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir/ritonavir, EIDD-1931, favipiravir, ribavirine, neutralizing antibodies, etc), vaccines, pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin/piperaquine. In some embodiments, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide. In some embodiments, the compounds disclosed herein are used in combination with amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, cholecalciferol, vitamin C, prednisone, mometasone, or budenoside. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as Panaphix (PAX-1), which inhibit production of pro-inflammatory cytokines. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as NCP-112 which inhibit excessive immune response such as cytokine storm. In some embodiments, the additional therapeutic agent is an antifungal agent, for example itraconazole or 17-0H- itraconazole. In some examples, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrll, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-Ll) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide. In some embodiments, the additional therapeutic agent is CD24Fc. In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonists, such as anakinra. In some embodiments, the additional therapeutic agent is a TLR4 antagonist, such as EB-05. In some embodiments, the additional therapeutic agent is nivolumab, efineptakin alfa, lactoferrin, ozanimod, astegolimab (MSTT1041A, RG-6149), or UTTR1147 A. In some embodiments, the additional therapeutic agent is Ampligen. In some embodiments, the additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor such as MEDI3506. In some embodiments, the additional therapeutic agent is an IL-5 receptor antagonist, such as mepolizumab. In some embodiments, the additional therapeutic agent is an IL-12 inhibitor, such as apilimod. In some embodiments, the additional therapeutic agent is a IL-15 receptor agonist, such as N-803. In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, or a combination thereof. In some embodiments, the additional therapeutic agent is tocilizumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, olokizumab, sirukumab, clazakizumab, levilimab or a combination thereof. In some embodiments, the additional therapeutic agent is a nicotinamide phosphoribosyltransferase inhibitors. For example, the additional therapeutic agent is enamptcumab. In some embodiments, the additional therapeutic agent is a di peptidase 1 (DPEP-1) inhibitor. For example, the additional therapeutic agent is Metablok (LSALT peptide). In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golirnurnab, infliximab, or a combination thereof. In some embodiments, the additional therapeutic agent is a TNF alpha ligand inhibitor, such as XPro1595. In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, olumiant, or a combination thereof. In some examples, the additional therapeutic agent is jaktinib. In some embodiments, the additional therapeutic agent is tofacitinib or TD-0903. In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone. In some embodiments, the additional therapeutic agent is L YT-100. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as dociparstat sodium. In some embodiments, the additional agent is used in the treatment of septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a CCRl antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent targets IKKβ and NFKβ, such as OP-101. In some embodiment, the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone or dexamethasone. In some embodiments, the additional therapeutic agent is an immunosuppressant, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, M-5049. In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758. In some embodiments, the additional therapeutic agent is a IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8). In some embodiments, the additional therapeutic agent is a CD 14 inhibitor, such as IC-14. In some embodiments, the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299. In some embodiments, the additional therapeutic is anti-fibrotic, such as RT- 1840,nintedanib, GB-0139, nintedanib, pamrevlumab. In some embodiments, the additional therapeutic is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777). In some embodiments, the additional therapeutic agent is an A3 adenosine receptor (A3AR) antagonist, for example the additional therapeutic agent is piclidenoson. In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia. For example, the additional therapeutic agent is macrolide antibiotics (e.g. azithromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g. ciprofloxacin and levofloxacin), tetracyclines (e.g. doxycycline and tetracycline), or a combination thereof. In some embodiments, the additional therapeutic agent is XEL 1004. In some embodiments, the additional therapeutic agent is eravacycline. In some embodiments, the compounds disclosed herein are used in combination with pneumonia standard of care (see e.g. Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment for pneumonia generally involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of pneumonia, age and overall health of the individuals. The options include: (i) antibiotics, (ii) cough medicine, and (iii) fever reducers/pain relievers (for e.g. aspirin, ibuprofen (Advil, Motrin IB, others) and acetaminophen (Tylenol, others)). In some embodiments, the additional therapeutic agent is bromhexine anti-cough. In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some examples, the compounds disclosed herein are used in combination with TAK-888 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)). In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immunoglobulin. In some embodiments, the compounds described herein are used in combination with COVID- EIG or COVID-HIG. In some embodiments, the compounds disclosed herein are used in combination with stem cells. For example, in some embodiments, the compounds disclosed herein are used in combination with MultiStem or Remestemcel-L (mesenchymal stem cells). In some embodiments, the compounds described herein are used in combination with allogenic mesenchymal-like cells, for example in combination with PLX cells. In some embodiments, the compounds described herein are used in combination with allogenic cell therapy, for example in combination with CK-0802. In some embodiments, the compounds described herein are used in combination with Pluristem or ACT-20. In some examples, the additional therapeutic agent is an TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531. In some embodiments the additional therapeutic agent is PUL-042. In some embodiments, the additional therapeutic agent is polyinosinic-polycytidylic acid (poly I:C). In some examples, the additional therapeutic agent is selected from the group consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof. In some examples, the additional therapeutic agent is simvastatin or rosuvastatin. In some examples, the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor, or a-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP). In some embodiments, the additional therapeutic agent is a recombinant human angiotensin-converting enzyme 2 (rhACE2), for example APN-01. In some embodiments, the additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the additional therapeutic agent is a partial agonist of A T2 or a partial antagonist of AT 1. In some embodiments, the additional therapeutic agent is L-163491. In some embodiments, the additional therapeutic agent is ACE2-Fc fusion protein, for example the additional therapeutic agent is STI-4398. In some embodiments, the additional therapeutic agent is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan. In some embodiments, the additional therapeutic agent is VP-01, TXA-127. In some embodiments, the additional therapeutic agent is telmisartan. In some embodiments, the additional therapeutic agent is an ACE inhibitor, such as ramipril, captopril, enalapril, or lisonopril. In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as AT-001. In some embodiments, the additional therapeutic agent is a platelet inhibitor. For example, the additional therapeutic agent is dipyridamole. In some embodiments, the additional therapeutic agent is an anti-coagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, fondaparinux. In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201. In some embodiments, the additional therapeutic is a Factor Xlla antagonist, such as garadacimab. In some embodiments, the additional therapeutic agent is a VE-PTP inhibitor, such as razuprotafib. In some embodiments, the additional therapeutic agent is a VIP 2 receptor agonist, such as PB-1046. In some embodiments, the additional therapeutic agent is an anti-thrombotic, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, tranexamic acid. In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, ventaprost, vazegepant, angiotensin 1-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301, sodium nitrite, TRV-027. In some embodiments, the additional therapeutic agent is a blood clotting modulator, such as lanadelumab. In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone. In some embodiments, the additional therapeutic agent is antihypoxic, such as trans-sodium crocetinate. In some embodiments, the additional therapeutic agent is MK-5475. In some embodiments, the additional therapeutic agent is a hypoxia-inducible factor (HF) prolyl hydroxylase-2 (PHD-2) inhibitor such as desidustat or vadadustat. In some embodiments, the additional therapeutic agent is a renin inhibitor, such as aliskiren. In some embodiments, the additional therapeutic agent is a calcium channel inhibitor such as nifedipine. In some embodiments, the additional therapeutic agent is a chelating agent, such as desferal, deferiprone, deferoxamine. In some embodiments, the additional therapeutic agent is a retinoic acid receptor agonist, such as isotretinoin or fenretinide. In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin. In some embodiments, the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i. In some embodiments, the additional therapeutic agent is a microbiome modulator, such as EDP-1815, KB-109. In some embodiments, the additional therapeutic agent is an estrogen receptor antagonist, such as tamoxifen. