Anti-COVID-19 highly active compounds

Abstract

The present invention is the use of a purine nucleotide phosphoramidate or a pharmaceutically acceptable salt thereof administered in an effective amount for the treatment or prevention of an infection caused by COVID-19, the SARS CoV-2 virus, in a host in need thereof, such as a human.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of February 24, 2021, application number 202180002433.9, and invention name “Highly active compounds against COVID-19”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 982,670, filed February 27, 2020, U.S. Provisional Application No. 62 / 994,206, filed March 24, 2020, U.S. Provisional Application No. 63 / 032,247, filed May 29, 2020, U.S. Provisional Application No. 63 / 039,352, filed June 15, 2020, U.S. Provisional Application No. 63 / 040,985, filed June 18, 2020, U.S. Provisional Application No. 63 / 054,680, filed July 21, 2020, U.S. Provisional Application No. 63 / 073,328, filed September 1, 2020, and U.S. Provisional Application No. 63 / 146,456, filed February 5, 2021. These applications are incorporated by reference in their entirety for all purposes. Technical Field

[0004] The present invention relates to the use of selective purine nucleotides and pharmaceutically acceptable salts thereof with superior activity and dosage convenience for treating or preventing the SARS-CoV-2 virus that causes COVID-19 in a host in need thereof, typically a human. Background Art

[0005] In December 2019, several patients were diagnosed with pneumonia. These patients displayed symptoms similar to those of the 2002-2003 SARS (Severe Acute Respiratory Syndrome) outbreak. In January 2020, the infectious agent was identified as a novel coronavirus, designated Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and the resulting illness was named COVID-19. This potentially severe and sometimes fatal illness quickly spread around the world. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic.

[0006] Most patients infected with the SARS-CoV-2 virus experience mild, cold-like symptoms, including fever, cough, fatigue, shortness of breath, muscle aches, and loss of taste and / or smell. These symptoms usually resolve within a few weeks with minimal medical care. However, occasionally, symptoms can persist for months. The virus can cause long-term damage to the lungs, heart, and brain. In addition, in some patients, especially the elderly, immunocompromised, or those with underlying medical conditions, the virus can cause severe symptoms leading to hospitalization, artificial respiration, and / or death.

[0007] SARS-CoV-2 is a coronavirus (CoV) belonging to the Nidovirales order, Coronaviridae family, and Coronavirinae subfamily, which are enveloped viruses with a single-stranded positive-sense RNA genome. SARS-CoV-2 is approximately 30 kilobases in size, making it one of the largest known RNA genomes. Related coronaviruses include severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). However, 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. Nature 2020, 579, 270). Compared with SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster rate of human-to-human transmission (Huang et al., Lancet 2000, 395, 497), making its control particularly challenging and dangerous. Coronaviruses typically originate from endemic animal infections that cross the animal-human species barrier and gradually 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 have made CoVs such as SARS CoV and Middle East Respiratory Syndrome CoV (MERS) into highly pathogenic human viruses (Schoeman and Fielding, Virology 2019, 16, 69). Similarly, genome sequencing showed that SARS-CoV-2 has 96% identity with bat coronaviruses at the whole genome level (Zhou et al., Nature 2020, 579, 270), and therefore most likely originated from bats.

[0008] SARS-CoV-2 enters human cells by binding to the angiotensin-converting enzyme 2 (hACE2) receptor. The spike glycoprotein on the surface of the viral envelope binds to the ACE2 receptor, and then the human transmembrane protease serine 2 cleaves and activates the spike protein, allowing SARS-CoV-2 to enter the cell through endocytosis or direct fusion with the host membrane (Luan et al. Biochem. Biophys. Res. Commun. 2020: 527, 165; Hoffman, M. et al. Cell, 2020, 181, 271; Yang et al. Int. J. Biol. Sci. 2020, 16, 1724).

[0009] Once inside the cell, SARS-CoV-2 transcription and replication are mediated by a multi-subunit polymerase complex. The catalytic subunit of this complex is an RNA-dependent RNA polymerase (RdRp), called nsp12. Although the isolated nsp12 subunit itself is capable of polymerase reactions, the presence of cofactors nsp7 and nsp8 significantly improves the efficiency of the polymerase reaction (Ahn et al. Arch Virol. 2012, 157, 2095; Subissi et al. Proc. Natl. Acad. Sci., 2014, 111, E3900).

[0010] In April 2020, the crystal structure of SARS-CoV-2 nsp-12 in complex with nsp-7 and nsp-8 was solved (Gao et al. Science 2020, 368: 779-782). The structure of nsp12 contains a polymerase C-terminal RdRp domain connected to an N-terminal extended domain called the venavirus RdRp-associated nucleotidyltransferase (NiRAN) domain. This NiRAN domain, which is conserved in all venaviruses and is capable of performing nucleotidyl transferase activity, is characterized by an α and β fold consisting of eight α helices and a five-stranded β fold (Gao et al. Science 2020, 368: 779-782). The C-terminal domain has been characterized as a "cup-shaped right-hand" domain with finger, thumb, and palm subdomains.

[0011] As the SARS-CoV-2 virus spreads around the world, it exhibits a high mutation rate, and multiple mutated forms of the virus are circulating globally. These mutations have the potential to affect the virus's ability to cause infection and its rate of transmission. For example, the B.1.1.7 variant, identified in the UK and designated variant of concern 202012 / 01 by Public Health England in the fall of 2020, has eight mutations in the spike protein region. Evidence suggests that this variant spreads faster and more easily and may be associated with an increased risk of death. In South Africa, additional variants, B.1.351 and 501Y.V2, have been identified. Both variants share some mutations with the B.11.7 variant, including the N501Y mutation. Brazil has also identified a variant, called P.1, which contains mutations that may affect the virus's ability to be recognized by antibodies. For this reason, developing therapies that can treat mutated forms of the virus, particularly those with mutations in the spike protein, is crucial.

[0012] The history of creating therapeutics for human coronavirus diseases illustrates the complexity and challenges of this problem. Although MERS-CoV and SARS-CoV were discovered in 2012 and 2003, respectively, no commercial vaccines or drugs have been approved.

[0013] The lack of approved treatments, combined with its high mortality rate and the ease and speed with which it spreads, highlights the need to develop effective antiviral drugs for COVID-19.

[0014] It is therefore an object of the present invention to provide compounds, compositions and methods for treating and preventing the SARS-CoV-2 virus that causes COVID-19. Summary of the Invention

[0015] The present invention provides methods for treating SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a selective purine nucleotide compound further described herein for advantageously treating, preventing, or preventing SARS-CoV-2 virus that causes COVID-19. These purine nucleotides exhibit concentrated activity against the virus.

[0016] In addition, and importantly, these compounds can be administered to a host in need, such as a human, using a simple solid oral dosage form that can be conveniently taken at home or, typically, outside a medical facility without the need for parenteral administration or hospitalization. If necessary or appropriate, the active compounds described herein can also be administered parenterally or orally in a medical facility. This therapy can be used to treat mild, moderate, or severe illnesses.

[0017] In one embodiment of the present invention, the compound of formula I

[0018]

[0019] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in an effective amount to be administered to a host in need thereof, typically a human, suffering from COVID-19, or a host at risk of infection or reinfection with the SARS-CoV-2 virus, for example, as a prophylactic agent (and wherein the term prophylaxis refers to the complete prevention or minimization of acquired infection relative to the disease in the absence of such prophylactic treatment), wherein:

[0020] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -C(O)C1-C6 alkyl;

[0021] R 2 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3-7 Cycloalkyl or aryl (including phenyl and naphthyl), and in an alternative embodiment, R 2 is aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0022] R 3 is hydrogen or C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl);

[0023] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3-7 cycloalkyl; and

[0024] R 5 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1-6 Haloalkyl or C 3-7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0025] Non-limiting examples of C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2. Non-limiting examples of C3-C6 cycloalkyl groups include cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl.

[0026] A non-limiting example of an aryl(C1-C4alkyl)- is benzyl. A non-limiting example of an aryl is phenyl.

[0027] In one embodiment, the SARS-CoV-2 virus is wild-type. In another embodiment, the SARS-CoV-2 virus has undergone natural or drug-induced mutations, such as, but not limited to, mutations in viral proteins selected from the group consisting of envelope (E) protein, membrane (M) protein, spike (S) protein, nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15, nsp16, ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, and ORF10.

[0028] A non-limiting example of a compound of Formula I is Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered to a host, such as a human, infected with SARS-CoV-2, or a host at risk of infection with the SARS-CoV-2 virus in need thereof, i.e., as a prophylactic agent.

[0029]

[0030] Compound 1 is described above without regard to stereochemistry at the phosphorus atom (which is chiral). Compound 1 can be used without regard to phosphorus stereochemistry and can be used in phosphorus-racemic form, or any desired ratio of the phosphorus R- and S-enantiomers of the compound can be used, including enantiomerically enriched (e.g., up to at least 90%, 95%, 98%, 99% or even 100% free of the opposite enantiomer, which is actually a diastereomer because there are multiple chiral carbons in the molecule). Compound 1A is the S-enantiomer and Compound 1B is the R-enantiomer.

[0031]

[0032] Compound 1, including Compound 1A and Compound 1B, is a potent inhibitor against COVID-19 caused by the SARS-CoV-2 virus. As described in Examples 5 and 6, Compound 1A exhibited an EC of 0.64 μM against SARS-Cov-2 in HAE cells (human airway epithelial cells). 90value. The assay using HAE cells is an in vitro model of the lung and a representative system for SARS-CoV-2 replication. It was also surprisingly found that the active triphosphate metabolite of compound 1A was robustly formed when exposed to normal primary bronchial and nasal epithelial cells. As described in Example 7, when compound 1A was incubated in human nasal and bronchial epithelial cells, the half-life of the active triphosphate substance in both bronchial and nasal epithelial cells was greater than 1.5 days. This cannot be predicted in advance, which is especially important for treating patients with early infection when the virus is concentrated in large quantities in the nasal cavity and bronchial cells.

[0033] The data presented herein show that the compound is concentrated in the lung relative to the liver, and previously reported data confirm that the compound is preferentially concentrated in the liver relative to the heart (see, e.g., Example 19 of PCT application PCT / US2018 / 016301). Taken together, the data confirm that the compound is concentrated in the target organ, lung, liver, or heart, thereby reducing toxicity.

[0034] In one embodiment, Compound 1, such as Compound 1A or Compound 1B, or a pharmaceutically acceptable salt thereof, is optionally administered in a pharmaceutically acceptable carrier in an effective amount to a host, such as a human, infected with the SARS-CoV-2 virus, or a host at risk of infection with the SARS-CoV-2 virus in need thereof, i.e., as a prophylactic agent. In one embodiment, the pharmaceutically acceptable salt is a hemisulfate salt, as shown below for Compound 2, Compound 2A, and Compound 2B:

[0035]

[0036]

[0037] As described in Example 8, 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 was concentrated in the lungs more than in the liver (Table 8), and the half-life of the active metabolite in the lungs was 9.4 hours ( Figure 7A This is important because COVID-19 often presents as a respiratory illness. In fact, after oral administration of 30 mg / kg of compound 2A twice daily, the concentration of active triphosphate species in the lung was 1.6 times that in the liver.

[0038] In addition, the compounds of the present invention can inhibit SARS-CoV-2 infection through a unique mechanism of action with high selectivity. CoV viral replication is achieved on the RNA-dependent RNA polymerase (RdRp) nsp12 subunit, which is activated by cofactors nsp7 and nsp8. As described in Example 6, there is a 30-fold difference in the activity of compound 1A against SARS-CoV-2 and MERS-CoV, even though MERS-CoV and other CoVs, such as SARS-CoV-1 and SARS-CoV-2, do not show significant structural differences in the RdRp active site. This suggests that polymerase inhibition is not the only basis for the different activities against these viruses.

[0039] COVID-19 is an acute viral infection, and antiviral treatment may be effective during the first stages of infection, when viral loads reach a maximum and rapid viral replication initially occurs in cells of the nasal cavity, throat, and lungs. Administering effective, safe oral antivirals to individuals infected with SARS-CoV-2 in the early stages of disease has the potential to avert clinical disease, minimize long-term damage, and mitigate the COVID-19 pandemic. As described above, selected compounds of the present invention have been shown to concentrate in the lungs relative to the liver. This is therapeutically beneficial in treating patients in the first stages of infection with the SARS-CoV-2 pathogen when prevention or alleviation of late viral damage is desired. High concentration in the lungs relative to the heart and liver is also beneficial in treating patients in later stages of infection.

[0040] The present invention also includes the use of an effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof, as described herein:

[0041]

[0042] in:

[0043] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -C(O)C1-C6 alkyl;

[0044] R 2 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3-7 Cycloalkyl or aryl (including phenyl and naphthyl), and in an alternative embodiment, R 2 is aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0045] R 3 is hydrogen or C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl);

[0046] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3-7 cycloalkyl; and

[0047] R 5 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1-6 Haloalkyl or C 3-7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0048] In one embodiment, the 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 re-infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0049] A non-limiting example of a compound of Formula II is Compound 3 or a pharmaceutically acceptable salt thereof.

[0050]

[0051] In one embodiment, 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 of SARS-CoV-2 virus infection, or to a host at risk of infection with SARS-CoV-2 virus, i.e., as a prophylactic. Compound 3 can be used in phosphorus-racemic form, or in any desired ratio of the phosphorus R- and S-enantiomers of the compound, including enantiomerically enriched materials up to pure enantiomers. Compound 3A is the S-enantiomer and compound 3B is the R-enantiomer.

[0052]

[0053]

[0054] Another non-limiting example of Formula II includes Compound 4. Alternative configurations of Compound 4 include Compound 4A and Compound 4B. In one embodiment, Compound 4, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof or at risk of infection with a SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0055]

[0056] The present invention also includes the use of a compound of Formula III or a pharmaceutically acceptable salt thereof for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof, as described herein:

[0057]

[0058] in:

[0059] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; and

[0060] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0061] In one embodiment, the compound of formula III used to treat or prevent COVID-19 disease is a compound of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe or formula IIIf, or a pharmaceutically acceptable salt thereof:

[0062]

[0063]

[0064] The present invention also includes the use of an effective amount of a compound of Formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof, as described herein:

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein:

[0067] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; and

[0068] R 1 , R2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0069] In one embodiment, the compound of formula IV used to treat or prevent COVID-19 disease is a compound of formula IVa, formula IVb, formula IVc, formula IVd, formula IVe or formula IVf, or a pharmaceutically acceptable salt thereof:

[0070]

[0071]

[0072] The present invention also includes the use of an effective amount of a compound of Formula V for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof, as described herein:

[0073]

[0074] or a pharmaceutically acceptable salt thereof, wherein:

[0075] Y and Y' are independently selected from Cl and F; and

[0076] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0077] Non-limiting examples of compounds of formula V include

[0078]

[0079] The present invention also includes the use of a compound of Formula VI for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0080]

[0081] in

[0082] R 6 Selected from hydrogen, -C(O)R 6A ,-C(O)OR 6A , C 1-6 Alkyl and -CH2-OR 6A In an alternative embodiment, -C(O)NR 6B R 6C ;

[0083] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl (e.g. -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl (C 1-6 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 Selected from C 1-20 Alkyl and C 2-20 alkenyl;

[0084] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl, wherein C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl may be optionally 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;

[0085] R 7 is NH2, H or -NR 8 R 9 ;

[0086] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0087] Y is selected from F and Cl;

[0088] Z is selected from methyl, C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen (including Cl and F). In an alternative embodiment, Z is C 1-4 alkyl; and

[0089] R 1 , R 2 , R 3 , R4a , R 4b , and R 5 As defined herein.

[0090] R 6 Non-limiting examples include

[0091]

[0092]

[0093] R 6 Other non-limiting examples include:

[0094]

[0095] R 6 Other non-limiting examples include:

[0096]

[0097] R 6 Other non-limiting examples include:

[0098]

[0099] Non-limiting examples of compounds of Formula VI include

[0100]

[0101]

[0102]

[0103]

[0104] The present invention also includes the use of a compound of Formula VII for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0105]

[0106] in

[0107] B is selected from

[0108]

[0109] R 6 Selected from hydrogen, -C(O)R 6A ,-C(O)OR 6A , C 1-6 Alkyl and -CH2-OR 6AIn an alternative embodiment, -C(O)NR 6B R 6C ;

[0110] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl (e.g. -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl (C 1-6 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 Selected from C 1-20 Alkyl and C 2-20 alkenyl;

[0111] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl, wherein C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl may be optionally 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;

[0112] R 7 is NH2, H or -NR 8 R 9 ;

[0113] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0114] Y is selected from F and Cl;

[0115] Z is selected from methyl, C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen (including Cl and F). In an alternative embodiment, Z is C 1-4 alkyl; and

[0116] R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen (including Cl and F);

[0117] R 41 Selected from H, C 1-3 Alkyl (including methyl) and halogen (including Cl, F and Br);

[0118] R 42a and R 42b Independently selected from C 1-3 Alkyl (including methyl), NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 ;and

[0119] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0120] In one embodiment, the present invention also includes compounds of Formula VIIa, Formula VIIb, Formula VIIc and Formula VIId:

[0121]

[0122] Non-limiting examples of B include:

[0123]

[0124] Non-limiting examples of compounds of Formula VII include:

[0125]

[0126]

[0127] The present invention also includes the use of compounds of formula VIII, formula IX or formula X, wherein R 10 Is a monophosphate, diphosphate, triphosphate or R 10A , where R 10A is a stable phosphate prodrug that is metabolized in vivo to a monophosphate, diphosphate, or triphosphate to treat or prevent COVID-19 disease in a host in need thereof, as described herein:

[0128]

[0129] in

[0130] R 10 Selected from and R 10A ;

[0131] R 10A It is a stable phosphate prodrug that can be metabolized into monophosphate, diphosphate or triphosphate in the body;

[0132] R 11 Selected from hydrogen and R 1 ;and

[0133] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl.

[0134] Non-limiting examples of compounds of Formula VIII, Formula IX, or Formula X include:

[0135]

[0136]

[0137] Other non-limiting examples of compounds of Formula VIII, Formula IX, or Formula X include:

[0138]

[0139]

[0140] Phosphorus in any formula described herein can be chiral and therefore can be provided as R or S enantiomers or mixtures thereof, including racemic mixtures. The compound is generally 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 otherwise indicated, the compound is at least 90% free of the opposite enantiomer. For example, the description of compound 1 does not take into account the stereochemistry at the phosphorus atom (which is chiral). Compound 1 can be used in racemic form or in any desired ratio of the phosphorus Rp- and Sp-enantiomers of the compound, including enantiomerically enriched materials until the pure enantiomer. Compound 1A has S-stereochemistry at phosphorus and compound 1B has R-stereochemistry at phosphorus. In some embodiments, compound 1 is used in a form that is at least 90% free of the opposite enantiomer and can be at least 98%, 99% or even 100% free of the opposite enantiomer. For example, compound 1A may be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Rp-enantiomer. Alternatively, compound 1B may be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Sp-enantiomer.

[0141] Similarly, the description of compound 2 does not take into account the stereochemistry at the phosphorus atom (which is chiral). Compound 2 can be used in racemic form, or in any desired ratio of the phosphorus R- and S-enantiomers of the compound, including enantiomerically enriched materials up to the pure enantiomer. Compound 2A has S-stereochemistry at phosphorus, and compound 2B has R-stereochemistry at phosphorus. In some embodiments, compound 2 is used in a form that is at least 90% free of the opposite enantiomer, and can be at least 98%, 99% or even 100% free of the opposite enantiomer. In one embodiment, compound 2A can be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Rp-enantiomer. In one embodiment, compound 2B can be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Sp-enantiomer.

[0142] Unless otherwise indicated, the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII are at least 90% free of the opposite enantiomer about the stereochemistry of the phosphorus atom.

[0143] Provided are compounds, compositions, dosage forms, and methods for treating COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof by administering an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, can also be used to effectively prevent or limit the progression of COVID-19 in a host in need thereof who has been exposed to the virus or is at risk of infection or reinfection.

[0144] Unless otherwise specifically indicated, the weight of the active compound in the dosage forms described herein is with respect to the free form or salt form of the compound. For example, about 600 mg of compound 2 is equivalent to about 550 mg of compound 1. In one non-limiting embodiment, the loading dose is 1100 mg / day (free base) (i.e., 1200 mg / day hemisulfate salt of compound 1) and the maintenance dose is 550 mg / day (free base) (i.e., 600 mg / day hemisulfate salt). In one embodiment, the loading dose is administered once and the maintenance dose is administered twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days.

[0145] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or 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. In certain embodiments, the 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.

[0146] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, including Compound 1 or a pharmaceutically acceptable salt thereof, such as Compound 2, is administered once daily in a dosage form of about 550 mg.

[0147] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, including Compound 1 or a pharmaceutically acceptable salt thereof, such as Compound 2, is administered once daily in a dosage form of about 600 mg.

[0148] In certain embodiments, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in a dosage form of about 550 mg twice a day.

[0149] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in a dosage form of about 600 mg twice a day.

