Highly Active Compounds against COVID-19

Abstract

Use of a purine nucleotide aminophosphonate or a pharmaceutically acceptable salt thereof, administered in an effective amount, for the treatment or prevention of COVID-19, an infection caused by the SARS CoV-2 virus, in a host in need thereof (such as a human).

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 982,670, filed on February 27, 2020; U.S. Provisional Application No. 62 / 994,206, filed on March 24, 2020; U.S. Provisional Application No. 63 / 032,247, filed on May 29, 2020; U.S. Provisional Application No. 63 / 039,352, filed on June 15, 2020; U.S. Provisional Application No. 63 / 040,985, filed on June 18, 2020; U.S. Provisional Application No. 63 / 054,680, filed on July 21, 2020; U.S. Provisional Application No. 63 / 073,328, filed on September 1, 2020; and U.S. Provisional Application No. 63 / 146,456, filed on February 5, 2021. These applications are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] The present invention relates to the use of selective purine nucleotides having superior activity and dosing convenience and pharmaceutically acceptable salts thereof for treating or preventing the SARS-CoV-2 virus that causes COVID-19 in a host in need thereof, typically a human. Background Art

[0004] In December 2019, multiple patients were diagnosed with pneumonia. These patients exhibited symptoms similar to those of the 2002 - 2003 SARS (Severe Acute Respiratory Syndrome) outbreak. In January 2020, the source of infection was identified as a novel coronavirus, named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and the resulting disease was called Coronavirus Disease 2019 (COVID-19). This potentially severe and sometimes fatal disease rapidly spread around the world. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic.

[0005] Most patients infected with the SARS-CoV-2 virus exhibit mild cold-like symptoms, including fever, cough, fatigue, shortness of breath, muscle aches, and loss of taste and / or smell. These symptoms typically resolve within a few weeks with minimal medical care. However, occasionally, the symptoms can persist for months. The virus can cause long-term damage to the lungs, heart, and brain. In addition, in certain patients, especially the elderly, immunocompromised, or those with underlying medical conditions, the virus can cause severe symptoms, leading to hospitalization, mechanical ventilation, and / or death.

[0006] SARS-CoV-2 is a coronavirus (CoV) belonging to the order Nidovirales, family Coronaviridae, subfamily Coronavirinae. They are enveloped viruses with a single-stranded positive-sense RNA genome. SARS-CoV-2 is approximately 30 kilobases in size and is 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 shares only 79.5% of its genome with SARS-CoV and is thus considered a novel 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 zoonoses in humans (Lau et al., PNAS 2005, 102, 14040-5; Rest et al., Infect Genet Evol. 2003, 3, 219-25). Cross-species barrier jumps enable CoVs such as SARS-CoV and Middle East Respiratory Syndrome CoV (MERS) to emerge as highly pathogenic human viruses (Schoeman and Fielding, Virology 2019, 16, 69). Similarly, genome sequencing shows that SARS-CoV-2 has 96% identity with bat coronaviruses at the whole-genome level (Zhou et al., Nature 2020, 579, 270) and thus most likely originated from bats.

[0007] 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 human transmembrane protease serine 2 cleaves and activates the spike protein, enabling SARS-CoV-2 to enter the cell via 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).

[0008] Once inside the cell, the transcription and replication of SARS-CoV-2 are mediated by a multi-subunit polymerase complex. The catalytic subunit of this complex is the RNA-dependent RNA polymerase (RdRp), called nsp12. Although the isolated nsp12 subunit is capable of performing the polymerase reaction on its own, the presence of cofactors nsp7 and nsp8 significantly enhances the efficiency of the polymerase reaction (Ahn et al. Arch Virol. 2012, 157, 2095; Subissi et al. Proc. Natl. Acad. Sci., 2014, 111, E3900).

[0009] In April 2020, the crystal structure of SARS-CoV-2 nsp-12 complexed with nsp-7 and nsp-8 was resolved (Gao et al. Science 2020, 368:779-782). The structure of nsp12 contains a polymerase C-terminal RdRp domain that is linked to an N-terminal extended domain called the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. This NiRAN domain, which is conserved in all nidoviruses, is capable of performing a nucleotidylation activity and is characterized by an α and β fold consisting of 8 α-helices and a 5-stranded β-sheet (Gao et al. Science 2020, 368:779-782). The C-terminal domain has been characterized as a "cupped right hand" domain with finger, thumb, and palm subdomains.

[0010] As the SARS-CoV-2 virus spreads worldwide, it exhibits a high mutation rate, and multiple mutant forms of the virus are circulating globally. These mutations have the potential to affect the virus's ability to cause infection and its transmission speed. For example, the B.1.1.7 variant was identified in the UK and named Variant Under Investigation 202012 / 01 by Public Health England in the fall of 2020. This variant has 8 mutations in the spike region. There is evidence that this variant spreads faster and more easily and may be associated with an increased risk of death. In South Africa, other 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. In Brazil, a variant called P.1 has also been identified, which contains mutations that may affect the virus's ability to be recognized by antibodies. For this reason, it is important to develop therapies that can treat mutant forms of the virus, especially those with mutations in the spike protein.

[0011] The history of creating therapeutic agents 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.

[0012] The lack of an approved treatment, combined with its high mortality rate and the ease and speed of its spread, highlights the need to develop effective antiviral drugs for COVID-19.

[0013] Accordingly, an object of the present invention is to provide compounds, compositions, and methods for treating and preventing the SARS-CoV-2 virus that causes COVID-19. Summary of the Invention

[0014] The present invention provides a method for treating the 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 the beneficial treatment, prevention, or prophylaxis of the SARS-CoV-2 virus that causes COVID-19. These purine nucleotides exhibit antiviral activity.

[0015] Furthermore, and importantly, these compounds can be administered to a host in need thereof, such as a human, using a simple solid oral dosage form that can be conveniently taken at home or generally outside a medical institution without the need for parenteral administration or hospitalization. If needed or appropriate, the active compounds described herein can also be administered parenterally or orally in a medical institution. The therapy can be used to treat mild, moderate, or severe diseases.

