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WO2021173713A1 - Composés hautement actifs contre la covid-19 - Google Patents

Composés hautement actifs contre la covid-19 Download PDF

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Publication number
WO2021173713A1
WO2021173713A1 PCT/US2021/019468 US2021019468W WO2021173713A1 WO 2021173713 A1 WO2021173713 A1 WO 2021173713A1 US 2021019468 W US2021019468 W US 2021019468W WO 2021173713 A1 WO2021173713 A1 WO 2021173713A1
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WIPO (PCT)
Prior art keywords
formula
compound
alkyl
hydrogen
aryl
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PCT/US2021/019468
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English (en)
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WO2021173713A8 (fr
Inventor
Jean-Pierre Sommadossi
Adel Moussa
Original Assignee
Atea Pharmaceuticals, 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.)
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Priority to MDA20220043A priority Critical patent/MD20220043A2/ro
Priority to JP2021529337A priority patent/JP7296460B2/ja
Application filed by Atea Pharmaceuticals, Inc. filed Critical Atea Pharmaceuticals, Inc.
Priority to KR1020227032719A priority patent/KR20230009361A/ko
Priority to PE2022001856A priority patent/PE20230172A1/es
Priority to IL295443A priority patent/IL295443A/en
Priority to EP21726031.4A priority patent/EP3897668A4/fr
Priority to MX2022010659A priority patent/MX2022010659A/es
Priority to MA57933A priority patent/MA57933A1/fr
Priority to CN202180002433.9A priority patent/CN113784721A/zh
Priority to JOP/2022/0200A priority patent/JOP20220200A1/ar
Priority to CA3166914A priority patent/CA3166914A1/fr
Priority to EP23171689.5A priority patent/EP4234565A3/fr
Priority to AU2021225851A priority patent/AU2021225851A1/en
Priority to BR112022016413A priority patent/BR112022016413A2/pt
Publication of WO2021173713A1 publication Critical patent/WO2021173713A1/fr
Publication of WO2021173713A8 publication Critical patent/WO2021173713A8/fr
Priority to ZA2022/08947A priority patent/ZA202208947B/en
Priority to CONC2022/0013750A priority patent/CO2022013750A2/es
Priority to ECSENADI202275410A priority patent/ECSP22075410A/es
Priority to JP2023096019A priority patent/JP7542888B2/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Definitions

  • the present invention is directed to the use of selected purine nucleotides and their pharmaceutically acceptable salts that have advantageous activity and dosage convenience for the treatment or prevention of the SARS-CoV-2 vims that causes COVID-19 in a host, typically a human, in need thereof.
  • SARS-CoV-2 is a coronavims (CoV), which is in the order Nidovirales , family Coronaviridae, subfamily Coronavirinae, which are enveloped vimses with a single-strand, positive-sense RNA genome.
  • SARS-CoV-2 is approximately 30 kilobases in size, which is among the largest known RNA genomes.
  • Related coronaviruses include severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).
  • SARS-CoV-2 only shares 79.5% of its genome with SARS-CoV, and is therefore considered a new human-infecting betacoronavirus (Zhou et al.
  • SARS-CoV-2 Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster human-to-human transmission rate (Huang et al., Lancet 2000, 395, 497), making it particularly challenging to contain and dangerous.
  • CoVs often originate as enzootic infections that cross the animal-human species barrier and progress to establish zoonotic diseases in humans (Lau et al., PNAS 2005, 102, 14040-5; Rest et al., Infect Genet Evol 2003, 3, 219-25).
  • Cross-species barrier jumps allowed CoVs such as the SARS CoV and the Middle Eastern respiratory syndrome CoV (MERS) to manifest as virulent human viruses (Schoeman and Fielding, Virology 2019, 16, 69).
  • SARS-CoV-2 is 96% identical at the whole-genome level to a bat coronavirus (Zhou et al. Nature 2020, 579, 270) and therefore most likely originated in bats.
  • SARS-CoV-2 enters human cells by binding to angiotensin converting enzyme 2 (hACE2) receptors.
  • hACE2 angiotensin converting enzyme 2
  • Spike glycoproteins on the surface of the virus envelope bind to the ACE2 receptor and then the human transmembrane protease serine 2 cleaves and activates the spike protein, which allows SARS-CoV-2 to enter the cell through endocytosis or direct fusion with the host membrane
  • nspl2 RNA-dependent RNA polymerase
  • RdRp RNA-dependent RNA polymerase
  • nspl2 contains a polymerase C-terminal RdRp domain that is connected to an N-terminal extension domain referred to as the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain.
  • NiRAN nidovirus RdRp-associated nucleotidyltransferase
  • NiRAN domain which is conserved in all nidoviruses that are able to conduct nucleotidylation activity, is characterized by an a and b fold composed of eight a helices and a five stranded b-sheet (Gao et al. Science 2020, 368:779-782).
  • the C-terminal domain has been characterized as a “cupped right hand” domain with finger, thumb, and palm subdomains.
  • the present invention provides a treatment for the SARS-CoV-2 vims in a host in need thereof comprising administering an effective amount of a selected purine nucleotide compound as further described herein for the advantageous treatment, prevention, or prophylaxis of the SARS- CoV-2 vims that causes COVID-19.
  • a selected purine nucleotide compound as further described herein for the advantageous treatment, prevention, or prophylaxis of the SARS- CoV-2 vims that causes COVID-19.
  • These purine nucleotides exhibit focused activity against the vims.
  • these compounds can be administered to hosts, such as humans, in need thereof, using a simple solid oral dosage form that can be conveniently taken at home or generally outside of a medical facility without requiring parenteral administration or hospitalization.
  • the active compounds described herein can alternatively be administered parenterally or orally in a medical facility.
  • the therapy can be used to treat mild, moderate or severe disease.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier is administered in an effective amount to a host, typically a human, in need thereof with COVID- 19 or a host at risk of infection or reinfection with the SARS-CoV-2 virus, i.e., as a prophylactic (and wherein the term prophylactic means total prevention or minimization of acquired infection relative to disease without such prophylactic treatment), wherein:
  • R 1 is selected from Ci-C 6 alkyl, C3-C6Cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • R 2 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), C3-7cycloalkyl, or aryl (including phenyl and napthyl) and in an alternative embodiment, R 2 is aryl(Ci-C4alkyl)-, heteroaryl, or heteroalkyl;
  • R 3 is hydrogen or Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl);
  • R 4a and R 4b are independently selected from hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), and C3-7cycloalkyl; and
  • R 5 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), Ci- 6 haloalkyl, or C3-7cycloalkyl and in an alternative embodiment, R 5 is aryl(Ci-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
  • Ci-Csalkyl include methyl, ethyl, propyl, isopropyl, butyl, t- butyl, sec-butyl, isobutyl, -C bC ⁇ CIE -CH(CH2CH3)2, and -CFhCF ⁇ C hCFF ⁇ .
  • C3-C6Cycloalkyl include cyclopropyl, CFh-cyclopropyl, cyclobutyl, and CFh- cyclobutyl.
  • aryl(Ci-C4alkyl)- is benzyl
  • aryl is phenyl
  • the SARS-CoV-2 virus is wild-type.
  • the SARS-CoV-2 virus has developed a natural or drug-induced mutation, for example, but not limited to, a mutation in a viral protein selected from an envelope (E) protein, membrane (M) protein, spike (S) protein, nspl, nsp2, nsp3, nsp4, nsp5, nsp 6, nsp7, nsp8, nsp9, nsplO, nspl2, nspl3, nspl4, nspl5, nsp 16, ORFlab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORFIO.
  • a non-limiting example of a compound of Formula I is Compound 1 or a pharmaceutically acceptable salt thereof.
  • Compound 1 or a pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier, is administered to a host in need thereof, such as a human, infected with SARS-CoV-2, or to a host at risk of infection with the SARS-CoV- 2 vims, i.e., as a prophylactic.
  • Compound 1 is depicted above without regard to stereochemistry at the phosphorus atom, which is chiral.
  • Compound 1 can be used either without regard to stereochemistry at the phosphorus, or a phosphoro-racemic form, or with any desired ratio of phosphorus R- and S-enantiomers of the compound, including enantiomerically enriched (i.e., up to at least 90%, 95%, 98%, 99%, or even 100% free of the opposite enantiomer, which are in fact diastereomers because there are multiple chiral carbons in the molecule).
  • Compound 1A is the S-enantiomer and Compound IB is the R- enantiomer.
  • Compound IB Compound 1, including Compound 1A and Compound IB are potent inhibitors against COVED- 19 caused by the SARS-CoV-2 virus. As described in Example 5 and Example 6, Compound 1A exhibits an EC90 value of 0.64 mM against SARS-Cov-2 in HAE cells (human airway epithelial cells). The assay using HAE cells is an in vitro model of the lung and is a representative system for SARS-CoV-2 replication. It has also surprisingly been discovered that the active triphosphate metabolite of Compound 1A is robustly formed when exposed to normal primary bronchial and nasal epithelial cells.
  • Example 7 when Compound 1A was incubated in human nasal and bronchial epithelial cells, the half-life of the active triphosphate species is greater than 1.5 days in both bronchial and nasal epithelial cells. This could not have been predicted in advance and is especially important in treating patients with early stages of the infection when the virus is heavily concentrated in the nasal and bronchial cells.
  • Compound 1, such as Compound 1A or Compound IB or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host, for example, a human, in need thereof infected with the SARS-CoV-2 virus, or a host at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic.
  • the pharmaceutically acceptable salt is a hemi-sulfate salt, shown below as Compound 2, Compound 2A, and Compound 2B:
  • Compound 2A was administered to non-human primates and the intracellular concentration of the active triphosphate species was measured in lung, kidney, and liver cells. Surprisingly, the active triphosphate metabolite concentrates in the lung over the liver (Table 8) and the half-life of the active metabolite in the lung is 9.4 hours (FIG. 7A). This is important because COVID-19 typically presents as a respiratory illness. In fact, the active triphosphate species concentration is 1.6 times higher in the lung than the liver after twice a day oral administration of 30 mg/kg of Compound 2A. Furthermore, the compounds of the present invention may inhibit SARS-CoV-2 infection via a unique mechanism of action that accounts for high selectivity.
  • CoV viral replication is achieved at the RNA-dependent RNA polymerase (RdRp) nspl2 subunit, which is activated by co factors nsp7 and nsp8.
  • RdRp RNA-dependent RNA polymerase
  • COVID-19 is an acute viral infection for which antiviral therapeutics may be effective within the first stage of the infection when viral load is at its maximum and there is rapid viral replication initially in nasal, throat and pulmonary cells.
  • the availability of a potent, safe, oral antiviral administered to individuals infected with SARS-CoV-2 in the early stages of the disease has the potential to avert clinical illness, minimize long term damage, and mitigate the COVED- 19 pandemic.
  • selected compounds of the present invention are able to concentrate in the lungs over the liver. This is therapeutically beneficial when treating patients in the first stages of infection with the SARS-CoV-2 pathogen when it is desirable to prevent or lessen late-stage viral damage.
  • High concentrations in the lung over the heart and liver is also therapeutically beneficial for treating patients in later stages of the infection.
  • the present invention also includes the use of a compound of Formula II in an effective amount to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof as described herein: or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from Ci-C 6 alkyl, C3-C6Cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • R 2 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), C3-7cycloalkyl, or aryl (including phenyl and napthyl) and in an alternative embodiment, R 2 is aryl(Ci-C4alkyl)-, heteroaryl, or heteroalkyl;
  • R 3 is hydrogen or Cnsalkyl (including methyl, ethyl, propyl, and isopropyl);
  • R 4a and R 4b are independently selected from hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), and C3-7cycloalkyl; and
  • R 5 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), Ci- 6 haloalkyl, or C3-7cycloalkyl and in an alternative embodiment, R 5 is aryl(Ci-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier is administered in an effective amount to a host in need thereof infected with the SARS-CoV-2 virus, or to a host at risk of infection or reinfection with the SARS-CoV-2 vims, i.e., as a prophylactic.
  • a non-limiting example of a compound of Formula II is Compound 3 or a pharmaceutically acceptable salt thereof.
  • Compound 3 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier is administered in an effective amount to a host in need thereof infected with the SARS-CoV-2 virus, or to a host at risk of infection with the SARS-CoV- 2 virus, i.e., as a prophylactic.
  • Compound 3 can be used in a phosphoro-racemic form, or with any desired ratio of phosphorus R- and S-enantiomers of the compound, including enantiomerically enriched material up to pure enantiomers.
  • Compound 3A is the S-enantiomer and Compound 3B is the R-enantiomer.
  • Compound 4 includes Compound 4A and Compound 4B.
  • Compound 4 optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof infected with the SARS-CoV-2 virus or to a host at risk of infection, i.e., as a prophylactic.
  • the present invention also includes the use of a compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof as described herein:
  • Ci-C3haloalkyl including Ci-3fluoroalkyl and Ci-3chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CFS, and CH C1), C 2 -C alkenyl, C 2 -C 4 alkynyl, and Ci-C3hydroxyalkyl; and R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • the compound of Formula III to treat or prevent COVID-19 disease is a compound or a pharmaceutically acceptable salt thereof of Formula Ilia, Formula Illb, Formula IIIc, Formula Hid, Formula Hie, or Formula Illf:
  • the present invention also includes the use of a compound of Formula IV in an effective amount to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof as described herein:
  • Ci-C3haloalkyl including Ci-3fluoroalkyl and Ci-3chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH , CF 2 CF 3 , and CH 2 C1), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and Ci-C3hydroxyalkyl; and
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • the compound of Formula IV to treat or prevent COVID-19 disease is a compound or a pharmaceutically acceptable salt thereof of Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, or Formula IVf:
  • the present invention also includes the use of a compound of Formula V in an effective amount to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof as described herein: or a pharmaceutically acceptable salt thereof, wherein: Y and Y’ are independently selected from Cl and F; and R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • Non-limiting examples of a compound of Formula V include
  • the present invention also includes the use of a compound of Formula VI to treat or prevent COVED- 19 in a host in need thereof as described herein: wherein
  • R 6 is selected from hydrogen, -C(0)R 6A , -C(0)0R 6A , Ci- 6 alkyl, and -CH 2 -0-R 6A and in an alternative embodiment, -C(0)NR 6B R 6C ;
  • R 6A is selected from hydrogen, Ci ⁇ alkyl, Ci-G,haloalkyl (for example, -CHCb, -CCb, -CH2CI, -CF3, -CHF2, -CH2F), aryl, and aryl(Ci- 6 alkyl)- wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl, and in an alternative embodiment, R 6A is selected from Ci-2oalkyl and C2-2oalkenyl;
  • R 6B and R 6C are independently selected from hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl wherein the Ci-2oalkyl, C2-2oalkenyl, aryl, aryl(Ci- ealkyl)-, heteroaryl, and heteroarylalkyl can optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;
  • R 7 is NFh, H, or -NR3 ⁇ 4 9 ;
  • R 8 and R 9 are independently selected from hydrogen, Ci- 6 alkyl, -C(0)R 6A , and -C(0)0R 6A ;
  • Y is selected from F and Cl;
  • Z is selected from methyl, Ci-C3haloalkyl (including Ci-3fluoroalkyl and Ci-3chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF , and CH 2 C1), C 2 - C4alkenyl, C 2 -C4alkynyl, Ci-C3hydroxyalkyl, and halogen (including Cl and F), and in an alternative embodiment, Z is Ciualkyl; and
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • Non-limiting examples of R 6 include Additional non-limiting examples of R 6 include: Additional non -limiting examples of R 6 include:
  • R 6 Additional non -limiting examples of R 6 include:
  • Non-limiting examples of a compound of Formula VI include
  • the present invention also includes the use of a compound of Formula VII to treat or prevent
  • R 6A is selected from hydrogen, Ci ⁇ alkyl, Ci-C 6 haloalkyl (for example, -CHCh, -CCI 3 , -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 F), aryl, and aryl(Ci- 6 alkyl)- wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl and in an alternative embodiment, R 6A is selected from Ci- 2 oalkyl and C 2-2 oalkenyl;
  • R 6B and R 6C are independently selected from hydrogen, Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl wherein the Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl can optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;
  • R 7 is NH 2 , H, or -NR 8 R 9 ;
  • R 8 and R 9 are independently selected from hydrogen, Ci- 6 alkyl, -C(0)R 6A , and -C(0)0R 6A ;
  • Y is selected from F and Cl;
  • Z is selected from methyl, Ci-C 3 haloalkyl (including Ci- 3 fluoroalkyl and Ci- 3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 C1), C 2 - C4alkenyl, C2-C4alkynyl, Ci-C3hydroxyalkyl, and halogen (including Cl and F), and in an alternative embodiment Z is Ci ⁇ alkyl;
  • R 40 is selected from H, Ci ⁇ alkoxy, Ci ⁇ alkyl, N 3 , CN, and halogen (including Cl and F);
  • R 41 is selected from H, Ci- 3 alkyl (including methyl) and halogen (including Cl, F, and Br);
  • R 42a and R 423 ⁇ 4 are independently selected from Ci alkyl (including methyl), NH 2 , H, - NR 8 R 9 , and -C(0)NR 8 R 9 ; and
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • the invention also includes a compound of Formula Vila, Formula Vllb, Formula Vile, and Formula Vlld:
  • Non-limiting examples of B include:
  • the present invention also includes the use of a compound of Formula VIII, Formula IX, or Formula X wherein R 10 is a monophosphate, a diphosphate, a triphosphate, or R 10A wherein R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate to treat or prevent COVID-19 disease in a host in need thereof as described herein:
  • R 10 is selected from
  • R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate;
  • R 11 is selected from hydrogen and R 1 ;
  • R 1 is selected from Ci-C 6 alkyl, C3-C6cycloalkyl, and -C(0)Ci-C 6 alkyl.