[0150] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 550 mg twice daily for at least five days, optionally with standard care. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 550 mg twice daily for at least five days, optionally with standard care. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound 1B.

[0151] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dosage of about 600 mg for at least several days, optionally with standard care. In one embodiment, Compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily at a dosage of about 600 mg for at least five days, optionally with standard care. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B.

[0152] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 550 mg twice daily for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with standard of care. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 550 mg twice daily for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with standard of care.

[0153] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 600 mg twice daily for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with standard of care. In one embodiment, a dosage of about 600 mg of Compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally with standard of care.

[0154] In certain embodiments, 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, such as Compound 1 or Compound 3 or a pharmaceutically acceptable salt thereof, including Compound 2 or Compound 4, is administered with an initial dose (or loading dose) followed by a maintenance dose, wherein the loading dose is determined by the doctor at his or her discretion based on the severity of the disease and the size of the patient. In certain embodiments, the loading dose is about or at least 1.5 times, about or at least 2 times, about or at least 2.5 times, or about or at least 3 times greater than the maintenance dose. In one embodiment, the loading dose is administered once, twice, three times, four times or more before the first maintenance dose, and can be administered once, twice, three times or four times daily as directed by the physician.

[0155] In one embodiment, 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, such as Compound 1 or Compound 3 or a pharmaceutically acceptable salt thereof, including Compound 2 or Compound 4, is administered with a daily loading dose 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 (which can be provided in one or more doses throughout the day), 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, with the maintenance dose taken once, twice or three times a day. In one embodiment, 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 daily 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.

[0156] In certain embodiments, 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 mg, taken once, twice, or three times daily.

[0157] In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, such as 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 a day. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, such as 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 a day. In one embodiment, the maintenance dose is administered for at least about 4, 5, 6, 7, 8, 9, 10, or more days. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound 1B. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B.

[0158] In one embodiment, Compound 1 is administered at a dose of 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 1B.

[0159] In one embodiment, Compound 2 is administered at a dose of 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.

[0160] In certain embodiments, the methods of the present invention comprise administering a compound as described herein, e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, e.g., Compound 1 or Compound 2, once, twice, three times, or four times a day or more, as needed to treat an infection. In one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, e.g., 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 period of time determined by a healthcare provider. Alternatively, the compound may be administered for a period of time suitable for avoiding infection or reducing the severity of infection in a human or other animal at risk of infection with the virus.

[0161] In one embodiment, the compound of the invention is administered indefinitely until the risk of infection or reinfection no longer exists. In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or 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 longer. In certain embodiments, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or more daily.

[0162] In another alternative embodiment, a method of preventing transmission is provided, comprising administering to a person in need thereof an effective amount of one of the compounds described herein for a sufficient period of time prior to exposure to a high-risk situation, including during travel or public events or meetings, or if the host belongs to a high-risk group, including, for example, before a communicable situation, then during potential exposure and optionally for up to 3, 5, 7, 10, 12, 14 days or more thereafter. Alternatively, a selected compound as described herein may be administered indefinitely at a maintenance dose to protect people in high-risk environments.

[0163] The present invention also includes compounds of Formula XI and Formula XII:

[0164]

[0165] or a pharmaceutically acceptable salt thereof

[0166] in

[0167] R 12a and R 12b is an oxygen protecting group and R 12a and R 12b At least one of them is -C(O)OC 1-6 Alkyl, such as -C(O)OtBu, or -C(O)O-benzyl, wherein the alkyl and benzyl groups may be optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl.

[0168] In one embodiment, R 12a Yes -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12b is an oxygen protecting group which, when attached to oxygen, is an ester, ether, or silyl ether moiety. 12b Yes -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12ais an oxygen protecting group which, when attached to oxygen, is an ester, ether, or silyl ether moiety. 12a and R 12b All are -C(O)OC 1-6 Alkyl, such as -C(O)OtBu. In one embodiment, R 12a and R 12b All are -C(O)O-benzyl.

[0169] In one embodiment, the compound of Formula XII is Formula XIIA:

[0170]

[0171] In one embodiment, the compound of Formula XII is Formula XIIB:

[0172]

[0173] Therefore, the present invention includes the following features:

[0174] (a) a method of treating COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof, comprising administering 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 a pharmaceutically acceptable carrier;

[0175] (b) a method of preventing or minimizing COVID-19 in a host in need thereof, comprising administering 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 a pharmaceutically acceptable carrier;

[0176] (c) The method of (b) for preventing or minimizing reinfection with SARS-CoV-2 virus or infection with COVID-19 in a host in need thereof;

[0177] (d) The method of (a)-(c), wherein the compound is Compound 1;

[0178] (e) The method of (a)-(c), wherein the compound is compound 1A;

[0179] (f) The method of (a)-(c), wherein the compound is compound 1B;

[0180] (g) The method of (a)-(c), wherein the compound is Compound 2;

[0181] (h) The method of (a)-(c), wherein the compound is compound 2A;

[0182] (i) The method of (a)-(c), wherein the compound is compound 2B;

[0183] (j) The method of (a)-(c), wherein the compound is compound 3;

[0184] (k) The method of (a)-(c), wherein the compound is compound 3A;

[0185] (l) The method of (a)-(c), wherein the compound is compound 3B;

[0186] (m) The method of (a)-(c), wherein the compound is compound 4;

[0187] (n) The method of (a)-(c), wherein the compound is compound 4A;

[0188] (o) The method of (a)-(c), wherein the compound is compound 4B;

[0189] (p) The method of (a)-(c), wherein the compound is of Formula IIIa;

[0190] (q) The method of (a)-(c), wherein the compound is of Formula IIIb;

[0191] (r) The method of (a)-(c), wherein the compound is of Formula IIIc;

[0192] (s) The method of (a)-(c), wherein the compound is of Formula IIId;

[0193] (t) The method of (a)-(c), wherein the compound is of Formula IIIe;

[0194] (u) The method of (a)-(c), wherein the compound is of Formula IIIf;

[0195] (v) The method of (a)-(c), wherein the compound is of Formula IVa;

[0196] (w) The method of (a)-(c), wherein the compound is of formula IVb;

[0197] (x) The method of (a)-(c), wherein the compound is of formula IVc;

[0198] (y) The method of (a)-(c), wherein the compound is of Formula IVd;

[0199] (z) The method of (a)-(c), wherein the compound is of formula IVe;

[0200] (aa) The method of (a)-(c), wherein the compound is of Formula IVf;

[0201] (bb) The method of (a)-(c), wherein the compound is of Formula V;

[0202] (cc) The method of (a)-(c), wherein the compound is of Formula VI;

[0203] (dd) The method of (a)-(c), wherein the compound is of Formula VII;

[0204] (ee) The method of (a)-(c), wherein the compound is of Formula VIII, Formula IX or Formula X;

[0205] (ff) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, for use in treating COVID-19 infection caused by SARS-CoV-2 virus in a host in need thereof, optionally in a pharmaceutically acceptable carrier;

[0206] (gg) a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, for use in preventing or minimizing (relative to no treatment) infection caused by a SARS-CoV-2 virus in a host in need thereof, optionally in a pharmaceutically acceptable carrier;

[0207] A compound of (hh)(gg) for preventing reinfection caused by SARS-CoV-2 virus in a host in need thereof;

[0208] (ii) the use 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 a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of COVID-19 caused by the SARS-CoV-2 virus;

[0209] (jj) Use 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 a pharmaceutically acceptable carrier, for the manufacture of a medicament for preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof;

[0210] (kk)(jj) for preventing reinfection caused by SARS-CoV-2 virus in a host in need thereof;

[0211] (ll) Any of the above embodiments, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for oral administration;

[0212] (mm)(ll) The dosage form, wherein the dosage form is a solid dosage form;

[0213] (nn)(mm) dosage form, which is in tablet form;

[0214] (oo)(mm) dosage form, which is in the form of a capsule;

[0215] (pp)(ll), wherein the dosage form is a liquid dosage form;

[0216] (qq)(pp) dosage form, which is in the form of a solution or suspension;

[0217] (rr) Any of embodiments (a)-(kk), wherein the pharmaceutically acceptable carrier is in a dosage form suitable for intravenous administration;

[0218] (ss) Any of embodiments (a)-(kk), wherein the pharmaceutically acceptable carrier is a dosage form suitable for parenteral administration;

[0219] (tt) Any of the above embodiments, wherein the 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 daily;

[0220] (uu) Any of the above embodiments, wherein the 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 twice daily;

[0221] (vv) Any of the above embodiments, wherein the 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 three times a day.

[0222] (ww) Any of the above embodiments, wherein the 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 one week, ten days, two weeks, three weeks, one month, at least two months, at least three months, at least four months, at least five months, or at least six months or longer.

[0223] (xx) Any of the above embodiments, wherein the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at least once, at least twice, or at least three times daily indefinitely until the risk of infection no longer exists;

[0224] (yy) Any of the above embodiments, wherein the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dose of at least about 400 mg;

[0225] (zz) Any of the above embodiments, wherein the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dose of at least about 500 mg;

[0226] (aaa) Any of the above embodiments, wherein the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dose of at least about 550 mg;

[0227] (bbb) Any of the above embodiments, wherein the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered at a dose of at least about 600 mg;

[0228] (ccc) A method for treating 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 daily;

[0229] (ddd) A method for treating 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 daily;

[0230] (eee) Embodiment (ccc or ddd), wherein Compound 1 is Compound 1A;

[0231] (fff) Embodiment (ccc or ddd), wherein Compound 1 is Compound 1B;

[0232] (ggg) A method of treating 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 daily;

[0233] (hhh) A method of treating 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 daily;

[0234] (iii) embodiment (ggg or hhh), wherein Compound 2 is Compound 2A;

[0235] (jjj) Embodiment (ggg or hhh), wherein Compound 2 is Compound 2B;

[0236] (kkk) a compound of formula II or a pharmaceutically acceptable salt thereof;

[0237] (III) Compound 4 as described herein or a pharmaceutically acceptable salt thereof;

[0238] (mmm) Compound 4A and Compound 4B as described herein;

[0239] (nnn) A pharmaceutical formulation comprising an effective amount of a compound of formula II, optionally in a pharmaceutically acceptable carrier.

[0240] (ooo) a compound of formula XI or formula XII;

[0241] (ppp) a compound of formula XIIA;

[0242] (qqq) a compound of formula XIIB;

[0243] (rrr) a compound of formula VII;

[0244] (sss) a compound of formula VIIa;

[0245] (ttt) a compound of formula VIIb;

[0246] (uuu) Compounds of formula VIIc;

[0247] (vvv) a compound of formula VIId; and

[0248] (www) A pharmaceutical composition comprising an effective amount of a compound of Formula VIIa, Formula VIIb, Formula VIIc or Formula VIId.

[0249] The present invention also relates to the following items:

[0250] 1. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula I:

[0251]

[0252] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein:

[0253] R 1Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0254] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0255] R 3 is hydrogen or C 1-6 alkyl;

[0256] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 cycloalkyl; and

[0257] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0258] 2. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula II:

[0259]

[0260] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein:

[0261] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0262] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0263] R 3 is hydrogen or C 1-6 alkyl;

[0264] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 cycloalkyl; and

[0265] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0266] 3. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of Formula III or Formula IV:

[0267]

[0268] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein:

[0269] X is selected from C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl;

[0270] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0271] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0272] R 3 is hydrogen or C 1-6 alkyl;

[0273] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 cycloalkyl; and

[0274] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0275] 4. The method of item 3, wherein the compound is selected from the group consisting of Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe and Formula IIIf:

[0276]

[0277]

[0278] or a pharmaceutically acceptable salt thereof.

[0279] 5. The method according to item 3, wherein the compound is selected from the group consisting of Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe and Formula IVf:

[0280]

[0281]

[0282]

[0283] or a pharmaceutically acceptable salt thereof.

[0284] 6. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula V:

[0285]

[0286] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein:

[0287] Y and Y' are independently selected from F and Cl;

[0288] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0289] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0290] R 3 is hydrogen or C 1-6 alkyl;

[0291] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 cycloalkyl; and

[0292] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0293] 7. The method according to item 6, wherein the compound has the following formula:

[0294]

[0295]

[0296] or a pharmaceutically acceptable salt thereof.

[0297] 8. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula VI:

[0298]

[0299] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein

[0300] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0301] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0302] R 3 is hydrogen or C 1-6 alkyl;

[0303] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl;

[0304] R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl;

[0305] R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A 、C 1-6 Alkyl, -CH2-OR 6A ;

[0306] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6 alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;

[0307] R 7 is NH2, H or -NR 8R 9 ;

[0308] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A , and -C(O)OR 6A ;

[0309] Y is selected from F and Cl; and

[0310] Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen.

[0311] 9. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula VII:

[0312]

[0313] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein

[0314] B is selected from

[0315]

[0316] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0317] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0318] R 3 is hydrogen or C 1-6 alkyl;

[0319] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0320] R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl;

[0321] R 6 Selected from hydrogen, -C(O)R6A 、-C(O)OR 6A 、C 1-6 Alkyl, -CH2-OR 6A , and -C(O)NR 6B R 6C ;

[0322] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, C 1-20 Alkyl and C 2-20 alkenyl;

[0323] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

[0324] R 7 is NH2, H or -NR 8 R 9 ;

[0325] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0326] Y is selected from F and Cl;

[0327] Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen;

[0328] R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen;

[0329] R 41 Selected from H, C 1-3 Alkyl and halogen; and

[0330] R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

[0331] 10. The method according to item 9, wherein B is selected from

[0332]

[0333]

[0334] 11. The method according to any one of items 1 to 10, wherein R 2 It is an aryl group.

[0335] 12. The method according to item 11, wherein R 2 It is phenyl.

[0336] 13. The method of any one of items 1 to 12, wherein R 3 It's hydrogen.

[0337] 14. The method of any one of items 1 to 12, wherein R 3 It's methyl.

[0338] 15. The method of any one of items 1 to 13, wherein R 4a is methyl and R 4b It's hydrogen.

[0339] 16. The method of any one of items 1 to 13, wherein R 4a is methyl and R 4b It's methyl.

[0340] 17. The method of any one of items 1 to 16, wherein R 5 It is a C1-C6 alkyl group.

[0341] 18. The method according to item 17, wherein R 5 Selected from methyl, ethyl and isopropyl.

[0342] 19. The method according to item 18, wherein R 5 It is isopropyl.

[0343] 20. The method according to any one of items 1 to 10,

[0344] in:

[0345] R 2 It is phenyl;

[0346] R 3 It is hydrogen;

[0347] R 4a It is a methyl group;

[0348] R 4b is hydrogen; and

[0349] R 5 It is isopropyl.

[0350] 21. The method according to any one of items 1 to 10,

[0351] in:

[0352] R 2 It is phenyl;

[0353] R 3 It is hydrogen;

[0354] R 4a It is a methyl group;

[0355] R 4b It is hydrogen;

[0356] R 5 is isopropyl; and

[0357] Phosphoramidate is S p configuration.

[0358] 22. The method according to any one of items 1 to 10,

[0359] in:

[0360] R 2 It is phenyl;

[0361] R 3 It is hydrogen;

[0362] R 4a It is a methyl group;

[0363] R 4b It is hydrogen;

[0364] R 5 is isopropyl; and

[0365] Phosphoramidate is in R p configuration.

[0366] 23. The method of claim 1, wherein the compound has the formula:

[0367]

[0368] or a pharmaceutically acceptable salt thereof.

[0369] 24. The method according to item 23, wherein the compound is selected from the following formula:

[0370]

[0371] or a pharmaceutically acceptable salt thereof.

[0372] 25. The method of item 23, wherein the compound has the following formula:

[0373]

[0374] or a pharmaceutically acceptable salt thereof.

[0375] 26. The method of item 23, wherein the compound has the following formula:

[0376]

[0377] or a pharmaceutically acceptable salt thereof.

[0378] 27. The method of item 23, wherein the compound has the following formula:

[0379]

[0380] or a pharmaceutically acceptable salt thereof.

[0381] 28. The method according to claim 23, wherein the compound is selected from the following formula:

[0382]

[0383] or a pharmaceutically acceptable salt thereof.

[0384] 29. The method of claim 23, wherein the compound has the formula:

[0385]

[0386] 30. The method according to claim 23, wherein the compound is selected from the following formula:

[0387]

[0388] 31. The method of claim 23, wherein the compound has the formula:

[0389]

[0390] 32. The method of claim 23, wherein the compound has the formula:

[0391]

[0392] 33. The method of claim 23, wherein the compound has the formula:

[0393]

[0394] 34. The method according to claim 23, wherein the compound is selected from the following formula:

[0395]

[0396] 35. The method of claim 4, wherein the compound is selected from the group consisting of:

[0397]

[0398]

[0399] or a pharmaceutically acceptable salt thereof.

[0400] 36. The method of item 7, wherein the compound has the following formula:

[0401]

[0402] or a pharmaceutically acceptable salt thereof.

[0403] 37. The method of item 36, wherein the compound has the formula:

[0404]

[0405] or a pharmaceutically acceptable salt thereof.

[0406] 38. A method of treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of Formula VIII, Formula IX, or Formula X:

[0407]

[0408]

[0409] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein

[0410] R 10 Selected from and R 10A ;

[0411] R 10A It is a stable phosphate prodrug that is metabolized into monophosphate, diphosphate or triphosphate in the body;

[0412] R 11 Selected from hydrogen and R 1 ;and

[0413] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl.

[0414] 39. The method of item 38, wherein the compound is selected from:

[0415]

[0416] or a pharmaceutically acceptable salt thereof.

[0417] 40. The method of item 38, wherein the compound has the formula

[0418]

[0419] in

[0420] R 10a It is a stable phosphate prodrug that is metabolized into monophosphate, diphosphate or triphosphate in the body.

[0421] 41. The method of any one of items 1-40, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for oral administration.

[0422] 42. The method of claim 41 , wherein the dosage form is a solid dosage form.

[0423] 43. The method of claim 42, wherein the solid dosage form is a tablet.

[0424] 44. The method of claim 42, wherein the solid dosage form is a capsule.

[0425] 45. The method of claim 41 , wherein the dosage form is a liquid dosage form.

[0426] 46. ​​The method of claim 45, wherein the liquid dosage form is a solution or a suspension.

[0427] 47. The method of any one of items 1-40, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for intravenous administration.

[0428] 48. The method of any one of items 1-40, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for parenteral administration.

[0429] 49. The method of any one of items 1-48, wherein the compound is administered for at least one week.

[0430] 50. The method of any one of items 1-48, wherein the compound is administered for at least two weeks.

[0431] 51. The method of any one of items 1-48, wherein the compound is administered for at least one month.

[0432] 52. The method of any one of items 1-48, wherein the compound is administered for at least six weeks.

[0433] 53. The method of any one of items 1-48, wherein the compound is administered for at least two months.

[0434] 54. The method of any one of items 1-53, wherein the compound is administered once a day.

[0435] 55. The method of any one of items 1-53, wherein the compound is administered twice daily.

[0436] 56. The method of any one of items 1-53, wherein the compound is administered three times a day.

[0437] 57. The method of any one of items 1-56, wherein at least about 500 mg of the compound is administered.

[0438] 58. The method of any one of items 1-56, wherein at least about 600 mg of the compound is administered.

[0439] 59. The method of any one of items 1-56, wherein at least about 700 mg of the compound is administered.

[0440] 60. The method of any one of items 1-56, wherein at least about 800 mg of the compound is administered.

[0441] 61. The method of any one of items 1-56, wherein at least about 1000 mg of the compound is administered.

[0442] 62. The method of any one of items 1-56, wherein at least 1200 mg of the compound is administered.

[0443] 63. The method of any one of items 1-56, wherein at least about 1500 mg of the compound is administered.

[0444] 64. The method of any one of items 1-56, wherein at least about 550 mg of the compound is administered once daily.

[0445] 65. The method according to any one of items 1-56, wherein at least about 550 mg of the compound is administered twice daily.

[0446] 66. The method of any one of items 1-56, wherein at least about 600 mg of the compound is administered once daily.

[0447] 67. The method of any one of items 1-56, wherein at least about 600 mg of the compound is administered twice daily.

[0448] 68. The method of any one of items 1-67, wherein the host is a human.

[0449] 69. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need thereof, comprising administering a compound of the formula:

[0450]

[0451] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein the compound is administered at an oral dose of about 550 mg twice daily.

[0452] 70. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need thereof, comprising administering a compound of the formula:

[0453]

[0454] Optionally in a pharmaceutically acceptable carrier, wherein the compound is administered at an oral dose of about 600 mg twice daily.

[0455] 71. The method of claim 69 or 70, wherein the oral dosage is a tablet.

[0456] 72. The method of claim 69 or 70, wherein the oral dosage is a capsule.

[0457] 73. The method of any one of items 69-72, wherein the compound is administered for at least one week.

[0458] 74. The method of any one of items 69-72, wherein the compound is administered for at least two weeks.

[0459] 75. The method of any one of items 69-72, wherein the compound is administered for at least one month.