[0016] In one embodiment of the present invention, a compound of formula I

[0017]

[0018] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof suffering from COVID-19, typically a human, 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 means complete prevention or minimization of acquired infection relative to the disease without such prophylactic treatment), wherein:

[0019] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0020] 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(C 1 -C4 alkyl)-, heteroaryl or heteroalkyl;

[0021] R 3 is hydrogen or C 1-6 alkyl (including methyl, ethyl, propyl and isopropyl);

[0022] 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

[0023] 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(C 1 -C 4 alkyl)-, aryl, heteroaryl or heteroalkyl.

[0024] C 1 -C 6 Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, -CH 2 C(CH 3 ) 3 , -CH(CH 2 CH 3 ) 2 and -CH 2 CH(CH 2 CH 3 ) 2 . C 3 -C 6 Non-limiting examples of cycloalkyl include cyclopropyl, CH 2 -cyclopropyl, cyclobutyl and CH 2 -cyclobutyl.

[0025] Non-limiting examples of aryl(C 1 -C 4 alkyl)- are benzyl. Non-limiting examples of aryl are phenyl.

[0026] 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 envelope (E) protein, membrane (M) protein, spike (S) protein, nsp1, nsp2, nsp3, nsp4, nsp5, nsp 6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15, nsp16, ORF1ab, ORF 3 a, ORF6, ORF7a, ORF7b, ORF10.

[0027] Non-limiting examples of the compound of formula I are 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 infected with SARS-CoV-2, such as a human, in need thereof, or a host at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0028]

[0029] Compound 1 described above does not involve the stereochemistry at the phosphorus atom (which is chiral). The use of compound 1 can be without regard to the stereochemistry of phosphorus, or it can be used in the 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 are actually diastereomers because there are multiple chiral carbons in the molecule). Compound 1A is the S-enantiomer and compound 1B is the R-enantiomer.

[0030]

[0031] 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 Example 5 and Example 6, compound 1A exhibited an EC of 0.64 μM against SARS-Cov-2 in HAE cells (human airway epithelial cells). 90Values. Assays using HAE cells are 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 is 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 species was greater than 1.5 days in both bronchial and nasal epithelial cells. This could not have been predicted in advance and is particularly important for treating patients in the early stages of infection when the virus is highly concentrated in nasal and bronchial cells.

[0032] The data provided herein show that the compound concentrates in the lung relative to the liver, and the data previously reported confirm that the compound concentrates preferentially in the liver relative to the heart (see, for example, Example 19 of PCT Application PCT / US2018 / 016301). Taken together, this data confirms that the compound concentrates in the target organs, the lung, the liver, or the heart, thereby reducing toxicity.

[0033] In one embodiment, Compound 1, such as Compound 1A or Compound 1B or a pharmaceutically acceptable salt thereof, is administered, optionally in a pharmaceutically acceptable carrier, in an effective amount to a host, such as a human, infected with the SARS-CoV-2 virus or at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent. In one embodiment, the pharmaceutically acceptable salt is the hemisulfate, shown below as Compounds 2, 2A, and 2B:

[0034]

[0035]

[0036] 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 concentrated in the lung more than in the liver (Table 8), and the half-life of the active metabolite in the lung was 9.4 hours ( Figure 7A ). This is important because COVID-19 typically presents as a respiratory disease. In fact, after twice-daily oral administration of 30 mg / kg of Compound 2A, the concentration of the active triphosphate species in the lung was 1.6 times that in the liver.

[0037] In addition, the compounds of the present invention can inhibit SARS-CoV-2 infection through a unique mechanism of action with high selectivity. CoV virus 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 at the RdRp active site. This indicates that polymerase inhibition is not the only basis for the different activities against these viruses.

[0038] COVID-19 is an acute viral infection. In the first stage of infection, when the viral load reaches its maximum and rapid viral replication initially occurs in nasal, throat, and lung cells, antiviral treatment may be effective. Administering an effective and safe oral antiviral drug to individuals infected with SARS-CoV-2 in the early stage of the disease has the potential to avoid clinical disease, minimize long-term damage, and alleviate the COVID-19 pandemic. As described above, it has been shown that the selected compounds of the present invention can concentrate in the lungs relative to the liver. This is therapeutically beneficial when treating patients in the first stage of SARS-CoV-2 pathogen infection when prevention or mitigation of late-stage viral damage is needed. The high concentration in the lungs relative to the heart and liver is also beneficial for treating patients in the late stage of infection.

[0039] 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:

[0040]

[0041] Wherein:

[0042] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0043] 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(C 1 -C 4-alkyl)-, heteroaryl or heteroalkyl;

[0044] R 3 is hydrogen or C 1-6 alkyl (including methyl, ethyl, propyl and isopropyl);

[0045] 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

[0046] 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(C 1 -C 4 alkyl)-, aryl, heteroaryl or heteroalkyl.

[0047] In one embodiment, a compound of formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof infected with the SARS-CoV-2 virus, or to a host at risk of infection or reinfection with the SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0048] Non-limiting examples of the compound of formula II are compound 3 or a pharmaceutically acceptable salt thereof.

[0049]

[0050] 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 thereof infected with the SARS-CoV-2 virus, or to a host at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent. Compound 3 can be used in the phospho-racemic form, or in any desired ratio of the phospho R- and S-enantiomers of the compound, including enantiomerically enriched material up to the pure enantiomer. Compound 3A is the S-enantiomer and compound 3B is the R-enantiomer.

[0051]

[0052] Another non-limiting example of Formula II includes Compound 4. Optional 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 infected with the SARS-CoV-2 virus or at risk of infection, i.e., as a prophylactic agent.

[0053]

[0054]

[0055] 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, as described herein:

[0056]

[0057] Wherein:

[0058] X is selected from C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 3 hydroxyalkyl; and

[0059] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 as defined herein.

[0060] In one embodiment, a compound of Formula III for treating or preventing 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:

[0061]

[0062]

[0063] 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 SARS-CoV-2 virus in a host in need thereof, as described herein:

[0064]

[0065] or a pharmaceutically acceptable salt thereof, wherein:

[0066] X is selected from C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 3 hydroxyalkyl; and

[0067] R 1 , R 2 , R 3 , R 4a , R 4b , and R 5 are as defined herein.