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide. In some embodiments, the additional therapeutic agent is a GNRH receptor antagonist, such as degarelix. In some embodiments, the additional therapeutic agent is a sex hormone modulator, such as dutasteride. In some embodiments, the additional therapeutic agent is a calpain inhibitor, such as BLD-2660. In some embodiments, the additional therapeutic agent is a GM-CSF ligand inhibitor such as gimsilumab, lenzilumab, namilumab, TJM2 or otilimab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as mavrilimumab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim. In some embodiments, the additional therapeutic agent is an alpha 1 adrenoreceptor antagonist such as prazosin. In some embodiments, the additional therapeutic agent is a neuropilin 2 inhibitor, such as ATYR-1923. In some embodiments, the additional therapeutic agent is an activated calcium (CRAC) channel inhibitor, such as CM- 4620. In some embodiments, the additional therapeutic agent is a proto-oncogene Mas agonist, such as BIO101. In some embodiments, the additional therapeutic agent is a DPP4 inhibitor, such as saxagliptin, sitagliptin, alogliptin, linagliptin. In some embodiments, the additional therapeutic agent is a sodium glucose cotransporter type 2 (SGLT-2) inhibitor such as dapagliflozin propanediol. In some embodiments, the additional therapeutic agent is a fractalkine receptor inhibitor such as KAND-567. In some embodiments, the additional therapeutic agent is an alpha2-receptor agonist. For example, the additional therapeutic agent is dexmedetomidine. In some embodiments, the additional therapeutic agent is a mCBM40 (multivalent carbohydrate-binding module Family 40 domain) product, for example the additional therapeutic agent is neumifil. In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine. In some embodiments, the additional therapeutic agent is tranilast. In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist. In some embodiments, the additional therapeutic agent is famotidine. In some embodiments, the additional therapeutic agent is anti-histamine. In some embodiments, the additional therapeutic agent is cloroperastine or clemastine. In some embodiments, the additional therapeutic agent is a vasoactive intestinal peptide receptor 1 agonists, such as aviptadil. In some embodiments, the additional therapeutic agent is a drug that treats acute respiratory distress syndrome (ARDS). In some embodiments, the additional therapeutic agent is a peptide, for example the additional therapeutic agent is BIO-11006. In some embodiments, the additional therapeutic agent is aliposomal formulation, for example the additional therapeutic agent is LEAF-4L6715, LEAF-4L7520. In some embodiments, the additional therapeutic agent is a respiratory stimulant, such as almitrine. In some embodiments, the additional therapeutic agent is a bronchodilator, such as brensocatib or formoterol. In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as CERC-002. In some embodiments, the additional therapeutic agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE. In some embodiments, the compounds described herein are used in combination with respiratory-specific small interfering RNA therapies. In some embodiments, these therapies are delivered by a nebulizer. In some embodiments, the additional therapeutic agent is a vimentin modulators. For example, the additional therapeutic agent is pritumumab. In some embodiments, the additional therapeutic agent is hzVSF-v13. In some embodiments, the additional therapeutic agent is a modulator of Nspl5 (nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, NSC-306711 and N-65828. In some embodiments, the additional therapeutic agent is a xanthine dehydrogenase inhibitor, such as oxypurinol (XRx-101). In some embodiments, the additional therapeutic agent is a cathepsin L-inhibitor. In some embodiments, the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825 or ONO-5334. In some embodiments, the additional therapeutic agent is a Transforming growth factor beta (TGF-~) inhibitor. For example, the additional therapeutic agent is OT-101. In some embodiments, the additional therapeutic agent is a N-methyl-D-aspartate (NMDA) receptor antagonist. For example, the additional therapeutic agent is ifenprodil. In some embodiments, the additional therapeutic agent is a glycolysis inhibitor. For example, the additional therapeutic agent is WP-1122. In some embodiments, the additional therapeutic is a Leukotriene D4 antagonist, such as montelukast. In some embodiments, the additional therapeutic is a Leukotriene BLT receptor antagonist, such as ebselen. In some embodiments, the additional therapeutic is a tubulin inhibitor, such as VERU-111 or colchicine. In some embodiments, the additional therapeutic agent is a glucosylceramide synthase inhibitor such as miglustat. In some embodiments, the additional therapeutic agent is a Nrf2 activator, such as PB 125. In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as ABX464. In some embodiments, the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV-15). In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as PPP003. In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide. In some embodiments, the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, aspirin/dipyridamole. In some embodiments, the additional therapeutic agent is an antitoxin such as CAL02. In some embodiments, the additional therapeutic agent is a nitric oxide stimulant, such as GLS-1200. In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064. In some embodiments, the additional therapeutic agent is a complement inhibitor, such as ravulizumab. In some embodiments, the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSFlR) inhibitor, such as avdoralimab. In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, zilucoplan, and C5a such as BDB-001, IFX-1, advoralimab, In some embodiments, the additional therapeutic agent is a complement C 1 s inhibitor, such as cone stat alpha. In some embodiments, the additional therapeutic agent is a C3 inhibitor, such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor 1 alpha 2 inhibitor, such as plitidepsin. In some embodiments, the additional therapeutic agent is an angiopoietin ligand-2 inhibitor, such as L Y-3127804. In some embodiments, the additional therapeutic agent is a lysine specific histone demethylase 1 inhibitor, such as vafidemstat. In some embodiments, the additional therapeutic agent is a hyaluronan inhibitor. In some embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole. In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609. In some embodiments, the compounds disclosed herein are used in combination with cell therapy, such as allogeneic natural killer cells, BM-Allo.MSC, CAStem, IL-15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, partially HLA-matched Virus Specific T cells (VSTs), RAPA-501, or SARS-CoV-2 Specific T Cells. It is also possible to combine any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient. Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours ( e.g., 1-12 hours), by administration of a unit dose of a compound of the invention. The combination therapy may provide "synergy" and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination. Embodiments Examples of embodiments of the present application include the following: Embodiment 1 A compound of Formula
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-CH(CH3)2; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; and (e) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen. The application further provides a compound of Formula (I)
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-(C1-C6)alkyl; when R4 = hydrogen, then R1, R2, and R3 cannot all be -C(=O)-CH(CH3)2 -C(=O)-CH3 - C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-(C1-C6)alkyl(C3-C7)cycloalkyl or -C(=O)- cyclopropyl; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; (e) when R2 = R3 and is selected from hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)- cyclopropyl, and R4 is hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)-cyclopropyl, then R1 cannot be -C(=O)-CH(CH3)2 , -C(=O)-hetero(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, - C(=O)((C1-C6)alkylPh((NHC=OO(C1-C6)alkyl, -C(=O)((C1-C6)alkyl((NHC=OO(C1- C6)alkyl, -C(=O)-hetero(C1-C6)alkyl-C(=O)O-hetero(C1-C6)alkyl, -C(=O)-hetero(C1- C6)alkyl-C(=O)OH, or -C(=O)-hetero(C1-C6)alkyl; (f) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen; and (g) when R2 = R3= R4= hydrogen, R1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C1-C10)alkyl, -C(=O)-(C1-C10)alkyl-C(=O)-(C1-C6)alkyl, -C(=O)-(C1- C6)alkenyl, -C(=O)-(C1-C6)alkynyl, -C(=O)-halo(C1-C6)alkyl, -C(=O)-halo(C1-C6)alkenyl, - C(=O)-hetero(C1-C6)alkyl, -C(=O)-hetero(C1-C6)alkenyl, -C(=O)-(C3-C7)cycloalkyl, -C(=O)- (C1-C6)alkyl-(C3-C7)cycloalkyl, -C(=O)-(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3- C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3-C7)heterocycloalkyl-(C1-C6)alkyl, -C(=O)- halo(C3-C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)cycloalkyl, -C(=O)-hydroxy(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)cycloalkyl, -C(=O)-amino(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)cycloalkyl, -C(=O)-(C1-C6)heteroalkyl(C3- C7)cycloalkyl, and -C(=O)-(C1-C6)alkyl-(C1-C6)heteroalkyl(C3-C7)cycloalkyl, -C(=O)- halo(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)heterocycloalkyl, -C(=O)- hydroxy(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)heterocycloalkyl, - C(=O)-amino(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)heterocycloalkyl, - C(=O)-(C1-C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C1- C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)heteroalkyl-C(=O)-(C1-C6)alkyl, - C(=O)-(C1-C6)heteroalkyl-phenyl, and -C(=O)-(C1-C6)heteroalkyl-(C5-C8)heteroaryl. Embodiment 2 The compound and/or pharmaceutically acceptable salt thereof of Embodiment 1, wherein in R1: the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, -C(=O)-(1-methylcyclohexyl), and -C(=O)-(4,4-dimethylcyclohexyl); the -C(=O)-(5 to 6-membered heterocyclyl) with the optional substituents of the 5 to 6-membered heterocyclyl is
Figure imgf000051_0001
