WO2022081973A1 - Phospholipid compounds and uses thereof - Google Patents

Phospholipid compounds and uses thereof Download PDF

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Publication number
WO2022081973A1
WO2022081973A1 PCT/US2021/055183 US2021055183W WO2022081973A1 WO 2022081973 A1 WO2022081973 A1 WO 2022081973A1 US 2021055183 W US2021055183 W US 2021055183W WO 2022081973 A1 WO2022081973 A1 WO 2022081973A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
infection
alkyl
Prior art date
Application number
PCT/US2021/055183
Other languages
French (fr)
Inventor
Scott E. Lazerwith
Jonathan William MEDLEY
Philip A. Morganelli
Thomas P. STRATTON
Peiyuan Wang
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2021361059A priority Critical patent/AU2021361059A1/en
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to CN202180069943.8A priority patent/CN116322759A/en
Priority to MX2023004188A priority patent/MX2023004188A/en
Priority to CA3193879A priority patent/CA3193879A1/en
Priority to JP2023523142A priority patent/JP2023547599A/en
Priority to CR20230164A priority patent/CR20230164A/en
Priority to IL301809A priority patent/IL301809A/en
Priority to KR1020237016209A priority patent/KR20230088432A/en
Priority to PE2023001411A priority patent/PE20230858A1/en
Priority to EP21805775.0A priority patent/EP4228685A1/en
Publication of WO2022081973A1 publication Critical patent/WO2022081973A1/en
Priority to DO2023000074A priority patent/DOP2023000074A/en
Priority to CONC2023/0004594A priority patent/CO2023004594A2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the disclosure provides a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZA R ZB -, or -CR ZA R ZB -C RZC R ZD -; Z 2 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZE R ZF -, or -CR ZE R ZF -C RZG R ZH ; R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH is each independently H, halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; R ZB and R ZF are each independently halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; X is a bond, -O
  • the disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the disclosure provides a method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, characterized in that a compound of Formula I, or a pharmaceutically acceptable salt thereof, is used.
  • the disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.
  • the invention relates generally to methods and compounds for treating or preventing viral infections, for example paramyxoviridae, pneumoviridae, picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus, and coronaviridae. II.
  • a compound of the disclosure or “a compound of Formula I” means a compound of Formula I, or a pharmaceutically acceptable salt, thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts thereof.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • an alkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 alkyl), 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl), or 1 to 3 carbon atoms (i.e., C 1 -C 3 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, - CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 )3), 1-pentyl (n- pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH(CH)CH
  • Alkoxy means a group having the formula –O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 1 2 alkoxy), 1 to 8 carbon atoms (i.e., C 1 -C8 alkoxy), 1 to 6 carbon atoms (i.e., C 1- C 6 alkoxy) or 1 to 3 carbon atoms (i.e., C 1 -C 3 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or –OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-O-C(CH 3 ) 3 or –OtBu) and the like.
  • “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 -C 1 2 haloalkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 haloalkyl), 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl) or 1 to 3 carbon atoms (i.e., C 1 -C 3 alkyl).
  • Suitable haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 , and the like.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Cycloalkyl refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halo refers to -F, -Cl, -Br or -I.
  • a halo group is -F or -Cl.
  • a halo group is -F.
  • “Heterocycle” or “heterocyclyl” refer to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • heterocyclyl has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4 to 12 membered heterocyclyl), 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyl).
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • heterocycle or heterocyclyl do not encompass or overlap with heteroaryls as defined below.
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • heteroaryl include 5 to 20 ring atoms, 5 to 12 ring atoms, 5 to 8 ring atoms, or 5 to 6 ring atoms; including 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • optionally substituted in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by the listed substituents.
  • the carbon atoms of the compounds of Formula I are intended to have a valence of four. If in some chemical structure representations, carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • therapeutically effective amount is the amount of compound of Formula I present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration.
  • adjacent carbons refers to consecutive carbons atoms that are directly attached to each other. For example, in , C 1 and C 2 are adjacent carbons, C 2 and C 3 are adjacent carbons, C 3 and C 4 are adjacent carbons, and C 4 and C 5 are adjacent carbons.
  • C 1 and C 2 are adjacent carbons
  • C 2 and C 3 are adjacent carbons
  • C 3 and C 4 are adjacent carbons
  • C 4 and C 5 are adjacent carbons
  • C 5 and C 6 are adjacent carbons
  • C 6 and C 1 are adjacent carbons.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent “cycloalkyl” group etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent “cycloalkyl” group etc.
  • an “alkylene” group or an “alkylenyl” group, or alkylyl group an “arylene” group or an “arylenyl” group, or arylyl group
  • Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZA R ZB -, or -CR ZA R ZB -C RZC R ZD -;
  • Z 2 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZE R ZF -, or -CR ZE R ZF -C RZG R ZH ;
  • R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH is each independently H, halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • R ZB and R ZF are each independently halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • X is a bond, -O-, -OC
  • Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZA R ZB -, or -CR ZA R ZB -C RZC R ZD -;
  • Z 2 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZE R ZF -, or -CR ZE R ZF -C RZG R ZH ;
  • R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH is each independently H, halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • R ZB and R ZF are each independently halo, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • X is -OCO-, -(CR 12A R 12B ) q
  • Z 1 is -CH 2 - and Z 2 is -CH 2 -. In some embodiments, one of Z 1 and Z 2 is -CH 2 -CH 2 -. In some embodiments, both Z 1 and Z 2 are - CH 2 -CH 2 -. In some embodiments, Z 1 is -CH 2 -CH 2 - and Z 2 is -CH 2 -. In some embodiments, Z 1 is -CH 2 - and Z 2 is -CH 2 -CH 2 -.
  • Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZA R ZB -, or -CR ZA R ZB -C RZC R ZD -;
  • Z 2 is a bond, - CH 2 -, -CH 2 -CH 2 -, -CR ZE R ZF -, or -CR ZE R ZF -C RZG R ZH ; wherein R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH is each independently H or C 1 -C 3 alkyl; and R ZB and R ZF are each independently C 1 -C 3 alkyl.
  • Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, - CR ZA R ZB -, or -CR ZA R ZB -C RZC R ZD -;
  • Z 2 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CR ZE R ZF -, or -CR ZE R ZF - C RZG R ZH ; wherein R ZA , R ZC , R ZD , R ZE , R ZG , and R ZH is each independently H or methyl; and R ZB and R ZF are both methyl.
  • Z 1 is a bond, -CH 2 -, -CH 2 -CH 2 -, or -CH(CH 3 )-;
  • Z 2 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-.
  • Z 1 is -CH 2 - and Z 2 is -CH 2 -,
  • Z 1 is -C(CH 3 )H- and Z 2 is -CH 2 -.
  • Z 1 is -CH 2 - and Z 2 is -C(CH 3 )H-.
  • Z 1 is -CH 2 - and Z 2 is a bond.
  • Z 1 is a bond and Z 2 is -CH 2 -.
  • X 1 is a bond, -O-, -NR x , or S; wherein R X is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -C(O)R XA and R XA is C 1 -C 3 alkyl.
  • X 1 is a bond, -O-, -NR x , or S; wherein R X is H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • X 1 is a bond, -O-, -NH-, -NCH 3 -, or S. In some embodiments, X 1 is a bond, -O-, or S. In some embodiments, X 1 is a bond or -O-. In some embodiments, X 1 is a bond. In some embodiments, X 1 is -O-. In some embodiments, X 1 is -S-. In some embodiments, X 1 is -NH-.
  • X 1 is -NR x - or -CONR X -; wherein R x is C 1 -C 3 alkyl or -C(O)R XA . In some embodiments, X 1 is -NR x - or -CONR X -; wherein R x is C 1 -C 3 alkyl. In some embodiments, X 1 is -NR x - or -CONR X -; wherein R x is methyl.
  • X 1 is -NR x - or -CONR X -; wherein R x is -C(O)R XA and R XA is methyl.
  • the compound of Formula I is a compound of Formula Ia: X 3 , X 4 , and m are as defined herein for Formula I.
  • X 2 is S.
  • X 2 is O.
  • X 3 is S.
  • X 3 is O.
  • X is a bond, -O-, -(CR 12A R 12B )q-, -O(CR 12A R 12B )q-, wherein q is 1 or 2.
  • X is a bond, -O-, -(CR 12A R 12B ) 2 -, -O(CR 12A R 12B ) 2 -.
  • X is a bond, -O-, - (CR 12A R 12B )-, -O(CR 12A R 12B )-.
  • X is O.
  • X is - (CR 12A R 12B )q-, where q is 1 or 2.
  • X is -(CR 12A R 12B )-. In some embodiments X is -(CR 12A R 12B ) 2 -. In some embodiments, X is -O(CR 12A R 12B ) q -,where q is 1 or 2. In some embodiments, X is -O(CR 12A R 12B )-. In some embodiments, X is -O(CR 12A R 12B ) 2 -.
  • each R 12A is independently H, C 1 - C 6 alkyl, or phenyl; each R 12B is independently H or C 1- C 6 alkyl; R 13 is H, C 1- C 6 alkyl, or phenyl; and R 14 is H, C 1- C 6 alkyl, or phenyl.
  • each R 12A is independently H or C 1 -C 3 alkyl
  • each R 12B is independently H or C 1 -C 3 alkyl
  • R 13 is H or C 1 -C 3 alkyl
  • R 14 is H or C 1 -C 3 alkyl.
  • each R 12A is H
  • each R 12B is H
  • R 13 is H
  • R 14 is H.
  • X is a bond, -O-, -(CR 12A R 12B )q-, - O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A is independently H, C 1- C 6 alkyl, or phenyl; and each R 12B is independently H or C 1- C 6 alkyl.
  • X is a bond, -O-, -(CR 12A R 12B )q-, -O(CR 12A R 12B )q-; where q is 1 or 2; each R 12A is independently H or C 1- C 6 alkyl; and each R 12B is independently H or C 1- C 6 alkyl.
  • X is a bond, -O-, -(CR 12A R 12B )q-, -O(CR 12A R 12B )q-; where q is 1 or 2; each R 12A is independently H or C 1- C 3 alkyl; and each R 12B is independently H or C 1 -C 3 alkyl.
  • X is a bond, -O-, - (CR 12A R 12B )q-, -O(CR 12A R 12B )q-; where q is 1 or 2; each R 12A is H; and each R 12B is H.
  • X is a bond, -O-, -CH 2 -, -CH 2 CH 2 -, -OCH 2 -, or - O(CH 2 ) 2 -.
  • X is a bond, -O-, -OCH 2 , or - CH 2 CH 2 .
  • X is -O-, -(CR 12A R 12B )q-, - O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A is independently H, C 1- C 6 alkyl, or phenyl; and each R 12B is independently H or C 1- C 6 alkyl.
  • X is -O-, -(CR 12A R 12B ) q -, -O(CR 12A R 12B ) q -; where q is 1 or 2; each R 12A is independently H or C 1- C 6 alkyl; and each R 12B is independently H or C 1- C 6 alkyl.
  • X is -O-, -(CR 12A R 12B )q-, -O(CR 12A R 12B )q-; where q is 1 or 2; each R 12A is independently H or C 1- C 3 alkyl; and each R 12B is independently H or C 1- C 3 alkyl.
  • X is -O-, -(CR 12A R 12B )q-, -O(CR 12A R 12B )q-; where q is 1 or 2; each R 12A is H; and each R 12B is H.
  • the compound of Formula IX is -O-, -(CR 12A R 12B )-, - O(CR 12A R 12B )-; where R 12A is H, C 1- C 6 alkyl, or phenyl; and R 12B is H or C 1- C 6 alkyl.
  • X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )-, where R 12A is H or C 1- C 6 alkyl, and R 12B H or C 1- C 6 alkyl.
  • X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )-, where R 12A is H or C 1- C 3 alkyl, and R 12B is H or C 1 -C 3 alkyl.
  • X is -O-, -(CR 12A R 12B )-, -O(CR 12A R 12B )-; where R 12A is H, and R 12B is H.
  • X is -O-, -(CR 12A R 12B ) 2 -, - O(CR 12A R 12B ) 2 -; where each R 12A is independently H, C 1- C 6 alkyl, or phenyl; and each R 12B is independently H or C 1- C 6 alkyl.
  • X is -O-, - (CR 12A R 12B ) 2 -, -O(CR 12A R 12B ) 2 -, where each R 12A is independently H or C 1- C 6 alkyl, and each R 12B is independently H or C 1- C 6 alkyl.
  • X is -O-, -(CR 12A R 12B ) 2 -, -O(CR 12A R 12B ) 2 -, where each R 12A is independently H or C 1 -C 3 alkyl, and each R 12B is independently H or C 1- C 3 alkyl.
  • X is -O-, -(CR 12A R 12B ) 2 -, -O(CR 12A R 12B ) 2 -; where each R 12A is H and each R 12B is H.
  • X is (CR 12A R 12B ) p -NR 12C - (CR 12A R 12B )p- or (CR 12A R 12B )p-NR 12C CO-(CR 12A R 12B )p-; wherein p is 0, 1, or 2.
  • X is (CR 12A R 12B )p-NR 12C -(CR 12A R 12B )p- or (CR 12A R 12B )p-NR 12C CO-(CR 12A R 12B )p- ; wherein p is 0 or 1.
  • X is -NR 12C - or -NR 12C CO-.
  • X is -NR 12C - or -NR 12C CO- wherein R 12C is H, C 1 -C 3 alkyl, or -COR 12D and R 12D is C 1 -C 3 methyl.
  • X is -NR 12C - or -NR 12C CO- wherein R 12C is H, methyl, or -COCH 3 .
  • X is -(CR 12A R 12B )p-NR 12C CO- (CR 12A R 12B ) p - wherein p is 0, 1, or 2.
  • X is -(CR 12A R 12B ) p -NR 12C CO- (CR 12A R 12B )p- wherein p is 0 or 1.
  • X is -NR 12C CO-.
  • X is -NR 12C CO- wherein R 12C is H, C 1 -C 3 alkyl, or -COR 12D and R 12D is C 1 -C 3 methyl.
  • X is -NR 12C CO- wherein R 12C is H, methyl, or -COCH 3 .
  • X is -NR 12C CO- wherein R 12C is H or methyl.
  • X is -NR 12C CO- wherein R 12C is H. In some embodiments, X is -NR 12C CO- wherein R 12C is methyl. In some embodiments of the compounds of Formula I, X is -(CR 12A R 12B ) p -NR 12C - (CR 12A R 12B )p-; wherein p is 0, 1, or 2. In some embodiments, X is -(CR 12A R 12B )p-NR 12C - (CR 12A R 12B ) p - wherein p is 0 or 1. In some embodiments X is -NR 12C -.
  • X is -NR 12C - wherein R 12C is H, C 1 -C 3 alkyl, or -COR 12D and R 12D is C 1 -C 3 methyl.
  • R 12C is H, methyl, or -COCH 3 .
  • X is - NR 12C - wherein R 12C is H or methyl.
  • X is -NR 12C - wherein R 12C is H.
  • X is -NR 12C - wherein R 12C is methyl.
  • X is -NR 12C - wherein R 12C is -COCH 3 .
  • X is -NR 12C -; wherein R 12C and R 1 are joined together to form a 5 to 6 membered heterocyclyl having one two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R 12F groups; wherein each R 12F is independently oxo or halo, or two R 12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl.
  • X is -NR 12C -; wherein R 12C and R 1 are joined together to form a 5 membered heterocyclyl containing one N atom and optionally substituted with one to four R 12F groups; wherein each R 12F is independently oxo or halo, or two R 12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl.
  • X is -NR 12C -; and R 12C and R 1 are joined together to form In some embodiments of the compounds of Formula I, X is a bond, -O-, -S-, -CH 2 O-, - NH-, -N(C(O)CH 3 )-, -NCH 3 -, or -N(CH 3 )CO-. In some embodiments, X is a bond, -O-, -S-, - CH 2 O-, -NH-, -N(C(O)CH 3 )-, -NCH 3 -, or -N(CH 3 )CO-.
  • X is -O-, -S-, or -CH 2 O-. In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -CH 2 O-. In some embodiments, X is -NH-, -N(C(O)CH 3 )-, -NCH 3 -, or -N(CH 3 )CO-. In some embodiments, X is -NH-, -N(C(O)CH 3 )-, or -NCH 3 -. In some embodiments, of the compounds of Formula I, X is a bond.
  • Y is phenylene or C 3 -C 6 cycloalkylene. In some embodiments, Y is . In some embodiments, Y is phenylene. In some embodiments, Y is . In some embodiments, Y is C 3 -C 6 cycloalkylene. In some embodiments, Y is cyclohexylene. In some embodiments, Y is . In some embodiments, Y is a bond. In some embodiments, Y is a bond or phenylene. In some embodiments, Y is a bond or C 3 -C 6 cycloalkylene.
  • R 1 is C 1 -C 20 alkyl, C 3 -C 10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C 6 -C 10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R 1 group is optionally substituted with one, two or three R 1A groups.
  • R 1 is H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C 6 - C 10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R 1 is not H, the R 1 group is optionally substituted with one or two R 1A groups.
  • R 1 is C 1 -C 20 alkyl, C 3 -C 10 cycloalkyl, or 5-6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S, and O; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1- C 6 alkyl, C 3 -C 10 cycloalkyl, or 5-6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S, and O; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1 -C 20 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1- C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1 -C 20 alkyl, C 3 -C 10 cycloalkyl, or C 6 -C 10 aryl; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or C 6 -C 10 aryl; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1 -C 20 alkyl or C 6 -C 10 aryl; wherein the R 1 group is optionally substituted with one, two, or three R 1A groups.
  • R 1 is C 1 -C 6 alkyl or C 6 - C 10 aryl; wherein the R 1 group is optionally substituted with one, two or three R 1A groups. In some embodiments, R 1 is C 1 -C 20 alkyl optionally substituted with one, two or three R 1A groups. In some embodiments, R 1 is C 1- C 6 alkyl optionally substituted with one, two or three R1A groups. In some embodiments of the compounds of Formula I or Ia, R 1 is C 6 -C 10 aryl optionally substituted with one, two or three R 1A groups.
  • R 1 is phenyl, napthyl, thiophenyl, cyclohexyl, methyl, ethyl, or propyl. In some embodiments of the compounds of Formula I or Ia, R 1 is unsubstituted. In some embodiments, R 1 is substituted with one R 1A group. In some embodiments, R 1 is substituted with two R 1A groups. In some embodiments, R 1 is substituted with three R 1A groups.
  • each R 1A is independently C 1 -C 3 alkyl, phenyl, halo, C 1 -C 3 alkoxy, cyano, - SO2R 1B , -COOR 1B , or C 1 -C 3 haloalkyl.
  • R 1A is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF3.
  • two R 1A are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O.
  • two R 1A are joined together to from a 3 to 6 membered cycloalkyl. In some embodiments, two R 1A are joined together to from a 5 membered cycloalkyl. In some embodiments, two R 1A are joined together to from a 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O.
  • R 1 is selected from a group consisting of H, , and In some embodiments of the compound of Formula I or Ia, or a pharmaceutically F acceptable salt thereof, R 1 is selected from the group consisting of H, N , and .
  • R 1 is selected from the group F consisting of , and in some embodiments of the compounds of Formula I or Ia, m is 10-20, in some embodiments, m is 14-20. In some embodiments, m is 16, 17, 18, 19, or 20. In some embodiments, m is 17, 18, or 19. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof: X 2 is O; X 3 is O; X 4 is O; R 2 is H; and R 1 is C 6 -C 10 aryl optionally substituted with one, two, or three R 1A groups.
  • the compound of Formula I is selected from the group consisting of: In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: , ,
  • the compound of Formula I or Ia is selected from the group consisting of:
  • the compound of Formula I or Ia is selected from the group consisting of: , and , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: , , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
  • the compound of Formula I or Ia is selected from the group consisting of:
  • the compound of Formula I or Ia is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof.
  • a compound of Formula: , or a pharmaceutically acceptable salt thereof A compound of Formula: , or a pharmaceutically acceptable salt thereof.
  • a compound of Formula: or a pharmaceutically acceptable salt thereof. Any reference to the compounds of the invention described herein also includes a reference to a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na + , Li + , K +, Ca +2 and Mg +2 ), ammonium and NR4 + (wherein R is defined herein).
  • salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid,
  • compositions of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + .
  • the compounds disclosed herein (e.g., compounds of Formula I) and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I, and their pharmaceutically acceptable salts.
  • the compounds disclosed herein (e.g., compounds of Formula I) and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I, and their pharmaceutically acceptable salts.
  • salts of active ingredients of the compounds of the invention will be pharmaceutically acceptable, i.e., they will be salts derived from a pharmaceutically acceptable acid or base.
  • salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I, and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.
  • the compounds of the invention, exemplified by Formula I may have chiral centers, e.g., chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
  • racemic mixtures are separated into their individual, substantially optically pure isomers through appropriate techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms "racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the compounds of the invention may also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • Any formula or structure given herein, including Formula I compounds, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • the disclosure also includes compounds of Formula I in which from 1 to x hydrogens attached to a carbon atom is/are replaced by deuterium, in which x is the number of hydrogens in the molecule.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.
  • such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • a compound described herein is substituted with more than one of the same designated group, e.g., “R” or “R ” , then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines, , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms. IV.
  • compositions may be formulated with conventional carriers and excipients.
  • tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations may optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but in certain embodiments is about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5. In other embodiments, the pH of the formulations ranges from about 3 to about 4. While it is possible for the compounds of the disclosure (“the active ingredients”) to be administered alone it may be preferable to present them as pharmaceutical formulations.
  • the formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any appropriate method known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compounds disclosed have pharmacokinetic properties (for e.g., good oral bioavailability) suitable for oral administration of the compounds.
  • the formulations of the present invention are suitable for oral administration and are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • the tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with one or more pharmaceutically acceptable excipients, such as a binder, lubricant, inert diluent, preservative, surface active and/or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner.
  • the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween ® 60, Span ® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. Further emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween ® 80.
  • Tween ® 80 The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvin
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • suspending agents include Cyclodextrin.
  • the suspending agent is Sulfobutyl ether beta-cyclodextrin (SEB-beta-CD), for example Captisol ® .
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • the compounds disclosed herein are administered by inhalation.
  • formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • the compounds used herein are formulated and dosed as dry powder.
  • the compounds used herein are formulated and dosed as a nebulized formulation.
  • the compounds used herein are formulated for delivery by a face mask.
  • the compounds used herein are formulated for delivery by a face tent.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and suspensions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention (“controlled release formulations”) in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient. V.
  • kits that includes a compound disclosed herein (e.g., compounds of Formula I), a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.
  • the kits described herein may comprise a label and/or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof.
  • the disease or condition is viral infection.
  • the kit may also comprise one or more additional therapeutic agents and/or instructions for use of additional therapeutic agents in combination with the compound of Formula I in the treatment of the disease or condition in a subject (e.g., human) in need thereof.
  • kits provided herein comprises individual dose units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof.
  • individual dosage units may include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof.
  • the kit may contain a single dosage unit and in others multiple dosage units are present, such as the number of dosage units required for a specified regimen or period.
  • articles of manufacture that include a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof; and a container.
  • the container of the article of manufacture is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, an intravenous bag, an inhaler, or a nebulizer.
  • Administration One or more compounds of the invention are administered by any route appropriate to the condition to be treated.
  • Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like.
  • the compounds disclosed herein are administered by inhalation or intravenously. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the compounds of the present invention can be administered at any time to a human who may come into contact with the virus or is already suffering from the viral infection.
  • the compounds of the present invention can be administered prophylactically to humans coming into contact with humans suffering from the viral infection or at risk of coming into contact with humans suffering from the viral infection, e.g., healthcare providers.
  • administration of the compounds of the present invention can be to humans testing positive for the viral infection but not yet showing symptoms of the viral infection.
  • administration of the compounds of the present invention can be to humans upon commencement of symptoms of the viral infection.
  • the methods disclosed herein comprise event driven administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the subject.
  • the terms “event driven” or “event driven administration” refer to administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and/or (2) during an event (or more than one recurring event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and/or (3) after an event (or after the final event in a series of recurring events) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection).
  • an event e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event
  • an event e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event
  • an event e.g.,
  • the event driven administration is performed pre-exposure of the subject to the virus. In some embodiments, the event driven administration is performed post-exposure of the subject to the virus. In some embodiments, the event driven administration is performed pre-exposure of the subject to the virus and post-exposure of the subject to the virus.
  • the methods disclosed herein involve administration prior to and/or after an event that would expose the individual to the virus or that would otherwise increase the individual’s risk of acquiring the viral infection, e.g., as pre-exposure prophylaxis (PrEP) and/or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP).
  • methods disclosed herein comprise post-exposure prophylaxis (PEP).
  • PEP post-exposure prophylaxis
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered before exposure of the subject to the virus.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered before and after exposure of the subject to the virus.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered after exposure of the subject to the virus.
  • An example of event driven dosing regimen includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to the virus, followed by administration of the compound of Formula I, or a pharmaceutically acceptable salt, every 24 hours during the period of exposure, followed by a further administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, after the last exposure, and one last administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.
  • a further example of an event driven dosing regimen includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours before the viral exposure, then daily administration during the period of exposure, followed by a last administration approximately 24 hours later after the last exposure (which may be an increased dose, such as a double dose).
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • administration can be for from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days.
  • the administration can also be for from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer periods of administration are also contemplated.
  • the compounds disclosed herein are administered once daily.
  • the compounds disclosed herein are administered once every alternate day.
  • the compounds disclosed herein are administered once a week.
  • the compounds disclosed herein are administered twice a week.
  • one or more compounds disclosed herein are administered once daily.
  • the once daily dose may be administered for as long as required, for example for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to a month or longer.
  • the once daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days or for one day.
  • the one or more compounds disclosed herein are dosed once daily, for about 6 to 12 days, for example for about 8-10 days. In some embodiments, the one or more compounds are administered once daily for about 9 days.
  • the one or more compounds are administered once daily for about 10 days. In some embodiments about 50- 150 mg of one or more compounds disclosed herein is administered once daily for about 5 to 12 days, for e.g., for about 10 days. In some embodiments about 100 mg of one or more compounds disclosed herein is administered once daily for about 5 to 12 days, for e.g., for about 10 days. VII. Methods of Use The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound described herein.
  • a subject e.g., human
  • the present disclosure provides a method of treating a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to a subject in need thereof a compound described herein. In some embodiments, the present disclosure provides for methods of treating or preventing a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent. In some embodiments, the present disclosure provides for methods of treating a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound disclosed herein, and at least one additional active therapeutic agent.
  • the present disclosure provides for methods of inhibiting a viral polymerase in a cell, the methods comprising contacting the cell infected a virus with a compound disclosed herein, whereby the viral polymerase is inhibited. In some embodiments, the present disclosure provides for methods of inhibiting a viral polymerase in a cell, the methods comprising contacting the cell infected a virus with a compound disclosed herein, and at least one additional active therapeutic agent, whereby the viral polymerase is inhibited. Also provided here are the uses of the compounds disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of the compounds disclosed herein for use in treating a viral infection in a subject in need thereof.
  • the viral infection is a paramyxoviridae virus infection.
  • the present disclosure provides methods for treating a paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein.
  • Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and parainfluenza virus.
  • the Paramyxoviridae virus is a Sosuga virus.
  • the viral infection is a pneumoviridae virus infection.
  • the present disclosure provides a method of treating a pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound provided herein.
  • Pneumoviridae viruses include, but are not limited to, respiratory snycytial virus and human metapneumovirus.
  • the pneumoviridae virus infection is a respiratory syncytial virus infection.
  • the pneumoviridae virus infection is human metapneumovirus infection.
  • the present disclosure provides a compound disclosed herein, for use in the treatment of a pneumoviridae virus infection in a human in need thereof.
  • the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is human metapneumovirus infection. In some embodiments, the present disclosure provides methods for treating a RSV (respiratory syncytial virus) infection in a human in need thereof, the method comprising administering to the human a compound provided herein. In some embodiments, the human is suffering from a chronic respiratory syncytial viral infection. In some embodiments, the human is acutely infected with RSV. In some embodiments, a method of inhibiting RSV replication is provided, wherein the method comprises administering to a human in need thereof, a compound disclosed herein, wherein the administration is by inhalation.
  • the present disclosure provides a method for reducing the viral load associated with RSV infection, wherein the method comprises administering to a human infected with RSV a compound disclosed herein.
  • the viral infection is a picornaviridae virus infection.
  • the present disclosure provides a method of treating a picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound of the present disclosure.
  • Picornaviridae viruses are enteroviruses causing a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome (human rhinovirus infection), a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot- mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
  • the Picornaviridae virus infection is human rhinovirus infection.
  • the Picornaviridae virus infection is enterovirus infection.
  • the Picornaviridae virus infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.
  • the present disclosure provides a compound, for use in the treatment of a picornaviridae virus infection in a human in need thereof.
  • the picornaviridae virus infection is human rhinovirus infection.
  • the viral infection is a flaviviridae virus infection.
  • the present disclosure provides a method of treating a flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein.
  • Representative flaviviridae viruses include, but are not limited to, dengue, Yellow fever, West Nile, Zika, Japanese encephalitis virus, and Hepatitis C (HCV).
  • the flaviviridae virus infection is a dengue virus infection.
  • the flaviviridae virus infection is a yellow fever virus infection.
  • the flaviviridae virus infection is a West Nile virus infection.
  • the flaviviridae virus infection is a zika virus infection.
  • the flaviviridae virus infection is a Japanese ensephalitis virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection. In some embodiments, the present disclosure provides use of a compound disclosed herein for treatment of a flaviviridae virus infection in a human in need thereof. In some embodiments, the flaviviridae virus infection is a dengue virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a zika virus infection.
  • the flaviviridae virus infection is a hepatitis C virus infection.
  • the viral infection is a filoviridae virus infection.
  • Representative filoviridae viruses include, but are not limited to, ebola (variants Zaire, Bundibugio, Sudan, Tai forest, or Reston) and marburg.
  • the filoviridae virus infection is an ebola virus infection.
  • the filoviridae virus infection is a marburg virus infection.
  • the present disclosure provides a compound for use in the treatment of a filoviridae virus infection in a human in need thereof.
  • the filoviridae virus infection is an ebola virus infection.
  • the filoviridae virus infection is a marburg virus infection.
  • the viral infection is a coronavirus infection.
  • provided herein is a method of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a compound provided herein.
  • the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections.
  • the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection.
  • the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection.
  • the viral infection is SARS-CoV-2 infection.
  • the viral infection is a zoonotic coronavirus infection
  • the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2.
  • the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2.
  • the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the present disclosure provides a compound for use in the treatment of a coronavirus virus infection in a human in need thereof.
  • the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections.
  • the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection.
  • the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection.
  • the viral infection is SARS-CoV-2 infection (COVID19).
  • the viral infection is an arenaviridae virus infection.
  • the disclosure provides a method of treating an arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein.
  • the arenaviridae virus infection is a Lassa infection or a Junin infection.
  • the present disclosure provides a compound for use in the treatment of a arenaviridae virus infection in a human in need thereof.
  • the arenaviridae virus infection is a Lassa infection or a Junin infection.
  • the viral infection is an orthomyxovirus infection, for example, an influenza virus infection.
  • the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.
  • the viral infection is a nairovirus infection.
  • the disclosure provides a method of treating a nairovirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein.
  • the nairovirus infection is a Crimean–Congo hemorrhagic fever virus infection.
  • the nairovirus infection is a Hazara virus infection.
  • the compounds described herein can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with a viral infection.
  • the additional therapeutic agent(s) can be administered to the infected individual at the same time as the compound of the present disclosure or before or after administration of the compound of the present disclosure.
  • the compounds described herein can also be used in combination with one or more additional therapeutic or prophylactic agents.
  • methods for treatment of viral infections in a subject in need thereof comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.
  • the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents.
  • the one or more additional therapeutic agents include one or more additional therapeutic agents from the same class or group (nonlimiting examples include one or more antiviral agents, one or more vaccines, one or more antibodies) and/or one or ore more additional therapeutic agents from different classes or groups.
  • 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, Cytochrome P4503A4 inhibitors, Peptidyl-prolyl cis-trans isomerase A inhibitors, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A/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 [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, ⁇ -D-N4-hydroxycytidine or a combination thereof.
  • the additional therapeutic agent is a pyrophosphate analogue.
  • the additional therapeutic agent is foscarnet or phosphonoacetic acid.
  • the additional therapeutic agent is foscarnet.
  • the additional therapeutic agent is nucleoside reverse transcriptase inhibitor.
  • the antiviral agent is zidovudine, didanosine z ⁇ alcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.
  • 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 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 embodiments, 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/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 AT-527, daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.
  • the additional therapeutic agent is an influenza virus inhibitor.
  • the additional therapeutic agent 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.
  • 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 an interferon.
  • the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFN ⁇ -2a), and PegIFN ⁇ -2b.
  • the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFN ⁇ -2a), and PegIFN ⁇ -2b.
  • the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFN ⁇ -2a), PegIFN ⁇ -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 agentnet is interferon-beta-1a, such as SNG-001.
  • the additional therapeutic agent is an interferon-inducing agent, such as tilorone hydrochloride.
  • the additional therapeutic agent is IL-17 antagonist such as ixekizumab, secukinumab, IMU-838, and 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 i ⁇ miquimod, sinecatechins, azoximer bromide, IMM-101 and combinations thereof.
  • the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, 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.
  • the antiviral agent is virafin.
  • the antiviral agent is berdazimer sodium.
  • the antiviral agent is KT-07.
  • the antiviral agent is iorta-carrageenan.
  • the antiviral agent is polyoxidonium.
  • the antiviral agent is bitespiramycin. In some embodiments, the antiviral agent is an anti-Adrenomedullin antibody, such as enibarcimab. In some embodiments, the antiviral agent is an annexin A5 stimulator, such as SY-005.spyke. In some embodiments, the antiviral agent is a COVID19 replicase polyprotein 1ab inhibitor, such as DC-402234. In some embodiments, the antiviral agent is a host cell factor modulator, such as GBV-006. In some embodiments, the antiviral agent is protoporphyrin. IX, stannous, SnPP protoporphyrin and verteporfin.
  • 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 picornavirus. 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 picornavirus 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.
  • the additional therapeutic agent is dihydroartemisinin piperaquine, Pyramax.
  • the additional therapeutic agent is chloroquine.
  • 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, anti- viroporins, 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-5H-pyrrolo[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 (1-N,7-N- bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinol
  • 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, AT-527, 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 AIC-649, alpha-hydroxytropolones, amdoxovir, antroquinonol, beta- hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, CV-431, 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, Hep
  • 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, autologous stem cell therapies).
  • HIV protease inhibitors HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase
  • 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 FT-516.
  • 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 HIV combination drug.
  • 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); TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine);
  • 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, balixafortide, motixafortide, and vMIP (Haimipu).
  • the additional therapeutic agent is a HIV nucleoside reverse transcriptase inhibitors.
  • the additional therapeutic agent is a HIV nonnucleoside 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 non- nucleotide 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 agent is a HIV ⁇ vaccine, such as DermaVir.
  • 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); TRUVADA ® (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
  • 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 a CD73 agonist, such as FP- 1201.
  • the additional therapeutic agent is a CGRP receptor antagonist, such as BHV-3500.
  • the additional therapeutic agent is a Cytochrome P4503A4 inhibitor/ Peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir.
  • the additional therapeutic agent is a progesterone receptor agonist, such as Progesterone-IBSA.
  • the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.
  • the additional therapeutic agent is an inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695).
  • BTK Bruton tyrosine kinase
  • the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-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 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 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 Syk tyrosine kinase inhibitor, such as fostamatinib disodium.
  • the additional therapeutic agent is a cholesterol ester transfer protein inhibitor, such as dalcetrapib.
  • 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. 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 casein kinase II inhibitor, such as silmitasertib. In some embodiments, the additional therapeutic agent is a Bcr-Abl tyrosine kinase inhibitor, such as radotinib.
  • the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapent ethyl.
  • 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 a 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 PARP1/2 and Tankyrase 1/2, such as stenoparib (2X-121).
  • the additional therapeutic agent is a cyclin dependent kinase inhibitor, such as CYC-065, CYC-202, fadraciclib, seliciclib.
  • the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine, azacytidine, DUR-928.
  • the additional therapeutic agent is a DHFR inhibitor, such as methotrexate.
  • the additional therapeutic agent is a Deoxyribonuclease stimulator, such as Descartes-30. In some embodiments, the additional therapeutic agent is a Ribonuclease stimulator, such as ranpirnase. In some embodiments, the additional therapeutic agent is an eukaryotic initiation factor 4A1 (eIF4A1) inhibitor, such as zotatifin. 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 a Ubiquitin ligase modulator, such as KPG-818. In some embodiments, the additional therapeutic agent is an integrin agonist such as 7HP-349.
  • eIF4A1 eukaryotic initiation factor 4A1
  • the additional therapeutic agent is a small ubiquitin related modifier inhibitor, such as TAK-981.
  • the additional therapeutic agent is a Ubiquitin ligase modulator, such as KPG-818.
  • 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 an ER1 inhibitor, such as toremifene. In some embodiments, 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 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac- RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.
  • KRpep-2 Ac-RRCPLYISYDPVCRR-NH2
  • KRpep-2d Ac- RRRRCPLYISYDPVCRRRR-NH2
  • the additional therapeutic agent is a proteasome inhibitor.
  • the additional therapeutic agent is selected from a group consisting of ixazomib, carfilzomib, marizomib, bortezomib, disulfiram + copper gluconate, 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, inactivated vaccine (i.e., inactivated SARS-CoV-2 vaccine), therapeutic vaccine, prophylactic vaccine, protein based vaccine, viral vector vaccine, cellular vaccine, dendritic cell vaccine (i.e., LV-SMENP-DC, LV-SMENP-DC, or AV-COVID-19) or a combination thereof.
  • the additional therapeutic agent is mRNA-1273, mRNA-1273.211, mRNA-1273.351, mRNA-1283, CVnCoV, DS-5670., SP-0254, ARCoV, Nanocovax.
  • the additional therapeutic agent is INO-4800 or INO-4700.
  • the therapeutic agent is a DNA vaccine, such as AG301-COVID19, bacTRL-Spike, GX-19, AG-0301-COVID19, ZyCoC-D, GLS-5310, CORVax.
  • 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 [H5N1] virus monovalent vaccine and influenza A [H1N1] 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
  • (iii) quadrivalent vaccine for influenza A and B viruses (FluMist, 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 G1, G3, G4, or G9 and RotaTeq for rotavirus serotype G1, 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., YF- Vax).
  • 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-R II and ProQuad).
  • the additional therapeutic agent is a mumps vaccine (e.g., M-M-R II and ProQuad).
  • the additional therapeutic agent is a rubella vaccine (e.g., M-M-R II and ProQuad).
  • the additional therapeutic agent is a varicella vaccine (e.g., ProQuad).
  • 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 MERS vaccine (e.g., MVA-MERS-S, VTP-500).
  • the additional therapeutic agent is a BCG vaccine.
  • the additional therapeutic agent is a recombinant protein subunit vaccine (e.g., ZF-2001), EuCorVAc-19, GBP-510, Sinopharma vaccine, SpyCatcher vaccine, SP-0253, VBI-2902, UB-612, MVC-COV1901.
  • the additional therapeutic agent is a live attenuated bacterial vaccine (e.g., MV- 130).
  • the additional therapeutic agent is a recombinant non-replicating vaccine (e.g., JNJ784326735 (Ad26 SARS-CoV-2)).
  • the additional therapeutic agent is poly-TLR agonist polyantigenic vaccine (e.g., Mycobacterium w).
  • the additional therapeutic agent is a QAZCOVID-IN vaccine. In some embodiments, the additional therapeutic agent is a GRAd-COV2 vaccine. In some embodiments, the additional therapeutic agent is a EpiVacCorona vaccine. In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine. In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 Prime-boost), Sputnik-Light vector vaccine (rAd26), Covax-19, NasoVAX, NDV-HXP-S vaccine, AdCOVID, VSV-vector based vaccine.
  • the additional therapeutic agents is TiterQuil-1055 adjuvanted vaccine.
  • 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, and/or TNX-1820, and/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-CoV2.
  • the additional agent is SCB-2019.
  • the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-M and 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, V-SARS., AdCLD-Cov19, AKS-452, BVRS- GamVac, BVRS-GamVac-Combi, CIGB-2020, COVAC-2, FINLAY-FR-1, KD-414, S-268019, T-COVID, CDX-005, COH-04S1, ABNCoV2, ERUCOV-VAC, fakhravac, Kocak-19 inaktif adjuvanl
  • 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 a PD-1 antibody.
  • the additional therapeutic agent is REGN-COV2.
  • the additional therapeutic agent is LY-CoV555.
  • 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 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 PDE3/PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin and ensifentrine. 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 and AK-119. In some embodiments, the additional therapeutic agent is recombinant cytokine gene- derived protein injection.
  • the additional therapeutic agent is amnion- derived cellular cytokine solution, such as ST-266.
  • 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 a RNA polymerase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of AT-527, ribavirin, favipiravir, lamivudine, galidesivir, pimodivir and combination 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, TAK-671.
  • the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat, Nafamostat, 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 A1, E- 52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, LTX-109, MAS- 825, Metformin, Metformin glycinate, MRG-001, Medregen, MRx-0004, thimerosal, Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623, Midostaurin, Ruxolitinib, ZINC1775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, Daunorubicin, GB110,
  • 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 agenet 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 LB1148, upamostat, RHB-107, alpha-1 antitrypsin, tranexamic acid.
  • the additional therapeutic agent is a replicase polyprotein 1a inhibitor/replicase polyprotein 1ab inhibitor/protease inhibitor/coronavirus 3C protease like inhibitor, such as PF-07304814.
  • the additional therapeutic agent is a SARS coronavirus 3C protease like inhibitor, such as PF-07321332.
  • the additional therapeutic agent is a serine protease inhibitor, such as DS-2319, repurposed nafamostat mesylate.
  • the additional therapeutic agent is a serine protease inhibitor/Transmembrane serine protease 2 inhibitor, such as nafamostat.
  • the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213
  • the additional therapeutic agent is a serine threonine protein kinase ATR inhibitor, such as berzosertib.
  • the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonodelestat.
  • the additional therapeutic agent is an ⁇ -ketoamide.
  • the additional therapeutic agent is a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, for example, the additional therapeutic agent is CVL218.