[0460] 76. A method as described in any of items 1-75, wherein the SARS-CoV-2 virus has undergone natural or drug-induced mutations.

[0461] 77. The method of claim 76, wherein the natural or drug-induced mutation is in a viral protein selected from the group consisting of envelope (E) protein, membrane (M) protein and spike (S) protein.

[0462] 78. The method of claim 77, wherein the mutation is in the spike (S) protein.

[0463] 79. A method as described in claim 76, wherein the natural or drug-induced mutation is in a viral protein selected from nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15 and nsp16.

[0464] 80. The method of claim 76, wherein the natural or drug-induced mutation is in a viral protein selected from the group consisting of ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8 and ORF10.

[0465] 81. Compounds of Formula I or Formula II:

[0466]

[0467] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in an effective amount for treating or preventing COVID-19 in a host in need thereof, wherein:

[0468] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0469] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0470] R 3 is hydrogen or C 1-6 alkyl;

[0471] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 cycloalkyl; and

[0472] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0473] 82. The compound of item 81, wherein the compound has the following formula:

[0474]

[0475] or a pharmaceutically acceptable salt thereof.

[0476] 83. The compound of item 81, wherein the compound has the following formula:

[0477]

[0478] or a pharmaceutically acceptable salt thereof.

[0479] 84. The compound of item 82, wherein the compound has the following formula:

[0480]

[0481] or a pharmaceutically acceptable salt thereof.

[0482] 85. The compound of item 82, wherein the compound has the following formula:

[0483] 86. The compound of item 85, wherein the compound has the following formula:

[0484]

[0485] 87. The compound of item 86, wherein the compound has the following formula:

[0486]

[0487] 88. Compounds of formula III or IV:

[0488]

[0489] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in an effective amount for treating or preventing COVID-19 in a host in need thereof, wherein:

[0490] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 Chloroalkyl groups, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl;

[0491] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0492] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0493] R 3 is hydrogen or C 1-6 alkyl;

[0494] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 cycloalkyl; and

[0495] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0496] 89. The compound of item 88, wherein the compound has formula IIIa, formula IIIb, formula IIIc, formula IIId or formula IIIe:

[0497]

[0498]

[0499] or a pharmaceutically acceptable salt thereof.

[0500] 90. The compound of item 88, wherein the compound has Formula IVa, Formula IVb, Formula IVc, Formula IVd or Formula VIe:

[0501]

[0502]

[0503] or a pharmaceutically acceptable salt thereof.

[0504] 91. Compounds of Formula V, Formula VI or Formula VII:

[0505]

[0506] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein

[0507] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0508] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0509] R3 is hydrogen or C 1-6 alkyl;

[0510] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl;

[0511] R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl;

[0512] R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A 、C 1-6 Alkyl, -CH2-OR 6A ;

[0513] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6 alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;

[0514] R 7 is NH2, H or -NR 8 R 9 ;

[0515] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0516] Y and Y' are independently selected from F and Cl;

[0517] Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen;

[0518] B is selected from

[0519]

[0520] R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen;

[0521] R41 Selected from H, C 1-3 Alkyl and halogen; and

[0522] R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

[0523] 92. The compound according to item 81-91, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for oral administration.

[0524] 93. The compound of claim 92, wherein the dosage form is a solid dosage form.

[0525] 94. The compound of claim 93, wherein the solid dosage form is a tablet.

[0526] 95. The compound of claim 93, wherein the solid dosage form is a capsule.

[0527] 96. The compound of claim 92, wherein the dosage form is a liquid dosage form.

[0528] 97. The compound of claim 96, wherein the liquid dosage form is a solution or a suspension.

[0529] 98. Compounds of Formula I, Formula II, Formula III or Formula IV:

[0530]

[0531]

[0532] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for the manufacture of a medicament for treating or preventing COVID-19 in a host in need thereof,

[0533] in

[0534] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 Chloroalkyl groups, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl;

[0535] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0536] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0537] R 3 is hydrogen or C 1-6 alkyl;

[0538] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl;

[0539] R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0540] 99. The use according to item 98, wherein the compound has the following formula:

[0541]

[0542] or a pharmaceutically acceptable salt thereof.

[0543] 100. The use according to item 99, wherein the compound has the following formula:

[0544]

[0545] or a pharmaceutically acceptable salt thereof.

[0546] 101. The use of item 100, wherein the compound has the following formula:

[0547]

[0548] or a pharmaceutically acceptable salt thereof.

[0549] 102. The use according to item 99, wherein the compound has the following formula:

[0550]

[0551] 103. The use according to item 102, wherein the compound has the following formula:

[0552]

[0553] 104. The use according to item 103, wherein the compound has the following formula:

[0554]

[0555] 105. Compounds of Formula V, Formula VI or Formula VII:

[0556]

[0557]

[0558] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for the manufacture of a medicament for treating or preventing COVID-19 in a host in need thereof,

[0559] in

[0560] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[0561] R 2 For hydrogen, C 1-6 Alkyl, C 3-7 cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0562] R 3 is hydrogen or C 1-6 alkyl;

[0563] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0564] R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl;

[0565] R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A 、C 1-6 Alkyl, -CH2-OR 6A ;

[0566] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;

[0567] R 7 is NH2, H or -NR 8 R 9 ;

[0568] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0569] Y is selected from F and Cl;

[0570] Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen;

[0571] B is selected from

[0572]

[0573] R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen;

[0574] R 41 Selected from H, C 1-3 Alkyl and halogen; and

[0575] R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

[0576] 106. The use according to any one of items 98 to 105, wherein the pharmaceutically acceptable carrier is a dosage form suitable for oral administration.

[0577] 107. The use of claim 106, wherein the dosage form is a solid dosage form.

[0578] 108. The use of claim 107, wherein the solid dosage form is a tablet.

[0579] 109. The use of claim 107, wherein the solid dosage form is a capsule.

[0580] 110. The use of claim 106, wherein the dosage form is a liquid dosage form.

[0581] 111. The use of claim 110, wherein the liquid dosage form is a solution or a suspension. BRIEF DESCRIPTION OF THE DRAWINGS

[0582] Figure 1 is a graph of the concentration of triphosphate compounds 1-6 in human bronchial and nasal epithelial cells after exposure to 10 μM compound 1A, as described in Example 7. The half-life of compounds 1-6 in bronchial and nasal cells is 39 hours and 38 hours, respectively. The x-axis is the time after washout measured in hours, and the y-axis is the concentration of compound 1-6 in pmol / million cells.

[0583] Figure 2 is a graph comparing the levels of triphosphate compounds 1-6 in human bronchial epithelial cells following exposure to compound 1A (1A), ALS-8112 (ALS), and the 4'-Me substituted prodrug ((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-alanine isopropyl ester (4'-Me), as described in Example 7. The x-axis is the time after washout measured in hours, and the y-axis is the concentration of compound 1-6 in pmol / million cells.

[0584] Figure 3 is a graph comparing the levels of triphosphate compounds 1-6 in human nasal epithelial cells exposed to compound 1A (1A), ALS-8112 (ALS), and the 4'-Me substituted prodrug ((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-alanine isopropyl ester (4'-Me), as described in Example 7. The x-axis is the time after washout measured in hours and the y-axis is the concentration of compound 1-6 in pmol / million cells.

[0585] Figure 4 is the mean plasma profile of Compound 1A in monkeys dosed orally with Compound 2A at 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The x-axis is the washout time measured in hours, and the y-axis is the plasma concentration of Compound 1A in ng / mL.

[0586] Figure 5is the mean plasma profile of metabolite Compound 1-2 in monkeys dosed orally with Compound 2A at 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The x-axis is the washout time measured in hours, and the y-axis is the plasma concentration of Compound 1-2 in ng / mL.

[0587] Figure 6 Figure 8 is the mean plasma profile of the triphosphate agent metabolite compounds 1-7 in monkeys dosed orally with 30 mg / kg of compound 2A twice daily (BID) for 3 days, as described in Example 8. The x-axis is the washout time measured in hours, and the y-axis is the plasma concentration of compounds 1-7 in ng / mL.

[0588] Figure 7A Graph showing the concentrations of triphosphate compounds 1-6 in the lung, kidney, and liver tissues of monkeys dosed orally with 30 mg / kg of compound 2A twice daily (BID) for 3 days, as described in Example 8. The half-lives in the lung, kidney, and liver were 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.

[0589] Figure 7B Graph showing the concentrations of triphosphate compounds 1-6 in lung, kidney, and liver tissues of monkeys dosed orally with 30 mg / kg of compound 2A twice daily (BID) for 3 days, as described in Example 8. Tissue concentrations of compounds 1-6 are shown 2 hours, 12 hours, 24 hours, and 48 hours after the last dose. The x-axis is the time after the last dose measured in hours, and the y-axis is the tissue concentration measured in μM.

[0590] Figure 8 Graph of triphosphate compound 1-6 levels in hepatocytes incubated with compound 2A, as described in Example 9 and previously described by Good, S. et al. 2020 PLoS ONE 15(1):e0227104. The concentration in human hepatocytes was 7-fold higher than in monkeys. The x-axis is the incubation time measured in hours and the y-axis is pmol / 10 6 The concentrations of compounds 1-6 were measured per cell.

[0591] Figure 9 is a simulation of the intracellular concentration of compounds 1-6 in human lung tissue, as described in Example 10. The predicted lung concentrations are based on the predicted trough (C 12h) Steady-state plasma compound 1-7, a plasma surrogate for the intracellular triphosphate compound 1-6 in humans, (Berliba, e. et al. 2019 Antimicrob. Agents Chemother. 63(12): e01201-19) multiplied by a ratio of 1.6 (the triphosphate concentration in the lung is 1.6 times the steady-state trough level in the liver, 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 μM.

[0592] Figure 10 The solid line represents the predicted lung concentration of the active triphosphate compound 1-6 metabolite after correction for a compound 1-6 lung to liver concentration ratio of 1.6. The dotted line represents the predicted lung concentration of the active triphosphate compound 1-6 metabolite after correction for a compound 1-6 lung to compound 1-7 plasma ratio of 1.2. The horizontal line represents the EC of compound 1A against SARS-CoV-2 in HAE cells in vitro. 90 (0.47 μM). The x-axis is time measured in days and the y-axis is simulated lung compound 1-6 concentration measured in μM.

[0593] Figure 11 is an illustration of a compound of formula I, which may also be administered as a pharmaceutically acceptable salt. Detailed Description of the Invention

[0595] Disclosed herein is a method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host (e.g., a human) in need thereof, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

[0596]

[0597] in

[0598] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -C(O)C1-C6 alkyl;

[0599] R 2 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3-7 Cycloalkyl or aryl (including phenyl and naphthyl), and in an alternative embodiment, R 2 is aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0600] R 3 is hydrogen or C 1-6Alkyl (including methyl, ethyl, propyl and isopropyl);

[0601] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3-7 cycloalkyl; and

[0602] R 5 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1-6 Haloalkyl or C 3-7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0603] Non-limiting examples of compounds of Formula I include Compound 1 and Compound 2. In one embodiment, the compound is administered as the S-enantiomer, for example, Compound 1A. In one embodiment, the compound is administered as the R-enantiomer, for example, Compound 1B. In one embodiment, the compound of Formula I is Compound 2, Compound 2A, or Compound 2B.

[0604]

[0605]

[0606]

[0607] Alternative configurations of Compound 1 or its pharmaceutically acceptable salts that may be used include:

[0608]

[0609] Alternative configurations of compound 2 that may be used include:

[0610]

[0611] Compound 1 or its pharmaceutically acceptable salt that can be used, for example, other alternative configurations of Compound 2 include:

[0612]

[0613] Non-limiting examples of compounds of Formula I include:

[0614]

[0615]

[0616]

[0617] or a pharmaceutically acceptable salt thereof.

[0618] Other non-limiting examples of compounds of Formula I include:

[0619]

[0620]

[0621]

[0622] or a pharmaceutically acceptable salt thereof.

[0623] Other non-limiting examples of compounds of Formula I include:

[0624]

[0625]

[0626]

[0627] or a pharmaceutically acceptable salt thereof.

[0628] The present invention also includes the use of an effective amount of a compound of formula II for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof:

[0629]

[0630] or a pharmaceutically acceptable salt thereof, wherein:

[0631] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -C(O)C1-C6 alkyl;

[0632] R 2 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3-7 Cycloalkyl or aryl (including phenyl and naphthyl), and in an alternative embodiment, R 2 is aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0633] R 3 is hydrogen or C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl);

[0634] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C3-7 cycloalkyl; and

[0635] R 5 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1-6 Haloalkyl or C 3-7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

[0636] In one embodiment, the 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 who has COVID-19 or is at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0637] Non-limiting examples of compounds of Formula II include Compound 3 and Compound 4. In one embodiment, the compound is administered as the S-enantiomer, such as Compounds 3A and 4A. In one embodiment, the compound is administered as the R-enantiomer, such as Compounds 3B and 4B.

[0638]

[0639]

[0640] Alternative configurations of compound 3 or a pharmaceutically acceptable salt thereof include:

[0641]

[0642] Other alternative configurations of compound 4 include:

[0643]

[0644] Other alternative configurations of compound 3 or a pharmaceutically acceptable salt thereof, such as compound 4, that can be used include:

[0645]

[0646] Non-limiting examples of compounds of Formula II include:

[0647]

[0648]

[0649]

[0650] or a pharmaceutically acceptable salt thereof.

[0651] Other non-limiting examples of compounds of Formula II include:

[0652]

[0653]

[0654]

[0655] or a pharmaceutically acceptable salt thereof.

[0656] Other non-limiting examples of compounds of Formula II include:

[0657]

[0658]

[0659]

[0660]

[0661] or a pharmaceutically acceptable salt thereof.

[0662] The present invention also includes the use of an effective amount of a compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof:

[0663]

[0664] or a pharmaceutically acceptable salt thereof, wherein:

[0665] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -C(O)C1-C6 alkyl;

[0666] R 2 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3-7 Cycloalkyl or aryl (including phenyl and naphthyl), and in an alternative embodiment, R 2 is aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl;

[0667] R 3 is hydrogen or C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl);

[0668] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3-7 cycloalkyl; and

[0669] R 5 is hydrogen, C 1-6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1-6 Haloalkyl or C 3-7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl;

[0670] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl.

[0671] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IIIa:

[0672]

[0673] or a pharmaceutically acceptable salt thereof.

[0674] In one embodiment of Formula IIIa, R 1 It's methyl.

[0675] In one embodiment of Formula IIIa, R 1 It is cyclopropyl.

[0676] In one embodiment of Formula IIIa, R 2 It is phenyl.

[0677] In one embodiment of Formula IIIa, R 2 It is naphthyl.

[0678] In one embodiment of Formula IIIa, R 4a is hydrogen and R 4b It's methyl.

[0679] In one embodiment of Formula IIIa, R 5 It is isopropyl.

[0680] In one embodiment of Formula IIIa, the compound is S p -isomer and the phosphoramidate is in the L-configuration.

[0681] In one embodiment of Formula IIIa, the compound is R p-isomer and the phosphoramidate is in the L-configuration.

[0682] In one embodiment of Formula IIIa, the pharmaceutically acceptable salt is a hemisulfate salt.

[0683] Non-limiting examples of compounds of Formula IIIa include:

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690] Other non-limiting examples of compounds of Formula IIIa include:

[0691]

[0692] In one embodiment, the compound of Formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of Formula IIIb:

[0693]

[0694] or a pharmaceutically acceptable salt thereof.

[0695] In one embodiment of Formula IIIb, R 1 It's methyl.

[0696] In one embodiment of Formula IIIb, R 1 It is cyclopropyl.

[0697] In one embodiment of Formula IIIb, R 2 It is phenyl.

[0698] In one embodiment of Formula IIIb, R 2 It is naphthyl.

[0699] In one embodiment of Formula IIIb, R 4a is hydrogen and R 4b It's methyl.

[0700] In one embodiment of Formula IIIb, R 5 It is isopropyl.

[0701] In one embodiment of Formula IIIb, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0702] In one embodiment of Formula IIIb, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0703] In one embodiment of Formula IIIb, the pharmaceutically acceptable salt is a hemisulfate salt.

[0704] Non-limiting examples of compounds of Formula IIIb include:

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712] Other non-limiting examples of compounds of Formula IIIb include:

[0713]

[0714] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IIIc:

[0715]

[0716] or a pharmaceutically acceptable salt thereof.

[0717] In one embodiment of Formula IIIc, R 1 It's methyl.

[0718] In one embodiment of Formula IIIc, R 1 It is cyclopropyl.

[0719] In one embodiment of Formula IIIc, R 2 It is phenyl.

[0720] In one embodiment of Formula IIIc, R 2 It is naphthyl.

[0721] In one embodiment of Formula IIIc, R 4a is hydrogen and R 4b It's methyl.

[0722] In one embodiment of Formula IIIc, R 5 It is isopropyl.

[0723] In one embodiment of Formula IIIc, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0724] In one embodiment of Formula IIIc, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0725] In one embodiment of Formula IIIc, the pharmaceutically acceptable salt is a hemisulfate salt.

[0726] Non-limiting examples of compounds of Formula IIIc include:

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734] Other non-limiting examples of compounds of Formula IIIc include:

[0735]

[0736]

[0737] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IIId:

[0738]

[0739] or a pharmaceutically acceptable salt thereof.

[0740] In one embodiment of Formula IIId, R 1 It's methyl.

[0741] In one embodiment of Formula IIId, R 1 It is cyclopropyl.

[0742] In one embodiment of Formula IIId, R 2 It is phenyl.

[0743] In one embodiment of Formula IIId, R 2 It is naphthyl.

[0744] In one embodiment of Formula IIId, R 4a is hydrogen and R 4b It's methyl.

[0745] In one embodiment of Formula IIId, R 5 It is isopropyl.

[0746] In one embodiment of Formula IHd, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0747] In one embodiment of Formula Illd, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0748] In one embodiment of Formula IIId, the pharmaceutically acceptable salt is a hemisulfate salt.

[0749] Non-limiting examples of compounds of Formula IIId include:

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757] Other non-limiting examples of compounds of Formula IIId include:

[0758]

[0759] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IIIe:

[0760]

[0761] or a pharmaceutically acceptable salt thereof.

[0762] In one embodiment of Formula IIIe, R 1 It's methyl.

[0763] In one embodiment of Formula IIIe, R 1 It is cyclopropyl.

[0764] In one embodiment of Formula IIIe, R 2 It is phenyl.

[0765] In one embodiment of Formula IIIe, R 2 It is naphthyl.

[0766] In one embodiment of Formula IIIe, R 4a is hydrogen and R 4b It's methyl.

[0767] In one embodiment of Formula IIIe, R 5 It is isopropyl.

[0768] In one embodiment of Formula IIIe, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0769] In one embodiment of Formula IIIe, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0770] In one embodiment of Formula IIIe, the pharmaceutically acceptable salt is a hemisulfate salt.

[0771] Non-limiting examples of compounds of Formula IIIe include:

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779] Other non-limiting examples of compounds of Formula IIIe include:

[0780]

[0781]

[0782] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IIIf:

[0783]

[0784] or a pharmaceutically acceptable salt thereof.

[0785] In one embodiment of Formula IIIf, R 1 It's methyl.

[0786] In one embodiment of Formula IIIf, R 1 It is cyclopropyl.

[0787] In one embodiment of Formula IIIf, R 2 It is phenyl.

[0788] In one embodiment of Formula IIIf, R 2 It is naphthyl.

[0789] In one embodiment of Formula IIIf, R 4a is hydrogen and R 4b It's methyl.

[0790] In one embodiment of Formula IIIf, R 5 It is isopropyl.

[0791] In one embodiment of Formula IIIf, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0792] In one embodiment of Formula IIIf, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0793] In one embodiment of Formula IIIf, the pharmaceutically acceptable salt is a hemisulfate salt.

[0794] Non-limiting examples of compounds of Formula IIIf include:

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802] Other non-limiting examples of compounds of Formula IIIe include:

[0803]

[0804]

[0805] Other non-limiting examples of compounds of Formula III include:

[0806]

[0807]

[0808] The present invention also includes the use of a compound of Formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof, as described herein:

[0809]

[0810] or a pharmaceutically acceptable salt thereof, wherein:

[0811] X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; and

[0812] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0813] In one embodiment, the compound of formula IV used to treat or prevent COVID-19 disease is a compound of formula IVa, formula IVb, formula IVc, formula IVd, formula IVe or formula IVf, or a pharmaceutically acceptable salt thereof:

[0814]

[0815]

[0816] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IVa:

[0817]

[0818] or a pharmaceutically acceptable salt thereof.

[0819] In one embodiment of Formula IVa, R 1 It's methyl.

[0820] In one embodiment of Formula IVa, R 1 It is cyclopropyl.

[0821] In one embodiment of Formula IVa, R 2 It is phenyl.

[0822] In one embodiment of Formula IVa, R 2 It is naphthyl.

[0823] In one embodiment of Formula IVa, R 4a is hydrogen and R 4b It's methyl.

[0824] In one embodiment of Formula IVa, R 5 It is isopropyl.