  • Non-limiting examples of compounds of Formula VIII, Formula IX, or Formula X include:
  • X include:
  • the phosphorus in any of the Formulas described herein may be chiral and thus can be provided as an R or S enantiomer or mixture thereof, including a racemic mixture.
  • the compound is typically at least 90% free of the opposite enantiomer, and can be at least 95%, 96%, 97%, 98%, 99% or even 100% free of the opposite enantiomer. Unless described otherwise, the compound is at least 90% free of the opposite enantiomer.
  • Compound 1 is depicted without regard to stereochemistry at the phosphorus atom, which is chiral.
  • Compound 1 can be used in a racemic form, or with any desired ratio of phosphorus R p - and S p -enantiomers of the compound, including enantiomerically enriched material up to pure enantiomers.
  • Compound 1A has S-stereochemistry at the phosphorus and Compound IB has R-stereochemistry at the phosphorus.
  • Compound 1 is used in a form at least 90% free of the opposite enantiomer, and can be at least 98%, 99% or even 100% free of the opposite enantiomer.
  • Compound 1A can be at least 90%, 95%, 98%, 99%, or even 100% free of the opposite R p - enantiomer.
  • Compound IB can be at least 90%, 95%, 98%, 99%, or even 100% free of the opposite S p -enantiomer.
  • Compound 2 is depicted without regard to stereochemistry at the phosphorus atom, which is chiral.
  • Compound 2 can be used in a racemic form, or with any desired ratio of phosphorus R- and S-enantiomers of the compound, including enantiomerically enriched material up to pure enantiomers.
  • Compound 2A has S-stereochemistry at the phosphorus and Compound 2B has R-stereochemistry at the phosphorus.
  • Compound 2 is used in a form at least 90% free of the opposite enantiomer, and can be at least 98%, 99% or even 100% free of the opposite enantiomer.
  • Compound 2A can be at least 90%, 95%, 98%, 99%, or even 100% free of the opposite R p -enantiomer.
  • Compound 2B can be at least 90%, 95%, 98%, 99%, or even 100% free of the opposite S p -enantiomer.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII drawn with regard to stereochemistry at the phosphorus atom is at least 90% free of the opposite enantiomer.
  • Compounds, compositions, dosage forms, and methods are provided for the treatment of COVED- 19 caused by the SARS-CoV-2 virus in a host in need thereof via administration of an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof can also be used in an effective amount prophylactically to prevent or restrict the progression of COVID-19 in a host in need thereof who has been exposed to the virus or who is at risk of infection or reinfection.
  • a loading dose is 1100 mg/day (free base) (i.e., 1200 mg/day hemisulfate salt of Compound 1)
  • a maintenance dose is 550 mg/day (free base) (i.e, 600 mg/day of hemisulfate salt)).
  • the loading dose is administered once and the maintenance dose is administered twice a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of at least about 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, or 1700 mg.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered at a dose of at least 250 mg, 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg or at least 1500 mg.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, including Compound 1 or a pharmaceutically acceptable salt thereof, for example Compound 2, is administered in a dosage form of about 550 mg once day.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, including Compound 1 or a pharmaceutically acceptable salt thereof, for example Compound 2, is administered in a dosage form of about 600 mg once a day.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 550 mg twice a day.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 600 mg twice a day.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 550 mg twice a day for at least five days, optionally with the standard of care.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 550 mg twice a day for at least five days, optionally with the standard of care.
  • Compound 1 is Compound 1A.
  • Compound 1 is Compound IB.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 600 mg twice a day for at least of days, optionally with the standard of care.
  • Compound 2 or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 600 mg twice a day for at least five days, optionally with the standard of care.
  • Compound 2 is Compound 2A.
  • Compound 2 is Compound 2B.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 550 mg twice a day for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with the standard of care.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 550 mg twice a day for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with the standard of care.
  • a compound of Formula I, Formula II, Formula IP, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 600 mg twice a day for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with the standard of care.
  • Compound 2 or a pharmaceutically acceptable salt thereof is administered in a dosage form of about 600 mg twice a day for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with the standard of care.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered at an initial dose (or loading dose) followed by a maintenance dose, wherein the loading dose is at the discretion of the physician based on the severity of the presented disease and the size of the patient.
  • the loading dose is about or at least 1.5 times greater, about or at least 2 times greater, about or at least 2.5 times greater, or about or at least 3 times greater than the maintenance dose.
  • the loading dose is administered once, twice, three, four, or more times before the first maintenance dose, and may be given once, twice, three, or four times a day as instructed by the physician.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered at a daily loading dose (which can be provided in one or several dosages throughout the day) of at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg, at least about 1200 mg, at least about 1300 mg, or at least about 1400 mg followed by a maintenance dose of at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, or at least about 750 mg and the maintenance dose is taken once, twice, or three times a day.
  • a daily loading dose (which can be provided in one or several dosages throughout the day) of at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1
  • the maintenance dose is taken twice a day, and optionally over 1, 2, 3, or 4 days. In one embodiment, the maintenance dose is thereafter administered 1, 2 or 3 times a day for at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or more.
  • Compound 1 or Compound 3 or a pharmaceutically acceptable salt thereof, including Compound 2 or Compound 4 is administered at a dose of at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 650, or at least about 750 and the dose is taken once, twice, or three times a day.
  • Compound 1 or a pharmaceutically acceptable salt thereof, for example Compound 2 is administered at a dose of at least about 500 mg, at least about 550 mg, or at least 600 mg and the dose is taken twice daily.
  • Compound 1 or a pharmaceutically acceptable salt thereof, for example Compound 2 is administered at a loading dose of at least about 1000 mg, at least about 1100 mg, or at least about 1200 mg followed by a maintenance dose of at least about 500 mg, at least about 550 mg, or at least 600 mg twice daily. In one embodiment, the maintenance dose is administered for at least about 4, 5, 6, 7, 8, 9, 10, or more days.
  • Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound IB.
  • Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B
  • Compound 1 is administered at a dose of at about 550 mg and the dose is taken twice daily. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound IB.
  • Compound 2 is administered at a dose of at about 600 mg and the dose is taken twice daily. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B.
  • the method of the present invention includes administering a compound as described herein, such as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, for example Compound 1 or Compound 2, once, twice, three, or four or more times a day as necessary to treat the infection.
  • a compound as described herein such as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, for example Compound 1 or Compound 2, once, twice, three, or four or more times a day as necessary to treat the infection.
  • a compound of Formula I, Formula II, Formula PI, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, for example Compound 1 or Compound 2 is administered for at least about 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more days, or for a length of time at the discretion of a healthcare provider.
  • the compound can be administered for a time period that is appropriate to avoid infection or reduce the severity of an infection of a human or other animal at risk of becoming infected with the virus.
  • the compound of the present invention is administered indefinitely until the risk of infection or reinfection no longer exits.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months or more.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered once, twice, three, or four or more times a day.
  • a method to prevent transmission includes administering an effective amount of one of the compounds described herein to a human in need thereof for a sufficient length of time prior to exposure to a high risk situation, including during travel or public events or meetings, or if the host is in a high risk group, including for example, up to 3, 5, 7, 10, 12, 14 or more days prior to a communicable situation, and then during and optionally after the potential exposure.
  • the selected compound as described herein can be administered for an indefinite period in a maintenance dosage to protect a person in a high-risk environment.
  • the present invention also includes compounds of Formula XI and Formula XII:
  • R 12a and R 12b are oxygen protecting groups and at least one of R 12a and R 12b is -C(0)0Ci- ealkyl, for example -C(0)0/Bu, or -C(0)0-benzyl wherein the alkyl and benzyl group can be optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl.
  • R 12a is -C(0)0Ci- 6 alkyl or -C(0)0-benzyl and R 12b is an oxygen protecting group which when attached to the oxygen is an ester, ether, or silyl ether moiety.
  • R 12b is -C(0)0Ci- 6 alkyl or -C(0)0-benzyl and R 12a is an oxygen protecting group which when attached to the oxygen is an ester, ether, or silyl ether moiety.
  • R 12a and R 12b are both -C(0)0Ci- 6 alkyl, for example -C(0)0/Bu.
  • R 12a and R 12b are both -C(0)0-benzyl.
  • a compound of Formula XII is Formula XIIA:
  • Formula XIIA In one embodiment, a compound of Formula XII is Formula XIIB:
  • the present invention thus includes the following features:
  • (ccc) A method for the treatment of COVID-19 in a host in need thereof comprising administering Compound 1, wherein Compound 1 is administered at a dose of at least about 550 mg and the dose is administered twice a day;
  • (ddd) A method for the treatment of COVID- 19 virus in a host in need thereof comprising administering Compound 1, wherein Compound 1 is administered at a loading dose of at least about 1100 mg followed by a maintenance dose of at least about 550 mg twice a day;
  • (ggg) A method for the treatment of COVID-19 in a host in need thereof comprising administering Compound 2, wherein Compound 2 is administered at a dose of at least about 600 mg and the dose is administered twice a day;
  • (hhh) A method for the treatment of COVID-19 in a host in need thereof comprising administering Compound 2, wherein Compound 2 is administered at a loading dose of at least about 1200 mg followed by a maintenance dose of at least about 600 mg twice a day;
  • (nnn) A pharmaceutical formulation comprising an effective amount of a compound of Formula II, optionally in a pharmaceutically acceptable carrier.
  • FIG. 1 is a graph of the concentration of triphosphate Compound 1-6 in human bronchial and nasal epithelial cells after exposure to 10 mM of Compound 1A as described in Example 7.
  • the half-life of Compound 1-6 in bronchial cells and nasal cells was 39 hours and 38 hours, respectively.
  • the x-axis is the time post-washout measured in hours and the y-axis is the concentration of Compound 1-6 in pmol/million cells.
  • FIG. 2 is a graph comparing the triphosphate Compound 1-6 levels in human bronchial epithelial cells following exposure to Compound 1A (1A), ALS-8112 (ALS), and the 4’-Me substituted prodrug isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)- 4-fluoro-3-hydroxy-2,4-dimethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (4’-Me) as described in Example 7.
  • the x-axis is the time post-washout measured in hours and the y-axis is the concentration of Compound 1-6 in pmol/million cells.
  • FIG. 3 is a graph comparing the triphosphate Compound 1-6 levels in human nasal epithelial cells following exposure to Compound 1A (1A), ALS-8112 (ALS), and 4’-Me substituted prodrug isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3 -hydroxy - 2,4-dimethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (4’-Me) as described in Example 7.
  • FIG. 4 is a graph of the mean plasma profile of Compound 1A in monkeys administered 30 mg/kg oral doses of Compound 2A twice a day (BID) for 3 days as described in Example 8.
  • the x- axis is the time post-dose measured in hours and the y-axis is the plasma concentration of Compound 1A measured in ng/mL.
  • FIG. 5 is a graph of the mean plasma profile of metabolite Compound 1-2 in monkeys administered 30 mg/kg oral doses of Compound 2A twice a day (BID) for 3 days as described in Example 8.
  • the x-axis is the time post-dose measured in hours and the y-axis is the plasma concentration of Compound 1-2 measured in ng/mL.
  • FIG. 6 is a graph of the mean plasma profile of triphosphate surrogate metabolite Compound 1-7 in monkeys administered 30 mg/kg oral doses of Compound 2A twice a day (BID) for 3 days as described in Example 8.
  • the x-axis is the time post-dose measured in hours and the y-axis is the plasma concentration of Compound 1-7 measured in ng/mL.
  • FIG. 7A is a graph of the triphosphate Compound 1-6 concentration in lung, kidney, and liver tissue in monkeys following administration of 30 mg/kg oral doses of Compound 2A twice a day (BID) for 3 days as described in Example 8.
  • BID twice a day
  • the half-life in the lung, kidney, and liver was 9.4 hours, 8.0 hours, and 4.3 hours, respectively.
  • the x-axis is the time post-dose measured in hours and the y-axis is the tissue concentration of Compound 1-6 measured in ng/g.
  • FIG. 7B is a graph of triphosphate Compound 1-6 concentration in lung, kidney, and liver tissue in monkeys following administration of 30 mg/kg oral doses of Compound 2A twice a day (BID) for 3 days as described in Example 8.
  • the tissue concentration of Compound 1-6 is shown 2 hours, 12 hours, 24 hours, and 48 hours post last dose.
  • the x-axis is time post the last dose measured in hours and the y-axis is tissue concentration measured in mM.
  • FIG. 8 is a graph of levels of triphosphate Compound 1-6 in hepatocytes incubated with Compound 2A as described in Example 9 and previously described in from Good, S.S. et al. 2020 PLoS ONE 15(l):e0227104.
  • the concentration was 7 times higher in human hepatocytes than in monkeys.
  • the x-axis is the incubation time measured in hours and the y-axis is the Compound 1-6 concentration measured in pmol/10 6 cells.
  • FIG. 9 is the simulation of intracellular concentrations of Compound 1-6 in human lung tissue as described in Example 10.
  • the predicted lung concentration is based on predicted trough (Co ) steady-state plasma Compound 1-7, a plasma surrogate for intracellular triphosphate Compound 1-6, (Berliba, e. et al. 2019 Antimicrob. Agents Chemother. 63(12):e01201-19) in humans multiplied by a ratio of 1.6 (the triphosphate concentration in the lung is 1.6 times greater than in the liver at steady-state trough levels as described in Example 8).
  • the x-axis is time measured in days and the y-axis is simulated lung Compound 1-6 concentration measured in mUI.
  • FIG. 10 is a stimulation of intracellular concentrations of Compound 1-6 in human lung tissue using the two approaches as described in Example 10.
  • the solid curve represents predicted lung concentrations of the active triphosphate Compound 1-6 metabolite after correcting for the Compound 1-6 lung-to-liver concentration ratio of 1.6.