  • the additional therapeutic agent is selected from the group consisting of 6’-fluorinated aristeromycin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, CNM-AgZn-17, genistein, JAN-101, nitric oxide (inhalant), nitric oxide based antiviral formulation (oral), RTD-1, PrEP-001, QBKPN, RUTI, GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10,
  • PARP1 poly
  • the additional therapeutic agent is an anti-CD147 antibody.
  • the additional therapeutic agent is meplazumab.
  • the additional therapeutic agent is an antibody.
  • the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS.
  • the additional therapeutic agent is a of 2019-nCoV virus antibody.
  • the antibody is ABBV-47D11.
  • the antibody is COVI-GUARD.
  • the antibody is C144-LS + C135-LS.
  • the antibody is DXP-604.
  • the antibody is JMB-2002.
  • the antibody is LY-CovMab. In some embodiments, the antibody is LY- CoV555. In some embodiments, the antibody is S309. In some embodiments, the antibody is SAB-185. In some embodiments, the antibody is SI-F019. In some embodiments, the antibody is CB6. In some embodiments, the antibody is COR-101. In some embodiments, the antibody is STI-1499. In some embodiments, the antibody is JS016. In some embodiments, the antibody is VNAR. In some embodiments, the antibody is VIR-7832 and/or VIR-7831. In some embodiments, the antibody is REGN-COV2 (casirivimab + imdevimab REGN10933 + RGN10987).
  • the antibody is BAT2020, BAT2019. In some embodiments, the antibody is 47D11. In some embodiments, the antibody cocktail is COVI- SHIELD. In some embodiments, the antibody is BRII-196, BRII-198. In some embodiments, the antibody is ADG-20. In some embodiments, the antibody is ABP-300. In some embodiments, the antibody is BI-767551. In some embodiments, the antibody is GSK-4182136. In some embodiments, the antibody is AZD-7442. In some embodiments, the antibody is regdanvimab. In some embodiments, the antibody is etesevimab. In some embodiments, the antibody is SAB- 301. In some embodiments, the antibody is AOD-01.
  • the antibody is COVI-AMG. In some embodiments, the antibody is MW-33. In some embodiments, the antibody is DXP-593. In some embodiments, the antibody is BSVEQAb. In some embodiments, the antibody is anti-SARS-CoV-2 IgY. In some embodiments, the antibody is COVID-EIG. In some embodiments, the antibody is CSL-760. In some embodiments, the antibody is REGN- 3048-3051. In some embodiments, the antibody is ADM-03820. In some embodiments, the antibody is HFB-30132A. In some embodiments, the additional therapeutic agent is an anti- Hemolysin alpha antibody, such as tosatoxumab.
  • the additional therapeutic agent is an anti-LPS antibody IMM-124-E.
  • the antibody is INM-005, SCTA01, TY-027, XAV-19.
  • the additional therapeutic agent in an steroid for example corticosteroid.
  • the additional therapeutic agent is dexamethasone.
  • 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, amphotericin B, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole 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 K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immonumodulatory medications (e.g., 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 molnupiravir. In some embodiments, the additional therapeutic agent is AT-527. In some embodiments, the additional therapeutic agent is PF-07321332. In some examples, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide or budesonide.
  • 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.
  • PAX-1 Panaphix
  • NCP-112 which inhibit excessive immune response such as cytokine storm.
  • the additional therapeutic agent is an antifungal agent, for example itraconazole or 17-OH- itraconazole.
  • the additional therapeutic agent is an immunomodulator.
  • immune-based therapies include toll-like receptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators (i.e., nivolumab); programmed death-ligand 1 (Pd-L1) modulators (i.e., camrelizumab, pembrolizumab); IL-15 modulators; DermaVir; interleukin-7 modulators (i.e., efineptakin alfa, plaquenil (hydroxychlor)
  • 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, astegolimab (MSTT1041A, RG-6149), UTTR1147A. 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 gamunex. In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralumab.
  • the additional therapeutic agent is a KEAP1 modulator, such as SFX-01.
  • the additional therapeutic agent is a PARP inhibitor, such as BGP-15.
  • the additional therapeutic agent is octagam.
  • the additional therapeutic agent is RPH-104.
  • the additional therapeutic agent is canakinumab.
  • the additional therapeutic agent is a leukocyte Ig like receptor A4 modulator, such as daxdilimab.
  • the additional therapeutic agent is a Melanocortin MC 1 receptor agonist, such as PL-8177.
  • the additional therapeutic agent is an IL-33 ligand inhibitor such as MEDI3506.
  • the additional therapeutic agent is an IL-5 receptor antagonist, such as mepolizumab.
  • the additional therapeutic agent is an IL-12/IL23 inhibitor, such as apilimod, apilimod dimesylate.
  • the additional therapeutic agent is a IL-15 receptor agonist, such as N-803.
  • the additional therapeutic agent is an IL-18 ligand inhibitor, such as tadekinig- alfa.
  • the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa, F-652.
  • 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, olokizumab, sirukumab, clazakizumab, levilimab or a combination thereof.
  • the additional therapeutic agent is tocilizumab biosimilar (e.g., CMAB-806).
  • the additional therapeutic agent is Apolipoprotein B modulator/IL-6 receptor antagonist/Serum amyloid A protein modulator/Transthyretin modulator.
  • the additional agent is Amilo-5MER.
  • the additional therapeutic agent is a Melanocortin MC1/MC3 receptor agonist.
  • the additional therapeutic agent is AP-1189.
  • the additional therapeutic agent is a NLRP3 inflammasome inhibitor. In some embodiments, the additional therapeutic agent is dapansutrile, DFV-890. 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 dipeptidase 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.
  • DPEP-1 dipeptidase 1
  • the additional therapeutic agent is Metablok (LSALT peptide). In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor.
  • the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.
  • the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, olumiant, TD-0903 or a combination thereof.
  • the additional therapeutic agent is jaktinib.
  • the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone or LYT-100.
  • the additional therapeutic agent is anti-inflammatory agent, such as dociparstat sodium, eicosapentaenoic acid, didodecyl methotrexate, rabeximod, EG-009.
  • the additional agent is a TREM receptor 1 antagonistused in the treatment of septic shock, such as nangibotide.
  • the additional therapeutic agent is a CCR1 antagonist, such as MLN-3897.
  • the additional therapeutic agent is a Complement C3 inhibitor, such as NGM-621, AMY-101.
  • the additional therapeutic agent is a Complement C1s subcomponent inhibitor, such as RLS-0071.
  • the additional therapeutic agent is a Complement factor C2 modulator, such as ARGX-117.
  • the additional therapeutic agent is a Galectin-3 inhibitor, such as belapectin.
  • the additional therapeutic agent is a heparanase inhibitor, such as tridecasodium pixatimod.
  • the additional therapeutic agent is an anti- MASP2 antibody, such as narsoplimab.
  • the additional therapeutic agent is a calcium channel modulator, such as dantrolene sodium.
  • the additional therapeutic agent is a sodium channel stimulator, such as solnatide.
  • the additional therapeutic agent is a alkaline phosphatase stimulator such as bovine alkaline phosphatase.
  • the additional therapeutic agent is a complement factor D inhibitor, such as ACH-0144471.
  • the additional therapeutic agent is a NK1 antagonist, such as LY-686017.
  • the additional therapeutic agent is a Zonulin inhibitor, such as larazotide acetate.
  • the additional therapeutic agent is an aryl hydrocarbon receptor agonist/ stem cell antigen-1 inhibitor, such as ampion.
  • the additional therapeutic agent is a dual complement C5 factor/Leukotriene BLT receptor antagonist, such as nomacopan.
  • the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.
  • the additional therapeutic agent is an opioid receptor antagonist, such as naltrexone.
  • the additional therapeutic agent is an opioid receptor agonist, such as metenkefalin.
  • the additional therapeutic agent is a BMP10/BMP15 gene inhibitor, such as lucinactant.
  • the additional therapeutic agent is an actin antagonist, such as gelsolin.
  • the additional therapeutic agent is a CD95 antagonist, such as asunercept.
  • the additional therapeutic agent is a Fractalkine ligand (CX3CL1) inhibitor, such as quetmolimab.
  • the additional therapeutic agent is a Platelet glycoprotein VI (GPVI) inhibitor, such as glenzocimab.
  • the additional therapeutic agent targets IKK ⁇ and NF ⁇ , such as OP-101.
  • the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone, dexamethasone, dexamethasone phosphate.
  • the additional therapeutic agent is a PDGF receptor antagonist/TGF beta receptor antagonist/p38 MAP kinase inhibitor, such as deupirfenidone.
  • the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.
  • the additional therapeutic agent is a prostaglandin E synthase-1 inhibitor, such as sonlicromanol hydrochloride.
  • the additional therapeutic agent is a superoxide dismutase modulator, such as Tempol.
  • the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.
  • the additional therapeutic agent is a TLR-2/TLR-4 antagonist, such as VB-201.
  • the additional therapeutic agent is a TLR-7/TLR-8 antagonist, such as M-5049.
  • 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 an IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8), DF-1681 (reparixin).
  • the additional therapeutic agent is a CD14 inhibitor, such as IC-14, atibuclimab.
  • the additional therapeutic agent is a cyclophilin A inhibitor, such as CRV-431.
  • the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299, ASLAN-003.
  • the additional therapeutic agent is a G-protein coupled bile acid receptor 1 agonist (GPCR19) agonist, such as HY-209.
  • the additional therapeutic agent is a Grp78 calcium binding protein inhibitor/Jun N terminal kinase inhibitor/Transferrin modulator/p38 MAP kinase modulator, such as IT-139.
  • the additional therapeutic agent is a Histone deacetylase-6 (HDAC-6) inhibitor, such as CKD-506.
  • HDAC-6 Histone deacetylase-6
  • the additional therapeutic agent is a Lyn tyrosine kinase stimulator, such as tolimidone.
  • the additional therapeutic agent is a Tek tyrosine kinase receptor stimulator, such as AV-001.
  • the additional therapeutic agent is an Integrin alpha-V/beta-1 and alpha-V/beta-6 antagonist, such as PLN-74809.
  • the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as PF- 06650833.
  • the additional therapeutic agent is a plasma kallikrein inhibitor/KLKB1 gene inhibitor, such as IONIS-PKK-LRx.
  • the additional therapeutic agent is a Leukocyte elastase inhibitor, such as alvelestat, lonodelestat acetate.
  • the additional therapeutic is a Maxi K potassium channel inhibitor, such as ENA-001.
  • the additional therapeutic is a Nuclear factor kappa B inhibitor/p38 MAP kinase inhibitor, such as GLS-1027.
  • the additional therapeutic is a Nuclear factor kappa B inhibitor such as timbetasin or liposomal curcumin.
  • the additional therapeutic is anti-fibrotic, such as RT-1840, nintedanib, GB-0139, nintedanib or pamrevlumab.
  • the additional therapeutic is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777).
  • HGF hepatocyte growth factor
  • 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, besifloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or a combination thereof.
  • the antibiotic is XEL 1004.
  • the antibiotic is eravacycline.
  • the additional therapeutic agent is a bactericidal permeability protein inhibitor/Outer membrane protein inhibitor, such as RECCE-327.
  • 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. In some embodiments, the compounds disclosed herein are used in combination with stem cells. In some embodiments, the compounds disclosed herein are used in combination with plasma-derived anti-SARS-CoV-2 IgG. In some embodiments, the compounds disclosed herein are used in combination with TAK- 888, NP-028 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)), or GC-5131A. In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immunoglobulin.
  • the compounds disclosed herein are used in combination with stem cells.
  • the compounds disclosed herein are used in combination with AdMSCs, ADR-001, Allo-hMSCs, CAP-1002, hCT-MSC, HB-adMSCs, itMSCs, MultiStem, Pluristem, Remestemcel-L (mesenchymal stem cells), NurOwn®, Rexlemestrocel-L, UCMSCs, or ACT-20.
  • 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, MT-2766, 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 selected from the group consisting of AVM-0703, bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, simvastatin, trimodulin, rosuvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.
  • the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor, or ⁇ -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 alunacedase alfa (APN-01), HLX-71.
  • the additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the additional therapeutic agent is a partial agonist of AT2 or a partial antagonist of AT1. In some embodiments, the additional therapeutic agent is L-163491. 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, lisonopril.
  • the additional therapeutic agent is an Angiotensin II AT-1 receptor antagonist/Beta-arrestin stimulator, such as TRV-027.
  • the additional therapeutic agent is an ACE2 inhibitor/COVID19 Spike glycoprotein inhibitor, such as MP-0420.
  • the additional therapeutic agent is a caspase inhibitor, such as emricasan.
  • the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.
  • the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as RP-7214.
  • the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor; Protein tyrosine kinase inhibitor, such as repurposed leflunomide.
  • 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 XIIa antagonist, such as garadacimab.
  • the additional therapeutic is a Factor XIa antagonist, such as EP-7041.
  • 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, tenecteplase.
  • 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, 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 (Nanomedivir).
  • 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. In some embodiments, the additional therapeutic agent is an estrogen receptor modulator, such as estetrol. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide, proxalutamide. 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 thyroid hormone receptor, such as sobetirome. In some embodiments, 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, otilimab, plonmarlimab.
  • 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 calcium activated chloride channel (CACC) inhibitor, such as crofelemer.
  • 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.
  • SGLT-2 sodium glucose cotransporter type 2
  • 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, tranilast.
  • the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.
  • the additional therapeutic agent is anti-histamine such as cloroperastine, and 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), such as FX-06.
  • ARDS acute respiratory distress syndrome
  • the additional therapeutic agent is BIO-11006.
  • the additional therapeutic agent is sodium pyruvate.
  • 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, formoterol.
  • the additional therapeutic agent is a beta 2 adrenoceptor agonist, such as salmeterol.
  • the additional therapeutic agent is hyaluronidase inhibitor such as astodrimer.
  • 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 additional therapeutic agent is a TLR4 antagonist, such as EB-05, NI-0101, or E-5564.
  • the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039.
  • the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.
  • 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 modulator.
  • the additional therapeutic agent is pritumumab, hzVSF-v13.
  • the additional therapeutic agent is a modulator of Nsp15 (nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, AB001, 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 xanthine oxidase inhibitor, such as bucillamine, Xrx-101.
  • the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825, ONO-5334.
  • the additional therapeutic agent is a Transforming growth factor beta (TGF- ⁇ ) inhibitor.
  • TGF- ⁇ Transforming growth factor beta
  • the additional therapeutic agent is OT-101.
  • the additional therapeutic agent is a N-methyl-D-aspartate (NMDA) receptor antagonist.
  • NMDA N-methyl-D-aspartate
  • the additional therapeutic agnent is ifenprodil, transcrocetin.
  • 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, colchicine.
  • the additional therapeutic agent is a glucosylceramide synthase inhibitor such as miglustat.
  • the additional therapeutic agent is a Nrf2 activator, such as PB125.
  • 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 (CSF1R) inhibitor, such as Avdoralimabaxatilimab.
  • CSF1R 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,
  • the additional therapeutic agent is a complement C 1 s inhibitor, such as conestat alpha.
  • the additional therapeutic agent is a C 3 inhibitor, such as APL-9, AMY-101
  • the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab or vilobelimab.
  • 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 LY-3127804.
  • the additional therapeutic agent is a lysine specific histone demethylase 1 inhibitor, such as vafidemstat.
  • the additional therapeutic agent is a histone inhibitor, such as STC-3141.
  • the additional therapeutic agent is a hyaluronan inhibitor.
  • the additional therapeutic agent is dopamine D2 receptor antagonist, such as chlorpromazine.
  • the additional therapeutic agent is a proton pump inhibitor, such as omeprazole. In some embodiments, the additional therapeutic agent is a PGI2 agonist, such as epoprostenol. In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such asTM-5614. In some embodiments, the additional therapeutic agent is a Ubiquinol cytochrome C reductase 14 kDa inhibitor, such as telacebec. 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.
  • additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.
  • the additional therapeutic agent is a cell therapy, such as allogeneic natural killer cells, antigen presenting cells (APC), invariant natural killer T (iNKT) cells, induced pluripotent stem cell (iPSC), allogeneic T-cells, autologous adipose-derived mesenchymal stem cells, allogeneic bone marrow-derived mesenchymal stem cells, allogeneic mesenchymoangioblast-derived mesenchymal stem cells, regulatory T cells (Tregs), dendritic cells.
  • APC antigen presenting cells
  • iNKT invariant natural killer T
  • iPSC induced pluripotent stem cell
  • allogeneic T-cells autologous adipose-derived mesenchymal stem cells
  • the additional therapeutic agent is SARS-CoV-2 specific cytotoxic T lymphocyte.
  • the additional therapeutic agent is agenT-797, Allocetra, ALVR-109, BM-Allo.MSC, BM-Allo-MSC, CAStem, Cellgram-AKI, CK-0802, CL-2020, IL- 15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, DWP-710, partially HLA- matched Virus Specific T cells (VSTs), FT-516, RAPA-501, SARS-CoV-2 Specific T Cells, HLCM-051, ExoFlo, HCR-040, it-hMSC, KI-MSC-PL-205, ORBCEL-C, pathogen-specific aAPC, ProTrans, SBI-101, StemVacs, STI-8282, taniraleucel, UMSC-01.
  • the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, XC-7, long-acting injectable ivermectin, Captopril, Lisinopril, Camostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof.
  • the additional therapeutic agent is selected form a group consisting of tilorone, cannabidiol, 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 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, ISPM-19, cipargamin, artemisone, and combinations thereof.
  • any compound of the disclosure 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 disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the disclosure and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the disclosure 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 disclosure 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 disclosure within seconds or minutes.
  • a unit dose of a compound of the disclosure may be desirable to administer a unit dose of a compound of the disclosure 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein are also used in combination with other active therapeutic agents.
  • the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and/or metapneumovirus infections.
  • Non-limiting examples of these other active therapeutic agents active against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam ® ), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS- 433771, ALN-RSV0, ALX-0171 and mixtures thereof.
  • respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir
  • RNA polymerase inhibitors such as lumicitabine and ALS-8112
  • anti- RSV G protein antibodies such as anti-G-protein mAb
  • viral replication inhibitors such as nitazoxanide.
  • the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI- 8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.
  • RSV including but not limited to MVA-BN RSV, RSV-F, MEDI- 8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.
  • Non-limiting examples of other active therapeutic agents active against metapneumovirus infections include sialidase modulators such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for the treatment of Metapneumovirus infections, such as EV-046113.
  • the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infections, including but not limited to mRNA- 1653 and rHMPV-Pa vaccine. 2.
  • Combination Therapy for the treatment of Picornaviridae The compounds provided herein are also used in combination with other active therapeutic agents.
  • the other active therapeutic agent is active against Picornaviridae virus infections, particularly Enterovirus infections.
  • Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu, et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase protein such as DAS-181; a capsid protein VP1 inhibitor such as VVX-003 and AZN-001; a viral protease inhibitor such as CW-33; a phosphatidylinositol 4 kinase beta inhibitor such as GSK- 480 and GSK-533; anti-EV71 antibody.
  • capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu, et al. (US 7,078,403) and Watson (US 7,166,604)
  • fusion sialidase protein such as DAS-181
  • a capsid protein VP1 inhibitor such as VVX-003 and AZN-001
  • the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infections, including but not limited to EV71 vaccines, TAK-021, and EV-D68 adenovector-based vaccine.
  • EV71 vaccines EV71 vaccines
  • TAK-021, and EV-D68 adenovector-based vaccine EV-D68 adenovector-based vaccine.
  • additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds provided herein.
  • the additional agents are preferably administered orally or by direct inhalation.
  • other preferred additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.
  • Glucocorticoids which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985).
  • oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001).
  • corticosteroids have been developed to mitigate the severe adverse effects of oral steroids.
  • corticosteroids that may be used in combinations with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, momet
  • Anti-inflammatory agents Other anti-inflammatory agents working through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections.
  • AISTM anti-inflammatory signal transduction modulators
  • phosphodiesterase inhibitors e.g., PDE-4, PDE-5, or PDE-7 specific
  • transcription factor inhibitors e.g., blocking NF ⁇ B through IKK inhibition
  • kinase inhibitors e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk
  • non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-1- isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4- difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4- methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro
  • ⁇ 2-adrenoreceptor agonist bronchodilators comprising inhaled ⁇ 2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds provided herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
  • Combinations of inhaled ⁇ 2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS’s are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively).
  • Beta 2 adrenoceptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.
  • Anticholinergics For the treatment or prophylaxis of pulmonary broncho-constriction, anticholinergics are of potential use and, therefore, useful as an additional therapeutic agent in combination with the compounds provided herein for the treatment of viral respiratory infections.
  • anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); 1- ⁇ 4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)- propionyl]-pyrrolidine-2-carbonyl ⁇ -pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4- ylmethyl)-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl- 8-azonia-bicyclo[3.2.1]octane
  • Mucolytic agents may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of a mucolytic agent is ambroxol.
  • the compounds may be combined with expectorants to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of an expectorant is guaifenesin.
  • Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266).
  • the compounds provided herein may also be combined with nebulized hypertonic saline particularly when the virus infection is complicated with bronchiolitis.
  • the combination of the compound provided herein with hypertonic saline may also comprise any of the additional agents discussed above. In some embodiments, about 3% hypertonic saline is used. 4.
  • Combination Therapy for the treatment of Flaviviridae virus infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae virus infections, preferably, the other active therapeutic agent is active against Flaviviridae virus infections.
  • non-limiting examples of the other active therapeutic agents are host cell factor modulators, such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors, such as celgosivir; platelet activating factor receptor (PAFR) antagonists, such as modipafant; cadherin-5/Factor Ia modulators, such as FX-06; NS4B inhibitors, such as JNJ-8359; viral RNA splicing modulators, such as ABX-202; a NS5 polymerase inhibitor; a NS3 protease inhibitor; and a TLR modulator.
  • host cell factor modulators such as GBV-006
  • alpha-glucosidase 1 inhibitors such as celgosivir
  • platelet activating factor receptor (PAFR) antagonists such as modipafant
  • the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, Dengvaxia ®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue fever vaccine, tetravalent DNA vaccine, rDEN2delta30-7169; and DENV-1 PIV. 5.
  • Combination Therapy for the treatment of Filoviridae virus infections The compounds provided herein are also used in combination with other active therapeutic agents.
  • the other active therapeutic agent is active against Filoviridae virus infections, particularly Marburg virus, Ebola virus and Cueva virus infections.
  • Non-limiting examples of these other active therapeutic agents are: 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-5H-pyrrolo[3,2-d]pyrimidin-7-yl)- 5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966
  • Non-limiting active therapeutic agents active against Ebola include an alpha- glucosidase 1 inhibitor, a cathepsin B inhibitor, a CD29 antagonist, a dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, an estrogen receptor antagonist, a factor VII antagonist HLA class II antigen modulator, a host cell factor modulator, an Interferon alpha ligand, a neutral alpha glucosidase AB inhibitor, a niemann-Pick C 1 protein inhibitor, a nucleoprotein inhibitor, a polymerase cofactor VP35 inhibitor, a Serine protease inhibitor, a tissue factor inhibitor, a TLR- 3 agonist, a viral envelope glycoprotein inhibitor, and an Ebola virus entry inhibitors (NPC 1 inhibitors).
  • NPC 1 inhibitors Ebola virus entry inhibitors
  • the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB Vector, HPIV3/EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.
  • VRC-EBOADC076-00-VP adenovirus-based Ebola vaccine
  • rVSV-EBOV rVSVN4CT1-EBOVGP
  • MVA-BN Filo + Ad26-ZEBOV regimen I
  • PMOs phosphoramidate morpholino oligomers
  • Examples of PMOs include but are not limited to AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.
  • the compounds provided herein are also intended for use with general care provided to patients with Filoviridae 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 K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), 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 amino
  • the present disclosure provides processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.
  • Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. During any of the processes for preparation of the compounds provided herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned.
  • the aqueous layer was extracted with dichloromethane (2 ⁇ 25 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (2 mL), and the resulting mixture was stirred and cooled to 0 °C.
  • Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 700 ⁇ L, 1.4 mmol) was added over 1 min via syringe, and the resulting mixture was warmed to room temperature over 4 min. The resulting mixture was heated to 60 °C. After 15 h, the resulting mixture was heated to 70 °C.
  • intermediate 1-4 (34.8 mg, 105 ⁇ mol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (9.7 ⁇ L, 121 ⁇ mol) were added sequentially.
  • a solution of intermediate 1-3 (40.7 mg, 91.3 ⁇ mol) in tetrahydrofuran (1.0 mL) was added via syringe.
  • 1-(mesitylsulfonyl)-3-nitro-1H- 1,2,4-triazole (27.1 mg, 91.3 ⁇ mol) and triethylamine (40.0 ⁇ L, 287 ⁇ L) were added sequentially.
  • Example 1 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(isoindolin-2-yl)-3-(octadecyloxy)propyl) hydrogen phosphate (1): Potassium trimethylsilanolate (38.0 mg, 296 ⁇ mol) was added to a vigorously stirred solution of intermediate 1-5 (47.6 mg, 50.1 ⁇ mol) in tetrahydrofuran (0.7 mL) at room temperature.
  • Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 3.80 mL, 7.6 mmol) was added over 2 min via syringe. After 2 min, the resulting mixture was heated to 61 °C. After 16.5 h, the resulting mixture was cooled to 0 °C, and water (302 ⁇ L), aqueous sodium hydroxide solution (2.0 M, 604 ⁇ L), and water (604 ⁇ L) were added sequentially. Water (50 mL) and brine (50 mL) were added sequentially, and the aqueous layer was extracted with dichloromethane (2 ⁇ 125 mL).
  • Example 2 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyl(methyl)amino)-3-(octadecyloxy)propyl) hydrogen phosphate (2): Compound 2 was synthesized in a manner similar to compound 1 using intermediate 2-2 instead of intermediate 1-3.
  • Example 3 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-chloro-4-fluorobenzyl)(methyl)amino)-3- (octadecyloxy)propyl) hydrogen phosphate (3): Compound 3 was synthesized in a manner similar to compound 2 using 3-chloro-4- fluorobenzaldehyde instead of benzaldehyde.
  • Example 4 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(3-chloro-4-fluoro-N-methylbenzamido)-3- (octadecyloxy)propyl) hydrogen phosphate (4): A vigorously stirred mixture of intermediate 4-2 (59.5 mg, 94.1 ⁇ mol), intermediate 4-1 (48.4 mg, 94.1 ⁇ mol), magnesium chloride (44.8 mg, 471 ⁇ mol), and tetrahydofuran (1.0 mL) was heated to 53 °C.
  • N,N-diisopropylethylamine 82.0 ⁇ L, 471 ⁇ mol was added over 1 min via syringe. After 44 min, the resulting mixture was heated to 90 °C. After 16 min, the resulting mixture was cooled to room temperature over 6 min, and 2,2,6,6- Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran/toluene, 157 ⁇ L, 157 ⁇ mol) was added via syringe. After 6 min, the resulting mixture was heated to 50 °C.
  • intermediate 1-4 37.4 mg, 113 ⁇ mol
  • tetrahydrofuran 0.5 mL
  • 1-methylimidazole 8.6 ⁇ L, 110 ⁇ mol
  • a solution of intermediate 5-3 (36.2 mg, 80.7 ⁇ mol) in tetrahydrofuran (0.7 mL) was added via syringe.1-Methylimidazole (20 ⁇ L, 250 ⁇ mol) was added via syringe.
  • saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially.
  • Example 5 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((2S,3S)-2-(benzyloxy)-3-(octadecyloxy)butyl) hydrogen phosphate (5): Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 242 ⁇ L, 240 ⁇ mol) was added via syringe to a stirred mixture of intermediate 5-4 (76.8 mg, 80.6 ⁇ mol), 4- (dimethylamino)pyridine (29.5 mg, 242 ⁇ mol), tetrahydrofuran (0.1 mL), and water (72.6 ⁇ L, 4.03 mmol) at room temperature, and the resulting mixture was heated to 50 °C.
  • Example 6 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)(methyl)amino)-3- (octadecyloxy)propyl) hydrogen phosphate (6): 1,8-Diazabicyclo[5.4.0]undec-7-ene (17.4 ⁇ L, 116 ⁇ mol) was added via syringe to a vigorously stirred mixture of intermediate 6-2 (21.8 mg, 38.8 ⁇ mol), intermediate 6-3 (19.0 mg, 38.8 ⁇ mol), and tetrahydrofuran (0.35 mL) at room temperature.
  • Example 7 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzylthio)-3-(octadecyloxy)propyl) hydrogen phosphate: (7) Compound 7 was synthesized in a manner similar to compound 5 using intermediate 7-3 instead of intermediate 5-3.
  • Example 8 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((2S,3R)-2-(benzyloxy)-3-(octadecyloxy)butyl) hydrogen phosphate (8): Compound 8 was synthesized in a manner similar to compound 5 using intermediate 8-1 instead of methyl (2R,3R)-2,3-dihydroxybutanoate.
  • Example 9 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(5,6-dichloroisoindolin-2-yl)-3- (octadecyloxy)propyl) hydrogen phosphate (9): 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (22.2 ⁇ L, 76.6 ⁇ mol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 9-1 (21.2 mg, 35.6 ⁇ mol), intermediate 6-2 (20.0 mg, 35.6 ⁇ mol), and tetrahydrofuran (0.35 mL) at 0 °C.
  • Example 11 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-(1-oxoisoindolin-2-yl)propyl) hydrogen phosphate (11): Compound 11 was synthesized in a manner similar to compound 10 using intermediate 11-1 instead of intermediate 10-2.
  • Example 12 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl) hydrogen phosphate (12): Compound 12 was synthesized in a manner similar to compound 10 using intermediate 12-2 instead of intermediate 10-2.
  • Example 13 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl) hydrogen phosphate (13): Compound 13 was synthesized in a manner similar to compound 10 using intermediate 13-1 instead of intermediate 10-2.
  • Example 14 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)carbamoyl)benzoic acid (14)
  • Example 15 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (
  • Example 16 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanophenyl)amino)-3-(octadecyloxy)propyl) hydrogen phosphate (16): Compound 16 was synthesized in a manner similar to compound 10 using intermediate 16-1 instead of intermediate 10-2.
  • Example 17 (2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl benzoate (17): Compound 17 was synthesized in a manner similar to compound 5 using intermediate 17-2 instead of intermediate 5-3.
  • reaction mixture was allowed to gradually warm to room temperature and stirred for 24 hours and which point solvent was removed under reduced pressure and crude product absorbed onto silica gel which was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to afford (S)-tert- butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane.
  • Example 18 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-(octadecyloxy)-3-phenoxypropan-2-yl) hydrogen phosphate (18): Aqueous sodium hydroxide solution (2.0 M, 60 ⁇ L, 120 ⁇ mol) was added via syringe to a vigorously stirred solution of intermediate 18-3 (11 mg, 11.8 ⁇ mol) in tetrahydrofuran (1 mL) at room temperature, and the resulting mixture was heated to 50 °C.
  • Example 19 ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (3-(hexadecylthio)propyl) hydrogen phosphate (19): 1,1,3,3-Tetramethylguanidine (156 mg, 1.35 mmol) and syn-2-pyridinealdoxime (275 g, 2.25 mmol) in THF (2 mL) were added to a solution of the 19-2 (185 mg, 0.225 mmol) in THF (4 mL) and stirred at room temperature overnight.
  • the reaction was concentrated in vacuo, the residue was purified by flash chromatography with 0-50% MeOH in DCM to give an intermediate.
  • the above intermediate was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.3 mL) was added. The cold bath was removed the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The solution was purified silica gel column chromatography with (0-40% MeOH in DCM) to give the product.
  • Example 20 ((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-(hexadecyloxy)ethyl) hydrogen phosphate (20): Compound 20 was synthesized in a manner similar to compound 19.
  • Example 21 ((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-(octadecyloxy)ethyl) hydrogen phosphate (21): Compound 21 was synthesized in a manner similar to compound 19.
  • Example 22 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(octadecyloxy)propyl) hydrogen phosphate (22): Intermediate 22-4 (111 mg, 0.118 mmol) was dissolved in THF (2.5 mL) and 0.5 N NaOH (0.9 mL) was added at 0 o C. The mixture was stirred at 50 o C for 2.5 h. The mixture was neutralized with 2 N HCl at 0 °C.
  • Intermediate 23-1 (R)-(3-(benzyloxy)-2-(hexadecyloxy)propoxy)(tert-butyl)diphenylsilane: Intermediate 23-1 was synthesized in a manner similar to 22-2 using 1-bromohexadecane as alkylation reagent. Intermediate 23-2: (S)-3-(Benzyloxy)-2-(hexadecyloxy)propan-1-ol: Intermediate 23-2 was synthesized in a manner similar to 22-3 using intermediate 23-1.
  • Example 23 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(hexadecyloxy)propyl) hydrogen phosphate (23): Compound 23 was synthesized in a manner similar to compound 22.
  • Intermediate 24-1 (R)-(3-(Benzyloxy)-2-(tetradecyloxy)propoxy)(tert-butyl)diphenylsilane: Intermediate 24-1 was synthesized in a manner similar to 22-2 using 1-bromotetradecane as alkylation reagent.
  • Intermediate 24-2 (S)-3-(benzyloxy)-2-(hexadecyloxy)propan-1-ol: Intermediate 24-2 was synthesized in a manner similar to 19-2 using intermediate 24-1.
  • Example 24 ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(tetradecyloxy)propyl) hydrogen phosphate (24): Compound 24 was synthesized in a manner similar to compound 22.
  • Example 25 ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (3-(nonyloxy)propyl) hydrogen phosphate (25): Compound 25 was synthesized in a manner similar to compound 19.
  • Example 26 ((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-(octyloxy)ethyl) hydrogen phosphate (26): Compound 26 was synthesized in a manner similar to compound 19.
  • Example 27 ((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-(undecyloxy)ethyl) hydrogen phosphate (27): Compound 27 was synthesized in a manner similar to compound 19.
  • Example 29 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(2,6-dicyano-4-methylphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (29): Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 300 ⁇ L, 300 ⁇ mol) was added via syringe to a vigorously stirred mixture of intermediate 29-3 (23.6 mg, 23.9 ⁇ mol), 4-(dimethylamino)pyridine (29.2 mg, 239 ⁇ mol), water (45.0 ⁇ L, 2.50 mmol), and tetrahydrofuran (0.1 mL) at room temperature.
  • Tetrabutylammonium fluoride solution 1.0 M in te
  • Example 30 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-benzamido-3-(octadecyloxy)propyl) hydrogen phosphate (30): Compound 30 was synthesized in a manner similar to compound 6 using intermediate 30-1 instead of intermediate 6-3.
  • Example 31 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)amino)benzoic acid (31): Compound 31 was synthesized in a manner similar to compound 6 using intermediate 31-1 instead of intermediate 6-3.
  • Example 32 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (32): Compound 32 was synthesized in a manner similar to compound 6 using intermediate 32-2 instead of intermediate 6-3.
  • Example 33 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (33): Compound 33 was synthesized in a manner similar to compound 6 using intermediate 33-2 instead of intermediate 6-3.
  • Example 35 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl) hydrogen phosphate (35): Concentrated hydrochloric acid (2.00 mL, 24.0 mmol) was added to a solution of 35-5 (1.71 g, 2.00 mmol) in tetrahydrofuran (10 mL).
  • aqueous layer was extracted sequentially with a mixture of diethyl ether and ethyl acetate (2:1 v:v, 50 mL) and a mixture of dichloromethane and 2-propanol (4:1 v:v, 50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure.
  • the residue was purified by flash column chromatography on silica gel (0 to 65% ethyl acetate in hexanes) to give intermediate 38-2.
  • Example 40 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((S)-1-(octadecyloxy)-3-phenylpropan-2-yl) hydrogen phosphate (40):
  • aqueous layer was extracted sequentially with a mixture of diethyl ether and ethyl acetate (2:1 v:v, 50 mL) and a mixture of dichloromethane and 2-propanol (4:1 v:v, 50 mL).
  • the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure.
  • the residue was purified by flash column chromatography on silica gel (0 to 65% ethyl acetate in hexanes) to give intermediate 44-3.
  • Example 45 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3- stearamidopropyl) hydrogen phosphate (45):
  • intermediate 1-4 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 ⁇ L, 3.49 mmol) were added sequentially.
  • water 1.0 mL
  • acetonitrile 1.0 mL
  • silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 49-2. LCMS: 522.1.
  • N,N- dimethylformamide (640 ⁇ L, 8.26 mmol) was added via syringe, and the resulting mixture was warmed to 0 °C.
  • saturated aqueous sodium bicarbonate solution (4.13 mL), sodium borohydride (781 mg, 20.7 mmol), and methanol (30 mL) were added sequentially.
  • ethyl acetate was added. The organic layer was washed sequentially with water, water, and a mixture of water and brine, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure.
  • Example 57 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(3-cyanobenzamido)-3-(octadecyloxy)propyl) hydrogen phosphate (57): 1,8-Diazabicyclo[5.4.0]undec-7-ene (13 ⁇ L, 90 ⁇ mol) was added over 1 min to a rapidly stirred mixture of intermediate 6-2 (25.2 mg, 44.8 ⁇ mol) and intermediate 57-1 (21.2 mg, 44.8 ⁇ mol) in tetrahydrofuran (0.5 mL) at room temperature.
  • Example 58 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(2-cyanobenzamido)-3-(octadecyloxy)propyl) hydrogen phosphate (58):
  • Example 59 [(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-tetradecoxyethyl hydrogen phosphate (59): Compound 59 was prepared in a manner similar to example 19 using intermediate 59-1.
  • Example 60 [(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-heptadecoxyethyl hydrogen phosphate (60): Compound 60 was prepared in a manner similar to example 19 using intermediate 60-1.
  • Example 61 [(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 3-tetradecylsulfanylpropyl hydrogen phosphate (61): Compound 61 was prepared in a manner similar to example 19 using intermediate 61-1.
  • Example 64 [(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 [(2R)-2-[(3-chloro-2,4-difluoro-phenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (64): Compound 64 was prepared in a manner similar to example 19 using intermediate 64-1.
  • Example 66 [(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-hexadecoxyethyl hydrogen phosphate (66): Compound 66 was prepared in a manner similar to example 19 using intermediate 66-1.
  • Example 67 O-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl) O-((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) O- hydrogen (R)-phosphorothioate (67): 1,8-Diazabicyclo[5.4.0]undec-7-ene (12.8 ⁇ L, 85.5 ⁇ mol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 67-1 (24.7 mg, 3.02 mmol), (2S)-2- benzyloxy-3-octadecoxy-propan-1-ol (37.2 mg, 85.5 ⁇ mol), and tetrahydrofuran (0.5 mL) at room temperature.
  • Example 70 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((4-cyano-2-fluorobenzyl)oxy)henicosan-2-yl) hydrogen phosphate (70):
  • Example 70 was prepared in a manner similar to example 35 using 3-fluoro-4- bromomethyl benzonitrile instead of 3-fluoro-5-bromomethyl benzonitrile (major regioisomer), utilizing coupling conditions demonstrated in example 68.
  • Example 71 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyano-3-fluorobenzyl)oxy)henicosyl) hydrogen phosphate (71):
  • Example 72 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)henicosyl) hydrogen phosphate (72):
  • Example 72 was prepared in a manner similar to Example 70 using benzyl bromide instead of 3-fluoro-4-bromomethyl benzonitrile.
  • tert-butyl (R)-glycidyl ether (605 mg, 3.21 mmol) was then added at once and allowed to stir for 2 h. The reaction was then quenched at 0 °C with saturated aqueous ammonium chloride (50 mL), and diluted with diethyl ether (100 mL). The aqueous phase was then extracted with additional diethyl ether (2x 50 mL), the pooled organic fractions were washed with brine (50 mL), and then dried over magnesium sulfate.
  • Example 73 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)nonadec-4-yn-1-yl) hydrogen phosphate (73):
  • Example 73 was prepared in a manner similar to Example 68 using Intermediate 8-3 instead of 3-fluoro-5-[[(1S)-1-(hydroxymethyl)-2-octadecoxy-ethoxy]methyl]benzonitrile.
  • Example 74 ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)nonadec-4-yn-1-yl) hydrogen phosphate (74):
  • Example 76 RSV-Fluc antiviral assay Normal human brochial epithelial (NHBE) cells donor 32027 are purchased from Lonza (Walkersville, MD Cat# CC-2540) and maintained in Bronchial Epithelial Cell Growth Medium (BEGM) (Lonza, Walkersville, MD, Cat# CC-3170) with all provided supplements in the BulletKit. Cells are passaged 2-3 times per week to maintain sub-confluent densities and were used for experiments at passages 2-4.
  • NHBE human brochial epithelial
  • Recombinant Respiratory Syncytial virus strain A2 containing the firefly luciferase reporter between the P and M genes (RSV-Fluc, 6.3 x 10 6 TCID50/mL) is purchased from Viratree (Durham, NC, Cat# R145).
  • NHBE cells (5 x 10 3 /well) are seeded in 100 ⁇ L white wall/clear bottom 96-well plates (Corning) with culture medium and are incubated for 24 hours at 37 o C with 5% CO2.
  • Example 77 SARS-CoV-2 antiviral assay Antiviral activity of compounds against SARS-CoV-2 is evaluated as described in Xue, Xi et al.2020. Briefly, the human alveolar epithelial cell line (A549) is maintained in a high- glucose DMEM supplemented with 10% fetal bovine serum, 1% P/S and 1% HEPES (ThermoFisher Scientific). The A549-hACE2 cells that stably express human angiotensin- converting enzyme 2 (hACE2) are grown in the culture medium supplemented with 10 ⁇ g/mL Blasticidin S (Mossel E. C., et al 2005). Cells are grown at 37 °C with 5% CO2.
  • All culture medium and antibiotics are purchased from ThermoFisher Scientific (Waltham, MA). All cell lines are tested negative for mycoplasma.
  • A549-hACE2 cells (12,000 cells per well in phenol- red free medium containing 2% FBS) are plated into a white opaque 96-well plate (Corning).
  • 2-fold serial dilutions of compounds are prepared in DMSO. The compounds are further diluted 100-fold in the phenol-red free culture medium containing 2% FBS.
  • Cell culture fluids are removed and incubated with 200 nL of diluted compound solutions and 50 ⁇ L of SARS-CoV2-Nluc viruses (MOI 0.025).
  • Nano luciferase substrates (Promega) are added to each well. Luciferase signals are measured using a SynergyTM Neo2 microplate reader. The relative luciferase signals are calculated by normalizing the luciferase signals of the compound-treated groups to that of the DMSO-treated groups (set as 100%). The relative luciferase signal (Y axis) versus the log 10 values of compound concentration (X axis) is plotted in software Prism 8. The EC50 (compound concentration for reducing 50% of luciferase signal) are calculated using a nonlinear regression model (four parameters). Two experiments are performed with technical duplicates.