the -C(=O)-(C1-C20 alkyl) with the optional substituents of the C1-C20 alkyl is selected from the group consisting of -C(=O)-CH(CH3)2, -C(=O)-CH(CH2CH3)2, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-cyclopentyl, -C(=O)-benzyl, -C(=O)-CH(CH3)- benzyl, -C(=O)-CH(CH3)-phenyl, -C(=O)-C(CH3)3, -C(=O)-CH2-C(CH3)3, -C(=O)-CH2- CH(CH2CH3)2, -C(=O)-CH(CH3)(CH2CH2CH3), -C(=O)-CH(CH3)(CH2CH2CH2CH3), -C(=O)-CH(CH3)((CH2 )4CH3), -C(=O)-(CH2 )5CH3, -C(=O)-CH(CH3)((CH2 )5CH3), -C(=O)-(CH2 )8CH3, -C(=O)-CH(CH3)((CH2 )9CH3), -C(=O)-(CH2 )10CH3, -C(=O)-(CH2 )12CH3, -C(=O)-CH2-(2-fluorophenyl), -C(=O)-CH2-(4-fluorophenyl), -C(=O)- CH2-(3-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)- CH2-(2-Naphthyl); the -C(=O)-(C6-C10 aryl) is selected from the group consisting of -C(=O)-phenyl; the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl) is selected from the group consisting of -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-phenyl), -P(=O)-(NH(CH(CH(CH3)2)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(benzyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(phenyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-Bromophenyl)) -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-1-naphthyl), and -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-2-naphthyl); and the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl) is -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(3-pyridinyl)). Embodiment 3 The compound or a pharmaceutically acceptable salt thereof of Embodiment 1 or 2, wherein in R2 and R3: the -C(=O)-(C1-C10 alkyl) with the optional substituents of the C1-C10 alkyl is selected from the group consisting of -C(=O)-CH3, -C(=O)-(CH2)5-CH3, -C(=O)-benzyl, -C(=O)-CH(CH2CH3)2, -C(=O)-CH(NH2)CH(CH3)2, -C(=O)-CH(NH2)-phenyl, -C(=O)-CH(CH3)2, -C(=O)-CH(CH3)-phenyl, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-(4-fluorophenyl), -C(=O)-CH2-(3-fluorophenyl), -C(=O)-CH2-(2-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)-CH2-(2-naphthyl); the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, and -C(=O)-(4,4- dimethylcyclohexyl); and the -C(=O)-(C6-C10 aryl) is selected from the group consisting of - C(=O)-phenyl. Embodiment 4 The compound or a pharmaceutically acceptable salt thereof of any one of Embodiments 1-3, wherein in R4: the C3-C7 cycloalkyl is selected from the group consisting of cyclopropyl; the –(C=O)-O-C1-C10 alkyl is selected from the group consisting of –(C=O)-O- (CH2)2CH3,and –(C=O)-O-(CH2)4CH3; the –(C=O)-(C1-C10 alkyl) is selected from the group consisting of –(C=O)-benzyl, and -C(=O)-(CH2)2CH3; and the -C(=O)-(C3-C7 cycloalkyl) is selected from the group consisting of -C(=O)-cyclobutyl. Embodiment 5 The compound of any one of Embodiments 1-4, selected from the group consisting of:
Figure imgf000053_0001
,
Figure imgf000054_0001
,
,
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Embodiment 6 The compound of any one of Embodiments 1-5, having the Formula:
Figure imgf000063_0001
pharmaceutically acceptable salt thereof. Embodiment 7 A pharmaceutical composition comprising at least one compound of any one of Embodiments 1-6, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 8 A method of inhibiting an RNA-dependent RNA polymerase in a patient infected with a virus, comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 9 A method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 10 The method of Embodiment 8 or 9, wherein the virus of Embodiment 8 comprises, or the viral infection of Embodiment 9 is caused by at least one virus selected from the table below listing the virus families and the respective viruses thereunder:
Figure imgf000064_0001
Embodiment 11 The method of Embodiment 9, wherein the viral infection is caused by at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus. Embodiment 12 The method of Embodiment 11, wherein the viral infection is caused by SARS-COV- 2 and its variants selected from the group consisting of delta, epsilon, kappa, zeta, UK SARS- COV-2 variant B.1.1.7 and South Africa SARS-CoV-2501.V2. Embodiment 13 The method of any one of claims 8-12, further comprising administering at least one additional antiviral agent selected from the group consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, an integrase inhibitor and/or an entry inhibitor. Embodiment 14 The method of Embodiment 13, wherein the protease inhibitor comprises at least one selected from the group consisting of PF-07321332, islatravir and lenacapavir. Embodiment 15 The method of Embodiment 14, wherein the protease inhibitor is PF-07321332. Embodiment 16 The method of any one of Embodiment s 8-15, wherein the compound is administered via a route selected from the group consisting of oral, inhalation, parenteral and implants. Embodiment 17 The method of any one of Embodiment s 8-16, wherein the administration is for pre- exposure or post-exposure prophylaxis. Administration and Pharmaceutical Composition In general, the compounds described herein will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of a compound described herein may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors. In general, compounds described herein will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous, intrasternal or subcutaneous) topical (e.g., application to skin) administration, or through an implant. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No.5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. The compositions are comprised of in general, a compound described herein in combination with at least one pharmaceutically acceptable carrier/excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be chosen from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compressed gases may be used to disperse a compound described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound described based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. A compound described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which a compound described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein. When a compound described herein is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and a compound described herein is preferred. However, the combination therapy may also include therapies in which a compound described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, a compound described herein and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, a pharmaceutical composition described herein also can include those that contain one or more other active ingredients, in addition to a compound described herein. EXAMPLES Synthetic Examples Abbreviations The following abbreviations are used: tetrahydrofuran (THF), dichloromethane (DCM), Acetonitrile (MeCN), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), trifluoroacetic acid (TFA), triethylamine (TEA), diisopropylethylamine (DIPEA), methanol (MeOH), Ethyl acetate (EtOAc), 4-Dimethylaminopyridine (DMAP), N-(3- Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl), N,N'- Dicyclohexylcarbodiimide (DCC). General Examples for the Preparation of Compounds of the Invention The starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008). Details of reagent and reaction options are also available by structure and reaction searches using commercial computer search engines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com). Part I: Preparation of Intermediates Example 1 Synthesis of intermediate-1, -2: Synthesis o ,4]triazin-7-yl)-6-
Figure imgf000068_0001
(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (Intermediate 1)
Figure imgf000068_0002
To a solution of (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy ‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (2.0 g, 6.86 mmol) in acetone (20 mL), were added H2SO4 (0.5 mL) and compound 2,2-dimethoxypropane (4.2 g, 34.33 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 45 min. After completion of reaction by TLC, solvent was evaporated and dried under reduced pressure to give a residue. The residue was basified by saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 X 50 mL). Then organic layer was washed with cold water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude compound which was purified by column chromatography over silica gel (Davisil) (using 0- 5% MeOH in DCM as an eluent) to afford 2.0 g (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4- carbonitrile (Intermediate 1) as off white solid. [TLC system: MeOH:DCM (0.5:9.5); Rf value: 0.2]. LC-MS: m/z= 332.3 (M + H+). Synthesis of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(((tert- butyldimethylsilyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-carbonitrile (Intermediate 2)
Figure imgf000069_0001
Intermediate 2 To a solution of tert-Butyldimethylsilyl chloride (TBSCl) (778 mg, 5.16 mmol) in pyridine (10 mL) was added (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑ dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1 g, 3.43 mmol) followed by 4-dimethylaminopyridine (42 mg, 0.343 mmol). The reaction was stirred at room temperature till SM was no longer observed by LCMS (~24 hrs). The reaction was concentrated by blowing under a N2 stream, then diluted with 0.5N HCl (30 mL) and extracted with EtOAc (3 x 55 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH), affording compound X (340 mg, 24%). LC-MS: m/z= 406.7 (M + H+). Part II: Preparation of Example Compounds Examples 1-3 Compounds 1-3 were prepared by using the procedure followed for the compound 4 as shown below. Example 4
Figure imgf000070_0001
Synthesis of ( 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-
Figure imgf000070_0002
dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) Preparation of A: Intermediate 1 (450 mg, 1.36 mmol) and 4-dimethylaminopyridine (17 mg, 0.139 mmol) were dissolved in DCM (15 mL) under argon and chilled to 0° C. After 30 min at 0° C, phenylacetic acid (236 mg, 1.73 mmol) and DCC (395 mg, 1.91 mmol) were added to the reaction, and then the mixture was stirred at room temperature for an hour. The mixture was filtered and the solid was rinsed with DCM (2 x 10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4] triazin-7-yl) -6-cyano-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (529 mg, 87%). LC-MS: m/z= 450.8 (M + H+). Preparation of Compound 4: 1:1 TFA/H2O (9 mL) was chilled to 0° C then added to ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (529 mg, 1.18 mmol) with stirring in an ice bath. The reaction was stirred at room temperature and monitored by LCMS until completion (~2-3 hrs). The reaction was concentration in vacuo then diluted with EtOAc (50 mL) and H2O (50 mL), before adding saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), then the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (0- 5% MeOH in DCM), affording ((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin -7-yl)- 5-cyano -3,4-dihydroxy tetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (337 mg, 70%). LC-MS: m/z= 410.4 (M + H+).1H NMR (500 MHz, DMSO) δ 7.93 (m, 3H), 7.33 – 7.18 (m, 5H), 6.92 (d, J = 4.5 Hz, 1H), 6.78 (d, J = 4.5 Hz, 1H), 6.30 (d, J = 5.8 Hz, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.66 (t, J = 5.3 Hz, 1H), 4.38 – 4.33 (m, 1H), 4.22 (ddt, J = 17.4, 11.8, 6.0 Hz, 2H), 3.94 (q, J = 5.7 Hz, 1H), 3.67 (s, 2H). Alternate Procedure for Preparation of Compound 4: A solution of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (1.1 g, 2.44 mmol) in formic acid (11 mL) was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was evaporated and dried under reduced pressure to get residue. The residue was basified by saturated solution of sodium bicarbonate (30 mL) and extracted with EtOAc (2 X 50 mL). Then organic layer was washed with cold water (50 mL) and Brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude which was purified by column chromatography over silica gel (Davisil) (using 0-5% MeOH in DCM as an eluent) to afford 0.75 g of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-phenyl acetate (Compound 4) as off white solid. LC-MS: m/z= 410.4 (M + H+). Examples 5-28 Compounds 5-28 were prepared by using the procedure followed for the compound 4. Example 29 Compounds 29 was prepared by using the procedure followed for the compound 30. Examples 30
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000071_0003
Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5- (hydroxymethyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 30) Preparation of B: Intermediate 2 (335 mg, 0.826 mmol) and 4-dimethylaminopyridine (10.3 mg, 0.084 mmol) were dissolved in DCM (12 mL) and MeCN (3.5 mL) under argon and chilled to 0°C. After 30 min at 0° C, phenylacetic acid (227 mg, 1.67 mmol) and DCC (392 mg, 1.90 mmol) were added to the reaction, and then the mixture was stirred at room temperature for 2 hrs. The mixture was filtered and the solid was rinsed with MeCN (2 x 10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(((tert- butyldimethylsilyl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2-phenylacetate) (B) (470 mg, 89%). LC-MS: m/z= 642.8 (M + H+). Preparation of Compound 30: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(((tert- butyldimethylsilyl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diyl bis(2-phenylacetate) (B) (315 mg, 0.491 mmol) was dissolved in THF (2.8 mL) under N2. Acetic acid (34 mL, 0.594 mmol) was added, then the reaction was chilled to 0°C. A 1M solution of TBAF in THF (0.539 mL, 0,539 mmol) was added dropwise to the reaction at 0°C, and then the mixture was stirred at room temperature overnight. The reaction was concentrated, then purified by silica gel column chromatography (0-5% MeOH in DCM) affording (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(hydroxymethyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 30) (219 mg, 85%). LC-MS: m/z= 528.5 (M + H+).1H NMR (500 MHz, DMSO) δ 7.92 (m, 3H), 7.33 (d, J = 4.4 Hz, 4H), 7.31 – 7.20 (m, 4H), 7.18 – 7.12 (m, 2H), 6.90 (d, J = 4.6 Hz, 1H), 6.76 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 5.9 Hz, 1H), 5.43 (dd, J = 5.8, 3.6 Hz, 1H), 5.15 (t, J = 5.6 Hz, 1H), 4.40 (q, J = 3.6 Hz, 1H), 3.71 – 3.52 (m, 4H), 3.40 (d, J = 16.1 Hz, 1H). Examples 31-37 Compounds 31-37 were prepared by using the procedure followed for the compound 30. Example 38 Compounds 38 was prepared by using the procedure followed for the compound 39. Example 39 and 56
Figure imgf000072_0001
Synthesis of ,4]triazin-7-yl)-2-cyano-5-((2-
Figure imgf000072_0002
phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 39) (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑dihydroxy‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1 g, 3.43 mmol), 4- dimethylaminopyridine (127 mg, 1.04 mmol), and phenylacetic acid (1.43 g, 10.5 mmol) were combined with DMF (7.5 mL) and MeCN (34 mL) under argon and chilled to 0°C. After 20 min at 0° C, DCC (2.34 g, 11.3 mmol) was added to the reaction, and then the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was rinsed with MeCN (2 x 10 mL), and EtOAc (10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 39) (1.61 g, 73%). LC-MS: m/z= 646.8 (M + H+).1H NMR (500 MHz, DMSO) δ 8.07 – 7.92 (m, 2H), 7.91 (s, 1H), 7.43 – 7.05 (m, 15H), 6.92 (d, J = 4.6 Hz, 1H), 6.74 (d, J = 4.6 Hz, 1H), 6.08 (d, J = 6.0 Hz, 1H), 5.45 (dd, J = 6.0, 4.4 Hz, 1H), 4.61 (q, J = 4.2 Hz, 1H), 4.40 (dd, J = 12.4, 3.3 Hz, 1H), 4.27 (dd, J = 12.4, 4.8 Hz, 1H), 3.70 – 3.56 (m, 5H), 3.46 (d, J = 16.1 Hz, 1H). Synthesis of (2R,3R,4R,5R)-2-cyano-2-(4-(2-phenylacetamido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 56) (2R,3R,4R,5R)-2-cyano-2-(4-(2-phenylacetamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) was a byproduct formed under reaction conditions to generate (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-2-cyano-5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate). Isolation of Compound 56 from Compound 39 was possible by separation with silica gel column chromatography (100% hexanes-100% EtOAc). LC-MS: m/z= 764.3 (M + H+).1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.38 – 7.12 (m, 22H), 6.94 (d, J = 4.9 Hz, 1H), 6.02 (d, J = 6.1 Hz, 1H), 5.47 (dd, J = 5.9, 4.1 Hz, 1H), 4.67 (m, 1H), 4.40 (dd, J = 12.4, 3.3 Hz, 1H), 4.28 (dd, J = 12.4, 4.7 Hz, 1H), 4.05 (s, 2H), 3.72 – 3.54 (m, 5H), 3.48 (d, J = 16.0 Hz, 1H). Example 40 Compounds 40 was prepared by using the procedure followed for the compound 41. Example 41
Figure imgf000074_0001
Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate (Compound 41) ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (152 mg, 0.371 mmol) and 4-dimethylaminopyridine (5 mg, 0.041 mmol) were dissolved in DCM (5 mL) and MeCN (2 mL) under argon and chilled to 0° C. After 30 min at 0° C, benzoic acid (93 mg, 0.762 mmol) and DCC (178 mg, 0.863 mmol) were added to the reaction, and then the mixture was stirred at room temperature for 4 hrs. The mixture was filtered and the solid was rinsed with DCM (2 x 5 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((2-phenylacetoxy)methyl)tetrahydrofuran- 3,4-diyl dibenzoate (Compound 41) (170 mg, 74%). LC-MS: m/z= 618.6 (M + H+).1H NMR (500 MHz, DMSO) δ 8.10 – 7.93 (m, 4H), 7.93 – 7.84 (m, 3H), 7.72 – 7.61 (m, 2H), 7.54 – 7.41 (m, 4H), 7.31 – 7.19 (m, 5H), 6.95 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.86 (dd, J = 6.0, 3.6 Hz, 1H), 4.91 (q, J = 3.7 Hz, 1H), 4.52 (dd, J = 12.3, 3.5 Hz, 1H), 4.43 (dd, J = 12.3, 4.6 Hz, 1H), 3.77 – 3.64 (m, 2H). Example 42 Compound 42 was prepared by using the procedure followed for the compound 41. Example 43 Compound 43 was prepared by using the procedure followed for the compound 39. Example 44 Compound 44 was prepared by using the procedure followed for the compound 41. Example 45 Compound 45 was prepared by using the procedure followed for the compound 39. Example 46 Compound 46 was prepared by using the procedure followed for the compound 41. Example 47 Compound 47 was prepared by using the procedure followed for the compound 39. Examples 48-49 Compounds 48-49 were prepared by using the procedure followed for the compound 41. Examples 50-52 Compounds 50-52 were prepared by using the procedure followed for the compound 39. Example 53
Figure imgf000075_0001
Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 8) Preparation of C: To a stirred solution of (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin‑7‑yl)‑3,4‑ dihydroxy‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (2.0 g, 6.87 mmol) in DMF (40 mL) was added t-Bu2Si(OTf)2 (2.5 mL, 7.56 mmol) at 0oC. Reaction mixture was stirred at 0°C for 3 h. After depletion of starting material, the reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified using column chromatography (silica gel 100- 200 mesh, 0-15% EtOAc in hexanes as an eluent) to afford (4aR,6R,7R,7aS)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-di-tert-butyl-7-hydroxytetrahydro-4H-furo[3,2- d][1,3,2]dioxasiline-6-carbonitrile (C) (2.0 g) as an off white solid. [TLC system: EtOAc:hexanes (1:1); Rf value: 0.5]. LC-MS: m/z= 432.2 (M + H+). Preparation of D: To a stirred solution of (4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-di- tert-butyl-7-hydroxytetrahydro-4H-furo[3,2-d][1,3,2]dioxasiline-6-carbonitrile (C) (1.4 g, 3.24 mmol) and phenylacetic acid (0.53 g, 3.89 mmol) in DCM (30 mL) was added DCC (1.3 g, 6.48 mmol) followed by DMAP (0.040 g, 0.32 mmol) at 00C and reaction mixture was stirred at room temperature for 16 h. After completion of starting material, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 X 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified using column chromatography (silica gel 100-200 mesh, 0-10% EtOAc in hexanes as an eluent) to afford 0.8 g of (4aR,6R,7R,7aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-di-tert- butyl-6-cyanotetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-7-yl 2-phenylacetate (D) as an off white solid. [TLC system: EtOAc:hexanes (3:7); Rf value: 0.5]. Preparation of Compound 53: To a stirred solution of (4aR,6R,7R,7aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-di- tert-butyl-6-cyanotetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-7-yl 2-phenylacetate (D) (0.2 g, 0.36 mmol) in THF (5 mL) was added Et3N.3HF (0.29 g, 1.80 mmol) at 0 °C and reaction mixture was stirred at room temperature for 2 h. After completion of starting material, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 X 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by reverse phase preparative-HPLC to afford (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2- phenylacetate (Compound 53) (0.092 g, 62%) as an off-white solid. [TLC system: MeOH:DCM (1:9); Rf value: 0.2]. LC-MS m/z= 408.32 (M-1).1H NMR (400 MHz, DMSO- d6) δ 7.94-7.90 (m, 3H), 7.34-7.26 (m, 5H), 6.91 (dd, J = 14.0, 4.4 Hz, 2H), 6.53 (d, J = 6.5 Hz, 1H), 5.20 (q, J = 3.1 Hz, 1H), 5.00 (t, J = 6.0 Hz, 2H), 4.27 (q, J = 3.7 Hz, 1H), 3.76 (q, J = 13.9 Hz, 2H), 3.63-3.52 (m, 2H). Example 54 Compound 54 was prepared by using the procedure followed for the compound 53. Example 55
Figure imgf000076_0001
Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy- 2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 55) To a solution of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (0.6 g, 1.46 mmol) in DCM (10 mL), were added DCC (0.44 g, 2.19 mmol) and DMAP (0.018 g, 0.14 mmol) at 0 °C. phenylacetic acid (0.2 g, 1.46 mmol) was added and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was quenched with cold water (20 mL) and extracted with DCM (30 mL). Then organic layer was washed with cold water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude compound which was purified by column chromatography over silica gel (Davisil) (using 0-5% MeOH in DCM as an eluent) to afford 0.4 g of crude product as an off white solid. Crude compound was further purified by Reverse Phase Prep-HPLC purification to get 0.1 g of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 55) as white solid. [TLC system: MeOH:DCM (1:9); Rf value: 0.5]. LC-MS: m/z= 528.56 (M+H+).1H NMR (400 MHz, DMSO-d6) δ 7.93 (br. s, 3H), 7.32 (d, J = 4.4 Hz, 4H), 7.29-7.23 (m, 4H), 7.19-7.17 (m, 2H), 6.94 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.47 (t, J = 4.2 Hz, 1H), 4.34 (dd, J = 12.4, 3.6 Hz, 1H), 4.23 (dd, J = 12.4, 5.2 Hz, 1H), 3.76 (q, J = 13.0 Hz, 2H), 3.64 (d, J = 1.1 Hz, 2H). Example 56 Compound 56 was prepared as a byproduct during the synthesis of the compound 39. Example 57 Step 1: (2R,3R,4R,5R)-2-cyano-2-(4-(cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- ((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate)
Figure imgf000077_0001
A mixture of DCC (71 mg, 0.344 mmol), DMAP (2 mg, 0.018 mmol), phenylacetic acid (43 mg, 0.317 mmol ) and (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (30 mg, 0.091 mmol) in DCM (4 mL) was stirred at room temperature overnight. Filtered and the filtrated was concentrated in vacuo to give the crude, which was purified by Prep-HPLC (Daisogel-C18-10-100, 30 x 250 mm, 5 um, mobile phase: ACN--H2O (0.1%FA), gradient: 5 ~ 95) to afford (2R,3R,4R,5R)-2-cyano-2-(4-(cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 57, 26 mg, 39.78% yield) as white solid. MS (ESI): mass calcd. for C39H35N5O7685.25, m/z found 685.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.02 (s, 1H), 7.30- 7.19 (m, 11H), 7.16-7.12 (m, 4H), 6.88 (d, J = 4.8 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 6.04 (d, J = 5.6 Hz, 1H), 5.43-5.40 (m, 1H), 4.63- 4.55 (m, 1H), 4.36 (dd, J = 3.2, 12.4 Hz, 1H), 4.23 (m, dd, J = 4.8, 12.4 Hz, 1H), 3.64-3.54 (m, 5H), 3.45-3.39 (m, 1H), 2.99-2.92 (m, 1H), 0.80- 0.75 (m, 2H), 0.62-0.58 (m, 2H). Example 58
Figure imgf000078_0001
Step 1: (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (X) (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile (400 mg, 0.712 mmol) and Isoamyl nitrite (417 mg, 3.561 mmol) was dissolved in MeCN (20 mL) and cooled to 0oC, then TMSCl (387 mg, 3.561 mmol) in MeCN (3 mL) was added and the mixture was heated to refluxed for 3 hours under N2. After the reaction was finished, the solvent was removed in vacuo to give the crude and the crude was purified by chromatography on silica gel, eluting (PE : EA = 1:1) to give (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 45.9% yield) as yellow oil. MS (ESI): mass calcd. for C33H29ClN4O4580.19, m/z found 580.6 [M+H]+. Step 2: (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (Y) (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 0.344 mmol) was dissolved in MeCN (10 mL), Cs2CO3 (168 mg, 0.516 mmol) was added, cyclopropanamine in MeCN (2 mL) was added. The mixture was stirred at room temperature overnight, after the reaction was finished, the solvent was remove in vacuo to give the crude, which was purified by chromatography on silica gel, eluting (PE : EA = 1:1) to give (2R,3R,4R,5R)-3,4- bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-(cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin- 7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 91.7% yield) as colorless oil. MS (ESI): mass calcd. for C36H35N5O4601.27, m/z found 601.6 [M+H]+. Step 3: (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1 triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile
Figure imgf000079_0001
(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (150 mg, 0.249 mmol) was dissolved in DCM (10 mL) and cooled to -78oC under N2, then boron trichloride (146 mg, 1.245 mmol) was added and the mixture was stirred at -78oC for 1 hour. After the reaction was finished, the mixture was quenched by a solution of Et3N in MeOH (Et3N:MeOH=1:5, 6 mL), then removed solvent in vactuo to give the crude, which was purified by chromatography on silica gel, eluting (DCM : MeOH = 10:1) to give (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile as white solid. MS (ESI): mass calcd. for C15H17N5O4331.13, m/z found 331.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 3.2 Hz, 1H), 8.04 (s, 1H), 6.91-6.83 (m, 2H), 6.12 (d, J = 6.0 Hz, 1H), 5.21 (d, J = 4.8 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.63 (t, J = 5.2 Hz, 1H), 4.08-4.03 (m, 1H), 3.99 -3.84 (m, 1H), 3.71-3.60 (m, 1H), 3.55-3.43 (m, 1H), 3.04-2.96 (m, 1H), 0.85-0.76 (m, 2H), 0.66-0.60 (m, 2H). Example 59 Compound 59 was prepared by using the procedure followed for the compound 60. Example 60
Figure imgf000079_0002
Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 60) 4-Dimethylaminopyridine (5.2 mg, 0.043 mmol), EDC-HCl (199 mg, 1.04 mmol), and phenylacetic acid (141 mg, 1.04) were dissolved in DCM (10 mL) under argon at 0° C. After 20 min at 0° C, 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (250 mg, 0.415 mmol) was added to the reaction, and then the mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM (50 mL), then washed with saturated sodium bicarbonate (2 x 25 mL). The combined aqueous layer was back extracted with EtOAc (50 mL), then the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (100% hexanes- 100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- cyano-5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 60, 257 mg, 74%). LC-MS: m/z= 839.8 (M + H+).1H NMR (400 MHz, DMSO) δ 8.12 – 7.93 (m, 2H), 7.91 (s, 1H), 7.35 – 7.20 (m, 10H), 7.19 – 7.07 (m, 5H), 6.88 (d, J = 4.6 Hz, 1H), 6.70 (d, J = 4.5 Hz, 1H), 6.15 – 6.04 (m, 1H), 6.00 (d, J = 5.8 Hz, 1H), 5.46 (s, 1H), 4.62 (s, 1H), 4.31 – 4.14 (m, 2H), 3.93 (dd, J = 11.0, 5.8 Hz, 1H), 3.82 (dd, J = 11.0, 5.7 Hz, 1H), 3.81 – 3.69 (m, 1H), 3.72 – 3.55 (m, 3H), 3.41 (d, J = 16.1 Hz, 2H), 1.40 (p, J = 6.3 Hz, 1H), 1.23 (m, 4H), 1.15 (d, J = 7.1 Hz, 3H), 0.78 (t, J = 7.5 Hz, 6H). Examples 61-64 Compounds 61-64 were prepared by using the procedure followed for the compound 60. Example 65
Figure imgf000080_0001
Step 1: (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-((((S)-(((S)-1- (2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4- hydroxytetrahydrofuran-3-yl tert-butyl succinate (Z) To a solution of 2-ethylbutyl (2S)-2-[({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (1 g, 1.7 mmol), 4-(tert-butoxy)-4- oxobutanoic acid [0.44 g, 2.5 mmol], 4-Dimethylaminopyridine (0.04 g, 0.3 mmol) in MeCN stirred under nitrogen at room temperature was added a solution of DCC (0.7 g, 3.4 mmol) in MeCN dropwise over 1 minute. The reaction mixture was stirred at room temperature for 4h, The mixture was filteredthrough Celite pad to remove by-product. The filtrate was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4-hydroxytetrahydrofuran-3-yl tert-butyl succinate (400 mg, 90%) as a white solid, . MS (ESI): mass calcd. for C35H47N6O11P 758.30, m/z found 759.31 [M+H]+. Step 2: 4-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4- hydroxytetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid (65) A solution of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-cyano-2- {[({[(2S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl]amino}(phenoxy)phosphoryl)oxy]methyl}-4- hydroxyoxolan-3-yl 1-tert-butyl butanedioate (600 mg, 0.79 mmol) in TFA/DCM=3:1 (10 mL) was stirred at room temperature for 2h. The mixture was concentrated and purified by Prep-HPLC (Gemini-C18150 x 21.2 mm, 5um, mobile phase: ACN-H2O, gradient: 30 ~ 70%) to give 4-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2- ((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl) oxy)methyl)- 4-hydroxytetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid (130 mg, 95%) as a white solid. MS (ESI): mass calcd. for C31H39N6O11P 702.24, m/z found 703.24 [M+H]+.1H NMR (301 MHz, CD3OD) δ 7.98 (d, J = 3.7 Hz, 1H), 7.29 (t, J = 7.1 Hz, 2H), 7.19 – 7.10 (m, 3H), 7.02 – 6.97 (m, 1H), 5.31 (dd, J = 7.0, 2.9 Hz, 1H), 5.05 (dd, J = 5.7, 1.5 Hz, 1H), 4.57 (s, 1H), 4.36 (dd, J = 6.2, 3.4 Hz, 2H), 4.09 – 3.78 (m, 4H), 2.78 – 2.65 (m, 4H), 1.47 (dd, J = 11.4, 6.0 Hz, 1H), 1.40 – 1.33 (m, 3H), 1.32 – 1.26 (m, 4H), 0.88 (m, 6H). Example 66 and 67
Figure imgf000082_0001
Step1: 2-ethylbutyl((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate & 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((R)-2-((tert-butoxycarbonyl)amino)-2- phenylacetoxy)-5-cyano-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Z1 and Z2) To a solution of 2-ethylbutyl (2S)-2-[({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (700 mg, 1.16 mmol), (R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetic acid (439 mg, 1.74 mmol), 4-Dimethylaminopyridine (28 mg, 0.23 mmol) in MeCN stirred under nitrogen at room temperature was added a solution of DCC (359 mg, 1.74 mmol) in MeCN dropwise over 1 minute. The reaction mixture was stirred at room temperature for 2h, The mixture was filteredthrough Celite pad to remove by-product. The filtrate was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give a mixture of 2- ethylbutyl((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Z1) and 2-ethylbutyl ((S)-(((2R,3R,4R,5R)- 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((R)-2-((tert-butoxycarbonyl)amino)-2- phenylacetoxy)-5-cyano-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (Z2) (450 mg, 90%) as a yellow solid. ES MS M/Z = 836.33 (M+1). Step 2: 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-3-((R)-2-amino-2-phenylacetoxy)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (66) 2-ethylbutyl((S)-(((2R,3R,4R,5R)-4-((R)-2-amino-2-phenylacetoxy)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(67) A mixture of 2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-3-{[(2R)-2-{[(tert-butoxy)carbonyl]amino}-2-phenylacetyl]oxy}-5- cyano-4-hydroxyoxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (Z1) and 2- ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Z2) (600 mg, 0.66 mmol) in TFA/DCM=3:1 (10 mL) was stirred at room temperature for 2h, The mixture was concentrated and purified by Prep-HPLC (Gemini-C18150 x 21.2 mm, 5um, mobile phase: ACN-H2O, gradient: 30 ~ 70%) to give 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-3-((R)-2-amino-2-phenylacetoxy)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (66, 128.3 mg, 95%) as a white solid, 2- ethylbutyl((S)-(((2R,3R,4R,5R)-4-((R)-2-amino-2-phenylacetoxy)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (67, 87.5 mg 95%) as a white soild .ES MS M/Z = 736.28 (M+1). Comp 66: 1H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 11.1 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.47 (dd, J = 6.0, 2.7 Hz, 3H), 7.30 (s, 2H), 7.17 (s, 3H), 7.06-7.00 (m, 1H), 6.96 (d, J = 4.7 Hz, 1H), 5.49 – 5.42 (m, 1H), 5.30 (s, 1H), 5.14 (d, J = 5.9 Hz, 1H), 4.60 (d, J = 3.8 Hz, 1H), 4.38-4.30 (m, 2H), 4.04 – 3.95 (m, 2H), 3.88 (dd, J = 11.0, 5.7 Hz, 1H), 3.81-3.79 (m, 1H), 1.49 – 1.41 (m, 1H), 1.33 – 1.27 (m, 4H), 1.25 (d, J = 7.2 Hz, 3H), 0.85-0.80 (m, 6H). Comp 67: 1H NMR (400 MHz, MeOD) δ 8.01 – 7.97 (m, 1H), 7.59 – 7.54 (m, 2H), 7.50-7.45 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 11.8 Hz, 3H), 7.12 (d, J = 1.0 Hz, 1H), 7.02- 7.00 (m, 1H), 5.57 (dd, J = 5.5, 2.2 Hz, 1H), 5.32 (s, 1H), 5.27 – 5.21 (m, 1H), 4.43 – 4.32 (m, 1H), 4.32 – 4.23 (m, 2H), 4.22 – 4.14 (m, 1H), 4.00-3.95 (m, 5.7 Hz, 1H), 3.90 (dd, J = 10.9, 5.7 Hz, 1H), 3.80 – 3.73 (m, 1H), 1.43 (dd, J = 12.4, 6.2 Hz, 1H), 1.33 – 1.28 (m, 4H), 1.24 (d, J = 7.2 Hz, 3H), 0.85 (t, J = 7.4 Hz, 6H). Example 68 Compound 68 was prepared by using the procedure followed for the compound 69. Example 69