  • the dotted curve represents predicted lung concentrations of the active triphosphate Compound 1-6 metabolite after correcting for the Compound 1-6 lung-to-Compound 1-7 plasma ratio of 1.2.
  • the horizontal line represents the EC90 of Compound 1A against SARS-CoV-2 in HAE cells in vitro (0.47 pM).
  • the x-axis is time measured in days and the y-axis is simulated lung Compound 1-6 concentration measured in m ⁇ 1
  • FIG. 11 is an illustration of a compound of Formula I, which can also be administered as a pharmaceutically acceptable salt.
  • the invention disclosed herein is a method for the treatment or prevention of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a host, for example a human, in need thereof comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof: wherein
  • R 1 is selected from Ci-C 6 alkyl, C3-C6cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • R 2 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), C3-7cycloalkyl, or aryl (including phenyl and napthyl) and in an alternative embodiment, R 2 is aryl(Ci-C4alkyl)-, heteroaryl, or heteroalkyl;
  • R 3 is hydrogen or Ci-ealkyl (including methyl, ethyl, propyl, and isopropyl);
  • R 4a and R 4b are independently selected from hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), and C3-7cycloalkyl; and
  • R 5 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), Ci- 6 haloalkyl, or C3-7cycloalkyl and in an alternative embodiment, R 5 is aryl(Ci-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
  • Non-limiting examples of a compound of Formula I include Compound 1 and Compound 2.
  • the compounds are administered as the S-enantiomer, such as Compound 1A
  • the compounds are administered as the R-enantiomer, such as Compound IB.
  • a compound of Formula I is Compound 2, Compound 2A, or Compound
  • Compound 1 or a pharmaceutically acceptable salt thereof, for example, Compound 2 that can be used include:
  • Non-limiting examples of a compound of Formula I include:
  • the present invention also includes the use of an effective amount of a compound of Formula II to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof:
  • R 1 is selected from Ci-C 6 alkyl, C3-C6Cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • R 2 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), C3-7cycloalkyl, or aryl (including phenyl and napthyl) and in an alternative embodiment, R 2 is aryl(Ci-C4alkyl)-, heteroaryl, or heteroalkyl;
  • R 3 is hydrogen or Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl);
  • R 4a and R 4b are independently selected from hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), and C3-7cycloalkyl; and
  • R 5 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), Ci- 6 haloalkyl, or C3-7cycloalkyl and in an alternative embodiment, R 5 is aryl(Ci-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier is administered in an effective amount to a host in need thereof with COVID-19, or at risk of infection with the SARS-CoV-2 vims, i.e., as a prophylactic.
  • Non-limiting examples of a compound of Formula II include Compound 3 and Compound 4.
  • the compounds are administered as the S-enantiomer, such as Compound 3A and Compound 4A.
  • the compounds are administered as the R-enantiomer, such as Compound 3B or Compound 4B.
  • Additional alternative configurations of Compound 4 include:
  • Compound 4 Additional alternative configurations of Compound 3 or a pharmaceutically acceptable salt thereof, for example, Compound 4 that can be used include:
  • Non-limiting examples of a compound of Formula II include: or a pharmaceutically acceptable salt thereof.
  • the present invention also includes the use of an effective amount of a compound of
  • Formula III to treat or prevent COVED- 19 disease caused by the SARS-CoV-2 virus in a host in need thereof:
  • R 1 is selected from Ci-C 6 alkyl, C3-C6Cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • R 2 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), C3-7cycloalkyl, or aryl (including phenyl and napthyl) and in an alternative embodiment, R 2 is aryl(Ci-C4alkyl)-, heteroaryl, or heteroalkyl;
  • R 3 is hydrogen or Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl);
  • R 4a and R 4b are independently selected from hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), and C3-7cycloalkyl; and R 5 is hydrogen, Ci- 6 alkyl (including methyl, ethyl, propyl, and isopropyl), Ci- 6 haloalkyl, or C3-7cycloalkyl and in an alternative embodiment, R 5 is aryl(Ci-C4alkyl)-, aryl, heteroaryl, or heteroalkyl; and
  • Ci-C3haloalkyl including Ci-3fluoroalkyl and Ci-3chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF , and CH 2 C1), C 2 -C alkenyl, C 2 -C4alkynyl, and Ci-C3hydroxy alkyl.
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula Ilia: or a pharmaceutically acceptable salt thereof.
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • a compound of Formula Ilia include:
  • a compound of Formula Ilia include:
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula Illb:
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl.
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration.
  • the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • Non-limiting examples of a compound of Formula Illb include: W ° 2021/173713
  • Additional non-limiting examples of a compound of Formula Illb include:
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula IIIc:
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • a compound of Formula IIIc include:
  • a compound of Formula IIIc include:
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula Hid:
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • Non-limiting examples of a compound of Formula Hid include:
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula Hie:
  • R 1 is methyl
  • R 1 is cyclopropyl. In one embodiment of Formula Hie, R 2 is phenyl.
  • R 2 is napthyl.
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration. In one embodiment of Formula Hie, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • a compound of Formula Hie include:
  • Additional non-limiting examples of a compound of Formula Hie include:
  • the compound of Formula III to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula Illf:
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl. In one embodiment of Formula Illf, R 2 is napthyl.
  • R 4a is hydrogen and R 4b is methyl In one embodiment of Formula Illf, R 5 is isopropyl.
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration. In one embodiment of Formula Illf, the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • a compound of Formula Illf include:
  • Additional non-limiting examples of a compound of Formula Hie include:
  • Non-limiting examples of a compound of Formula III include:
  • the present invention also includes the use of a compound of Formula IV to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof as described herein:
  • Ci-C3haloalkyl including Ci-3fluoroalkyl and Ci-3chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH , CF 2 CF 3 , and CH 2 C1), C -C 4 alkenyl, C 2 -C 4 alkynyl, and Ci-C3hydroxyalkyl; and
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • the compound of Formula IV to treat or prevent COVID-19 disease is a compound or a pharmaceutically acceptable salt thereof of Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, or Formula IVf:
  • the compound of Formula IV to treat or prevent COVID-19 disease caused by the SARS-CoV-2 vims is a compound of Formula IVa: or a pharmaceutically acceptable salt thereof.
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4h is methyl.
  • R 5 is isopropyl
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • Non-limiting examples of a compound of Formula IVa include:
  • the compound of Formula IV to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus is a compound of Formula IVb: or a pharmaceutically acceptable salt thereof.
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 43 ⁇ 4 is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration.
  • the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.
  • Non-limiting examples of a compound of Formula IVb include:
  • the compound of Formula IV to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus is a compound of Formula IVc:
  • R 1 is methyl
  • R 1 is cyclopropyl.
  • R 2 is phenyl.
  • R 2 is napthyl
  • R 4a is hydrogen and R 43 ⁇ 4 is methyl.
  • R 5 is isopropyl
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • a compound of Formula IVc include:
  • the compound of Formula IV to treat or prevent COVID-19 disease is a compound of Formula IVd:
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the S p -isomer and the phosphoramidate is in the L-configuration.
  • the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • Non-limiting examples of a compound of Formula IVd include:
  • the compound of Formula IV to treat or prevent COVID-19 disease is a compound of Formula IVe: R
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl
  • R 2 is napthyl
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.
  • the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • Non-limiting examples of a compound of Formula IVe include:
  • the compound of Formula IV to treat or prevent COVID-19 disease caused by the SARS-CoV-2 virus is a compound of Formula IVf: Formula IVf or a pharmaceutically acceptable salt thereof.
  • R 1 is methyl
  • R 1 is cyclopropyl
  • R 2 is phenyl. In one embodiment of Formula IVf, R 2 is napthyl.
  • R 4a is hydrogen and R 4b is methyl.
  • R 5 is isopropyl
  • the compound is the Sp-isomer and the phosphoramidate is in the L-configuration. In one embodiment of Formula IVf, the compound is the R p -isomer and the phosphoramidate is in the L-configuration.
  • the pharmaceutically acceptable salt is the hemi- sulfate salt.
  • the present invention also includes the use of a compound of Formula V to treat or prevent COVET- 19 disease caused by the SARS-CoV-2 vims as described herein:
  • Y and Y’ are independently selected from Cl and F;
  • R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 are as defined herein.
  • Y’ is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Y’ is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Y’ is F
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cealkyl.
  • Y’ is F
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Y’ is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-G,alkyl.
  • Y’ is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cealkyl.
  • Y’ is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Y’ is Cl
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Y’ is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-Cealkyl.
  • Y’ is F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-C 6 alkyl.
  • Y’ is F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Non-limiting examples of a compound of Formula V include
  • the present invention also includes the use of a compound of Formula VI to treat or prevent COVED- 19 in a host in need thereof as described herein: wherein
  • R 6 is selected from hydrogen, -C(0)R 6A , -C(0)0R 6A , Ci- 6 alkyl, and -CH 2 -0-R 6A and in an alternative embodiment, -C(0)NR 6B R 6C ;
  • R 6A is selected from hydrogen, Ci ⁇ alkyl, Ci-G, haloalkyl (for example, -CHC , -CCI3, -CH2CI, -CF3, -CHF2, -CH2F), aryl, and aryl(Ci- 6 alkyl)- wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl and in an alternative embodiment, R 6A is selected from Ci-2oalkyl and C2-2oalkenyl;
  • R 6B and R 6C are independently selected from hydrogen, Ci-2oalkyl, C2-2oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl wherein the Ci-2oalkyl, C2-2oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl can optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;
  • R 7 is NH 2 , H, or -NR 8 R 9 ;
  • R 8 and R 9 are independently selected from hydrogen, Ci- 6 alkyl, -C(0)R 6A , and -C(0)0R 6A ; Y is selected from F and Cl;
  • Z is selected from methyl, Ci-C 3 haloalkyl (including Ci- 3 fluoroalkyl and Ci- 3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH2CF3, CH2CHF2, CH 2 CH 2 F, CF2CH3, CF2CF3, and CH2CI), C - C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 3 hydroxyalkyl, and halogen (including Cl and F), and in an alternative embodiment Z is Ci- 4 alkyl; and R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • R 6 include In one embodiment of Formula VI, Z is CFb, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is NFb
  • Z is CFb
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CFb
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CFb
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A
  • Z is CFb, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is NHC(0)0R 6A .
  • Z is CFb, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Z is CFb
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cealkyl.
  • Z is CFh
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CF 3
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C 4 alkyl
  • R 5 is Ci-C6alkyl
  • R 7 is NFh
  • Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is H.
  • Z is CF 3
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C 4 alkyl
  • R 5 is Ci-C6alkyl
  • R 7 is NR 8 R 9 .
  • Z is CF3, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is HC(0)R 6A
  • Z is CF 3
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Z is CF 3
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C 4 alkyl
  • R 5 is Ci-C6alkyl.
  • Z is CF 3
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is Fh.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is R 8 R 9 .
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is HC(0)R 6A .
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-C 6 alkyl.
  • Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-Cr,alkyl.
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is M
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is HC(0)0R 6A .
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CFhF
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CFhF
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-Cealkyl.
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is Mh.
  • Z is CFhCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CFhCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CFhCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A .
  • Z is CFhCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-G,alkyl.
  • Z is CHCH2
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CHCH2, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Cealkyl, and R 7 is NFh.
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A .
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-Cealkyl
  • Z is CCH
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CCH
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is N ⁇ 2.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A .
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C 4 alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is F
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cealkyl.
  • Z is F
  • Y is F
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is C3 ⁇ 4, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is NH2.
  • Z is CFb, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Cealkyl, and R 7 is H.
  • Z is CFb
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CFb
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A
  • Z is CFb
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CFb
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CFb
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CFb
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CF 3
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C 4 alkyl
  • R 5 is Ci-C6alkyl
  • R 7 is NFb.
  • Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C 4 alkyl, R 5 is Ci-C6alkyl, and R 7 is H.
  • Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C 4 alkyl, R 5 is Ci-C6alkyl, and R 7 is NR 8 R 9 .
  • Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C 4 alkyl, R 5 is Ci-C6alkyl, and R 7 is NHC(0)R 6A
  • Z is CF3, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is NHC(0)0R 6A .
  • Z is CF3, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Z is CF3, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C 4 alkyl, and R 5 is Ci-C6alkyl.
  • Z is CF 3 , Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-Cbalkyl.
  • Z is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NFb.
  • Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is H.
  • Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Galkyl, and R 7 is NR 8 R 9 .
  • Z is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A
  • Z is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A
  • Z is Cl
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is Cl
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is Cl
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-Cealkyl
  • Z is C3 ⁇ 4F
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is Mh.
  • Z is CFhF
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CFhF
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NR 8 R 9 .
  • Z is CFhF
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A .
  • Z is CFhF
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CFhF
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is G-Galkyl.
  • Z is CFhF
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CFhF
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CHCFh
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is Nth.
  • Z is CFhCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CFhCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Galkyl, and R 7 is NR 8 R 9 .
  • Z is CFhCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Cealkyl, and R 7 is NHC(0)R 6A .
  • Z is CFhCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CHCH2
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CHCH2
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cealkyl.
  • Z is CHCH2
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Z is CCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NH2.
  • Z is CCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is H.
  • Z is CCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, and R 7 is NR 8 R 9 .
  • Z is CCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)R 6A
  • Z is CCH
  • Y is Cl
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 7 is NHC(0)0R 6A .
  • Z is CCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is Ci-C 6 alkyl.
  • Z is CCH, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, and R 5 is Ci-Cealkyl.
  • Z is CCH
  • Y is Cl
  • R 1 is cyclopropyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is methyl
  • R 5 is Ci-C 6 alkyl.
  • Non-limiting examples of a compound of Formula VI include Additional non-limiting examples of a compound of Formula VI include:
  • the present invention also includes the use of a compound of Formula VII to treat or prevent COVID-19 in a host in need thereof as described herein: wherein
  • R 6 is selected from hydrogen, -C(0)R 6A , -C(0)0R 6A , Ci ⁇ alkyl, and -CH 2 -0-R 6A and in an alternative embodiment, -C(0)NR 6B R 6C ;
  • R 6A is selected from hydrogen, Ci ⁇ alkyl, Ci-C 6 haloalkyl (for example, -CHCh, -CCI3, -CH2CI, -CF3, -CHF2, -CH2F), aryl, and aryl(Ci- 6 alkyl)- wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl and in an alternative embodiment, R 6A is selected from Ci-2oalkyl and C2-2oalkenyl; R 6B and R 6C are independently selected from hydrogen, Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl(Ci- 6 alkyl)-, heteroaryl, and heteroarylalkyl wherein the Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl(Ci- 6 alkyl)
  • R 7 is NH 2 , H, or -NR 8 R 9 ,
  • R 8 and R 9 are independently selected from hydrogen, Ci- 6 alkyl, -C(0)R 6A , and -C(0)0R 6A ;
  • Y is selected from F and Cl;
  • Z is selected from methyl, Ci-C 3 haloalkyl (including Ci- 3 fluoroalkyl and Ci- 3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 C1), C - C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 3 hydroxyalkyl, and halogen (including Cl and F), and in an alternative embodiment Z is Ciualkyl;
  • R 40 is selected from H, Ci- 3 alkoxy, Ci alkyl, N 3 , CN, and halogen (including Cl and F);
  • R 41 is selected from H, Ci- 3 alkyl (including methyl) and halogen (including Cl, F, and Br);
  • R 42a and R 42b are selected from Ci. 3 alkyl (including methyl), NFh, H, -NR 8 R 9 , and -
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • Non-limiting examples of B include: in one embodiment, the invention also includes a compound of Formula Vila, Formula Vllb, Formula Vile, and Formula Vlld: In one embodiment of Formula VII, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coalkyl. R 6 is hydrogen, R 40 is hydrogen; and B is
  • R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NH2.
  • Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coalkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is Ci-6alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NFh. In a further embodiment, R 41 is methyl and R 42a is NFh.
  • Z is CFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is H, and R 42b is Ci-ealkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci-6alkyl or H. In a further embodiment, R 41 is Ci-oalkyl or H, R 42a is -NHCH3, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCFh, and R 42b is NH 2 .
  • Z is CFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is NFh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCFh, and R 42b is H. In a further embodiment, R 41 is Ci-6alkyl or H, R 42a is NH2, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Nth.
  • Z is Cth, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 .
  • R 41 is halogen and R 42a is -C(0)NHCH3.
  • R 41 is Br and R 42a is -C(0)NR 8 R 9 .
  • R 41 is Br and R 42a is -C(0)NHCth.
  • Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Cealkyl, R 6 is hydrogen, R 40 is cyano or nitro; and B is
  • R 1 is Ci- 6 alkyl and R 7 is Nth. In a further embodiment, R 1 is methyl and R 7 is NH 2 .
  • Z is CH3, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is Ci- 6 alkyl and R 42a is H In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NFh. In a further embodiment, R 41 is methyl and R 42a is Nth.
  • Z is Cth
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro;
  • R 41 is H, R 42a is H, and R 42b is Ci-ealkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is Nth, and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci-ealkyl or H
  • R 42a is -NHCH 3
  • R 42b is Ci- 6 alkyl or H
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCFh
  • R 42b is NH 2.
  • Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is C 1 -C h alky 1, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is H, R 42a is NFh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NllCIIi, and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is
  • Z is CFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3. In a further embodiment, R 41 is Br and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(0)NHCH 3 .
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • B is
  • R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NFh. In one embodiment of Formula Vila, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coalkyl. R 6 is hydrogen, R 40 is hydrogen; and B is
  • R 41 is Ci- 6 alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci-6alkyl and R 42a is Mh. In a further embodiment, R 41 is methyl and R 42a is Fh.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Coalkyl, R 6 is hydrogen, R 40 is hydrogen; and B is In a further embodiment, R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment,
  • R 41 is H, R 42a is H, and R 42b is methyl.
  • R 41 is Ci-6alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H, R 42a is -NHCFh, and R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H, R 42a is -NHCFh, and R 42b is B.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and B is
  • R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is Mh, and R 42b is Ci-6alkyl or H. In a further embodiment, R 41 is Ci-6alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci.
  • R 42a is -NHCH 3
  • R 42b is NH 2
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • B is
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is
  • R 41 is Br and R 42a is -C(0)NHCFb.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is In a further embodiment, R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NFh.
  • Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coalkyl, R 6 is hydrogen, R 40 is cyano or nitro; and B is In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NFh. In a further embodiment, R 41 is methyl and R 42a is NFh.
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is H, R 42a is Fh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is - HCH 3 , and R 423 ⁇ 4 is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH 2 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is C 1 -r,al kyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci. 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .
  • Z is Cl
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is halogen and R 42a is -C(0) R 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is
  • R 41 is Br and R 42a is -C(0)NHCH 3.
  • Z is CH2F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 1 is Ci- 6 alkyl and R 7 is NFh.
  • R 1 is methyl and R 7 is NH2.
  • Z is CH2F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is Ci- 6 alkyl and R 42a is H.
  • R 41 is methyl and R 42a is H.
  • R 41 is Ci- 6 alkyl and R 42a is NFh.
  • R 41 is methyl and R 42a is NFh.
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cr
  • alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH 2 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci. 6 alkyl or H, R 42a is -NHCFb, and R 42b is NH 2 .
  • Z is CH2F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is NFh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci. 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci. 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is
  • Z is CFhF
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(0)NHCFh.
  • Z is CFBF, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Gal kyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 1 is Ci- 6 alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 is NH2.
  • Z is CH2F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is G-Galkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • R 41 is Ci-6alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is MB. In a further embodiment, R 41 is methyl and R 42a is MB.
  • Z is CFBF, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is H
  • R 42a is H
  • R 42b is Ci-ealkyl
  • Z is CFBF, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is G-Galkyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is H, R 42a is d2, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -MICH3, and R 42b is H. In a further embodiment, R 41 is Ci-6alkyl or H, R 42a is Mir, and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is NH2.
  • Z is CH2F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 .
  • R 41 is halogen and R 42a is -C(0)NHCH3.
  • R 41 is Br and R 42a is -C(0)NR 8 R 9 .
  • R 41 is Br and R 42a is -C(0) HCH 3 .
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NH2.
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is Ci- 6 alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a is NH2.
  • Z is CHCH2, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Cr, alkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl.
  • R 41 is H, R 42a is H, and R 42b is methyl.
  • R 41 is Ci- 6 alkyl or H
  • R 42a is NH 2
  • R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NR 8 R 9
  • R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCH 3
  • R 42b is Ci- 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCH 3
  • R 42b is NH 2 .
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is Fh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is - HCH 3 , and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH 2 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci ⁇ alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is halogen and R 42a is -C(0) R 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(0)NHCH 3.
  • Z is CHCH2, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 1 is Ci- 6 alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 is NH2. In one embodiment of Formula Vila, Z is CHCFh, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is C i -C h alky 1, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is Ci- 6 alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci-6alkyl and R 42a is MB. In a further embodiment, R 41 is methyl and R 42a is IB.
  • Z is CHCFh
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cr
  • alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • R 41 is H
  • R 42a is H
  • R 42b is Ci- 6 alkyl.
  • Z is CHCH2, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is H, R 42a is MB, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is MB, and R 42b is Ci-6alkyl or H. In a further embodiment, R 41 is Ci-6alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci.
  • R 42a is -NHCH 3
  • R 42b is NH 2
  • Z is CHCH2
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is C 1 -C h alky 1
  • R 6 is hydrogen
  • R 40 is cyano or nitro;
  • R 4i is halogen and R 42a is -C(0)NR 8 R y .
  • R 41 is halogen and R 42a is -C(0)NHCH 3 .
  • R 41 is Br and R 42a is -C(0)NR 8 R 9 .
  • R 41 is Br and R 42a is -C(0)NHCH 3 .
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 1 is Ci- 6 alkyl and R 7 is MB. In a further embodiment, R 1 is methyl and R 7 is NFh.
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is Ci- 6 alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a is NH2.
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cr
  • alkyl R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH2, and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci-ealkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is - HCH 3 , and R 42b is NH 2 .
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and
  • R 41 is H, R 42a is N3 ⁇ 4, and R 42b is H. In a further embodiment, R 41 is H, R 42a is - HCH 3 , and R 423 ⁇ 4 is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH 2 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is C 1 -r,al kyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci. 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • R 41 is halogen and R 42a is -C(0) R 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(0)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(0)NHCH 3.
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coal kyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 1 is Ci- 6 alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 is NH2.
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci -Coal kyl, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is Ci- 6 alkyl and R 42a is H.
  • R 41 is methyl and R 42a is H.
  • R 41 is Ci- 6 alkyl and R 42a is NH 2 .
  • R 41 is methyl and R 42a is NH 2.
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is C 1 -Chalky 1
  • R 6 is hydrogen
  • R 40 is cyano or nitro;
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH2, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is
  • R 42b is Ci. 6 alkyl or H.
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCH3
  • R 42b is NH 2
  • Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is C 1 -Chalky 1, R 6 is hydrogen, R 40 is cyano or nitro;
  • R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is NH 2.
  • Z is CCH
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is C 1 -Chalky 1
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 .
  • R 41 is halogen and R 42a is -C(0)NHCH 3 .
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • B is
  • R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NFh.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • B is
  • R 41 is Ci-6alkyl and R 42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is Ci- 6 alkyl and R 42a is NFh. In a further embodiment, R 41 is methyl and R 42a is NFh.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and B is
  • R 41 is H, R 42a is H, and R 42b is Ci-ealkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCFh
  • R 42b is Ci- 6 alkyl or H
  • R 41 is Ci- 6 alkyl or H
  • R 42a is -NHCth
  • R 42b is NFh.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci -Coalkyl
  • R 6 is hydrogen
  • R 40 is hydrogen
  • B is
  • R 41 is H, R 42a is NFh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCFh, and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 423 ⁇ 4 is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCFh, and R 42b is Ci-6alkyl or H.
  • R 41 is Ci-6alkyl or H
  • R 42a is -NHCH3
  • R 42b is NH 2
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen, R 4a is Ci-C4alkyl, R 5 is Ci-Coalkyl, R 6 is hydrogen, R 40 is hydrogen; and B is
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 In a further embodiment, R 41 is halogen and R 42a is -0(0)NHO3 ⁇ 4. In a further embodiment, R 41 is Br and R 42a is -C(0)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(0)NHCH 3 .
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 1 is Ci- 6 alkyl and R 7 is NFh. In a further embodiment, R 1 is methyl and R 7 is NFh.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C ,alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is Ci- 6 alkyl and R 42a is H.
  • R 41 is methyl and R 42a is H.
  • R 41 is Ci- 6 alkyl and R 42a is NH 2 .
  • R 41 is methyl and R 42a is NFh.
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C ,alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is H, R 42a is H, and R 42b is Ci- 6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NH2, and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH 3 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is NH 2
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-C 6 alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is H, R 42a is NFh, and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCFb, and R 42b is H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is NFh, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is Ci. 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCFb, and R 42b is Ci- 6 alkyl or H. In a further embodiment, R 41 is Ci- 6 alkyl or H, R 42a is -NHCH3, and R 42b is NH 2
  • Z is F
  • Y is F
  • R 1 is methyl
  • R 2 is aryl
  • R 3 is hydrogen
  • R 4a is hydrogen
  • R 4a is Ci-C4alkyl
  • R 5 is Ci-Cr
  • alkyl
  • R 6 is hydrogen
  • R 40 is cyano or nitro
  • B is
  • R 41 is halogen and R 42a is -C(0)NR 8 R 9 .
  • R 41 is halogen and R 42a is -C(0)NHCH 3 .
  • R 41 is Br and R 42a is -C(0)NR 8 R 9 .
  • R 41 is Br and R 42a is -0(0)NHO3 ⁇ 4.
  • Non-limiting examples of compounds of Formula VII include:
  • the present invention also includes the use of a compound of Formula VIII, Formula IX, or Formula X wherein R 10 is a monophosphate, a diphosphate, a triphosphate, or R 10A wherein R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate to treat or prevent COVID-19 disease in a host in need thereof as described herein:
  • R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate;
  • R 11 is selected from hydrogen and R 1 ;
  • R 1 is selected from Ci-C 6 alkyl, C3-C6Cycloalkyl, and -C(0)Ci-C 6 alkyl;
  • the present invention also includes compounds of Formula XI and Formula CP:
  • R 12a and R 12b are oxygen protecting groups and at least one of R 12a and R 12b is -C(0)0Ci- 6 alkyl, for example -C(0)0/Bu, or -C(0)0-benzyl wherein the alkyl and benzyl group can be optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl.
  • R 12a is -C(0)OCi- 6 alkyl or -C(0)0-benzyl and R 123 ⁇ 4 is an oxygen protecting group which when attached to the oxygen is an ester, ether, or silyl ether moiety.
  • R 12b is -C(0)OCi- 6 alkyl or -C(0)0-benzyl and R 12a is an oxygen protecting group which when attached to the oxygen is an ester, ether, or silyl ether moiety.
  • R 12a and R 123 ⁇ 4 are both -C(0)OCi- 6 alkyl, for example -C(0)0/Bu.
  • R 12a and R 12b are both -C(0)0-benzyl.
  • a compound of Formula XII is Formula XIIA:
  • a compound of Formula XII is Formula XIIB: Formula XIIB
  • the protecting group that when attached to the oxygen can be an ester moiety, for example benzoate acetate.
  • the oxygen protecting group that when attached to the oxygen is a silyl ether moiety (for example (trimethyl silyl (TMS), triisopropyl silyl (TIPS), tert-butyldimethylsilyl (TBDMS or TBS) or tert-butyldiphenylsilyl (TBDPS).
  • TMS trimethyl silyl
  • TIPS triisopropyl silyl
  • TDMS or TBS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • the oxygen protecting group that when attached to the oxygen is an ether moiety, for example methyl ether, methoxymethyl ether, or benzyl ether.
  • the compound of Formula XI or Formula XII can be prepared according to the conditions described in the text on page 149-178 and when the oxygen protecting group is a silyl ether moiety when attached to the oxygen, the compound of Formula XI or Formula XII can be prepared according to the conditions described in the text on page 113-147.
  • the protecting group is a tert-butyldimethylsilyl (TBS) group.
  • the TBS group is selectively installed on the primary alcohol over the secondary alcohol using the conditions described in the text on page 128 and in Ogilvie et al. Can. J Chem. 1979, 57, 2230. These conditions include the use of TBSC1, DMAP, and M3 ⁇ 4 in DMF at 25 °C.
  • Non-limiting examples of additional protecting groups which when attached to the oxygen also include bromobenzoate, /?-methoxybenzyloxymethyl ether (MPBM), o-nitrobenzyloxymethyl ether (NBOM), / nitrobenzyloxymethyl ether, /-butoxymethyl ether, 2,2,2-trichloroethoxymethyl ether, 3-bromotetrahydropyranyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 1- m ethoxy cyclohexyl ether, l,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, a substituted phenyl ether, 2-picolyl ether, 4-picolyl ether, l,3-benzodithiolan-2-yl ether, /;- chlorophenoxyacetate ester, 3-phenylprop
  • Non-limiting examples of R 12a and R 12b include:
  • Non-limiting examples of a compound of Formula XI and XII include:
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula IX, Formula X, or Formula XIII for example Compound 1A, Compound IB, Compound 2A, Compound 2B, Compound 3A, Compound 3B, Compound 4A, or Compound 4B is used in a form at least 90% free of the opposite phosphorus enantiomer, and can be at least 98%, 99% or even 100% free of the opposite phosphorus enantiomer.
  • Compound 2 was previously disclosed in U.S. Patent No. 10,519,186; 10,906,928; 10,894,804; and, 10,874,687 and PCT Applications WO 2018/144640; WO 2019/200005, and, WO 2020/117966 assigned to Atea Pharmaceuticals.
  • Compound 2A has demonstrated potent in vitro activity against clinical isolates of hepatitis C virus (HCV) by inhibiting the RNA-dependent RNA polymerase (RdRp) (Good, S. S. et al. PLoS ONE 15(1), e0227104 (2020)).
  • Compound 2A has been evaluated in a Phase lb study (Berliba, E. et al. Antimicrob. Agents Chemther.
  • Compound 2 is provided in a pharmaceutically acceptable composition or solid dosage form thereof.
  • a non-limiting illustrative process for the preparation of Compound 2 includes
  • a first step of dissolving Compound 1 in an organic solvent for example, acetone, ethyl acetate, methanol, acetonitrile, or ether, or the like, in a flask or container;
  • step (ii) charging a second flask or container with a second organic solvent, which may be the same as or different from the organic solvent in step (i), optionally cooling the second solvent to 0-10 degrees C, and adding dropwise H2SO4 to the second organic solvent to create a TkSCri/organic solvent mixture; and wherein the solvent for example may be methanol;
  • step (iii) adding dropwise the fhSCE/solvent mixture at a molar ratio of 0.5/1.0 from step (ii) to the solution of Compound 1 of step (i) at ambient or slightly increased or decreased temperature (for example 23-35 degrees C);
  • step (iv) stirring the reaction of step (iii) until precipitate of Compound 2 is formed, for example at ambient or slightly increased or decreased temperature;
  • step (v) optionally filtering the resulting precipitate from step (iv) and washing with an organic solvent; and (vi) optionally drying the resulting Compound 2 in a vacuum, optionally at elevated a temperature, for example, 55, 56, 57, 58, 59, or 60 °C.