  • Example 78 A549 cytotoxicity analysis The cytotoxicity of compounds is determined in A549 cells in the following manner. Compounds (40 nL) are spotted onto 384-well Grenier plates prior to seeding 5000 A549 cells/well in a volume of 40 ⁇ L culture medium. The plates are incubated at 37 0C for 48 hours with 5% CO 2 . On day 2, 40 ⁇ L of CellTiter-Glo (Promega) is added and mixed 5 times. Plates are read for luminescence on an Envision (PerkinElmer) and the CC50 (compound concentration for reducing 50% of luminescence signal as a measure of cell viability) are calculated using a nonlinear regression model (four parameters). Two experiments are performed with technical duplicates.
  • Example 79 MT4 cytotoxicity analysis 3-fold serially diluted compound in DMSO, ranging from 2.5 uM to 10 mM, were added by acoustic transfer (Echo) in quadruplicate into black 384-well plates at 200 nl/well. After compound addition, 40 ul MT-4 cells at 80,000/ml were added to each well using a MicroFlo liquid dispenser (BioTek, Winooski, VT) and the cells were cultured for five days at 37 °C. Following the incubation, cell viability was determined by adding 35 ⁇ L of CellTiter-Glo viability reagent and mixed thoroughly using ViaFlo 384 well workstation. The mixture was incubated for at least 10 minutes at 25 °C, and the luminescence signal was quantified on an EnVision plate reader.
  • Echo acoustic transfer
  • Table 1 RSV antiviral data for exemplary compounds.
  • Table 2 SARS-CoV-2 antiviral data for exemplary compounds.
  • Table 3 A549 cytotoxicity data for exemplary compounds.
  • Table 4 MT4 CC 50 for exemplary compounds.
  • Example 80 Rat lung phosphate (monophosphate, diphosphate and triphosphate) data with exemplary compounds Measurement of GS-441524 (compound A below) and its phosphorylated metabolites (compounds B, C, and D below) in lung tissues was performed according to the following protocol. The concentrations of GS-441524 (A) and its phosphorylated metabolites (B, C, and D) were determined in Sprague-Dawley (SD) rats following oral gavage administration of the test compounds. The in-life phase of studies was conducted at Covance Laboratories (Madison, WI). Animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources.
  • the protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC).
  • Male SD rats weighing approximately 0.3 kg were used for in-life portion of the studies.
  • the animals were fasted overnight prior to the test compound administration and up to 4 hours post-dose.
  • the animals were administered with the test compound at 5, 8, 10 or 20 mg/kg via oral gavage (3 rats per group).
  • the aqueous formulation contains ethanol, dimethyl sulfoxide, Kolliphor HS-15, Labrasol, and propylene glycol.
  • Approximately 0.5 grams of lung tissue samples were collected from each animal and analyzed by LC/MS/MS for determination of the concentrations of GS- 441524 and its phosphorylated metabolites.
  • tissue samples were homogenized and extracted with 4-fold volume of 70% methanol containing 0.1% potassium hydroxide, 67 mM ethylenediamine tetraacetic acid, and internal standard. Approximately 200 ⁇ L aliquot of the homogenate was filtered using a 96-well filter plate (0.2 ⁇ m polypropylene; Agilent Captiva, Santa Clara, CA). The filtrate was evaporated to dryness and reconstituted with equal volume of 1 mM ammonium phosphate buffer (pH 7). The samples were then analyzed on a Sciex 6500+ LC-MS/MS instrument (Redwood City, CA).

Abstract

Compounds and methods of using said compounds, alone or in combination with additional agents, and pharmaceutical compositions of said compounds for the treatment of viral infections are disclosed.

Description

PHOSPHOLIPID COMPOUNDS AND USES THEREOF CROSS REFERENCE This application claims priority to U.S. Provisional Application No.63/093,037, filed October 16, 2020 and U.S. Provisional Application No.63/151,456, filed February 19, 2021, each of which application is incorporated herein in its entirety for all purposes. BACKGROUND There is a need for compounds and methods for treating viral infections, for example Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae infections. The present disclosure addresses these and other needs. SUMMARY In one aspect, the disclosure provides a compound of Formula I:
Figure imgf000002_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein: Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; RZB and RZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is a bond, -O-, -OCO-, -(CR12AR12B)q-, -O(CR12AR12B)q-, -OCR12AR12B- (CR13=CR14)-, -(CR12AR12B)q-O-(CR12AR12B)q-, -S-, (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein each R12A is independently H, C1-C6 alkyl, or phenyl; or R2 and R12A are joined to form a four to six membered cycloalkyl or a four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S; each R12B is independently H or C1-C6 alkyl; or R12A and R12B on same carbon are joined together to form a C3-C6 cycloalkylene; R12C is H, C1-C3 alkyl, -COR12D, or -SO2R12E, or R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl; R12D is C1-C3 alkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein R12D is optionally substituted with one, two, or three R12G groups; each R12G is independently a C1-C3 alkyl, phenyl, halo, C1- C3 alkoxy, cyano, C1-C3haloalkyl, or -COOR12H; R12H is H or C1-C3 alkyl; R12E is H or C1-C3 alkyl; R13 is H, C1-C6 alkyl, or phenyl; R14 is H, C1-C6 alkyl, or phenyl; and each q is independently 1 or 2; each p is independently 0, 1, or 2; X1 is a bond, -O-, NRX, or -CONRX-, or -S-; RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA; RXA is C1-C3 alkyl; X2 is -O- or -S-; X3 is -O- or -S-; X4 is =O or =S; R1 is H, C1-C20 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S and O, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one, two, or three R1A groups; wherein each R1A is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R1B, -COOR1B, or C1-C3haloalkyl; or two R1A on same or adjacent carbons are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O; R1B is H or C1-C3 alkyl; R2 is H or C1-C3 alkyl; Y is a bond, phenylene, or C3-C6 cycloalkylene; R3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; each R4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R4 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon double bond; each R5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; R6 is H or -C(O)C1-C6 alkyl; R7 is H or -C(O)C1-C6 alkyl; and m is an integer from 7 to 21; wherein when X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)- then: (a) Z1 is a bond, -CRZARZB-, or -CRZARZB-CRZCRZD-; (b) Z2 is a bond, -CRZERZF-, or -CRZERZF-CRZGRZH-; (c) R2 and R12A are joined to form a four to six membered cycloalkyl or four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S; (d) X1 is a bond, NRX, or -CONRX-, or -S-; (e) X2 is -S-; (f) X3 is -S-; (g) X4 is =S; (h) R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is substituted with three R1A groups; (i) R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; (j) at least one R1A is -SO2R1B, -COOR1B; or (k) m is 7, 8, or 9. In another aspect, the disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In another aspect, the disclosure provides a method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, characterized in that a compound of Formula I, or a pharmaceutically acceptable salt thereof, is used. In another aspect the disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof. DETAILED DESCRIPTION OF THE INVENTION I. General The invention relates generally to methods and compounds for treating or preventing viral infections, for example paramyxoviridae, pneumoviridae, picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus, and coronaviridae. II. Definitions Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings: As used herein, “a compound of the disclosure” or “a compound of Formula I” means a compound of Formula I, or a pharmaceutically acceptable salt, thereof. Similarly, the phrase “a compound of Formula (number)” means a compound of that formula and pharmaceutically acceptable salts thereof. “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, - CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n- pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. “Alkoxy” means a group having the formula –O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy) or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or –OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-O-C(CH3)3 or –OtBu) and the like. “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like. “Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “halo” as used herein, refers to -F, -Cl, -Br or -I. In some embodiments, a halo group is -F or -Cl. In some embodiments, a halo group is -F. “Heterocycle” or “heterocyclyl” refer to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4 to 12 membered heterocyclyl), 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The terms heterocycle or heterocyclyl do not encompass or overlap with heteroaryls as defined below. “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). As used herein, heteroaryl include 5 to 20 ring atoms, 5 to 12 ring atoms, 5 to 8 ring atoms, or 5 to 6 ring atoms; including 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above. The term “optionally substituted” in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by the listed substituents. Unless otherwise specified, the carbon atoms of the compounds of Formula I are intended to have a valence of four. If in some chemical structure representations, carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen. The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above. The term “therapeutically effective amount”, as used herein, is the amount of compound of Formula I present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein. The term “adjacent carbons” as used herein refers to consecutive carbons atoms that are directly attached to each other. For example, in , C1 and C2 are adjacent
Figure imgf000011_0002
carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons. Similarly, in C1 and C2 are adjacent carbons, C2 and C3 are adjacent
Figure imgf000011_0003
carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons and C6 and C1 are adjacent carbons. Certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent “cycloalkyl” group etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, or alkylyl group; an “arylene” group or an “arylenyl” group, or arylyl group; a “cycloalkylene” group or an “cycloalkylenyl” group, or cycloalkylyl group respectively. III. Compounds Provided herein are compounds of Formula I:
Figure imgf000011_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein: Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; RZB and RZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is a bond, -O-, -OCO-, -(CR12AR12B)q-, -O(CR12AR12B)q-, -OCR12AR12B- (CR13=CR14)-, -(CR12AR12B)q-O-(CR12AR12B)q-, -S-, (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein each R12A is independently H, C1-C6 alkyl, or phenyl; or R2 and R12A are joined to form a four to six membered cycloalkyl or heterocyclyl having one, two or three heteroatoms selected from N, O, and S; each R12B is independently H or C1-C6 alkyl; or R12A and R12B on same carbon are joined together to form a C3-C6 cycloalkylene; R12C is H, C1-C3 alkyl, -COR12D, or -SO2R12E, or R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl; R12D is C1-C3 alkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein R12D is optionally substituted with one, two, or three R12G groups; wherein each R12G is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3haloalkyl, or -COOR12H; R12H is H or C1-C3 alkyl; R12E is H or C1-C3 alkyl; R13 is H, C1-C6 alkyl, or phenyl; R14 is H, C1-C6 alkyl, or phenyl; and each q is independently 1 or 2; each p is independently 0, 1, or 2; X1 is a bond, -O-, NRX, or -CONRX-, or -S-; RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA; RXA is C1-C3 alkyl; X2 is -O- or -S-; X3 is -O- or -S-; X4 is =O or =S; R1 is H, C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one, two, or three R1A groups; wherein each R1A is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R1B, -COOR1B, or C1-C3haloalkyl; or two R1A on same or adjacent carbons are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O; R1B is H or C1-C3 alkyl; R2 is H or C1-C3 alkyl; Y is a bond, phenylene, or C3-C6 cycloalkylene; R3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; each R4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or or two R4 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon double bond; each R5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; R6 is H or -C(O)C1-C6 alkyl; R7 is H or -C(O)C1-C6 alkyl; and m is an integer from 7 to 21; wherein when X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or - OCR12AR12B-(CR13=CR14)- then: (a) Z1 is a bond, -CRZARZB-, or -CRZARZB-CRZCRZD-; (b) Z2 is a bond, -CRZERZF-, or -CRZERZF-CRZGRZH; (c) R2 and R12A are joined to form a four to six membered cycloalkyl or heterocycle having one, two or three heteroatoms selected from N, O, and S; (d) X1 is a bond, NRX, or -CONRX-, or -S-; (e) X2 is -S-; (f) X3 is -S-; (g) X4 is S; (h) R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is substituted with three R1A groups; (i) R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; (j) at least one R1A is -SO2R1B, -COOR1B; or (k) m is 7, 8, or 9. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and Z1 is a bond, -CRZARZB-, or -CRZARZB- CRZCRZD-. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and Z2 is a bond, -CRZERZF-, or -CRZERZF- CRZGRZH. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and R2 and R12A are joined to form a four to six membered cycloalkyl or four to six membered heterocycle having one, two or three heteroatoms selected from N, O, and S. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and X1 is a bond, NRX, or -CONRX-, or -S-. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and X2 is -S-. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and X3 is -S-. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and X4 is S. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is substituted with three R1A groups. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond. In some embodiments, for the compounds of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)- and m is 7, 8, or 9. In some embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; RZB and RZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is -OCO-, -(CR12AR12B)q-O-(CR12AR12B)q-, -S-, (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein each R12A is independently H, C1-C6 alkyl, or phenyl; or R2 and R12A are joined to form a four to six membered cycloalkyl or heterocyclyl having one, two or three heteroatoms selected from N, O, and S; each R12B is independently H or C1-C6 alkyl; or R12A and R12B on same carbon are joined together to form a C3-C6 cycloalkylene; R12C is H, C1-C3 alkyl, -COR12D, or -SO2R12E, or R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl; R12D is C1-C3 alkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein R12D is optionally substituted with one, two, or three R12G groups; wherein each R12G is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3haloalkyl, or -COOR12H; R12H is H or C1-C3 alkyl; R12E is H or C1-C3 alkyl; and each q is independently 1 or 2; each p is independently 0, 1, or 2; X1 is a bond, -O-, NRX, or -CONRX-, or -S-; RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA; RXA is C1-C3 alkyl; X2 is -O- or -S-; X3 is -O- or -S-; X4 is =O or =S; R1 is H, C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one, two, or three R1A groups; wherein each R1A is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R1B, -COOR1B, or C1-C3haloalkyl; or two R1A on same or adjacent carbons are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O; R1B is H or C1-C3 alkyl R2 is H or C1-C3 alkyl; Y is a bond, phenylene, or C3-C6 cycloalkylene; R3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; each R4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or or two R4 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon double bond; each R5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; R6 is H or -C(O)C1-C6 alkyl; R7 is H or -C(O)C1-C6 alkyl; and m is an integer from 7 to 21. In some embodiments of the compounds of Formula I, Z1 is -CH2- and Z2 is -CH2-. In some embodiments, one of Z1 and Z2 is -CH2-CH2-. In some embodiments, both Z1 and Z2 are - CH2-CH2-. In some embodiments, Z1 is -CH2-CH2- and Z2 is -CH2-. In some embodiments, Z1 is -CH2- and Z2 is -CH2-CH2-. In some embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, - CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; wherein RZA, RZC, RZD, RZE, RZG, and RZH is each independently H or C1-C3 alkyl; and RZB and RZF are each independently C1-C3 alkyl. In some embodiments of the compounds of Formula I, Z1 is a bond, -CH2-, -CH2-CH2-, - CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF- CRZGRZH; wherein RZA, RZC, RZD, RZE, RZG, and RZH is each independently H or methyl; and RZB and RZF are both methyl. In some embodiments of the compounds of Formula I, Z1 is a bond, -CH2-, -CH2-CH2-, or -CH(CH3)-; Z2 is a bond, -CH2-, -CH2-CH2-, -CH(CH3)-. In some embodiments, Z1 is -CH2- and Z2 is -CH2-, In some embodiments, Z1 is -C(CH3)H- and Z2 is -CH2-. In some embodiments, Z1 is -CH2- and Z2 is -C(CH3)H-. In some embodiments, Z1 is -CH2- and Z2 is a bond. In some embodiments, Z1 is a bond and Z2 is -CH2-. In some embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein X1 is a bond, -O-, -NRx, or S; wherein RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA and RXA is C1-C3 alkyl. In some embodiments, X1 is a bond, -O-, -NRx, or S; wherein RX is H, C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, X1 is a bond, -O-, -NH-, -NCH3-, or S. In some embodiments, X1 is a bond, -O-, or S. In some embodiments, X1 is a bond or -O-. In some embodiments, X1 is a bond. In some embodiments, X1 is -O-. In some embodiments, X1 is -S-. In some embodiments, X1 is -NH-. In some embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, X1 is -NRx- or -CONRX-; wherein Rx is C1-C3 alkyl or -C(O)RXA. In some embodiments, X1 is -NRx- or -CONRX-; wherein Rx is C1-C3 alkyl. In some embodiments, X1 is -NRx- or -CONRX-; wherein Rx is methyl. In some embodiments, X1 is -NRx- or -CONRX-; wherein Rx is -C(O)RXA and RXA is methyl. In some embodiments, the compound of Formula I is a compound of Formula Ia:
Figure imgf000020_0001
X3, X4, and m are as defined herein for Formula I. In some embodiments of the compounds of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is S. In some embodiments, X2 is O. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X3 is S. In some embodiments, X3 is O. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X4 is S. In some embodiments, X4 is O. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H. In some embodiments, R2 is C1-C3 alkyl. In some embodiments, R2 is methyl. In some embodiments of the compounds of Formula I, X is -O-, -(CR12AR12B)q-, - O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)-, wherein q is 1 or 2. In some embodiments X is a bond, -O-, -(CR12AR12B)-, -O(CR12AR12B)-, or -OCR12AR12B-(CR13=CR14)-. In some embodiments, X is a bond, -O-, -(CR12AR12B)2-, -O(CR12AR12B)2-, or -OCR12AR12B-(CR13=CR14)- . In some embodiments, X is -O-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)-, wherein q is 1 or 2. In some embodiments, X is -O-, -O(CR12AR12B)-, or -OCR12AR12B-(CR13=CR14)-. In some embodiments, X is -O-, -O(CR12AR12B)2-, or -OCR12AR12B-(CR13=CR14)-. In some embodiments X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, wherein q is 1 or 2. In some embodiments X is a bond, -O-, -(CR12AR12B)2-, -O(CR12AR12B)2-. In some embodiments X is a bond, -O-, - (CR12AR12B)-, -O(CR12AR12B)-. In some embodiments, X is O. In some embodiments X is - (CR12AR12B)q-, where q is 1 or 2. In some embodiments X is -(CR12AR12B)-. In some embodiments X is -(CR12AR12B)2-. In some embodiments, X is -O(CR12AR12B)q-,where q is 1 or 2. In some embodiments, X is -O(CR12AR12B)-. In some embodiments, X is -O(CR12AR12B)2-. In some embodiments of the compounds of Formula I, each R12A is independently H, C1- C6 alkyl, or phenyl; each R12B is independently H or C1-C6 alkyl; R13 is H, C1-C6 alkyl, or phenyl; and R14 is H, C1-C6 alkyl, or phenyl. In some embodiments, each R12A is independently H or C1- C6 alkyl; each R12B is independently H or C1-C6 alkyl; R13 is H or C1-C6 alkyl; and R14 is H or C1- C6 alkyl. In some embodiments, each R12A is independently H or C1-C3 alkyl, each R12B is independently H or C1-C3 alkyl, R13 is H or C1-C3 alkyl, and R14 is H or C1-C3 alkyl. In some embodiments, each R12A is H, each R12B is H, R13 is H and R14 is H. In some embodiments of the compound of Formula I, X is a bond, -O-, -(CR12AR12B)q-, - O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H, C1-C6 alkyl, or phenyl; and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H or C1-C6 alkyl; and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H or C1-C3 alkyl; and each R12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is a bond, -O-, - (CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is H; and each R12B is H. In some embodiments of the compound of Formula I, X is a bond, -O-, -CH2-, -CH2CH2-, -OCH2-, or - O(CH2)2-.In some embodiment of the compound of Formula I, X is a bond, -O-, -OCH2, or - CH2CH2. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)q-, - O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H, C1-C6 alkyl, or phenyl; and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H or C1-C6 alkyl; and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is independently H or C1-C3 alkyl; and each R12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-; where q is 1 or 2; each R12A is H; and each R12B is H. In some embodiments of the compound of Formula IX is -O-, -(CR12AR12B)-, - O(CR12AR12B)-; where R12A is H, C1-C6 alkyl, or phenyl; and R12B is H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)-, -O(CR12AR12B)-, where R12A is H or C1-C6 alkyl, and R12B H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)-, -O(CR12AR12B)-, where R12A is H or C1-C3 alkyl, and R12B is H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)-, -O(CR12AR12B)-; where R12A is H, and R12B is H. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)2-, - O(CR12AR12B)2-; where each R12A is independently H, C1-C6 alkyl, or phenyl; and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, - (CR12AR12B)2-, -O(CR12AR12B)2-, where each R12A is independently H or C1-C6 alkyl, and each R12B is independently H or C1-C6 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)2-, -O(CR12AR12B)2-, where each R12A is independently H or C1-C3 alkyl, and each R12B is independently H or C1-C3 alkyl. In some embodiments of the compound of Formula I, X is -O-, -(CR12AR12B)2-, -O(CR12AR12B)2-; where each R12A is H and each R12B is H. In some embodiments of the compounds of Formula I, X is -O-, -OCH2-,-OCH2-CH2-, - CH2-,-CH2-CH2- or -OCH2-(CH=CH)-. In some embodiments, X is -O-, -OCH2-, -CH2- or - OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -CH2- or -CH2- CH2-. In some embodiments, X is -CH2-CH2-. In some embodiments, X is -CH2-. In some embodiments of the compounds of Formula I, X is -O-, -OCH2-,-OCH2-CH2- or -OCH2-(CH=CH)-. In some embodiments, X is -O-, -OCH2-, or -OCH2-(CH=CH)-. In some embodiments, X is -O-. In some embodiments, X is -OCH2-. In some embodiments, X is - OCH2-CH2-. In some embodiments, X is -OCH2-(CH=CH)-. In some embodiments of the compounds of Formula I, X is (CR12AR12B)p-NR12C- (CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein p is 0, 1, or 2. In some embodiments, X is (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p- ; wherein p is 0 or 1. In some embodiments, X is -NR12C- or -NR12CCO-. In some embodiments of the compounds of Formula I, X is -NR12C- or -NR12CCO- wherein R12C is H, C1-C3 alkyl, or -COR12D and R12D is C1-C3 methyl. In some embodiments, X is -NR12C- or -NR12CCO- wherein R12C is H, methyl, or -COCH3. In some embodiments of the compounds of Formula I, X is -(CR12AR12B)p-NR12CCO- (CR12AR12B)p- wherein p is 0, 1, or 2. In some embodiments, X is -(CR12AR12B)p-NR12CCO- (CR12AR12B)p- wherein p is 0 or 1. In some embodiments X is -NR12CCO-. In some embodiments X is -NR12CCO- wherein R12C is H, C1-C3 alkyl, or -COR12D and R12D is C1-C3 methyl. In some embodiments, X is -NR12CCO- wherein R12C is H, methyl, or -COCH3. In some embodiments, X is -NR12CCO- wherein R12C is H or methyl. In some embodiments, X is -NR12CCO- wherein R12C is H. In some embodiments, X is -NR12CCO- wherein R12C is methyl. In some embodiments of the compounds of Formula I, X is -(CR12AR12B)p-NR12C- (CR12AR12B)p-; wherein p is 0, 1, or 2. In some embodiments, X is -(CR12AR12B)p-NR12C- (CR12AR12B)p- wherein p is 0 or 1. In some embodiments X is -NR12C-. In some embodiments X is -NR12C- wherein R12C is H, C1-C3 alkyl, or -COR12D and R12D is C1-C3 methyl. In some embodiments, X is -NR12C- wherein R12C is H, methyl, or -COCH3. In some embodiments, X is - NR12C- wherein R12C is H or methyl. In some embodiments, X is -NR12C- wherein R12C is H. In some embodiments, X is -NR12C- wherein R12C is methyl. In some embodiments, X is -NR12C- wherein R12C is -COCH3. In some embodiments of the compounds of Formula I, X is -NR12C-; wherein R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; wherein each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl. In some embodiments, X is -NR12C-; wherein R12C and R1 are joined together to form a 5 membered heterocyclyl containing one N atom and optionally substituted with one to four R12F groups; wherein each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl. In some embodiments, X is -NR12C-; and R12C and R1 are joined together to form
Figure imgf000024_0001
In some embodiments of the compounds of Formula I, X is a bond, -O-, -S-, -CH2O-, - NH-, -N(C(O)CH3)-, -NCH3-, or -N(CH3)CO-. In some embodiments, X is a bond, -O-, -S-, - CH2O-, -NH-, -N(C(O)CH3)-, -NCH3-, or -N(CH3)CO-. In some embodiments, X is -O-, -S-, or -CH2O-. In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -CH2O-. In some embodiments, X is -NH-, -N(C(O)CH3)-, -NCH3-, or -N(CH3)CO-. In some embodiments, X is -NH-, -N(C(O)CH3)-, or -NCH3-. In some embodiments, of the compounds of Formula I, X is a bond. In some embodiments of the compound of Formula I, Y is phenylene or C3-C6 cycloalkylene. In some embodiments, Y is
Figure imgf000025_0001
. In some embodiments, Y is phenylene. In some embodiments, Y is
Figure imgf000025_0002
. In some embodiments, Y is C3-C6 cycloalkylene. In some embodiments, Y is cyclohexylene. In some embodiments, Y is
Figure imgf000025_0003
. In some embodiments, Y is a bond. In some embodiments, Y is a bond or phenylene. In some embodiments, Y is a bond or C3-C6 cycloalkylene. In some embodiments of the compounds of Formula I or Ia, R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is optionally substituted with one, two or three R1A groups. In some embodiments, R1 is H, C1-C6 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6- C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one or two R1A groups. In some embodiments, R1 is C1-C20 alkyl, C3-C10 cycloalkyl, or 5-6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C6 alkyl, C3-C10 cycloalkyl, or 5-6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C20 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C20 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C6 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C20 alkyl or C6-C10 aryl; wherein the R1 group is optionally substituted with one, two, or three R1A groups. In some embodiments, R1 is C1-C6 alkyl or C6- C10 aryl; wherein the R1 group is optionally substituted with one, two or three R1A groups. In some embodiments, R1 is C1-C20 alkyl optionally substituted with one, two or three R1A groups. In some embodiments, R1 is C1-C6 alkyl optionally substituted with one, two or three R1A groups. In some embodiments of the compounds of Formula I or Ia, R1 is C6-C10 aryl optionally substituted with one, two or three R1A groups. In some embodiments, R1 is phenyl, napthyl, thiophenyl, cyclohexyl, methyl, ethyl, or propyl. In some embodiments of the compounds of Formula I or Ia, R1 is unsubstituted. In some embodiments, R1 is substituted with one R1A group. In some embodiments, R1 is substituted with two R1A groups. In some embodiments, R1 is substituted with three R1A groups. In some embodiments, each R1A is independently C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, - SO2R1B, -COOR1B, or C1-C3haloalkyl. In some embodiments, R1A is independently methyl, phenyl, chloro, fluoro, methoxy, cyano, or CF3. In some embodiments, two R1A are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O. In some embodiments, two R1A are joined together to from a 3 to 6 membered cycloalkyl. In some embodiments, two R1A are joined together to from a 5 membered cycloalkyl. In some embodiments, two R1A are joined together to from a 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O. In some embodiments of the compounds of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R1 is selected from a group consisting of H,
Figure imgf000027_0001
, and
Figure imgf000027_0002
Figure imgf000027_0003
In some embodiments of the compound of Formula I or Ia, or a pharmaceutically F acceptable salt thereof, R1 is selected from the group consisting of H,
Figure imgf000027_0004
N , and . In some embodiments, R1 is selected from the group
Figure imgf000028_0002
Figure imgf000028_0001
F consisting of , and
Figure imgf000028_0004
Figure imgf000028_0003
In some embodiments of the compounds of Formula I or Ia, m is 10-20, in some embodiments, m is 14-20. In some embodiments, m is 16, 17, 18, 19, or 20. In some embodiments, m is 17, 18, or 19. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof: X2 is O; X3 is O; X4 is O; R2 is H; and R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof: X2 is O; X3 is O; X4 is O; R2 is H; R6 is H; R7 is H; and R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is O; X3 is O; X4 is O; R2 is H; R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups; R6 is H; R7 is H; R3 is H or C1-C3 alkyl; each R4 is independently H or C1-C3 alkyl; each R5 is independently H or C1-C3 alkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon triple bond; and m is an integer form 8-20. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is O; X3 is O; X4 is O; R2 is H; R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups; R6 is H; R7 is H; R3 is H; each R4 is H; each R5 is H; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon triple bond; and m is an integer form 10-20. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is O; X3 is O; X4 is O; R2 is H; R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups; R6 is H; R7 is H; R3 is H; each R4 is H; each R5 is H; and m is an integer form 14-20. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is O; X3 is O; X4 is O; R2 is H; R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups; R6 is H; R7 is H; R3 is H; each R4 is H; each R5 is H; and m is 17, 18, or 19. In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, X2 is O; X3 is O; X4 is O; R2 is H; R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups; R6 is H; R7 is H; R3 is H; each R4 is H; each R5 is H; and m is 18 or 19. In some embodiments, the compound of Formula I, is selected from the group consisting of:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: ,
Figure imgf000035_0001
,
Figure imgf000036_0001
,
Figure imgf000037_0001
Figure imgf000038_0001
, ,
Figure imgf000039_0001
Figure imgf000040_0001
pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
Figure imgf000041_0001
Figure imgf000042_0001
pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: , and
Figure imgf000043_0001
, or a pharmaceutically acceptable salt thereof.
Figure imgf000043_0002
In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
Figure imgf000044_0001
,
Figure imgf000045_0001
, or a pharmaceutically acceptable salt thereof.
Figure imgf000045_0002
In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
Figure imgf000046_0001
,
Figure imgf000047_0001
, a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
, and
Figure imgf000048_0001
N , or a pharmaceutically acceptable salt thereof.
Figure imgf000048_0002
In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of:
Figure imgf000048_0003
, or a
Figure imgf000048_0004
pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or Ia, is selected from the group consisting of: and
Figure imgf000049_0001
, or a pharmaceutically acceptable salt thereof.
Figure imgf000049_0002
A compound of Formula: , or a pharmaceutically acceptable salt thereof.
Figure imgf000049_0003
A compound of Formula:
Figure imgf000049_0004
, or a pharmaceutically acceptable salt thereof. A compound of Formula: , or a pharmaceutically acceptable salt thereof.
Figure imgf000050_0003
A compound of Formula:
Figure imgf000050_0001
, or a pharmaceutically acceptable salt thereof. A compound of Formula:
Figure imgf000050_0002
, or a pharmaceutically acceptable salt thereof. A compound of Formula:
Figure imgf000051_0001
, or a pharmaceutically acceptable salt thereof. A compound of Formula:
Figure imgf000051_0002
, or a pharmaceutically acceptable salt thereof. Any reference to the compounds of the invention described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na+, Li+, K+, Ca+2 and Mg+2), ammonium and NR4+ (wherein R is defined herein). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NR4 +. The compounds disclosed herein (e.g., compounds of Formula I) and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I, and their pharmaceutically acceptable salts. The compounds disclosed herein (e.g., compounds of Formula I) and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises all amorphous forms of the compounds of Formula I, and their pharmaceutically acceptable salts. For therapeutic use, salts of active ingredients of the compounds of the invention will be pharmaceutically acceptable, i.e., they will be salts derived from a pharmaceutically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention. It is also to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I, and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention. The compounds of the invention, exemplified by Formula I, may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through appropriate techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, D and L, or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (-), or 1 meaning that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The compounds of the invention may also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention. Any formula or structure given herein, including Formula I compounds, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. The disclosure also includes compounds of Formula I in which from 1 to x hydrogens attached to a carbon atom is/are replaced by deuterium, in which x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci.5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., “R” or “R”, then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines, , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms. IV. Pharmaceutical Formulations The compounds disclosed herein (e.g., compounds of Formula I) may be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations may optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but in certain embodiments is about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5. In other embodiments, the pH of the formulations ranges from about 3 to about 4. While it is possible for the compounds of the disclosure (“the active ingredients”) to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any appropriate method known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. In some embodiments, the compounds disclosed have pharmacokinetic properties (for e.g., good oral bioavailability) suitable for oral administration of the compounds. In some embodiments, the formulations of the present invention are suitable for oral administration and are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. In some embodiments, the tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with one or more pharmaceutically acceptable excipients, such as a binder, lubricant, inert diluent, preservative, surface active and/or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. Further emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 80. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used. Pharmaceutical formulations according to the present invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include Cyclodextrin. In some embodiments, the suspending agent is Sulfobutyl ether beta-cyclodextrin (SEB-beta-CD), for example Captisol®. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution isotonic sodium chloride solution, and hypertonic sodium chloride solution. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ^g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and dosed as dry powder. In some embodiments, the compounds used herein are formulated and dosed as a nebulized formulation. In some embodiments, the compounds used herein are formulated for delivery by a face mask. In some embodiments, the compounds used herein are formulated for delivery by a face tent. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and suspensions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention (“controlled release formulations”) in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient. V. Kits Also provided herein are kits that includes a compound disclosed herein (e.g., compounds of Formula I), a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof. In some embodiments the kits described herein may comprise a label and/or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof. In some embodiments, the disease or condition is viral infection. In some embodiments, the kit may also comprise one or more additional therapeutic agents and/or instructions for use of additional therapeutic agents in combination with the compound of Formula I in the treatment of the disease or condition in a subject (e.g., human) in need thereof. In some embodiments, the kits provided herein comprises individual dose units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof. Examples of individual dosage units may include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof. In some embodiments, the kit may contain a single dosage unit and in others multiple dosage units are present, such as the number of dosage units required for a specified regimen or period. Also provided are articles of manufacture that include a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, an intravenous bag, an inhaler, or a nebulizer. VI. Administration One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. It will be appreciated that the preferred route may vary with for example the condition of the recipient. In the methods of the present invention for the treatment of a viral infection, the compounds of the present invention can be administered at any time to a human who may come into contact with the virus or is already suffering from the viral infection. In some embodiments, the compounds of the present invention can be administered prophylactically to humans coming into contact with humans suffering from the viral infection or at risk of coming into contact with humans suffering from the viral infection, e.g., healthcare providers. In some embodiments, administration of the compounds of the present invention can be to humans testing positive for the viral infection but not yet showing symptoms of the viral infection. In some embodiments, administration of the compounds of the present invention can be to humans upon commencement of symptoms of the viral infection. In some embodiments, the methods disclosed herein comprise event driven administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the subject. As used herein, the terms “event driven” or “event driven administration” refer to administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and/or (2) during an event (or more than one recurring event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and/or (3) after an event (or after the final event in a series of recurring events) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection). In some embodiments, the event driven administration is performed pre-exposure of the subject to the virus. In some embodiments, the event driven administration is performed post-exposure of the subject to the virus. In some embodiments, the event driven administration is performed pre-exposure of the subject to the virus and post-exposure of the subject to the virus. In certain embodiments, the methods disclosed herein involve administration prior to and/or after an event that would expose the individual to the virus or that would otherwise increase the individual’s risk of acquiring the viral infection, e.g., as pre-exposure prophylaxis (PrEP) and/or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, methods disclosed herein comprise post-exposure prophylaxis (PEP). In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered before exposure of the subject to the virus. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered before and after exposure of the subject to the virus. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered after exposure of the subject to the virus. An example of event driven dosing regimen includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to the virus, followed by administration of the compound of Formula I, or a pharmaceutically acceptable salt, every 24 hours during the period of exposure, followed by a further administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, after the last exposure, and one last administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later. A further example of an event driven dosing regimen includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours before the viral exposure, then daily administration during the period of exposure, followed by a last administration approximately 24 hours later after the last exposure (which may be an increased dose, such as a double dose). Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses. Any suitable period of time for administration of the compounds of the present invention is contemplated. For example, administration can be for from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. The administration can also be for from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer periods of administration are also contemplated. In some embodiments, the compounds disclosed herein are administered once daily. In some embodiments, the compounds disclosed herein are administered once every alternate day. In some embodiments, the compounds disclosed herein are administered once a week. In some embodiments, the compounds disclosed herein are administered twice a week. In some embodiments, one or more compounds disclosed herein are administered once daily. The once daily dose may be administered for as long as required, for example for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to a month or longer. In some embodiments, the once daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days or for one day. In some embodiments, the one or more compounds disclosed herein are dosed once daily, for about 6 to 12 days, for example for about 8-10 days. In some embodiments, the one or more compounds are administered once daily for about 9 days. In some embodiments, the one or more compounds are administered once daily for about 10 days. In some embodiments about 50- 150 mg of one or more compounds disclosed herein is administered once daily for about 5 to 12 days, for e.g., for about 10 days. In some embodiments about 100 mg of one or more compounds disclosed herein is administered once daily for about 5 to 12 days, for e.g., for about 10 days. VII. Methods of Use The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound described herein. In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to a subject in need thereof a compound described herein. In some embodiments, the present disclosure provides for methods of treating or preventing a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent. In some embodiments, the present disclosure provides for methods of treating a viral infection in a subject (e.g., human) in need thereof, the method comprising administering to the subject a compound disclosed herein, and at least one additional active therapeutic agent. In some embodiments, the present disclosure provides for methods of inhibiting a viral polymerase in a cell, the methods comprising contacting the cell infected a virus with a compound disclosed herein, whereby the viral polymerase is inhibited. In some embodiments, the present disclosure provides for methods of inhibiting a viral polymerase in a cell, the methods comprising contacting the cell infected a virus with a compound disclosed herein, and at least one additional active therapeutic agent, whereby the viral polymerase is inhibited. Also provided here are the uses of the compounds disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of the compounds disclosed herein for use in treating a viral infection in a subject in need thereof. In some embodiments, the viral infection is a paramyxoviridae virus infection. As such, in some embodiments, the present disclosure provides methods for treating a paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and parainfluenza virus. In some embodiments, the Paramyxoviridae virus is a Sosuga virus. In some embodiments, the viral infection is a pneumoviridae virus infection. As such, in some embodiments, the present disclosure provides a method of treating a pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, respiratory snycytial virus and human metapneumovirus. In some embodiments, the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is human metapneumovirus infection. In some embodiments, the present disclosure provides a compound disclosed herein, for use in the treatment of a pneumoviridae virus infection in a human in need thereof. In some embodiments, the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is human metapneumovirus infection. In some embodiments, the present disclosure provides methods for treating a RSV (respiratory syncytial virus) infection in a human in need thereof, the method comprising administering to the human a compound provided herein. In some embodiments, the human is suffering from a chronic respiratory syncytial viral infection. In some embodiments, the human is acutely infected with RSV. In some embodiments, a method of inhibiting RSV replication is provided, wherein the method comprises administering to a human in need thereof, a compound disclosed herein, wherein the administration is by inhalation. In some embodiments, the present disclosure provides a method for reducing the viral load associated with RSV infection, wherein the method comprises administering to a human infected with RSV a compound disclosed herein. In some embodiments, the viral infection is a picornaviridae virus infection. As such, in some embodiments, the present disclosure provides a method of treating a picornaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound of the present disclosure. Picornaviridae viruses are enteroviruses causing a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome (human rhinovirus infection), a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot- mouth syndrome, pediatric and adult pancreatitis and serious myocarditis. In some embodiments, the Picornaviridae virus infection is human rhinovirus infection. In some embodiments, the Picornaviridae virus infection is enterovirus infection. In some embodiments, the Picornaviridae virus infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection. In some embodiments, the present disclosure provides a compound, for use in the treatment of a picornaviridae virus infection in a human in need thereof. In some embodiments, the picornaviridae virus infection is human rhinovirus infection. In some embodiments, the viral infection is a flaviviridae virus infection. As such, in some embodiments, the present disclosure provides a method of treating a flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative flaviviridae viruses include, but are not limited to, dengue, Yellow fever, West Nile, Zika, Japanese encephalitis virus, and Hepatitis C (HCV). In some embodiments, the flaviviridae virus infection is a dengue virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a zika virus infection. In some embodiments, the flaviviridae virus infection is a Japanese ensephalitis virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection. In some embodiments, the present disclosure provides use of a compound disclosed herein for treatment of a flaviviridae virus infection in a human in need thereof. In some embodiments, the flaviviridae virus infection is a dengue virus infection. In some embodiments, the flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the flaviviridae virus infection is a West Nile virus infection. In some embodiments, the flaviviridae virus infection is a zika virus infection. In some embodiments, the flaviviridae virus infection is a hepatitis C virus infection. In some embodiments, the viral infection is a filoviridae virus infection. As such, in some embodiments, provided herein is a method of treating a filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative filoviridae viruses include, but are not limited to, ebola (variants Zaire, Bundibugio, Sudan, Tai forest, or Reston) and marburg. In some embodiments, the filoviridae virus infection is an ebola virus infection. In some embodiments, the filoviridae virus infection is a marburg virus infection. In some embodiments, the present disclosure provides a compound for use in the treatment of a filoviridae virus infection in a human in need thereof. In some embodiments, the filoviridae virus infection is an ebola virus infection. In some embodiments, the filoviridae virus infection is a marburg virus infection. In some embodiments, the viral infection is a coronavirus infection. As such, in some embodiments, provided herein is a method of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering to the human a compound provided herein. In some embodiments, the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections. In some embodiments, the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS CoV polymerase, MERS CoV polymerase and SARS-CoV-2. In some embodiments, the present disclosure provides a compound for use in the treatment of a coronavirus virus infection in a human in need thereof. In some embodiments, the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections. In some embodiments, the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID19). In some embodiments, the viral infection is an arenaviridae virus infection. As such, in some embodiments, the disclosure provides a method of treating an arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the arenaviridae virus infection is a Lassa infection or a Junin infection. In some embodiments, the present disclosure provides a compound for use in the treatment of a arenaviridae virus infection in a human in need thereof. In some embodiments, the arenaviridae virus infection is a Lassa infection or a Junin infection. In some embodiments, the viral infection is an orthomyxovirus infection, for example, an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection. In some embodiments, the viral infection is a nairovirus infection. As such, in some embodiments, the disclosure provides a method of treating a nairovirus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the nairovirus infection is a Crimean–Congo hemorrhagic fever virus infection. In some embodiments, the nairovirus infection is a Hazara virus infection. As described more fully herein, the compounds described herein can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with a viral infection. The additional therapeutic agent(s) can be administered to the infected individual at the same time as the compound of the present disclosure or before or after administration of the compound of the present disclosure. VIII. Combination Therapy The compounds described herein can also be used in combination with one or more additional therapeutic or prophylactic agents. As such, also provided herein are methods for treatment of viral infections in a subject in need thereof, wherein the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents. In some embodiments, the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents include one or more additional therapeutic agents from the same class or group (nonlimiting examples include one or more antiviral agents, one or more vaccines, one or more antibodies) and/or one or ore more additional therapeutic agents from different classes or groups. 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, Cytochrome P4503A4 inhibitors, Peptidyl-prolyl cis-trans isomerase A inhibitors, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A/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 [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, β-D-N4-hydroxycytidine or a combination thereof. 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 z¸alcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof. 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 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 embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, 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/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 AT-527, 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 agent 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. 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 an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. e embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-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 agentnet is interferon-beta-1a, such as SNG-001. In some embodiments, the additional therapeutic agent is an interferon-inducing agent, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent is IL-17 antagonist such as ixekizumab, secukinumab, IMU-838, and 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 i¸miquimod, sinecatechins, azoximer bromide, IMM-101 and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, 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 virafin. In some embodiments, the antiviral agent is berdazimer sodium. In some embodiments, the antiviral agent is KT-07. In some embodiments, the antiviral agent is iorta-carrageenan. In some embodiments, the antiviral agent is polyoxidonium. In some embodiments, the antiviral agent is bitespiramycin. In some embodiments, the antiviral agent is an anti-Adrenomedullin antibody, such as enibarcimab. In some embodiments, the antiviral agent is an annexin A5 stimulator, such as SY-005.spyke. In some embodiments, the antiviral agent is a COVID19 replicase polyprotein 1ab inhibitor, such as DC-402234. In some embodiments, the antiviral agent is a host cell factor modulator, such as GBV-006. In some embodiments, the antiviral agent is protoporphyrin. IX, stannous, 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 picornavirus. 