[0068] In one embodiment, a compound of Formula IV for treating or preventing 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:

[0069]

[0070]

[0071] 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:

[0072]

[0073] or a pharmaceutically acceptable salt thereof, wherein:

[0074] Y and Y' are independently selected from Cl and F; and

[0075] R 1 R 2 R 3 R 4a R 4b and R 5 are as defined herein.

[0076] Non-limiting examples of the compound of formula V include

[0077]

[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] wherein

[0082] R 6 is selected from hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1-6 alkyl and -CH 2 -O-R 6A , and in an alternative embodiment, -C(O)NR 6B R 6C ;

[0083] R 6A is selected from hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl (e.g., -CHCl 2 , -CCl 3 , -CH 2 Cl, -CF 3, -CHF 2 , -CH 2 F), aryl and aryl(C 1-6 alkyl)-, wherein the aryl is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl. In an alternative embodiment, R 6A is 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 optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl;

[0085] R 7 is NH 2 , 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, C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 , CF 2 , CH 3 , CF 2 , CF 3 , and CH 2Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 hydroxyalkyl and halogen (including Cl and F), and in an alternative embodiment, Z is C 1-4 alkyl; and

[0089] R 1 ,R 2 ,R 3 ,R 4a ,R 4b ,and R 5 as defined herein.

[0090] R 6 Non-limiting examples of

[0091]

[0092] R 6 Other non-limiting examples of:

[0093]

[0094] R 6 Other non-limiting examples of:

[0095]

[0096] R 6 Other non-limiting examples of:

[0097]

[0098]

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

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] The present invention also encompasses the use of the compounds of Formula VII for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0106]

[0107] wherein

[0108] B is selected from

[0109]

[0110] R 6 selected from hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1-6 alkyl, and -CH 2 -O-R 6A , and in an alternative embodiment, -C(O)NR 6B R 6C ;

[0111] R 6A is selected from hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl (e.g., -CHCl 2 , -CCl 3 , -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 F), aryl, and aryl(C 1-6 alkyl)-, wherein the aryl is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl, and in an alternative embodiment, R 6A is selected from C 1-20 alkyl and C 2-20 alkenyl;

[0112] 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 the C 1-20 alkyl, C 2-20 alkenyl, aryl, aryl(C 1-6 alkyl)-, heteroaryl, and heteroarylalkyl may optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;

[0113] R 7 is NH 2 , H, or -NR 8 R 9 ;

[0114] R8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0115] Y is selected from F and Cl;

[0116] Z is selected from methyl, C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 hydroxyalkyl and halogen (including Cl and F), and in an alternative embodiment, Z is C 1-4 alkyl; and

[0117] R 40 is selected from H, C 1-3 alkoxy, C 1-3 alkyl, N 3 , CN and halogen (including Cl and F);

[0118] R 41 is selected from H, C 1-3 alkyl (including methyl) and halogen (including Cl, F and Br);

[0119] R 42a and R 42b are independently selected from C 1-3 alkyl (including methyl), NH 2 , H, -NR 8 R 9 and -C(O)NR 8 R 9 ; and

[0120] R 1 , R2 ,R 3 ,R 4a ,R 4b ,and R 5 as defined herein.

[0121] In one embodiment, the present invention further includes compounds of Formula VIIa, Formula VIIb, Formula VIIc, and Formula VIId:

[0122]

[0123]

[0124] Non-limiting examples of B include:

[0125]

[0126] Non-limiting examples of the compounds of Formula VII include:

[0127]

[0128]

[0129] 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 , wherein 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:

[0130]

[0131] wherein

[0132] R 10 is selected from and R 10A ;

[0133] R 10A is a stable phosphate prodrug that can be metabolized in vivo to a monophosphate, diphosphate, or triphosphate;

[0134] R 11 is selected from hydrogen and R 1 ; and

[0135] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C6 Alkyl

[0136] Non-limiting examples of compounds of Formula VIII, Formula IX or Formula X include:

[0137]

[0138]

[0139] Other non-limiting examples of compounds of Formula VIII, Formula IX or Formula X include:

[0140]

[0141]

[0142] The phosphorus in any of the formulas described herein can be chiral and can thus be provided as the R or S enantiomer or a mixture thereof, including a racemic mixture. The compound is typically at least 90% free of the opposite enantiomer and can be at least 95%, 96%, 97%, 98%, 99% or even 100% free of the opposite enantiomer. Unless otherwise stated, the compound is at least 90% free of the opposite enantiomer. For example, the description of Compound 1 does not consider the stereochemistry at the phosphorus atom (which is chiral). Compound 1 can be used in racemic form or in any desired ratio of the Rp- and Sp-enantiomers of the compound, including enantiomerically enriched materials up to 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 can be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Rp-enantiomer. Alternatively, Compound 1B can be at least 90%, 95%, 98%, 99% or even 100% free of the opposite Sp-enantiomer.

[0143] Similarly, the description of compound 2 does not consider 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 enantiomers. 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.

[0144] Unless otherwise stated, 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 with respect to the stereochemistry at the phosphorus atom are at least 90% free of the opposite enantiomer.

[0145] Compounds, compositions, dosage forms and methods are provided 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, 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 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 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.

[0146] 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 a non-limiting embodiment, the loading dose is 1100 mg / day (free base) (i.e., 1200 mg / day of the hemisulfate of compound 1) and the maintenance dose is 550 mg / day (free base) (i.e., 600 mg / day of the hemisulfate). 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.

[0147] 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, 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, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered in a 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, a dose of at least 1400 mg or at least 1500 mg.

[0148] 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, 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.

[0149] 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, 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.

[0150] 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, is administered twice daily in a dosage form of about 550 mg.

[0151] 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, is administered twice daily in a dosage form of about 600 mg.

[0152] 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, is administered twice daily in a dosage form of about 550 mg for at least five days, optionally in combination with standard of care. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily in a dosage form of about 550 mg for at least five days, optionally in combination with standard of care. In one example, Compound 1 is Compound 1A. In one example, Compound 1 is Compound 1B.