  • the solvent of step (iii) is an alcohol, for example methanol, ethanol, or isopropyl alcohol. In one embodiment, the solvent of step (iii) is an alkyl ester, for example ethyl acetate.
  • Scheme 1 provides the metabolic pathway of a compound of Formula I, which involves the initial de-esterification of the phosphoramidate (Compound 1) to form metabolite 1-1, which spontaneously decomposes to metabolite 1-2.
  • Metabolite 1-2 is next converted to the N 6 -methyl- 2, 6-diaminopurine-5’ -monophosphate derivative (metabolite 1-3), which is in turn metabolized to the free 5’-hydroxyl-N 6 -methyl-2,6-diaminopurine nucleoside (metabolite 1-8) and ((2//,3//,4//,5//)-5-(2-amino-6-oxo-l ,6-dihydro-9H-purin-9-yl)-4-fluoro-3-hydroxy-4- methyltetrahydrofuran-2-yl)methyl dihydrogen phosphate as the 5’ -monophosphate (metabolite 1- 4).
  • Metabolite 1-4 is anabolized to the corresponding diphosphate (metabolite 1-5) and then the active triphosphate derivative (metabolite 1-6).
  • the 5’ -triphosphate can be further metabolized to generate 2-amino-9-((2i?,3i?,4f?,5i?)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)-l,9-dihydro-6H-purin-6-one (1-7).
  • Metabolite 1-7 is measurable in plasma and is therefore a surrogate for the active triphosphate (1-6), which is not measurable in plasma.
  • a “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of COVED- 19 caused by the SARS-CoV-2 virus.
  • the host is a human.
  • a “patient” or “host” or “subject” also refers to, for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mice, bird, bat and the like.
  • prophylactic refers to the administration of an active compound to prevent, reduce the likelihood of an occurrence or a reoccurrence of COVID- 19, or to minimize a new infection relative to infection that would occur without such treatment.
  • the present invention includes both treatment and prophylactic or preventative therapies.
  • the active compound is administered to a host who has been exposed to and is thus at risk of contracting COVID-19.
  • a method to prevent transmission includes administering an effective amount of one of the compounds described herein to humans for a sufficient length of time prior to exposure to crowds that can be infected, including during travel or public events or meetings, including for example, up to 3, 5, 7, 10, 12, 14 or more days prior to a communicable situation.
  • coadminister means “coadminister,” “coadministration,” or “in combination” are used to describe the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, according to the present invention in combination with at least one other antiviral active agent.
  • the timing of the coadministration is best determined by the medical specialist treating the patient. It is sometimes desired that the agents be administered at the same time. Alternatively, the drugs selected for combination therapy may be administered at different times to the patient. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with other agents to treat that other infection or condition as required.
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified to an inorganic and organic, acid or base addition salt thereof without undue toxicity.
  • the salts of the present compounds can be synthesized from the parent compound with a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable.
  • Salts of the present compounds may optionally be provided in the form of a solvate.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional salts and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic acids that are not unduly toxic.
  • acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sul
  • the compound can be delivered in any molar ratio of salt that delivers the desired result.
  • the compound can be provided with less than a molar equivalent of a counter ion, such as in the form of a hemi-sulfate salt.
  • the compound can be provided with more than a molar equivalent of counter ion, such as in the form of a di-sulfate salt.
  • molar ratios of the compound to the counter ion include 1 : 0.25, 1 : 0.5, 1 : 1, and 1 : 2
  • Alkyl is a straight chain or branched saturated aliphatic hydrocarbon group.
  • the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length) .
  • the specified ranges as used herein indicate an alkyl group with length of each member of the range described as an independent species.
  • C1-C6 alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species
  • Ci-C4alkyl as used herein indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, e/V-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.
  • Cycloalkyl is a saturated mono-cycle hydrocarbon ring system.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkenyl refers to a non-aromatic hydrocarbon group which contains at least one double bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein.
  • an alkenyl group can have to 4 carbon atoms (i.e., C 2 -C 4 alkenyl).
  • alkynyl refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein.
  • an alkynyl group can have 2 to 4 carbon atoms (i.e., C2-C4 alkynyl).
  • alkynyl groups include, but are not limited to ethynyl and propargyl.
  • Aryl indicates aromatic groups containing only carbon in the aromatic ring or rings.
  • the aryl groups contain 1 to 3 separate or fused rings and is 6 to about 14 or 18 ring atoms, without heteroatoms as ring members.
  • Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • aryl groups include, for example, dihydroindole, dihydrobenzofuran, isoindoline-l-one and indolin-2-one.
  • Aryl(alkyl)- is an alkyl group as described herein substituted with an aryl group as described herein.
  • aryl(CH2)- is benzyl.
  • Examples of aryl(alkyl)- include benzyl, 2- phenyl (alkyl), 3-phenyl(alkyl), and napthyl(alkyl).
  • Heteroaryl refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another.
  • heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2- hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4- hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indoli
  • heteroalkyl refers to an alkyl, alkenyl, alkynyl, or haloalkyl moiety as defined herein wherein a CEE group is either replaced by a heteroatom or a carbon atom is substituted with a heteroatom for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • heteroalkyl is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
  • phosphoramidate is used throughout the specification to describe a moiety at the 5’ position of the furanose ring of the nucleoside and forms a prodrug form of the nucleoside compound, wherein the phosphorus atom is linked through a 5’-0- bond and wherein the phosphorus is also covalently bound to at least one nitrogen, forming a P-N bond.
  • the phosphorus is covalently linked to the amino moiety of a natural or synthetic amino acid (which may be in the form of an ester).
  • Phosphoramidate groups for use in the present invention include, for example, those of the structures:
  • R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a linked combination thereof; and R P2 is a -NR N1 R N2 group or a B’ group; wherein: R N1 and R N2 are each independently H, Ci-salkyl, (C 3 -C 7C ycloalkyl)Co-C 4 alkyl-, (aryl)Co- C 4 alkyl-, (C 3 -Csheterocyclo)Co-C 4 alkyl-, or (heteroaryl)Co-C 4 alky-; which may be optionally substituted; or
  • R N1 and R N2 along with the nitrogen atom to which that are attached, join to form a 3 to 7 membered heterocyclic ring; group; wherein:
  • R 13 is hydrogen, (Ci-Cg)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, (C 3 -C 8 cycloalkyl)Co-
  • R 14 is hydrogen, (Ci-Cs)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, (C 3 -C 8C ydoalkyl)Co- C 4 alkyl-, (aryl)Co-C 4 alkyl-, (C 3 -C 6 heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, b-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyros
  • R 15 is hydrogen or Ci-C 3 alkyl
  • R 13 and R 14 can form a (C 3 -C7)cycloalkyl or (C3-C7)heterocyclic group; or
  • R 13 and R 14 or R 16 can form (C 3 -C 6 )heterocyclic group
  • R 16 is hydrogen, (Ci-Cs)alkyl, (C 3 -C 6 )alkenyl, (C 3 -C 6 )alkynyl, (C 3 -C 8 cycloalkyl)Co-C 4 alkyl, (aryl)Co-C 4 alkyl-, (C 3 -C 6 heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-.
  • Preferred R P1 groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds in the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).
  • Stabilized Phosphate Prodrugs include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds in the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).
  • Stabilized phosphate prodrugs are moieties that can deliver a mono, di, or triphosphate in vivo.
  • McGuigan has disclosed phosphoramidates in US Patent Nos : 8,933,053; 8,759,318; 8,658,616; 8,263,575; 8,119,779; 7,951,787 and 7,115,590.
  • Alios has disclosed thiophosphoramidates in US 8,895,723 and 8,871,737 incorporated by reference herein.
  • Alios has also disclosed cyclic nucleotides in US Patent No. 8,772,474 incorporated by reference herein.
  • Idenix has disclosed cyclic phosphoramidates and phosphoramidate/SATE derivatives in WO 2013/177219 incorporated by reference herein. Idenix has also disclosed substituted carbonyloxymethylphosphoramidate compounds in WO 2013/039920 incorporated by reference herein.
  • Hostetler has disclosed lipid phosphate prodrugs, see, for example, US 7,517,858. Hostetler has also disclosed lipid conjugates of phosphonate prodrugs, see, for example, US 8,889,658; 8,846,643; 8,710,030; 8,309,565; 8,008,308; and 7,790,703.
  • Emory University has disclosed nucleotide sphingoid and lipid derivatives in WO 2014/124430.
  • RFS Pharma has disclosed purine nucleoside monophosphate prodrugs in WO 2010/091386.
  • Cocrystal Pharma Inc. has also disclosed purine nucleoside monophosphate prodrugs in US Patent No.: 9,173,893 incorporated by reference herein.
  • HepDirectTM technology is disclosed in the article "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154-5163 (2004).
  • Additional phosphate prodrugs include, but are not limited to phosphate esters, 3’,5’-cyclic phosphates including CycloSAL, SATE derivatives (S-acyl-2thioesters) and DTE (dithiodiethyl) prodrugs.
  • CycloSAL SATE derivatives
  • DTE dithiodiethyl
  • the stabilized phosphate prodrugs include, but are not limited to those described inU.S. Patent No. 9,173,893 and U S. Patent No. 8,609,627, incorporated by reference herein, including for processes of preparation.
  • 5 ’-prodrugs can be represented by the group: wherein Z is O or S; R 17 and R 18 , when administered in vivo, are capable of providing the nucleoside monophosphate, diphosphate, or triphosphate.
  • Representative R 12 and R 13 are independently selected from:
  • R 19 is selected from H, Li, Na, K, phenyl and pyridinyl and wherein phenyl and pyridinyl are optionally substituted with one to three substituents independently selected from the group consisting of (CH2)o-6C02R 20 and (CH2)o-6CON(R 20 )2;
  • R 20 is independently H, Ci- 20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or Ci- 20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
  • a fatty alcohol such as oleyl alcohol,
  • R 21 is restricted to those sidechains occurring in natural L-amino acids
  • R 22 is H, Ci- 20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or C 1.20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1.5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)- amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl
  • R 17 and R 18 can come together to form a ring: wherein
  • R 23 is H, Ci - 2 o alkyl, Ci- 20 alkenyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc) or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
  • R 17 and R 18 can come together to form a ring selected from wherein
  • R 24 is selected from H, Ci- 20 alkyl, Ci- 20 alkenyl, the carbon chain derived from a fatty acid (such as oleic acid, linoleic acid, and the like), and Ci- 20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di (lower alkyl)- amino, fluoro, C3-10 cycloalkyl, or cycloalkyl; and
  • R 25 is O or NH.
  • 3 ’,5 ’-prodrugs can be represented by:
  • Formula X wherein: when chirality exists at the phosphorous center it may be wholly or partially R p or S p or any mixture thereof, and can be enantiomertically enriched;
  • R 26 is selected from fatty alcohol derived (for example but not limited to linoleyl-O- and oleyl-O-; R 11 is selected from R 1 and hydrogen; and R 1 , R 21 , R 22 , and R 19 are as defined herein.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium (3 ⁇ 4) may be used anywhere in described structures.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • An example of an isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
  • the deuterium can be bound in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a b-deuterium kinetic isotope effect).
  • Achillion Pharmaceuticals, Inc. (WO/2014/ 169278 and WO/2014/169280) describes deuteration of nucleotides to improve their pharmacokinetic or pharmacodynamic, including at the 5-position of the molecule.
  • substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond.
  • the hydrogen atom can be any isotope of hydrogen, including protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).
  • isotopically-labeled refers to an analog that is a "deuterated analog", a " 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
  • deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium ( 1 H), is substituted by a H-isotope, i.e., deuterium ( 2 H).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location. Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results.
  • a compound of Formula XIII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically carrier is used to treat or prevent COVID-19 disease caused by SARS-CoV-2 in a host in need thereof as described herein:
  • R 6 is selected from hydrogen, -C(0)R 6A , -C(0)0R 6A , Ci-ealkyl, and -CH 2 -0-R 6A ;
  • R 6 is selected from hydrogen, -C(0)R 6A , -C(0)0R 6A , Ci- 6 alkyl, and -CH 2 -0-R 6A and in an alternative embodiment, -C(0)NR 6B R 6C ;
  • R 6A is selected from hydrogen, Ci ⁇ alkyl, Ci-G, haloalkyl (for example, -CHCb, -CCI 3 , -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 F), aryl, and aryl(Ci- 6 alkyl)- wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl and in an alternative embodiment, R 6A is selected from Ci- 2 oalkyl and C 2-2 oalkenyl;
  • R 6B and R 6C are independently selected from hydrogen, Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl alkyl, heteroaryl, and heteroarylalkyl wherein the Ci- 2 oalkyl, C 2-2 oalkenyl, aryl, aryl alkyl, heteroaryl, and heteroarylalkyl can optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;
  • R 30 is CH 3 , CD 3 , CHD 2 , or CH 2 D;
  • R 31 is NH 2 or D or in an alternative embodiment, CD 3 ;
  • R 32 is CH 3 , CD 3 , CHD 2 , or CH 2 D;
  • Y is selected from F and Cl;
  • R 1 , R 2 , R 3 , R 4a , R 43 ⁇ 4 , and R 5 are as defined herein.
  • non-limiting examples of compounds of Formula XIII include: ,CH
  • Treatment refers to the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, in an effective amount to a host, for example a human, that is or may become infected with the SARS-CoV-2 virus.
  • the method of treatment comprises administration of an effective amount of Compound 1A or Compound 3A or a pharmaceutically acceptable salt thereof, for example Compound 2A or Compound 4A.
  • the method of treatment comprises administration of an effective amount of Compound IB or Compound 3B or a pharmaceutically acceptable salt thereof, for example Compound 2B or Compound 4B.
  • the present invention also includes prophylactic or preventative therapies.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered to a host who has been exposed to and thus is at risk of infection or at risk of reinfection with the SARS-CoV-2 virus.
  • Prophylactic treatment may be administered, for example, to a subject not yet exposed to or infected with SARS-CoV-2, but who is susceptible to, or otherwise at risk of exposure or infection with COVID-19.
  • a host at risk for infection or reinfection is administered a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof indefinitely until the risk of exposure no longer exists.
  • a method to prevent transmission includes administering an effective amount of one of the compounds described herein to humans for a sufficient length of time prior to exposure to crowds that can be infected, including during travel or public events or meetings, including for example, up to 3, 5, 7, 10, 12, 14 or more days prior to a communicable situation, either because the human is infected or to prevent infection from an infected person in the communicable situation.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in an effective amount for at least two weeks, three weeks, one month, two months, three months, four months, five months, or six months or more after infection.
  • the invention is directed to a method of treatment of COVID-19, including drug resistant and multidrug resistant forms of the virus and related disease states, conditions, or complications of the viral infection, including pneumonia, such as 2019 novel coronavirus-infected pneumonia (NCIP), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Additional non limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, blood clots, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis, and cytokine storm.
  • NIP 2019 novel coronavirus-infected pneumonia
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Additional non limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, blood clots, multisystem inflammatory syndrome, chronic fatigue, rhab
  • the method also comprises administering to a host in need thereof, typically a human, an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, optionally in combination with at least one additional bioactive agent, for example, an additional anti-viral agent, further optionally in combination with a pharmaceutically acceptable carrier additive and/or excipient.
  • a host in need thereof typically a human
  • an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof optionally in combination with at least one additional bioactive agent, for example, an additional anti-viral agent, further optionally in combination with a pharmaceutically acceptable carrier additive and/or excipient.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduction in the incidence of progressive respiratory insufficiency (PRI) as measured by greater than or equal to a 1-tier or even a 2-tier or more increase in respiratory support methods required to maintain satisfactory oxygenation (SpC > 93%) using the 6-tier hierarchical levels of respiratory support methods described below.