[0825] In one embodiment of Formula IVa, the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.

[0826] In one embodiment of Formula IVa, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0827] Non-limiting examples of compounds of Formula IVa include:

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IVb:

[0835]

[0836] or a pharmaceutically acceptable salt thereof.

[0837] In one embodiment of Formula IVb, R 1 It's methyl.

[0838] In one embodiment of Formula IVb, R 1 It is cyclopropyl.

[0839] In one embodiment of Formula IVb, R 2 It is phenyl.

[0840] In one embodiment of Formula IVb, R 2 It is naphthyl.

[0841] In one embodiment of Formula IVb, R 4a is hydrogen and R 4b It's methyl.

[0842] In one embodiment of Formula IVb, R 5 It is isopropyl.

[0843] In one embodiment of Formula IVb, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0844] In one embodiment of Formula IVb, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0845] Non-limiting examples of compounds of Formula IVb include:

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IVc:

[0853]

[0854] or a pharmaceutically acceptable salt thereof.

[0855] In one embodiment of Formula IVc, R 1 It's methyl.

[0856] In one embodiment of Formula IVc, R 1 It is cyclopropyl.

[0857] In one embodiment of Formula IVc, R 2 It is phenyl.

[0858] In one embodiment of Formula IVc, R 2 It is naphthyl.

[0859] In one embodiment of Formula IVc, R 4a is hydrogen and R 4b It's methyl.

[0860] In one embodiment of Formula IVc, R 5 It is isopropyl.

[0861] In one embodiment of Formula IVc, the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.

[0862] In one embodiment of Formula IVc, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0863] In one embodiment of Formula IVc, the pharmaceutically acceptable salt is a hemisulfate salt.

[0864] Non-limiting examples of compounds of Formula IVc include:

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease in a host in need thereof is a compound of formula IVd:

[0873]

[0874] or a pharmaceutically acceptable salt thereof.

[0875] In one embodiment of Formula IVd, R 1 It's methyl.

[0876] In one embodiment of Formula IVd, R 1 It is cyclopropyl.

[0877] In one embodiment of Formula IVd, R 2 It is phenyl.

[0878] In one embodiment of Formula IVd, R 2 It is naphthyl.

[0879] In one embodiment of Formula IVd, R 4a is hydrogen and R 4b It's methyl.

[0880] In one embodiment of Formula IVd, R 5 It is isopropyl.

[0881] In one embodiment of Formula IVd, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0882] In one embodiment of Formula IVd, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0883] In one embodiment of Formula IVd, the pharmaceutically acceptable salt is a hemisulfate salt.

[0884] Non-limiting examples of compounds of Formula IVd include:

[0885]

[0886]

[0887]

[0888]

[0889] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease in a host in need thereof is a compound of formula IVe:

[0890]

[0891] or a pharmaceutically acceptable salt thereof.

[0892] In one embodiment of Formula IVe, R 1 It's methyl.

[0893] In one embodiment of Formula IVe, R 1 It is cyclopropyl.

[0894] In one embodiment of Formula IVe, R 2 It is phenyl.

[0895] In one embodiment of Formula IVe, R 2 It is naphthyl.

[0896] In one embodiment of Formula IVe, R 4a is hydrogen and R 4b It's methyl.

[0897] In one embodiment of Formula IVe, R 5 It is isopropyl.

[0898] In one embodiment of Formula IVe, the compound is an Sp-isomer and the phosphoramidate is in the L-configuration.

[0899] In one embodiment of Formula IVe, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0900] In one embodiment of Formula IVe, the pharmaceutically acceptable salt is a hemisulfate salt.

[0901] Non-limiting examples of compounds of Formula IVe include:

[0902]

[0903]

[0904]

[0905]

[0906]

[0907] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need thereof is a compound of formula IVf:

[0908]

[0909] or a pharmaceutically acceptable salt thereof.

[0910] In one embodiment of Formula IVf, R 1 It's methyl.

[0911] In one embodiment of Formula IVf, R 1 It is cyclopropyl.

[0912] In one embodiment of Formula IVf, R 2 It is phenyl.

[0913] In one embodiment of Formula IVf, R 2 It is naphthyl.

[0914] In one embodiment of Formula IVf, R 4a is hydrogen and R 4b It's methyl.

[0915] In one embodiment of Formula IVf, R 5 It is isopropyl.

[0916] In one embodiment of Formula IVf, the compound is the Sp-isomer and the phosphoramidate is in the L-configuration.

[0917] In one embodiment of Formula IVf, the compound is the Rp-isomer and the phosphoramidate is in the L-configuration.

[0918] In one embodiment of Formula IVf, the pharmaceutically acceptable salt is a hemisulfate salt. Non-limiting examples of compounds of Formula IVf include:

[0919]

[0920]

[0921]

[0922]

[0923] The present invention also includes the use of a compound of formula V in treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus described herein:

[0924]

[0925] or a pharmaceutically acceptable salt thereof, wherein:

[0926] Y and Y' are independently selected from Cl and F; and

[0927] R 1 、R 2 、R 3 、R 4a 、R 4b and R 5 As defined herein.

[0928] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is methyl, R 2 is an aryl group, R3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0929] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0930] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0931] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0932] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0933] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0934] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 It is a C1-C6 alkyl group.

[0935] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0936] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 It is a C1-C6 alkyl group.

[0937] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0938] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 It is a C1-C6 alkyl group.

[0939] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0940] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R4a is a C1-C4 alkyl group, R 5 It is a C1-C6 alkyl group.

[0941] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0942] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0943] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[0944] Non-limiting examples of compounds of formula V include

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953] Non-limiting examples of compounds of Formula V include:

[0954]

[0955]

[0956] The present invention also includes the use of a compound of Formula VI for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0957]

[0958] in

[0959] R 6 Selected from hydrogen, -C(O)R 6A ,-C(O)OR 6A , C 1-6 Alkyl and -CH2-OR 6A In an alternative embodiment, -C(O)NR 6B R 6C ;

[0960] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl (e.g. -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl (C 1-6 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 Selected from C 1-20 Alkyl and C 2-20 alkenyl;

[0961] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl, wherein C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl may be optionally 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;

[0962] R 7 is NH2, H or -NR 8 R 9 ;

[0963] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A;

[0964] Y is selected from F and Cl;

[0965] Z is selected from methyl, C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen (including Cl and F). In an alternative embodiment, Z is C 1-4 alkyl; and

[0966] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[0967] R 6 Non-limiting examples include

[0968]

[0969] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[0970] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[0971] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7NR 8 R 9 .

[0972] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[0973] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[0974] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[0975] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0976] In one embodiment of Formula VI, Z is CH3, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[0977] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[0978] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[0979] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[0980] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[0981] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[0982] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is methyl, R 2 is an aryl group, R3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[0983] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0984] In one embodiment of Formula VI, Z is CF3, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[0985] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[0986] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[0987] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[0988] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[0989] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[0990] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[0991] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[0992] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[0993] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4ais a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[0994] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[0995] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[0996] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[0997] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[0998] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R5 It is a C1-C6 alkyl group.

[0999] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1000] In one embodiment of Formula VI, Z is CH2F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[1001] In one embodiment of Formula VI, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is C1-C6 alkyl, and R7 is NH2.

[1002] In one embodiment of Formula VI, Z is CH2CH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1003] In one embodiment of Formula VI, Z is CH2CH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1004] In one embodiment of Formula VI, Z is CH2CH2, Y is F, R 1 is methyl, R2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[1005] In one embodiment of Formula VI, Z is CH2CH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[1006] In one embodiment of Formula VI, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1007] In one embodiment of Formula VI, Z is CHCH2, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1008] In one embodiment of Formula VI, Z is CHCH2, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1009] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5is a C1-C6 alkyl group, and R 7 is NH2.

[1010] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1011] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1012] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[1013] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[1014] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1015] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1016] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1017] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1018] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1019] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1020] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4ais hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[1021] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[1022] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1023] In one embodiment of Formula VI, Z is F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1024] In one embodiment of Formula VI, Z is F, Y is F, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1025] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1026] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1027] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1028] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[1029] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[1030] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1031] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 It is a C1-C6 alkyl group.

[1032] In one embodiment of Formula VI, Z is CH3, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1033] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1034] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1035] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1036] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[1037] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[1038] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1039] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1040] In one embodiment of Formula VI, Z is CF3, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1041] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1042] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1043] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1044] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[1045] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[1046] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1047] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1048] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1049] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1050] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1051] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1052] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R6A .

[1053] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[1054] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1055] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1056] In one embodiment of Formula VI, Z is CH2F, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1057] In one embodiment of Formula VI, Z is CHCH2, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is C1-C6 alkyl, and R7 is NH2.

[1058] In one embodiment of Formula VI, Z is CH2CH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1059] In one embodiment of Formula VI, Z is CH2CH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1060] In one embodiment of Formula VI, Z is CH2CH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)R 6A .

[1061] In one embodiment of Formula VI, Z is CH2CH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It is NHC(O)OR 6A .

[1062] In one embodiment of Formula VI, Z is CHCH2, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 It is a C1-C6 alkyl group.

[1063] In one embodiment of Formula VI, Z is CHCH2, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4ais a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1064] In one embodiment of Formula VI, Z is CHCH2, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a methyl group, and R 5 It is a C1-C6 alkyl group.

[1065] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 is NH2.

[1066] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 7 It’s H.

[1067] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NR 8 R 9 .

[1068] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)R 6A .

[1069] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, and R 7 NHC(O)OR 6A .

[1070] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1071] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, and R 5 It is a C1-C6 alkyl group.

[1072] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is cyclopropyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 It is a C1-C6 alkyl group.

[1073] Non-limiting examples of compounds of Formula VI include:

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080] Other non-limiting examples of compounds of Formula VI include:

[1081]

[1082]

[1083]

[1084]

[1085] The present invention also includes the use of a compound of Formula VII for treating or preventing COVID-19 in a host in need thereof, as described herein:

[1086]

[1087] in

[1088] B is selected from

[1089]

[1090] R 6 Selected from hydrogen, -C(O)R 6A ,-C(O)OR 6A , C 1-6 Alkyl and -CH2-OR 6A In an alternative embodiment, -C(O)NR 6B R 6C ;

[1091] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl (e.g. -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl (C 1-6 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 Selected from C 1-20 Alkyl and C 2-20 alkenyl;

[1092] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6 alkyl)-, heteroaryl and heteroarylalkyl, wherein C 1-20 Alkyl, C 2-20 Alkenyl, aryl, aryl (C 1-6alkyl)-, heteroaryl and heteroarylalkyl may be optionally 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;

[1093] R 7 is NH2, H or -NR 8 R 9 ;

[1094] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ;

[1095] Y is selected from F and Cl;

[1096] Z is selected from methyl, C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 chloroalkyl, such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3, and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen (including Cl and F). In an alternative embodiment, Z is C 1-4 alkyl;

[1097] R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen (including Cl and F);

[1098] R 41 Selected from H, C 1-3 Alkyl (including methyl) and halogen (including Cl, F and Br);

[1099] R 42a and R 42b Selected from C 1-3 Alkyl (including methyl), NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 ;and

[1100] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 As defined herein.

[1101] Non-limiting examples of B include:

[1102]

[1103] In one embodiment, the present invention also includes compounds of Formula VIIa, Formula VIIb, Formula VIIc and Formula VIId:

[1104]

[1105] In one embodiment of Formula VII, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; and B is

[1106] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1107] In one embodiment of Formula VIIa, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; and B is

[1108] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1109] In one embodiment of Formula VIIb, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; and B is

[1110] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1111] In one embodiment of Formula VIIc, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; and B is

[1112] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1113] In one embodiment of Formula VIId, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1114] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1115] In one embodiment of Formula VII, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1116] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1117] In one embodiment of Formula VIIa, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1118] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1119] In one embodiment of Formula VIIb, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1120] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1121] In one embodiment of Formula VIIc, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1122] In a further embodiment, R 41 H, R 42a is NH2, and R42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1123] In one embodiment of Formula VIId, Z is CH3, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1124] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42aIt is -C(O)NHCH3.

[1125] In one embodiment of Formula VII, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1126] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1127] In one embodiment of Formula Vila, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1128] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1129] In one embodiment of Formula VIIb, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6is hydrogen, R 40 is hydrogen; B is

[1130] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1131] In one embodiment of Formula VIIc, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1132] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42bis H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1133] In one embodiment of Formula VIId, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1134] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1135] In one embodiment of Formula VII, Z is Cl, Y is F, R 1 is methyl, R2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1136] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1137] In one embodiment of Formula Vila, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1138] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1139] In one embodiment of Formula VIIb, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1140] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1141] In one embodiment of Formula VIIc, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1142] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42ais NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1143] In one embodiment of Formula VIId, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1144] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1145] In one embodiment of Formula VII, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1146] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1147] In one embodiment of Formula VIIa, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1148] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1149] In one embodiment of Formula VIIb, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1150] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1151] In one embodiment of Formula VIIc, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1152] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1153] In one embodiment of Formula VIId, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1154] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1155] In one embodiment of Formula VII, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40is cyano or nitro; B is

[1156] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1157] In one embodiment of Formula VIIa, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1158] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1159] In one embodiment of Formula VIIb, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1160] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1161] In one embodiment of Formula VIIc, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1162] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1163] In one embodiment of Formula VIId, Z is CH2F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1164] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1165] In one embodiment of Formula VII, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1166] In a further embodiment, R1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1167] In one embodiment of Formula VIIa, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1168] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1169] In one embodiment of Formula VIIb, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1170] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1171] In one embodiment of Formula VIIc, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1172] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1173] In one embodiment of Formula VIId, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1174] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1175] In one embodiment of Formula VII, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1176] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R1 is methyl and R 7 It's NH2.

[1177] In one embodiment of Formula VIIa, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1178] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1179] In one embodiment of Formula VIIb, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1180] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1181] In one embodiment of Formula VIIc, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1182] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1183] In one embodiment of Formula VIId, Z is CHCH2, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1184] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1185] In one embodiment of Formula VII, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1186] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1187] In one embodiment of Formula Vila, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1188] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1189] In one embodiment of Formula VIIb, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1190] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a-NR 8 R 9 , and R 42b C 1-6 In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It's NH2.

[1191] In one embodiment of Formula VIIc, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1192] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b C 1-6 Alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1193] In one embodiment of Formula VIId, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1194] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1195] In one embodiment of Formula VII, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1196] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1197] In one embodiment of Formula Vila, Z is CCH, Y is F, R 1 is methyl, R 2is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1198] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1199] In one embodiment of Formula VIIb, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1200] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b It is C 1-6alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1201] In one embodiment of Formula VIIc, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1202] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a Yes-NR 8 R 9 , and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1203] In one embodiment of Formula VIId, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1204] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1205] In one embodiment of Formula VII, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1206] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1207] In one embodiment of Formula VIIa, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4ais a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1208] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1209] In one embodiment of Formula VIIb, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1210] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42ais -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1211] In one embodiment of Formula VIIc, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1212] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a Yes-NR 8 R 9 , and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1213] In one embodiment of Formula VIId, Z is F, Y is F, R 1 is methyl, R 2is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is hydrogen; B is

[1214] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1215] In one embodiment of Formula VII, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1216] In a further embodiment, R 1 It is C 1-6 Alkyl and R 7 is NH2. In a further embodiment, R 1 is methyl and R 7 It's NH2.

[1217] In one embodiment of Formula VIIa, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1218] In a further embodiment, R 41 C 1-6 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 C 1-6 Alkyl and R 42a is NH2. In a further embodiment, R 41 is methyl and R 42a It's NH2.

[1219] In one embodiment of Formula VIIb, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1220] In a further embodiment, R 41 It's H, R 42a is H, and R 42b It is C 1-6 In a further embodiment, R 41 It's H, R 42a is H, and R 42b In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b C 1-6 alkyl or H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a -NR 8 R 9 , and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1221] In one embodiment of Formula VIIc, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R 5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1222] In a further embodiment, R 41 H, R 42a is NH2, and R 42b is H. In a further embodiment, R 41 H, R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 C 1-6 Alkyl or H, R 42a is NH2, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a Yes-NR 8 R 9 , and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b It is C 1-6 alkyl or H. In a further embodiment, R 41 It is C 1-6 Alkyl or H, R 42a is -NHCH3, and R 42b is NH2.

[1223] In one embodiment of Formula VIId, Z is F, Y is F, R 1 is methyl, R 2 is an aryl group, R 3 is hydrogen, R 4a is hydrogen, R 4a is a C1-C4 alkyl group, R5 is a C1-C6 alkyl group, R 6 is hydrogen, R 40 is cyano or nitro; B is

[1224] In a further embodiment, R 41 is a halogen and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen and R 42a is -C(O)NHCH3. In a further embodiment, R 41 is Br and R 42a Yes -C(O)NR 8 R 9 In a further embodiment, R 41 is Br and R 42a It is -C(O)NHCH3.

[1225] Non-limiting examples of compounds of Formula VII include:

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234] The present invention also includes the use of compounds of formula VIII, formula IX or formula X, wherein R 10 Is a monophosphate, diphosphate, triphosphate or R 10A , where R 10A is a stable phosphate prodrug that is metabolized in vivo to a monophosphate, diphosphate, or triphosphate to treat or prevent COVID-19 disease in a host in need thereof, as described herein:

[1235]

[1236] in

[1237] R10 Selected from And R 10A ;

[1238] R 10A It is a stable phosphate prodrug that can be metabolized into monophosphate, diphosphate or triphosphate in vivo;

[1239] R 11 Selected from hydrogen and R 1 ;and

[1240] R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl;

[1241] The present invention also includes compounds of Formula XI and Formula XII:

[1242]

[1243] or a pharmaceutically acceptable salt thereof;

[1244] in

[1245] R 12a and R 12b is an oxygen protecting group and R 12a and R 12b At least one of them is -C(O)OC 1-6 Alkyl, such as -C(O)OtBu, or -C(O)O-benzyl, wherein the alkyl and benzyl groups may be optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl.

[1246] In one embodiment, R 12a Yes -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12b is an oxygen protecting group which, when attached to oxygen, is an ester, ether, or silyl ether moiety. In a further embodiment, R 12b Yes -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12a is an oxygen protecting group which, when attached to oxygen, is an ester, ether, or silyl ether moiety. 12a and R 12b All are -C(O)OC 1-6 Alkyl, such as -C(O)OtBu. In one embodiment, R 12a and R 12b All are -C(O)O-benzyl.

[1247] In one embodiment, the compound of Formula XII is Formula XIIA:

[1248]

[1249] In one embodiment, the compound of Formula XII is Formula XIIB:

[1250]

[1251] For example, the protecting group attached to oxygen can be an ester moiety, such as benzoic acid acetate. In one embodiment, when attached to oxygen, the oxygen protecting group is a silyl ether moiety (e.g., trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS or TBS), or tert-butyldiphenylsilyl (TBDPS). In one embodiment, when attached to oxygen, the oxygen protecting group is an ether moiety, such as methyl ether, methoxymethyl ether, or benzyl ether. These protecting groups can be described in Theodora W. Green, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, incorporated by reference. One of the methods described in Wiley & Sons (1999) is set up for protecting hydroxyl groups. For example, when the oxygen protecting group connected to oxygen is an ester moiety, the compound of formula XI or formula XII can be prepared according to the conditions described in the text of pages 149-178, and when the oxygen protecting group is a silyl ether moiety when connected to oxygen, the compound of formula XI or formula XII can be prepared according to the conditions described in the text of pages 113-147. In one embodiment, the protecting group is a tert-butyldimethylsilyl (TBS) group. Using the conditions described in the text of page 128 and Ogilvie et al. Can. J. Chem. 1979, 57, 2230., the TBS group is selectively set on a primary alcohol rather than a secondary alcohol. These conditions include using TBSCl, DMAP and NEt3 in DMF at 25°C.

[1252] Non-limiting examples of additional protecting groups attached to the oxygen include bromobenzoate, p-methoxybenzyloxymethyl ether (MPBM), o-nitrobenzyloxymethyl ether (NBOM), p-nitrobenzyloxymethyl ether, tert-butoxymethyl ether, 2,2,2-trichloroethoxymethyl ether, 3-bromotetrahydropyranyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 1-methoxycyclohexyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiopyranyl ether, substituted phenyl ethers, 2-methylpyridyl ether, 4-methylpyridyl ether, 1,3-benzodithiolan-2-yl ether, p-chlorophenoxyacetate, 3-phenylpropionate, p-phenylbenzoate, alkyl p-nitrophenylcarbonyl, alkylbenzylcarbonyl, alkyl p-methoxybenzylcarbonyl, alkyl o-nitrobenzylcarbonyl, and alkyl p-nitrobenzylcarbonyl.

[1253] R 12a and R 12b Non-limiting examples include:

[1254]

[1255]

[1256] Non-limiting examples of compounds of Formula XI and XII include:

[1257]

[1258]

[1259]

[1260] In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula IX, Formula X, or Formula XIII, such as Compound 1A, Compound 1B, Compound 2A, Compound 2B, Compound 3A, Compound 3B, Compound 4A, or Compound 4B, is used in a form that is at least 90% free of the opposite phosphorus enantiomer, and can be at least 98%, 99%, or up to 100% free of the opposite phosphorus enantiomer.