[0153] 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, is administered twice daily in a dosage form of about 600 mg for at least several days, optionally in combination with standard of care. In one embodiment, Compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily in a dosage form of about 600 mg for at least five days, optionally in combination with standard of care. In one example, Compound 2 is Compound 2A. In one example, Compound 2 is Compound 2B.

[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, is administered twice daily in a dosage form of about 550 mg for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more days, optionally in combination with standard of care. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily in a dosage form of about 550 mg for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 days or more, optionally in combination with standard of care.

[0155] 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, is administered twice daily in a dosage form of about 600 mg for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more days, optionally in combination with standard of care. In one embodiment, Compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily in a dosage form of about 600 mg for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 days or more, optionally in combination with standard of care.

[0156] 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 as an initial dose (or loading dose) followed by a maintenance dose, wherein the loading dose is determined by the physician at their discretion based on the severity of the disease presentation and the size of the patient. In certain embodiments, the loading dose is about or at least 1.5-fold, about or at least 2-fold, about or at least 2.5-fold, or about or at least 3-fold greater than the maintenance dose. In one embodiment, the loading dose is administered one, two, three, four or more times before the first maintenance dose and may be administered once, twice, three or four times per day as directed by the physician.

[0157] 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 at 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 may 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, the maintenance dose being taken once, twice or three times per day. In one embodiment, the maintenance dose is taken twice per day and optionally for more than 1, 2, 3 or 4 days. In one embodiment, the maintenance dose is then administered 1, 2 or 3 times per day for at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days or more.

[0158] 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, the dose being taken once, twice or three times per day.

[0159] 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 daily. 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 daily. 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 example, compound 2 is compound 2A. In one embodiment, compound 2 is compound 2B.

[0160] In one embodiment, compound 1 is administered at a dose of about 550 mg and the dose is taken twice daily. In one example, compound 1 is compound 1A. In one example, compound 1 is compound 1B.

[0161] In one embodiment, compound 2 is administered at a dose of about 600 mg and the dose is taken twice daily. In one example, compound 2 is compound 2A. In one example, compound 2 is compound 2B.

[0162] In certain embodiments, depending on the need to treat an infection, the methods of the invention include administering a compound as described herein, such as 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, once, twice, three times, four times, or more times daily. 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 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 health care provider. Alternatively, the compound can be administered for a period of time suitable to avoid an infection or reduce the severity of an infection in a human or other animal at risk of infection.

[0163] In one embodiment, the compounds of the invention are administered indefinitely until the risk of infection or reinfection no longer exists. 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 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, a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X or formula XIII or a pharmaceutically acceptable salt thereof is administered once, twice, three times, four times or more times a day.

[0164] In another alternative embodiment, a method of preventing transmission is provided, which comprises administering to a person in need an effective amount of one of the compounds described herein for a sufficient length of time prior to exposure to a high-risk situation, including during travel or a public event or meeting, or if the host is in a high-risk group, including, for example, prior to an infectious situation, and then during and optionally for up to 3, 5, 7, 10, 12, 14 days or more after potential exposure. Alternatively, a selected compound as described herein can be administered indefinitely at a maintenance dose to protect a person in a high-risk environment.

[0165] The invention also includes compounds of formula XI and formula XII:

[0166]

[0167] or a pharmaceutically acceptable salt thereof

[0168] wherein

[0169] R 12a and R 12b are oxygen protecting groups and at least one of R 12a and R 12b is -C(O)OC 1-6 alkyl, such as -C(O)OtBu, or -C(O)O-benzyl, wherein the alkyl and benzyl can optionally be substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl.

[0170] In one embodiment, R 12a is -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12b is an oxygen protecting group which is an ester, ether or silyl ether moiety when attached to oxygen. In another embodiment, R 12b is -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12ais an oxygen protecting group which is an ester, ether or silyl ether moiety when attached to oxygen. In one embodiment, R 12a and R 12b are both -C(O)OC 1-6 alkyl, such as -C(O)OtBu. In one example, R 12a and R 12b are both -C(O)O-benzyl.

[0171] In one embodiment, the compound of formula XII is of formula XIIA:

[0172]

[0173] In one embodiment, the compound of formula XII is of formula XIIB:

[0174]

[0175] Accordingly, the present invention includes the following features:

[0176] (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;

[0177] (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;

[0178] (c) The method of (b) for preventing or minimizing reinfection with the SARS-CoV-2 virus or infection with COVID-19 in a host in need thereof;

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

[0180] (e) The method of (a)-(c), wherein the compound is compound 1A;

[0181] (f) The method of (a)-(c), wherein the compound is compound 1B;

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

[0183] (h) The method of (a)-(c), wherein the compound is compound 2A;

[0184] (i) The method of (a)-(c), wherein the compound is Compound 2B;

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

[0186] (k) The method of (a)-(c), wherein the compound is Compound 3A;

[0187] (l) The method of (a)-(c), wherein the compound is Compound 3B;

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

[0189] (n) The method of (a)-(c), wherein the compound is Compound 4A;

[0190] (o) The method of (a)-(c), wherein the compound is Compound 4B;

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

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

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

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

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

[0196] (u) The method of (a)-(c), wherein the compound is of Formula IIIf;

[0197] (v) The method of (a)-(c), wherein the compound is of Formula IVa;

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

[0199] (x) The method of (a)-(c), wherein the compound is of Formula IVc;

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

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

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

[0203] (bb) A method of (a)-(c), wherein the compound is of formula V;

[0204] (cc) A method of (a)-(c), wherein the compound is of formula VI;

[0205] (dd) A method of (a)-(c), wherein the compound is of formula VII;

[0206] (ee) A method of (a)-(c), wherein the compound is of formula VIII, formula IX or formula X;

[0207] (ff) 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 treating COVID-19 infection caused by the SARS-CoV-2 virus in a host in need thereof, optionally in a pharmaceutically acceptable carrier;