  • PRI progressive respiratory insufficiency
  • the scale of increasing respiratory support levels includes:
  • Level 3 Requirement for higher levels of passive supplemental O2 by nasal cannular or mask (up to 2L/min) to maintain SpCh > 93
  • Level 4 Requirement for oxygenation by positive-pressure devices, e.g., Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) or other non- invasive positive-pressure respiratory support methods to main satisfactory oxygenation and/or ventilation
  • CPAP Continuous Positive Airway Pressure
  • BiPAP Bi-level Positive Airway Pressure
  • the reduction in PRI is an increase from level 5 to level 3, level 5 to level 2, or level 5 to level 1. In one embodiment, the reduction in PRI is an increase from level 4 to level 2 or level 4 to level 1. In one embodiment, the reduction in PRI is an increase from level 3 to level 1.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces the median time to Clinical Recovery (status 6, 7, or 8 in the NIAID Clinical Status scale using an adapted National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of Clinical Status) by at least 3, 4, 5, or more days.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof results in an improvement as measured by the adapted ordinal scale of Clinical Status.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces the median time to Clinical Recovery (status 6, 7, or 8 in the NIAID Clinical Status scale using an adapted National Institute of Allergy and Infectious Diseases (NIAED) ordinal scale of Clinical Status) by at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days.
  • NIAED National Institute of Allergy and Infectious Diseases
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces the duration of hospitalization for a patient infected with the SARS-CoV-2 virus.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces the time to sustained non- detectable SARS-CoV-2 virus in the nose and/or throat in a patient infected with the SARS-CoV-2 virus.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces respiratory failure or death.
  • the administration of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof reduces the proportion of patients in a hospital population who are SARS-CoV-2 positive after at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of treatment.
  • a method of treating or preventing a SARS-CoV-2 infection in a host is provided by administering to the host an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, wherein the SARS-CoV-2 infection is caused by a viral variant that has developed a natural or drug-induced mutation over the wild-type.
  • the SARS-CoV-2 variant has a natural mutation or drug-induced mutation in a viral protein selected from an envelope (E) protein, membrane (M) protein, spike (S) protein, nspl, nsp2, nsp3, nsp4, nsp5, nsp 6, nsp7, nsp8, nsp9, nsplO, nspl2, nspl3, nspl4, nspl5, nspl6, ORFlab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORFIO.
  • the SARS-CoV-2 variant has a mutation which results in the acquired resistance to one or more anti viral drugs.
  • the SARS-CoV-2 variant has a deletion of the spike protein amino acids H69 and V70.
  • the SARS-CoV-2 variant has a deletion of the spike protein amino acids D614G.
  • the SARS-CoV-2 variant has a deletion of the spike protein amino acid Y 144.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution N501Y.
  • the SARS-CoV-2 variant which has a spike protein amino acid substitution A570D.
  • the SAR.S-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SAR.S-CoV-2 variant has a spike protein amino acid substitution
  • the SAR.S-CoV-2 variant has a spike protein amino acid substitution D1118H.
  • the SARS-CoV-2 variant has a premature stop codon mutation Q27stop in the protein product of ORF8.
  • the SAR.S-CoV-2 variant has a spike protein amino acid substitution K417N.
  • the SAR.S-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution D215G.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution A701V.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein deletion at amino acids 242-244
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution M1229I.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution N439K.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution A222V.
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a spike protein amino acid substitution
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution
  • the SARS-CoV-2 variant has a Orf8 protein amino acid substitution
  • the SARS-CoV-2 variant has an ORF8 protein amino acid substitution Y73C.
  • the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution D3L. In some embodiments, the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution S235F.
  • the SARS-CoV-2 variant has a ORFlab protein amino acid substitution T 100 II.
  • the SARS-CoV-2 variant has a ORFlab protein amino acid substitution A1708D
  • the SARS-CoV-2 variant has a ORFlab protein amino acid substitution I2230T.
  • the SARS-CoV-2 variant has a ORFlab protein amino acid SGF 3675-3677 deletion.
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution S861X, wherein X is any amino acid.
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution
  • the SARS-CoV-2 variant has a nspl2 protein amino acid substitution D484Y.
  • the SARS-CoV-2 variant includes a deletion of the spike protein amino acids 69-70, deletion of the spike protein amino acid Y144, the spike protein amino acid substitution N501 Y, the spike protein amino acid substitution A570D, the spike protein amino acid substitution D614G, the spike protein amino acid substitution P681H, the spike protein amino acid substitution T716I, the spike protein amino acid substitution S982A, the spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.
  • the SARS-CoV-2 variant includes amino acid substitutions in the spike protein of N501 Y, K417N, E484K, D80A, D215G, L18F, and R246I in the spike protein, and amino acid deletion at amino acids 242-244 of the spike protein.
  • the SARS-CoV-2 variant is selected from SARS-CoV-2 clade O, S, L, V, G, GH, or GR as described by Aim et al., "Geographical and temporal distribution of SARS- CoV-2 clades in the WHO European Region, January to June 2020".
  • Euro Surveillance: Bulletin European Sur les Maladies Transmissibles European Communicable Disease Bulletin. 25 (32).
  • the SARS-CoV-2 variant is selected from SARS-CoV-2 clade G614, S84, V251, 1378 or D392 as described by Guan et al., A genetic barcode of SARS-CoV-2 for monitoring global distribution of different clades during the COVID-19 pandemic. Int J Infect Dis. 2020 Nov; 100: 216-223.
  • the SARS-CoV-2 variant is selected from SARS-CoV-2 clade 19A, 19B, 20A, or 20C as described by Nextstrain: Genomic epidemiology of novel coronavirus - Global sub-sampling. Available from: https://nextstrain.org/ncov.
  • the SARS-CoV-2 variant is selected from SARS-CoV-2 lineage A, B, B.l, B.l.l, or B.1.177 as described by Rambaut et al., Phylogenetic Assignment of Named Global Outbreak LINeages (pangolin). San Francisco: GitHub. Available from: https://github.com/cov-lineages/pangolin; Rambaut et al. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol. 2020Nov;5(l 1): 1403-1407; Rambaut et al. SARS-CoV-2 lineages. Available from: https://cov-lineages.org/.
  • the SARS-CoV-2 variant is the “Cluster 5” variant, which includes the spike protein amino acid substitution D614G.
  • the SARS-CoV-2 variant is VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01) (also known as B.l.1.7 lineage and 20B/501Y.V1), which has been defined by multiple spike protein changes including deletion of the spike protein amino acids 69-70, deletion of the spike protein amino acid Y144, the spike protein amino acid substitution N501 Y, the spike protein amino acid substitution A570D, the spike protein amino acid substitution D614G, the spike protein amino acid substitution P681H, the spike protein amino acid substitution T716I, the spike protein amino acid substitution S982A, the spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.
  • the SARS-CoV-2 variant is the B.l.351 lineage variant (also known as 501. V2, 20C/501Y.V2), which includes several mutations in the receptor-binding domain (RBD) in the spike protein: N501Y, K417N, and E484K, which allows the virus to attach more easily to human cells, as well as amino acid substitution D80A in the spike protein, an amino acid substitution D215G in the spike protein, an amino acid substitution A701V in the spike protein, an amino acid substitution L18F in the spike protein, an amino acid substitution R246I in the spike protein, and amino acid deletion at amino acids 242-244 of the spike protein.
  • B.l.351 lineage variant also known as 501. V2, 20C/501Y.V2
  • RGD receptor-binding domain
  • the SARS-CoV-2 variant is the 501 Y.V2 lineage variant (also known as 501Y.V2, 20C/20H/501 Y.V2), which also includes the spike protein mutations N501 Y, K417N, and E484K.
  • the SARS-CoV-2 variant is the P.l lineage variant (also known as the Brazil(ian) variant), which includes ten mutations in the spike protein mutations, including N501Y and E484K.
  • the SARS-CoV-2 variant is the B.1.1.207 lineage variant, which includes a P681H mutation in the spike protein.
  • the SARS-CoV-2 variant is the danish mink variant which includes an amino acid deletion of H69 and Y70 in the spike protein, and an amino acid substitution Y453F in the spike protein.
  • the SARS-CoV-2 variant is the danish mink cluster 5 variant, which includes an amino acid deletion of H69 and V70 in the spike protein, an amino acid substitution Y453F in the spike protein, an amino acid substitution I692V in the spike protein, and an amino acid substitution M1229I in the spike protein.
  • the SARS-CoV-2 variant includes an amino acid deletion of H69 and V70 in the spike protein, and an amino acid substitution N439K in the spike protein.
  • the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU1 variant, which includes an amino acid substitution A222V in the spike protein.
  • the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU2 variant, which includes an amino acid substitution S477N in the spike protein, and an amino acid substitution A376T in the nucleocapsid protein.
  • the SARS-CoV-2 variant has one or more of the following mutations selected from: an amino acid substitution T1001I in the protein product of ORFlab; an amino acid substitution A1708D in the protein product of ORFla; an amino acid substitution I2230T in the protein product of ORFlab; a deletion of amino acids SGF at 3675-3677 in the protein product of ORFlab; an amino acid substitution G251V in the protein product of ORF3a; an amino acid substitution S24L in the protein product of ORF8; an amino acid substitution R52I in the protein product of ORF8; an amino acid substitution Y73C in the protein product of ORF8; an amino acid substitution L84S in the protein product of ORF8; an amino acid substitution P323L in the nspl2 domain; an amino acid substitution Y455I in the nspl2 domain; an amino acid substitution Q57H in the protein product of ORF3a; an amino acid substitution R27C in nsp2; an amino acid substitution VI
  • the SARS-CoV-2 variant contains one or more of the following mutations in the envelope (E) protein: S68F; L73F; P71L; S55F; R69I; T9I; V24M; D72H; T30I; S68C; V75L; V58F; V75F; or L21F; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the membrane (M) protein: T175M; D3G; V23L; W31C; A2V; V70F; W75L; Ml 091; I52T; L46F; V70I; D3Y; K162N; H125Y; K15R; D209Y; R146H; R158C; L87F; A2S; A69S; S214I; T208I; L124F; or S4F; and combinations thereof.
  • M membrane protein
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nucleocapsid (N) protein: RG203KR; S194L; S197L; P13L; D103Y; S 1931; S188L; I292T; S202N; D401Y; S190I; D22G; A208G; T205I; S183Y; S33I; D81Y; T393I; A119S; D377Y; S37P; T247I; A156S; D128Y; P199L; R195I; P207L; E62V; R209T; T362I; G18C; T24N; R185C; SI 801; M234I; Q9H; P383L; A35S; P383S; D348H; K374N; R32H; S327L; G179C; G238C; A55S; S190G; H300Y; A119V; D144Y; L139
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nspl protein: M85; D75E; G82 deletion; V84 deletion; P80 deletion; H83 deletion; V86 deletion; H81 deletion; E87 deletion; L88 deletion; K141 deletion;A79 deletion;V89 deletion; V56I; R124C; D75G; A90 deletion; Y118C; D139N; Y136 deletion; G30D; R24C; D139Y; E37K; H45Y; H110Y; G52S; I71V; D156 deletion; A76T; E37D; S135 deletion; S166G; A138T; F157 deletion; G49C; M85I; or D144A; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsplO protein: D64E; P136S; A104V; A32V; T12I; Ti l II; P84S; T51I; I55V; T102I; or T51A; and combinations thereof.
  • the SARS-CoV2 variant contains one or more of the following mutations in the nspl2 protein: P323L; T141I; A449V; S434F; M666I; H613Y; S647I; M3801; E922D; M629I; G774S; M601I; E436G; N491S; Q822H, A443V, T85I; A423V; M463I, T26I; A656T; M668I; T806I; T276M; T801N; V588L; K267N; V880I; K718R; L514F; F415S; T252N; Y38H; E744D; H752Q; I171V; S913L; A526V; A382V; G228C; P94L; E84K; K59N; P830S; T908I; P21S; D
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nspl3 protein: Y541C; P504L; A18V; R392C; P47L; S485L; L297P; H290Y; T127I; L176F; V193I; V570L; D260Y; V49I; Q518H; S468L; A598V; D204Y; S74L; T588I; G206C; V226L; V348L; M576I; A302D; P53S; T481M; K524N; A338V; P419S; V479F; P77L; V169F; N124S; P78S; S80G; V496L; A4V; T413I; A296S; A368S; K460R; L297F; P172S; A302S; P402S; T530I; L428F; P504
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nspl4 protein: A320V; F233L; T250I; V182L; A225V; R289C; A274S; P24L; I150T; S374A; H26Y; L177F; L157F; T16I; A482V; P297S; V120A; S255I; P203L; A23 deletion; K311N; M72I; V290F; F431L; K349N; M58I; P140S; R205C; T193A; L409F; P443S; Y260C; D345G; E204D; R163C; R81K; T524I; T113I; T31I; L493F; A119V; D345Y; M501I; A360V; A371V; T206I; V287F; A360S; I74T; M315I; P142
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nspl5 protein: V320L; A217V; V22L; V172L; D219N; P205S; V127F; Q19H; M218 deletion; A92V; D282G; I252V; T33I; G129S; L331F; A81V; V69L; S312F; T325I; A171V; R206S; D272Y; D87N; S288F; K109R; P270S; P65S; D267Y; D128Y; E215I; T144I; S261L; S287L; T112I; E260K; P205L; S161I; V66L; D39Y; or T114A; or combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nspl6 protein: S33R; K160R; P134S; Q28K; T195I; Y78G; T35I; G265V; K249N; A204S; K182N; R287I; A188S; A116V; T140I; L111F; M270T; R216N; A188V; A34V; D108N; L163F; L163H; Ml 71; T91M; A226S; G77R; L126F; N298L, R216S; T48I; Q238H; or R279K; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp2 protein: T85I P585S; I559V; D268; G212D; V198I; H237R; F10L; G339S; T166I; R27C; L271F; S211F; P91S; G199E; T371I; A336Y; I120F; S122F; A476V; S138L; V480A; T388I; T634I; P129S; R218C; I188T; T170I; P568L; E574A; I367V; H208Y; S99F; T429I; A306V; M405V; P129L; R222C; T44I; Q275H; R380C; A360V; A361V; G115C; L353F; H237Y; L462F; E261G; R4C; S263F; T
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp3 protein: A58T; T1198K; T428I; P153L; S1197R; D218E; S1424F; A1431V; S1285F; P74L; Q1884H; P1326L; L1221F; P141S; P1103S; S126L; Y916H; L557F; E391D; A1311V; S650F; P1103L; Y952H; P340S; A534V; P1787S; L1791F; N1587S; S371N; K1693N; G282V; P278S; T1335I; A1711V; K19R; A994D; K1325R; P822L; K412N; A465V; T1004I; T808I; G489D; S1699F; M1436V; S1265R;
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp4 protein: F308Y; T295I; M33I; A307V; A457V; G309C; L360F; A231V; H313Y; K399E; V20F; S137L; S34F; A380V; H470Y; T204I; S336L; L264F; L438F; M33L; S209F; C296S; L475I; G79V; T327N; T350I; L206F; M324I; E230G; L436 deletion; T237I; T492I; A260V; A446V; M458I; S395G; S481L; H36Y; T73I; L323F; L349F; S59F; T214I; or T60I; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp5 protein: G15S; D248E; K90R; L89F; A266V; P108S; A70T; A129V; T45I; G71S; L75F; A191V; L220F; N274D; L67F; P241L; K236R; V157L; K61R; P184S; S62Y; T21I; L50F; P108L; S254F; T93I; A255V; A94V; P132S; A234V; A260V; R60C; P96L; V247F; or T199I; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp6 protein: L37F; G277S; A46V; L75F; F37 deletion; T10I; V149F; L260F; Q208H; M83I; A136V; V145I; N156D; M86I; Y153C; G188V; L230I; F34 deletion; I189V; R233H; V114A; L33F; A287V; H11Y; A287T; A51V; G188S; I162T; M126V; M183I; N40Y; SI 04; F35L; M58L; or V84F; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp7 protein: S25L; S26F; L71F; S15T; M75I; orN78S; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp8 protein: M129I; I156V; T145I; R51C; T123I; L95F; T89I; P133S; S41F; K37N; T141M; V34F; R51L; A14T; A74V; I107V; A16V; P10S; A194V; D30G; A152V; or T187I; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the nsp9 protein: T77I; T109I; L42F; T34I; T19I; M101V; T62I; or T19K; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORFIO: L17P; A28V; P10S; I4L; S23F; R24C; *39Q; Q29 stop; Y14C, R20I; orA8V; and combinations thereof
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF3a: Q57H; G251V; V13L; G196V; A54S; A99V; H93Y; T14I; L46F; Q185H; T175I; Q213K; L108F; K61N; Y264C; A72S; T151I; A23S; G224C, K67N; S171L; W69L; H78Y; K136E; L86F; W131C; L147F; S58N; Y91H; I63T; D155Y; G172C; P240L; Y189C; W131R; KN136NY; T223I; G100C; S195Y; V112F; W131L; G44V; D27H; G174C; K21N, S165F; L65F; T229I; T89I; S74F; A99S; G254R; H204N
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF6: I33T; W27L; D53G; F22 deletion; P57L; D61Y; D61L; K42N; D53Y; H3Y; I32T; or R20S; or combinations thereof
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7a: S81L; A8T; L96F; A50V; V104F; Q62 stop; S83L; E16D; T14I; T28I; V93F; G38V; H47Y; T39I; T120S; Q62 deletion; Q62L; S37T; V104; P34S; P99L; T120I; V108L; H73Y; V24F; V29L; A13T; or L5F; or combinations thereof
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7b: C41F; T40I; A43V; LI IF; S31L; C41 deletion; H42; H42L; S5L; L20F; L32F; E33 stop; A15S; or F13 deletion; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF8: El 10 stop; G66 deletion; S69L; Till; F104L; F120L; G8R; P38S; D119E; II OS; or I39V; and combinations thereof.