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 picornavirus 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, Pyramax. In some embodiments, the additional therapeutic agent is chloroquine. 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, anti- viroporins, 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-5H-pyrrolo[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 (1-N,7-N- bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-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, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 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, AT-527, 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 AIC-649, alpha-hydroxytropolones, amdoxovir, antroquinonol, beta- hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, CV-431, 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-II-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), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (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 (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-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, autologous stem 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 FT-516. 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 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); TRUVADA® (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); SYMFITM (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDUTM (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 embodiments, 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 embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, 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, balixafortide, motixafortide, 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 nonnucleoside 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 embodiments, the additional therapeutic agent is a HIV non-nucleoside or non- nucleotide 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 examples, the additional therapeutic agent is a HIV^vaccine, such as DermaVir. 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); TRUVADA® (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 a CD73 agonist, such as FP- 1201. In some embodiments, the additional therapeutic agent is a CGRP receptor antagonist, such as BHV-3500. In some embodiments, the additional therapeutic agent is a Cytochrome P4503A4 inhibitor/ Peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir. In some embodiments, the additional therapeutic agent is a progesterone receptor agonist, such as Progesterone-IBSA. In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone. In some embodiments, the additional therapeutic agent is an inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, 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-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-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 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 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 Syk tyrosine kinase inhibitor, such as fostamatinib disodium. In some embodiments, the additional therapeutic agent is a cholesterol ester transfer protein inhibitor, such as dalcetrapib. 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 casein kinase II inhibitor, such as silmitasertib. In some embodiments, the additional therapeutic agent is a Bcr-Abl tyrosine kinase inhibitor, such as radotinib. In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapent ethyl. 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 a 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 PARP1/2 and Tankyrase 1/2, such as stenoparib (2X-121). In some embodiments, the additional therapeutic agent is a cyclin dependent kinase inhibitor, such as CYC-065, CYC-202, fadraciclib, seliciclib. In some embodiments, the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine, azacytidine, DUR-928. In some embodiments, the additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments, the additional therapeutic agent is a Deoxyribonuclease stimulator, such as Descartes-30. In some embodiments, the additional therapeutic agent is a Ribonuclease stimulator, such as ranpirnase. In some embodiments, the additional therapeutic agent is an eukaryotic initiation factor 4A1 (eIF4A1) inhibitor, such as zotatifin. 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 a Ubiquitin ligase modulator, such as KPG-818. 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 an ER1 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 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac- RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof. 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, disulfiram + copper gluconate, 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, inactivated vaccine (i.e., inactivated SARS-CoV-2 vaccine), therapeutic vaccine, prophylactic vaccine, protein based vaccine, viral vector vaccine, cellular vaccine, dendritic cell vaccine (i.e., LV-SMENP-DC, LV-SMENP-DC, or AV-COVID-19) or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273, mRNA-1273.211, mRNA-1273.351, mRNA-1283, CVnCoV, DS-5670., SP-0254, ARCoV, Nanocovax. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the therapeutic agent is a DNA vaccine, such as AG301-COVID19, bacTRL-Spike, GX-19, AG-0301-COVID19, ZyCoC-D, GLS-5310, CORVax. 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 [H5N1] virus monovalent vaccine and influenza A [H1N1] 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 G1, G3, G4, or G9 and RotaTeq for rotavirus serotype G1, 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., YF- Vax). 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 MERS vaccine (e.g., MVA-MERS-S, VTP-500). In some embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the additional therapeutic agent is a recombinant protein subunit vaccine (e.g., ZF-2001), EuCorVAc-19, GBP-510, Sinopharma vaccine, SpyCatcher vaccine, SP-0253, VBI-2902, UB-612, MVC-COV1901. In some embodiments, the additional therapeutic agent is a live attenuated bacterial vaccine (e.g., MV- 130). In some embodiments, the additional therapeutic agent is a recombinant non-replicating vaccine (e.g., JNJ784326735 (Ad26 SARS-CoV-2)). In some embodiments, the additional therapeutic agent is poly-TLR agonist polyantigenic vaccine (e.g., Mycobacterium w). In some embodiments, the additional therapeutic agent is a QAZCOVID-IN vaccine. In some embodiments, the additional therapeutic agent is a GRAd-COV2 vaccine. In some embodiments, the additional therapeutic agent is a EpiVacCorona vaccine. In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine. In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 Prime-boost), Sputnik-Light vector vaccine (rAd26), Covax-19, NasoVAX, NDV-HXP-S vaccine, AdCOVID, VSV-vector based vaccine. In some embodiments, the additional therapeutic agents is TiterQuil-1055 adjuvanted vaccine. 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, and/or TNX-1820, and/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-CoV2. 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-M and 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, V-SARS., AdCLD-Cov19, AKS-452, BVRS- GamVac, BVRS-GamVac-Combi, CIGB-2020, COVAC-2, FINLAY-FR-1, KD-414, S-268019, T-COVID, CDX-005, COH-04S1, ABNCoV2, ERUCOV-VAC, fakhravac, Kocak-19 inaktif adjuvanlı COVID-19 vaccine, NBP-2001, CoVepiT, VXA-CoV2-1, CoVac-1, AT-301, LNP- nCoVsaRNA, AdimrSC-2f, BBV-154, COVID-19 XWG-03, FINLAY-FR-2, MV-014-212, MVA-SARS-2-S, RAZI Cov Pars, SPFN_1B-06-PL, V-590, Ad5-Covid-S/N, CORAL. 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 a PD-1 antibody. In some embodiments, the additional therapeutic agent is REGN-COV2. In some embodiments, the additional therapeutic agent is LY-CoV555. 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 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 embodiemnst, 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 PDE3/PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin and ensifentrine. 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 and AK-119. In some embodiments, the additional therapeutic agent is recombinant cytokine gene- derived protein injection. In some embodiments, the additional therapeutic agent is amnion- derived cellular cytokine solution, such as ST-266. 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 a RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of AT-527, ribavirin, favipiravir, lamivudine, galidesivir, pimodivir and combination 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, TAK-671. In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat, Nafamostat, 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 A1, E- 52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, LTX-109, MAS- 825, Metformin, Metformin glycinate, MRG-001, Medregen, MRx-0004, thimerosal, Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623, Midostaurin, Ruxolitinib, ZINC1775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, Daunorubicin, GB110, 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 agenet 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 LB1148, upamostat, RHB-107, alpha-1 antitrypsin, tranexamic acid. In some embodiments, the additional therapeutic agent is a replicase polyprotein 1a inhibitor/replicase polyprotein 1ab inhibitor/protease inhibitor/coronavirus 3C protease like inhibitor, such as PF-07304814. In some embodiments, the additional therapeutic agent is a SARS coronavirus 3C protease like inhibitor, such as PF-07321332. In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as DS-2319, repurposed nafamostat mesylate. In some embodiments, the additional therapeutic agent is a serine protease inhibitor/Transmembrane serine protease 2 inhibitor, such as nafamostat. In some embodiments, the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213 In some embodiments, the additional therapeutic agent is a serine threonine protein kinase ATR inhibitor, such as berzosertib. 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 α-ketoamide. In some examples, the additional therapeutic agent is a poly-ADP-ribose polymerase 1 (PARP1) 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, CNM-AgZn-17, genistein, JAN-101, nitric oxide (inhalant), nitric oxide based antiviral formulation (oral), RTD-1, PrEP-001, QBKPN, RUTI, GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, Dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E- HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5] decan-3-one derivatives, S-1226, gemcitabine hydrochloride, loperamide, recombinant interferons, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzo-heterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof. 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 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 antibody is ABBV-47D11. In some embodiments, the antibody is COVI-GUARD. In some embodiments, the antibody is C144-LS + C135-LS. In some embodiments, the antibody is DXP-604. In some embodiments, the antibody is JMB-2002. In some embodiments, the antibody is LY-CovMab. In some embodiments, the antibody is LY- CoV555. In some embodiments, the antibody is S309. In some embodiments, the antibody is SAB-185. In some embodiments, the antibody is SI-F019. In some embodiments, the antibody is CB6. In some embodiments, the antibody is COR-101. In some embodiments, the antibody is STI-1499. In some embodiments, the antibody is JS016. In some embodiments, the antibody is VNAR. In some embodiments, the antibody is VIR-7832 and/or VIR-7831. In some embodiments, the antibody is REGN-COV2 (casirivimab + imdevimab REGN10933 + RGN10987). In some embodiments, the antibody is BAT2020, BAT2019. In some embodiments, the antibody is 47D11. In some embodiments, the antibody cocktail is COVI- SHIELD. In some embodiments, the antibody is BRII-196, BRII-198. In some embodiments, the antibody is ADG-20. In some embodiments, the antibody is ABP-300. In some embodiments, the antibody is BI-767551. In some embodiments, the antibody is GSK-4182136. In some embodiments, the antibody is AZD-7442. In some embodiments, the antibody is regdanvimab. In some embodiments, the antibody is etesevimab. In some embodiments, the antibody is SAB- 301. In some embodiments, the antibody is AOD-01. In some embodiments, the antibody is COVI-AMG. In some embodiments, the antibody is MW-33. In some embodiments, the antibody is DXP-593. In some embodiments, the antibody is BSVEQAb. In some embodiments, the antibody is anti-SARS-CoV-2 IgY. In some embodiments, the antibody is COVID-EIG. In some embodiments, the antibody is CSL-760. In some embodiments, the antibody is REGN- 3048-3051. In some embodiments, the antibody is ADM-03820. In some embodiments, the antibody is HFB-30132A. In some embodiments, the additional therapeutic agent is an anti- Hemolysin alpha antibody, such as tosatoxumab. In some embodiments, the additional therapeutic agent is an anti-LPS antibody IMM-124-E. In some embodiments, the antibody is INM-005, SCTA01, TY-027, XAV-19. In some embodiments, the additional therapeutic agent in an steroid, for example corticosteroid. In some embodiments, the additional therapeutic agent is dexamethasone. 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, amphotericin B, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole 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 K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immonumodulatory medications (e.g., 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 molnupiravir. In some embodiments, the additional therapeutic agent is AT-527. In some embodiments, the additional therapeutic agent is PF-07321332. In some examples, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide or budesonide. 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-OH- itraconazole. In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators (i.e., nivolumab); programmed death-ligand 1 (Pd-L1) modulators (i.e., camrelizumab, pembrolizumab); IL-15 modulators; DermaVir; interleukin-7 modulators (i.e., efineptakin alfa, plaquenil (hydroxychloroquine), CYT-107); 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, peginterferon lambda-1a, 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, astegolimab (MSTT1041A, RG-6149), UTTR1147A. 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 gamunex. In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralumab. In some embodiments, the additional therapeutic agent is a KEAP1 modulator, such as SFX-01. In some embodiments, the additional therapeutic agent is a PARP inhibitor, such as BGP-15. In some embodiments, the additional therapeutic agent is octagam. 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 a leukocyte Ig like receptor A4 modulator, such as daxdilimab. In some embodiments, the additional therapeutic agent is a Melanocortin MC1 receptor agonist, such as PL-8177. 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/IL23 inhibitor, such as apilimod, apilimod dimesylate. 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 IL-18 ligand inhibitor, such as tadekinig- alfa. In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa, F-652. 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, olokizumab, sirukumab, clazakizumab, levilimab or a combination thereof. In some embodiments, the additional therapeutic agent is tocilizumab biosimilar (e.g., CMAB-806). In some embodiments, the additional therapeutic agent is Apolipoprotein B modulator/IL-6 receptor antagonist/Serum amyloid A protein modulator/Transthyretin modulator. For example, the additional agent is Amilo-5MER. In some embodiments, the additional therapeutic agent is a Melanocortin MC1/MC3 receptor agonist. For example, the additional therapeutic agent is AP-1189. In some embodiments, the additional therapeutic agent is a NLRP3 inflammasome inhibitor. In some embodiments, the additional therapeutic agent is dapansutrile, DFV-890. 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 dipeptidase 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, golimumab, infliximab, or a combination thereof. In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, olumiant, TD-0903 or a combination thereof. In some examples, the additional therapeutic agent is jaktinib. In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone or LYT-100. In some embodiments, the additional therapeutic agent is anti-inflammatory agent, such as dociparstat sodium, eicosapentaenoic acid, didodecyl methotrexate, rabeximod, EG-009. In some embodiments, the additional agent is a TREM receptor 1 antagonistused in the treatment of septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a CCR1 antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent is a Complement C3 inhibitor, such as NGM-621, AMY-101. In some embodiments, the additional therapeutic agent is a Complement C1s subcomponent inhibitor, such as RLS-0071. In some embodiments, the additional therapeutic agent is a Complement factor C2 modulator, such as ARGX-117. In some embodiments, the additional therapeutic agent is a Galectin-3 inhibitor, such as belapectin. In some embodiments, the additional therapeutic agent is a heparanase inhibitor, such as tridecasodium pixatimod. In some embodiments, the additional therapeutic agent is an anti- MASP2 antibody, such as narsoplimab. In some embodiments, the additional therapeutic agent is a calcium channel modulator, such as dantrolene sodium. In some embodiments, the additional therapeutic agent is a sodium channel stimulator, such as solnatide. In some embodiments, the additional therapeutic agent is a alkaline phosphatase stimulator such as bovine alkaline phosphatase. In some embodiments, the additional therapeutic agent is a complement factor D inhibitor, such as ACH-0144471. In some embodiments, the additional therapeutic agent is a NK1 antagonist, such as LY-686017. In some embodiments, the additional therapeutic agent is a Zonulin inhibitor, such as larazotide acetate. In some embodiments, the additional therapeutic agent is an aryl hydrocarbon receptor agonist/ stem cell antigen-1 inhibitor, such as ampion. In some embodiments, the additional therapeutic agent is a dual complement C5 factor/Leukotriene BLT receptor antagonist, such as nomacopan. In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese. In some embodiments, the additional therapeutic agent is an opioid receptor antagonist, such as naltrexone. In some embodiments, the additional therapeutic agent is an opioid receptor agonist, such as metenkefalin. In some embodiments, the additional therapeutic agent is a BMP10/BMP15 gene inhibitor, such as lucinactant. In some embodiments, the additional therapeutic agent is an actin antagonist, such as gelsolin. In some embodiments, the additional therapeutic agent is a CD95 antagonist, such as asunercept. In some embodiments, the additional therapeutic agent is a Fractalkine ligand (CX3CL1) inhibitor, such as quetmolimab. In some embodiments, the additional therapeutic agent is a Platelet glycoprotein VI (GPVI) inhibitor, such as glenzocimab. In some embodiments, the additional therapeutic agent targets IKKβ and NFκβ, such as OP-101. In some embodiment, the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone, dexamethasone, dexamethasone phosphate. In some embodiment, the additional therapeutic agent is a PDGF receptor antagonist/TGF beta receptor antagonist/p38 MAP kinase inhibitor, such as deupirfenidone. In some embodiment, the additional therapeutic agent is a PGD2 antagonist, such as asapiprant. In some embodiment, the additional therapeutic agent is a prostaglandin E synthase-1 inhibitor, such as sonlicromanol hydrochloride. In some embodiment, the additional therapeutic agent is a superoxide dismutase modulator, such as Tempol. In some embodiment, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99. In some embodiment, the additional therapeutic agent is a TLR-2/TLR-4 antagonist, such as VB-201. In some embodiment, the additional therapeutic agent is a TLR-7/TLR-8 antagonist, such as M-5049. 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 an IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8), DF-1681 (reparixin). In some embodiments, the additional therapeutic agent is a CD14 inhibitor, such as IC-14, atibuclimab. In some embodiments, the additional therapeutic agent is a cyclophilin A inhibitor, such as CRV-431. In some embodiments, the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299, ASLAN-003. In some embodiments, the additional therapeutic agent is a G-protein coupled bile acid receptor 1 agonist (GPCR19) agonist, such as HY-209. In some embodiments, the additional therapeutic agent is a Grp78 calcium binding protein inhibitor/Jun N terminal kinase inhibitor/Transferrin modulator/p38 MAP kinase modulator, such as IT-139. In some embodiments, the additional therapeutic agent is a Histone deacetylase-6 (HDAC-6) inhibitor, such as CKD-506. In some embodiments, the additional therapeutic agent is a Lyn tyrosine kinase stimulator, such as tolimidone. In some embodiments, the additional therapeutic agent is a Tek tyrosine kinase receptor stimulator, such as AV-001. In some embodiments, the additional therapeutic agent is an Integrin alpha-V/beta-1 and alpha-V/beta-6 antagonist, such as PLN-74809. In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as PF- 06650833. In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor/KLKB1 gene inhibitor, such as IONIS-PKK-LRx. In some embodiments, the additional therapeutic agent is a Leukocyte elastase inhibitor, such as alvelestat, lonodelestat acetate. In some embodiments, the additional therapeutic is a Maxi K potassium channel inhibitor, such as ENA-001. In some embodiments, the additional therapeutic is a Nuclear factor kappa B inhibitor/p38 MAP kinase inhibitor, such as GLS-1027. In some embodiments, the additional therapeutic is a Nuclear factor kappa B inhibitor such as timbetasin or liposomal curcumin. In some embodiments, the additional therapeutic is anti-fibrotic, such as RT-1840, nintedanib, GB-0139, nintedanib or 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, besifloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or a combination thereof. In some embodiments, the antibiotic is XEL 1004. In some embodiments, the antibiotic is eravacycline. In some embodiments, the additional therapeutic agent is a bactericidal permeability protein inhibitor/Outer membrane protein inhibitor, such as RECCE-327. 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 embodiments, the compounds disclosed herein are used in combination with stem cells. In some embodiments, the compounds disclosed herein are used in combination with plasma-derived anti-SARS-CoV-2 IgG. In some embodiments, the compounds disclosed herein are used in combination with TAK- 888, NP-028 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)), or GC-5131A. In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immunoglobulin. 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 AdMSCs, ADR-001, Allo-hMSCs, CAP-1002, hCT-MSC, HB-adMSCs, itMSCs, MultiStem, Pluristem, Remestemcel-L (mesenchymal stem cells), NurOwn®, Rexlemestrocel-L, UCMSCs, or ACT-20. In some embodiments, 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, MT-2766, 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 selected from the group consisting of AVM-0703, bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, simvastatin, trimodulin, rosuvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof. In some embodiments, the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor, or α-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 alunacedase alfa (APN-01), HLX-71. 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 AT2 or a partial antagonist of AT1. In some embodiments, the additional therapeutic agent is L-163491. 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, lisonopril. In some embodiments, the additional therapeutic agent is an Angiotensin II AT-1 receptor antagonist/Beta-arrestin stimulator, such as TRV-027. In some embodiments, the additional therapeutic agent is an ACE2 inhibitor/COVID19 Spike glycoprotein inhibitor, such as MP-0420. In some embodiments, the additional therapeutic agent is a caspase inhibitor, such as emricasan. In some embodiments, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629. In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as RP-7214. In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor; Protein tyrosine kinase inhibitor, such as repurposed leflunomide. 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 XIIa antagonist, such as garadacimab. In some embodiments, the additional therapeutic is a Factor XIa antagonist, such as EP-7041. 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, tenecteplase. 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, 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 (Nanomedivir). 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 estrogen receptor modulator, such as estetrol. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide, proxalutamide. 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 thyroid hormone receptor, such as sobetirome. 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, otilimab, plonmarlimab. 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 calcium activated chloride channel (CACC) inhibitor, such as crofelemer. 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, tranilast. In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine. In some embodiments, the additional therapeutic agent is anti-histamine such as cloroperastine, and 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), such as FX-06. In some embodiments, the additional therapeutic agent is BIO-11006. In some embodiments, the additional therapeutic agent is sodium pyruvate. In some embodiments, 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, formoterol. In some embodiments, the additional therapeutic agent is a beta 2 adrenoceptor agonist, such as salmeterol. In some embodiments, the additional therapeutic agent is hyaluronidase inhibitor such as astodrimer. 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 additional therapeutic agent is a TLR4 antagonist, such as EB-05, NI-0101, or E-5564. In some embodiments, the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039. In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine. 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 modulator. For example, the additional therapeutic agent is pritumumab, hzVSF-v13. In some embodiments, the additional therapeutic agent is a modulator of Nsp15 (nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, AB001, 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 xanthine oxidase inhibitor, such as bucillamine, Xrx-101. In some embodiments, the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825, ONO-5334. In some embodiments, the additional therapeutic agent is a Transforming growth factor beta (TGF-β) 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 agnent is ifenprodil, transcrocetin. 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, 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 PB125. 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 (CSF1R) inhibitor, such as Avdoralimabaxatilimab. 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 C1s inhibitor, such as conestat alpha. In some embodiment, the additional therapeutic agent is a C3 inhibitor, such as APL-9, AMY-101 In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab or vilobelimab. 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 LY-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 histone inhibitor, such as STC-3141. In some embodiments, the additional therapeutic agent is a hyaluronan inhibitor. In some embodiments, the additional therapeutic agent is dopamine D2 receptor antagonist, such as chlorpromazine. In some embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole. In some embodiments, the additional therapeutic agent is a PGI2 agonist, such as epoprostenol. In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such asTM-5614. In some embodiments, the additional therapeutic agent is a Ubiquinol cytochrome C reductase 14 kDa inhibitor, such as telacebec. 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 additional therapeutic agent is a cell therapy, such as allogeneic natural killer cells, antigen presenting cells (APC), invariant natural killer T (iNKT) cells, induced pluripotent stem cell (iPSC), allogeneic T-cells, autologous adipose-derived mesenchymal stem cells, allogeneic bone marrow-derived mesenchymal stem cells, allogeneic mesenchymoangioblast-derived mesenchymal stem cells, regulatory T cells (Tregs), dendritic cells. In some embodiments, the additional therapeutic agent is SARS-CoV-2 specific cytotoxic T lymphocyte. In some embodiments, the additional therapeutic agent is agenT-797, Allocetra, ALVR-109, BM-Allo.MSC, BM-Allo-MSC, CAStem, Cellgram-AKI, CK-0802, CL-2020, IL- 15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, DWP-710, partially HLA- matched Virus Specific T cells (VSTs), FT-516, RAPA-501, SARS-CoV-2 Specific T Cells, HLCM-051, ExoFlo, HCR-040, it-hMSC, KI-MSC-PL-205, ORBCEL-C, pathogen-specific aAPC, ProTrans, SBI-101, StemVacs, STI-8282, taniraleucel, UMSC-01. In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZ1, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, XC-7, long-acting injectable ivermectin, Captopril, Lisinopril, Camostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof. In some embodiments, the additional therapeutic agent is selected form a group consisting of tilorone, cannabidiol, 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 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, ISPM-19, cipargamin, artemisone, and combinations thereof. It is also possible to combine any compound of the disclosure 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 disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the disclosure and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the disclosure 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 disclosure 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 disclosure within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the disclosure 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 disclosure. 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. 1. Combination Therapy for the Treatment of Pneumoviridae The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, preferably, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and/or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents active against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS- 433771, ALN-RSV0, ALX-0171 and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infections include respiratory syncytial virus protein F inhibitors, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors, such as lumicitabine and ALS-8112; anti- RSV G protein antibodies, such as anti-G-protein mAb; viral replication inhibitors, such as nitazoxanide. In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI- 8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine. Non-limiting examples of other active therapeutic agents active against metapneumovirus infections include sialidase modulators such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for the treatment of Metapneumovirus infections, such as EV-046113. In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infections, including but not limited to mRNA- 1653 and rHMPV-Pa vaccine. 2. Combination Therapy for the treatment of Picornaviridae The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infections, preferably, the other active therapeutic agent is active against Picornaviridae virus infections, particularly Enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu, et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase protein such as DAS-181; a capsid protein VP1 inhibitor such as VVX-003 and AZN-001; a viral protease inhibitor such as CW-33; a phosphatidylinositol 4 kinase beta inhibitor such as GSK- 480 and GSK-533; anti-EV71 antibody. In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infections, including but not limited to EV71 vaccines, TAK-021, and EV-D68 adenovector-based vaccine. 3. Combination Therapy for Respiratory Infections Many of the infections of the Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds provided herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combinations with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or a pharmaceutically acceptable salts thereof. Anti-inflammatory agents Other anti-inflammatory agents working through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. Applying “anti-inflammatory signal transduction modulators” (referred to in this text as AISTM), like phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to switching off inflammation as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-1- isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4- difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4- methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol- 3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-Methoxy-2-trifluoromethyl-quinoline- 5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5- (4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB- 203850); 4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3- yn-1-ol (P38 inhibitor RWJ-67657); 4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)- cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl- propoxy)-quinazolin-4-yl]-amine (Gefitinib, EGFR inhibitor); and 4-(4-Methyl-piperazin-1- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (Imatinib, EGFR inhibitor). β2-adrenoreceptor agonist bronchodilators Combinations comprising inhaled β2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds provided herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections. Combinations of inhaled β2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS’s are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively). The combinations comprising these ICS and β2-adrenoreceptor agonist combinations along with the compounds provided herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections. Other examples of Beta 2 adrenoceptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergics For the treatment or prophylaxis of pulmonary broncho-constriction, anticholinergics are of potential use and, therefore, useful as an additional therapeutic agent in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); 1-{4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)- propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4- ylmethyl)-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl- 8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate); 1-Cyclohexyl-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin); 2- Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate); 2-{1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl- acetamide (Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2- Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia- tricyclo[3.3.1.02,4]nonane (Oxitropium-N,N-diethylglycinate); 7-[2-(2-Diethylamino-acetoxy)- 2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (Tiotropium-N,N-diethylglycinate); Dimethylamino-acetic acid 2-(3-diisopropylamino-1- phenyl-propyl)-4-methyl-phenyl ester (Tolterodine-N,N-dimethylglycinate); 3-[4,4-Bis-(4- fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium; 1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one; 1- Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2- Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia- bicyclo[2.2.2]octane (Aclidinium-N,N-diethylglycinate); or (2-Diethylamino-acetoxy)-di- thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; revefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencycloquidium bromide. Mucolytic agents The compounds provided herein may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin. Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266). Thus, the compounds provided herein may also be combined with nebulized hypertonic saline particularly when the virus infection is complicated with bronchiolitis. The combination of the compound provided herein with hypertonic saline may also comprise any of the additional agents discussed above. In some embodiments, about 3% hypertonic saline is used. 4. Combination Therapy for the treatment of Flaviviridae virus infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae virus infections, preferably, the other active therapeutic agent is active against Flaviviridae virus infections. For treatment of the dengue virus infection, non-limiting examples of the other active therapeutic agents are host cell factor modulators, such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors, such as celgosivir; platelet activating factor receptor (PAFR) antagonists, such as modipafant; cadherin-5/Factor Ia modulators, such as FX-06; NS4B inhibitors, such as JNJ-8359; viral RNA splicing modulators, such as ABX-202; a NS5 polymerase inhibitor; a NS3 protease inhibitor; and a TLR modulator. In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, Dengvaxia ®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue fever vaccine, tetravalent DNA vaccine, rDEN2delta30-7169; and DENV-1 PIV. 5. Combination Therapy for the treatment of Filoviridae virus infections The compounds provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae virus infections, preferably, the other active therapeutic agent is active against Filoviridae virus infections, particularly Marburg virus, Ebola virus and Cueva virus infections. Non-limiting examples of these other active therapeutic agents are: 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-5H-pyrrolo[3,2-d]pyrimidin-7-yl)- 5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors, such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators, such as GMV-006; cadherin-5/factor Ia modulators, such as FX-06; and antibodies for the treatment of Ebola, such as REGN-3470-3471-3479 and ZMapp. Other non-limiting active therapeutic agents active against Ebola include an alpha- glucosidase 1 inhibitor, a cathepsin B inhibitor, a CD29 antagonist, a dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, an estrogen receptor antagonist, a factor VII antagonist HLA class II antigen modulator, a host cell factor modulator, an Interferon alpha ligand, a neutral alpha glucosidase AB inhibitor, a niemann-Pick C1 protein inhibitor, a nucleoprotein inhibitor, a polymerase cofactor VP35 inhibitor, a Serine protease inhibitor, a tissue factor inhibitor, a TLR- 3 agonist, a viral envelope glycoprotein inhibitor, and an Ebola virus entry inhibitors (NPC1 inhibitors). In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB Vector, HPIV3/EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302. The compounds provided herein may also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Examples of PMOs include but are not limited to AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003. The compounds provided herein are also intended for use with general care provided to patients with Filoviridae 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 K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), 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. IX. Compound Preparation In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof. Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. During any of the processes for preparation of the compounds provided herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Skilled artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. The methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure. Representative syntheses of compounds of the present disclosure are described in the schemes below, and the particular examples that follow. EXAMPLES Intermediate 1-1: tert-butyl (R)-2,2-dimethyl-4-((octadecyloxy)methyl)oxazolidine-3- carboxylate:
Figure imgf000131_0001
1-1 Sodium hydride (60% wt dispersion in mineral oil, 1.58 g, 40 mmol) was added to a vigorously stirred solution of tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyloxazolidine-3- carboxylate (3.05 g, 13.2 mmol) in N,N-dimethylformamide (25 mL) at 0 °C. After 40 min, a solution of 1-bromooctadecane (11.0 g, 33.0 mmol) in tetrahydrofuran (10 mL) was added via syringe, and the resulting mixture was warmed to room temperature. After 58 h, saturated aqueous ammonium chloride solution (25 mL) and diethyl ether (450 mL) were added sequentially. The organic layer was washed with water (2 × 400 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 15% ethyl acetate in hexanes) to give intermediate 1-1. LCMS: 478.4 [M+Na]+. Intermediate 1-2: (S)-2-amino-3-(octadecyloxy)propan-1-ol:
Figure imgf000132_0001
Hydrogen chloride solution (4.0 M in 1,4-dioxane, 9.15 mL, 37 mmol) was added via syringe to a stirred solution of intermediate 1-1 (4.80 g, 9.92 mmol) in 1,4-dioxane (21.6 mL) and water (0.62 mL) at 0 °C. After 1 min, the resulting mixture was warmed to room temperature. After 4 h, saturated aqueous sodium carbonate solution (30 mL), diethyl ether (300 mL), and tetrahydrofuran (300 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 300 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure to give intermediate 1-2. LCMS: 344.3. Intermediate 1-3: (S)-2-(isoindolin-2-yl)-3-(octadecyloxy)propan-1-ol:
Figure imgf000132_0002
Phthalaldehyde (36.1 mg, 269 μmol) was added to a vigorously stirred solution of intermediate 1-2 (84.0 mg, 244 μmol) in dichloromethane (3.5 mL) at room temperature. After 2 min, sodium triacetoxyborohydride (259 mg, 1.22 mmol) was added, and the resulting mixture was heated to 60 °C. After 80 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium carbonate solution (6 mL) and water (15 mL) were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 25 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), and the resulting mixture was stirred and cooled to 0 °C. Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 700 μL, 1.4 mmol) was added over 1 min via syringe, and the resulting mixture was warmed to room temperature over 4 min. The resulting mixture was heated to 60 °C. After 15 h, the resulting mixture was heated to 70 °C. After 3.5 h, the resulting mixture was cooled to 0 °C, and water (55 μL), aqueous sodium hydroxide solution (2.0 M, 110 μL), and water (110 μL) were added sequentially. The resulting suspension was filtered through celite, and the filter cake was extracted sequentially with ethyl acetate (20 mL) and dichlororomethane (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 1-3. LCMS: 446.3. Intermediate 1-5: ((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-chlorophenyl) ((R)-2-(isoindolin-2-yl)- 3-(octadecyloxy)propyl) phosphate:
Figure imgf000133_0001
2-Chlorophenyl phosphorodichloridate (19.6 μL, 121 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (16.8 mg, 244 μmol), triethylamine (34.0 μL, 244 μmol), and tetrahydrofuran (0.3 mL) at room temperature. After 35 min, intermediate 1-4 (34.8 mg, 105 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (9.7 μL, 121 μmol) were added sequentially. After 60 min, a solution of intermediate 1-3 (40.7 mg, 91.3 μmol) in tetrahydrofuran (1.0 mL) was added via syringe. After 223 min, 1-(mesitylsulfonyl)-3-nitro-1H- 1,2,4-triazole (27.1 mg, 91.3 μmol) and triethylamine (40.0 μL, 287 μL) were added sequentially. After 13 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 1-5. LCMS: 949.5. Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(isoindolin-2-yl)-3-(octadecyloxy)propyl) hydrogen phosphate (1):
Figure imgf000134_0001
Potassium trimethylsilanolate (38.0 mg, 296 μmol) was added to a vigorously stirred solution of intermediate 1-5 (47.6 mg, 50.1 μmol) in tetrahydrofuran (0.7 mL) at room temperature. After 48 min, concentrated hydrochloric acid (300 μL, 3.6 mmol) was added via syringe. After 60 min, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give compound 1.1H NMR (400 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.40 (s, 4H), 7.06 (d, J = 4.6 Hz, 1H), 7.00 (d, J = 4.7 Hz, 1H), 4.97 – 4.73 (m, 5H), 4.42 – 4.34 (m, 1H), 4.24 – 4.05 (m, 5H), 3.90 – 3.71 (m, 3H), 3.50 – 3.40 (m, 2H), 1.67 – 1.47 (m, 2H), 1.38 – 1.21 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 799.3. Intermediate 2-1: (S)-2-(methylamino)-3-(octadecyloxy)propan-1-ol:
Figure imgf000135_0001
A vigorously stirred mixture of intermediate 1-2 (520 mg, 1.51 mmol) and ethyl formate (20 mL) was heated to 72 °C. After 43 h, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was dried azeotropically by concentration under reduced pressure from toluene (2 × 5 mL). The residue was dissolved in tetrahydrofuran, and the resulting mixture was cooled to 0 °C and stirred. Lithium aluminum hydride solution (2.0 M in tetrahydrofuran, 3.80 mL, 7.6 mmol) was added over 2 min via syringe. After 2 min, the resulting mixture was heated to 61 °C. After 16.5 h, the resulting mixture was cooled to 0 °C, and water (302 μL), aqueous sodium hydroxide solution (2.0 M, 604 μL), and water (604 μL) were added sequentially. Water (50 mL) and brine (50 mL) were added sequentially, and the aqueous layer was extracted with dichloromethane (2 × 125 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 33% methanol in dichloromethane) to give intermediate 2-1. LCMS: 358.4. Intermediate 2-2: (S)-2-(benzyl(methyl)amino)-3-(octadecyloxy)propan-1-ol:
Figure imgf000136_0002
Benzaldehyde (25.6 μL, 252 μmol) was added via syringe to a vigorously stirred solution of intermediate 2-1 (60.0 mg, 168 μmol) in dichloromethane (3.0 mL) at room temperature. After 2 min, sodium triacetoxyborohydride (178 mg, 839 μmol) was added, and the resulting mixture was heated to 50 °C. After 14 h, the resulting mixture was cooled to room temperature, and saturated aqueous sodium carbonate solution (5 mL) and water (15 mL) were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 125 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 8% methanol in dichloromethane) to give intermediate 2-2. LCMS: 448.4. Example 2: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyl(methyl)amino)-3-(octadecyloxy)propyl) hydrogen phosphate (2):
Figure imgf000136_0001
Compound 2 was synthesized in a manner similar to compound 1 using intermediate 2-2 instead of intermediate 1-3.1H NMR (400 MHz, Methanol-d4) δ 7.97 (s, 1H), 7.60 – 7.33 (m, 5H), 7.14 – 7.02 (m, 2H), 5.00 – 4.71 (m, 3H), 4.46 – 4.34 (m, 1H), 4.31 – 3.99 (m, 5H), 3.81 – 3.66 (m, 3H), 3.56 – 3.44 (m, 2H), 2.67 (s, 3H), 1.72 – 1.07 (m, 32H), 0.91 (t, J = 6.7 Hz, 3H). LCMS: 801.3. Example 3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-chloro-4-fluorobenzyl)(methyl)amino)-3- (octadecyloxy)propyl) hydrogen phosphate (3):
Figure imgf000137_0001
Compound 3 was synthesized in a manner similar to compound 2 using 3-chloro-4- fluorobenzaldehyde instead of benzaldehyde.1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.72 (dd, J = 6.9, 2.2 Hz, 1H), 7.60 – 7.49 (m, 1H), 7.36 (t, J = 8.8 Hz, 1H), 7.17 (d, J = 4.7 Hz, 1H), 7.11 (d, J = 4.7 Hz, 1H), 5.00 – 4.81 (m, 2H), 4.79 (d, J = 5.3 Hz, 1H), 4.53 – 4.34 (m, 1H), 4.29 – 4.15 (m, 3H), 4.15 – 4.01 (m, 2H), 3.82 – 3.67 (m, 3H), 3.58 – 3.46 (m, 2H), 2.88 (s, 3H), 1.69 – 1.56 (m, 2H), 1.43 – 1.22 (m, 30H), 0.92 (t, J = 6.5 Hz, 3H). LCMS: 851.4 [M−H]−. Intermediate 4-1: (S)-3-chloro-4-fluoro-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)-N- methylbenzamide:
Figure imgf000138_0001
3-Chloro-4-fluorobenzoyl chloride (23.1 mg, 120 μmol) was added to a stirred mixture of intermediate 2-1 (42.8 mg, 120 μmol), triethylamine (33.4 μL, 239 μmol), and dichloromethane (2.0 mL) at room temperature. After 60 min, the resulting mixture was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 4-1. LCMS: 514.3. Intermediate 4-2: ((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 bis(2-chlorophenyl) phosphate:
Figure imgf000138_0002
2-Chlorophenyl phosphorodichloridate (84.5 μL, 524 μmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (72.6 mg, 1.05 mmol), triethylamine (147 μL, 1.05 mmol), and tetrahydrofuran (0.9 mL) at room temperature. After 30 min, intermediate 1-4 (150 mg, 453 μmol), tetrahydrofuran (0.45 mL), and 1-methylimidazole (41.9 μL, 525 μmol) were added sequentially. After 60 min, 2-chlorophenol (235 μL, 2.26 mmol) and triethylamine (350 μL, 2.50 mmol) were added sequentially. After 16 h, the resulting mixture was purified by flash column chromatography on silica gel (0 to 3.75% methanol in dichloromethane) to give intermediate 4-2. LCMS: 963.2. Example 4: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(3-chloro-4-fluoro-N-methylbenzamido)-3- (octadecyloxy)propyl) hydrogen phosphate (4):
Figure imgf000139_0001
A vigorously stirred mixture of intermediate 4-2 (59.5 mg, 94.1 μmol), intermediate 4-1 (48.4 mg, 94.1 μmol), magnesium chloride (44.8 mg, 471 μmol), and tetrahydofuran (1.0 mL) was heated to 53 °C. After 5 min, N,N-diisopropylethylamine (82.0 μL, 471 μmol) was added over 1 min via syringe. After 44 min, the resulting mixture was heated to 90 °C. After 16 min, the resulting mixture was cooled to room temperature over 6 min, and 2,2,6,6- Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran/toluene, 157 μL, 157 μmol) was added via syringe. After 6 min, the resulting mixture was heated to 50 °C. After 40 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (30 mL) were added. The organic layer was washed with water (2 × 20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.6 mL), and the resulting mixture was stirred vigorously at room temperature. Potassium tert-pentoxide solution (1.7 M in toluene, 111 μL, 188 μmol) was added over 1 min via syringe, and the resulting mixture was heated to 50 °C. After 25 min, the resulting mixture was cooled to room temperature, and concentrated hydrochloric acid (350 μL, 4.2 mmol) was added via syringe. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 4 as a 2:1 mixture of amide rotamers.1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.76 – 7.04 (m, 5H), 5.03 – 4.51 (m, 1H), 4.49 – 3.45 (m, 11H), 2.93 (s, 1H), 2.91 (s, 2H), 1.69 – 1.50 (m, 2H), 1.46 – 1.20 (m, 30H), 0.96 – 0.87 (m, 3H). LCMS: 865.3 [M−H]−. Intermediate 5-1: methyl (2R,3S)-2-hydroxy-3-(octadecyloxy)butanoate:
Figure imgf000140_0001
4-toluenesulfonic acid monohydrate (28.4 mg, 149 μmol) was added to a vigorously stirred mixture of methyl (2R,3S)-2,3-dihydroxybutanoate (200 mg, 1.49 mmol) (Servi, S. J. Org. Chem.1985, 50, 5865), octadecanal (420 mg, 1.57 mmol), anhydrous magnesium sulfate (332 mg, 2.76 mmol), and dichloromethane (4.0 mL) at room temperature, and the resulting mixture was heated to 60 °C. After 2 h, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and the resulting mixture was submerged in a −78 °C dry ice/acetone bath. After 1 min, titanium tetrachloride (327 μL, 2.98 mmol) was added via syringe. After 5 min, triethylsilane (1.19 mL, 7.46 mmol) was added via syringe, and the resulting mixture was warmed to room temperature over 19.5 h. Water (30 mL) was added. After 3 min, the aqueous layer was extracted with dichloromethane (2 × 50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 15% ethyl acetate in hexanes) to give intermediate 5-1. LCMS: 409.3 [M+Na]+. Intermediate 5-2: methyl (2R,3S)-2-(benzyloxy)-3-(octadecyloxy)butanoate:
Figure imgf000141_0001
Trifluromethanesulfonic acid (2.3 μL, 26 μmol) was added via syringe to a stirred mixture of intermediate 5-1 (100 mg, 259 μmol) and benzyl 2,2,2-trichloroacetimidate (120 μL, 647 μmol) in 1,4-dioxane (2.0 mL) at room temperature. After 2 h, 4-methylmorpholine (30 μL) was added via syringe, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% ethyl acetate in hexanes) to give intermediate 5-2. LCMS: 499.4 [M+Na]+. Intermediate 5-3: (2S,3S)-2-(benzyloxy)-3-(octadecyloxy)butan-1-ol:
Figure imgf000141_0002
Lithium aluminum hydride solution (1.0 M in tetrahydrofuran, 455 μL, 460 μmol) was added over 1 min via syringe to a stirred solution of intermediate 5-2 (72.3 mg, 152 μmol) in tetrahydrofuran (4.0 mL) at 0 °C. After 1 h, water (20 μL), aqueous sodium hydroxide solution (2.0 M, 40 μL), and water (20 μL) were added sequentially. The resulting suspension was filtered through celite, and the filter cake was extracted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0 to 25% ethyl acetate in hexanes) to give intermediate 5-3. LCMS: 471.4 [M+Na]+. Intermediate 5-4: ((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 ((2S,3S)-2-(benzyloxy)-3- (octadecyloxy)butyl) (2-chlorophenyl) phosphate:
Figure imgf000142_0001
2-Chlorophenyl phosphorodichloridate (18.9 μL, 117 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (16.2 mg, 234 μmol), triethylamine (32.6 μL, 234 μmol), and tetrahydrofuran (0.2 mL) at room temperature. After 30 min, intermediate 1-4 (37.4 mg, 113 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (8.6 μL, 110 μmol) were added sequentially. After 60 min, a solution of intermediate 5-3 (36.2 mg, 80.7 μmol) in tetrahydrofuran (0.7 mL) was added via syringe.1-Methylimidazole (20 μL, 250 μmol) was added via syringe. After 22 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane) to give intermediate 5-4. LCMS: 951.5. Example 5: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((2S,3S)-2-(benzyloxy)-3-(octadecyloxy)butyl) hydrogen phosphate (5):
Figure imgf000143_0001
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 242 μL, 240 μmol) was added via syringe to a stirred mixture of intermediate 5-4 (76.8 mg, 80.6 μmol), 4- (dimethylamino)pyridine (29.5 mg, 242 μmol), tetrahydrofuran (0.1 mL), and water (72.6 μL, 4.03 mmol) at room temperature, and the resulting mixture was heated to 50 °C. After 1 h, the resulting mixture was cooled to room temperature, and chlorotrimethylsilane (30.7 μL, 242 μmol) and concentrated hydrochloric acid (300 μL, 3.6 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 5.1H NMR (400 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.39 – 7.33 (m, 2H), 7.33 – 7.20 (m, 4H), 7.19 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.39 – 4.30 (m, 1H), 4.27 (t, J = 5.5 Hz, 1H), 4.24 – 4.17 (m, 1H), 4.17 – 4.04 (m, 2H), 4.04 – 3.91 (m, 1H), 3.67 – 3.54 (m, 2H), 3.54 – 3.46 (m, 1H), 3.46 – 3.36 (m, 1H), 1.57 – 1.46 (m, 2H), 1.40 – 1.21 (m, 30H), 1.11 (d, J = 5.9 Hz, 3H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 800.4 [M−H]−. Intermediate 6-1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl- 6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2- sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile:
Figure imgf000144_0001
1,8-Diazabicyclo[5.4.0]undec-7-ene (609 µL, 4.07 mmol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 1-4 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-Methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2- yl)hexahydrobenzo[d][1,3,2]oxathiaphosphole 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) at room temperature. After 10 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 6-1. LCMS: 578.2.