[0208] (gg) 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 preventing or minimizing (relative to untreated) infection caused by the SARS-CoV-2 virus in a host in need thereof, optionally in a pharmaceutically acceptable carrier;

[0209] (hh) The compound of (gg), for preventing reinfection caused by the SARS-CoV-2 virus in a host in need thereof;

[0210] (ii) 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 use in the manufacture of a medicament for treating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus;

[0211] (jj) 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 use in the manufacture of a medicament for preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof;

[0212] (kk) The use of (jj), for preventing reinfection caused by the SARS-CoV-2 virus in a host in need thereof;

[0213] (ll) Any of the above embodiments, wherein the pharmaceutically acceptable carrier is a dosage form suitable for oral administration;

[0214] A dosage form of (mm)(ll), wherein the dosage form is a solid dosage form;

[0215] A dosage form of (nn)(mm), which is in the form of a tablet;

[0216] A dosage form of (oo)(mm), which is in the form of a capsule;

[0217] A dosage form of (pp)(ll), wherein the dosage form is a liquid dosage form;

[0218] A dosage form of (qq)(pp), which is in the form of a solution or suspension;

[0219] Embodiment (rr) of any one of (a)-(kk), wherein the pharmaceutically acceptable carrier is a dosage form suitable for intravenous administration;

[0220] Embodiment (ss) of any one of (a)-(kk), wherein the pharmaceutically acceptable carrier is a dosage form suitable for parenteral administration;

[0221] 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 a day;

[0222] 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 a day;

[0223] 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.

[0224] 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;

[0225] 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 at least once, at least twice or at least three times a day indefinitely until the risk of infection no longer exists;

[0226] (yy) 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 at a dose of at least about 400 mg;

[0227] (zz) 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 at a dose of at least about 500 mg;

[0228] (aaa) 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 at a dose of at least about 550 mg;

[0229] (bbb) 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 at a dose of at least about 600 mg;

[0230] (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;

[0231] (ddd) A method for treating the 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 and then at a maintenance dose of at least about 550 mg twice a day;

[0232] (eee) Embodiment (ccc or ddd), wherein Compound 1 is Compound 1A;

[0233] (fff) Embodiment (ccc or ddd), wherein Compound 1 is Compound 1B;

[0234] (ggg) A method for 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;

[0235] (hhh) A method for 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 and then at a maintenance dose of at least about 600 mg twice a day;

[0236] (iii) Embodiment (ggg or hhh), wherein Compound 2 is Compound 2A;

[0237] (jjj) Embodiment (ggg or hhh), wherein Compound 2 is Compound 2B;

[0238] (kkk) A compound of Formula II or a pharmaceutically acceptable salt thereof;

[0239] (lll) Compound 4 as described herein or a pharmaceutically acceptable salt;

[0240] (mmm) Compound 4A and Compound 4B as described herein;

[0241] (nnn) A pharmaceutical formulation comprising an effective amount of a compound of Formula II, optionally in a pharmaceutically acceptable carrier.

[0242] (ooo) A compound of Formula XI or Formula XII;

[0243] (ppp) A compound of Formula XIIA;

[0244] (qqq) A compound of Formula XIIB;

[0245] (rrr) A compound of Formula VII;

[0246] (sss) A compound of Formula VIIa;

[0247] (ttt) A compound of Formula VIIb;

[0248] (uuu) A compound of Formula VIIc;

[0249] (vvv) A compound of Formula VIId; and

[0250] (www) A pharmaceutical composition comprising an effective amount of a compound of Formula VIIa, Formula VIIb, Formula VIIc or Formula VIId. Description of the Drawings

[0251] Figure 1 Is a graph of the concentrations of triphosphate compounds 1 - 6 in human bronchial and nasal epithelial cells after exposure to 10 μM of Compound 1A, as described in Example 7. The half-lives of Compounds 1 - 6 in bronchial cells and nasal cells are 39 hours and 38 hours, respectively. The x-axis is the time after washing measured in hours, and the y-axis is the concentration of Compounds 1 - 6 in pmol / million cells.

[0252] Figure 2Graph comparing the levels of triphosphate compounds 1-6 in human bronchial epithelial cells after 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 post-rinse time measured in hours, and the y-axis is the concentration of compounds 1-6 in pmol / million cells.

[0253] Figure 3 Graph comparing the levels of triphosphate compounds 1-6 in human nasal epithelial cells after 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 post-rinse time measured in hours, and the y-axis is the concentration of compounds 1-6 in pmol / million cells.

[0254] Figure 4 Graph showing the mean plasma profile of compound 1A in monkeys dosed orally with compound 2A at a dose of 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The x-axis is the post-rinse time measured in hours, and the y-axis is the plasma concentration of compound 1A in ng / mL.

[0255] Figure 5 Graph showing the mean plasma profile of metabolite compounds 1-2 in monkeys dosed orally with compound 2A at a dose of 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The x-axis is the post-rinse time measured in hours, and the y-axis is the plasma concentration of compounds 1-2 in ng / mL.

[0256] Figure 6 Graph showing the mean plasma profile of triphosphate surrogate metabolite compounds 1-7 in monkeys dosed orally with compound 2A at a dose of 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The x-axis is the post-rinse time measured in hours, and the y-axis is the plasma concentration of compounds 1-7 in ng / mL.

[0257] Figure 7AGraph of the concentrations of triphosphate compounds 1-6 in the lung, kidney, and liver tissues of monkeys dosed orally with compound 2A at a dose of 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The half-lives in the lung, kidney, and liver are 9.4 hours, 8.0 hours, and 4.3 hours, respectively. The x-axis is the time after dosing measured in hours, and the y-axis is the tissue concentration of compounds 1-6 measured in ng / g.

[0258] Figure 7B Graph of the concentrations of triphosphate compounds 1-6 in the lung, kidney, and liver tissues of monkeys dosed orally with compound 2A at a dose of 30 mg / kg twice daily (BID) for 3 days, as described in Example 8. The tissue concentrations of compounds 1-6 are shown at 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.