Figure imgf000084_0001
Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L- alaninate (Compound 69) Preparation of E: To a solution of naphthalen-1-ol (5.0 g, 34.7 mmol) and phosphoryl trichloride (5.3 g, 34.7 mmol) in Et2O (50 mL) under nitrogen at -78 ℃ was added a solution of TEA (3.5 g, 34.7 mmol) in Et2O (10 mL) dropwise. The reaction mixture was stirred at room temperature for 2h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude naphthalen-1-yloxy)phosphonoyl dichloride (E) (9.0 g, 100%) as a colorless oil. MS (ESI): m/z= 262 [M+H]+. Preparation of F: To a solution of (naphthalen-1-yloxy) phosphonoyl dichloride (A) (2.0 g, 7.7 mmol) and 2- ethylbutyl (2R)-2-aminopropanoate (1.33 g, 7.7 mmol) in DCM (200 mL) was added TEA (3.12g, 30.8 mmol) at -78 oC under nitrogen. The mixture was stirred at room temperature for 2h, then 2,3,4,5,6-pentafluorophenol (2.83 g, 15.4 mmol) was added to the reaction mixture at 0 oC. The mixture was stirred at room temperature for 2h. The mixture was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give 2-ethylbutyl ((naphthalen-1-yloxy) (perfluorophenoxy)phosphoryl)-L-alaninate (F) (3.8 g, 81.8%) as a yellow oil. MS (ESI): m/z= 546 [M+H]+. Preparation of Compound 69: A solution of 2-ethylbutyl (2S)-2-{[(naphthalen-1-yloxy) (2,3,4,5,6-pentafluorophenoxy) phosphoryl]amino}propanoate (F) (2.0 g, 3.708 mmol), (2R,3R,4S,5R)-2-{4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2- carbonitrile (0.72 g, 2.472 mmol) in THF (30 mL) and was added tert-butyl magnesium chloride (4.89 mL, 4.89 mmol) dropwise at 0oC, then the reaction mixture was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM: MeOH = 20:1) to give 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1- yloxy)phosphoryl)-L-alaninate (Compound 69) (0.42 g, 17.6%) as a white solid. MS (ESI): m/z= 653.8.1H NMR (400 MHz, DMSO) δ 8.14 – 8.06 (m, 1H), 8.03 – 7.82 (m, 4H), 7.73 (dd, J = 8.6, 4.7 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.47 – 7.39 (m, 2H), 6.88 (t, J = 5.1 Hz, 1H), 6.82 (dd, J = 4.5, 1.6 Hz, 1H), 6.32 (dd, J = 16.3, 6.1 Hz, 1H), 6.27 – 6.18 (m, 1H), 5.43 – 5.36 (m, 1H), 4.63 (m, 1H), 4.38 – 4.25 (m, 2H), 4.25 – 4.12 (m, 1H), 4.03 – 3.77 (m, 4H), 1.43 – 1.32 (m, 1H), 1.26 – 1.13 (m, 7H), 0.80 – 0.71 (m, 6H). Example 70
Figure imgf000085_0001
Synthesis of neopentyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L- alaninate (Compound 9) mCMQ720 Preparation of G: To a solution of (tert-butoxycarbonyl)-L-alanine (20 g,105.1 mmol) , 2,2-dimethylpropan-1- ol (11.1 g,126 mmol) and DMAP (1.28 g,10.5 mmol) in DCM (200 mL) under nitrogen at 0℃ was added a EDCI (30.2 g,157.6 mmol) portionwise . The reaction mixture was stirred at room temperature for 18h. The mixture was diluted with water (500 mL) and extracted with DCM (100 mL x 3). The DCM layers were washed with brine (100 mL), then dried over Na2SO4, concentrated to afford 26 g crude product (G) as a yellow oil. MS (ESI): m/z= 281.9 [M+Na]+. Preparation of H: A solution of neopentyl (tert-butoxycarbonyl)-L-alaninate (G) (26 g, 99.9 mmol) in dioxane/HCl (4 M, 250 mL) was stirred under nitrogen at room temperature for 18hrs. The mixture was concentrated. The residue was treated with EA (200 mL). The solid was filtered and dried to afford 15 g product (H) as a white solid (90% purity, 69.1 % yield). MS (ESI): m/z= 160.0 [M+H]+. Preparation of I: Neopentyl L-alaninate hydrochloride (H) (1.0 g, 5.12 mmol) was added to a stirred solution of naphthalen-1-yl phosphorodichloridate (2.0 g, 7.69 mmol) in DCM (30 mL) at -78 oC, then TEA (4.01 g, 39.9 mmol) was added slowly. The reaction mixture was stirred at -78 oC for 1h, then pentafluorophenol (1.8 g 10.2 mmol) was added dropwise. The reaction mixture was stirred at 0 oC for 2hrs. Filtered the reaction system and collected the filtrate.The filtrate was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give neopentyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alaninate (I) (1.8 g, 66.6%) as a white solid. MS (ESI): m/z= 532.5 [M+H]+. Preparation of Compound 70: A solution of neopentyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alaninate (I) (1.0 g, 1.88 mmol), (2R,3R,4S,5R)-2-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (365 mg, 1.25 mmol) and tert- butyl magnesium chloride (2.5 mL, 2.5 mmol) in THF (30 mL) was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM:MeOH = 20:1) to give neopentyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1- yloxy)phosphoryl)-L-alaninate (Compound 70) (0.26 g, 21.6%) as a white solid. MS (ESI): m/z= 639.8 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.16 – 8.05 (m, 1H), 8.00 – 7.80 (m, 4H), 7.73 (dd, J = 7.8, 4.5 Hz, 1H), 7.55 (m, 2H), 7.48 – 7.38 (m, 2H), 6.88 (t, J = 4.0 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.32 (dd, J = 17.2, 6.2 Hz, 1H), 6.28 – 6.20 (m, 1H), 5.41 (t, J = 6.3 Hz, 1H), 4.67 – 4.58 (m, 1H), 4.38 – 4.26 (m, 2H), 4.20 (dd, J = 10.3, 4.4 Hz, 1H), 4.03 – 3.95 (m, 1H), 3.94 – 3.83 (m, 1H), 3.68 (m, 2H), 1.24 (d, J = 7.0 Hz, 1H), 1.19 (d, J = 7.1 Hz, 2H), 0.83 (s, 9H). Examples 71-73 Compounds 71-73 were prepared by using the procedure followed for the compound 70. Example 74 Compound 74 was prepared by using the procedure followed for the compound 75. Example 75
Figure imgf000087_0001
Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1 triazin-7-yl)-
Figure imgf000087_0002
5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 75) Preparation of K: A mixture of 2-ethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L- alaninate (J) (800 mg, 1.24 mmol) and butanoyl butanoate (295.4mg,1.87 mmol) in pyridine was stirred at 60 ℃ for 8h. The mixture was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give 2- ethylbutyl((((3aR,4R,6R,6aR)-6-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (K) (600 mg, 80%) as a yellow solid. MS (ESI): m/z= 723.0 (M+1). Preparation of Compound 75: A solution of 2-ethylbutyl (2S)-2-[({[(3aR,4R,6R,6aR)-6-{4-butanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl}-6-cyano-2,2-dimethyl-dihydro-3aH-furo[3,4-d][1,3]dioxol-4- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (A) (600 mg, 0.84 mmol) in acetone/H2O (4:1) (10 mL) was stirred at rt for 12h. The mixture was concentrated and purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give 2- ethylbutyl((((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 75) (200 mg, 85%) as a white solid. MS (ESI): m/z= 673.27 (M+1).1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), 7.32 (t, J = 7.9 Hz, 2H), 7.17-7.10 (m, 5H), 4.78 (d, J = 5.3 Hz, 1H), 4.46 – 4.35 (m, 2H), 4.30 (dd, J = 11.2, 5.5 Hz, 1H), 4.14 (t, J = 5.7 Hz, 1H), 4.02 (dd, J = 10.9, 5.7 Hz, 1H), 3.96 – 3.84 (m, 2H), 2.65 (t, J = 7.3 Hz, 2H), 1.85 – 1.69 (m, 2H), 1.45 (m, 1H), 1.31 (m, 7H), 1.04 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 6H). Example 76 Compound 76 was prepared by using the procedure followed for the compound 75. Example 77 Compound 77 was prepared by using the procedure followed for the compound 78. Example 78
Figure imgf000088_0001
Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-phenylalaninate (Compound 78) Preparation of A1: (tert-butoxycarbonyl)-L-phenylalanine (5.0 g, 24.6 mmol) was added to a stirred solution of 2-ethylbutan-1-ol (3.01 g, 29.5 mmol) in DCM (50 mL) at 0oC, then EDCI (9.40 g, 49.2 mmol) and DMAP (0.3 g.2.46 mmol) was added slowly. The reaction mixture was stirred at 25 oC for 12h. The residue was then purified by chromatography on silica gel, eluting (PE:EA = 10:1) to afford 2-ethylbutyl (tert-butoxycarbonyl)-L-phenylalaninate (A1) (4.4 g, 68.3%) as a colorless oil. MS (ESI): m/z= 372.5 [M+Na]+. Preparation of B1: A solution of 2-ethylbutyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (A1) (4.4 g, 12.6 mmol) in HCl/dioxiane (4M/L, 40 mL) was stirred at 25℃ for 12 hrs. The reaction mixture was concentrated to give 2-ethylbutyl L-phenylalaninate (B1) (2.9 g, 93.1%) as a white solid. MS (ESI): m/= 272.2 [M+Na]+. Preparation of C1: 2-ethylbutyl L-phenylalaninate (B1) (600 mg, 2.4 mmol) was added to a stirred solution of phenyl phosphorodichloridate (607 mg, 2.89 mmol) in DCM (10 mL) at -78 oC, then TEA (969.6 mg, 9.6 mmol) was added slowly. The reaction mixture was stirred at -78oC for 1h, then pentafluorophenol (878 mg, 4.8 mmol) was added slowly. The reaction mixture was stirred at 0oC for 2hrs. Filter the reaction system and collect the filtrate.The filtrated was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give 2- ethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-phenylalaninate (C1) (840 mg, 54.5%) as a white solid. MS (ESI): m/z= 572 [M+H]+. Preparation of Compound 78: A solution of 2-ethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-phenylalaninate (C1) (840 mg, 1.47 mmol), (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (285 mg, 0.98 mmol) and tert- butyl magnesium chloride (1.96 mL, 1.96 mmol) in THF (20 mL) was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM:MeOH = 