Intermediate 6-2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl- 6-((((2S,3aR,6S,7aR)-3a-methyl-2-oxido-6-(prop-1-en-2- yl)hexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile:
Figure imgf000145_0001
Selenium dioxide (316 mg, 2.84 mmol) was added to a vigorously stirred solution of intermediate 6-1 (1.57 g, 2.71 mmol) in acetonitrile (23.5 mL) and water (8.9 mL) at room temperature. After 60 min, ethyl acetate (250 mL) was added, and the resulting suspension was filtered through celite. The organic layer of the filtrate was washed with a mixture of water and brine (1:1 v:v, 120 mL), and the aqueous layer was extracted with ethyl acetate (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 6-2. LCMS: 562.2. Intermediate 6-3: (S)-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2- yl)(methyl)amino)methyl)benzonitrile:
Figure imgf000145_0002
Intermediate 6-3 was synthesized in a manner similar to intermediate 2-2 using 3-fluoro- 5-formylbenzonitrile instead of benzaldehyde. LCMS: 491.4. Example 6: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)(methyl)amino)-3- (octadecyloxy)propyl) hydrogen phosphate (6):
Figure imgf000146_0001
1,8-Diazabicyclo[5.4.0]undec-7-ene (17.4 µL, 116 µmol) was added via syringe to a vigorously stirred mixture of intermediate 6-2 (21.8 mg, 38.8 µmol), intermediate 6-3 (19.0 mg, 38.8 µmol), and tetrahydrofuran (0.35 mL) at room temperature. After 55 min, concentrated hydrochloric acid (250 µL, 3.0 mmol) was added via syringe. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) followed by flash column chromatography on silica gel (0 to 70% methanol in dichloromethane) to give compound 6.1H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.98 – 4.74 (m, 1H), 4.60 (s, 1H), 4.40 – 4.34 (m, 1H), 4.33 – 4.28 (m, 1H), 4.24 – 3.37 (m, 8H), 2.24 (s, 3H), 1.62 – 1.48 (m, 2H), 1.42 – 1.21 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 844.2. Intermediate 7-1: (S)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl 4- methylbenzenesulfonate:
Figure imgf000147_0001
4-Toluenesulfonyl chloride (929 mg, 4.87 mmol) was added to a stirred mixture of (S)-1- ((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (1.40 g, 3.04 mmol) (Xia, J.; Hui, Y.-Z. Tetrahedron: Asymmetry 1997, 8, 3131), N,N-diisopropylethylamine (848 μL, 4.87 mmol), 4-(dimethylamino)pyridine (37.2 mg, 304 μmol), and dichloromethane (7.0 mL) at 0 °C. After 2 min, the resulting mixture was warmed to room temperature. After 170 min, 4- (dimethylamino)pyridine (67.0 mg, 548 μmol) was added. After 30 min, the resulting mixture was heated to 65 °C. After 17 h, the resulting mixture was cooled to room temperature, and diethyl ether (120 mL), ethyl acetate (20 mL), and aqueous hydrogen chloride solution (2.0 M, 5 mL) were added sequentially. The organic layer was washed sequentially with water (100 mL) and a mixture of water and saturated aqueous sodium bicarbonate solution (5:1 v:v, 100 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 50% dichloromethane in hexanes) to give intermediate 7-1. LCMS: 635.4 [M+Na]+. Intermediate 7-2: (R)-(2-(benzylthio)-3-(octadecyloxy)propoxy)(tert-butyl)dimethylsilane:
Figure imgf000148_0001
Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 367 μL, 370 μmol) was added via syringe to a vigorously stirred solution of benzyl mercaptan (43.1 μL, 367 μmol) in N,N-dimethylformamide (0.6 mL) at room temperature. After 4 min, intermediate 7-1 was added, and the resulting mixture was heated to 90 °C. After 30 min, the resulting mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 50 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 8% ethyl acetate in hexanes) to give intermediate 7-2. LCMS: 587.4 [M+Na]+. Intermediate 7-3: (S)-2-(benzylthio)-3-(octadecyloxy)propan-1-ol:
Figure imgf000148_0002
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 194 μL, 190 μmol) was added via syringe to a stirred solution of intermediate 7-2 (46.3 mg, 81.9 μmol) in tetrahydrofuran (0.2 mL) at room temperature. After 40 min, saturated aqueous ammonium chloride solution (5 mL), diethyl ether (10 mL), and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with water (10 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 9% ethyl acetate in hexanes) to give intermediate 7-3. LCMS: 473.4 [M+Na]+. Example 7: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzylthio)-3-(octadecyloxy)propyl) hydrogen phosphate: (7)
Figure imgf000149_0001
Compound 7 was synthesized in a manner similar to compound 5 using intermediate 7-3 instead of intermediate 5-3.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.40 – 7.18 (m, 7H), 4.84 – 4.73 (m, 1H), 4.44 – 3.39 (m, 12H), 2.96 – 2.85 (m, 1H), 1.68 – 1.43 (m, 2H), 1.30 (d, J = 3.1 Hz, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 802.4 [M−H]−. Intermediate 8-1: methyl (2R,3R)-2,3-dihydroxybutanoate:
Figure imgf000149_0002
A solution of sodium nitrite (3.13 g, 45.5 mmol) in water (4.76 mL) was added over 30 min via addition funnel to a stirred mixture of D-allothreonine (5.00 g, 41.9 mmol) in concentrated sulfuric acid (1.26 mL, 2.21 mmol) and water (10.2 mL) at 0 °C, and the resulting mixture was warmed to room temperature. After 23 h, the resulting mixture was concentrated under reduced pressure, and the residue was suspended in ethanol (95.2 mL). The resulting suspension was filtered, and the filtrate was concentrated to a volume of approximately 24 mL. Ethanol (47.6 mL) was added, and the resulting suspension was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was dried azeotropically by concentration under reduced pressure from a mixture of methanol and toluene (1:1 v:v, 47.6 mL). The residue was dissolved in methanol (28.6 mL), and the resulting mixture was stirred at room temperature. Hydrogen chloride solution (3.0 M in methanol, 50.0 mL, 150 mmol) was added via syringe. After 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 50% ethyl acetate in hexanes) to give intermediate 8-1.1H NMR (400 MHz, Chloroform-d) δ 4.25 (d, J = 3.7 Hz, 1H), 4.09 (qd, J = 6.5, 3.7 Hz, 1H), 3.85 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H). Example 8: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((2S,3R)-2-(benzyloxy)-3-(octadecyloxy)butyl) hydrogen phosphate (8):
Figure imgf000150_0001
Compound 8 was synthesized in a manner similar to compound 5 using intermediate 8-1 instead of methyl (2R,3R)-2,3-dihydroxybutanoate.1H NMR (400 MHz, Methanol-d4) δ 8.00 (s, 1H), 7.34 (d, J = 7.0 Hz, 2H), 7.31 – 7.26 (m, 2H), 7.26 – 7.20 (m, 2H), 7.17 (d, J = 4.7 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.71 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 4.42 – 4.28 (m, 1H), 4.26 (t, J = 5.5 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.13 – 3.97 (m, 2H), 3.97 – 3.88 (m, 1H), 3.65 – 3.59 (m, 1H), 3.59 – 3.36 (m, 3H), 1.56 – 1.45 (m, 2H), 1.41 – 1.24 (m, 30H), 1.15 (d, J = 6.3 Hz, 3H), 0.91 (t, J = 6.7 Hz, 3H). LCMS: 800.4 [M−H]−. Intermediate 9-1: (S)-2-(5,6-dichloroisoindolin-2-yl)-3-(octadecyloxy)propan-1-ol:
Figure imgf000151_0001
Intermediate 1-2 (93.0 mg, 271 μmol), tetrahydrofuran (1.5 mL), and N,N- diisopropylethylamine (120 μL, 690 μmol) were added sequentially to 1,2-bis(bromomethyl)- 4,5-dichlorobenzene (90.7 mg, 273 μmol) (Xu, F.; Peng, L.; Shinohara, K.; Morita, T.; Yoshida, S.; Hosoya, T.; Orita, A.; Otera, J. J. Org. Chem.2014, 79, 11592) at room temperature, and the resulting mixture was stirred vigorously and was heated to 65 °C. After 3 h, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 9% methanol in dichloromethane) to give intermediate 9-1. LCMS: 514.3. Example 9: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(5,6-dichloroisoindolin-2-yl)-3- (octadecyloxy)propyl) hydrogen phosphate (9):
Figure imgf000152_0001
2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (22.2 μL, 76.6 μmol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 9-1 (21.2 mg, 35.6 μmol), intermediate 6-2 (20.0 mg, 35.6 μmol), and tetrahydrofuran (0.35 mL) at 0 °C. After 1 min, the resulting mixture was warmed to room temperature. After 14 min, 2- tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (20.7 μL, 71.3 μmol) was added over 1 min via syringe. After 32 min, the resulting mixture was heated to 50 °C. After 25 min, the resulting mixture was cooled to room temperature, and water (50 μL) and concentrated hydrochloric acid (300 μL, 3.6 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 9.1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.59 (s, 2H), 7.13 (d, J = 4.9 Hz, 1H), 7.10 (d, J = 4.6 Hz, 1H), 4.95 – 4.73 (m, 5H), 4.44 – 4.34 (m, 1H), 4.28 – 4.09 (m, 5H), 3.96 – 3.73 (m, 3H), 3.53 – 3.42 (m, 2H), 1.64 – 1.50 (m, 2H), 1.40 – 1.21 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 866.3 [M−H]−. Intermediate 10-1: (S)-2-((3-chloro-4-fluorobenzyl)amino)-3-(octadecyloxy)propan-1-ol:
Figure imgf000153_0001
3-Chloro-4-fluorobenzaldehyde (55.7 mg, 351 μmol) was added to a vigorously stirred mixture of intermediate 1-2 (80.4 mg, 234 μmol), anhydrous sodium sulfate (49.9 mg, 1.17 mmol), and tetrahydrofuran (1.0 mL) at room temperature, and the resulting mixture was heated to 60 °C. After 180 min, the resulting mixture was cooled to room temperature. After 103 min, sodium borohydride (44.3 mg, 1.17 mmol) and methanol (2.0 mL) were added sequentially. After 360 min, ethyl acetate (60 mL), saturated aqueous sodium carbonate solution (10 mL), and brine (20 mL) were added sequentially. The organic layer was washed sequentially with water (20 mL) and a mixture of water and brine (1:1 v:v, 20 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 25% methanol in dichloromethane) to give intermediate 10-1. LCMS: 486.3.
Intermediate 10-2: (S)-N-(3-chloro-4-fluorobenzyl)-N-(1-hydroxy-3-(octadecyloxy)propan-2- yl)acetamide:
Figure imgf000154_0001
Acetic anhydride (5.8 μL, 62 μmol) was added via syringe to a stirred mixture of intermediate 10-1 (30.0 mg, 61.7 μmol), triethylamine (25.8 μL, 185 μmol), and dichloromethane at room temperature. After 30 min, the resulting mixture was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 10-2. LCMS: 550.4 [M+Na]+. Example 10: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(N-(3-chloro-4-fluorobenzyl)acetamido)-3- (octadecyloxy)propyl) hydrogen phosphate (10):
Figure imgf000154_0002
1,8-Diazabicyclo[5.4.0]undec-7-ene (8.0 µL, 53 µmol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 6-2 (15.0 mg, 26.7 µmol), intermediate 10-2 (14.1 mg, 26.7 µmol), and tetrahydrofuran (0.70 mL) at room temperature. After 25 min, water (50 µL) and concentrated hydrochloric acid (250 µL, 3.0 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 10 as a 2.4:1 mixture of amide rotamers.1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 0.37H), 8.03 (s, 0.63H), 7.48 – 7.04 (m, 5H), 4.96 – 2.99 (m, 14H), 2.25 (s, 1.9H), 2.01 (s, 1.1H), 1.59 – 1.19 (m, 30H), 0.96 – 0.82 (m, 3H). LCMS: 879.4 [M−H]−. Intermediate 11-1: (S)-2-(1-hydroxy-3-(octadecyloxy)propan-2-yl)isoindolin-1-one:
Figure imgf000155_0001
Phthalaldehyde (21.5 mg, 160 μmol) was added to a vigorously stirred solution of intermediate 1-2 (50.0 mg, 146 μmol) in dichloromethane (2.5 mL) at room temperature. After 2 min, acetic acid (41.7 μL, 728 μmol) was added via syringe, and the resulting mixture was heated to 50 °C. After 45 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (6 mL) and ethyl acetate (60 mL) were added sequentially. The organic layer was washed sequentially with a mixture of water and brine (3:1 v:v, 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 8% methanol in dichloromethane) to give intermediate 11-1. LCMS: 460.4. Example 11: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(octadecyloxy)-2-(1-oxoisoindolin-2-yl)propyl) hydrogen phosphate (11):
Figure imgf000156_0001
Compound 11 was synthesized in a manner similar to compound 10 using intermediate 11-1 instead of intermediate 10-2.1H NMR (400 MHz, Methanol-d4) δ 8.08 (d, J = 2.6 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.52 – 7.43 (m, 1H), 7.33 – 7.27 (m, 1H), 7.24 – 7.15 (m, 1H), 4.95 – 4.48 (m, 3H), 4.38 – 3.93 (m, 7H), 3.81 – 3.64 (m, 2H), 3.53 – 3.32 (m, 2H), 1.59 – 1.06 (m, 32H), 1.08 – 0.82 (m, 3H). LCMS: 811.4 [M−H]−. Intermediate 12-1: (R)-2-(benzyloxy)-3-(octadecyloxy)propanal:
Figure imgf000156_0002
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (787 mg, 1.86 mmol) was added to a stirred solution of (S)-2-(benzyloxy)-3-(octadecyloxy)propan-1-ol (403 mg, 928 μmol) at room temperature. After 70 min, diethyl ether (100 mL), ethyl acetate (25 mL), aqueous sodium thiosulfate solution (1.0 M, 5 mL), and saturated aqueous sodium bicarbonate solution (40 mL) were added sequentially. The organic layer was washed sequentially with water (60 mL), a mixture of water and saturate aqueous sodium bicarbonate solution (100 mL), and water (60 mL); was dried over anhydrous magnesium sulfate; was filtered; and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to give intermediate 12-1. LCMS: 455.4 [M+Na]+. Intermediate 12-2: (3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-ol (faster eluting diastereomer on silica gel): Intermediate 13-1: (3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-ol (slower eluting diastereomer on silica gel):
Figure imgf000157_0001
A solution of intermediate 12-1 (327 mg, 755 μmol) in tetrahydrofuran (8.0 mL) at −10 °C was added over 3 min via cannula to methylmagnesium bromide solution (3.2 M in 2- methyltetrahydrofuran, 1.20 mL, 3.8 mmol) at 0 °C. After 120 min, saturated aqueous ammonium chloride solution (5 mL) and diethyl ether (100 mL) were added sequentially. The organic layer was washed with water (60 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 4.5% tetrahydrofuran in hexanes) to give intermediate 12-2 (faster eluting diastereomer) and 13-1 (slower eluting diastereomer). Intermediate 12-2: LCMS: 471.4 [M+Na]+. Intermediate 13-1: LCMS: 471.4 [M+Na]+. Example 12: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl) hydrogen phosphate (12):
Figure imgf000158_0001
Compound 12 was synthesized in a manner similar to compound 10 using intermediate 12-2 instead of intermediate 10-2.1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.36 – 7.20 (m, 6H), 7.16 (d, J = 4.7 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.39 – 4.30 (m, 1H), 4.29 – 4.02 (m, 3H), 3.79 – 3.37 (m, 6H), 1.63 – 1.47 (m, 2H), 1.41 – 1.21 (m, 33H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 800.4 [M−H]−.
Example 13: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((3R)-3-(benzyloxy)-4-(octadecyloxy)butan-2-yl) hydrogen phosphate (13):
Figure imgf000159_0001
Compound 13 was synthesized in a manner similar to compound 10 using intermediate 13-1 instead of intermediate 10-2.1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.36 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.26 – 7.20 (m, 2H), 7.16 (d, J = 4.7 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.72 (s, 1H), 4.68 (d, J = 11.7 Hz, 1H), 4.48 – 4.39 (m, 1H), 4.39 – 4.31 (m, 1H), 4.30 – 4.16 (m, 2H), 4.16 – 4.05 (m, 1H), 3.80 – 3.39 (m, 5H), 1.61 – 1.48 (m, 2H), 1.43 – 1.21 (m, 33H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 800.4 [M−H]−. Intermediate 14-1: (S)-2-(1-hydroxy-3-(octadecyloxy)propan-2-yl)isoindoline-1,3-dione:
Figure imgf000159_0002
Ethyl 1,3-dioxoisoindoline-2-carboxylate (35.1 mg, 160 μmol) was added to a vigorously stirred solution of intermediate 1-2 (55.0 mg, 160 μmol) in tetrahydrofuran (1.0 mL) at room temperature. After 15.5 h, the resulting mixture was heated to 65 °C. After 75 min, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 12% ethyl acetate in dichloromethane) to give intermediate 14-1. LCMS: 496.4 [M+Na]+. Example 14: 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)carbamoyl)benzoic acid (14) Example 15: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(1,3-dioxoisoindolin-2-yl)-3- (octadecyloxy)propyl) hydrogen phosphate (15):
Figure imgf000160_0001
Compound 14 and compound 15 were synthesized in a manner similar to compound 10 using intermediate 14-1 instead of intermediate 10-2. Compound 14: 1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.56 – 7.51 (m, 1H), 7.51 – 7.45 (m, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 5.1 Hz, 1H), 4.38 – 4.34 (m, 1H), 4.34 – 4.25 (m, 2H), 4.24 – 4.14 (m, 1H), 4.14 – 4.04 (m, 1H), 4.02 – 3.95 (m, 2H), 3.62 (dd, J = 9.8, 5.6 Hz, 1H), 3.56 (dd, J = 9.8, 6.7 Hz, 1H), 3.52 – 3.42 (m, 2H), 1.62 – 1.50 (m, 2H), 1.42 – 1.19 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 843.4 [M−H]−. Compound 15: 1H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.84 – 7.79 (m, 2H), 7.79 – 7.73 (m, 2H), 7.28 – 7.12 (m, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.42 – 3.91 (m, 7H), 3.90 – 3.32 (m, 4H), 1.78 – 1.03 (m, 32H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 825.4 [M−H]−. Intermediate 16-1: (S)-3-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzonitrile:
Figure imgf000161_0001
Sodium tert-butoxide solution (2.0 M in tetrahydrofuran, 177 μL, 350 μmol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 1-2 (105 mg, 305 μmol), 3-bromobenzonitrile (55.5 mg, 305 μmol), and [(2-di-cyclohexylphosphino-3,6-dimethoxy- 2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-methylamino-1,1' -biphenyl)]palladium(II) methanesulfonate (15.9 mg, 17.3 μmol) in 1,4-dioxane (1.3 mL) at 50 °C, and the resulting mixture was heated to 100 °C. After 35 min, the resulting mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (50 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 28% ethyl acetate in dichloromethane) to give intermediate 16-1. LCMS: 445.4. Example 16: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyanophenyl)amino)-3-(octadecyloxy)propyl) hydrogen phosphate (16):
Figure imgf000162_0001
Compound 16 was synthesized in a manner similar to compound 10 using intermediate 16-1 instead of intermediate 10-2.1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.24 – 7.16 (m, 2H), 6.95 – 6.87 (m, 2H), 6.85 (dt, J = 7.5, 1.1 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.42 – 4.32 (m, 1H), 4.25 (t, J = 5.5 Hz, 1H), 4.19 (ddd, J = 11.6, 5.2, 3.1 Hz, 1H), 4.07 (dt, J = 11.8, 4.8 Hz, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.77 – 3.66 (m, 1H), 3.55 – 3.42 (m, 4H), 1.64 – 1.47 (m, 2H), 1.41 – 1.23 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 796.4 [M−H]−. Intermediate 17-1: (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl benzoate:
Figure imgf000162_0002
Benzoyl chloride (38.0 μL, 327 μmol) was added via syringe to a stirred mixture of (R)- 1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (137 mg, 297 μmol), triethylamine (124 μL, 892 μmol), 4-(dimethylamino)pyridine (7.3 mg, 60 μmol), and dichloromethane (1.2 mL) at room temperature. After 40 min, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 8% ethyl acetate in hexanes) to give intermediate 17-1. LCMS: 585.4 [M+Na]+. Intermediate 17-2: (S)-1-hydroxy-3-(octadecyloxy)propan-2-yl benzoate:
Figure imgf000163_0001
Triethylamine trihydrofluoride (485 μL, 2.97 mmol) was added via syringe to a vigorously stirred solution of intermediate 17-2 (72.2 mg, 128 μmol) in tetrahydrofuran (2.0 mL) at room temperature. After 14 h, diethyl ether (40 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed sequentially with water (2 × 40 mL) and a mixture of saturated aqueous sodium bicarbonate and brine (5:1 v:v, 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 35% ethyl acetate in hexanes) to give intermediate 17-2. LCMS: 471.4 [M+Na]+. Example 17: (2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl benzoate (17):
Figure imgf000163_0002
Compound 17 was synthesized in a manner similar to compound 5 using intermediate 17-2 instead of intermediate 5-3.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 8.04 – 7.98 (m, 2H), 7.62 – 7.55 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.37 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 5.38 – 5.24 (m, 1H), 4.72 (d, J = 5.2 Hz, 1H), 4.41 – 4.32 (m, 1H), 4.32 – 4.22 (m, 1H), 4.23 – 4.08 (m, 4H), 3.76 – 3.66 (m, 2H), 3.57 – 3.40 (m, 2H), 1.58 – 1.46 (m, 2H), 1.41 – 1.16 (m, 30H), 0.99 – 0.80 (m, 3H). LCMS: 800.4 [M−H]−. Intermediate 18-1: (R)-1-(octadecyloxy)-3-phenoxypropan-2-ol:
Figure imgf000164_0001
Triphenylphosphane (80.0 mg, 0.305 mmol) was added to a 0 °C chilled solution of (R)- 1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (109 mg, 0.237 mmol), phenol (41.0 mg, 0.436 mmol), and diisopropyl azodicarboxylate (0.0750 mL, 0.359 mmol) in tetrahydrofuran (2 mL) THF. The reaction mixture was allowed to gradually warm to room temperature and stirred for 24 hours and which point solvent was removed under reduced pressure and crude product absorbed onto silica gel which was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to afford (S)-tert- butyldimethyl(3-(octadecyloxy)-2-phenoxypropoxy)silane.1H NMR (400 MHz, Chloroform-d) δ 7.33 – 7.22 (m, 2H), 7.03 – 6.90 (m, 3H), 4.43 (q, J = 5.1 Hz, 1H), 3.89 – 3.79 (m, 2H), 3.67 (qd, J = 10.4, 4.9 Hz, 2H), 3.49 (td, J = 6.5, 1.9 Hz, 2H), 1.63 – 1.53 (m, 2H), 1.27 (s, 30H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). A 1 M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (0.500 mL, 0.500 mmol) was added to a solution of (S)-tert-butyldimethyl(3-(octadecyloxy)-2- phenoxypropoxy)silane (84.0 mg, 0.157 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred for one hour at which point the reaction mixture was diluted with ethyl acetate and washed sequentially with 3*water followed by a saturated aqueous sodium chloride solution. The organic phase was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to afford intermediate 18-1.1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.17 (m, 2H), 7.12 – 6.94 (m, 3H), 4.50 (dq, J = 6.2, 4.7 Hz, 1H), 3.92 (qd, J = 11.8, 4.7 Hz, 2H), 3.79 – 3.62 (m, 2H), 3.49 (td, J = 6.6, 1.3 Hz, 2H), 1.59 (q, J = 6.9 Hz, 2H), 1.28 (s, 30H), 0.93 – 0.87 (m, 3H). Intermediate 18-2: (R)-bis(4-nitrophenyl) (1-(octadecyloxy)-3-phenoxypropan-2-yl) phosphate:
Figure imgf000165_0001
Triethylamine (25 μL, 18 μmol) was added via syringe to a stirred mixture of intermediate 18-1 (31 mg, 73.7 μmol), 4-nitrophenyl phosphorodichloridate (46.8 mg, 18.3 μmol), and dichloromethane (2.0 mL) at 0 °C. After 60 min, the resulting mixture was warmed to room temperature. After 30 min, 4-nitrophenyl phosphorodichloridate (27.0 mg, 105 μmol) and triethylamine (20.0 μL, 143 μmol) were added sequentially. After 30 min, 4-nitrophenol (56 mg, 0.43 mmol) and triethylamine (50 μL, 0.36 mmol) were added sequentially. After 18 h, diethyl ether (60 mL) and aqueous citric acid solution (10% wt, 10 mL) were added sequentially. The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to give intermediate 18-2.1H NMR (400 MHz, Chloroform-d) δ 8.21 (dd, J = 9.0, 1.4 Hz, 4H), 7.36 (dt, J = 9.1, 1.4 Hz, 4H), 7.32 – 7.22 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.89 – 6.83 (m, 2H), 4.71 – 4.54 (m, 3H), 3.67 (dd, J = 10.2, 4.0 Hz, 1H), 3.59 (dd, J = 10.2, 6.2 Hz, 1H), 3.45 (t, J = 6.6 Hz, 2H), 1.55 (t, J = 6.9 Hz, 2H), 1.27 (d, J = 2.9 Hz, 30H), 0.97 – 0.85 (m, 3H). Intermediate 18-3: ((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 (4-nitrophenyl) ((R)-1- (octadecyloxy)-3-phenoxypropan-2-yl) phosphate:
Figure imgf000166_0001
A vigorously stirred mixture of intermediate 18-2 (23 mg, 31 μmol), intermediate 1-4 (11.3 mg, 34 μmol), magnesium chloride (17 mg, 0.18 mmol), and tetrahydrofuran (1 mL) was stirred at room temperature. After 30 min, N,N-diisopropylethylamine (30 μL, 0.17 mmol) was added. After 18 h, the resulting mixture was adsorbed under reduced pressure onto silica gel and purified by flash column chromatography on silica gel (0 to 4% methanol in dichloromethane) to give intermediate 18-3.1H NMR (400 MHz, Acetonitrile-d3) δ 8.10 – 7.99 (m, 2H), 7.89 (s, 1H), 7.32 – 7.15 (m, 4H), 7.04 – 6.84 (m, 4H), 6.74 (dd, J = 14.7, 4.6 Hz, 1H), 5.38 (dd, J = 14.6, 6.6 Hz, 1H), 4.95 (ddd, J = 14.3, 6.6, 3.6 Hz, 1H), 4.60 (ddd, J = 10.1, 6.9, 4.2 Hz, 2H), 4.45 – 4.22 (m, 4H), 3.56 (dd, J = 5.1, 3.8 Hz, 2H), 3.41 (td, J = 6.5, 2.5 Hz, 2H), 1.70 (d, J = 1.2 Hz, 3H), 1.49 (t, J = 6.7 Hz, 2H), 1.39 (d, J = 2.4 Hz, 3H), 1.28 (d, J = 9.9 Hz, 30H), 0.93 – 0.83 (m, 3H). Example 18: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-(octadecyloxy)-3-phenoxypropan-2-yl) hydrogen phosphate (18):
Figure imgf000167_0001
Aqueous sodium hydroxide solution (2.0 M, 60 μL, 120 μmol) was added via syringe to a vigorously stirred solution of intermediate 18-3 (11 mg, 11.8 μmol) in tetrahydrofuran (1 mL) at room temperature, and the resulting mixture was heated to 50 °C. After 4.5 h the resulting mixture was cooled to room temperature. Concentrated aqueous hydrogen chloride solution (12 M) was added dropwise until a pH of 1 was achieved. This solution was stirred at room temperature for 18 hours at which point pH was raised to ~8 by dropwise addition of triethylamine and the reaction mixture then partitioned between a pH 3.5 phosphate buffer and 3:22-methyltetrahydrofuran:ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, concentrated under reduced pressured, and purified by reverse phase preparative HPLC (methanol/water + 0.1% trifluoroacetic acid) to give compound 18.1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.29 – 7.13 (m, 5H), 6.96 (d, J = 7.9 Hz, 2H), 4.80 (d, J = 4.7 Hz, 1H), 4.56 (d, J = 7.4 Hz, 1H), 4.35 (s, 1H), 4.27 (d, J = 6.0 Hz, 1H), 4.05 (dd, J = 51.4, 17.4 Hz, 4H), 3.79 – 3.52 (m, 4H), 3.52 – 3.40 (m, 3H), 1.53 (s, 2H), 1.29 (d, J = 9.6 Hz, 35H), 0.92 (t, J = 6.6 Hz, 4H). LCMS: 774.1. Intermediate 19-1: 3-(Hexadecylthio)propan-1-ol:
Figure imgf000167_0002
To a solution of 3-mercapto-1-propanol (829 mg, 9 mmol) and 1-bromohexadecane (916 mg, 3 mmol) in DMSO (3 mL) and THF (3 mL) was added KOH powder (673 mg, 12 mol) at rt. The mixture was stirred at room temperature overnight. After cooling, the mixture was poured into ice-water and extracted with DCM. The extracts were concentrated, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide a product as a solid. Intermediate 19-2: ((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-chlorophenyl) (3- (hexadecylthio)propyl) phosphate:
Figure imgf000168_0001
To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31 mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, 3-(hexadecylthio)propan-1-ol (75 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford the compound. Example 19: ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (3-(hexadecylthio)propyl) hydrogen phosphate (19):
Figure imgf000169_0002
1,1,3,3-Tetramethylguanidine (156 mg, 1.35 mmol) and syn-2-pyridinealdoxime (275 g, 2.25 mmol) in THF (2 mL) were added to a solution of the 19-2 (185 mg, 0.225 mmol) in THF (4 mL) and stirred at room temperature overnight. The reaction was concentrated in vacuo, the residue was purified by flash chromatography with 0-50% MeOH in DCM to give an intermediate. The above intermediate was dissolved in THF (1.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.3 mL) was added. The cold bath was removed the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The solution was purified silica gel column chromatography with (0-40% MeOH in DCM) to give the product.1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 4.20 – 3.98 (m, 2H), 3.91 – 3.79 (m, 2H), 2.47 (m, 4H), 1.84 – 1.70 (m, 2H), 1.52 (m, 2H), 1.29 (d, J = 3.6 Hz, 28H), 0.98 – 0.83 (m, 3H).31P NMR (162 MHz, Methanol-d4) δ -0.43. MS: 670.19 (M+1). Intermediate 20-1: 2-(hexadecyloxy)ethan-1-ol:
Figure imgf000169_0001
To a solution of ethylene glycol (838 mg, 13.5 mmol) in dry DMF (6 mL) was added NaH (60% oil dispersion 172 mg, 4.5 mmol) in installments at 0 °C and the mixture was stirred at room temperature for 10 min.1-bromohexadecane (916 mg, 3 mmol) and KI (498 mg, 3 mmol) were added and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice-water and extracted with DCM. The extracts were combined, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide a product as a solid. 1H NMR (400 MHz, Chloroform-d) δ 3.75 (dd, J = 5.2, 4.0 Hz, 2H), 3.62 – 3.53 (m, 2H), 3.49 (t, J = 6.7 Hz, 2H), 1.81 (s, 2H), 1.67 – 1.54 (m, 2H), 1.28 (s, 28H), 0.90 (t, J = 6.7 Hz, 3H). Intermediate 20-2: ((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-chlorophenyl) (2- (hexadecyloxy)ethyl) phosphate:
Figure imgf000170_0001
Intermediate 20-2 was synthesized in a manner similar to 19-2 using intermediate 2- (hexadecyloxy)ethan-1-ol. Example 20: ((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-(hexadecyloxy)ethyl) hydrogen phosphate (20):
Figure imgf000170_0002
Compound 20 was synthesized in a manner similar to compound 19.1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 4.75 (s, 1H), 4.49 – 4.00 (m, 6H), 3.64 (s, 2H), 3.49 (m, 2H), 1.57 (m, 2H), 1.47 – 1.15 (m, 26H), 0.91 (t, J = 6.6 Hz, 3H).31P NMR (162 MHz, Methanol-d4) δ -0.93. MS: 640.25 (M+1). Intermediate 21-1: ((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-chlorophenyl) (2- (hexadecyloxy)ethyl) phosphate:
Figure imgf000171_0001
Intermediate 21-1 was synthesized in a manner similar to 19-2 using intermediate 2- (octadecyloxy)ethan-1-ol. Example 21: ((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-(octadecyloxy)ethyl) hydrogen phosphate (21):
Figure imgf000171_0002
Compound 21 was synthesized in a manner similar to compound 19.1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 4.77 (m, 1H), 4.38 (t, J = 4.6 Hz, 1H), 4.33 – 4.14 (m, 3H), 4.09 – 3.99 (m, 2H), 3.61 (m, 2H), 3.48 (m, 2H), 1.55 (m, 2H), 1.40 – 1.18 (m, 30H), 0.98 – 0.84 (m, 3H). 31P NMR (162 MHz, Methanol-d4) δ - 0.24. MS: 668.25 (M+1). Intermediate 22-1: (R)-1-(Benzyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2-ol:
Figure imgf000172_0001
A solution of tert-butyldiphenylsilyl chloride (3.59 g, 13.1 mmol) in anhydrous DMF (7 mL) was added to a stirred mixture of imidazole (897 mg, 13.2 mmol) and 1-O-benzylglycerol 1 (2 g, 11 mmol) in dry DMF (10 mL). Then the mixture was stirred at rt overnight. Water was added into the mixture which was then extracted with EtOAc. The organic phase was combined, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-50 EtOAc in hexanes) to afford a product as colorless oil. Intermediate 22-2: (R)-(3-(Benzyloxy)-2-(octadecyloxy)propoxy)(tert-butyl)diphenylsilane:
Figure imgf000172_0002
NaH (60% oil dispersion, 88 mg, 2.29 mmol) was suspended in THF (6 ml) and cooled to 0 C. A solution of 1-O-Octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (275 mg, 0.654 mmol) in THF (2.5 ml) was added over 30 seconds. After 30 min at 0 oC a solution of 1- bromooctadecane (872 mg, 2.62 mmol) in THF (2.5 ml) was added. The mixture was heated at reflux for 12 h. Then, the reaction was quenched with water (15 ml). The mixture was extracted with EtOAc. The combined organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-60% EtOAc in hexanes) to give the product. Intermediate 22-3: (S)-3-(Benzyloxy)-2-(octadecyloxy)propan-1-ol:
Figure imgf000173_0002
Intermediate 22-2 (96 mg, 0.143 mmol) obtained in the previous step was dissolved in 1 mL THF, 1 N TBAF solution in THF (1 N, 0.214 mL, 0.214 mmol) was added. The reaction mixture was stirred at ambient temperature for 5 hours. Then water (2.5 mL) was added, the resultant mixture was extracted with EtOAc (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0-60% EtOAc in hexanes) to give the product. Intermediate 22-4: ((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 ((R)-3-(benzyloxy)-2- (octadecyloxy)propyl) (2-chlorophenyl) phosphate:
Figure imgf000173_0001
Intermediate 22-4 was synthesized in a manner similar to 19-2 using intermediate 22-3. Example 22: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(octadecyloxy)propyl) hydrogen phosphate (22):
Figure imgf000174_0001
Intermediate 22-4 (111 mg, 0.118 mmol) was dissolved in THF (2.5 mL) and 0.5 N NaOH (0.9 mL) was added at 0 oC. The mixture was stirred at 50 oC for 2.5 h. The mixture was neutralized with 2 N HCl at 0 °C. The mixture was diluted with methanol and Na2SO4 was added. The mixture was filtered and the filtrate was evaporated to give a residue. The residue was dissolved in THF (0.5 mL). The resulting solution was cooled in an ice bath. Concentrated aqueous HCl (0.1 mL) was added. The cold bath was removed the reaction was stirred vigorously for 3 h. The mixture was neutralized with Na2CO3, diluted with MeOH, and filtered. The filtrate was evaporated to give a residue which was purified by silica gel column chromatography (0-40% MeOH in DCM) to give the product. 1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.36 – 7.20 (m, 5H), 6.98 (d, J = 4.6 Hz, 1H), 6.92 (d, J = 4.7 Hz, 1H), 4.50 (s, 2H), 4.36 (m, 1H), 4.25 (m, 1H), 4.11 (m, 2H), 3.95 – 3.81 (m, 2H), 3.68 – 3.43 (m, 4H), 1.50 (m, 2H), 1.28 (d, 30H), 0.98 – 0.85 (m, 3H). 31P NMR (162 MHz, Methanol-d4) δ -0.49. Intermediate 23-1: (R)-(3-(benzyloxy)-2-(hexadecyloxy)propoxy)(tert-butyl)diphenylsilane:
Figure imgf000175_0003
Intermediate 23-1 was synthesized in a manner similar to 22-2 using 1-bromohexadecane as alkylation reagent. Intermediate 23-2: (S)-3-(Benzyloxy)-2-(hexadecyloxy)propan-1-ol:
Figure imgf000175_0001
Intermediate 23-2 was synthesized in a manner similar to 22-3 using intermediate 23-1. Intermediate 23-3: ((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 ((R)-3-(benzyloxy)-2- (hexadecyloxy)propyl) (2-chlorophenyl) phosphate:
Figure imgf000175_0002
Intermediate 23-3 was synthesized in a manner similar to intermediate 19-2 using intermediate 23-2. Example 23: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(hexadecyloxy)propyl) hydrogen phosphate (23):
Figure imgf000176_0001
Compound 23 was synthesized in a manner similar to compound 22. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 10.2 Hz, 1H), 7.41 (m, 1H), 7.36 – 7.09 (m, 6H), 4.74 (m, 1H), 4.53 (m, 1H), 4.38 (s, 1H), 4.19 (m, 2H), 4.12 – 3.86 (m, 1H), 3.76 – 3.48 (m, 2H), 1.68 – 1.47 (m, 2H), 1.45 – 1.19 (m, 26H), 0.92 (t, J = 6.7 Hz, 3H).31P NMR (162 MHz, Methanol-d4) δ -0.35. Intermediate 24-1: (R)-(3-(Benzyloxy)-2-(tetradecyloxy)propoxy)(tert-butyl)diphenylsilane:
Figure imgf000176_0002
Intermediate 24-1 was synthesized in a manner similar to 22-2 using 1-bromotetradecane as alkylation reagent. Intermediate 24-2: (S)-3-(benzyloxy)-2-(hexadecyloxy)propan-1-ol:
Figure imgf000177_0003
Intermediate 24-2 was synthesized in a manner similar to 19-2 using intermediate 24-1. Intermediate 24-3: ((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 ((R)-3-(benzyloxy)-2- (tetradecyloxy)propyl) (2-chlorophenyl) phosphate:
Figure imgf000177_0001
Intermediate 24-3 was synthesized in a manner similar to 19-2 using intermediate 24-2. Example 24: ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-3-(benzyloxy)-2-(tetradecyloxy)propyl) hydrogen phosphate (24):
Figure imgf000177_0002
Compound 24 was synthesized in a manner similar to compound 22.1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.37 – 7.17 (m, 5H), 7.03 (t, J = 4.2 Hz, 1H), 7.00 – 6.94 (m, 1H), 4.50 (s, 2H), 4.36 (m, 1H), 4.25 (m, 1H), 4.12 (m, 2H), 3.89 (m, 1H), 3.72 – 3.45 (m, 3H), 1.50 (m, 2H), 1.28 (d, 22H), 0.91 (t, J = 6.2 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) δ - 0.38. Intermediate 25-1: Preparation of 3-nonoxypropan-1-ol:
Figure imgf000178_0001
To a solution of 1,3-propanediol (1.03 g, 13.5 mmol) in dry DMF (6 mL) was added NaH (60% oil dispersion; 172 mg, 4.5 mmol) in installments at 0 °C and the mixture was stirred at room temperature for 10 min.1-bromononane (621 mg, 3 mmol) and KI (498 mg, 3 mmol) were added and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice-water and extracted with AcOEt. The extracts were washed with brine, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide the product.1H NMR (400 MHz, DMSO-d6) δ 4.36 (t, J = 5.2 Hz, 1H), 3.51 – 3.36 (m, 5H), 1.63 (m, 2H), 1.47 (m, 2H), 1.26 (d, 14H), 0.91 – 0.79 (m, 3H). Intermediate 25-2: ((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-chlorophenyl) (3-(nonyloxy)propyl) phosphate:
Figure imgf000178_0002
Intermediate 25-2 was synthesized in a manner similar to 19-2 using intermediate 3- (nonyloxy)propan-1-ol. Example 25: ((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl (3-(nonyloxy)propyl) hydrogen phosphate (25):
Figure imgf000179_0001
Compound 25 was synthesized in a manner similar to compound 19.1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.32 (d, J = 4.7 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.38 (m, 1H), 4.31 – 4.19 (m, 2H), 4.18 – 4.06 (m, 1H), 3.98 (m, 2H), 3.51 (m, 2H), 3.41 (m, 2H), 1.87 (m, 2H), 1.53 (m, 2H), 1.42 – 1.17 (m, 12H), 0.91 (t, J = 6.7 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) δ 0.22. MS: 556.11 (M+1). Intermediate 26-1: ((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-chlorophenyl) (2-(octyloxy)ethyl) phosphate:
Figure imgf000179_0002
Intermediate 26-1 was synthesized in a manner similar to 19-2 using intermediate 2- (octyloxy)ethan-1-ol. MS: 568.17 (M+1). Example 26: ((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-(octyloxy)ethyl) hydrogen phosphate (26):
Figure imgf000180_0001
Compound 26 was synthesized in a manner similar to compound 19.1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 4.78 (d, J = 5.3 Hz, 1H), 4.43 – 4.31 (m, 1H), 4.25 (mz, 2H), 4.15 (m, 1H), 4.05 – 3.95 (m, 2H), 3.65 – 3.56 (m, 2H), 3.47 (m, 2H), 3.33 (m, 2H), 1.62 – 1.48 (m, 2H), 1.29 (d, 10H), 0.94 – 0.81 (m, 3H).31P NMR (162 MHz, Methanol-d4) δ 0.13. MS: 528.07 (M+1). Intermediate 27-1: ((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-chlorophenyl) (2- (undecyloxy)ethyl) phosphate:
Figure imgf000180_0002
Intermediate 27-1 was synthesized in a manner similar to 19-2 using intermediate 2- (undecyloxy)ethan-1-ol. Example 27: ((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-(undecyloxy)ethyl) hydrogen phosphate (27):
Figure imgf000181_0001
Compound 27 was synthesized in a manner similar to compound 19.1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 4.79 (d, J = 5.2 Hz, 1H), 4.37 (m, 1H), 4.30 – 4.20 (m, 2H), 4.13 (m, 1H), 3.99 (m, 2H), 3.63 – 3.55 (m, 2H), 3.46 (m, 2H), 3.33 (m, 4H), 1.54 (m, 2H), 1.28 (s, 16H), 0.96 – 0.86 (m, 3H). 31P NMR (162 MHz, Methanol-d4) δ 0.17 (t, J = 6.3 Hz). MS: 570.16 (M+1). Example 28: O-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl) O-((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) S- hydrogen (R)-phosphorothioate (28):
Figure imgf000181_0002
1,8-Diazabicyclo[5.4.0]undec-7-ene (12.8 µL, 85.5 µmol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 6-1 (24.7 mg, 3.02 mmol), (2S)-2- benzyloxy-3-octadecoxy-propan-1-ol (37.2 mg, 85.5 µmol), and tetrahydrofuran (0.5 mL) at room temperature. After 30 min, concentrated hydrochloric acid (0.18 mL) was added. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 28.1H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.39 – 7.18 (m, 5H), 6.98 – 6.90 (m, 2H), 4.95 (t, J = 4.1 Hz, 1H), 4.79 (d, J = 2.8 Hz, 1H), 4.60 (s, 1H), 4.50 – 4.30 (m, 2H), 4.29 – 4.14 (m, 1H), 3.84 – 3.75 (m, 1H), 3.55 – 3.48 (m, 3H), 3.45 – 3.37 (m, 3H), 3.20 – 3.13 (m, 1H), 1.52 (s, 2H), 1.29 (d, J = 8.3 Hz, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 802.4. Intermediate 29-1: (R)-2-((1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-yl)oxy)- 5-methylisophthalonitrile:
Figure imgf000182_0001
Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 490 μL, 490 μmol) was added via syringe to a stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3- (octadecyloxy)propan-2-ol (150 mg, 327 μmol) in tetrahydrofuran (0.5 mL) at 0 °C. After 5 min, a solution of 5-(iodomethyl)isophthalonitrile (437 mg, 1.63 mmol) in tetrahydrofuran (2.0 mL) was added via syringe, and the resulting mixture was warmed to room temperature. After 16 h, saturated aqueous ammonium chloride solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 ml), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to give intermediate 29-1. LCMS: 621.5 [M+Na]+. Intermediate 29-2: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-5- methylisophthalonitrile:
Figure imgf000183_0001
Intermediate 29-2 was synthesized in a manner similar to intermediate 2-2 using intermediate 29-1 instead of intermediate 2-1. LCMS: 507.4 [M+Na]+. Intermediate 29-3: ((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-chlorophenyl) ((R)-2-(2,6-dicyano- 4-methylphenoxy)-3-(octadecyloxy)propyl) phosphate:
Figure imgf000183_0002
Intermediate 29-3 and intermediate 26-3 was synthesized in a manner similar to intermediate 23-2 using intermediate 29-2 instead of intermediate 23-1. LCMS: 988.4. Example 29: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(2,6-dicyano-4-methylphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (29):
Figure imgf000184_0001
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 300 μL, 300 μmol) was added via syringe to a vigorously stirred mixture of intermediate 29-3 (23.6 mg, 23.9 μmol), 4-(dimethylamino)pyridine (29.2 mg, 239 μmol), water (45.0 μL, 2.50 mmol), and tetrahydrofuran (0.1 mL) at room temperature. After 82 min, chlorotrimethylsilane (38.2 μL, 301 μmol) and concentrated hydrochloric acid (300 μL, 3.60 mmol) were added sequentially. After 140 min, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 29.1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.90 – 7.70 (m, 2H), 7.32 – 7.23 (m, 1H), 7.21 – 7.12 (m, 1H), 5.00 – 4.62 (m, 3H), 4.57 – 3.40 (m, 9H), 2.37 (s, 3H), 1.56 – 1.04 (m, 32H), 0.92 (t, J = 6.6 Hz, 3H). LCMS: 836.4 [M−H]−.