[0259] Figure 8 Graph of the levels of triphosphate compounds 1-6 in hepatocytes incubated with compound 2A, as described in Example 9 and previously by Good, S.S. et al. (2020 PLoS ONE 15(1):e0227104). The concentration in human hepatocytes is 7-fold higher than that in monkeys. The x-axis is the incubation time measured in hours, and the y-axis is the concentration of compounds 1-6 measured in pmol / 10 6 cells.

[0260] Figure 9 Simulation of the intracellular concentrations 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 compounds 1-7, the plasma surrogate for intracellular triphosphate compounds 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 the time measured in days and the y-axis is the simulated lung compound 1-6 concentration measured in μM.

[0261] Figure 10is a simulation of the intracellular concentrations of Compounds 1-6 in human lung tissue using two methods, as described in Example 10. The solid lines represent the predicted lung concentrations of the active triphosphate metabolites of Compounds 1-6 after correction for the lung-liver concentration ratio of 1.6 for Compounds 1-6. The dashed lines represent the predicted lung concentrations of the active triphosphate metabolites of Compounds 1-6 after correction for the lung to Compound 1-7 plasma ratio of 1.2. The horizontal lines represent the EC 90 (0.47 μM) of Compound 1A against SARS-CoV-2 in vitro HAE cells. The x-axis is time measured in days and the y-axis is the simulated lung Compound 1-6 concentration measured in μM.

[0262] Figure 11 is an illustration of a Compound of Formula I, which may also be administered as a pharmaceutically acceptable salt. DETAILED DESCRIPTION Detailed Description of the Invention

[0264] Disclosed herein is a method of treating or preventing Coronavirus Disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a host in need thereof (e.g., a human), comprising administering an effective amount of a Compound of Formula I or a pharmaceutically acceptable salt thereof:

[0265]

[0266]

[0267] wherein

[0268] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0269] 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(C 1 -C 4 alkyl)-, heteroaryl or heteroalkyl;

[0270] R 3 is hydrogen or C 1-6 alkyl (including methyl, ethyl, propyl, and isopropyl);

[0271] R4a and R 4b are independently selected from hydrogen, C 1-6 alkyl (including methyl, ethyl, propyl, and isopropyl) and C 3-7 cycloalkyl; and

[0272] 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(C 1 -C 4 alkyl)-, aryl, heteroaryl, or heteroalkyl.

[0273] Non-limiting examples of the compound of Formula I include Compound 1 and Compound 2. In one embodiment, the compound is administered as the S-enantiomer, such as Compound 1A. In one embodiment, the compound is administered as the R-enantiomer, such as Compound 1B. In one embodiment, the compound of Formula I is Compound 2, Compound 2A, or Compound 2B.

[0274]

[0275]

[0276]

[0277] Alternative configurations of Compound 1 or a pharmaceutically acceptable salt thereof that can be used include:

[0278]

[0279] Alternative configurations of Compound 2 that can be used include:

[0280]

[0281] Other alternative configurations of Compound 1 or a pharmaceutically acceptable salt thereof, such as Compound 2, that can be used include:

[0282]

[0283] Non-limiting examples of the compound of Formula I include:

[0284]

[0285]

[0286]

[0287] or a pharmaceutically acceptable salt thereof.

[0288] Other non-limiting examples of the compound of formula I include:

[0289]

[0290]

[0291]

[0292]

[0293] or a pharmaceutically acceptable salt thereof.

[0294] Other non-limiting examples of the compound of formula I include:

[0295]

[0296]

[0297]

[0298] or a pharmaceutically acceptable salt thereof.

[0299] 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:

[0300]

[0301] or a pharmaceutically acceptable salt thereof, wherein:

[0302] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0303] 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(C 1 -C 4 alkyl)-, heteroaryl or heteroalkyl;

[0304] R 3 is hydrogen or C 1-6Alkyl (including methyl, ethyl, propyl and isopropyl);

[0305] 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

[0306] 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(C 1 -C 4 alkyl)-, aryl, heteroaryl or heteroalkyl.

[0307] In one embodiment, a compound of formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof, which has COVID-19, or is at risk of infection with the SARS-CoV-2 virus, i.e., as a prophylactic agent.

[0308] Non-limiting examples of the compound of formula II include Compound 3 and Compound 4. In one embodiment, the compound is administered as the S-enantiomer, such as Compound 3A and 4A. In one embodiment, the compound is administered as the R-enantiomer, such as Compound 3B and 4B.

[0309]

[0310]

[0311]

[0312] Alternative configurations of Compound 3 or a pharmaceutically acceptable salt thereof include:

[0313]

[0314] Other alternative configurations of Compound 4 include:

[0315]

[0316]

[0317] Other alternative configurations of Compound 3 or a pharmaceutically acceptable salt thereof, such as Compound 4, that can be used include:

[0318]

[0319] Non-limiting examples of the compound of formula II include:

[0320]

[0321]

[0322]

[0323] or a pharmaceutically acceptable salt thereof.

[0324] Other non-limiting examples of the compound of formula II include:

[0325]

[0326]

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] Other non-limiting examples of the compound of formula II include:

[0330]

[0331]

[0332]

[0333]

[0334] or a pharmaceutically acceptable salt thereof.

[0335] The present invention also includes the use of an effective amount of the compound of formula III in a host in need thereof for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus:

[0336]

[0337] or a pharmaceutically acceptable salt thereof, wherein:

[0338] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0339] R 2 is hydrogen, C 1-6Alkyl (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(C 1 -C 4 alkyl)-, heteroaryl or heteroalkyl;

[0340] R 3 is hydrogen or C 1-6 alkyl (including methyl, ethyl, propyl and isopropyl);

[0341] 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

[0342] 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(C 1 -C 4 alkyl)-, aryl, heteroaryl or heteroalkyl;

[0343] X is selected from C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 3 hydroxyalkyl.

[0344] 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:

[0345]

[0346] or a pharmaceutically acceptable salt thereof.

[0347] In one embodiment of Formula IIIa, R 1 is methyl.

[0348] In one embodiment of Formula IIIa, R 1 is cyclopropyl.

[0349] In one embodiment of Formula IIIa, R 2 is phenyl.

[0350] In one embodiment of Formula IIIa, R 2 is naphthyl.