[1261] Compound 1 (((S)-(((2R,3R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester) was previously described in U.S. Pat. Nos. 9,828,41; 10,000,523; 10,005,811; 10,239,911; 10,815,266; 10,870 ,672; 10,870,673; 10,875,885; and, 10,874,687; and U.S. applications US2019-0201433 and US2020-0222442; and PCT applications WO2016 / 144918; WO2018 / 048937; WO2019 / 200005; and WO2020 / 117966 assigned to Atea Pharmaceuticals. The synthesis of compound 1 is described in Example 1 below.

[1262] Compound 2 was previously described in U.S. Patents 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 RNA-dependent RNA polymerase (RdRp) (Good, S Set al. PLoS ONE 15(1), e0227104 (2020)). Compound 2A has been evaluated in a Phase 1b study (Berliba, E. et al. Antimicrob. Agents Chemther. 63, e011201-19 (2020)) and a Phase 2 clinical trial (Mungar, Q. et al. EASL abstract (2020)). In the latter study, compound 2A was safe and well tolerated in HCV-infected subjects for up to 12 weeks and achieved a high efficacy rate.

[1263] The synthesis of Compound 2 (((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester hemisulfate salt) is described in Example 1 below.

[1264] In one embodiment, Compound 2 is provided in a pharmaceutically acceptable composition or solid dosage form.

[1265] Non-limiting illustrative methods for preparing Compound 2 include

[1266] (i) In the first step, compound 1 is dissolved in an organic solvent such as acetone, ethyl acetate, methanol, acetonitrile or ether in a flask or container;

[1267] (ii) adding a second organic solvent, which is the same as or different from the organic solvent in step (i), to a second flask or container, optionally cooling the second solvent to 0-10 degrees Celsius, and adding H2SO4 dropwise to the second organic solvent to produce a H2SO4 / organic solvent mixture; wherein the solvent can be, for example, methanol;

[1268] (iii) adding the 0.5 / 1.0 molar ratio of H2SO4 / solvent mixture from step (ii) dropwise to the solution of compound 1 from step (i) at ambient temperature or slightly elevated or reduced temperature (e.g., 23-35 degrees Celsius);

[1269] (iv) stirring the reaction of step (iii) until a precipitate of compound 2 forms, for example at ambient temperature or slightly elevated or reduced temperature;

[1270] (v) optionally filtering the precipitate obtained from step (iv) and washing it with an organic solvent; and

[1271] (vi) optionally drying the resulting compound 2 in vacuo, optionally at an elevated temperature, such as 55, 56, 57, 58, 59 or 60 °C.

[1272] In one embodiment, the solvent of step (iii) is an alcohol, such as methanol, ethanol or isopropanol. In one embodiment, the solvent of step (iii) is an alkyl ester, such as ethyl acetate.

[1273] Scheme 1 provides a metabolic pathway for compounds of Formula I, which involves an initial deesterification of the phosphoramidate (Compound 1) to form metabolite 1-1, which spontaneously decomposes to metabolite 1-2. Metabolite 1-2 is then converted to N 6 -methyl-2,6-diaminopurine-5'-monophosphate derivatives (metabolites 1-3), which are metabolized to free 5'-hydroxy-N 6 2-Methyl-2,6-diaminopurine nucleoside (metabolite 1-8) and ((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl dihydrogen phosphate as the 5'-monophosphate (metabolite 1-4). Metabolites 1-4 are anabolic-synthesized to the corresponding diphosphate (metabolite 1-5) and then to the active triphosphate derivative (metabolite 1-6). The 5'-triphosphate can be further metabolized to 2-amino-9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-1,9-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.

[1274]

[1275]

[1276] definition

[1277] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of COVID-19, the disease caused by the SARS-CoV-2 virus. Typically, the host is a human. "Patient" or "host" or "subject" also refers to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, bats, and the like.

[1278] The terms "prophylactic" or "preventative" when used herein refer to the administration of an active compound to prevent, reduce the likelihood of the occurrence or reoccurrence of COVID-19, or to minimize new infections associated with an infection that would occur without such treatment. The invention encompasses both therapeutic and prophylactic or preventative treatments. In one embodiment, the active compound is administered to a host that has been exposed to COVID-19 and is therefore at risk for infection with COVID-19. In another alternative embodiment, a method of preventing transmission is provided, comprising administering to a human an effective amount of one of the compounds described herein for a sufficient period of time prior to exposure to a potentially infected person, including during travel or public events or meetings, including, for example, up to 3, 5, 7, 10, 12, 14 days or more before a transmissible situation occurs.

[1279] The terms "co-administered," "co-administered," or "combination" are used to describe the combination of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, according to the present invention and at least one other antiviral agent. The timing of co-administration is preferably determined by the medical professional treating the patient. Sometimes it is desirable to administer these agents simultaneously. Alternatively, the selected agents for the combination therapy may be administered to the patient at different times. Of course, when more than one viral or other infection or other condition is present, the compounds of the present invention may be combined with other agents as needed to treat the other infection or condition.

[1280] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds, wherein the parent compound is modified into its inorganic and organic, acid or base addition salts without excessive toxicity. The salts of the compounds of the present invention can be synthesized by conventional chemical methods from the parent compound with an alkaline or acidic portion. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxide, carbonate, bicarbonate, etc., of Na, Ca, Mg, or K), or by reacting the free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or in a mixture of the two. Typically, where feasible, typical non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The salts of the compounds of the present invention can optionally be provided in the form of a solvate.

[1281] Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as amines of mineral or organic acid salts; acidic residues such as carboxylic acids of alkali metal or organic salts; and the like. Pharmaceutically acceptable salts include conventional salts and quaternary ammonium salts of the parent compound, formed, for example, with non-overly toxic inorganic or organic acids. For example, acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2)n-COOH wherein n is 0-4, and the like, or using different acids that produce the same counterion. A list of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[1282] The compound can be provided as a salt in any molar ratio to provide the desired result. For example, the compound can be provided with less than a molar equivalent of the counterion, such as in the form of a hemisulfate salt. Alternatively, the compound can be provided with an excess of the counterion, such as in the form of a disulfate salt. Non-limiting examples of molar ratios of compound to counterion include 1:0.25, 1:0.5, 1:1, and 1:2.

[1283] "Alkyl" is a saturated aliphatic hydrocarbon group that is straight or branched. In certain embodiments, an alkyl group 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). As used herein, a specified range represents an alkyl group having the length of each member of a range that is described as an independent species. For example, C1-C6 alkyl as used herein represents an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to represent that each of these is described as an independent species, while C1-C4 alkyl is described as an alkyl group as used herein. "Alkyl" represents an alkyl group having 1, 2, 3, or 4 carbon atoms, and is intended to represent that each of these is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[1284] "Cycloalkyl" is a saturated monocyclic hydrocarbon ring system. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[1285] "Alkenyl" refers to a non-aromatic hydrocarbon group containing at least one double bond between adjacent carbon atoms and having a structure similar to the alkyl groups described herein. For example, an alkenyl group can have up to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-butenyl (-C=CH-CH2CH3), and 2-butenyl (-CH2CH=CHCH2).

[1286] The term "alkynyl" refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and a structure similar to the alkyl groups described elsewhere herein. For example, an alkynyl group can have 2 to 4 carbon atoms (i.e., a C2-C4 alkynyl group). Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

[1287] "Aryl" means an aryl group containing only carbon in one or more aromatic rings. In one embodiment, the aryl group comprises 1 to 3 separate or fused rings and is 6 to about 14 or 18 ring atoms, with no heteroatoms as ring members. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is side-joined. An example of a side ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above. In one embodiment, the aryl group includes, for example, dihydroindole, dihydrobenzofuran, isoindolin-1-one, and indolin-2-one.

[1288] "Aryl(alkyl)-" is an alkyl group as described herein substituted with an aryl group as described herein. For example, aryl(CH2)- is benzyl. Examples of aryl(alkyl)- include benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[1289] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing 1 to 3, or in some embodiments 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S), wherein the remaining ring atoms are carbon, or a stable bicyclic or tricyclic ring system containing at least one 5-, 6-, or 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2 heteroatoms selected from N, O, S, B, or P, and the remaining ring atoms are carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 or 6 ring atoms. When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. Examples of 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, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[1290] The term "heteroalkyl" refers to an alkyl, alkenyl, alkynyl, or haloalkyl moiety as defined herein, wherein a CH group is replaced by a heteroatom or a carbon atom is replaced by a heteroatom, such as an amine, carbonyl, carboxyl, oxo, thioxo, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. In one embodiment, "heteroalkyl" is used to refer to a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 6 carbon atoms.

[1291] The term phosphoramidate is used to describe the part of nucleoside furanose ring 5 ' position and forms the prodrug form of nucleoside compounds in whole specification sheets, wherein phosphorus atom is connected by 5 '-O-key, and wherein phosphorus also forms the PN key with at least one nitrogen covalent bond.In some embodiments, phosphorus is covalently bound to the amino moiety of natural or synthetic amino acid (it can be the form of ester).For example, comprise those with following structure for phosphoramidate group of the present invention:

[1292]

[1293] Other phosphoramidates useful in the present invention include those having the following structure:

[1294]

[1295] in:

[1296] 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

[1297] R P2 -NR N1 R N2 group or B' group;

[1298] in:

[1299] R N1 and R N2 Each independently is H, C 1-8 alkyl, (C3-C7 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocycle)C0-C4 alkyl- or (heteroaryl)C0-C4 alkyl-; which may be optionally substituted; or

[1300] R N1 and R N2 Together with the nitrogen atom to which it is attached, they form a 3- to 7-membered heterocyclic ring;

[1301] B' is

[1302] in:

[1303] R 13 is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8cycloalkyl)C0-C4alkyl-, (aryl)C0-C4alkyl-, (C3-C6heterocyclo)C0-C4alkyl-, (heteroaryl)C0-C4alkyl-, or the side chain of an amino acid, for example, typically the side chain of an amino acid (as otherwise described herein) selected from alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine. 13 is hydrogen, methyl, isopropyl or isobutyl);

[1304] R 14is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8cycloalkyl)C0-C4alkyl-, (aryl)C0-C4alkyl-, (C3-C6heterocyclo)C0-C4alkyl-, (heteroaryl)C0-C4alkyl-, or the side chain of an amino acid, for example, typically the side chain of an amino acid (as otherwise described herein) selected from alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine. 14 is hydrogen, methyl, isopropyl or isobutyl);

[1305] R 15 is hydrogen or C1-C3 alkyl; or

[1306] R 13 and R 14 can form a (C3-C7)cycloalkyl group or a (C3-C7)heterocyclic group; or

[1307] R 13 and R 14 or R 16 can form a (C3-C6) heterocyclic group; and

[1308] R 16 It is hydrogen, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, (C3-C8cycloalkyl)C0-C4alkyl, (aryl)C0-C4alkyl-, (C3-C6heterocycle)C0-C4alkyl-, (heteroaryl)C0-C4alkyl-.

[1309] Preferred R P1 Groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) that enhance the bioavailability of the compound in the patient's cells and exhibit reduced toxicity, enhanced therapeutic index, and enhanced pharmacokinetics (slower metabolism and excretion of the compound).

[1310] Stable phosphate prodrugs

[1311] Stable phosphate prodrugs are moieties that can deliver monophosphates, diphosphates, or triphosphates in vivo. For example, McGuigan discloses phosphoramidates in U.S. 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 discloses thiophosphoramidates in US 8,895,723 and 8,871,737 (incorporated herein by reference). Alios also discloses cyclic nucleotides in U.S. Patent No. 8,772,474 (incorporated herein by reference). Idenix discloses cyclic phosphoramidates and phosphoramidate / SATE derivatives in WO 2013 / 177219 (incorporated herein by reference). Idenix also discloses substituted carbonyloxymethyl phosphoramidate compounds in WO 2013 / 039920 (incorporated herein by reference). Hostetler discloses lipid phosphate prodrugs, see, for example, US 7,517,858. Hostetler also discloses 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 discloses nucleotide sphingoids and lipid derivatives in WO 2014 / 124430. RFS Pharma discloses purine nucleoside monophosphate prodrugs in WO 2010 / 091386. Cocrystal Pharma Inc. also discloses purine nucleoside monophosphate prodrugs in U.S. Patent No.: 9,173,893 (incorporated herein by reference). HepDirect TMThe technology is disclosed in the paper "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-2-thioesters) and DTE (dithiodiethyl) prodrugs. For a review of references disclosing non-limiting examples, see: A. Ray and K. Hostetler, "Application of kinase bypass strategies to nucleoside antivirals," Antiviral Research (2011) 277-291; M. Sofia, "Nucleotide prodrugs for HCV therapy,” Antiviral Chemistry and Chemotherapy 2011; 22-23-49; and S. Peyrottes et al., “SATE Pronucleotide Approaches: An Overview,” Mini Reviews in Medicinal Chemistry 2004, 4, 395. In one embodiment, the 5′-prodrugs described in any of these patent applications or references can be used for the R 10A Bit.

[1312] In an alternative embodiment, stable phosphate prodrugs include, but are not limited to, those described in U.S. Patent No. 9,173,893 and U.S. Patent No. 8,609,627, which are incorporated herein by reference, including methods of preparation. For example, the 5'-prodrug can be represented by the following group:

[1313]

[1314] in

[1315] Z is O or S;

[1316] R 17 and R 18 When administered in vivo, the nucleoside monophosphate, diphosphate or triphosphate can be provided.12 and R 13 Independently selected from:

[1317] (a)OR 19 , where R 19 is selected from H, Li, Na, K, phenyl and pyridyl and wherein phenyl and pyridyl are optionally substituted by one to three independently selected from (CH2) 0-6 CO2R 20 and (CH2) 0-6 CON(R 20 ) 2 is substituted by a substituent;

[1318] R 20 Independent H, C 1-20 Alkyl, carbon chain derived from fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or C 1-20 Alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl (such as phenyl), heteroaryl (such as pyridyl), substituted aryl or substituted heteroaryl; wherein the substituent is C 1-5 Alkyl, or substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl or cycloalkyl-substituted C 1-5 alkyl;

[1319]

[1320] (c) Esters of D-amino acids or L-amino acids:

[1321]

[1322] in

[1323] R 21 are limited to those side chains that occur in naturally occurring L-amino acids, and

[1324] R 22 H, C 1-20 Alkyl, carbon chain derived from fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or C 1-20 Alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl (such as phenyl), heteroaryl (such as pyridyl), substituted aryl or substituted heteroaryl; wherein the substituent is C 1-5 Alkyl, or substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl or cycloalkyl-substituted C 1-5 alkyl;

[1325] (d)R 17 and R 18 Can be combined to form a ring:

[1326]

[1327] in

[1328] R 23 H, C 1-20 Alkyl, C 1-20 Alkenyl, carbon chain derived from fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or C substituted by lower alkyl 1-20 Alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl (such as phenyl), heteroaryl (such as pyridyl), substituted aryl or substituted heteroaryl; wherein the substituent is C 1-5 Alkyl, or substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl or cycloalkyl-substituted C 1-5 alkyl;

[1329] (e)R 17 and R 18 can form a ring together, selected from

[1330]

[1331] in

[1332] R 24 Selected from H, C 1-20 Alkyl, C 1-20 Alkenyl, carbon chains derived from fatty acids (such as oleic acid, linoleic acid, etc.), and C 1-20 Alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl (such as phenyl), heteroaryl (such as pyridyl), substituted aryl or substituted heteroaryl; wherein the substituent is C 1-5 Alkyl, or substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 3-10 Cycloalkyl or cycloalkyl-substituted C 1-5 alkyl; and

[1333] R 25 is O or NH.

[1334] In an alternative embodiment, the 3',5'-prodrug can be represented as:

[1335]

[1336] in:

[1337] When chirality is present at the phosphorus center, it can be wholly or partially R p or S p or any mixture thereof, and may be enantiomerically enriched;

[1338] R 26 Selected from OR 19 、 or derived from fatty alcohols (such as, but not limited to, linoleyl-O- and oleyl-O-);

[1339] R 11 Selected from R 1 and hydrogen; and

[1340] R 1 、R 21 、R 22 and R 19 As defined herein.

[1341] Isotope substitution

[1342] The present invention includes an effective amount of a compound of Formula I (including, for example, Compound 1, 1A, or 1B), Formula II (including, for example, Compound 3, 3A, or 3B), Formula III (including, for example, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, or Formula IIIf), Formula IV (including, for example, 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 a pharmaceutically acceptable salt thereof, wherein the compound has an amount greater than the natural abundance of the isotope, i.e., enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. As a general example and not limitation, isotopes of hydrogen, for example, deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the structure. Alternatively or additionally, isotopes of carbon can be used, such as 13 C and 14 C. An example of isotopic substitution is the replacement of hydrogen with deuterium at one or more positions in a molecule to improve the performance of a drug. Deuterium can be incorporated at a position where a bond breaks during metabolism (α-deuterium kinetic isotope effect) or next to or near the bond breakage site (β-deuterium kinetic isotope effect). Achillion Pharmaceuticals, Inc. (WO / 2014 / 169278 and WO / 2014 / 169280) describes deuteration of nucleotides to improve their pharmacokinetics or pharmacodynamics, including at position 5 of the molecule.

[1343] Substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Substitution of deuterium for hydrogen at a metabolic breakdown site may reduce the metabolic rate at that bond or eliminate metabolism of that bond. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Therefore, unless the context clearly dictates otherwise, reference to a compound herein encompasses all potential isotopic forms.

[1344] The term "isotopically labeled" analogue refers to a "deuterated analogue," 13 C-labeled analogs" or "deuterated / 13 C-labeled analogs". The term "deuterated analogs" refers to compounds described herein in which an H-isotope, such as hydrogen / protium ( 1 H) is replaced by H-isotopes, such as deuterium ( 2 Deuteration can be partial or complete. Partial deuteration means that at least one hydrogen is replaced by at least one deuterium.

[1345] In certain embodiments, the isotope is enriched at 90, 95, or 99% or more of the isotope at any position of interest. In certain embodiments, the deuterium is enriched at 90, 95, or 99% of the desired position. Unless otherwise indicated, the deuterium rate at the selected position is at least 80%. The deuterium of the nucleoside can occur at any replaceable hydrogen that can provide the desired result.

[1346] In one embodiment, a compound of Formula XIII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical carrier, is used to treat or prevent COVID-19 disease caused by SARS-CoV-2 in a host in need thereof, as described herein:

[1347]

[1348] in

[1349] R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A 、C 1-6 Alkyl and -CH2-OR 6A ;

[1350] R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A 、C 1-6 Alkyl and -CH2-OR 6A In an alternative embodiment, -C(O)NR6B R 6C ;

[1351] R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl (C 1-6 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 Selected from C 1-20 Alkyl and C 2-20 alkenyl;

[1352] R 6B and R 6C are independently selected from hydrogen, C 1-20 Alkyl, C 2-20 alkenyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, wherein C 1-20 Alkyl, C 2-20 Alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups may be optionally 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;

[1353] R 30 is CH3, CD3, CHD2, or CH2D;

[1354] R 31 is NH2 or D or in an alternative embodiment, CD3;

[1355] R 32 is CH3, CD3, CHD2 or CH2D; and

[1356] Y is selected from F and Cl; and

[1357] R 1 、R 2 、R 3 、R 4a 、R 4b and R 5 As defined herein.

[1358] For example, non-limiting examples of compounds of Formula XIII include:

[1359]

[1360]

[1361]

[1362] Other examples of compounds of Formula XIII include:

[1363]

[1364]

[1365]

[1366]

[1367] Treatment or prevention methods

[1368] As used herein, treatment refers to administering 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, to a host (e.g., a human) that is infected or may be infected with the SARS-CoV-2 virus. In one embodiment, the treatment method comprises administering an effective amount of Compound 1A or Compound 3A, or a pharmaceutically acceptable salt thereof, such as Compound 2A or Compound 4A. In one embodiment, the treatment method comprises administering an effective amount of Compound 1B or Compound 3B, or a pharmaceutically acceptable salt thereof, such as Compound 2B or Compound 4B.

[1369] The present invention also includes prevention or prophylactic treatment. In one embodiment, 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 that has been exposed to the SARS-CoV-2 virus and is therefore at risk of infection or reinfection with the SARS-CoV-2 virus. For example, a subject who has not yet been exposed to or infected with SARS-CoV-2 but is susceptible or at risk of exposure or infection with COVID-19 can be treated prophylactically. In one embodiment, 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 at risk of infection or reinfection until there is no longer a risk of exposure.

[1370] In another alternative embodiment, a method of preventing transmission is provided, comprising administering to a human an effective amount of one of the compounds described herein for a sufficient period of time prior to exposure to a potentially infected human, including during travel or public events or meetings, including, for example, up to 3, 5, 7, 10, 12, 14 days or more before a transmissible situation occurs because the human becomes infected or to prevent infection by an infected person in a transmissible situation.