  • the SARS-CoV-2 variant contains one or more of the following mutations in the spike protein: D614G; D936Y; P1263L; L5F; N439K; R21I; D839Y; L54F; A879S; L18F; F1121L; R847K; T478I; A829T; Q675H; S477N; H49Y; T29I; G769V; G1124V; V1176F; K1073N; P479S; S1252P; Y145 deletion; E583D; R214L; A1020V; Q1208H; D215G; H146Y; S98F; T95I; G1219C; A846V; I197V; R102I; V367F; T572I; A1078S; A831V; P1162L; T73I; A845S; G1219V; H245Y; L8V; Q675R; S25
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof can be administered in an effective amount for the treatment of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a host, typically a human, in need thereof.
  • the compound is Compound 1A or Compound 3A or a pharmaceutically acceptable salt thereof, for example Compound 2A or Compound 4A.
  • the compound is Compound IB or Compound 3B or a pharmaceutically acceptable salt thereof, for example Compound 2B or Compound 4B.
  • the compound or its salt can be provided as the neat chemical but is more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of a treatment for COVID-19.
  • the disclosure provides pharmaceutical compositions comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier for the treatment of COVID-19.
  • the pharmaceutical composition may contain a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, as the only active agent, or, in an alternative embodiment, in combination with at least one additional active agent.
  • a compound of Formula I including but not limited to Compound 1, 1A or IB), Formula II (including but not limited to Compound 3, 3A or 3B), Formula III (including, Formula Ilia, Formula Illb, Formula IIIc, Formula Hid, Formula Hie, or Formula Illf), Formula IV (including, Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, or Formula IVf), Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, can be formulated with one or more pharmaceutically acceptable carriers. Oral dosage forms are sometimes selected due to ease of administration and prospective favorable patient compliance.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula CIP or a pharmaceutically acceptable salt thereof is provided in a solid dosage form, such as a tablet or pill, which are well known in the art and described further below.
  • Enteric coated oral tablets may also be used to enhance bioavailability of the compounds for an oral route of administration.
  • Pharmaceutical compositions (formulations) may be administered via oral, parenteral, intravenous, inhalation, intramuscular, topical, transdermal, buccal, subcutaneous, suppository, or other route, including intranasal spray routes of delivery.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered intravenously.
  • a compound of the present invention is administered intravenously at a loading dose of 550 mg/day and a maintenance dose of 275 mg/day.
  • the loading dose is administered once and the maintenance dose is administered twice a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days.
  • an intravenous loading dose is 550 mg/day of Compound 1 (i.e., 600 mg/day hemisulfate salt of Compound 1), and a maintenance dose is 275 mg/day (i.e, 300 mg/day of hemisulfate salt)).
  • Effective dosage form will depend upon the bioavailability/pharmacokinetic of the particular agent chosen as well as the severity of disease in the patient.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof can be administered, for example, in one or more tablets, capsules, injections, intravenous formulations, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • Intravenous and intramuscular formulations are often administered in sterile saline.
  • One of ordinary skill in the art may modify the formulations to render them more soluble in water or another vehicle, for example, this can be easily accomplished by minor modifications (salt formulation, esterification, etc.).
  • compositions contemplated here optionally include a carrier, as described further below.
  • Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Representative carriers include solvents, diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agent, viscosity agents, tonicity agents, stabilizing agents, and combinations thereof.
  • the carrier is an aqueous carrier.
  • One or more viscosity agents may be added to the pharmaceutical composition to increase the viscosity of the composition as desired.
  • useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof and mixtures thereof.
  • Solutions, suspensions, or emulsions for administration may be buffered with an effective amount of buffer necessary to maintain a pH suitable for the selected administration.
  • Suitable buffers are well known by those skilled in the art. Some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers.
  • a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof may be admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • any of the usual pharmaceutical media may be used.
  • suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used.
  • suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used.
  • the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.
  • the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included.
  • sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.
  • Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl/alkyl nucleosides or phosphate ester pro-drug forms of the nucleoside compounds according to the present invention.
  • Amounts and weights mentioned in this disclosure typically refer to the free form (i.e., non salt, hydrate or solvate form).
  • the typically values described herein represent free-form equivalents, i.e., quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.
  • the amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, in the pharmaceutically acceptable formulation according to the present invention is an effective amount to achieve the desired outcome of treating COVID- 19, reducing the likelihood of COVID-19, or the inhibition, reduction, and/or elimination of COVID-19 or its secondary effects, including disease states, conditions, and/or complications which occur secondary to the virus.
  • a therapeutically effective amount of the present compounds in a pharmaceutical dosage form may range, for example, from about 0.001 mg/kg to about 100 mg/kg per day or more.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof may for example in non limiting embodiments be administered in amounts ranging from about 0.1 mg/kg to about 15 mg/kg per day of the patient, depending upon the pharmacokinetics of the agent in the patient.
  • the weight of active compound in the dosage form described herein is with respect to either the free form or the salt form of the compound unless otherwise specifically indicated.
  • approximately 600 mg of Compound 2 is the equivalent of approximately 550 mg of Compound 1.
  • the pharmaceutical composition is in a dosage form that contains from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, or from about 400 mg to about 450 mg of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, in a unit dosage form.
  • the pharmaceutical composition is in a dosage form, for example in a solid dosage form, that contains up to about 10, about 50, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, about 675, about 700, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 900, about 925, about 950, about 975, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg or more of a compound of Formula I, Formula II, Formula III, Formula IV,
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, for example Compound 1 or Compound 2 is administered at an initial dose (or loading dose) followed by a maintenance dose of at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 650, or at least about 750 and the dose is taken once or twice a day.
  • the loading dose is about 1.5 times greater, about 2 times greater, about 2.5 times greater, or 3-fold times greater than the maintenance dose.
  • the loading dose is administered once, twice, three, four, or more times before the first maintenance dose.
  • the pharmaceutical composition is in a dosage form, for example in a solid dosage form, that contains at least 500 mg, at least 550 mg, 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200, at least 1300 mg, at least 1400 mg, or at least 1500 mg of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, in a unit dosage form.
  • the pharmaceutical composition for example, a solid dosage form, contains at least about 450 mg, 550 mg, 650 mg, 750 mg or 850 mg of Compound 1 or Compound 3. In one embodiment, the pharmaceutical composition contains at least about 500 mg, at least about 550 mg, or at least about 600 mg of Compound 1 or Compound 3 and the composition is administered twice a day. In one embodiment, the pharmaceutical composition contains at least about 550 mg of Compound 1 and the pharmaceutical composition is administered twice a day.
  • the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 900 mg, 1000 mg, 1100 mg, 1100 mg, or 1200 mg of Compound 1 followed by a dose of at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550, at least about 600 mg, or at least about 650 mg of Compound 1 twice a day.
  • the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1100 mg of Compound 1 followed by a dose of at least about 450 mg, 550 mg, 650 mg, 750 mg, or 850 mg of Compound 1 twice a day.
  • the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1100 mg of Compound 1 followed by a dose of at least about 550 mg of Compound 1 twice a day.
  • the maintenance dose is administered for at about 4, 5, 6, 7, 8, 9, 10, or more days.
  • Compound 1 is Compound 1A.
  • Compound 1 is Compound IB
  • an effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered for the treatment of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof wherein the compound is administered according to the following schedule:
  • an effective amount of a compound of the Formula: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier is administered for the treatment of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof wherein the compound is administered according to the following schedule:
  • an effective amount of a compound of the Formula: optionally in a pharmaceutically acceptable carrier, is administered for the treatment of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof wherein the compound is administered according to the following schedule:
  • the pharmaceutical composition for example, a solid dosage form, contains at least about 400 mg, at least about 500 mg, 600 mg, 700 mg, or 800 mg of Compound 2 or Compound 4. In one embodiment, the pharmaceutical composition contains at least about 500 mg, at least about 600 mg, or at least about 700 mg of Compound 2 or Compound 4 and the composition is administered twice a day. In one embodiment, the pharmaceutical composition contains at least about 600 mg of Compound 2 and the pharmaceutical composition is administered twice a day. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1300 mg of Compound 2 followed by a dose of at least about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of Compound
  • the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1000 mg, 1200 mg, or 1400 mg of Compound 2 followed by a dose of at least about 600 mg of Compound 2 twice a day. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1200 mg of Compound 2 followed by a dose of at least about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of Compound 2 twice a day. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1200 mg of Compound 2 followed by a dose of at least about 600 mg of Compound 2 twice a day. In one embodiment, the maintenance dose is administered for at about 4, 5, 6, 7, 8, 9, 10, or more days. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound IB
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered for at least five days, six days, seven days, eight days, nine days, ten days, two weeks, three weeks, one month, at least two months, at least three months, at least four months, at least five months, at least six months or more.
  • VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered once, twice, three, or more times a day In one embodiment, it is administered orally twice a day.
  • a prophylactically or preventive effective amount of the compositions according to the present invention may generally fall within the ranges set out above, and can be determined in the best judgement of the health care provider.
  • a compound of the present invention is administered seasonally as the risk of the virus increases to prevent infection, or can be administered, for example, before, during and/or after travel or exposure.
  • a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetic of the agent used, as well as the patient or subject (animal or human) to be treated, and such therapeutic amount can be determined by the attending physician or specialist.
  • An aspect of the invention is a solid dosage form that includes an effective amount of a compound of Formula I (including but not limited to Compound 1, 1A, IB, 2, 2A or 2B), Formula II (including but not limited to Compound 3), Formula III (including Formula Ilia, Formula Illb, Formula IIIc, Formula Hid, Formula Hie, or Formula Illf), Formula IV (including Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, or Formula IVf), Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  • a compound of Formula I including but not limited to Compound 1, 1A, IB, 2, 2A or 2B
  • Formula II including but not limited to Compound 3
  • Formula III including Formula Ilia, Formula Illb, Formula IIIc, Formula Hid, Formula Hie, or Formula Illf
  • Formula IV including Formula IVa, Formula IVb, Formula IVc, Formula IVd
  • the solid dosage form includes a spray dried solid dispersion of a compound of Formula I, Formula II, Formula PI, Formula IV, Formula V, Formula VI, Formula
  • the solid dosage form is a granulo layered solid dispersion of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral delivery.
  • the solid dispersion also contains at least one excipient selected from copovidone, poloxamer and HPMC-AS.
  • the poloxamer is Poloxamer 407 or a mixture of poloxamers that may include Poloxamer 407.
  • HPMC-AS is HPMC- AS-L.
  • a solid dosage form prepared from a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof also comprises one or more of the following excipients: a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid
  • polycaprolactam polyacetal, polyether, polyester (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g., poly((p-hydroxyalkanoate)
  • a solid dosage form prepared from a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof also comprises one or more of the following surfactants: polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and poloxamers.
  • surfactants polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol al
  • poloxamers examples include, poloxamers 188, 237, 338 and 407. These poloxamers are available under the trade name Pluronic® (available from BASF, Mount Olive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127, respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic® F-87) is a block copolymer with an average molecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da.
  • Pluronic® available from BASF, Mount Olive, N.J.
  • Pluronic® F-68 is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about
  • Poloxamer 338 is a block copolymer with an average molecular mass of about 12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da.
  • Poloxamer 407 is a polyoxyethylene-polyoxypropylene triblock copolymer in a ratio of between about E101 P56 E101 to about E106 P70 E106, or about E101 P56E101, or about El 06 P70 El 06, with an average molecular mass of about 10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 to about 13,000 Da, or about 12,600 Da.
  • a solid dosage form prepared from a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof also comprises one or more of the following surfactants: polyvinyl acetate, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethyl ammonium bromide, saponin, sugar esters, Triton X series, sorbitan trioleate, sorbitan mono-oleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, diethylene glycol dioleate, tetrahydrofurfuryl ole
  • a solid dosage form prepared from a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is prepared by a process that includes solvent or dry granulation optionally followed by compression or compaction, spray drying, nano-suspension processing, hot melt extrusion, extrusion/spheronization, molding, spheronization, layering (e.g., spray layering suspension or solution), or the like.
  • Examples of such techniques include direct compression, using appropriate punches and dies, for example wherein the punches and dies are fitted to a suitable tableting press; wet granulation using suitable granulating equipment such as a high shear granulator to form wetted particles to be dried into granules; granulation followed by compression using appropriate punches and dies, wherein the punches and dies are fitted to a suitable tableting press; extrusion of a wet mass to form a cylindrical extrudate to be cut into desire lengths or break into lengths under gravity and attrition; extrusion/spheronization where the extrudate is rounded into spherical particles and densified by spheronization; spray layering of a suspension or solution onto an inert core using a technique such as a convention pan or Wurster column; injection or compression molding using suitable molds fitted to a compression unit; and the like.
  • suitable granulating equipment such as a high shear granulator to form we
  • Exemplary disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), powdered cellulose, chitosan, croscarmellose sodium, crospovidone, guar gum, low substituted hydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch, sodium carboxymethyl starch, and the like, or a combination thereof.
  • Exemplary lubricants include calcium stearate, magnesium stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, light mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, silicon dioxide, colloidal silicon dioxide, dimethyldichlorosilane treated with silica, talc, or a combination thereof.
  • the dosage form cores described herein may be coated to result in coated tablets.
  • the dosage from cores can be coated with a functional or non-functional coating, or a combination of functional and non-functional coatings.
  • “Functional coating” includes tablet coatings that modify the release properties of the total composition, for example, a sustained-release or delayed-release coating.