[0351] In one embodiment of Formula IIIa, R 4a is hydrogen and R 4b is methyl.

[0352] In one embodiment of Formula IIIa, R 5 is isopropyl.

[0353] In one embodiment of Formula IIIa, the compound is the S p -isomer and the aminophosphate is in the L-configuration.

[0354] In one embodiment of Formula IIIa, the compound is the R p -isomer and the aminophosphate is in the L-configuration.

[0355] In one embodiment of Formula IIIa, the pharmaceutically acceptable salt is the hemisulfate.

[0356] Non-limiting examples of the compound of Formula IIIa include:

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363] Other non-limiting examples of the compound of formula IIIa include:

[0364]

[0365] 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:

[0366]

[0367] or a pharmaceutically acceptable salt thereof.

[0368] In one embodiment of formula IIIb, R 1 is methyl.

[0369] In one embodiment of formula IIIb, R 1 is cyclopropyl.

[0370] In one embodiment of formula IIIb, R 2 is phenyl.

[0371] In one embodiment of formula IIIb, R 2 is naphthyl.

[0372] In one embodiment of formula IIIb, R 4a is hydrogen and R 4b is methyl.

[0373] In one embodiment of formula IIIb, R 5 is isopropyl.

[0374] In one embodiment of formula IIIb, the compound is the Sp-isomer and the aminophosphate is in the L-configuration.

[0375] In one embodiment of formula IIIb, the compound is the Rp-isomer and the aminophosphate is in the L-configuration.

[0376] In one embodiment of formula IIIb, the pharmaceutically acceptable salt is the hemisulfate.

[0377] Non-limiting examples of the compound of formula IIIb include:

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385] Other non-limiting examples of the compound of formula IIIb include:

[0386]

[0387] 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:

[0388]

[0389] or a pharmaceutically acceptable salt thereof.

[0390] In one embodiment of formula IIIc, R 1 is methyl.

[0391] In one embodiment of formula IIIc, R 1 is cyclopropyl.

[0392] In one embodiment of formula IIIc, R 2 is phenyl.

[0393] In one embodiment of formula IIIc, R 2 is naphthyl.

[0394] In one embodiment of formula IIIc, R 4a is hydrogen and R 4b is methyl.

[0395] In one embodiment of formula IIIc, R 5 is isopropyl.

[0396] In one embodiment of formula IIIc, the compound is the Sp-isomer and the aminophosphate is in the L-configuration.

[0397] In one embodiment of formula IIIc, the compound is the Rp-isomer and the aminophosphate is in the L-configuration.

[0398] In one embodiment of formula IIIc, the pharmaceutically acceptable salt is the hemisulfate salt.

[0399] Non-limiting examples of the compound of formula IIIc include:

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407] Other non-limiting examples of the compound of formula IIIc include:

[0408]

[0409]

[0410] 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:

[0411]

[0412] or a pharmaceutically acceptable salt thereof.

[0413] In one embodiment of formula IIId, R 1 is methyl.

[0414] In one embodiment of formula IIId, R 1 is cyclopropyl.

[0415] In one embodiment of formula IIId, R 2 is phenyl.

[0416] In one embodiment of formula IIId, R 2 is naphthyl.

[0417] In one embodiment of formula IIId, R 4a is hydrogen and R 4b is methyl.

[0418] In one embodiment of formula IIId, R 5 is isopropyl.

[0419] In one embodiment of formula IIId, the compound is the Sp-isomer and the aminophosphate is in the L-configuration.

[0420] In one embodiment of formula IIId, the compound is the Rp-isomer and the aminophosphate is of the L-configuration.

[0421] In one embodiment of formula IIId, the pharmaceutically acceptable salt is the hemisulfate salt.

[0422] Non-limiting examples of the compound of formula IIId include:

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] Other non-limiting examples of the compound of formula IIId include:

[0431]

[0432] 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:

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] In one embodiment of formula IIIe, R 1 is methyl.

[0436] In one embodiment of formula IIIe, R 1 is cyclopropyl.

[0437] In one embodiment of formula IIIe, R 2 is phenyl.

[0438] In one embodiment of formula IIIe, R 2 is naphthyl.

[0439] In one embodiment of formula IIIe, R 4a is hydrogen and R 4b is methyl.

[0440] In one embodiment of formula IIIe, R 5 is isopropyl.

[0441] In one embodiment of formula IIIe, the compound is the Sp-isomer and the phosphoroamidate is of the L-configuration.

[0442] In one embodiment of formula IIIe, the compound is the Rp-isomer and the phosphoroamidate is of the L-configuration.

[0443] In one embodiment of formula IIIe, the pharmaceutically acceptable salt is the hemisulfate.

[0444] Non-limiting examples of the compound of formula IIIe include:

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452] Other non-limiting examples of the compound of formula IIIe include:

[0453]

[0454]

[0455] 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 the compound of formula IIIf:

[0456]

[0457] or a pharmaceutically acceptable salt thereof.

[0458] In one embodiment of formula IIIf, R 1 is methyl.

[0459] In one embodiment of formula IIIf, R 1 is cyclopropyl.

[0460] In one embodiment of formula IIIf, R2 is phenyl.

[0461] In one embodiment of formula IIIf, R 2 is naphthyl.

[0462] In one embodiment of formula IIIf, R 4a is hydrogen and R 4b is methyl.

[0463] In one embodiment of formula IIIf, R 5 is isopropyl.

[0464] In one embodiment of formula IIIf, the compound is the Sp-isomer and the aminophosphate is of the L-configuration.

[0465] In one embodiment of formula IIIf, the compound is the Rp-isomer and the aminophosphate is of the L-configuration.

[0466] In one embodiment of formula IIIf, the pharmaceutically acceptable salt is the hemisulfate.