[1371] In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or 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 longer after infection.

[1372] The present invention relates to a method for treating COVID-19, including drug-resistant and multidrug-resistant forms of the virus, and related disease states, conditions, or complications of viral infection, including pneumonia, such as SARS-CoV-2 viral pneumonia (NCIP), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Other non-limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute heart injury, acute kidney injury, septic shock, disseminated intravascular coagulation, thrombosis, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis, and cytokine storm.

[1373] The method also includes administering to a host in need thereof, typically a human, an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XIII, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one additional biologically active agent, for example, an additional antiviral agent, further optionally in combination with a pharmaceutically acceptable carrier additive and / or excipient.

[1374] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or 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 evidenced by an increase of greater than or equal to 1 grade, or even 2 grades or more, in the respiratory support method required to maintain satisfactory oxygenation (SpO2 ≥ 93%) using the 6-grade respiratory support method described below.

[1375] Gradations of increasing levels of respiratory support include:

[1376] Level 1: Normal oxygenation on room air (SpO2 ≥ 93%), no need for supplemental O2

[1377] Grade 2: Persistent hypoxemia on room air (SpO2 ≥ 93), requiring low-level oxygen supplementation via nasal cannula or mask (up to 2 L / min) to maintain SpO2 ≥ 93

[1378] Level 3: Higher levels of passive supplemental oxygen (up to 2 L / min) are required via nasal cannula or mask to maintain SpO2 ≥ 93

[1379] Grade 4: Oxygenation with a positive pressure device, such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), or other noninvasive positive pressure respiratory support methods is required to maintain satisfactory oxygenation and / or ventilation

[1380] Level 5: Invasive respiratory support (intubation, mechanical ventilation, or ECMO) is required

[1381] Level 6: Death

[1382] In one embodiment, the reduction in PRI is from level 5 to level 3, from level 5 to level 2, or from level 5 to level 1. In one embodiment, the reduction in PRI is from level 4 to level 2 or level 4 to level 1. In one embodiment, the reduction in PRI is from level 3 to level 1.

[1383] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, reduces the median time to clinical recovery (state 6, 7, or 8 on the NIAID Clinical Status Scale using an adaptation of the National Institute of Allergy and Infectious Diseases (NIAID) Ordinal Scale of Clinical Status) by at least 3, 4, 5, or more days. In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, results in an improvement as measured by the Adaptive Ordinal Scale of Clinical Status.

[1384] The stages of the Adaptive Ordinal Scale of Global Clinical Status, from most severe illness to gradually less severe illness, are defined as follows:

[1385] 1. Death

[1386] 2. Hospitalization, invasive mechanical ventilation or ECMO

[1387] 3. Hospitalization, use of non-invasive ventilation or high-flow oxygen equipment

[1388] 4. Hospitalization, requiring supplemental oxygen

[1389] 5. Hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (COVID-19 related or otherwise)

[1390] 6. Hospitalized, not requiring supplemental oxygen; no longer requiring close medical care for COVID-19

[1391] 7. Not hospitalized, but with limited activity and requiring close outpatient care due to COVID-19 symptoms

[1392] 8. No need for hospitalization, no restrictions on activities, and no need for continuous close medical care

[1393] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, reduces the median time to clinical recovery (status 6, 7, or 8 on the NIAID Clinical Status Scale using an adaptation of the National Institute of Allergy and Infectious Diseases (NIAID) 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.

[1394] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, reduces the length of hospital stay in patients infected with the SARS-CoV-2 virus.

[1395] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, reduces the time to sustained undetectable SARS-CoV-2 virus in the nose and / or throat of a patient infected with SARS-CoV-2 virus.

[1396] In one embodiment, 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.

[1397] In one embodiment, administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, reduces the proportion of patients in a hospital population who are positive for SARS-CoV-2 after at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of treatment.

[1398] In another embodiment, a method of treating or preventing SARS-CoV-2 infection in a host (typically a human) in need thereof is provided by administering to the host an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XIII, or a pharmaceutically acceptable salt thereof, wherein the SARS-CoV-2 infection is caused by a viral variant that has undergone natural or drug-induced mutations from the wild type.

[1399] In some embodiments, the SARS-CoV-2 variant has a natural or drug-induced mutation in a viral protein selected from the group consisting of envelope (E) protein, membrane (M) protein, spike (S) protein, nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15, nsp16, ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10. In some embodiments, the SARS-CoV-2 variant has a mutation that confers acquired resistance to one or more antiviral drugs.

[1400] In some embodiments, the SARS-CoV-2 variant has a deletion of amino acids H69 and V70 of the spike protein.

[1401] In some embodiments, the SARS-CoV-2 variant has a deletion of amino acid D614G in the spike protein.

[1402] In some embodiments, the SARS-CoV-2 variant has a deletion of amino acid Y144 of the spike protein.

[1403] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N501Y.

[1404] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A570D.

[1405] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution P681H.

[1406] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution T716I.

[1407] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution S982A.

[1408] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D1118H.

[1409] In some embodiments, the SARS-CoV-2 variant has a premature stop codon mutation, Q27stop, in the protein product of ORF8.

[1410] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[1411] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution E484K.

[1412] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[1413] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D215G.

[1414] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A701V.

[1415] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution L18F.

[1416] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution R246I.

[1417] In some embodiments, the SARS-CoV-2 variant has a deletion at amino acids 242-244 of the spike protein

[1418] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution Y453F.

[1419] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution I692V.

[1420] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution M1229I.

[1421] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N439K.

[1422] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A222V.

[1423] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution S477N.

[1424] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A376T.

[1425] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution P323L.

[1426] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution Y455I.

[1427] In some embodiments, the SARS-CoV-2 variant has the Orf8 protein amino acid substitution R52I.

[1428] In some embodiments, the SARS-CoV-2 variant has an ORF8 protein amino acid substitution Y73C.

[1429] In some embodiments, the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution D3L.

[1430] In some embodiments, the SARS-CoV-2 variant has the nucleoside (N) protein amino acid substitution S235F.

[1431] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution T1001I.

[1432] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution A1708D.

[1433] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution I2230T.

[1434] In some embodiments, the SARS-CoV-2 variant has a deletion of amino acids SGF3675-3677 of the ORF1ab protein.

[1435] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution S861X, where X is any amino acid.

[1436] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution F480V.

[1437] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution V557L.

[1438] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution D484Y.

[1439] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution F480X, where X = any amino acid.

[1440] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution V557X, where X = any amino acid.

[1441] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution D484X, where X = any amino acid.

[1442] In some embodiments, the SARS-CoV-2 variant includes a deletion of spike protein amino acids 69-70, a deletion of spike protein amino acid Y144, a spike protein amino acid substitution N501Y, a spike protein amino acid substitution A570D, a spike protein amino acid substitution D614G, a spike protein amino acid substitution P681H, a spike protein amino acid substitution T716I, a spike protein amino acid substitution S982A, a spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.

[1443] In some embodiments, the SARS-CoV-2 variant includes spike protein amino acid substitutions of N501Y, K417N, E484K, D80A, D215G, L18F, and R246I in the spike protein, and an amino acid deletion at amino acids 242-244 in the spike protein.

[1444] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 evolutionary clade O, S, L, V, G, GH or GR, as described in Alm et al. "Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020". Euro Surveillance: BulletinEuropean Sur les Maladies Transmissibles=European Communicable Disease Bulletin. 25(32).

[1445] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clade G614, S84, V251, I378, or D392, as described in 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.

[1446] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clade 19A, 19B, 20A, or 20C, as described in Nextstrain: Genomic epidemiology of novel coronavirus - Global sub-sampling. Available from: https: / / nextstrain.org / ncov.

[1447] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 lineages A, B, B.1, B.1.1 or B.1.177, as described in 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. 2020 Nov; 5(11): 1403-1407; Rambaut et al. SARS-CoV-2 lineages. Available from: https: / / cov-lineages.org / .

[1448] In some embodiments, the SARS-CoV-2 variant is a "Cluster 5" variant, which includes the spike protein amino acid substitution D614G.

[1449] In some embodiments, the SARS-CoV-2 variant is VUI202012 / 01 (Variant Under Investigation, December 2020, variant 01) (also known as the B.1.1.7 lineage and 20B / 501Y.V1), which is determined by multiple spike protein changes, including deletion of spike protein amino acids 69-70, deletion of spike protein amino acid Y144, spike protein amino acid substitution N501Y, spike protein amino acid substitution A570D, spike protein amino acid substitution D614G, spike protein amino acid substitution P681H, spike protein amino acid substitution T716I, spike protein amino acid substitution S982A, spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the ORF8 protein product.

[1450] In some embodiments, the SARS-CoV-2 variant is a B.1.351 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 make it easier for the virus to attach to human cells, as well as amino acid substitution D80A in the spike protein, amino acid substitution D215G in the spike protein, amino acid substitution A701V in the spike protein, amino acid substitution L18F in the spike protein, amino acid substitution R246I in the spike protein, and amino acid deletion at amino acids 242-244 of the spike protein.

[1451] In some embodiments, the SARS-CoV-2 variant is a 501Y.V2 lineage variant (also known as 501Y.V2, 20C / 20H / 501Y.V2), which also includes the spike protein mutations N501Y, K417N, and E484K.

[1452] In some embodiments, the SARS-CoV-2 variant is a P.1 lineage variant (also known as the Brazil(ian) variant), which includes ten mutations in the spike protein, including N501Y and E484K.

[1453] In some embodiments, the SARS-CoV-2 variant is a B.1.1.207 lineage variant that includes a P681H mutation in the spike protein.

[1454] In some embodiments, the SARS-CoV-2 variant is a Danish mink variant, which includes amino acid deletions of H69 and V70 in the spike protein, and an amino acid substitution Y453F in the spike protein.

[1455] In some embodiments, the SARS-CoV-2 variant is a Danish mink cluster 5 variant, which includes amino acid deletions 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.

[1456] In some embodiments, the SARS-CoV-2 variant includes amino acid deletions of H69 and V70 in the spike protein, and an amino acid substitution N439K in the spike protein.

[1457] In some embodiments, the SARS-CoV-2 variant is a Nexstrain cluster 20A.EU1 variant comprising the amino acid substitution A222V in the spike protein.

[1458] In some embodiments, the SARS-CoV-2 variant is a Nexstrain cluster 20A.EU2 variant comprising the amino acid substitution S477N in the spike protein and the amino acid substitution A376T in the nucleocapsid protein.

[1459] In some embodiments, the SARS-CoV-2 variant has one or more mutations selected from the group consisting of: amino acid substitution T1001I in the ORF1ab protein product; amino acid substitution A1708D in the ORF1a protein product; amino acid substitution I2230T in the ORF1ab protein product; deletion of amino acids SGF at positions 3675-3677 in the ORF1ab protein product; amino acid substitution G251V in the ORF3a protein product; amino acid substitution S24L in the ORF8 protein product; amino acid substitution R52I in the ORF8 protein product; amino acid substitution Y73C in the ORF8 protein product; amino acid substitution L84 in the ORF8 protein product. S; amino acid substitution P323L in the nsp12 domain; amino acid substitution Y455I in the nsp12 domain; amino acid substitution Q57H in the protein product of ORF3a; amino acid substitution R27C in nsp2; amino acid substitution V198I in nsp2; amino acid substitution T85I in nsp2; amino acid substitution P585S in nsp2; amino acid substitution I559V in nsp2; amino acid substitution M33I in nsp4; amino acid substitution G15S in nsp5; amino acid substitution L37F in nsp6; amino acid substitution Y541C in nsp13; amino acid substitution P504L in nsp13; amino acid substitution S47 in the spike protein 7N; amino acid substitution N439K in the spike protein; amino acid substitution N501Y in the spike protein; amino acid substitution Y453F in the spike protein; amino acid substitution K417N in the spike protein; amino acid substitution E484K in the spike protein; amino acid substitution A222V in the spike protein; amino acid substitution S98F in the spike protein; amino acid substitution D80Y in the spike protein; amino acid substitution A626S in the spike protein; amino acid substitution V1122L in the spike protein; amino acid substitution A570D in the spike protein; amino acid substitution P681H in the spike protein; amino acid substitution V1122L in the spike protein; amino acid substitution T716I in the spike protein; amino acid substitution Amino acid substitution S982A; Amino acid substitution D1118H in the spike protein; Amino acid substitution E583D in the spike protein; Amino acid substitution V483A in the spike protein; Amino acid substitution Q675R in the spike protein; Amino acid substitution A344S in the spike protein; Amino acid substitution T345S in the spike protein; Amino acid substitution R346K in the spike protein; Amino acid substitution A348S in the spike protein; Amino acid substitution A348T in the spike protein; Amino acid substitution N354K in the spike protein; Amino acid substitution S359N in the spike protein; Amino acid substitution V367F in the spike protein; Amino acid substitution V382L in the spike protein; Amino acid substitution P384L in the spike protein;Amino acid substitution P384S in the spike protein; Amino acid substitution T385S in the spike protein; Amino acid substitution V395I in the spike protein; Amino acid substitution R403K in the spike protein; Amino acid substitution D405V in the spike protein; Amino acid substitution Q414P in the spike protein; Amino acid substitution Q414E in the spike protein; Amino acid substitution I418V in the spike protein; Amino acid substitution L441I in the spike protein; Amino acid substitution R457K in the spike protein; The amino acid substitutions K458Q in the spike protein; P463S in the spike protein; A475V in the spike protein; G476S in the spike protein; T478A in the spike protein; P479L in the spike protein; V483A in the spike protein; F490L in the spike protein; Q493L in the spike protein; A520S in the spike protein; Amino acid substitution L5F in the spike protein; Amino acid substitution P521R in the spike protein; Amino acid substitution A522S in the spike protein; Amino acid substitution A831V in the spike protein; Amino acid substitution D839Y in the spike protein; Amino acid substitution D839N in the spike protein; Amino acid substitution D839E in the spike protein; Amino acid substitution L8V in the spike protein; Amino acid substitution L8W in the spike protein; Amino acid substitution H49Y in the spike protein; Deletion of amino acid H69 in the spike protein; Deletion of amino acid V70 in the protein; deletion of amino acid Y144 in the spike protein; amino acid substitution D3L in the nucleocapsid protein; amino acid substitution S253F in the nucleocapsid protein; amino acid substitution RG203KR in the nucleocapsid protein; amino acid substitution G214C in the nucleocapsid protein; amino acid substitution S194L in the nucleocapsid protein; amino acid substitution F377L in the nsp14 protein; amino acid substitution K1186R in nsp3; or amino acid substitution A58T in nsp3.

[1460] In some embodiments, 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.

[1461] In some embodiments, 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; M109I; I52T; L46F; V70I; D3Y; K162N; H125Y; K15R; D209Y; R146H; R158C; L87F; A2S; A69S; S214I; T208I; L124F; or S4F; and combinations thereof.

[1462] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nucleocapsid (N) protein: RG203KR; S194L; S197L; P13L; D103Y; S193I; 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;S180I;M234I;Q9H;P383L;A35S;P383S;D348H;K374N;R32H ;S327L;G179C;G238C;A55S;S190G;H300Y;A119V;D144Y;L139F;P199S;P344S;P6L;R203K;P364L;R209I;S188P;A 35V; K387N; P122L; R191C; R195K; T391I; A252S; Q418L; T271I; T325I; G18V; L161F; Q289H; R203S; P162L; D340N; K3 73N; P168Q; A211V; D3L; G212V; K370N; P151L; T334I; A359S; G34W; P67T; R203M; D144N; R191L; S232I; D402Y; P168S ; S187L; T366I; A152S; A381T; N140T; T198I; A251V; A398V; A90S; D348Y; D377G; G204R; G243C; G34E; Q229H; R185L; T24I; T379I; A134V; N196I; P365S; Q384H; R276I; S235F; D216A; M210I; M322I; P20S; Q389H; R209 deletion; or V246I; and combinations thereof.

[1463] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp1 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.

[1464] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp10 protein: D64E; P136S; A104V; A32V; T12I; T111I; P84S; T51I; I55V; T102I; or T51A; and combinations thereof.

[1465] In some embodiments, the SARS-CoV2 variant contains one or more of the following mutations in the nsp12 protein: P323L;T141I;A449V;S434F;M666I;H613Y;S647I;M380I;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; D879Y; G108D; K780N; R279S; D258Y; T259I; K263N; D284Y; Q292H; T293I; N2 97S; V299F; D304Y; T319I; F321L; P328S; V330E; I333T; G337C; T344I; Y346 H; L351P; V354L; Q357H; E370G; L372F; A400S; T402I; V405F; V410I; D418N; K426N; K430N; V435F; Q444H; D445G; A448V; R457C; P461T; C464F; I466V; V4 73F; K478N; D481G; D517G; D523N; A529V; P537S; S549N; A555V; C563F; M566 I; A581T; G584V; A585T; G596S; T604I; S607I; D608G; V609I; M615V; W617L; M629V; I632V; L636F; L638F; A639V; T643I; T644M; L648F; V667I; A699S; N7 13S; H725; N734T; D736N; V737F; T739I; V742M; N743S; M756I; L758I; A771V ;L775V; A777T; K780T; F793L; T801I; T803A; H810Y; G823C; D825Y; V827A; Y 828H; V848L; T870I; K871R; N874D; Q875R; E876D; H882Y; H892Y; D901Y; M906I; N909D; T912N; P918S; E919D; A923T; F480V; V557L; D484Y; or S433G; and combinations thereof.

[1466] In some embodiments, the SARS-CoV-2 variant comprises one or more of the following mutations in the nsp13 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; S80 G; V496L; A4V; T413I; A296S; A368S; K460R; L297F; P172S; A302S; P402S; T5 30I; L428F; P504S; A368V; D458Y; P364S; S74P; T416A; A568V; M474I; S166L ; S350L; D344N; E341D; I432T; L581F; S38L; T250I; Y253H; A509V; E244D; H164Y; S74A; T141I; V356F; E319D; E365D; G170S; L526F; R155C; or Y396C; and combinations thereof.

[1467] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp14 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;P142L; or Q343K; and combinations thereof.

[1468] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp15 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 a combination thereof.

[1469] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp16 protein: S33R; K160R; P134S; Q28K; T195I; V78G; T35I; G265V; K249N; A204S; K182N; R287I; A188S; A116V; T140I; L111F; M270T; R216N; A188V; A34V; D108N; L163F; L163H; M17I; T91M; A226S; G77R; L126F; N298L; R216S; T48I; Q238H; or R279K; and combinations thereof.

[1470] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp2 protein: T85IP585S; I559V; D268; G212D; V198I; H237R; F10L; G339S; T166I; R27C; L271F; S211F; P91S; G199E; T371I; A336V; I120F; S122F; A476V; S138L; V480A; T388I; T634I; P129S; R 218C; I188T; T170I; P568L; E574A; I367V; H208Y; S99F; T429I; A306V; M405V; P129L; R222C; T44I; Q275H; R380C; A360V; A361V; G115C; L353F; H237Y; L462F; E261G; R4C; S263F; T573I; A318V; G262V; P624L; S430L; T422I; A357S ;I100V; E272G; L400F; A192V; D464A; E172D; G262S; L501F; S369F; E172K; G465S; K219R; A411V; A522V; H194Y; S3 2L; F437L; P181S; P446L; G115V; H532Y; N92H; P13S; A159V; A184S; A306S; I273T; L274F; P13L; R370H; T223I; T59 0I;E453D;H145Y;K618N;S301F;T153M;V244I;V530I;A127V;L24F;P191L;Q182L;S196L;S248G;S378F;T139I;T434I;A205V;A375V;A411S;C51Y;F300L;M135T;P568S;Q496H;S348P;T412I;T528I;T547I;V447F;or V577I;and combinations thereof.

[1471] In some embodiments, 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; T13 35I; A1711V; K19R; A994D; K1325R; P822L; K412N; A465V; T1004I; T808I; G4 89D; S1699F; M1436V; S1265R; V1768G; A231V; M951I; K384N; T1288I; Q966H; R1614K; T1036I; T1306I; A1179V; P395L; N1785D; P679L; S166G; A1769V; T1 81I; L1718F; P822S; T1022I; A1381V; A602T; I1720V; K837N; T73I; A1033V; S 1204;C1223Y;P389L;T398A;M1441I;M494I;T1303I;T181A;P1228L;R1135 K; V267F; A1883V; A655V; S1296F; T686I; L198I; P1403S; L781F; T1046A; A12 15V;E374D;I205 deletion;V477F;E324K;I707V;P109L;P1558L;P74S;S1212L;S1807F;T819I;T864I;H1000Y;P340L;S697F;T1189I;A480V;D729Y;K1771R;S 1717L; T749I; M829I; Q172R; T1482I; A1395V; I385T; M560I; S1206L; S1699 P; T1269I; T779I; V1315I; V1795F; V325F; A1892V; A579V; E493G; H1274Y; S1 467F; T1063I; T350I; V61F; A1736V; K1804N; R646W; T583I; T611I; V1243I; V190I; A41V; H290Y; H295Y; H342Y; L1244F; Q128H; V1673I; A1305V; A1526S;E948K; L72F; P125S; P402T; A1766V; D1214N; E1271D; G1440D; G283D; K1211N; K902N; K945 N; L1839S; L312F; N1263S; P1292S; S1670F; S743A; T771I; V1936I; A1262V; A1321V; A358V; A41T; C55Y; G1273S; K463E; K497Q; P1044S; R30K; S1375F; S1682F; T133I; T1348I; 465I; T 1830I; T237I; V1248L; A225V; A496V; G1217R; I1816T; L956I; N1369T; N506S; P153S; P2L; T 1275I; T1459I; V1234M; E595D; F90L; G1585S; H1307Y; I1409V; L1034V; L1328F; L292F; N1 264;P1326T;S1197G;T1456I;T64I;T703I;T720I;T820I;V1229F;V234I;A1279V;A333V;A 54S; D1121G; D1761N; E731D; I1672T; I789V; K1037R; K487N; L142F; N1177H; P1228S; P723S; Q180H; Q474R; Q940L; S370L; T1180I; T275I; T422I; T526I; T724I; V1434G; or V207L; or a combination thereof. ;

[1472] In some embodiments, 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.