  • “Non-functional coating” includes a coating that is not a functional coating, for example, a cosmetic coating. A non-functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
  • a non-functional coating can also mask the taste of the uncoated composition including the active pharmaceutical ingredient.
  • a coating may comprise a light blocking material, a light absorbing material, or a light blocking material and a light absorbing material.
  • Exemplary polymethacrylates include copolymers of acrylic and methacrylic acid esters, such as a. an ami nomethacrylate copolymer USP/NF such as a poly(butyl methacrylate, (2 -dimethyl aminoethyl)methacrylate, methyl methacrylate) 1:2:1 (e g., EUDRAGIT E 100, EUDRAGIT EPO, andEUDRAGITE 12.5; CAS No. 24938-16-7); b.
  • an ami nomethacrylate copolymer USP/NF such as a poly(butyl methacrylate, (2 -dimethyl aminoethyl)methacrylate, methyl methacrylate) 1:2:1 (e g., EUDRAGIT E 100, EUDRAGIT EPO, andEUDRAGITE 12.5; CAS No. 24938-16-7); b.
  • a poly(methacrylic acid, ethyl acrylate) 1:1 e g., EUDRAGIT L30 D-55, EUDRAGIT L100-55, EASTACRYL 30D, KOLLICOAT MAE 30D AND 30DP; CAS No. 25212-88-8
  • a poly(methacrylic acid, methyl methacrylate) 1:1 e g., EUDRAGIT L 100, EUDRAGIT L 12.5 and 12.5 P; also known as methacrylic acid copolymer, type A NF; CAS No. 25806-15-1
  • a poly(methacrylic acid, methyl methacrylate) 1:2 (e g., EUDRAGIT S 100, EUDRAGIT S 12.5 and 12.5P; CAS No. 25086-15-1); e. a poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 (e.g., Eudragit FS 30 D; CAS No. 26936- 24-3); f.
  • a poly(ethyl acrylate, methylmethacrylate, trimethylammonioethyl methacrylate chloride) 1:2:02 or 1:2:0.1 e g , EUDRAGIT S RL 100, RL PO, RL 30 D, RL 12.5, RS 100, RS PO, RS 30 D, or RS 12.5; CAS No. 33434-24-1
  • g. a poly(ethyl acrylate, methyl methacrylate) 2:1 e g., EUDRAGIT NE 30 D, Eudragit NE 40D, Eudragit NM 30D; CAS No. 9010-88-2; and the like, or a combination thereof.
  • Suitable alkylcelluloses include, for example, methylcellulose, ethylcellulose, and the like, or a combination thereof.
  • Exemplary water based ethylcellulose coatings include AQUACOAT, a 30% dispersion further containing sodium lauryl sulfate and cetyl alcohol, available from FMC, Philadelphia, PA; SURELEASE a 25% dispersion further containing a stabilizer or other coating component (e g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.) available from Colorcon, West Point, PA; ethyl cellulose available from Aqualon or Dow Chemical Co (Ethocel), Midland, MI.
  • a stabilizer or other coating component e g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.
  • ethyl cellulose available from Aqualon
  • Suitable materials that can be used to prepare a functional coating include hydroxypropyl methylcellulose acetate succinate (UPMCAS); cellulose acetate phthalate (CAP); a polyvinylacetate phthalate; neutral or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or specifically cetostearyl alcohol), fatty acids, including fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials having hydrocarbon backbones, or a combination thereof.
  • UPMCAS hydroxypropyl methylcellulose acetate succinate
  • CAP cellulose acetate phthalate
  • a polyvinylacetate phthalate a polyvinylacetate phthalate
  • neutral or synthetic waxes such as lauryl, myristyl, stearyl,
  • Suitable waxes include beeswax, glycowax, castor wax, camauba wax, microcrystalline wax, candelilla, and wax -like substances, e g., material normally solid at room temperature and having a melting point of from about 30°C to about 100°C, or a combination thereof.
  • a functional coating may include digestible, long chain (e g., C8- C50, specifically C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, waxes, or a combination thereof. Hydrocarbons having a melting point of between about 25 °C and about 90 °C may be used. Specifically, long chain hydrocarbon materials, fatty (aliphatic) alcohols can be used.
  • the coatings can optionally contain additional pharmaceutically acceptable excipients such as a plasticizer, a stabilizer, a water-soluble component (e.g., pore formers), an anti-tacking agent (e.g., talc), a surfactant, and the like, or a combination thereof.
  • additional pharmaceutically acceptable excipients such as a plasticizer, a stabilizer, a water-soluble component (e.g., pore formers), an anti-tacking agent (e.g., talc), a surfactant, and the like, or a combination thereof.
  • a functional coating may include a release-modifying agent, which affects the release properties of the functional coating.
  • the release-modifying agent can, for example, function as a pore-former or a matrix disrupter.
  • the release-modifying agent can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the release-modifying agent can comprise one or more hydrophilic polymers including cellulose ethers and other cellulosics, such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl cellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; an acrylic polymer, such as gastric soluble Eudragit FS 30D, pH sensitive Eudragit L30D 55, L 100, S 100, or L 100- 55; or a combination thereof.
  • hydrophilic polymers including cellulose ethers and other cellulosics, such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl cellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; an acrylic polymer, such as gastric soluble Eudragit FS 30D, pH sensitive Eudra
  • exemplary release-modifying agents include a povidone; a saccharide (e.g., lactose, and the like); a metal stearate; an inorganic salt (e.g., dibasic calcium phosphate, sodium chloride, and the like); a polyethylene glycol (e.g., polyethylene glycol (PEG) 1450, and the like); a sugar alcohol (e.g., sorbitol, mannitol, and the like); an alkali alkyl sulfate (e.g., sodium lauryl sulfate); a polyoxyethylene sorbitan fatty acid ester (e.g., polysorbate); or a combination thereof.
  • a povidone e.g., a saccharide (e.g., lactose, and the like); a metal stearate; an inorganic salt (e.g., dibasic calcium phosphate, sodium chloride, and the like); a polyethylene glycol (
  • Exemplary matrix disrupters include water insoluble organic or inorganic material.
  • Organic polymers including but not limited to cellulose, cellulose ethers such as ethylcellulose, cellulose esters such as cellulose acetate, cellulose acetate butyrate and cellulose acetate propionate; and starch can function as matrix disrupters.
  • examples or inorganic disrupters include many calcium salts such as mono-, di- and tri calcium phosphate; silica and, talc.
  • the coating may optionally contain a plasticizer to improve the physical properties of the coating.
  • a plasticizer to improve the physical properties of the coating.
  • the amount of plasticizer included in a coating solution is based on the concentration of the polymer, e.g., can be from about 1% to about 200% depending on the polymer but is most often from about 1 wt% to about 100 wt% of the polymer. Concentrations of the plasticizer, however, can be determined by routine experimentation.
  • plasticizers for ethylcellulose and other celluloses include plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, or a combination thereof, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.
  • plasticizers for acrylic polymers include citric acid esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, triacetin, or a combination thereof, although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.
  • citric acid esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, triacetin, or a combination thereof, although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.
  • Suitable methods can be used to apply the coating material to the surface of the dosage form cores.
  • Processes such as simple or complex coacervation, interfacial polymerization, liquid drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, or electrostatic deposition may be used.
  • an optional intermediate coating is used between the dosage form core and an exterior coating.
  • Such an intermediate coating can be used to protect the active agent or other component of the core subunit from the material used in the exterior coating or to provide other properties.
  • Exemplary intermediate coatings typically include water-soluble film forming polymers.
  • Such intermediate coatings may include film forming polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, hydroxypropyl methylcellulose, polyethylene glycol, polyethylene oxide, and the like, or a combination thereof; and a plasticizer.
  • Plasticizers can be used to reduce brittleness and increase tensile strength and elasticity.
  • Exemplary plasticizers include polyethylene glycol propylene glycol and glycerin.
  • the compounds or their pharmaceutically acceptable salts as described herein can be administered on top of the current standard of care for COVID patients, or in combination or alternation with any other compound or therapy that the healthcare provider deems beneficial for the patient.
  • the combination and/or alternation therapy can be therapeutic, adjunctive, or palliative.
  • COVID patients can pass through various stages of disease, and that the standard of care can differ based on what stage of illness the patient presents with or advances to. COVID is noteworthy for the development of “cross-talk” between the immune system and the coagulation system. As the disease progresses, the patient can mount an overreaction by the immune system, which can lead to a number of serious implications, including a cytokine storm. Via the cross-talk between the immune system and the coagulation system, the patient can begin clotting in various areas of the body, including the respiratory system, brain, heart and other organs. Multiple clots throughout the body have been observed in COVID patients, requiring anticoagulant therapy. It is considered that these clots may cause long term, or even permanent damage if not treated and disease alleviated.
  • stage 1 early infection
  • stage 2 pulmonary phase
  • stage 3 hypererinflammation phase / cytokine storm
  • Stage 1 is characterized by non-specific, and often mild, symptoms. Viral replication is occurring, and it is appropriate to begin immediate treatment with the compounds described herein and perhaps in combination or alternation with another anti-viral therapy. Interferon-b may also be administered to augment the innate immune response to the virus. In one embodiment, therefore, a compound of Formula I, Formula II, Formula PI, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is used in an effective amount in combination or alternation with interferon-b and or an additional anti-viral drug. Zinc supplements and or Vitamin C is also sometimes administered at this stage or as the illness progresses.
  • Stage 2 of COVID-19 is the pulmonary phase where patients may experience acute hypoxemic respiratory failure.
  • the primary organ failure of COVED-19 is hypoxemic respiratory failure.
  • moderate immunosuppression via a steroid for example, dexamethasone, can be beneficial to patients with acute hypoxemic respiratory failure and/or patients on mechanical ventilation.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is used in an effective amount in combination with a corticosteroid which may be a glucocorticoid.
  • Non-limiting examples are budesonide (Entocort EC), bethamethasone, (Celestone), prednisone (Prednisone Intensol), prednisolone (Orapred, Prelone), triamcinolone (Aristospan Intra-Articular, Aristospan Intralesional, Kenalog), methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol), hydrocortisone, or dexamethasone (Dexamethasone Intensol, DexPak 10 Day, DexPak 13 Day, DexPak 6 Day).
  • the NS5B inhibitor Remdesivir has provided mixed results when given to COVID-19 patients. It can only be administered in a hospital setting, and only by intravenous injection, typically three times a day, which makes it inappropriate for mild to moderate COVID-19 patients.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with Remdesivir to amplify the overall antiviral effect.
  • Stage 3 the final stage of the disease, is characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small blood clots develop throughout the bloodstream.
  • DIC progressive disseminated intravascular coagulation
  • This stage also can include multi-organ failure (e.g. vasodilatory shock, myocarditis).
  • cytokine storm There does appear to be a bi-directional, synergistic relationship between DIC and cytokine storm.
  • an anti -coagulant agent which may, for example, be an indirect thrombin inhibitor or a direct oral anticoagulant (“DO AC”).
  • DO AC direct oral anticoagulant
  • Non-limiting examples are low-molecular weight heparin, warfarin, bivalirudin (Angiomax), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), or edoxaban (Lixiana).
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XTTT or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with anti-coagulant therapy.
  • TPA can be administered (tissue plasminogen activator).
  • IL-6 interleukin-6
  • patients can be administered an IL-6-targeting monoclonal antibody, pharmaceutical inhibitor or protein degrader such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation.
  • IL-6-targeting monoclonal antibody such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation.
  • antibodies include tocilizumab, sarilumab, siltuximab, olokizumab and clazakizumab.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with tocilizumab or sarilumab.
  • immunosuppressant drugs used to treat the overreacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and, IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolate (CellCept, Myfortic)).
  • Additional antibodies and biologies include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta)).
  • IL-1 blocks the production of IL-6 and other proinflammatory cytokines. COVID patients are also sometimes treated with anti-IL-1 therapy to reduce a hyperinflammatory response, for example, an intravenous administration of anakinra.
  • Anti-IL-1 therapy generally may be for example, a targeting monoclonal antibody, pharmaceutical inhibitor or protein degrader such as a bispecific compound that binds to IL-1 and also to a protein that mediates degradation.
  • Treatment for bacterial pneumonia secondary to COVID or for sepsis includes the administration of antibiotics, for example a macrolide antibiotic, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin.
  • antibiotics for example a macrolide antibiotic, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with an antibiotic, for example, azithromycin.
  • an antibiotic for example, azithromycin.
  • Some of these antibiotics such as azithromycin have independent anti-inflammatory properties.
  • Such dmgs may be used both as anti-inflammatory agents for COVID patients and have a treatment effect on secondary bacterial infections.
  • analgesics can be added sequentially, and for ongoing anxiety, sedatives can be added sequentially.
  • analgesics include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine).
  • Non-limiting examples of sedatives include melatonin, atypical antipsychotics with sedative- predominant properties (olanzapine, quetiapine), propofol or dexmedetomidine, haloperidol, and phenobarbital.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with a pain reliever, such as acetaminophen, ketamine, hydromorphone, fentanyl, or morphine.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital.
  • Investigational drugs for COVID-19 include chloroquine and hydroxychloroquine.
  • a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula CIP or a pharmaceutically acceptable salt thereof is administered in combination or in alternation with chloroquine or hydroxychloroquine.
  • a protease inhibitor such as lopinavir or ritonavir, previously approved for HIV, may also be administered.
  • Additional drugs that may be used in the treatment of a COVID patient include, but are not limited to favipiravir, fingolimod (Gilenya), methylprednisolone, bevacizumab (Avastin), Actemra (tocilizumab), umifenovir, losartan and the monoclonal antibody combination of REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with an active compound provided herein to treat a viral infection susceptible to such.
  • a compound of the present invention is used in an effective amount in combination with anti-coronavirus vaccine therapy, including but not limited to mRNA-1273 (Moderna, Inc.), AZD-1222 (AstraZeneca and University of Oxford), BNT162 (Pfizer and BioNTech), CoronaVac (Sinovac), NVX-CoV 2372 (NovoVax), SCB-2019 (Sanofi and GSK), ZyCoV-D (Zydus Cadila), and CoVaxin(Bharat Biotech).
  • a compound of the present invention is used in an effective amount in combination with passive antibody therapy or convalescent plasma therapy.
  • SAR.S-CoV-2 is constantly mutating, which many increase virulence and transmission rates.
  • Drug-resistant variants of viruses may emerge after prolonged treatment with an antiviral agent. Drug resistance may occur by mutation of a gene that encodes for an enzyme used in viral replication.
  • the efficacy of a drug against an RNA virus infection in certain cases can be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the principle drug.
  • the pharmacokinetics, bio distribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted).
  • combination therapy which may include alternation therapy if considered concerted.
  • the disclosed purine nucleotides are polymerase inhibitors, it may be useful to administer the compound to a host in combination with, for example a:

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Abstract

La présente invention concerne l'utilisation de phosphoramidates de nucléotides de purine ou de leurs sels pharmaceutiquement acceptables administrés en quantité efficace pour le traitement ou la prévention de la COVID -19, une infection provoquée par le virus SARS-CoV-2 chez un hôte, par exemple un être humain, en ayant besoin.
PCT/US2021/019468 2020-02-27 2021-02-24 Composés hautement actifs contre la covid-19 WO2021173713A1 (fr)

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WO2023034617A1 (fr) * 2021-09-03 2023-03-09 Atea Pharmaceuticals, Inc. Nucléotides 2'-chloro-2'-fluoro-n2-amino-n6-méthylamino puriques pour le traitement des flavivirus
WO2023065683A1 (fr) * 2021-10-22 2023-04-27 广州谷森制药有限公司 Nouveau composé nucléosidique de purine deutéré, son procédé de préparation, composition et utilisation associées
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