Intermediate 30-1: (S)-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)benzamide:
Figure imgf000185_0001
Benzoyl chloride (10.1 μL, 87.3 μmol) was added via syringe to a vigorously stirred mixture of intermediate 1-2 (30.0 mg, 87.3 μmol), triethylamine (36.5 μL, 262 μmol), and dichloromethane (0.8 mL) at room temperature. After 30 min, the resulting mixture was purified by flash column chromatography on silica gel (0 to 65% ethyl acetate in hexanes) to give intermediate 30-1. LCMS: 470.4 [M+Na]+. Example 30: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-benzamido-3-(octadecyloxy)propyl) hydrogen phosphate (30):
Figure imgf000185_0002
Compound 30 was synthesized in a manner similar to compound 6 using intermediate 30-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.89 – 7.83 (m, 2H), 7.56 – 7.49 (m, 1H), 7.45 (dd, J = 8.3, 6.7 Hz, 2H), 7.28 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.7 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.38 – 4.29 (m, 2H), 4.26 (t, J = 5.3 Hz, 1H), 4.16 (dt, J = 8.2, 4.0 Hz, 1H), 4.12 – 4.04 (m, 1H), 4.00 (t, J = 5.6 Hz, 2H), 3.62 – 3.25 (m, 4H), 1.61 – 1.49 (m, 2H), 1.41 – 1.20 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 799.4 [M−H]−. Intermediate 31-1: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzoic acid:
Figure imgf000186_0001
Potassium phosphate (48.2 mg, 227 μmol) was added to a vigorously stirred mixture of intermediate 1-2 (30.0 mg, 87.3 μmol), copper(I) iodide (5.0 mg, 26 μmol), 2-bromobenzoic acid (17.6 mg, 87.3 μmol), (±)-1,1′-binaphthalene-2,2′-diol (15.0 mg, 52.4 μmol), and N,N- dimethylformamide (0.6 mL) at room temperature. After 21 h, the resulting mixture was heated to 100 °C. After 150 min, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous citric acid solution (10% wt, 10 mL) were added sequentially, The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 55% ethyl acetate in hexanes) to give intermediate 31-1. LCMS: 462.4 [M−H]−. Example 31: 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)amino)benzoic acid (31):
Figure imgf000187_0001
Compound 31 was synthesized in a manner similar to compound 6 using intermediate 31-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.85 (dd, J = 8.0, 1.7 Hz, 1H), 7.31 – 7.22 (m, 1H), 7.15 – 7.00 (m, 2H), 6.79 (d, J = 8.6 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 4.82 (d, J = 5.2 Hz, 1H), 4.42 – 4.33 (m, 1H), 4.29 (t, J = 5.3 Hz, 1H), 4.25 – 4.14 (m, 1H), 4.14 – 4.04 (m, 1H), 4.03 – 3.95 (m, 1H), 3.95 – 3.77 (m, 2H), 3.64 (dd, J = 9.6, 4.4 Hz, 1H), 3.57 (dd, J = 9.8, 4.8 Hz, 1H), 3.46 (t, J = 6.5 Hz, 2H), 1.61 – 1.50 (m, 2H), 1.41 – 1.22 (m, 30H), 0.95 – 0.87 (m, 3H). LCMS: 815.4 [M−H]−.
Intermediate 32-1: (R)-(2-((3-bromo-5-fluorobenzyl)oxy)-3-(octadecyloxy)propoxy)(tert- butyl)dimethylsilane: Intermediate 33-1: (R)-((1-((3-bromo-5-fluorobenzyl)oxy)-3-(octadecyloxy)propan-2- yl)oxy)(tert-butyl)dimethylsilane:
Figure imgf000188_0001
Sodium hydride (60% wt dispersion in mineral oil, 109 mg, 2.7 mmol) was added to a vigorously stirred solution of (R)-1-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propan-2-ol (500 mg, 1.09 mmol) in tetrahydrofuran (3.0 mL) at 0 °C. After 30 min, 1-bromo-3- (bromomethyl)-5-fluorobenzene (438 mg, 1.63 mmol) was added, and the resulting mixture was warmed to room temperature. After 9.5 h, saturated aqueous ammonium chloride solution (6 mL), water (6 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 8% ethyl acetate in hexanes) to give a mixture of intermediate 32-1 and intermediate 33-1. LCMS: 667.4 [M+Na]+. Intermediate 32-2: (S)-2-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propan-1- ol: Intermediate 33-2: (R)-1-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3-(octadecyloxy)propan-2- ol:
Figure imgf000189_0001
Sodium methanesulfinate (47.4 mg, 465 μmol) was added to a vigorously stirred mixture of intermediate 69-1 (200 mg, 310 μmol), (±)-trans-1,2-diaminocyclohexane (14.9 μL, 124 μmol), copper(I) trifluoromethanesulfonate benzene complex (9.0 mg, 31 μmol), tetrahydrofuran (0.2 mL), and dimethylsulfoxide (1.0 mL) at room temperature, and the resulting mixture was heated to 110 °C. After 17 h, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous ammonia solution (30% wt, 10 mL) were added sequentially. The organic layer was washed with water (2 × 30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.5 mL), and the resulting mixture was stirred at room temperature. Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 929 μL, 930 μmol) was added via syringe. After 30 min, saturated aqueous ammonium chloride solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to give intermediate 32-2 and intermediate 33-2. Intermediate 32-2: LCMS: 531.3. Intermediate 33-2: LCMS: 531.3. Example 32: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (32):
Figure imgf000190_0001
Compound 32 was synthesized in a manner similar to compound 6 using intermediate 32-2 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.56 (dt, J = 7.9, 2.0 Hz, 1H), 7.51 (dt, J = 9.3, 1.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 4.84 (d, J = 13.3 Hz, 1H), 4.78 (d, J = 13.2 Hz, 1H), 4.74 (d, J = 5.2 Hz, 1H), 4.42 – 4.33 (m, 1H), 4.30 – 4.19 (m, 2H), 4.19 – 4.05 (m, 2H), 4.05 – 3.96 (m, 1H), 3.89 – 3.79 (m, 1H), 3.64 – 3.52 (m, 2H), 3.47 (td, J = 6.6, 2.1 Hz, 2H), 3.14 (s, 3H), 1.63 – 1.50 (m, 2H), 1.41 – 1.21 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 882.4 [M−H]−.
Example 33: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((3-fluoro-5-(methylsulfonyl)benzyl)oxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (33):
Figure imgf000191_0001
Compound 33 was synthesized in a manner similar to compound 6 using intermediate 33-2 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.71 (s, 1H), 7.67 – 7.44 (m, 2H), 7.33 – 7.22 (m, 1H), 7.21 – 7.15 (m, 1H), 5.37 – 5.32 (m, 1H), 4.95 – 4.68 (m, 3H), 4.41 – 3.73 (m, 6H), 3.72 – 3.37 (m, 4H), 3.13 (s, 3H), 1.76 – 1.40 (m, 2H), 1.37 – 1.19 (m, 30H), 1.01 – 0.83 (m, 3H). LCMS: 882.4 [M−H]−. Intermediate 34-1: (S)-4-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-2,6- dimethoxybenzonitrile:
Figure imgf000191_0002
Sodium hydride (60% wt dispersion in mineral oil, 68.1 mg, 1.70 mmol) was added to a vigorously stirred solution of (R)-1-(octadecyloxy)-3-(trityloxy)propan-2-ol (WO2010052718) (400 mg, 682 μmol) in tetrahydrofuran (2.0 mL) at room temperature. After 23 min, 4-chloro- 2,6-dimethoxybenzonitrile (Li, W; Sun, P. J. Org. Chem.2012, 77, 8362) (202 mg, 1.02 mmol) and N,N-dimethylformamide (3.0 mL) were added sequentially, and the resulting mixture was heated to 90 ° C. After 31 min, the resulting mixture was cooled to room temperature. After 30 min, 2-propanol (3.0 mL), methanol (3.0 mL), and concentrated hydrochloric acid (0.6 mL) were added sequentially, and the resulting mixture was heated to 50 ° C. After 120 min, the resulting mixture was cooled to room temperature. Saturated aqueous sodium bicarbonate solution (30 mL), diethyl ether (100 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 80 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 45% ethyl acetate in hexanes) to give intermediate 34-1. LCMS: 506.4. Intermediate 34-2: ((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-chlorophenyl) ((R)-2-(4-cyano-3,5- dimethoxyphenoxy)-3-(octadecyloxy)propyl) phosphate:
Figure imgf000192_0001
2-Chlorophenyl phosphorodichloridate (625 μL, 3.80 mmol) was added over 1 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (557 mg, 8.07 mmol), triethylamine (1.12 mL, 8.07 mmol), pyridine (1.0 mL), and acetonitrile (2.5 mL) at room temperature. After 25 min, a mixture of intermediate 34-1 (1.20 g, 2.37 mmol), pyridine (5.0 mL), and acetonitrile (1.5 mL) was added via syringe. After 76 min, intermediate 1-4 (1.89 g, 5.69 mmol), 1- methylimidazole (567 μL, 7.12 mmol), and acetonitrile (2.0 mL) were added sequentially. After 410 min, a solution of citric acid (6.0 g) in water (80 mL) was added, and the aqueous layer was extracted with ethyl acetate (120 mL). The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane) to give intermediate 34-2. LCMS: 1009.5. Example 34: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(4-cyano-3,5-dimethoxyphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (34):
Figure imgf000193_0001
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 3.00 mL, 3.0 mmol) was added via syringe to a stirred mixture of intermediate 34-2 (2.02 g, 2.00 mmol), 4- (dimethylamino)pyridine (733 mg, 6.00 mmol), tetrahydrofuran (1.5 mL), and water (541 μL, 30.0 mmol) at room temperature, and the resulting mixture was heated to 50 °C. After 18 min, the resulting mixture was cooled to room temperature, and chlorotrimethylsilane (381 μL, 3.00 mmol) and concentrated hydrochloric acid (4.80 mL, 58 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 34.1H NMR (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.34 (s, 2H), 4.87 – 4.79 (m, 1H), 4.70 (d, J = 5.3 Hz, 1H), 4.37 (dq, J = 4.5, 2.5 Hz, 1H), 4.27 (ddd, J = 11.6, 5.7, 3.0 Hz, 1H), 4.21 – 4.10 (m, 4H), 3.88 (s, 6H), 3.72 (dd, J = 10.8, 4.0 Hz, 1H), 3.66 (dd, J = 10.8, 5.8 Hz, 1H), 3.56 – 3.41 (m, 2H), 1.60 – 1.48 (m, 2H), 1.39 – 1.23 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 857.4 [M−H]−. Intermediate 35-1: (R)-1-((tert-butyldiphenylsilyl)oxy)henicosan-2-ol:
Figure imgf000194_0001
To a mixture of tert-butyl-[[(2R)-oxiran-2-yl]methoxy]-diphenyl-silane (2.00 g, 6.40 mmol) (Jiri, P.; Istvan, M. E. Tetrahedron Lett.2006, 47, 5933) and copper(I) iodide (244 mg, 1.28 mmol) in tetrahydrofuran (20 mL) at 0 °C was added chloro(octadecyl)magnesium (0.5 M in THF, 19.2 mL, 9.60 mmol) in a dropwise fashion. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was then quenched at 0 °C with saturated aqueous ammonium chloride (50 mL), and diluted with diethyl ether (100 mL). The aqueous phase was then extracted with additional diethyl ether (2x 50 mL), the pooled organic fractions were washed with brine (50 mL), and then dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography (0 to 20% ethyl acetate in hexanes) to afford the intermediate 35-1.1H NMR (400 MHz, Chloroform-d) δ 7.67 (dt, J = 7.9, 1.5 Hz, 4H), 7.47 – 7.35 (m, 6H), 3.75 – 3.60 (m, 2H), 3.48 (dd, J = 10.0, 7.4 Hz, 1H), 1.45 – 1.16 (m, 36H), 1.07 (s, 9H), 0.88 (t, J = 6.8 Hz, 3H). Intermediate 35-2: (R)-3-(((1-((tert-butyldiphenylsilyl)oxy)henicosan-2-yl)oxy)methyl)-5- fluorobenzonitrile:
Figure imgf000195_0001
Sodium hydride (60% wt dispersion in mineral oil, 516 mg, 13.5 mmol) was added to a stirred solution of 35-1 (3.06 g, 5.39 mmol) in tetrahydrofuran (24 mL) at 0 °C. After 30 min, 3- (bromomethyl)-5-fluoro-benzonitrile (1.73 g, 8.09 mmol) was added, and the resulting mixture was warmed to 55 °C and stirred overnight. The suspension was then cooled to 0 °C, quenched with water (20 mL), and extracted with ethyl acetate (3x 30 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 30% ethyl acetate in hexanes) to give intermediate 35-2.1H NMR (400 MHz, Chloroform-d) δ 7.73 – 7.61 (m, 4H), 7.53 – 7.20 (m, 9H), 4.72 (d, J = 12.9 Hz, 1H), 4.56 (d, J = 12.9 Hz, 1H), 3.83 – 3.62 (m, 2H), 3.55 – 3.46 (m, 1H), 1.73 – 1.15 (m, 36H), 1.08 (s, 9H), 0.91 (t, J = 6.8 Hz, 3H). Intermediate 35-3: (R)-3-fluoro-5-(((1-hydroxyhenicosan-2-yl)oxy)methyl)benzonitrile:
Figure imgf000196_0001
Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6.03 mL, 6.03 mmol) was added to a stirred solution of intermediate 35-2 (3.52 g, 5.03 mmol) in tetrahydrofuran (20 mL) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 1 hour, at which time water was added (20 mL), and the mixture was extracted with ethyl acetate (3x 30 mL). The combined organic fractions were then washed with brine (25 mL) and dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 50% ethyl acetate in hexanes) to give intermediate 35-3.1H NMR (400 MHz, Chloroform-d) δ 7.47 (s, 1H), 7.36 (dt, J = 9.1, 1.7 Hz, 1H), 7.32 – 7.23 (m, 1H), 4.65 (s, 2H), 3.77 (dd, J = 11.6, 3.2 Hz, 1H), 3.63 (dd, J = 11.6, 6.3 Hz, 1H), 3.55 (qd, J = 6.2, 3.2 Hz, 1H), 1.85 – 1.05 (m, 36H), 0.90 (t, J = 6.7 Hz, 3H).
Intermediate 35-4: ((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-chlorophenyl) ((R)-2-((3-cyano-5- fluorobenzyl)oxy)henicosyl) phosphate:
Figure imgf000197_0001
2-Chlorophenyl phosphorodichloridate (505 μL, 3.07 mmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (455 mg, 6.59 mmol), triethylamine (919 μL, 6.59 mmol), acetonitrile (6 mL), and pyridine (6 mL) at room temperature. After 40 min, intermediate 35-3 (1.42 g, 3.07 mmol) in acetonitrile (6 mL) and pyridine (6 mL) was added and stirred at room temperature for 1 h. (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 (864 mg, 2.61 mmol) was then added at once and the resulting suspension was allowed to stir at room temperature. After 15 h, the mixture was concentrated, and to the resulting product was added citric acid (20 mL, 20% w/w in water), sodium hydroxide (5 mL, 1 N), and ethyl acetate (100 mL). The aqueous phase was extracted with additional ethyl acetate (2x 50 mL), and the combined organic fractions were washed with brine (50 mL) and dried over magnesium sulfate. After filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 15% methanol in dichloromethane) to give intermediate 35-4. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.94 – 7.86 (m, 1H), 7.54 – 7.32 (m, 5H), 7.24 – 7.10 (m, 2H), 6.94 – 6.83 (m, 1H), 6.80 – 6.70 (m, 1H), 6.37 (s, 2H), 5.44 – 5.24 (m, 1H), 5.02 – 4.86 (m, 1H), 4.73 – 4.30 (m, 5H), 4.29 – 4.16 (m, 1H), 4.13 – 4.02 (m, 1H), 3.68 – 3.52 (m, 1H), 1.69 – 1.66 (m, 3H), 1.55 – 1.17 (m, 39H), 0.90 (t, J = 6.6 Hz, 3H). LCMS: 965.4. Intermediate 35-5: ((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 ((R)-2-((3-cyano-5- fluorobenzyl)oxy)henicosyl) hydrogen phosphate:
Figure imgf000198_0001
To a solution of 35-4 (2.25 g, 2.23 mmol) and N,N-dimethylpyridin-4-amine (859 mg, 6.99 mmol) in tetrahydrofuran (10 mL) and acetonitrile (5 mL) at room temperature was added cesium fluoride (1062 mg, 6.99 mmol) in water (2.2 mL). The mixture was warmed to 80 °C and stirred for 2 h. Sodium hydroxide (1 N, 2.5 mL) and citric acid (20% w/w in water, 12.5 mL) were then added sequentially, and the mixture was extracted with a 3:2 mixture of 2- methyltetrahydrofuran and ethyl acetate (3x 50 mL). The pooled organic fractions were then washed with brine (50 mL) and dried over magnesium sulfate. Following filtration and concentration, the residue was purified by flash column chromatography on silica gel (0 to 50% methanol in dichloromethane) to afford 35-5.1H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.50 (s, 1H), 7.45 – 7.35 (m, 2H), 6.94 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 5.41 (d, J = 6.6 Hz, 1H), 5.06 (dd, J = 6.6, 3.2 Hz, 1H), 4.72 (d, J = 13.0 Hz, 1H), 4.60 – 4.54 (m, 1H), 4.52 (d, J = 13.1 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.90 – 3.73 (m, 2H), 3.59 – 3.44 (m, 1H), 1.72 (s, 3H), 1.48 – 1.20 (m, 39H), 0.91 (t, J = 6.8 Hz, 3H). LCMS: 853.5 [M−H]−. Example 35: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)henicosyl) hydrogen phosphate (35):
Figure imgf000199_0001
Concentrated hydrochloric acid (2.00 mL, 24.0 mmol) was added to a solution of 35-5 (1.71 g, 2.00 mmol) in tetrahydrofuran (10 mL). After 3 hours, the reaction was cooled to 0 °C and was quenched with sodium hydroxide (2.32 mL) and phosphoric acid (0.308 mL). The mixture was extracted with a 3:2 mixture of 2-methyltetrahydrofuran and ethyl acetate (3x 50 mL). The pooled organic fractions were then washed with brine (50 mL) and dried over magnesium sulfate. Following filtration and concentration, the residue was purified by flash column chromatography on silica gel (0 to 50% methanol in dichloromethane) to afford compound 35.1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.51 (s, 1H), 7.47 – 7.36 (m, 2H), 7.26 (d, J = 4.7 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 4.82 – 4.72 (m, 2H), 4.59 (d, J = 13.0 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.29 – 4.14 (m, 2H), 4.14 – 4.03 (m, 1H), 3.98 – 3.90 (m, 1H), 3.90 – 3.80 (m, 1H), 3.66 – 3.55 (m, 1H), 1.57 – 1.21 (m, 36H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 813.4 [M−H]−. Intermediate 36-1: (R)-3-((2-((tert-butyldimethylsilyl)oxy)-3-(octadecyloxy)propoxy)methyl)- 5-fluorobenzonitrile:
Figure imgf000200_0001
Intermediate 36-1 was prepared in a manner similar to intermediate 33-1 using 5- (bromomethyl)-3-fluorobenzonitrile instead of 1-bromo-3-(bromomethyl)-5-fluorobenzene. LCMS: 614.4 [M+Na]+. Intermediate 36-2: (R)-3-fluoro-5-((2-hydroxy-3-(octadecyloxy)propoxy)methyl)benzonitrile:
Figure imgf000200_0002
Intermediate 36-2 was prepared in a manner similar to intermediate 2-2 using intermediate 36-1 instead of intermediate 2-1. LCMS: 478.4.
Example 36: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((3-cyano-5-fluorobenzyl)oxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (36):
Figure imgf000201_0002
Compound 36 was prepared in a manner similar to compound 33 using intermediate 36-2 instead of intermediate 33-2.1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.60 – 7.37 (m, 3H), 7.24 (d, J = 4.4 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.38 – 5.04 (m, 1H), 4.97 – 3.87 (m, 9H), 3.83 – 3.40 (m, 4H), 1.64 – 1.49 (m, 2H), 1.29 (d, J = 5.6 Hz, 30H), 0.92 (t, J = 6.4 Hz, 3H). LCMS: 829.4 [M−H]−. Intermediate 37-1: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)benzoic acid
Figure imgf000201_0001
Potassium phosphate (48.2 mg, 227 μmol) was added to a vigorously stirred mixture of intermediate 1-2 (30.0 mg, 87.3 μmol), copper(I) iodide (5.0 mg, 26 μmol), (±)-1,1′-bi(2- naphthol) (15.0 mg, 52.4 μmol), 2-bromobenzoic acid (17.6 mg, 87.3 μmol), and N,N- dimethylformamide (0.6 mL) at room temperature. After 21 h, the resulting mixture was heated to 100 °C. After 150 min, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous citric acid solution (10% wt, 10 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 55% ethyl acetate in hexanes) to give intermediate 37-1. LCMS: 462.4 [M−Na]−. Example 37: 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)amino)benzoic acid (37):
Figure imgf000202_0001
Compound 37 was prepared in a manner similar to compound 6 using intermediate 37-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.85 (dd, J = 8.0, 1.7 Hz, 1H), 7.31 – 7.22 (m, 1H), 7.15 – 7.00 (m, 2H), 6.79 (d, J = 8.6 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 4.82 (d, J = 5.2 Hz, 1H), 4.42 – 4.33 (m, 1H), 4.29 (t, J = 5.3 Hz, 1H), 4.25 – 4.14 (m, 1H), 4.14 – 4.04 (m, 1H), 4.03 – 3.95 (m, 1H), 3.95 – 3.77 (m, 2H), 3.64 (dd, J = 9.6, 4.4 Hz, 1H), 3.57 (dd, J = 9.8, 4.8 Hz, 1H), 3.46 (t, J = 6.5 Hz, 2H), 1.61 – 1.50 (m, 2H), 1.41 – 1.22 (m, 30H), 0.95 – 0.87 (m, 3H). LCMS: 815.4 [M−H]−. Intermediate 38-1: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)benzonitrile
Figure imgf000203_0001
Sodium hydride (60% wt dispersion in mineral oil, 34.1 mg, 852 μmol) was added to a vigorously stirred solution of (R)-1-(octadecyloxy)-3-(trityloxy)propan-2-ol (WO2010052718) (200 mg, 341 μmol) in tetrahydrofuran (0.7 mL) at room temperature. After 25 min, 2- fluorobenzonitrile (165 mg, 1.36 mmol) and N,N-dimethylformamide (0.7 mL) were added sequentially, and the resulting mixture was heated to 65 ° C. After 30 min, the resulting mixture was cooled to room temperature over 5 min, and 2-propanol (1.0 mL), methanol (1.0 mL), chlorotrimethylsilane (172 μL, 1.35 mmol), and concentrated hydrochloric acid (0.1 mL) were added sequentially, and the resulting mixture was heated to 50 ° C. After 210 min, the resulting mixture was cooled to room temperature. Saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to give intermediate 38-1. LCMS: 446.4. Intermediate 38-2: (S)-2-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)benzoic acid
Figure imgf000204_0001
Aqueous potassium hydroxide solution (50% wt, 200 μL, 2.6 mmol) was added via syringe to a vigorously stirred mixture of intermediate 38-1 (49.0 mg, 110 μmol), ethanol (1.0 mL), and tetrahydrofuran (0.5 mL) at room temperature, and the resulting mixture was heated to 90 °C. After 15 h, the resulting mixture was cooled to room temperature, and aqueous hydrogen chloride solution (2.0 M, 10 mL) and water (20 mL) were added sequentially. The aqueous layer was extracted sequentially with a mixture of diethyl ether and ethyl acetate (2:1 v:v, 50 mL) and a mixture of dichloromethane and 2-propanol (4:1 v:v, 50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 65% ethyl acetate in hexanes) to give intermediate 38-2. LCMS: 463.4 [M−H]−.
Example 38: 2-(((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)oxy)benzoic acid (38):
Figure imgf000205_0001
Compound 38 was prepared in a manner similar to compound 6 using intermediate 38-2 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.52 – 7.41 (m, 1H), 7.32 – 6.96 (m, 4H), 4.83 – 4.48 (m, 2H), 4.40 – 4.33 (m, 1H), 4.33 – 4.29 (m, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.23 (d, J = 4.8 Hz, 1H), 4.20 – 4.12 (m, 1H), 4.12 – 4.03 (m, 1H), 3.75 (d, J = 4.9 Hz, 1H), 3.71 – 3.69 (m, 1H), 3.46 (t, J = 6.0 Hz, 2H), 1.55 – 1.46 (m, 2H), 1.38 – 1.16 (m, 30H), 0.92 (t, J = 6.6 Hz, 3H). LCMS: 816.4 [M−H]−. Intermediate 39-1: (R)-3-fluoro-5-(2-hydroxy-3-(octadecyloxy)propoxy)benzonitrile
Figure imgf000205_0002
Cesium carbonate (115 mg, 351 μmol) was added to a vigorously stirred mixture of (R)- 2-hydroxy-3-(octadecyloxy)propyl 4-methylbenzenesulfonate (J. Med. Chem.2009, 52, 3408) (100 mg, 200 μmol), 3-fluoro-5-hydroxybenzonitrile (28.9 mg, 211 μmol), and N,N- dimethylformamide (1.0 mL) at room temperature, and the resulting mixture was heated to 90 °C. After 19 h, the resulting mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 15% ethyl acetate in hexanes) to give intermediate 39-1. LCMS: 464.3. Example 39: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-(3-cyano-5-fluorophenoxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (39):
Figure imgf000206_0001
Compound 39 was prepared in a manner similar to compound 33 using intermediate 39-1 instead of intermediate 33-2.1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.22 (d, J = 4.9 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 7.11 – 7.00 (m, 3H), 5.13 – 4.65 (m, 1H), 4.56 – 4.44 (m, 1H), 4.40 – 4.32 (m, 1H), 4.29 (t, J = 5.4 Hz, 1H), 4.25 – 4.17 (m, 2H), 4.17 – 4.08 (m, 2H), 3.73 – 3.61 (m, 2H), 3.49 – 3.41 (m, 2H), 1.57 – 1.48 (m, 2H), 1.40 – 1.18 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 815.4 [M−H]−. Intermediate 40-1: (S)-1-(octadecyloxy)-3-phenylpropan-2-ol
Figure imgf000207_0001
Phenyl lithium solution (1.8 M in dibutyl ether, 1.11 mL, 2.0 mmol) was added via syringe to a vigorously stirred mixture of copper(I) iodide (191 mg, 1.00 mmol) in diethyl ether (1.25 mL) at 0 °C. After 30 min, (R)-2-hydroxy-3-(octadecyloxy)propyl 4- methylbenzenesulfonate (J. Med. Chem.2009, 52, 3408) (100 mg, 200 μmol) and diethyl ether (1.0 mL) were added sequentially, and the resulting mixture was warmed to room temperature. After 22 h, saturated aqueous ammonium chloride solution (1 mL), aqueous ammonia solution (30% wt, 10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 25 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to give intermediate 40-1. LCMS: 405.4.
Example 40: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((S)-1-(octadecyloxy)-3-phenylpropan-2-yl) hydrogen phosphate (40):
Figure imgf000208_0001
Compound 40 was prepared in a manner similar to compound 33 using intermediate 40-1 instead of intermediate 33-2.1H NMR (400 MHz, Methanol-d4) δ 7.98 (s, 1H), 7.27 – 7.14 (m, 6H), 7.12 (d, J = 4.8 Hz, 1H), 5.26 – 4.65 (m, 2H), 4.48 – 4.39 (m, 1H), 4.36 – 4.28 (m, 1H), 4.25 (t, J = 5.3 Hz, 1H), 4.00 (t, J = 4.3 Hz, 2H), 3.55 – 3.12 (m, 3H), 2.99 – 2.91 (m, 2H), 1.58 – 1.48 (m, 2H), 1.41 – 1.22 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 756.4 [M−H]−. Intermediate 41-1: (R)-6-(2-hydroxy-3-(octadecyloxy)propoxy)nicotinonitrile
Figure imgf000208_0002
Intermediate 41-1 was prepared in a manner similar to intermediate 36-1 using 6- fluoronicotinonitrile instead of intermediate 36-1. LCMS: 447.4. Example 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 ((R)-1-((5-cyanopyridin-2-yl)oxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (41):
Figure imgf000209_0001
Compound 41 was prepared in a manner similar to compound 33 using intermediate 41-1 instead of intermediate 33-2.1H NMR (400 MHz, Methanol-d4) δ 8.49 (dd, J = 2.4, 0.7 Hz, 1H), 8.08 (s, 1H), 7.93 (dd, J = 8.6, 2.5 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.23 – 7.14 (m, 1H), 6.96 – 6.90 (m, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.61 – 3.99 (m, 7H), 3.74 – 3.68 (m, 2H), 3.52 – 3.40 (m, 2H), 1.60 – 1.42 (m, 2H), 1.38 – 1.17 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 798.4 [M−H]−. Intermediate 42-1: (S)-6-((1-hydroxy-3-(octadecyloxy)propan-2-yl)amino)nicotinonitrile
Figure imgf000209_0002
6-Fluoronicotinonitrile (11.9 mg, 97.8 μmol) was added to a stirred mixture of intermediate 1-2 (33.6 mg, 97.8 μmol), N,N-diisopropylethylamine (34.1 μL, 196 μmol), and 1- methylpyrrolidin-2-one (1.2 mL) at room temperature, and the resulting mixture was heated to 120 °C. After 18 h 20 min, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 7% methanol in dichloromethane) to give intermediate 42-1. LCMS: 446.4. Example 42: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((5-cyanopyridin-2-yl)amino)-3- (octadecyloxy)propyl) hydrogen phosphate (42):
Figure imgf000210_0001
Compound 42 was prepared in a manner similar to compound 6 using intermediate 42-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 7.59 (dd, J = 9.0, 2.3 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 4.76 (d, J = 5.2 Hz, 1H), 4.39 – 4.30 (m, 2H), 4.23 (t, J = 5.5 Hz, 1H), 4.21 – 4.14 (m, 1H), 4.12 – 4.02 (m, 1H), 3.98 (t, J = 5.5 Hz, 2H), 3.56 (d, J = 5.8 Hz, 2H), 3.46 (td, J = 6.5, 1.9 Hz, 2H), 1.61 – 1.48 (m, 2H), 1.41 – 1.22 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 797.4 [M−H]−. Intermediate 43-1: (S)-2-((5-bromopyridin-3-yl)methoxy)-3-(octadecyloxy)propan-1-ol
Figure imgf000211_0002
Intermediate 43-1 was prepared in a manner similar to intermediate 36-1 using 3-bromo- 5-(bromomethyl)pyridine hydrobromide instead of 4-chloro-2,6-dimethoxybenzonitrile. LCMS: 514.3. Intermediate 43-2: (S)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)-3-(octadecyloxy)propan- 1-ol
Figure imgf000211_0001
Sodium methanesulfinate (22.3 mg, 219 μmol) was added to a vigorously stirred mixture of intermediate 43-1 (75.0 mg, 146 μmol), copper(I) trifluoromethanesulfonate−benzene complex (4.2 mg, 15 μmol), (±)-trans-1,2-diaminocyclohexane (7.0 μL, 120 μmol), dimethylsulfoxide (1.0 mL), and tetrahydrofuran (0.2 mL) at room temperature, and the resulting mixture was heated to 110 °C. After 17 h, the resulting mixture was cooled to room temperature, and diethyl ether (40 mL), ethyl acetate (20 mL), and aqueous ammonia solution (30% wt, 10 mL) were added sequentially. The organic layer was washed with water (2 × 30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 43-2. LCMS: 514.3. Example 43: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((5-(methylsulfonyl)pyridin-3-yl)methoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (43):
Figure imgf000212_0001
Compound 43 was prepared in a manner similar to compound 6 using intermediate 43-2 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.96 (s, 1H), 8.83 (s, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.26 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 4.94 – 4.80 (m, 2H), 4.77 (d, J = 5.2 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.25 (t, J = 5.4 Hz, 1H), 4.23 – 4.15 (m, 1H), 4.12 – 4.05 (m, 1H), 4.04 – 3.96 (m, 1H), 3.96 – 3.88 (m, 1H), 3.88 – 3.81 (m, 1H), 3.60 – 3.52 (m, 2H), 3.46 (td, J = 6.7, 2.5 Hz, 2H), 1.62 – 1.50 (m, 2H), 1.42 – 1.23 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 867.4. Intermediate 44-1: (R)-3-fluoro-5-(((1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2- yl)oxy)methyl)benzonitrile
Figure imgf000213_0001
Sodium hydride (60% wt dispersion in mineral oil, 2.92 g, 73 mmol) was added to a vigorously stirred solution of (R)-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2-ol (14.6 g, 29.2 mmol) in tetrahydrofuran (60 mL) at 0 °C. After 30 min, 3-(bromomethyl)-5- fluorobenzonitrile (7.81 g, 36.5 mmol) and tetrahydrofuran (23.5 mL) were added sequentially, and the resulting mixture was heated to 65 °C. After 16 h, the resulting mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution (8.5 mL), water (8.5 mL), saturated ammonium chloride solution (35 mL), brine (67 mL), and diethyl ether (400 mL) were added sequentially. The organic layer was washed with water (125 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 3.5% ethyl acetate in hexanes) to give intermediate 44-1.1H NMR (400 MHz, Chloroform-d) δ 7.48 (d, J = 1.6 Hz, 1H), 7.41 (dt, J = 9.3, 1.9 Hz, 1H), 7.26 (dt, J = 7.9, 1.9 Hz, 1H), 4.78 (s, 2H), 3.82 (d, J = 5.5 Hz, 2H), 3.74 – 3.65 (m, 1H), 3.61 (dd, J = 10.3, 4.0 Hz, 1H), 3.54 (dd, J = 10.3, 6.1 Hz, 1H), 3.46 (t, J = 6.7 Hz, 2H), 1.67 – 1.53 (m, 2H), 1.43 – 1.21 (m, 30H), 1.20 – 0.95 (m, 21H), 0.95 – 0.83 (m, 3H). Intermediate 44-2: (S)-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2- yl)oxy)methyl)benzonitrile
Figure imgf000214_0001
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 56.1 mL, 56 mmol) was added via syringe to a stirred solution of intermediate 44-1 (17.8 g, 28.1 mmol) in tetrahydrofuran (37 mL) at room temperature. After 60 min, saturated aqueous ammonium chloride solution (100 mL), brine (75 mL), and diethyl ether (400 mL) were added sequentially. The organic layer was washed with water (150 mL), and the aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 20% ethyl acetate in hexanes) to give intermediate 44-2. LCMS: 478.4.
Intermediate 44-3: (S)-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2- yl)oxy)methyl)benzonitrile
Figure imgf000215_0001
Aqueous potassium hydroxide solution (50% wt, 1.90 mL, 25 mmol) was added via syringe to a vigorously stirred mixture of intermediate 44-2 (500 mg, 1.05 mmol), ethanol (8.0 mL), and tetrahydrofuran (3.0 mL) at room temperature, and the resulting mixture was heated to 90 °C. After 15 h, the resulting mixture was cooled to room temperature, and aqueous hydrogen chloride solution (2 M, 10 mL) and water (20 mL) were added sequentially. The aqueous layer was extracted sequentially with a mixture of diethyl ether and ethyl acetate (2:1 v:v, 50 mL) and a mixture of dichloromethane and 2-propanol (4:1 v:v, 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 65% ethyl acetate in hexanes) to give intermediate 44-3. LCMS: 495.4 [M−H]−.