[1473] In some embodiments, 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.

[1474] In some embodiments, 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; S104; F35L; M58L; or V84F; and combinations thereof.

[1475] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp7 protein: S25L; S26F; L71F; S15T; M75I; or N78S; and combinations thereof.

[1476] In some embodiments, 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.

[1477] In some embodiments, 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.

[1478] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF10: L17P; A28V; P10S; I4L; S23F; R24C; *39Q; Q29Stop; Y14C; R20I; or A8V; and combinations thereof.

[1479] In some embodiments, 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;K75N;F43L;L53F;Q38P;S26L;S40L;M260I;V256 deletion;K16N;Q218R;S2 53P; V163L; W69C; A23V; L41F; L106F; V55F; V88A; A99D; E239D; L52F; T24I; A31T; D27Y; I186V; L73F; P104L; D22Y; F114V; L95F; P240S; P42L; T268M; or T32I; and combinations thereof.

[1480] In some embodiments, 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 a combination thereof.

[1481] In some embodiments, 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 a combination thereof.

[1482] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7b: C41F; T40I; A43V; L11F; S31L; C41 deletion; H42; H42L; S5L; L20F; L32F; E33 stop; A15S; or F13 deletion; and combinations thereof.

[1483] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF8: E110 stop; G66 deletion; S69L; T11I; F104L; F120L; G8R; P38S; D119E; I10S; or I39V; and combinations thereof.

[1484] In some embodiments, 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; A846 V;I197V;R102I;V367F;T572I;A1078S;A831V;P1162L;T73I;A845S;G1219 V; H245Y; L8V; Q675R; S254F; V483A; Q677H; D138H; D80Y; M1237T; D1146H; E 654D; H655Y; S50L; S939F; S943P; G485R; Q613H; T76I; V341I; M153I; S221L ;T859I; W258L; L242F; P681L; V289I; A520S; V1104L; V1228L; L176F; M1237I ;T307I;T716I;L141;M1229I;A1087S;P26S;P330S;P384L;R765L;S940F;T 323I; V826L; E1202Q; L1203F; L611F; V615I; A262S; A522V; A688V; A706V; A 892S; E554D; Q836H; T1027I; T22I; A222V; A27S; A626V; C1247F; K1191N; M7 31I; P26L; S1147L; S1252F; S255F; V1264L; V308L; D80A; I670L; P251L; P631 S; *1274Q; A344S; A771S; A879T; D1084Y; D253G; H1101Y; L1200F; Q14H; Q23 9K; A623V; D215Y; E1150D; G476S; K77M; M177I; P812S; S704L; T51I; T547I; T791I; V1122L; Y145H; D574Y; G142D; G181V; I834T; N370S; P812L; S12F; T7 91P; V90F; W152L; A292S; A570V; A647S; A845V; D1163Y; G181R; L84I; L938F;P1143L; P809S; R78M; T1160I; V1133F; V213L; V615F; A831V; D839Y; D839N; D839E; S943P; P1263L; or V622F; and combinations thereof. ;

[1485] Pharmaceutical compositions and dosage forms

[1486] 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 treating COVID-19 caused by the SARS-CoV-2 virus in a host (typically a human) in need thereof. In one embodiment, the compound is Compound 1A or Compound 3A, or a pharmaceutically acceptable salt thereof, such as Compound 2A or Compound 4A. In one embodiment, the compound is Compound 1B or Compound 3B, or a pharmaceutically acceptable salt thereof, such as Compound 2B or Compound 4B.

[1487] The compound or its salt can be provided as a pure chemical, but is more typically administered as a pharmaceutical composition comprising an effective amount for a host (usually a human) in need of treatment for COVID-19. Therefore, in one embodiment, the pharmaceutical composition provided by the present disclosure comprises 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, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, and 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 sole active agent, or, in an alternative embodiment, in combination with at least one additional active agent.

[1488] Formula I (including but not limited to compound 1, 1A or 1B), Formula II (including but not limited to compound 3, 3A or 3B), Formula III (including, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe or Formula IIIf), 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 compounds or pharmaceutically acceptable salts thereof can be formulated together with one or more pharmaceutically acceptable carriers. Oral dosage forms are sometimes selected because of ease of administration and expected patient compliance. In one embodiment, the compounds 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 pharmaceutically acceptable salts thereof are provided in solid dosage forms, such as tablets or pills, which are well known in the art and are further described below. Enteric-coated oral tablets can also be used to improve the bioavailability of the compound for oral administration. The pharmaceutical composition (formulation) can be administered orally, parenterally, intravenously, by inhalation, intramuscularly, topically, transdermally, buccally, subcutaneously, by suppository or other routes, including intranasal spray delivery routes.

[1489] In one embodiment, the 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 its pharmaceutically acceptable salt is administered intravenously. In a non-limiting embodiment, the compound of the present invention is administered intravenously with a loading dose of 550mg / days and a maintenance dose of 275mg / days. In one embodiment, the loading dose is administered once and the maintenance dose is administered twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days. In a non-limiting embodiment, the intravenous loading dose is 550 mg / day compound 1 (i.e., 600 mg / day compound 1 hemisulfate), and the maintenance dose is 275 mg / day (i.e., 300 mg / day compound 1 hemisulfate)).

[1490] The effective dosage form will depend on the bioavailability / pharmacokinetics of the particular agent selected and the severity of the patient's disease. The compounds 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 pharmaceutically acceptable salts thereof, can be administered in one or more forms, for example, tablets, capsules, injections, intravenous formulations, suspensions, liquids, emulsions, implants, particles, microspheres, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gel, mucosal, etc.

[1491] Intravenous and intramuscular formulations are typically administered in sterile saline. One of ordinary skill in the art can modify the formulation to make it more soluble in water or another carrier, for example, this can be easily achieved by minor modifications (salt formulation, esterification, etc.).

[1492] The pharmaceutical compositions contemplated herein optionally include a carrier, as further described below. The carrier must have sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the patient being treated. The carrier can be inert or have its own pharmaceutical benefits. The amount of the carrier used in conjunction with the compound is sufficient to provide the actual amount of material for administration for each unit dose of the compound. Representative carriers include solvents, diluents, pH regulators, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, tonicity agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier.

[1493] One or more adhesives can be added to the pharmaceutical composition to increase the viscosity of the composition as needed. Examples of useful adhesives include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinyl pyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof, and mixtures thereof.

[1494] The solution, suspension or emulsion for administration can be buffered with an effective amount of a buffer to maintain a pH suitable for the selected administration. Suitable buffers are well known to those skilled in the art. Examples of some useful buffers are acetate, borate, carbonate, citrate and phosphate buffers.

[1495] To prepare a pharmaceutical composition according to the present invention, 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, can be mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical formulation techniques to produce a dosage. The carrier can take a variety of forms depending on the desired dosage form, e.g., oral or parenteral.

[1496] When preparing pharmaceutical compositions in oral dosage forms, any conventional pharmaceutical medium can be used. Therefore, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives can be used, including water, ethylene glycol, oils, alcohol, flavorings, preservatives, colorants, etc. For solid oral preparations such as powders, tablets, capsules and solid preparations such as suppositories, suitable carriers and additives include starch, sugar carriers such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. can be used. If necessary, tablets or capsules can be enteric-coated or sustained-released by standard techniques. The use of these dosage forms can significantly improve the bioavailability of the compound in patients.

[1497] For parenteral formulations, the carrier typically comprises sterile water or aqueous sodium chloride solution, but may also include other ingredients, including those that aid dispersion. Of course, when sterile water is used and sterility is maintained, the composition and carrier must also be sterilized. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used.

[1498] Liposomal suspensions (including liposomes targeted to viral antigens) can also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be suitable for delivering free nucleosides, acyl / alkyl nucleosides or phosphate prodrug forms of the nucleoside compounds according to the invention.

[1499] The amounts and weights mentioned in this disclosure generally refer to the free form (i.e., not in salt, hydrate or solvate form). The typical values ​​described herein represent the equivalent amount of the free form, i.e., the amount as if the free form were to be administered. If a salt is administered, the amount needs to be calculated based on the molecular weight ratio between the salt and the free form.

[1500] 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 a pharmaceutically acceptable formulation according to the present invention is an effective amount for achieving the desired result of treating COVID-19, reducing the possibility of COVID-19, or inhibiting, reducing and / or eliminating COVID-19 or its secondary effects (including disease states, conditions and / or complications secondary to the virus). As a non-limiting embodiment, the therapeutically effective amount of the compound of the present invention in the pharmaceutical dosage form can be, for example, in the range of about 0.001 mg / kg to about 100 mg / kg or more per day. 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, in a non-limiting embodiment, can be administered in an amount of about 0.1 mg / kg to about 15 mg / kg of the patient per day, depending on the pharmacokinetics of the agent in the patient.

[1501] Unless otherwise specified, the weights of active compounds in the dosage forms described herein refer to the free form or salt form of the compound. For example, approximately 600 mg of Compound 2 is equivalent to approximately 550 mg of Compound 1.

[1502] In certain embodiments, the dosage form of the pharmaceutical composition comprises about 1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, about 200 mg to about 600 mg, about 300 mg to about 500 mg, or 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.

[1503] In certain embodiments, the pharmaceutical composition is a dosage form, e.g., a solid dosage form, comprising at most 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, or about 880. 5. 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, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof.

[1504] In certain embodiments, 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, such as Compound 1 or Compound 2, is administered with an initial dose (or loading dose), followed by administration of 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 mg or at least about 750 mg, and the dosage is taken once or twice a day. In one embodiment, the loading dose is about 1.5 times, about 2 times, about 2.5 times or 3 times the maintenance dose. In one embodiment, the loading dose is administered once, twice, three times, four times or more before the first maintenance dose.

[1505] In one embodiment, the pharmaceutical composition is a dosage form, e.g., a solid dosage form, containing 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 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.

[1506] In certain embodiments, the pharmaceutical composition, such as 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. In one embodiment, the pharmaceutical composition is administered with 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 administration 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. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1100 mg of compound 1 followed by administration of compound 1 twice daily at a dose of at least about 450 mg, 550 mg, 650 mg, 750 mg, or 850 mg. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 1100 mg of compound 1 followed by administration of compound 1 twice daily at a dose of at least about 550 mg. In one embodiment, the maintenance dose is administered for about 4, 5, 6, 7, 8, 9, 10, or more days. In one embodiment, compound 1 is compound 1A. In one embodiment, compound 1 is compound 1B.

[1507] In one embodiment, an effective amount of a compound of formula I:

[1508]

[1509] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for use in treating 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:

[1510] (i) A single loading dose of 1100 mg free base in one day; followed by

[1511] (ii) A maintenance dose of 550 mg free base per day.

[1512] In one embodiment, an effective amount of a compound of the formula:

[1513]

[1514] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for use in treating 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:

[1515] (i) A single loading dose of 1100 mg free base in one day; followed by

[1516] (ii) A maintenance dose of 550 mg free base per day.

[1517] In one embodiment, an effective amount of a compound of the formula:

[1518]

[1519] Optionally, in a pharmaceutically acceptable carrier, for use in treating 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:

[1520] (i) a single loading dose of 1200 mg of salt in one day; followed by

[1521] (ii) A maintenance dose of 600 mg of salt per day.

[1522] In certain embodiments, the pharmaceutical composition, such as 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 with 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 administration of at least about 400 mg of a dose, 500 mg, 600 mg, 700 mg or 800 mg of compound 2 once, twice or three times a day. In one embodiment, the pharmaceutical composition is administered with an initial dose (or loading dose) of at least about 1000 mg, 1200 mg or 1400 mg of compound 2, followed by administration twice a day at a dose of at least about 600 mg of compound 2. In one embodiment, the pharmaceutical composition is administered twice a day at an initial dose (or loading dose) of at least about 1200 mg of compound 2, followed by administration twice a day at a dose of at least about 400 mg, 500 mg, 600 mg, 700 mg or 800 mg of compound 2. In one embodiment, the pharmaceutical composition is administered with an initial dose (or loading dose) of at least about 1200 mg of compound 2, followed by administration twice a day at a dose of at least about 600 mg of compound 2. In one embodiment, the maintenance dose is administered for 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 1B.

[1523] In certain embodiments, the 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 longer. In one embodiment, the 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 times or more daily. In one embodiment, it is administered orally twice daily.

[1524] For the purposes of the present invention, a prophylactic or preventatively effective amount of a composition according to the present invention can generally fall within the above ranges and can be determined according to the best judgment of a healthcare provider. In one embodiment, the compounds of the present invention are administered seasonally to prevent infection when the risk of a virus is increased, or can be administered, for example, before, during, and / or after travel or exposure.

[1525] Those of ordinary skill in the art will recognize that the therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be adopted, the pharmacokinetics of the agent used, and the patient or subject (animal or human) being treated. Such therapeutic amounts can be determined by the attending physician or specialist.

[1526] Solid dosage form

[1527] One aspect of the present invention is a solid dosage form comprising an effective amount of a compound of Formula I (including but not limited to Compound 1, 1A, 1B, 2, 2A or 2B), Formula II (including but not limited to Compound 3), Formula III (including Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe or Formula IIIf), 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.

[1528] In one embodiment, the solid dosage form comprises a spray-dried solid dispersion of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral administration. In another embodiment, the solid dosage form is a particulate layered solid dispersion of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral administration.

[1529] In other embodiments, the solid dispersion further comprises at least one excipient selected from copovidone, poloxamer, and HPMC-AS. In one embodiment, the poloxamer is poloxamer 407 or a mixture of poloxamers including poloxamer 407. In one embodiment, the HPMC-AS is HPMC-AS-L.

[1530] In other embodiments, solid dosage forms prepared from a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, further comprise one or more of the following excipients: phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleylphosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; diacylglycerols; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate Glycocholate; Sorbitan monolaurate Polysorbate 20 Polysorbate 60 Polysorbate 65 Polysorbate 80 Polysorbate 85 Polyoxyethylene monostearate; surfactin; poloxamer; sorbitan fatty acid esters such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebrosides; dihexadecyl phosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; acetylapalmitate; ricinoleylglycerol; cetyl stearate; isopropyl myristate; tyloxapol; poly(ethylene glycol) 5000-phosphatidylethanolamine; poly(ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents with high surfactant properties; deoxycholic acid Bile salts; cyclodextrins; chaotropic salts; ion pairing agents; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid; pullulan, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextrins, glycogen, hydroxyethyl starch, carrageenan, glycosides, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pyruvate , heparin, hyaluronic acid, curdlan and xanthan gum, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, pluronic polymers, polyethylene, polycarbonates (e.g., poly(1,3-dioxane-2-one)), polyanhydrides (e.g., poly(sebacic anhydride)), polypropyl fumarate, polyamides (e.g., polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, polyhydroxy acids (e.g., poly(β-hydroxyalkanoate))), poly(orthoesters), polycyanoacrylates, polyvinyl alcohol, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes Alkenes and polyamines, polylysine, polyethylene glycol lysine-PEG copolymer and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glyceryl monocaprylate, propylene glycol, vitamin E TPGS (also known as d-alpha-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[1531] In other embodiments, the solid dosage form prepared from a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, further comprises one or more of the following surfactants: polyethylene glycol, polypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyethylene glycol octylphenol, Triton X-100, glyceryl alkyl esters, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and poloxamer. Examples of poloxamers include poloxamer 188, 237, 338, and 407. These poloxamers are available under the trade names (available from BASF, Mount Olive, NJ) and corresponding to F-68, F-87, F-108 and F-127. Poloxamer 188 (corresponding to F-68) is a block copolymer having an average molecular weight 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 F-87) is a block copolymer having an average molecular weight of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to F-108) is a block copolymer having an average molecular weight 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 (corresponding to F-127) is a polyoxyethylene-polyoxypropylene triblock copolymer having a ratio between about E101 P56 E101 and about E106 P70 E106, or about E101 P56 E101 or about E106 P70 E106, with an average molecular weight 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.

[1532] In other embodiments, the solid dosage form prepared from the 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 further comprises one or more of the following surfactants: polyvinyl acetate, sodium salt of cholic acid, sodium dioctyl sulfosuccinate, hexadecyltrimethylammonium bromide, saponin, sugar ester, Triton X series, sorbitan trioleate, sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymer of oxyethylene and oxypropylene, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil and sunflower oil.

[1533] In alternative embodiments, solid dosage forms prepared from a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, are prepared by a process comprising solvent or dry granulation, optionally followed by compression or compaction, spray drying, nanosuspension processing, hot melt extrusion, extrusion / spheronization, molding, spheronization, layering (e.g., spray layering a suspension or solution), and the like. Examples of such techniques include direct compression using a suitable punch and die, for example, wherein the punch and die are mounted on a suitable tablet press; wet granulation using a suitable granulating apparatus such as a high shear granulator to form wet granules which are then dried to form granules; granulation followed by compression using a suitable punch and die, wherein the punch and die are mounted on a suitable tablet press; extrusion of the wet mass into cylindrical extrudates which are cut to the desired length or broken to length under gravity and attrition; extrusion / spheronization, wherein the extrudate is rounded into spherical granules and densified by spheronization; spraying of a suspension or solution onto an inert core using techniques such as a conventional pan or Wurster column; injection or compression molding using a suitable die mounted on a compression unit; and the like.

[1534] Exemplary disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium (croscarmellose sodium), powdered cellulose, chitosan, cross-linked carboxymethylcellulose sodium, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, sodium methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch, sodium carboxymethyl starch, and the like, or combinations thereof.

[1535] 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, silica, colloidal silica, dimethyldichlorosilane treated with silica, talc, or combinations thereof.

[1536] The dosage form cores described herein can be coated to produce coated tablets. The dosage of the core can be coated with a functional or non-functional coating, or a combination of functional and non-functional coatings. "Functional coatings" include tablet coatings that change the release characteristics of the entire composition, such as sustained release or delayed release coatings. "Non-functional coatings" include coatings that are not functional coatings, such as decorative coatings. Due to the initial dissolution, hydration, perforation, etc. of the coating, non-functional coatings may have some effect on the release of the active agent, but will not be considered a significant deviation from the non-coated composition. Non-functional coatings can also mask the taste of the uncoated composition containing the active pharmaceutical ingredient. The coating can include light blocking materials, light absorbing materials, or light blocking materials and light absorbing materials.

[1537] Exemplary polymethacrylates include copolymers of acrylates and methacrylates, for example, a. aminomethacrylate copolymers USP / NF, such as poly(butyl methacrylate, (2-dimethylaminoethyl)methyl methacrylate, methyl methacrylate) 1:2:1 (e.g., EUDRAGIT E 100, EUDRAGIT EPO, and EUDRAGIT E12.5; CAS Reg. No. 24938-16-7); b. 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); c. poly(methacrylic acid, methyl methacrylate) 1:1 (e.g., EUDRAGIT L 100, EUDRAGIT L 12.5 and 12.5P; also known as methacrylic acid copolymer, type A NF; CAS No. 25806-15-1); d. poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., EUDRAGIT S100, EUDRAGIT S12.5 and 12.5P; CAS No. 25086-15-1); e. poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 (e.g., Eudragit FS 30D; CAS No. 26936-24-3); f. poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) 1:2:0.2 or 1:2:0.1 (e.g., EUDRAGITS RL 100, RL PO, RL 30D, RL 12.5, RS100, RS PO, RS 30D, or RS12.5; CAS No. 33434-24-1); g. poly(ethyl acrylate, methyl methacrylate) 2:1 (e.g., EUDRAGIT NE 30D, Eudragit NE 40D, Eudragit NM 30D; CAS No. 9010-88-2); etc., or a combination thereof.