20:1) to give 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-phenylalaninate (Compound 78) (300 mg, 17.2%) as a white solid. MS (ESI): m/z= 679.6 [M+H]+.1H NMR (400 MHz, DMSO) δ 7.92 (d, J = 3.8 Hz, 3H), 7.34 – 7.09 (m, 8H), 7.00 (t, J = 9.0 Hz, 2H), 6.90 (t, J = 4.5 Hz, 1H), 6.82 (dd, J = 4.5, 2.6 Hz, 1H), 6.32 (dd, J = 13.1, 6.2 Hz, 1H), 6.26 – 6.12 (m, 1H), 5.36 (s, 1H), 4.61 (t, J = 4.9 Hz, 1H), 4.14 (d, J = 4.0 Hz, 1H), 4.02 – 3.75 (m, 6H), 2.98 – 2.88 (m, 1H), 2.80 (dd, J = 13.4, 8.4 Hz, 1H), 1.31 (m, 1H), 1.21 – 1.09 (m, 4H), 0.77 – 0.70 (m, 6H). Example 79 Compound 79 was prepared by using the procedure followed for the compound 78. Biological Examples Virus generation. Vero E6 cells (ATCC CRL-1586) were plated in a T225 flask with complete DMEM (Corning 15-013-CV) containing 10% FBS, 1×PenStrep (Corning 20-002- CL), 2 mM L-Glutamine (Corning 25-005-CL) overnight at 37℃ 5% CO2. The media in the flask was removed and 2 mL of SARS-CoV-2 strain USA-WA1/2020 (BEI Resources NR- 52281) in complete DMEM was added to the flask at an MOI of 0.5 and was allowed to incubate for 30 minutes at 34℃ 5% CO2. After incubation, 30 mL of complete DMEM was added to the flask. The flask was then placed in a 34℃ incubator at 5% CO2 for 5 days. On day 5 post infection the supernatant was harvested and centrifuged at 1,000×g for 5 minutes. The supernatant was filtered through a 0.22 µM filter and stored at -80℃. HeLa-ACE2 stable cell line. HeLa-ACE2 cells were generated through transduction of human ACE2 lentivirus. The lentivirus was created by co-transfection of HEK293T cells with pBOB-hACE2 construct and lentiviral packaging plasmids pMDL, pREV, and pVSV-G (Addgene) using Lipofectamine 2000 (Thermo Fisher Scientific, 11668019). Supernatant was collected 48 h after transfection then used to transduce pre-seeded HeLa cells.12 h after transduction stable cell lines were collected, scaled up and stored. Cells were maintained in DMEM (Gibco, 11965-092) with 10% FBS (Gibco, 10438026) and 1× sodium pyruvate (Gibco, 11360070) at 37℃ 5% CO2. SARS-CoV-2/HeLa-ACE2 high-content screening assay. Compounds were acoustically transferred into 384-well µclear-bottom plates (Greiner, Part. No.781090-2B). HeLa-ACE2 cells were seeded in 13 µL DMEM with 2% FBS at a density of 1.0×103 cells per well. Plated cells were transported to the BSL3 facility where 13 µL of SARS-CoV-2 diluted in assay media was added to achieve ~30 – 50% infected cells. Plates were incubated for 24 h at 34℃ 5% CO2, and then fixed with final concentration of 4% formaldehyde for 1 h at 34℃ 5% CO2. Plates were washed with 1xPBS 0.05% Tween 20 in between fixation and subsequent primary and secondary antibody staining. Human polyclonal plasma diluted 1:500 in Perm/Wash buffer (BD Biosciences 554723) was added to the plate and incubated at RT for 2 h. Six µg/mL of goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) together with 8 µM of antifade-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) in SuperBlock T20 (PBS) buffer (Thermo Fisher Scientific 37515) was added to the plate and incubated at RT for 1.5-2hr h in the dark. Plates were imaged using the ImageXpress Micro Confocal High-Content Imaging System (Molecular Devices) with a 10× objective, with 4 fields imaged per well. Images were analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), with DAPI staining identifying the host-cell nuclei (the total number of cells in the images) and the SARS-CoV-2 immunofluorescence signal leading to identification of infected cells. Calu-3 high-content screening assay. The assay is carried out as outlined for the HeLa- ACE2 assay, with the following exceptions. Calu-3 cells (ATCC HTB-55), a kind gift from Dr. Catherine Chen at NCATS/NIH and Dr. Juan Carlos de la Torre at Scripps Research, were seeded at a density of 5,000 cells per 20 µL per well in assay media (MEM with 2% FBS) before SARS-CoV-2 diluted in assay media was added to achieve ~30 – 60% infected cells. Plates were incubated for 48 h at 34℃ 5% CO2, and then fixed with a final concentration of 4% formaldehyde. Fixed cells were stained and imaged as in the HeLa- ACE2 assay. Uninfected host cell cytotoxicity counter screens. For both the HeLa-ACE2 and Calu3 cells, compounds were acoustically transferred into 1,536-well µclear plates (Greiner Part. No.789091). HeLa-ACE2 cells were seeded in the assay-ready plates at 400 cells/well in DMEM with 2% FBS and plates were incubated for 24 h at 37℃ 5% CO2. Calu-3 cells were seeded in MEM with 2% FBS at a density of 600 cells per 5 µL per well and plates were incubated for 48 h at 37℃ 5% CO2. To assess cell viability, 2 µL of 50% Cell-Titer Glo (Promega No G7573) diluted in water was added to the cells and luminescence measured on an EnVision Plate Reader (Perkin Elmer). Example 80 Results from the assays and characterizing data on exemplary compounds are presented in Table 2 below.
Table 2.
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
General formulations of Compounds of the Invention F1: 5% ethanol, 30% propylene glycol, 45% PEG 400, 20% water (pH 1.9 with conc HCl) F2: 5% EtOH, 40% PEG 400, 55% 50 mM citrate buffer, pH 4-5 F3: 5% EtOH, 40% PEG 400, 55% 50 mM citrate buffer containing 0.5% Tween80, pH 4-5 F4: 15% Transcutol P, 20% Kolliphor HS-15, 65% water, pH 5.8 Pharmacokinetic Studies 1. Animals Animals (Male Cyno monkeys ~ 2-3 kg and Male rhesus macaques ~6.1-6.3 kg) were obtained from an approved vendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China and/or Topgene Biotechnology, Wuhan city, Hubei Province, China and/or Suzhou Xishan Zhongke Drug R&D Co.,Ltd, Suzhou, Jiangsu, China) Acclimation/Quarantine: Following arrival, animals were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animals were acclimated for at least 3 days before being placed on study. Animal Husbandry: Animals were group housed during acclimation and individually housed during the study. The animal room environment will be controlled (target conditions: temperature 18 to 26°C, relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Temperature and relative humidity were monitored daily. Animal Cannulation: No Animals were fasted at least 12 hours prior to the administration. All animals had access to Certified Rodent and non-Rodent Diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours post dosing. Water was autoclaved before provided to the animals ad libitum. Periodic analyses of the water were performed and the results archived. There are no known contaminants in the diet or water that, at the levels of detection, is expected to interfere with the purpose, conduct or outcome of the study. 2. Dose Formulation Formulation: The formulations were prepared on the day of dosing. Animals were dosed within four hours after the formulation is prepared. Two 20 μL aliquots of each formulation were removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS. 3. Dose Administration The dose formulation was administered following facility SOPs. 4. Sample Collection Approximately 200 μL blood was collected from saphenous vein at each time point for rats and 0.5 mL for rhesus macaques. All blood samples were transferred into microcentrifuge tubes containing 4μL of K2EDTA (0.5M) as anti-coagulant and placed on wet ice until processed for plasma. 5. Blood/Plasma processing Blood: Blood samples were processed for plasma by centrifugation at approximately 4 °C, 3000 g 15 min within half an hour of collection. Plasma samples was stored in polypropylene tubes, quick frozen over dry ice and kept at −70±10 °C until LC/MS/MS analysis. 6. Sample Analysis Dose formulation concentration verification ^ Aliquots of the formulations were collected in the middle position of each dose formulation in duplicate ^ The concentrations of the test compound in dose formulation samples were determined by the LC/UV or LC/MS/MS method Bioanalytical method and sample analysis ^ LC-MS/MS methods for the quantitative determination of test compound in corresponded biological matrix was developed under non-GLP compliance. ^ A calibration curve with 8 non-zero calibration standards was applied for the method including LLOQ. ^ A set of QC samples consisting of low, middle, and high concentration was applied for the method. ^ The study sample analysis will be performed concurrently with a set of calibration standards and two sets of QC samples using the LC-MS/MS method (If sample numbers were more than 48, then two calibration curves with 2 sets of QC samples were applied). ^ Acceptance criteria: Linearity: a minimum of 6 calibration standards was back calculated to within ±20% of their nominal values in plasma Accuracy: A minimum of 4 out of 6 QC samples was back calculated to within ±20% of their nominal values in plasma. Specificity: The mean calculated concentration in the single blank matrix should be 0.5 times the LLOQ. Sensitivity: the LLOQ will be tried to target 1~3 ng/mL. Carryover: the mean calculated carry-over concentration in the single blank matrix immediately after the highest standard injection should be £ LLOQ. If the carryover couldn’t meet the criteria, then the percent of carryover should be estimated following in-house bioanalytical SOP. 7. Data Analysis Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. Cmax, Tmax, T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf), %F and graphs of plasma concentration versus time profile were reported. Example 81: Compounds 19, 25, 39, 59, GS-441524, GS-5734 and GS-621763 were subjected to a single dose Cyno/rhesus macaque PK studies via oral route of administration with equivalent doses of 2.3-10 mg/kg of GS-441524. Oral administration of comp 39 shows ~9x increase in dose-normalized (DN) area under curve (AUC) exposure vs. GS-441524 in Rhesus; ~5.2x better DN AUC and 4x better MRT than GS-621763. Comp 39 is 3-fold more stable in a human primary hep assay than GS-5734 (t1/2: 21.5 vs 7.5 min) and has improved permeability Caco-2 Papp A-B/B-A than GS-5734 (2.2 vs 0.1). In addition, compounds 19, 25, 59 have shown improved DN AUC by 1.8x, 3.8x and 2.2x fold respectively when compared to GS-441524 in Cyno PK studies. Compounds 19 and 25 have higher Cmax than compound 39, but faster elimination and lower AUC. Table 3 shows the Cyno/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, GS- 5734 and GS-621763 (structure shown below) following PO administration at 2.3-10 mg/kg equivalent dose of GS-441524. The data are shown in graphic form in Figure 1.