Example 44: 3-((((2R)-1-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)-3- (octadecyloxy)propan-2-yl)oxy)methyl)-5-fluorobenzoic acid (44):
Figure imgf000216_0001
Compound 44 was prepared in a manner similar to compound 6 using intermediate 44-3 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.79 (s, 1H), 7.61 – 7.47 (m, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.7 Hz, 1H), 4.81 – 4.73 (m, 2H), 4.70 (d, J = 12.7 Hz, 1H), 4.40 – 4.35 (m, 1H), 4.30 – 4.18 (m, 2H), 4.16 – 4.07 (m, 1H), 4.06 – 3.89 (m, 2H), 3.84 – 3.75 (m, 1H), 3.64 – 3.52 (m, 2H), 3.49 – 3.42 (m, 2H), 1.63 – 1.49 (m, 2H), 1.39 – 1.21 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 850.2. Intermediate 45-1: (R)-N-(2,3-dihydroxypropyl)stearamide
Figure imgf000216_0002
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.84 mg, 25.3 mmol) was added to a stirred mixture of (R)-3-aminopropane-1,2-diol (1.77 g, 19.4 mmol), stearic acid (5.42 g, 19.0 mmol), 4-(dimethylamino)pyridine (237 mg, 1.94 mmol), dichloromethane (120 mL), and N,N-dimethylformamide (65 mL) at room temperature. After 72 h, the resulting mixture was concentrated under reduced pressure to approximately half of its original volume, and the resulting biphasic mixture was heated to 65 °C. The resulting homogeneous mixture was poured into ice-water (800 mL), and the resulting biphasic mixture was filtered. The filter cake was washed with water (150 mL) and was dissolved in boiling ethanol (50 mL). The resulting solution was allowed to cool to room temperature, and the resulting suspension was filtered. The filter cake was washed with ethanol (4 °C, 100 mL) and was dried under reduced pressure to give intermediate 45-1. LCMS: 358.3. Intermediate 45-2: (R)-N-(2-hydroxy-3-(trityloxy)propyl)stearamide
Figure imgf000217_0001
Trityl chloride (1.80 g, 6.44 mmol) was added to a vigorously stirred solution of intermediate 45-1 (2.10 g, 5.86 mmol) in pyridine (14.6 mL, 181 mmol) at room temperature, and the resulting mixture was heated to 50 °C. After 46 h, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. Ethyl acetate (250 mL) and tetrahydrofuran (50 mL) were added sequentially. The organic layer was washed sequentially with an ice-cold mixture of aqueous hydrogen chloride solution (0.3 M) and brine (3:1 v:v, 200 mL) and a mixture of water, brine, and saturated aqueous sodium bicarbonate solution (1:1:1 v:v:v, 150 mL); was dried over anhydrous magnesium sulfate; was filtered; and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 35% ethyl acetate in dichloromethane) to give intermediate 45-2. LCMS: 622.4 [M+Na]+. Intermediate 45-3: (R)-N-(2-((3-cyano-5-fluorobenzyl)oxy)-3-hydroxypropyl)stearamide
Figure imgf000218_0001
Intermediate 45-3 was prepared in a manner similar to intermediate 34-1 using intermediate 45-2 instead of (R)-1-(octadecyloxy)-3-(trityloxy)propan-2-ol and using 5- (bromomethyl)-3-fluorobenzonitrile instead of intermediate 36-1. LCMS: 491.4. Example 45: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3- stearamidopropyl) hydrogen phosphate (45):
Figure imgf000218_0002
Compound 45 was prepared in a manner similar to compound 6 using intermediate 45-3 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 9.6 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.20 (d, J = 4.7 Hz, 1H), 4.86 – 4.72 (m, 2H), 4.65 (d, J = 12.9 Hz, 1H), 4.39 – 4.31 (m, 1H), 4.28 – 4.15 (m, 2H), 4.13 – 4.04 (m, 1H), 4.04 – 3.96 (m, 1H), 3.95 – 3.86 (m, 1H), 3.77 – 3.28 (m, 3H), 2.20 (t, J = 7.5 Hz, 2H), 1.67 – 1.50 (m, 2H), 1.40 – 1.16 (m, 28H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 842.4 [M−H]−. Intermediate 46-1: (R)-6-((1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2- yl)oxy)pyridazine-3-carbonitrile
Figure imgf000219_0001
Sodium hydride (60% wt dispersion in mineral oil, 26.8 mg, 669 μmol) was added to a vigorously stirred solution of (R)-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2-ol (112 mg, 223 μmol) in tetrahydrofuran (1.4 mL) at 0 °C. After 30 min, 6-chloropyridazine-3- carbonitrile (109 mg, 780 μmol) was added, and the resulting mixture was heated to 70 °C. After 60 min, the resulting mixture was cooled to room temperature, and saturated ammonium chloride solution (2 mL), diethyl ether (40 mL), ethyl acetate (20 mL), and brine (15 mL) were added sequentially. The organic layer was washed with water (20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate in hexanes) to give intermediate 46-1. LCMS: 626.5 [M+Na]+. Intermediate 46-2: (R)-6-(2-hydroxy-3-(octadecyloxy)propoxy)pyridazine-3-carbonitrile
Figure imgf000220_0001
Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 446 μL, 450 μmol), was added via syringe to a stirred solution of intermediate 46-1 (112 mg, 185 μmol) in tetrahydrofuran (0.5 mL) at room temperature. After 18 min, saturated ammonium chloride solution (3 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to give intermediate 46-2. LCMS: 448.3. Example 46: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((6-cyanopyridazin-3-yl)oxy)-3- (octadecyloxy)propan-2-yl) hydrogen phosphate (46):
Figure imgf000220_0002
Compound 46 was prepared in a manner similar to compound 33 using intermediate 46-2 instead of intermediate 33-2.1H NMR (400 MHz, Methanol-d4) δ 8.12 (d, J = 1.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.43 – 7.31 (m, 2H), 7.19 (d, J = 4.8 Hz, 1H), 4.81 – 4.54 (m, 2H), 4.44 – 4.32 (m, 1H), 4.32 – 4.04 (m, 5H), 4.03 – 3.42 (m, 4H), 1.61 – 1.48 (m, 2H), 1.42 – 1.10 (m, 30H), 0.96 – 0.87 (m, 3H). LCMS: 799.4 [M−H]−. Intermediate 47-1: methyl (S)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(trityloxy)propanoate
Figure imgf000221_0001
Sodium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 580 μL, 580 μmol) was added over 3 min via syringe to a stirred solution of methyl (S)-2-hydroxy-3- (trityloxy)propanoate (ACS Med. Chem. Lett.2018, 9, 434) (221 mg, 610 μmol) in tetrahydrofuran (1.5 mL) at −78 °C. After 7 min, 3-(bromomethyl)-5-fluorobenzonitrile (170 mg, 793 μmol) was added. After 3 min, the resulting mixture was warmed to 0 °C. After 140 min, saturated aqueous ammonium chloride solution (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% dichloromethane in hexanes) to give intermediate 47-1. LCMS: 518.2 [M+Na]+. Intermediate 47-2: (S)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(trityloxy)propanoic acid
Figure imgf000222_0001
Aqueous lithium hydroxide solution (2.0 M, 601 μL, 1.2 mmol) was added to a vigorously stirred solution of intermediate 47-1 (238 mg, 481 μmol) in tetrahydrofuran (1 mL) at room temperature. After 120 min, aqueous phosphoric acid solution (85% wt, 134 μL, 1.9 mmol) and ethyl acetate (60 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (4:1 v:v, 2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure to give intermediate 47-2. LCMS: 480.2 [M−H]−. Intermediate 47-3: (S)-2-((3-cyano-5-fluorobenzyl)oxy)-3-hydroxy-N-octadecylpropanamide
Figure imgf000222_0002
N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (137 mg, 361 μmol) was added to a vigorously stirred mixture of intermediate 47-2 (116 mg, 241 μmol), 1-aminooctadecane (130 mg, 481 μmol), 4-methylmorpholine (39.6 μL, 361 μmol), dichloromethane (1.0 mL), and N,N- dimethylformamide (1.0 mL) at room temperature. After 18 h, concentrated hydrochloric acid (210 μL, 2.5 mmol), methanol (1.0 mL), and 2-propanol (1.0 mL) were added sequentially, and the resulting mixture was heated to 50 °C. After 60 min, the resulting mixture was cooled to room temperature, and ethyl acetate (20 mL), saturated sodium bicarbonate solution (5 mL), and diethyl ether (20 mL) were added sequentially. The organic layer was washed sequentially with water (40 mL) and aqueous citric acid solution (5% wt, 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 7% methanol in dichloromethane) to give intermediate 47-3. LCMS: 491.4. Example 47: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((S)-2-((3-cyano-5-fluorobenzyl)oxy)-3- (octadecylamino)-3-oxopropyl) hydrogen phosphate (47):
Figure imgf000223_0001
Compound 47 was prepared in a manner similar to compound 6 using intermediate 47-3 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.63 (s, 1H), 7.56 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.21 (dd, J = 4.8, 1.4 Hz, 1H), 4.81 – 4.71 (m, 2H), 4.69 (d, J = 12.7 Hz, 1H), 4.38 – 4.30 (m, 1H), 4.25 (t, J = 5.5 Hz, 1H), 4.23 – 4.12 (m, 1H), 4.12 – 4.01 (m, 3H), 3.47 – 3.11 (m, 3H), 1.58 – 1.45 (m, 2H), 1.40 – 1.22 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 842.4 [M−H]−. Example 48: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(4-cyano-2-fluoro-3-methoxyphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (48):
Figure imgf000224_0001
Compound 48 was prepared in a manner similar to compound 34-1 using 3,4-difluoro-2- methoxybenzonitrile instead of 4-chloro-2,6-dimethoxybenzonitrile.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.27 (dd, J = 8.9, 2.0 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.06 (dd, J = 8.9, 7.3 Hz, 1H), 4.79 (p, J = 5.2 Hz, 1H), 4.73 (d, J = 5.2 Hz, 1H), 4.37 – 4.30 (m, 1H), 4.25 – 4.20 (m, 1H), 4.20 – 4.15 (m, 1H), 4.12 – 4.01 (m, 6H), 3.74 (dd, J = 11.0, 3.6 Hz, 1H), 3.68 (dd, J = 11.0, 6.3 Hz, 1H), 3.51 – 3.41 (m, 2H), 1.57 – 1.45 (m, 2H), 1.40 – 1.21 (m, 30H), 0.98 – 0.88 (m, 3H). LCMS: 845.4 [M−H]−. Intermediate 49-1: (S)-5-fluoro-4-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-2- methylbenzonitrile
Figure imgf000224_0002
Intermediate 49-1 was prepared in a manner similar to intermediate 34-1 using 4,5- difluoro-2-methylbenzonitrile instead of 4-chloro-2,6-dimethoxybenzonitrile. LCMS: 478.4. Intermediate 49-2: ((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-chlorophenyl) hydrogen phosphate
Figure imgf000225_0001
2-Chlorophenyl phosphorodichloridate (564 μL, 3.49 mmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (484 mg, 7.01 mmol), triethylamine (977 μL, 7.01 mmol), and tetrahydrofuran (2.0 mL) at room temperature. After 50 min, intermediate 1-4 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 μL, 3.49 mmol) were added sequentially. After 130 min, water (1.0 mL) and acetonitrile (1.0 mL) were added sequentially. After 10 min, silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 49-2. LCMS: 522.1.
Intermediate 49-3: ((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-chlorophenyl) ((R)-2-(4-cyano-2- fluoro-5-methylphenoxy)-3-(octadecyloxy)propyl) phosphate
Figure imgf000226_0001
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (84.1 mg, 330 μmol) was added to a vigorously stirred mixture of intermediate 49-1 (78.9 mg, 165 μmol), intermediate 49-2 (86.2 mg, 165 μmol), triethylamine (27.6 μL, 198 μmol), 1-methylimidazole (26.3 μL, 330 μmol), and dichloromethane (2.0 mL) at room temperature. After 30 min, bis(2-oxo-3- oxazolidinyl)phosphinic chloride (42.1 mg, 165 μmol) and 1-methylimidazole (13.2 μL, 165 μmol) were added sequentially. After 90 min, diethyl ether (40 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with a mixture of water and saturated aqueous sodium bicarbonate solution (4:1 v:v, 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane) to give intermediate 49-3. LCMS: 981.4. Example 49: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(4-cyano-2-fluoro-5-methylphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (49):
Figure imgf000227_0001
Compound 49 was prepared in a manner similar to compound 34 using intermediate 49-3 instead of intermediate 34-2.1H NMR (400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 4.85 – 4.78 (m, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.38 – 4.31 (m, 1H), 4.24 (t, J = 5.5 Hz, 1H), 4.22 – 4.15 (m, 1H), 4.12 – 4.03 (m, 3H), 3.74 (dd, J = 11.0, 3.6 Hz, 1H), 3.67 (dd, J = 11.0, 6.2 Hz, 1H), 3.51 – 3.39 (m, 2H), 2.44 (s, 3H), 1.57 – 1.44 (m, 2H), 1.39 – 1.20 (m, 30H), 0.92 (t, J = 6.6 Hz, 3H). LCMS: 829.4 [M−H]−. Intermediate 50-1: (S)-2-chloro-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2- yl)oxy)methyl)benzonitrile
Figure imgf000227_0002
n-Butyllithium solution (2.50 M in hexanes, 942 μL, 2.36 mmol) was added over 1 min via syringe to a vigorously stirred solution of 2,2,6,6-tetramethylpiperidine (397 μL, 2.36 mmol) in tetrahydrofuran (2.5 mL) at 0 °C. After 15 min, the resulting mixture was cooled to −78 °C over 10 min. A solution of intermediate 44-2 (500 mg, 1.05 mmol) in tetrahydrofuran (6.0 mL) was added over 2 min via syringe. After 133 min, a solution of hexachloroethane (372 mg, 1.57 mmol) in tetrahydrofuran (6.0 mL) was added via syringe, and the resulting mixture was warmed to 0 °C. After 70 min, the resulting mixture was warmed to room temperature. After 60 min, aqueous citric acid solution (10% wt, 40 mL), diethyl ether (100 mL), and ethyl acetate (25 mL) were added sequentially. The organic layer was washed with water (80 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 25% ethyl acetate in hexanes) to give intermediate 50-1. LCMS: 512.3. Example 50: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-chloro-3-cyano-5-fluorobenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (50):
Figure imgf000228_0001
Compound 50 was prepared in a manner similar to compound 6 using intermediate 50-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.65 – 7.56 (m, 2H), 7.20 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 4.95 – 4.73 (m, 2H), 4.67 (d, J = 13.6 Hz, 1H), 4.40 – 4.31 (m, 1H), 4.25 (t, J = 5.5 Hz, 1H), 4.23 – 4.14 (m, 1H), 4.13 – 4.04 (m, 1H), 4.03 – 3.85 (m, 2H), 3.85 – 3.74 (m, 1H), 3.61 – 3.41 (m, 4H), 1.64 – 1.49 (m, 2H), 1.43 – 1.22 (m, 30H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 863.4 [M−H]−. Intermediate 51-1: (S)-2-allyl-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2- yl)oxy)methyl)benzonitrile
Figure imgf000229_0001
Allyltributylstannane (182 μL, 586 μmol) was added via syringe to a vigorously stirred mixture of intermediate 50-1 (50.0 mg, 97.6 μmol), 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl (18.6 mg, 39.1 μmol), tris(dibenzylideneacetone)dipalladium(0) (8.9 mg, 9.8 μmol), and 1,4-dioxane (1.5 mL) at room temperature, and the resulting mixture was heated to 105 °C. After 35 min, the resulting mixture was cooled to room temperature and was purified by flash column chromatography on silica gel (0 to 25% ethyl acetate in hexanes) to give intermediate 51-1. LCMS: 518.4. Intermediate 51-2: (R)-2-((4-allyl-3-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy)propyl (((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl) hydrogen phosphate
Figure imgf000230_0001
Intermediate 51-2 was prepared in a manner similar to compound 52 using intermediate 51-1 instead of intermediate 52-1. LCMS: 869.4 [M−H]−. Example 51: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluoro-4-propylbenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (51):
Figure imgf000230_0002
A vigorously stirred mixture of intermediate 51-2 (45.0 mg, 51.7 μmol), palladium (10% wt on carbon, 16.5 mg, 15.5 μmol), tetrahydrofuran (2.0 mL), dichloromethane (0.3 mL), and ethanol (0.8 mL) at room temperature was placed under an atmosphere of hydrogen gas (balloon). After 72 min, the resulting mixture was filtered through celite. The filter cake was extracted with dichloromethane (3 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 51.1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.50 (d, J = 11.4 Hz, 1H), 7.43 (t, J = 11.5 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.20 – 7.13 (m, 1H), 5.17 – 5.00 (m, 1H), 4.80 – 4.59 (m, 2H), 4.39 – 4.30 (m, 1H), 4.28 – 4.16 (m, 2H), 4.14 – 4.03 (m, 1H), 3.95 (dt, J = 11.0, 5.5 Hz, 2H), 3.78 (s, 1H), 3.62 – 3.48 (m, 2H), 3.48 – 3.40 (m, 2H), 2.83 (t, J = 7.6 Hz, 2H), 1.74 – 1.61 (m, 2H), 1.61 – 1.50 (m, 2H), 1.39 – 1.17 (m, 30H), 0.99 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 871.5 [M−H]−. Intermediate 52-1: (S)-5-fluoro-4-((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)-2- methoxybenzonitrile
Figure imgf000231_0001
Intermediate 52-1 was prepared in a manner similar to intermediate 34-1 using 4,5- difluoro-2-methoxybenzonitrile instead of 4-chloro-2,6-dimethoxybenzonitrile. LCMS: 494.4. Example 52-: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(4-cyano-2-fluoro-5-methoxyphenoxy)-3- (octadecyloxy)propyl) hydrogen phosphate (52):
Figure imgf000232_0001
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (150 mg, 590 μmol) was added to a vigorously stirred mixture of intermediate 52-1 (97.1 mg, 197 μmol), intermediate 49-2 (103 mg, 197 μmol), triethylamine (32.9 μL, 242 μmol), 1-methylimidazole (47.0 μL, 590 μmol), and dichloromethane (2.0 mL) at room temperature. After 16 h 45 min, the resulting mixture was concentrated under reduced pressure. Tetrahydrofuran (0.3 mL), water (177 μL, 9.83 mmol), and 4-(dimethylamino)pyridine (72.1 mg, 590 μmol) were added sequentially, and the resulting mixture was stirred vigorously at room temperature. Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 393 μL, 390 μmol) was added via syringe, and the resulting mixture was heated to 65 °C. After 30 min, the resulting mixture was cooled to room temperature. After 5 min, chlorotrimethylsilane (49.9 μL, 393 μmol) and concentrated hydrochloric acid (650 μL, 7.8 mmol) were added sequentially. After 3 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 53.1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.36 – 7.25 (m, 2H), 7.17 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 4.95 – 4.80 (m, 1H), 4.76 (d, J = 5.3 Hz, 1H), 4.39 – 4.31 (m, 1H), 4.24 (t, J = 5.5 Hz, 1H), 4.22 – 4.14 (m, 1H), 4.12 – 4.02 (m, 3H), 3.91 (s, 3H), 3.76 (dd, J = 11.0, 3.4 Hz, 1H), 3.67 (dd, J = 11.0, 6.4 Hz, 1H), 3.55 – 3.38 (m, 2H), 1.62 – 1.44 (m, 2H), 1.43 – 1.17 (m, 30H), 0.95 – 0.85 (m, 3H). LCMS: 845.4 [M−H]−. Intermediate 53-1: (S)-3-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2- methylbenzonitrile
Figure imgf000233_0001
53-1 Intermediate 53-1 was prepared in a manner similar to intermediate 51-1 using tetramethylstannane instead of allyltributylstannane. LCMS: 492.4. Example 53: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluoro-4-methylbenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (53):
Figure imgf000233_0002
Compound 53 was prepared in a manner similar to compound 6 using intermediate 53-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 10.1 Hz, 1H), 7.13 – 7.01 (m, 2H), 4.98 – 4.76 (m, 1H), 4.70 (d, J = 13.1 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H), 4.38 – 4.31 (m, 1H), 4.25 (t, J = 5.4 Hz, 1H), 4.22 – 4.13 (m, 1H), 4.11 – 4.04 (m, 1H), 4.03 – 3.82 (m, 2H), 3.81 – 3.69 (m, 1H), 3.61 – 3.34 (m, 4H), 2.42 (d, J = 2.0 Hz, 3H), 1.60 – 1.50 (m, 2H), 1.41 – 1.22 (m, 30H), 0.92 (t, J = 6.6 Hz, 3H). LCMS: 843.4 [M−H]−. Intermediate 54-1: (S)-2-chloro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-3- methoxybenzonitrile
Figure imgf000234_0001
Sodium methoxide solution (25% wt in methanol, 389 μL, 1.7 mmol) was added via syringe to a vigorously stirred solution of intermediate 50-1 (17.0 mg, 33.2 μmol) in dimethylsulfoxide (0.5 mL) at room temperature. After 75 min, saturated aqueous ammonium chloride solution (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (2 × 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 60% ethyl acetate in hexanes) to give intermediate 54-1. LCMS: 524.3. Example 54: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-chloro-3-cyano-5-methoxybenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (54):
Figure imgf000235_0001
Compound 54 was prepared in a manner similar to compound 6 using intermediate 54-1 instead of intermediate 6-3.1H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.37 (s, 1H), 7.32 (d, J = 1.7 Hz, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 4.96 – 4.80 (m, 1H), 4.69 (d, J = 13.0 Hz, 1H), 4.60 (d, J = 13.1 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.26 (t, J = 5.4 Hz, 1H), 4.20 – 4.11 (m, 1H), 4.11 – 4.02 (m, 1H), 3.95 (s, 3H), 3.94 – 3.79 (m, 2H), 3.77 – 3.68 (m, 1H), 3.53 – 3.36 (m, 4H), 1.59 – 1.48 (m, 2H), 1.41 – 1.21 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 875.4 [M−H]−. Intermediate 55-1: 4-(hydroxymethyl)-2,6-dimethoxybenzonitrile
Figure imgf000235_0002
N-Butyl lithium solution (2.55 M in hexanes, 1.62 mL, 4.13 mmol) was added dropwise via syringe to a stirred solution of 4-bromo-2,6-dimethoxybenzonitrile (J. Med. Chem.2020, 63, 4978) (1.00 g, 4.13 mmol) in tetrahydrofuran (40 mL) at −78 °C. After 32 min, N,N- dimethylformamide (640 μL, 8.26 mmol) was added via syringe, and the resulting mixture was warmed to 0 °C. After 61 min, saturated aqueous sodium bicarbonate solution (4.13 mL), sodium borohydride (781 mg, 20.7 mmol), and methanol (30 mL) were added sequentially. After 1 h, ethyl acetate was added. The organic layer was washed sequentially with water, water, and a mixture of water and brine, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (20 to 80% ethyl acetate in hexanes) to give intermediate 55-1.1H NMR (400 MHz, Chloroform-d) δ 6.60 (s, 2H), 4.76 (s, 2H), 3.94 (s, 6H). Intermediate 55-2: 4-(bromomethyl)-2,6-dimethoxybenzonitrile
Figure imgf000236_0001
Carbon tetrabromide (721 mg, 2.17 mmol) was added to a stirred mixture of intermediate 55-1 (336 mg, 1.74 mmol), triphenylphosphine (570 mg, 2.17 mmol), and dichloromethane (27 mL) at 0 °C. After 15 min, methanol (0.1 mL) was added, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to give intermediate 55-2.1H NMR (400 MHz, Chloroform-d) δ 6.60 (s, 2H), 4.44 (s, 2H), 3.95 (s, 6H). Intermediate 55-3: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2,6- dimethoxybenzonitrile
Figure imgf000237_0001
Intermediate 55-3 was prepared in a manner similar to intermediate 44-2 using intermediate 55-2 instead of 3-(bromomethyl)-5-fluorobenzonitrile. LCMS: 520.4. Example 55: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyano-3,5-dimethoxybenzyl)oxy)-3- (octadecyloxy)propyl) hydrogen phosphate (55):
Figure imgf000237_0002
Compound 55 was prepared in a manner similar to compound 36 using intermediate 55-3 instead of intermediate 34-1.1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.73 (s, 2H), 4.78 – 4.66 (m, 3H), 4.38 – 4.31 (m, 1H), 4.26 – 4.17 (m, 2H), 4.15 – 3.94 (m, 3H), 3.91 (s, 6H), 3.85 – 3.78 (m, 1H), 3.65 – 3.53 (m, 2H), 3.53 – 3.43 (m, 2H), 1.62 – 1.49 (m, 2H), 1.40 – 1.24 (m, 30H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 871.4 [M−H]−. Intermediate 56-1: (R)-3-(((1-(allyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2- yl)oxy)methyl)-5-fluorobenzonitrile
Figure imgf000238_0001
Intermediate 56-1 was prepared in a manner similar to intermediate 44-1 using (R)-1- (allyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2-ol (J. Org. Chem.2003, 68, 6760) instead of (R)-1-(octadecyloxy)-3-((triisopropylsilyl)oxy)propan-2-ol.1H NMR (400 MHz, Chloroform-d) δ 7.72 – 7.61 (m, 4H), 7.54 – 7.30 (m, 8H), 7.30 – 7.22 (m, 1H), 6.00 – 5.83 (m, 1H), 5.29 (dq, J = 17.3, 1.6 Hz, 1H), 5.22 (dq, J = 10.4, 1.4 Hz, 1H), 4.66 (s, 2H), 4.02 (dt, J = 5.7, 1.5 Hz, 2H), 3.83 – 3.52 (m, 5H), 1.08 (s, 9H). Intermediate 56-2: (R)-3-(((1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2- yl)oxy)methyl)-5-fluorobenzonitrile
Figure imgf000238_0002
Tetrakis(triphenylphosphine)palladium(0) (60.1 mg, 52.0 μmol) was added to a stirred mixture of intermediate 56-1 (1.31 g, 2.61 mmol), 1,3-dimethylbarbituric acid (812 mg, 5.20 mmol), methanol (6.4 mL), and dichloromethane (6.4 mL) at room temperature, and the resulting mixture was heated to 35 °C. After 16 h, the resulting mixture was cooled to room temperature and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 27% ethyl acetate in hexanes) to give a mixture of intermediate 56-2 and 1,3-dimethylbarbituric acid. The obtained mixture was purified by flash column chromatography on a column of basic alumina atop silica gel (0 to 60% ethyl acetate in hexanes) to give intermediate 56-2.1H NMR (400 MHz, Chloroform-d) δ 7.74 – 7.58 (m, 4H), 7.52 – 7.24 (m, 9H), 4.65 (d, J = 12.8 Hz, 1H), 4.59 (d, J = 12.9 Hz, 1H), 3.91 – 3.72 (m, 4H), 3.67 – 3.56 (m, 1H), 1.08 (s, 9H). Intermediate 56-3: (S)-3-((tert-butyldiphenylsilyl)oxy)-2-((3-cyano-5- fluorobenzyl)oxy)propanoic acid
Figure imgf000239_0001
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.17 g, 2.76 mmol) was added to a vigorously stirred solution of intermediate 56-2 (852 mg, 1.84 mmol) in dichloromethane (6.0 mL) at 0 °C. After 46 min, the resulting mixture was warmed to room temperature. After 46 min, the resulting mixture was cooled to 0 °C, and aqueous sodium thiosulfate solution (1.0 M, 6.43 mL, 6.4 mmol), saturated aqueous sodium bicarbonate solution (30 mL), diethyl ether (100 mL), and ethyl acetate (25 mL) were added sequentially. The organic layer was washed sequentially with water (70 mL), a mixture of water and saturated aqueous sodium bicarbonate solution (5:1 v:v, 100 mL), and water (100 mL); was dried over anhydrous sodium sulfate; was filtered; and was concentrated under reduced pressure. The residue was dissolved in a mixture of tert-butyl alcohol (7.5 mL), tetrahydrofuran (4.0 mL), and water (5.0 mL), and the resulting mixture was cooled to 0 °C. Sodium dihydrogen phosphate monohydrate (1.02 g, 7.35 mmol), 2-methyl-2-butene (3.90 mL, 36.8 mmol), and sodium chlorite (333 mg, 3.68 mmol) were added sequentially, and the resulting mixture was warmed to 15 °C over 5 min. After 300 min, aqueous sodium hydrogen sulfate solution (0.1 M, 110 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 125 mL). The combined organic layers were washed with water (100 mL), were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure to give intermediate 56-3. LCMS: 476.2 [M−H]−. Intermediate 56-4: (S)-2-((3-cyano-5-fluorobenzyl)oxy)-3-hydroxy-N-methyl-N- octadecylpropanamide
Figure imgf000240_0001
N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (135 mg, 355 μmol) was added to a vigorously stirred mixture of intermediate 56-3 (113 mg, 237 μmol), N-methyloctadecan-1- amine (101 mg, 355 μmol), 4-methylmorpholine (39.0 μL, 355 μmol), dichloromethane (1.5 mL), and N,N-dimethylformamide (1.0 mL) at room temperature. After 18 h, ethyl acetate (20 mL), saturated sodium bicarbonate solution (5 mL), and diethyl ether (40 mL) were added sequentially. The organic layer was washed sequentially with water (40 mL) and aqueous citric acid solution (5% wt, 40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.5 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (32.4 μL, 308 μmol) and tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 710 μL, 710 μmol) were added sequentially. After 30 min, saturated aqueous ammonium chloride solution (5 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (40 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 56-4. LCMS: 505.4. Example 56: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((S)-2-((3-cyano-5-fluorobenzyl)oxy)-3- (methyl(octadecyl)amino)-3-oxopropyl) hydrogen phosphate (56):
Figure imgf000241_0001
Compound 56 was prepared in a manner similar to compound 49 using intermediate 56-4 instead of intermediate 49-1.1H NMR (400 MHz, Methanol-d4) δ 8.10 (d, J = 1.7 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 4.8 Hz, 1H), 4.95 – 4.65 (m, 2H), 4.65 – 4.57 (m, 2H), 4.39 – 4.31 (m, 1H), 4.28 – 4.15 (m, 2H), 4.15 – 4.02 (m, 3H), 3.61 – 3.43 (m, 2H), 3.12 (s, 2H), 2.95 (s, 1H), 1.67 – 1.43 (m, 1H), 1.41 – 1.18 (m, 30H), 1.02 – 0.78 (m, 3H). LCMS: 856.4 [M−H]−. Intermediate 57-1: (S)-3-cyano-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)benzamide
Figure imgf000242_0001
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.6 mg, 180 µmol) was added to a rapidly stirring mixture of intermediate 1-2 (31.0 mg, 90.2 µmol), N,N- dimethylpyridin-4-amine (2.2 mg, 18 µmol), and 3-cyanobenzoic acid (13.3 mg, 90.2 µmol) in dichloromethane (0.5 mL) at room temperature. After 16 h, the reaction was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 57-1. LCMS: 473.2.
Example 57: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(3-cyanobenzamido)-3-(octadecyloxy)propyl) hydrogen phosphate (57):
Figure imgf000243_0001
1,8-Diazabicyclo[5.4.0]undec-7-ene (13 µL, 90 µmol) was added over 1 min to a rapidly stirred mixture of intermediate 6-2 (25.2 mg, 44.8 µmol) and intermediate 57-1 (21.2 mg, 44.8 µmol) in tetrahydrofuran (0.5 mL) at room temperature. After 20 min, water (50 µL) and concentrated hydrochloric acid (300 µL, 3.60 mmol) were added sequentially. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give example 57.1H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 8.1 Hz, 1H), 8.23 – 8.15 (m, 2H), 7.86 (d, J = 6.6 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.7 Hz, 1H), 4.33 (s, 2H), 4.26 (t, J = 5.2 Hz, 1H), 4.17 – 4.00 (m, 2H), 3.94 (t, J = 5.9 Hz, 1H), 3.87 (s, 1H), 3.59 (s, 1H), 3.48 – 3.40 (m, 4H), 1.67 – 1.57 (m, 2H), 1.31 (d, J = 2.8 Hz, 30H), 0.97 – 0.86 (m, 3H). LCMS: 826.1. Intermediate 58-1: (S)-2-cyano-N-(1-hydroxy-3-(octadecyloxy)propan-2-yl)benzamide
Figure imgf000244_0001
Intermediate 58-1 was prepared in a manner similar to intermediate 57-1, using 2- cyanobenzoic acid instead of 3-cyanobenzoic acid. LCMS: 473.4. Example 58: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(2-cyanobenzamido)-3-(octadecyloxy)propyl) hydrogen phosphate (58):
Figure imgf000244_0002
Example 59 was prepared in a manner similar to example 57, using intermediate 58-1 instead of 57-1.1H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.84 – 7.73 (m, 4H), 7.04 (d, J = 4.8 Hz, 1H), 6.98 (s, 1H), 4.30 (s, 2H), 4.23 (t, J = 5.1 Hz, 2H), 4.11 (dd, J = 10.5, 6.2 Hz, 1H), 4.06 – 3.98 (m, 2H), 3.89 (t, J = 10.0 Hz, 1H), 3.65 (dd, J = 10.2, 5.3 Hz, 2H), 3.47 (d, J = 9.2 Hz, 1H), 3.42 – 3.38 (m, 1H), 1.41 (s, 2H), 1.31 (s, 30H), 0.92 (t, J = 6.6 Hz, 3H). LCMS: 826.5. Intermediate 59-1: 2-Tetradecoxyethanol
Figure imgf000245_0001
60-1 To a solution of ethylene glycol (0.838 g, 13.5 mmol) in dry DMF (6 mL) was added NaH (60% oil dispersion; 172 mg, 45 mmol) at 0 °C and the mixture was stirred at room temperature for 10 min.1-bromotetradecane (0.832 g, 3 mmol) and KI (498 mg, 3 mmol) were added and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice-water and extracted with DCM. The extracts were washed with brine, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide 59-1.1H NMR (400 MHz, Chloroform-d) δ 3.81 – 3.70 (m, 2H), 3.61 – 3.53 (m, 2H), 3.49 (t, J = 6.7 Hz, 2H), 1.68 – 1.55 (m, 2H), 1.42 – 1.20 (m, 22H), 0.98 – 0.83 (m, 3H). Example 59: [(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-tetradecoxyethyl hydrogen phosphate (59):
Figure imgf000245_0002
Compound 59 was prepared in a manner similar to example 19 using intermediate 59-1. 1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 4.6 Hz, 1H), 4.39 (m, 1H), 4.28 (t, J = 5.3 Hz, 1H), 4.12 (m, 2H), 3.88 (t, J = 5.8 Hz, 2H), 3.48 (q, J = 5.1 Hz, 2H), 3.44 – 3.24 (m, 3H), 1.50 (q, J = 6.8 Hz, 2H), 1.28 (d, J = 7.1 Hz, 22H), 0.91 (t, J = 6.8 Hz, 3H).31P NMR (162 MHz, Methanol-d4) δ -0.71. MS: 612.24 (M+1). Intermediate 60-1: 2-Heptadecoxyethanol
Figure imgf000246_0001
To a solution of ethylene glycol (0.838 g, 13.5 mmol) in dry DMF (6 mL) was added NaH (60% oil dispersion; 172 mg, 45 mmol) at 0 °C and the mixture was stirred at room temperature for 10 min.1-bromoheptadecane (0.958 g, 3 mmol) and KI (498 mg, 3 mmol) were added and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice-water and extracted with DCM. The extracts were washed with brine, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide intermediate 60-1.1H NMR (400 MHz, Chloroform-d) δ 3.78 – 3.72 (m, 2H), 3.56 (dd, J = 5.3, 3.9 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H), 1.68 – 1.50 (m, 2H), 1.28 (s, 28H), 0.90 (t, J = 6.7 Hz, 3H).
Example 60: [(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-heptadecoxyethyl hydrogen phosphate (60):
Figure imgf000247_0001
Compound 60 was prepared in a manner similar to example 19 using intermediate 60-1. 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.06 – 6.96 (m, 2H), 4.38 (m, 1H), 4.29 (m, 1H), 4.20 – 4.00 (m, 2H), 3.87 (m, 2H), 3.49 (m, 2H), 3.43 – 3.36 (m, 2H), m 1.51 (q, J = 6.8 Hz, 2H), 1.29 (d, J = 8.0 Hz, 28H), 0.91 (t, J = 6.7 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) δ 0.55. MS: 654.30 (M+1). Intermediate 61-1: 3-Tetradecylsulfanylpropan-1-ol
Figure imgf000247_0002
To a solution of 3-mercapto-1-propanol (829 mg, 9 mmol) and 1-bromotetradecane (0.832 g, 3 mmol) in DMSO (3 mL) and THF (3 mL) was added KOH powder (673 mg, 12 mmol) at rt. The mixture was stirred at room temperature overnight. The mixture was poured into ice-water and extracted with DCM. The extracts were concentrated, dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (silica gel; AcOEt/hexane, 1:2) to provide 61-1.1H NMR (400 MHz, Chloroform-d) δ 3.79 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.59 – 2.49 (m, 2H), 1.92 – 1.81 (m, 2H), 1.65 – 1.55 (m, 2H), 1.28 (s, 22H), 0.90 (t, J = 6.8 Hz, 3H). Example 61: [(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 3-tetradecylsulfanylpropyl hydrogen phosphate (61):
Figure imgf000248_0001
Compound 61 was prepared in a manner similar to example 19 using intermediate 61-1. 1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.00 (d, J = 4.6 Hz, 1H), 6.91 (d, J = 4.4 Hz, 1H), 4.37 (d, J = 4.5 Hz, 1H), 4.28 (m, 1H), 4.21 – 3.99 (m, 2H), 3.91 – 3.69 (m, 2H), 2.48 (m, 4H), 1.76 (m, 2H), 1.52 (m, 2H), 1.30 (d, J = 3.3 Hz, 22H), 0.92 (t, J = 6.7 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) δ 0.15. MS: 642.18 (M+1). Intermediate 62-1: 3-heptadecylsulfanylpropan-1-ol
Figure imgf000248_0002
Intermediate 62-1 was prepared in a manner similar to compound 61-1. Example 62: [(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 3-heptadecylsulfanylpropyl hydrogen phosphate (62):
Figure imgf000248_0003
Compound 62 was prepared in a manner similar to 61 using intermediate 62-1 instead of 61-1.1H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 4.75 (s, 1H), 4.56 – 3.93 (m, 6H), 2.73 – 2.35 (m, 4H), 1.90 (s, 2H), 1.56 (d, J = 8.8 Hz, 2H), 1.29 (s, 28H), 0.90 (t, J = 6.5 Hz, 3H). 31P NMR (162 MHz, Methanol-d4) δ -0.89. MS: 684.17 (M+1). Example 63: [(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 3-dodecylsulfanylpropyl hydrogen phosphate (63):
Figure imgf000249_0001
Compound 63 was prepared in a manner similar to 61 using intermediate 3- (dodecylthio)propan-1-ol.1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 4.80 (d, J = 5.3 Hz, 1H), 4.38 (m, 1H), 4.31 – 4.17 (m, 2H), 4.12 (m, 1H), 4.02 – 3.87 (m, 2H), 2.52 (dt, J = 28.7, 7.3 Hz, 4H), 1.84 (p, J = 6.6 Hz, 2H), 1.54 (q, J = 7.6 Hz, 2H), 1.30 (m, 18H), 0.92 (t, J = 6.7 Hz, 3H).31P NMR (162 MHz, Methanol-d4) δ 0.18. MS: 614.10 (M+1). Intermediate 64-1: (2S)-2-[(3-Chloro-2,4-difluoro-phenyl)methoxy]-3-octadecoxy-propan-1-ol:
Figure imgf000249_0002
Intermediate 64-1 was prepared in a manner similar to intermediate 36-2 using 1- (bromomethyl)-3-chloro-2,4-difluorobenzene as alkylation agent. Example 64: [(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 [(2R)-2-[(3-chloro-2,4-difluoro-phenyl)methoxy]-3- octadecoxy-propyl] hydrogen phosphate (64):
Figure imgf000250_0001
Compound 64 was prepared in a manner similar to example 19 using intermediate 64-1. 1H NMR (400 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.45 (td, J = 8.3, 6.2 Hz, 1H), 7.04 (td, J = 8.7, 1.9 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.85 (m, 1H), 4.73 – 4.57 (m, 2H), 4.42 – 4.32 (m, 1H), 4.27 (m, 1H), 4.21 – 4.01 (m, 2H), 3.89 (m, 2H), 3.78 – 3.70 (m, 1H), 3.58 – 3.36 (m, 4H), 1.50 (t, J = 6.8 Hz, 2H), 1.28 (d, J = 10.7 Hz, 30H), 0.99 – 0.82 (m, 3H). 31P NMR (162 MHz, Methanol-d4) δ -0.88. MS: 858.36 (M+1). Intermediate 65-1: 3-(Hexadecylthio)propan-1-ol
Figure imgf000250_0002
Compound 65-1 was prepared in a manner similar to intermediate 61-1. Example 65: [(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 3-hexadecylsulfanylpropyl hydrogen phosphate (65):
Figure imgf000251_0001
Compound 65 was prepared in a manner similar to example 19 using intermediate 65-1. 1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 6.99 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 4.89 (m, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 4.20 – 3.98 (m, 2H), 3.91 – 3.79 (m, 2H), 2.47 (m, 4H), 1.84 – 1.70 (m, 2H), 1.52 (m, 2H), 1.29 (d, J = 3.6 Hz, 26H), 0.98 – 0.83 (m, 3H). 31P NMR (162 MHz, Methanol-d4) δ -0.43. MS: 670.19 (M+1). Intermediate 66-1: 2-Hexadecoxyethanol
Figure imgf000251_0002
Compound 66-1 was prepared in a manner similar to 59-1. 1H NMR (400 MHz, Chloroform-d) δ 3.75 (dd, J = 5.2, 4.0 Hz, 2H), 3.62 – 3.53 (m, 2H), 3.49 (t, J = 6.7 Hz, 2H), 1.67 – 1.54 (m, 2H), 1.28 (s, 26H), 0.90 (t, J = 6.7 Hz, 3H). Example 66: [(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-hexadecoxyethyl hydrogen phosphate (66):
Figure imgf000252_0001
Compound 66 was prepared in a manner similar to example 19 using intermediate 66-1. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 4.75 (s, 1H), 4.49 – 4.00 (m, 6H), 3.64 (m, 2H), 3.49 (m, 2H), 1.57 (t, J = 6.5 Hz, 2H), 1.47 – 1.15 (m, 26H), 0.91 (t, J = 6.6 Hz, 3H).31P NMR (162 MHz, Methanol-d4) δ -0.93. MS: 640.25 (M+1). Intermediate 67-1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2- dimethyl-6-((((2R,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2- sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile
Figure imgf000252_0002
1,8-Diazabicyclo[5.4.0]undec-7-ene (609 µL, 4.07 mmol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-Methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2- yl)hexahydrobenzo[d][1,3,2]oxathiaphosphole 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) at room temperature. After 10 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give Intermediate 67-1. LCMS: 578.2. Example 67: O-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl) O-((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) O- hydrogen (R)-phosphorothioate (67):
Figure imgf000253_0001
1,8-Diazabicyclo[5.4.0]undec-7-ene (12.8 µL, 85.5 µmol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 67-1 (24.7 mg, 3.02 mmol), (2S)-2- benzyloxy-3-octadecoxy-propan-1-ol (37.2 mg, 85.5 µmol), and tetrahydrofuran (0.5 mL) at room temperature. After 30 min, concentrated hydrochloric acid (0.18 mL) was added. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 67.1H NMR (400 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.38 – 7.20 (m, 9H), 7.16 – 6.99 (m, 2H), 4.73 – 4.55 (m, 3H), 4.35 (d, J = 4.3 Hz, 1H), 4.31 – 4.26 (m, 1H), 4.23 (s, 1H), 4.14 (d, J = 10.5 Hz, 1H), 4.01 – 3.94 (m, 1H), 3.78 (s, 1H), 3.61 – 3.48 (m, 4H), 3.42 (t, J = 6.5 Hz, 4H), 3.28 – 3.25 (m, 2H), 3.20 – 3.12 (m, 2H), 1.53 (d, J = 7.3 Hz, 3H), 1.30 (d, J = 4.2 Hz, 62H), 0.92 (t, J = 6.7 Hz, 7H). LCMS: 802.4. [M-H]. Example 68: O-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl) O-((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) O- hydrogen (S)-phosphorothioate (68):
Figure imgf000254_0001
1,8-Diazabicyclo[5.4.0]undec-7-ene (12.8 µL, 85.5 µmol) was added over 1 min via syringe to a vigorously stirred mixture of intermediate 67-1 (31 mg, 0.0357 mmol), 3-fluoro-5- [[(1S)-1-(hydroxymethyl)-2-octadecoxy-ethoxy]methyl]benzonitrile (51.3 mg, 107 µmol), and tetrahydrofuran (0.5 mL) at room temperature. After 30 min, concentrated hydrochloric acid (0.18 mL) was added. After 2 h, the resulting mixture was purified by reverse phase preparative HPLC (0.1% trifluoroacetic acid in methanol/water) to give compound 68.1H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.39 – 7.18 (m, 5H), 6.98 – 6.90 (m, 2H), 4.95 (t, J = 4.1 Hz, 1H), 4.79 (d, J = 2.8 Hz, 1H), 4.60 (s, 1H), 4.50 – 4.30 (m, 2H), 4.29 – 4.14 (m, 1H), 3.84 – 3.75 (m, 1H), 3.55 – 3.48 (m, 3H), 3.45 – 3.37 (m, 3H), 3.20 – 3.13 (m, 1H), 1.52 (s, 4H), 1.29 (d, J = 8.3 Hz, 49H), 0.92 (t, J = 6.7 Hz, 5H). LCMS: 845.4 [M-H]. Example 69: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((4-cyano-2-fluorobenzyl)oxy)henicosan-2-yl) hydrogen phosphate (69):
Figure imgf000255_0001
Compound 69 was prepared in a manner similar to example 68 using 3-fluoro-4- bromomethyl benzonitrile instead of 3-fluoro-5-bromomethyl benzonitrile (minor regioisomer), using coupling conditions demonstrated in example 68.1H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.08 – 6.97 (m, 2H), 4.65 – 4.44 (m, 2H), 4.33 (d, J = 4.7 Hz, 1H), 4.26 (t, J = 5.4 Hz, 2H), 4.16 (dd, J = 9.4, 5.2 Hz, 1H), 4.09 (dd, J = 10.3, 5.8 Hz, 1H), 3.77 – 3.64 (m, 1H), 3.64 – 3.52 (m, 2H), 3.50 (p, J = 1.6 Hz, 1H), 3.15 (p, J = 1.7 Hz, 1H), 1.72 – 1.59 (m, 2H), 1.28 (d, J = 13.2 Hz, 41H), 1.01 – 0.80 (m, 4H). LCMS: 813.4 [M−H]−.