[1538] Suitable alkylcelluloses include, for example, methylcellulose, ethylcellulose, and the like, or combinations thereof. Exemplary water-based ethylcellulose coatings include AQUACOAT, a 30% dispersion further comprising sodium lauryl sulfate and cetyl alcohol, available from FMC, Philadelphia, PA; SURELEASE 25% dispersion further comprising stabilizers or other coating ingredients (e.g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.), available from Colorcon, West Point, PA; and ethylcellulose available from Aqualon or Dow Chemical Co (Ethocel), Midland, MI. Those skilled in the art will appreciate that other cellulosic polymers, including other alkylcellulose polymers, may replace some or all of the ethylcellulose.

[1539] Other suitable materials that can be used to prepare the functional coating include hydroxypropylmethylcellulose acetate succinate (HPMCAS); cellulose acetate phthalate (CAP); polyvinyl acetate phthalate; neutral or synthetic waxes, fatty alcohols (e.g., lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or particularly cetostearyl alcohol), fatty acids, including fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fats, hydrocarbons, ordinary waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials with a hydrocarbon backbone, or combinations thereof. Suitable waxes include beeswax, sugar wax, castor wax, carnauba wax, microcrystalline wax, candelilla wax, and waxy substances, such as materials that are generally solid at room temperature and have a melting point of about 30° C. to about 100° C., or combinations thereof.

[1540] In other embodiments, the functional coating may include digestible, long chain (e.g., C8-C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glycerides of fatty acids, mineral oils and vegetable oils, waxes, or combinations thereof. Hydrocarbons having a melting point between about 25° C. and about 90° C. can be used. In particular, long-chain hydrocarbon materials, fatty (aliphatic) alcohols can be used.

[1541] The coating may optionally contain additional pharmaceutically acceptable excipients, such as plasticizers, stabilizers, water-soluble components (eg, pore formers), anti-adherents (eg, talc), surfactants, and the like, or combinations thereof.

[1542] Functional coatings may include release modifiers that affect the release characteristics of the functional coating. For example, release modifiers may be used as pore formers or matrix disruptors. Release modifiers may be organic or inorganic and include materials that can dissolve, extract, or leach from the coating in the environment of use. Sustained release agents may include one or more hydrophilic polymers, including cellulose ethers and other celluloses, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; acrylic acid polymers, such as gastric soluble Eudragit FS 30D, pH sensitive Eudragit L30D 55, L 100, S100, or L 100-55; or combinations thereof. Other exemplary release modifiers include povidone; sugars (e.g., lactose, etc.); metal stearates; inorganic salts (e.g., calcium hydrogen phosphate, sodium chloride, etc.); polyethylene glycols (e.g., polyethylene glycol (PEG) 1450, etc.); sugar alcohols (e.g., sorbitol, mannitol, etc.); alkali metal alkyl sulfates (e.g., sodium lauryl sulfate); polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate); or combinations thereof. Exemplary matrix disruptors include water-insoluble organic or inorganic materials. Organic polymers include, but are not limited to, cellulose, cellulose ethers such as ethyl cellulose, cellulose esters such as cellulose acetate, cellulose acetate butyrate, and cellulose acetate propionate; starch can serve as a matrix disruptor. Examples of inorganic disruptors include various calcium salts, such as monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate; silicon dioxide, and talc.

[1543] The coating may optionally contain a plasticizer to improve the physical properties of the coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form a flexible film under normal coating conditions, it may be advantageous to add a plasticizer to the ethylcellulose before using it as a coating material. Typically, the amount of plasticizer included in the coating solution is based on the concentration of the polymer, for example, depending on the polymer, it can range from about 1% to about 200%, but most typically from about 1 wt% to about 100 wt% of the polymer. However, the concentration of the plasticizer can be determined by routine experimentation.

[1544] Examples of plasticizers for ethyl cellulose and other celluloses include plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, or combinations thereof, although other water-insoluble plasticizers (e.g., acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[1545] Examples of plasticizers for acrylic polymers include citrate esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, triacetin, or combinations thereof, although other plasticizers (e.g., acetylated monoglycerides, phthalates, castor oil, etc.) may also be used.

[1546] The coating material can be applied to the surface of the dosage form core using a suitable method. Methods such as simple or complex coacervation, interfacial polymerization, liquid drying, thermal and ionic gelation, spray drying, spray cooling, fluidized bed coating, pan coating, or electrostatic deposition can be used.

[1547] In certain embodiments, an optional intermediate coating is used between the dosage form core and the outer coating. Such an intermediate coating can be used to protect the active agent or other components of the core subunit from the effects of the materials used in the outer coating or to provide other properties. Exemplary intermediate coatings generally include water-soluble film-forming polymers. Such intermediate coatings can include film-forming polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, or the like, or combinations thereof; and plasticizers. Plasticizers can be used to reduce brittleness and increase tensile strength and elasticity. Exemplary plasticizers include polyethylene glycol propylene glycol and glycerol.

[1548] Combination and alternation therapy

[1549] The compounds described herein, or pharmaceutically acceptable salts thereof, can be administered in addition to the current standard of care for COVID patients, or in combination or alternation with any other compound or therapy that a healthcare provider deems beneficial for the patient. Combination and / or alternation therapy can be therapeutic, adjunctive, or palliative.

[1550] It has been observed that COVID patients may experience different stages of the disease, and the standard of care may vary depending on the stage of the disease that the patient presents with or progresses to. What is notable about COVID is the development of "cross talk" between the immune system and the coagulation system. As the disease progresses, the patient's immune system may overreact, which can lead to a number of serious consequences, including a cytokine storm. Through this interaction between the immune system and the coagulation system, the patient can begin to clot in various parts of the body, including the respiratory system, brain, heart, and other organs. Multiple clots throughout the body have been observed in COVID patients, requiring anticoagulation therapy. It is believed that these clots may cause long-term or even permanent damage if the disease is not treated and alleviated.

[1551] More specifically, COVID-19 has been described as progressing through three general disease phases: Phase 1 (early infection), Phase 2 (pulmonary phase), and Phase 3 (hyperinflammatory phase / cytokine storm).

[1552] Stage 1 is characterized by nonspecific, usually mild symptoms. Viral replication is occurring and it is appropriate to start treatment with the compounds described herein immediately, and it may be combined or alternated with another antiviral therapy. Interferon-β may also be administered to enhance the innate immune response to the virus. Therefore, in one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XIII, or a pharmaceutically acceptable salt thereof, is used in an effective amount in combination or alternated with interferon-β and / or another antiviral drug. Zinc supplements and / or vitamin C are sometimes taken at this stage or as the disease progresses.

[1553] The second stage of COVID-19 is the pulmonary stage, and patients may experience acute hypoxic respiratory failure. In fact, the main organ failure of COVID-19 is hypoxic respiratory failure. It has been shown that moderate immunosuppression by steroids (such as dexamethasone) is beneficial for patients with acute hypoxic respiratory failure and / or mechanical ventilation. In one embodiment, 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 that can be a glucocorticoid. Non-limiting examples are budesonide (Entocort EC), betamethasone (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).

[1554] The NS5B inhibitor Remdesivir has provided mixed results for COVID-19 patients. It can only be administered in a hospital setting and only by intravenous injection, usually three times a day, which makes it unsuitable for mild to moderate COVID-19 patients. In one embodiment, 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 alternating with Remdesivir to enhance the overall antiviral effect.

[1555] Stage 3 is the final stage of the disease and is characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small blood clots form throughout the bloodstream. This stage may also include multi-organ failure (e.g., vasodilatory shock, myocarditis). It has also been observed that many patients react to this severe stage of COVID-19 infection with a "cytokine storm." There does seem to be a two-way synergistic relationship between DIC and cytokine storms. To combat DIC, patients often take anticoagulants, which can be indirect thrombin inhibitors or direct oral anticoagulants ("DOACs"). Non-limiting examples are low molecular weight heparin, warfarin, bivalirudin (Angiomax), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), or edoxaban (Lixiana). In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternating with anticoagulant therapy. In some cases of severe coagulation in COVID patients, TPA (tissue plasminogen activator) may be used.

[1556] It has been observed that high levels of the cytokine interleukin 6 (IL-6) are a precursor to respiratory failure and death in patients with COVID-19. To treat this surge in immune response that may constitute a cytokine storm, patients can be administered monoclonal antibodies, drug inhibitors, or protein degraders targeting IL-6, such as bispecific compounds that bind to IL-6 and proteins that mediate degradation. Examples of antibodies include tocilizumab, sarilumab, siltuximab, olokizumab, and clazakizumab. In one embodiment, 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 alternating with tocilizumab or sarilumab. Other non-limiting examples of immunosuppressant drugs used to treat an overreactive 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 mofetil (CellCept, Myfortic)). Other antibodies and biologics include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (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).

[1557] IL-1 blocks the production of IL-6 and other pro-inflammatory cytokines. COVID patients are sometimes also treated with anti-IL-1 therapies to reduce excessive inflammation, such as intravenous anakinra. Anti-IL-1 therapies typically take the form of targeted monoclonal antibodies, drug inhibitors, or protein degraders, such as bispecific compounds that bind to both IL-1 and the protein it mediates degradation.

[1558] COVID patients often develop viral pneumonia, which can lead to bacterial pneumonia. Patients with severe COVID-19 may also be affected by sepsis or "septic shock." Treatment of bacterial pneumonia secondary to COVID or sepsis includes the use of antibiotics, such as macrolide antibiotics, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Other antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin. In one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternating with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such drugs can be used as anti-inflammatory drugs for COVID patients and can also have a therapeutic effect on secondary bacterial infections.

[1559] A unique challenge in treating patients infected with COVID-19 is that if the patient requires mechanical ventilation for up to or more than 5, 10 or even 14 days, relatively long-term sedation is required. For persistent pain during treatment, analgesics can be added in sequence, and for persistent anxiety, sedatives can be added in sequence. Non-limiting examples of analgesics include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with sedative advantages (olanzapine, quetiapine), propofol or dexmedetomidine, haloperidol, and phenobarbital. In one embodiment, 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 the following form: in combination or alternating with an analgesic, such as acetaminophen, ketamine, hydromorphone, fentanyl, or morphine. In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital.

[1560] Investigational drugs for COVID-19 include chloroquine and hydroxychloroquine. In one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with chloroquine or hydroxychloroquine.

[1561] Protease inhibitors, such as lopinavir or ritonavir, which have been previously approved for HIV treatment, may also be used.

[1562] Other drugs that can be used to treat COVID patients include, but are not limited to, favipiravir, fingolimod (Gilenya), methylprednisolone, bevacizumab (Avastin), Actemra (tocilizumab), uminovir, losartan, and a monoclonal antibody combination of REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with the active compounds provided herein to treat viral infections that are susceptible thereto.

[1563] In one embodiment, the compounds of the present invention are used in effective amounts in combination with anti-coronavirus vaccine therapies, 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). In another embodiment, the compounds of the present invention are used in effective amounts in combination with passive antibody therapy or convalescent plasma therapy.

[1564] SARS-CoV-2 is constantly mutating, and many mutations increase virulence and transmissibility. Resistant viral variants may emerge after long-term treatment with antiviral drugs. Resistance may develop through mutations in genes encoding enzymes used in viral replication. In some cases, the efficacy of a drug against RNA viral infections may be prolonged, enhanced, or restored by combining or alternating the administration of a compound with another, or perhaps even two or three, other antiviral compounds that induce different mutations or act through a different pathway than the primary drug.

[1565] Alternatively, the pharmacokinetics, biodistribution, half-life or other parameters of the drug may be altered by such combination therapy (which may include alternation therapy if synergy is considered). Since the disclosed purine nucleotides are polymerase inhibitors, it may be useful to administer the compound to a host in combination with, for example:

[1566] (1) Protease inhibitors;

[1567] (2) another polymerase inhibitor;

[1568] (3) Allosteric polymerase inhibitors;

[1569] (4) interferon alfa-2a, which may be pegylated or otherwise modified, and / or ribavirin;

[1570] (5) non-substrate-based inhibitors;

[1571] (6) Helicase inhibitors;

[1572] (7) antisense oligodeoxynucleotide (S-ODN);

[1573] (8) aptamer;

[1574] (9) Nuclease-resistant ribozymes;

[1575] (10) iRNA, including microRNA and siRNA;

[1576] (11) antibodies, partial antibodies, or domain antibodies to the virus; or

[1577] (12) Viral antigens or parts of antigens that induce host antibody responses. Example

[1578] General Methods

[1579] 1 H. 19 F and 31 P NMR spectra were recorded on a 400 MHz Fourier transform Brücker spectrometer. Unless otherwise indicated, spectra are in DMSO-d6. Spin multiplicities are represented by the symbols s (singlet), d (doublet), t (triplet), m (multiplet), and Br (broad peak). Coupling constants (J) are reported in Hz. Reactions were typically carried out under a dry nitrogen atmosphere using Sigma-Aldrich anhydrous solvents. All common chemicals were purchased from commercial sources.

[1580] The following abbreviations are used in the examples:

[1581] BID: twice a day

[1582] DCM: dichloromethane

[1583] EtOAc: ethyl acetate

[1584] EtOH: ethanol

[1585] GT: genotype

[1586] HPLC: High Performance Liquid Chromatography

[1587] LD: loading dose

[1588] NaOH: sodium hydroxide

[1589] Na2SO4: sodium sulfate (anhydrous)

[1590] MeOH: methanol

[1591] Na2SO4: Sodium sulfate

[1592] NH4Cl: ammonium chloride

[1593] PE:Petroleum ether

[1594] Silica gel (230 to 400 mesh, Sorbent)

[1595] t-BuMgCl: tert-butylmagnesium chloride

[1596] THF: Tetrahydrofuran (THF), anhydrous

[1597] TP: triphosphate

[1598] Example 1. Synthesis of Compound 1A and Compound 2A

[1599] Part A: Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (1-7)

[1600]

[1601]

[1602] In step 1, compound 1-1 is dissolved in DCM and the reaction is cooled to 10°C, followed by the addition of benzyl chloroformate and NEt3. The reaction is allowed to cool to room temperature and stirred for 12-14 hours. Compound 1-2 is then isolated under appropriate workup and purification conditions. In step 2, compound 1-2 is dissolved in acetonitrile and cooled to -15 to 5°C before adding Morpho DAST. The reaction is stirred for 6 hours. Compound 1-3 is then isolated under appropriate workup and purification conditions. In step 3, compound 1-3 is dissolved in toluene and the reaction is cooled to 0-10°C before adding reduced aluminum. Compound 1-4 is then separated into diastereomers with (R)-stereochemistry at the hydroxyl position under appropriate workup and purification conditions. In step 4, compound 1-4 is dissolved in acetonitrile and cooled to -15 to 5°C, followed by the addition of CBr4 and PPh3. Compound 1-5 is then isolated under appropriate workup and purification conditions. In step 5, compound 1-5 is dissolved in acetonitrile and t-BuOH, t-BuOK, and 6-chloro-9H-purin-2-amine are added. The reaction is heated to 40–50°C. Compound 1-6 is then isolated under appropriate workup and purification conditions. In step 6, compound 1-6 is dissolved in MeOH and MeNH2 is added. The reaction is heated to 20–30°C. Compound 1-7 is then isolated under appropriate workup and purification conditions.

[1603] Part B: Synthesis of dihydroquinine salt of (hydroxy(phenoxy)phosphoryl)-L-alanine isopropyl ester (1-12)

[1604]

[1605] Phenyl dichlorophosphate (1-8, 150 g, 1.0 eq.) was added to 1300 mL of isopropyl acetate. The solution was cooled to -10°C ± 5°C, and then a solution of benzyl alcohol (1-9, 80.6 g, 1.05 eq.) and Et3N (86.3 g, 1.2 eq.) was added. The mixture was stirred at -10±5°C for 3 hours. The reaction endpoint was monitored by TLC.

[1606] L-Alanine isopropyl ester hydrochloride (1-10, 125 g, 1.05 eq.) and Et3N (152 g, 2.1 eq.) were added at -10°C ± 5°C. The reaction mixture was stirred at -10°C ± 5°C for 2 hours. The reaction endpoint was monitored by TLC.

[1607] The reaction mixture was filtered, and the filter cake was washed with 20 mL of isopropyl acetate. The filtrate was washed with 1N HCl, water, and aqueous sodium bicarbonate. The separated organic layer was dried over anhydrous NaSO and then concentrated to dryness in vacuo at 40-50°C to yield 240 g of crude product 1-11 as a mixture of diastereomers (approximately 1:1 ratio). (Pale yellow oil; yield: 89.6% mol / mol; HPLC purity: 83.4% area; HPLC analysis: 86.2% w / w). This product contained approximately 6%-7% residual benzyl alcohol. Crude product 1-4 was used directly in the next step.

[1608] Compound 1-11 (135 g, 1.0 eq., 86.2% assay) and quinine (100 g, 1.0 eq.) were added to 650 mL of isopropanol. 5% Pd / C (19.2 g, 60% water, according to KF) was added and hydrogenated in a closed system using a hydrogen bag at 20°C-25°C for 8 hours. After the reaction was complete, the mixture was filtered through a Buchner funnel. The filtrate was concentrated in vacuo to remove the solvent.

[1609] To the above residue was added 300 mL of TBME. The mixture was concentrated under vacuum at 40-45° C. to remove the solvent, and the process was repeated with another 300 mL of MTBE. 600 mL of MTBE was added, and the mixture was stirred at 40-45° C. for 1 hour, then at 0-5° C. for an additional hour. The mixture was filtered, and the filter cake wa...

Claims

1. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein: R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

2. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula II: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein: R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

3. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula III or formula IV: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein: X is selected from C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

4. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula V: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein: Y and Y' are independently selected from F and Cl; R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

5. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula VI: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl; R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A , C 1-6 Alkyl, -CH2-OR 6A ; R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6 alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl; R 7 is NH2, H or -NR 8 R 9 ; R 8 and R 9are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A , and -C(O)OR 6A ; Y is selected from F and Cl; and Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen.

6. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of formula VII: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein B is selected from R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl; R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl; R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A , C 1-6 Alkyl, -CH2-OR 6A , and -C(O)NR 6B R 6C ; R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, C 1-20 Alkyl and C 2-20 alkenyl; R 6B and R 6Care independently selected from hydrogen, C 1-20 Alkyl, C 2-20 alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R 7 is NH2, H or -NR 8 R 9 ; R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ; Y is selected from F and Cl; Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen; R 40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen; R 41 Selected from H, C 1-3 Alkyl and halogen; and R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

7. A method for treating or preventing COVID-19 caused by SARS-CoV-2 virus in a host in need thereof, comprising administering an effective amount of a compound of Formula VIII, Formula IX or Formula X: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein R 10 Selected from and R 10A ; R 10A It is a stable phosphate prodrug that is metabolized to monophosphate, diphosphate or triphosphate in vivo; R 11 Selected from hydrogen and R 1 ;and R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl.

8. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a person in need thereof, comprising administering a compound of the formula: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein the compound is administered at an oral dose of about 550 mg twice a day.

9. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a person in need thereof, comprising administering a compound of the formula: Optionally in a pharmaceutically acceptable carrier, wherein the compound is administered at an oral dose of about 600 mg twice daily.

10. Compounds of formula I or II: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for use in an effective amount for treating or preventing COVID-19 in a host in need thereof, wherein: R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

11. Compounds of formula III or IV: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for use in an effective amount for treating or preventing COVID-19 in a host in need thereof, wherein: X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 Chloroalkyl groups such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl and C1-C3 hydroxyalkyl; R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; and R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

12. Compounds of Formula V, Formula VI or Formula VII: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl; R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A , C 1-6 Alkyl, -CH2-OR 6A ; R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6 alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl; R 7 is NH2, H or -NR 8 R 9 ; R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ; Y and Y' are independently selected from F and Cl; Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen; B is selected from R 40 Selected from H, C 1-3 Alkoxy, C1-3 Alkyl, N3, CN and halogen; R 41 Selected from H, C 1-3 Alkyl and halogen; and R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

13. Compounds of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating or preventing COVID-19 in a host in need thereof, wherein X is selected from C1-C3 haloalkyl (including C 1-3 Fluoroalkyl and C 1-3 Chloroalkyl groups such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl), C2-C4 alkenyl, C2-C4 alkynyl and C1-C3 hydroxyalkyl; R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, and C 3-7 Cycloalkyl; R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl.

14. Compounds of formula V, VI or VII: or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for the manufacture of a medicament for treating or preventing COVID-19 in a host in need thereof, in R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -C(O)C1-C6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, aryl, aryl(C1-C4alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1-6 alkyl; R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl; R 5 For hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl or heteroalkyl; R 6 Selected from hydrogen, -C(O)R 6A 、-C(O)OR 6A , C 1-6 Alkyl, -CH2-OR 6A ; R 6A Selected from hydrogen, C 1-6 Alkyl, C1-C6 haloalkyl, aryl, aryl (C 1-6 alkyl) - wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl; R 7 is NH2, H or -NR 8 R 9 ; R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, -C(O)R 6A and -C(O)OR 6A ; Y is selected from F and Cl; Z is selected from methyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 hydroxyalkyl and halogen; B is selected from R40 Selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N3, CN and halogen; R 41 Selected from H, C 1-3 Alkyl and halogen; and R 42a and R 42b Selected from C 1-3 Alkyl, NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 .

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