Figure imgf000112_0001
Figure imgf000113_0001
As set forth above, the present invention provides an approach to improve oral exposure by modifying RDV or its parent nucleoside (GS-441524) to increase absorption. This patent application discloses various molecules that are ester prodrugs of GS-441524 that show increased absorption and exposure. The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I)
Figure imgf000115_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-(C1-C6)alkyl; when R4 = hydrogen, then R1, R2, and R3 cannot all be -C(=O)-CH(CH3)2 -C(=O)-CH3 - C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-(C1-C6)alkyl(C3-C7)cycloalkyl or -C(=O)- cyclopropyl; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; (e) when R2 = R3 and is selected from hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)- cyclopropyl, and R4 is hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)-cyclopropyl, then R1 cannot be -C(=O)-CH(CH3)2 , -C(=O)-hetero(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, - C(=O)((C1-C6)alkylPh((NHC=OO(C1-C6)alkyl, -C(=O)((C1-C6)alkyl((NHC=OO(C1- C6)alkyl, -C(=O)-hetero(C1-C6)alkyl-C(=O)O-hetero(C1-C6)alkyl, -C(=O)-hetero(C1- C6)alkyl-C(=O)OH, or -C(=O)-hetero(C1-C6)alkyl; (f) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen; and (g) when R2 = R3= R4= hydrogen, R1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C1-C10)alkyl, -C(=O)-(C1-C10)alkyl-C(=O)-(C1-C6)alkyl, -C(=O)-(C1- C6)alkenyl, -C(=O)-(C1-C6)alkynyl, -C(=O)-halo(C1-C6)alkyl, -C(=O)-halo(C1-C6)alkenyl, - C(=O)-hetero(C1-C6)alkyl, -C(=O)-hetero(C1-C6)alkenyl, -C(=O)-(C3-C7)cycloalkyl, -C(=O)- (C1-C6)alkyl-(C3-C7)cycloalkyl, -C(=O)-(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3- C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C3-C7)heterocycloalkyl-(C1-C6)alkyl, -C(=O)- halo(C3-C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)cycloalkyl, -C(=O)-hydroxy(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)cycloalkyl, -C(=O)-amino(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)cycloalkyl, -C(=O)-(C1-C6)heteroalkyl(C3- C7)cycloalkyl, and -C(=O)-(C1-C6)alkyl-(C1-C6)heteroalkyl(C3-C7)cycloalkyl, -C(=O)- halo(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)heterocycloalkyl, -C(=O)- hydroxy(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)heterocycloalkyl, - C(=O)-amino(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)heterocycloalkyl, - C(=O)-(C1-C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C1- C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)heteroalkyl-C(=O)-(C1-C6)alkyl, - C(=O)-(C1-C6)heteroalkyl-phenyl, and -C(=O)-(C1-C6)heteroalkyl-(C5-C8)heteroaryl. 2. The compound or a pharmaceutically acceptable salt thereof of claim 1 wherein in R1: the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, -C(=O)-(1-methylcyclohexyl), and -C(=O)-(4,4-dimethylcyclohexyl); the -C(=O)-(5 to 6-membered heterocyclyl) with the optional substituents of the 5 to 6-membered heterocyclyl is
Figure imgf000117_0001
the -C(=O)-(C1-C20 alkyl) with the optional substituents of the C1-C20 alkyl is selected from the group consisting of -C(=O)-CH(CH3)2, -C(=O)-CH(CH2CH3)2, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-cyclopentyl, -C(=O)-benzyl, -C(=O)-CH(CH3)- benzyl, -C(=O)-CH(CH3)-phenyl, -C(=O)-C(CH3)3, -C(=O)-CH2-C(CH3)3, -C(=O)-CH2- CH(CH2CH3)2, -C(=O)-CH(CH3)(CH2CH2CH3), -C(=O)-CH(CH3)(CH2CH2CH2CH3), -C(=O)-CH(CH3)((CH2 )4CH3), -C(=O)-(CH2 )5CH3, -C(=O)-CH(CH3)((CH2 )5CH3), -C(=O)-(CH2 )8CH3, -C(=O)-CH(CH3)((CH2 )9CH3), -C(=O)-(CH2 )10CH3, -C(=O)-(CH2 )12CH3, -C(=O)-CH2-(2-fluorophenyl), -C(=O)-CH2-(4-fluorophenyl), -C(=O)- CH2-(3-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)- CH2-(2-Naphthyl); the -C(=O)-(C6-C10 aryl) is selected from the group consisting of -C(=O)-phenyl; the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl) is selected from the group consisting of -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-phenyl), -P(=O)-(NH(CH(CH(CH3)2)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(benzyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(phenyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-Bromophenyl)) -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-1-naphthyl), and -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-2-naphthyl); and the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl) is -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(3-pyridinyl)). 3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein in R2 and R3: the -C(=O)-(C1-C10 alkyl) with the optional substituents of the C1-C10 alkyl is selected from the group consisting of -C(=O)-CH3, -C(=O)-(CH2)5-CH3, -C(=O)-benzyl, -C(=O)-CH(CH2CH3)2, -C(=O)-CH(NH2)CH(CH3)2, -C(=O)-CH(NH2)-phenyl, -C(=O)-CH(CH3)2, -C(=O)-CH(CH3)-phenyl, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-(4-fluorophenyl), -C(=O)-CH2-(3-fluorophenyl), -C(=O)-CH2-(2-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)-CH2-(2-naphthyl); the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, and -C(=O)-(4,4- dimethylcyclohexyl); and the -C(=O)-(C6-C10 aryl) is selected from the group consisting of - C(=O)-phenyl. 4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein in R4: the C3-C7 cycloalkyl is selected from the group consisting of cyclopropyl; the –(C=O)-O-C1-C10 alkyl is selected from the group consisting of –(C=O)-O- (CH2)2CH3,and –(C=O)-O-(CH2)4CH3; the –(C=O)-(C1-C10 alkyl) is selected from the group consisting of –(C=O)-benzyl, and -C(=O)-(CH2)2CH3; and the -C(=O)-(C3-C7 cycloalkyl) is selected from the group consisting of -C(=O)-cyclobutyl. 5. The compound of any one of claims 1-4, selected from the group consisting of: ,
Figure imgf000119_0001
, , ,
,
Figure imgf000120_0001
,
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
6. The compound of any one of claims 1-5, having the Formula:
Figure imgf000128_0001
pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising an effect amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. A method of inhibiting an RNA-dependent RNA polymerase in a patient infected with a virus, comprising administering to the patient a therapeutically effective amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 9. A method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 10. The method of claim 8, wherein the virus is at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus,. 11. The method of claim 9, wherein the viral infection is caused by at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus. 12. The method of claim 11, wherein the viral infection is caused by SARS-COV-2 and its variants selected from the group consisting of delta, epsilon, kappa, zeta, UK SARS-COV-2 variant B.1.1.7 and South Africa SARS-CoV-2501.V2. 13. The method of any one of claims 8-12, further comprising administering at least one additional antiviral agent selected from the group consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, an integrase inhibitor and/or an entry inhibitor. 14. The method of claim 13, wherein the protease inhibitor comprises at least one selected from the group consisting of PF-07321332, islatravir and lenacapavir. 15. The method of claim 14, wherein the protease inhibitor is PF-07321332. 16. The method of any one of claims 8-15, wherein the compound is administered via a route selected from the group consisting of oral, inhalation, parenteral and implants. 17. The method of any one of claims 8-16, wherein the administration is for pre-exposure or post-exposure prophylaxis.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002877A2 (en) * 2008-07-03 2010-01-07 Biota Scientific Management Bycyclic nucleosides and nucleotides as therapeutic agents
WO2012012776A1 (en) * 2010-07-22 2012-01-26 Gilead Sciences, Inc. Methods and compounds for treating paramyxoviridae virus infections
WO2019129059A1 (en) * 2017-12-29 2019-07-04 上海和誉生物医药科技有限公司 Phosphonic acid derivative having cd73 inhibitory activity, and preparation method and use thereof
US20210161927A1 (en) * 2020-10-20 2021-06-03 Anzalp Pharmasolutions Pvt. Ltd. Isomorphs of remdesivir and methods for synthesis of same
WO2021216427A1 (en) * 2020-04-21 2021-10-28 Ligand Pharmaceuticals, Inc. Nucleotide prodrug compounds
US20210388019A1 (en) * 2020-06-15 2021-12-16 Metro International Biotech, Llc Anti-viral compounds and methods of use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002877A2 (en) * 2008-07-03 2010-01-07 Biota Scientific Management Bycyclic nucleosides and nucleotides as therapeutic agents
WO2012012776A1 (en) * 2010-07-22 2012-01-26 Gilead Sciences, Inc. Methods and compounds for treating paramyxoviridae virus infections
WO2019129059A1 (en) * 2017-12-29 2019-07-04 上海和誉生物医药科技有限公司 Phosphonic acid derivative having cd73 inhibitory activity, and preparation method and use thereof
WO2021216427A1 (en) * 2020-04-21 2021-10-28 Ligand Pharmaceuticals, Inc. Nucleotide prodrug compounds
US20210388019A1 (en) * 2020-06-15 2021-12-16 Metro International Biotech, Llc Anti-viral compounds and methods of use
US20210161927A1 (en) * 2020-10-20 2021-06-03 Anzalp Pharmasolutions Pvt. Ltd. Isomorphs of remdesivir and methods for synthesis of same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile", XP093072231, retrieved from PUBCHEM *

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