Example 70: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-1-((4-cyano-2-fluorobenzyl)oxy)henicosan-2-yl) hydrogen phosphate (70):
Figure imgf000256_0001
Example 70 was prepared in a manner similar to example 35 using 3-fluoro-4- bromomethyl benzonitrile instead of 3-fluoro-5-bromomethyl benzonitrile (major regioisomer), utilizing coupling conditions demonstrated in example 68.1H NMR (400 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.57 – 7.38 (m, 2H), 7.23 – 7.07 (m, 2H), 4.96 – 4.91 (m, 2H), 4.82 – 4.78 (m, 1H), 4.64 (d, J = 13.3 Hz, 1H), 4.18 – 4.14 (m, 2H), 4.07 (dt, J = 11.6, 4.5 Hz, 1H), 3.89 (dt, J = 9.8, 4.6 Hz, 1H), 3.82 (dt, J = 11.2, 6.0 Hz, 1H), 3.50 (p, J = 1.6 Hz, 1H), 3.15 (p, J = 1.7 Hz, 1H), 1.50 – 1.41 (m, 2H), 1.28 (d, J = 17.5 Hz, 32H), 0.91 (t, J = 6.8 Hz, 3H). LCMS: 813.4 [M−H]−.
Example 71: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyano-3-fluorobenzyl)oxy)henicosyl) hydrogen phosphate (71):
Figure imgf000257_0001
Example 71 was prepared in a manner similar to example 70 using 2-fluoro-4- bromomethyl benzonitrile instead of 3-fluoro-4-bromomethyl benzonitrile.1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 9.2 Hz, 2H), 7.22 – 7.11 (m, 2H), 4.81 – 4.73 (m, 2H), 4.61 (d, J = 13.8 Hz, 1H), 4.34 (s, 1H), 4.23 (t, J = 5.5 Hz, 1H), 4.21 – 4.13 (m, 1H), 4.12 – 4.03 (m, 1H), 3.97 – 3.88 (m, 1H), 3.88 – 3.79 (m, 1H), 3.60 (s, 1H), 3.50 (t, J = 1.6 Hz, 1H), 1.56 – 1.44 (m, 1H), 1.29 (d, J = 9.9 Hz, 25H), 0.94 – 0.88 (m, 3H). LCMS: 813.4 [M−H]−. Example 72: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)henicosyl) hydrogen phosphate (72):
Figure imgf000257_0002
Example 72 was prepared in a manner similar to Example 70 using benzyl bromide instead of 3-fluoro-4-bromomethyl benzonitrile.1H NMR (400 MHz, Methanol-d4) δ 7.98 (s, 1H), 7.35 – 7.21 (m, 5H), 7.21 – 7.11 (m, 2H), 5.00 – 4.91 (m, 2H), 4.66 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.36 (s, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.16 (d, J = 7.0 Hz, 1H), 3.85 (q, J = 5.6 Hz, 1H), 3.75 – 3.65 (m, 1H), 3.28 (q, J = 1.6 Hz, 1H), 1.46 (d, J = 5.6 Hz, 2H), 1.31 (s, 32H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 770.4 [M−H]−. Intermediate 73-1: (R)-1-((tert-butyldimethylsilyl)oxy)nonadec-4-yn-2-ol
Figure imgf000258_0001
- To a solution of hexadec-1-yne (1.05 g, 4.72 mmol) in THF (10 mL) at -78 C was added n-butyllithium (1.5 M in hexanes, 3.01 mL, 4.82 mmol). The reaction was warmed to 0 C and stirred for 30 mins, at which point boron trifluoride diethyl etherate (0.37 mL, 3.21 mmol) was added and stirred at the same temperature for 15 mins. tert-butyl (R)-glycidyl ether (605 mg, 3.21 mmol) was then added at once and allowed to stir for 2 h. The reaction was then quenched at 0 °C with saturated aqueous ammonium chloride (50 mL), and diluted with diethyl ether (100 mL). The aqueous phase was then extracted with additional diethyl ether (2x 50 mL), the pooled organic fractions were washed with brine (50 mL), and then dried over magnesium sulfate. Following filtration and concentration, the crude residue was purified by flash column chromatography (0 to 20% ethyl acetate in hexanes) to afford intermediate 73-1.1H NMR (400 MHz, Chloroform-d) δ 4.14 (dq, J = 5.2, 1.3 Hz, 1H), 3.87 (dd, J = 11.9, 3.2 Hz, 1H), 3.81 – 3.59 (m, 2H), 3.19 – 3.04 (m, 1H), 2.79 (dd, J = 5.2, 4.0 Hz, 1H), 2.66 (dd, J = 5.2, 2.7 Hz, 1H), 2.47 – 2.31 (m, 1H), 2.17 (tt, J = 7.2, 2.4 Hz, 1H), 2.11 – 1.96 (m, 1H), 1.53 – 1.43 (m, 1H), 1.39 – 1.20 (m, 13H), 0.99 – 0.82 (m, 27H), 0.15 – 0.02 (m, 14H). Intermediate 73-2: (R)-((2-(benzyloxy)nonadec-4-yn-1-yl)oxy)(tert-butyl)dimethylsilane
Figure imgf000259_0001
- Intermediate 73-2 was prepared in a manner similar to Intermediate 35-2 using Intermediate 8-1 instead of Intermediate 3-1 and using benzyl bromide instead of 3-fluoro-5- bromomethyl benzonitrile.1H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.31 (m, 5H), 4.79 – 4.46 (m, 2H), 3.87 (dd, J = 11.9, 3.2 Hz, 1H), 3.81 – 3.67 (m, 2H), 3.65 – 3.56 (m, 1H), 3.51 – 3.44 (m, 1H), 3.43 – 3.37 (m, 1H), 3.15 – 3.07 (m, 1H), 2.79 (dd, J = 5.2, 4.0 Hz, 1H), 2.66 (dd, J = 5.1, 2.7 Hz, 1H), 2.54 – 2.38 (m, 1H), 2.16 (tq, J = 7.2, 2.5 Hz, 1H), 1.56 – 1.44 (m, 1H), 1.43 – 1.20 (m, 16H), 0.98 – 0.81 (m, 24H), 0.15 – 0.02 (m, 13H). Intermediate 73-3: (R)-2-(benzyloxy)nonadec-4-yn-1-ol
Figure imgf000259_0002
Intermediate 73-3 was prepared in a manner similar to Intermediate 70-3 using Intermediate 8-2 instead of Intermediate 3-2.1H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 4.4 Hz, 4H), 7.36 – 7.30 (m, 1H), 4.74 (d, J = 11.6 Hz, 1H), 2.53 (ddt, J = 16.4, 4.7, 2.5 Hz, 1H), 2.48 – 2.36 (m, 1H), 2.16 (tt, J = 7.1, 2.4 Hz, 2H), 1.50 (p, J = 6.9 Hz, 2H), 1.28 (s, 22H), 0.90 (t, J = 6.8 Hz, 3H). Example 73: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(benzyloxy)nonadec-4-yn-1-yl) hydrogen phosphate (73):
Figure imgf000260_0001
Example 73 was prepared in a manner similar to Example 68 using Intermediate 8-3 instead of 3-fluoro-5-[[(1S)-1-(hydroxymethyl)-2-octadecoxy-ethoxy]methyl]benzonitrile.1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.35 (d, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.26 – 7.21 (m, 2H), 7.16 (d, J = 4.7 Hz, 1H), 4.79 (d, J = 5.2 Hz, 1H), 4.63 (s, 2H), 4.35 (s, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.19 (d, J = 9.5 Hz, 1H), 4.09 (dd, J = 10.3, 5.8 Hz, 1H), 3.94 (dp, J = 16.4, 5.7 Hz, 1H), 3.75 – 3.62 (m, 1H), 2.13 (t, J = 6.9 Hz, 2H), 1.45 (q, J = 7.2, 6.5 Hz, 1H), 1.29 (d, J = 7.0 Hz, 27H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: 738.3 [M-H]. Example 74: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl)oxy)nonadec-4-yn-1-yl) hydrogen phosphate (74):
Figure imgf000260_0002
Example 74 was prepared in a manner similar to Example 73 using 3-fluoro-5- bromomethyl benzonitrile instead of benzyl bromide.1H NMR (400 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.56 (s, 1H), 7.50 – 7.46 (m, 1H), 7.39 (dt, J = 8.3, 1.9 Hz, 1H), 7.17 – 7.08 (m, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.77 – 4.64 (m, 2H), 4.39 – 4.34 (m, 1H), 4.26 (t, J = 5.5 Hz, 1H), 4.20 (ddd, J = 11.6, 5.4, 3.3 Hz, 1H), 4.13 – 4.06 (m, 1H), 4.02 – 3.89 (m, 1H), 3.72 (p, J = 5.5 Hz, 1H), 2.44 (tt, J = 6.4, 2.4 Hz, 1H), 2.14 (ddt, J = 6.9, 4.6, 2.4 Hz, 2H), 1.39 – 1.22 (m, 23H), 0.91 (t, J = 6.8 Hz, 3H). LCMS: 781.4 [M-H]. Example 75: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-((4-cyano-3-fluorobenzyl)oxy)nonadec-4-yn-1-yl) hydrogen phosphate (75):
Figure imgf000261_0001
Example 75 was prepared in a manner similar to Example 73 using 2-fluoro-4- bromomethyl benzonitrile instead of benzyl bromide.1H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.65 (dd, J = 8.0, 6.7 Hz, 1H), 7.36 (dd, J = 22.9, 9.2 Hz, 2H), 7.00 (dd, J = 32.2, 4.6 Hz, 2H), 4.82 (d, J = 5.2 Hz, 2H), 4.79 – 4.66 (m, 4H), 4.35 (d, J = 5.1 Hz, 1H), 4.27 (t, J = 5.4 Hz, 1H), 4.15 (t, J = 4.3 Hz, 1H), 4.11 – 4.03 (m, 1H), 3.92 (dq, J = 21.5, 5.4 Hz, 2H), 3.68 (dd, J = 10.5, 5.4 Hz, 1H), 2.40 (t, J = 6.9 Hz, 2H), 2.11 (d, J = 7.3 Hz, 2H), 1.43 (t, J = 7.2 Hz, 1H), 1.30 (s, 15H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: 781.4 [M-H]. Example 76: RSV-Fluc antiviral assay Normal human brochial epithelial (NHBE) cells donor 32027 are purchased from Lonza (Walkersville, MD Cat# CC-2540) and maintained in Bronchial Epithelial Cell Growth Medium (BEGM) (Lonza, Walkersville, MD, Cat# CC-3170) with all provided supplements in the BulletKit. Cells are passaged 2-3 times per week to maintain sub-confluent densities and were used for experiments at passages 2-4. Recombinant Respiratory Syncytial virus strain A2 containing the firefly luciferase reporter between the P and M genes (RSV-Fluc, 6.3 x 106 TCID50/mL) is purchased from Viratree (Durham, NC, Cat# R145). NHBE cells (5 x 103/well) are seeded in 100 µL white wall/clear bottom 96-well plates (Corning) with culture medium and are incubated for 24 hours at 37 oC with 5% CO2. On the following day, three-fold serial dilutions (starting at 5 µM and ending at 0.002 µM) of compounds prepared in DMSO are added to the wells using the HP D300e digital dispenser with normalization to the highest concentration of DMSO in all wells (>0.1% final volume). The cells are then infected with RSV-Fluc diluted with BEGM media at an MOI of 0.1 for a final volume of 200 µl media/well. Uninfected and untreated wells are included as controls to determine compound efficacy against RSV-Fluc. Following incubation with compound and virus for three days at 37 oC with 5% CO2, 100 µL of culture supernatant is removed from each well and replaced with 100 µL of ONE-Glo luciferase reagent (Promega, Madison, WI, Cat# E6110). The plates are gently mixed by rocking for 10 minutes at 25 oC and luminescence signal is measured using an Envision plate reader (PerkinElmer). Values are normalized to the uninfected and infected DMSO controls (0% and 100% infection, respectively). Non-linear regression analysis is applied to determine the compound concentration at which 50% luminescence signal is reduced (EC50) using the XLfit4 add-in for Microsoft®; Excel®. All experiments are performed in duplicate with two technical repeats each. Example 77: SARS-CoV-2 antiviral assay Antiviral activity of compounds against SARS-CoV-2 is evaluated as described in Xue, Xi et al.2020. Briefly, the human alveolar epithelial cell line (A549) is maintained in a high- glucose DMEM supplemented with 10% fetal bovine serum, 1% P/S and 1% HEPES (ThermoFisher Scientific). The A549-hACE2 cells that stably express human angiotensin- converting enzyme 2 (hACE2) are grown in the culture medium supplemented with 10 μg/mL Blasticidin S (Mossel E. C., et al 2005). Cells are grown at 37 °C with 5% CO2. All culture medium and antibiotics are purchased from ThermoFisher Scientific (Waltham, MA). All cell lines are tested negative for mycoplasma. A549-hACE2 cells (12,000 cells per well in phenol- red free medium containing 2% FBS) are plated into a white opaque 96-well plate (Corning). On the next day, 2-fold serial dilutions of compounds are prepared in DMSO. The compounds are further diluted 100-fold in the phenol-red free culture medium containing 2% FBS. Cell culture fluids are removed and incubated with 200 nL of diluted compound solutions and 50 μL of SARS-CoV2-Nluc viruses (MOI 0.025). At 48 h post-infection, 50 μL Nano luciferase substrates (Promega) are added to each well. Luciferase signals are measured using a Synergy™ Neo2 microplate reader. The relative luciferase signals are calculated by normalizing the luciferase signals of the compound-treated groups to that of the DMSO-treated groups (set as 100%). The relative luciferase signal (Y axis) versus the log10 values of compound concentration (X axis) is plotted in software Prism 8. The EC50 (compound concentration for reducing 50% of luciferase signal) are calculated using a nonlinear regression model (four parameters). Two experiments are performed with technical duplicates. Example 78: A549 cytotoxicity analysis The cytotoxicity of compounds is determined in A549 cells in the following manner. Compounds (40 nL) are spotted onto 384-well Grenier plates prior to seeding 5000 A549 cells/well in a volume of 40 µL culture medium. The plates are incubated at 37 ⁰C for 48 hours with 5% CO2. On day 2, 40 µL of CellTiter-Glo (Promega) is added and mixed 5 times. Plates are read for luminescence on an Envision (PerkinElmer) and the CC50 (compound concentration for reducing 50% of luminescence signal as a measure of cell viability) are calculated using a nonlinear regression model (four parameters). Two experiments are performed with technical duplicates. Example 79: MT4 cytotoxicity analysis 3-fold serially diluted compound in DMSO, ranging from 2.5 uM to 10 mM, were added by acoustic transfer (Echo) in quadruplicate into black 384-well plates at 200 nl/well. After compound addition, 40 ul MT-4 cells at 80,000/ml were added to each well using a MicroFlo liquid dispenser (BioTek, Winooski, VT) and the cells were cultured for five days at 37 °C. Following the incubation, cell viability was determined by adding 35 μL of CellTiter-Glo viability reagent and mixed thoroughly using ViaFlo 384 well workstation. The mixture was incubated for at least 10 minutes at 25 °C, and the luminescence signal was quantified on an EnVision plate reader.
Table 1: RSV antiviral data for exemplary compounds.
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Table 2: SARS-CoV-2 antiviral data for exemplary compounds.
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Table 3: A549 cytotoxicity data for exemplary compounds.
Figure imgf000271_0001
Table 4: MT4 CC50 for exemplary compounds.
Figure imgf000271_0002
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0002
Example 80: Rat lung phosphate (monophosphate, diphosphate and triphosphate) data with exemplary compounds Measurement of GS-441524 (compound A below) and its phosphorylated metabolites (compounds B, C, and D below) in lung tissues was performed according to the following protocol.
Figure imgf000274_0001
The concentrations of GS-441524 (A) and its phosphorylated metabolites (B, C, and D) were determined in Sprague-Dawley (SD) rats following oral gavage administration of the test compounds. The in-life phase of studies was conducted at Covance Laboratories (Madison, WI). Animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources. The protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC). Male SD rats weighing approximately 0.3 kg were used for in-life portion of the studies. The animals were fasted overnight prior to the test compound administration and up to 4 hours post-dose. The animals were administered with the test compound at 5, 8, 10 or 20 mg/kg via oral gavage (3 rats per group). The aqueous formulation contains ethanol, dimethyl sulfoxide, Kolliphor HS-15, Labrasol, and propylene glycol. Approximately 0.5 grams of lung tissue samples were collected from each animal and analyzed by LC/MS/MS for determination of the concentrations of GS- 441524 and its phosphorylated metabolites. For LC-MS/MS analysis, tissue samples were homogenized and extracted with 4-fold volume of 70% methanol containing 0.1% potassium hydroxide, 67 mM ethylenediamine tetraacetic acid, and internal standard. Approximately 200 ^L aliquot of the homogenate was filtered using a 96-well filter plate (0.2 ^m polypropylene; Agilent Captiva, Santa Clara, CA). The filtrate was evaporated to dryness and reconstituted with equal volume of 1 mM ammonium phosphate buffer (pH 7). The samples were then analyzed on a Sciex 6500+ LC-MS/MS instrument (Redwood City, CA). Analytes were eluted on a 2.5 μm 50 × 2.0 mm Phenomenex Luna C18 HST column (Torrance, CA) using mobile phases containing 3 mM ammonium formate and 10 mM dimethylhexylamine and a linear gradient from 9% to 50% acetonitrile at a flow rate of 360 μL/min. Data acquisition and processing were accomplished using Sciex Analyst® Software. Total summed levels of GS-441524 phosphorylate metabolites (B+C+D) in lung tissues were generated from the sum of GS-441524 mono-, di- and tri-phosphate (B, C, and D respectively).
Figure imgf000276_0001
All references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

CLAIMS 1. A compound of Formula I:
Figure imgf000278_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein: Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; RZB and RZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is a bond, -O-, -OCO-, -(CR12AR12B)q-, -O(CR12AR12B)q-, -OCR12AR12B- (CR13=CR14)-, -(CR12AR12B)q-O-(CR12AR12B)q-, -S-, (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein each R12A is independently H, C1-C6 alkyl, or phenyl; or R2 and R12A are joined to form a four to six membered cycloalkyl or a four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S; each R12B is independently H or C1-C6 alkyl; or R12A and R12B on same carbon are joined together to form a C3-C6 cycloalkylene; R12C is H, C1-C3 alkyl, -COR12D, or -SO2R12E, or R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl; R12D is C1-C3 alkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein R12D is optionally substituted with one, two, or three R12G groups; each R12G is independently a C1-C3 alkyl, phenyl, halo, C1- C3 alkoxy, cyano, C1-C3haloalkyl, or -COOR12H; R12H is H or C1-C3 alkyl; R12E is H or C1-C3 alkyl; R13 is H, C1-C6 alkyl, or phenyl; R14 is H, C1-C6 alkyl, or phenyl; and each q is independently 1 or 2; each p is independently 0, 1, or 2; X1 is a bond, -O-, NRX, or -CONRX-, or -S-; RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA; RXA is C1-C3 alkyl; X2 is -O- or -S-; X3 is -O- or -S-; X4 is =O or =S; R1 is H, C1-C20 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, S and O, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one, two, or three R1A groups; wherein each R1A is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R1B, -COOR1B, or C1-C3haloalkyl; or two R1A on same or adjacent carbons are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O; R1B is H or C1-C3 alkyl; R2 is H or C1-C3 alkyl; Y is a bond, phenylene, or C3-C6 cycloalkylene; R3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; each R4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R4 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon double bond; each R5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; R6 is H or -C(O)C1-C6 alkyl; R7 is H or -C(O)C1-C6 alkyl; and m is an integer from 7 to 21; wherein when X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)- then: (a) Z1 is a bond, -CRZARZB-, or -CRZARZB-CRZCRZD-; (b) Z2 is a bond, -CRZERZF-, or -CRZERZF-CRZGRZH-; (c) R2 and R12A are joined to form a four to six membered cycloalkyl or four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S; (d) X1 is a bond, NRX, or -CONRX-, or -S-; (e) X2 is -S-; (f) X3 is -S-; (g) X4 is =S; (h) R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is substituted with three R1A groups; (i) R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; (j) at least one R1A is -SO2R1B or -COOR1B; or (k) m is 7, 8, or 9.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B-(CR13=CR14)-.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and Z1 is a bond, -CRZARZB-, or -CRZARZB-CRZCRZD-.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and Z2 is a bond, -CRZERZF-, or -CRZERZF-CRZGRZH-.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and R2 and R12A are joined to form a four to six membered cycloalkyl or four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and X1 is a bond, NRX, or -CONRX-, or -S-.
7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and X2 is -S-.
8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and X3 is -S-.
9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and X4 is =S.
10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and R1 is C1-C20 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein the R1 group is substituted with three R1A groups.
11. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond.
12. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and at least one R1A is -SO2R1B, -COOR1B.
13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is a bond, -O-, -(CR12AR12B)q-, -O(CR12AR12B)q-, or -OCR12AR12B- (CR13=CR14)-; and m is 7, 8, or 9.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl; RZB and RZF are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; X is -OCO-, -(CR12AR12B)q-O-(CR12AR12B)q-, -S-, (CR12AR12B)p-NR12C- (CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-; wherein each R12A is independently H, C1-C6 alkyl, or phenyl; or R2 and R12A are joined to form a four to six membered cycloalkyl or a four to six membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S; each R12B is independently H or C1-C6 alkyl; or R12A and R12B on same carbon are joined together to form a C3-C6 cycloalkylene; R12C is H, C1-C3 alkyl, -COR12D, or -SO2R12E, or R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl; R12D is C1-C3 alkyl, C6-C10 aryl, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein R12D is optionally substituted with one, two, or three R12G groups; wherein each R12G is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, C1-C3haloalkyl, or -COOR12H; R12H is H or C1-C3 alkyl; R12E is H or C1-C3 alkyl; and R13 is H, C1-C6 alkyl, or phenyl; R14 is H, C1-C6 alkyl, or phenyl; and each q is independently 1 or 2; each p is independently 0, 1, or 2; X1 is a bond, -O-, NRX, or -CONRX-, or -S-; RX is H, C1-C3 alkyl, C1-C3 haloalkyl, or -C(O)RXA; RXA is C1-C3 alkyl; X2 is -O- or -S-; X3 is -O- or -S-; X4 is =O or =S; R1 is H, C1-C20 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 4 to 6 membered heterocyclyl containing one, two or three heteroatoms selected from N, O, and S, or 5-10 membered heteroaryl containing one, two or three heteroatoms selected from N, S, and O; wherein when R1 is not H, the R1 group is optionally substituted with one, two, or three R1A groups; wherein each R1A is independently a C1-C3 alkyl, phenyl, halo, C1-C3 alkoxy, cyano, -SO2R1B, -COOR1B, or C1-C3haloalkyl; or two R1A on same or adjacent carbons are joined together to from a 3 to 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring containing one, two or three heteroatoms selected from N, S, and O; R1B is H or C1-C3 alkyl; R2 is H or C1-C3 alkyl; Y is a bond, phenylene, or C3-C6 cycloalkylene; R3 is H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; each R4 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or or two R4 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon double bond; each R5 is independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; R6 is H or -C(O)C1-C6 alkyl; R7 is H or -C(O)C1-C6 alkyl; and m is an integer from 7 to 21.
15. The compound claim 1 or 14, or the pharmaceutically acceptable salt thereof, wherein X is (CR12AR12B)p-NR12C-(CR12AR12B)p- or (CR12AR12B)p-NR12CCO-(CR12AR12B)p-.
16. The compound of any one of claims 1, 14, or 15, or the pharmaceutically acceptable salt thereof, wherein X is -(CR12AR12B)p-NR12CCO-(CR12AR12B)p-.
17. The compound of any one of claims 1, 14, or 15, or the pharmaceutically acceptable salt thereof, wherein X is -(CR12AR12B)p-NR12C-(CR12AR12B)p-.
18. The compound of any one of claims 1 and 14-17, or the pharmaceutically acceptable salt thereof, wherein each p is independently 0 or 1.
19. The compound of any one of claims 1 and 14-18, or the pharmaceutically acceptable salt thereof, wherein each p is 0.
20. The compound of any one of claims 1 and 14-19, or the pharmaceutically acceptable salt thereof, R12C is H, C1-C3 alkyl, or -COR12D.
21. The compound of any one of claims 1 and 14-20, or the pharmaceutically acceptable salt thereof, wherein R12D is methyl.
22. The compound of any one of claims 1 and 14-21, or the pharmaceutically acceptable salt thereof, R12C is H, methyl, or -COCH3.
23. The compound of any one of claims 1 and 14-19, or the pharmaceutically acceptable salt thereof, wherein R12C and R1 are joined together to form a 5 to 6 membered heterocyclyl having one, two or three heteroatoms selected from N, O, and S, and optionally substituted with one to four R12F groups; wherein each R12F is independently oxo or halo, or two R12F on adjacent carbons are joined to form a fused phenyl optionally substituted with one or two substituents independently selected from F and Cl.
24. The compound of claim 23, or the pharmaceutically acceptable salt thereof, wherein each p is 0; X is -NR12C-; and R12C and R1 are joined together to form
Figure imgf000288_0001
, , ,
Figure imgf000288_0002
.
25. The compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, wherein X is a bond, -O-, -S-, -CH2O-, -NH-, -N(C(O)CH3)-, -NCH3-, or - N(CH3)CO-.
26. The compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H or C1-C3 alkyl; and RZB and RZF are each independently C1-C3 alkyl.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -CH2-, -CH2-CH2-, -CRZARZB-, or -CRZARZB-CRZCRZD-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-, or -CRZERZF-CRZGRZH; RZA, RZC, RZD, RZE, RZG, and RZH is each independently H or methyl; and RZB and RZF are both methyl.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -CH2-, -CH2-CH2-, or -CRZARZB-; Z2 is a bond, -CH2-, -CH2-CH2-, -CRZERZF-; RZA and RZE, RZG, and RZH is each independently H or methyl; and RZB and RZF are both methyl.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -CH2-, -CH2-CH2-, or -CH(CH3)-; and Z2 is a bond, -CH2-, -CH2- CH2-, or -CH(CH3)-.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Z1 is -CH2- and Z2 is -CH2-.
31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Z1 is -C(CH3)H- and Z2 is -CH2-.
32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Z1 is -CH2- and Z2 is -C(CH3)H-.
33. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Z1 is -CH2- and Z2 is a bond.
34. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond and Z2 is -CH2-.
35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X1 is a bond, -O-, -NRx, or S.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein X1 is a bond, -O-, or S.
37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein X1 is a bond or -O-.
38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein X1 is a bond.
39. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein X1 is -NRx or -CONRX-.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Rx is C1-C3 alkyl or -C(O)RXA.
41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein Rx is C1-C3 alkyl.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein Rx is methyl.
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein Rx is -C(O)RXA.
44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein RXA is methyl.
45. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein X1 is O.
46. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein X1 is S.
47. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein the compound is of a Formula Ia:
Figure imgf000291_0001
48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein X2 is S.
49. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein X2 is O.
50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein X3 is S.
51. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein X3 is O.
52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein X4 is S.
53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein X4 is O.
54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
55. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C3 alkyl.
56. The compound of any one of claims 1-53 and 55, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
57. The compound of any one of claims 1-56, or the pharmaceutically acceptable salt thereof, wherein R1 is selected form the group consisting of H
Figure imgf000292_0001
, and
Figure imgf000292_0002
.
58. The compound of any one of claims 1-57, or the pharmaceutically acceptable salt thereof, wherein R1 is H.
59. The compound of any one of claims 1-56, or the pharmaceutically acceptable salt thereof, wherein R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups.
60. The compound of claim 47 and 59, wherein X2 is O; X3 is O; X4 is O; R2 is H and R1 is C6-C10 aryl optionally substituted with one, two, or three R1A groups.
61. The compound of any one of claims 1-60, or the pharmaceutically acceptable salt thereof, wherein each R6 and R7 is H.
62. The compound of any one of claims 1-61, or the pharmaceutically acceptable salt thereof, wherein: R3 is H or C1-C3 alkyl; each R4 is independently H or C1-C3 alkyl; each R5 is independently H or C1-C3 alkyl; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; and m is an integer form 8-20.
63. The compound of any one of claims 1-62, or the pharmaceutically acceptable salt thereof, wherein R3 is H; each R4 is H; each R5 is H; or R4 and R5 groups on adjacent carbon atoms together with the carbons to which they are attached form a carbon carbon triple bond; and m is an integer form 10-20.
64. The compound of any one of claims 1-63, or the pharmaceutically acceptable salt thereof, wherein R3 is H; each R4 is H; each R5 is H; and m is an integer form 14-20.
65. The compound of any one of claims 1-64, or the pharmaceutically acceptable salt thereof, wherein R3 is H; each R4 is H; each R5 is H; and m is 17, 18, or 19.
66. The compound of any one of claims 1-65, or the pharmaceutically acceptable salt thereof, wherein m is 17.
67. The compound of any one of claims 1-65, or the pharmaceutically acceptable salt thereof, wherein m is 18.
68. The compound of any one of claims 1-65, or the pharmaceutically acceptable salt thereof, wherein m is 19.
69. The compound of any one of claims 1-68, or the pharmaceutically acceptable salt thereof, wherein each R1A is independently C1-C3 alkyl, cyano, halo, or C1-C3 alkoxy.
70. The compound of any one of claims 1-68, or the pharmaceutically acceptable salt thereof, wherein each R1A is independently halo or cyano.
71. The compound of any one of claims 1-70, or the pharmaceutically acceptable salt thereof, wherein each R1A is independently fluoro, chloro, or cyano.
72. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000295_0001
,
Figure imgf000296_0001
Figure imgf000297_0001
,
Figure imgf000298_0001
, and
Figure imgf000298_0002
or a pharmaceutically acceptable salt thereof.
73. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000299_0001
,
Figure imgf000300_0001
,
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
pharmaceutically acceptable salt thereof.
74. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000304_0002
,
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000306_0002
, and or a pharmaceutically acceptable salt thereof.
Figure imgf000306_0003
75. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000307_0001
, and
Figure imgf000307_0002
Figure imgf000307_0003
, or a pharmaceutically acceptable salt thereof.
76. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000308_0001
,
Figure imgf000309_0001
Figure imgf000310_0001
, or a pharmaceutically acceptable salt thereof.
77. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of:
Figure imgf000310_0002
,
Figure imgf000311_0001
Figure imgf000312_0001
, or a pharmaceutically acceptable salt thereof.
78. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of: , and
Figure imgf000312_0002
Figure imgf000312_0003
, or a pharmaceutically acceptable salt thereof.
79. The compound of any one of claims 1-71, wherein the compound is selected from a group consisting of:
Figure imgf000313_0001
pharmaceutically acceptable salt thereof.
80. The compound of any one of claims 1-71, wherein the compound is of formula: , or a pharmaceutically acceptable salt thereof.
Figure imgf000313_0002
81. The compound of any one of claims 1-71, wherein the compound is of formula:
Figure imgf000313_0003
, or a pharmaceutically acceptable salt thereof.
82. The compound of any one of claims 1-71, wherein the compound is of formula:
Figure imgf000314_0001
, or a pharmaceutically acceptable salt thereof.
83. The compound of any one of claims 1-71, wherein the compound is of formula: , or a pharmaceutically
Figure imgf000314_0002
acceptable salt thereof.
84. The compound of any one of claims 1-71, wherein the compound is of formula:
Figure imgf000314_0003
, or a pharmaceutically acceptable salt thereof.
85. The compound of any one of claims 1-71, wherein the compound is of formula:
Figure imgf000315_0001
, or a pharmaceutically acceptable salt thereof.
86. The compound of any one of claims 1-71, wherein the compound is of formula:
Figure imgf000315_0002
, or a pharmaceutically acceptable slat thereof.
87. The compound of any one of claims 1-71, wherein the compound is selected from the group consisting of: and
Figure imgf000315_0003
, or a pharmaceutically acceptable salt thereof.
Figure imgf000316_0001
88. A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
89. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for subcutaneous administration.
90. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for intravenous administration.
91. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for oral administration.
92. The pharmaceutical formulation of claim 88, wherein the pharmaceutical formulation is for administration by inhalation.
93. A method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human the compound of any one of claims 1- 87, or a pharmaceutically acceptable salt thereof.
94. The method of claim 93, wherein the compound is administered to the human via oral, intravenous, subcutaneous, or inhalation administration.
95. The method of claim 93 or 94, wherein the method comprises administering to the human at least one additional therapeutic or prophylactic agent.
96. The method of any one of claims 93-95, wherein the viral infection is a coronavirus infection.
97. The method of any one of claims 93-96, wherein the viral infection is a zoonotic coronavirus infection.
98. The method of any one of claims 93-97, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
99. The method of any one of claims 93-98, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
100. The method of any one of claims 93-99, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
101. The method of any one of claims 93-100, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
102. The method of any one of claims 93-96, wherein the viral infection is selected form the group consisting of 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection.
103. The method of any one of claims 93-101, wherein the viral infection is SARS-CoV-2 infection.
104. The method of any one of claims 93-101, wherein the viral infection is a SARS virus infection.
105. The method of any one of claims 93-101, wherein the viral infection is a MERS virus infection.
106. The method of any one of claims 93-95, wherein the viral infection is a pneumoviridae virus infection.
107. The method of claim 106, wherein the pneumoviridae virus infection is respiratory syncytial virus infection.
108. The method of claim 106, wherein the pneumoviridae virus infection is human metapneumovirus infection.
109. The method of any one of claims 93-95, wherein the viral infection is a picornaviridae virus infection.
110. The method of claim 109, wherein the viral infection is an enterovirus infection.
111. The method of claim 109 or 110, wherein the viral infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.
112. The method of claim 109, wherein the picornaviridae virus infection is human rhinovirus infection.
113. The method of any one of claims 93-95, wherein the viral infection is a flaviviridae virus infection.
114. The method of claim 113, wherein the flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, zika virus infection, or a HCV infection.
115. The method of any one of claims 93-95, wherein the viral infection is a filoviridae virus infection.
116. The method of claim 115, wherein the filoviridae virus infection is an ebola virus infection or a Marburg virus infection.
117. The method of any one of claims 93-95, wherein the viral infection is an orthomyxovirus infection.
118. The method of claim 117, wherein the viral infection is an influenza virus infection.
119. The method of claim 117 or 118, wherein the viral infection is an influenza A virus infection or influenza B virus infection.
120. The method of any one of claims 93-95, wherein the viral infection is a paramyxoviridae virus infection.
121. The method of claim 120, wherein the viral infection is a human parainfluenza virus, nipah virus, Hendra virus, measles, or mumps infection.
122. A method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, characterized in that a compound of any one of claims 1-87, or a pharmaceutically acceptable salt thereof, is used.
123. Use of a compound of any one of claims 1-87, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.
124. The use of claim 123, wherein the medicament is used with at least one additional therapeutic agent.
125. The compound of any one of claims 1-87, or a pharmaceutically acceptable salt thereof, for use in treatment or prevention of a viral infection in a human in need thereof.
126. The compound of claim 125, wherein the compound is for use with at least one additional therapeutic agent.
127. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-87 for use in a method of treating or preventing a viral infection in a human in need thereof.
128. The compound or pharmaceutically acceptable salt thereof for use of claim 127, wherein the compound is administered to the human via oral, intravenous, subcutaneous, or inhalation administration.
129. The compound or pharmaceutically acceptable salt thereof for use of claim 127 or 128, further comprising administering to the human at least one additional therapeutic or prophylactic agent.
130. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a coronavirus infection.
131. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-130, wherein the viral infection is a zoonotic coronavirus infection.
132. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-131, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
133. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-132, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
134. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-133, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
135. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-134, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS polymerase, MERS polymerase and SARS-CoV-2.
136. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-130, wherein the viral infection is selected form the group consisting of 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection.
137. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-135, wherein the viral infection is SARS-CoV-2 infection.
138. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-135, wherein the viral infection is a SARS virus infection.
139. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-135, wherein the viral infection is a MERS virus infection.
140. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a pneumoviridae virus infection.
141. The compound or pharmaceutically acceptable salt thereof for use of claim 140, wherein the pneumoviridae virus infection is respiratory syncytial virus infection.
142. The compound or pharmaceutically acceptable salt thereof for use of claim 140, wherein the pneumoviridae virus infection is human metapneumovirus infection.
143. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a picornaviridae virus infection.
144. The compound or pharmaceutically acceptable salt thereof for use of claim 143, wherein the viral infection is an enterovirus infection.
145. The compound or pharmaceutically acceptable salt thereof for use of claim 143 or 144, wherein the viral infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.
146. The compound or pharmaceutically acceptable salt thereof for use of claim 143, wherein the picornaviridae virus infection is human rhinovirus infection.
147. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a flaviviridae virus infection.
148. The compound or pharmaceutically acceptable salt thereof for use of claim 147, wherein the flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, zika virus infection, or a HCV infection.
149. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a filoviridae virus infection.
150. The compound or pharmaceutically acceptable salt thereof for use of claim 149, wherein the filoviridae virus infection is an ebola virus infection or a Marburg virus infection.
151. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is an orthomyxovirus infection.
152. The compound or pharmaceutically acceptable salt thereof for use of claim 151, wherein the viral infection is an influenza virus infection.
153. The compound or pharmaceutically acceptable salt thereof for use of claim 151 or 152, wherein the viral infection is an influenza A virus infection or influenza B virus infection.
154. The compound or pharmaceutically acceptable salt thereof for use of any one of claims 127-129, wherein the viral infection is a paramyxoviridae virus infection.
155. The compound or pharmaceutically acceptable salt thereof for use of claim 154, wherein the viral infection is a human parainfluenza virus, nipah virus, Hendra virus, measles, or mumps infection.
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