[0467] Non-limiting examples of compounds of formula IIIf include:

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475] Other non-limiting examples of compounds of formula IIIe include:

[0476]

[0477]

[0478] Other non-limiting examples of compounds of formula III include:

[0479]

[0480]

[0481] 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:

[0482]

[0483] or a pharmaceutically acceptable salt thereof, wherein:

[0484] X is selected from C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 2, CF 3 3, CH 2 2CF 3 3, CH 2 2CHF 2 2, CH 2 2CH 2 2F, CF 2 2CH 3 3, CF 2 2CF 3 3, and CH 2 2Cl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 3 hydroxyalkyl; and

[0485] R 1 1, R 2 2, R 3 3, R 4a 4, R 4b 5, and R 5 6 are as defined herein.

[0486] In one embodiment, the compound of Formula IV for treating or preventing 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:

[0487]

[0488]

[0489] 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 IVa:

[0490]

[0491] or a pharmaceutically acceptable salt thereof.

[0492] In one embodiment of Formula IVa, R 1 is methyl.

[0493] In one embodiment of Formula IVa, R 1 is cyclopropyl.

[0494] In one embodiment of Formula IVa, R 2 is phenyl.

[0495] In one embodiment of Formula IVa, R 2 is naphthyl.

[0496] In one embodiment of Formula IVa, R 4a is hydrogen and R 4b is methyl.

[0497] In one embodiment of Formula IVa, R 5 is isopropyl.

[0498] In one embodiment of Formula IVa, the compound is the Sp-isomer and the aminophosphate is of the L-configuration.

[0499] In one embodiment of Formula IVa, the compound is the Rp-isomer and the aminophosphate is of the L-configuration.

[0500] Non-limiting examples of compounds of Formula IVa include:

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507] 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:

[0508]

[0509] or a pharmaceutically acceptable salt thereof.

[0510] In one embodiment of formula IVb, R 1 is methyl.

[0511] In one embodiment of formula IVb, R 1 is cyclopropyl.

[0512] In one embodiment of formula IVb, R 2 is phenyl.

[0513] In one embodiment of formula IVb, R 2 is naphthyl.

[0514] In one embodiment of formula IVb, R 4a is hydrogen and R 4b is methyl.

[0515] In one embodiment of formula IVb, R 5 is isopropyl.

[0516] In one embodiment of formula IVb, the compound is the Sp* isomer and the phosphoramidate is of the L-configuration.

[0517] In one embodiment of formula IVb, the compound is the Rp-isomer and the phosphoramidate is of the L-configuration.

[0518] Non-limiting examples of the compound of formula IVb include:

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] 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:

[0526]

[0527] or a pharmaceutically acceptable salt thereof.

[0528] In one embodiment of formula IVc, R 1 is methyl.

[0529] In one embodiment of formula IVc, R 1 is cyclopropyl.

[0530] In one embodiment of formula IVc, R 2 is phenyl.

[0531] In one embodiment of formula IVc, R 2 is naphthyl.

[0532] In one embodiment of formula IVc, R 4a is hydrogen and R 4b is methyl.

[0533] In one embodiment of formula IVc, R 5 is isopropyl.

[0534] In one embodiment of formula IVc, the compound is the Sp-isomer and the aminophosphate is in the L-configuration.

[0535] In one embodiment of formula IVc, the compound is the Rp-isomer and the aminophosphate is in the L-configuration.

[0536] In one embodiment of formula IVc, the pharmaceutically acceptable salt is the hemisulfate salt.

[0537] Non-limiting examples of the compound of formula IVc include:

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545] 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:

[0546]

[0547] or a pharmaceutically acceptable salt thereof.

[0548] In one embodiment of formula IVd, R 1 is methyl.

[0549] In one embodiment of formula IVd, R 1 is cyclopropyl.

[0550] In one embodiment of formula IVd, R 2 is phenyl.

[0551] In one embodiment of formula IVd, R 2 is naphthyl.

[0552] In one embodiment of formula IVd, R 4a is hydrogen and R 4b is methyl.

[0553] In one embodiment of formula IVd, R 5 is isopropyl.

[0554] In one embodiment of formula IVd, the compound is the Sp-isomer and the aminophosphate is in the L-configuration.

[0555] In one embodiment of formula IVd, the compound is the Rp-isomer and the aminophosphate is in the L-configuration.

[0556] In one embodiment of formula IVd, the pharmaceutically acceptable salt is the hemisulfate.

[0557] Non-limiting examples of the compound of formula IVd include:

[0558]

[0559]

[0560]

[0561]

[0562] 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:

[0563]

[0564] or a pharmaceutically acceptable salt thereof.

[0565] In one embodiment of formula IVe, R 1 is methyl.

[0566] In one embodiment of formula IVe, R 1 is cyclopropyl.

[0567] In one embodiment of formula IVe, R 2 is phenyl.

[0568] In one embodiment of formula IVe, R 2 is naphthyl.

[0569] In one embodiment of formula IVe, R 4a is hydrogen and R 4b is methyl.

[0570] In one embodiment of formula IVe, R 5 is isopropyl.

[0571] In one embodiment of formula IVe, the compound is the Sp-isomer and the aminophosphate is of the L-configuration.

[0572] In one embodiment of formula IVe, the compound is the Rp-isomer and the aminophosphate is of the L-configuration.

[0573] In one embodiment of formula IVe, the pharmaceutically acceptable salt is the hemisulfate salt.

[0574] Non-limiting examples of compounds of formula IVe include:

[0575]

[0576]

[0577]

[0578]

[0579]

[0580] In one embodiment, 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 is a compound of formula IVf:

[0581]

[0582] or a pharmaceutically acceptable salt thereof.

[0583] In one embodiment of formula IVf, R 1 is methyl.

[0584] In one embodiment of formula IVf, R 1 is cyclopropyl.

[0585] In one embodiment of formula IVf, R 2 is phenyl.

[0586] In one embodiment of formula IVf, R2 is naphthyl.

[0587] In one embodiment of formula IVf, R 4a is hydrogen and R 4b is methyl.

[0588] In one embodiment of formula IVf, R 5 is isopropyl.

[0589] In one embodiment of formula IVf, the compound is the Sp-isomer and the aminophosphate is of the L-configuration.

[0590] In one embodiment of formula IVf, the compound is the Rp-isomer and the aminophosphate is of the L-configuration.

[0591] In one embodiment of formula IVf, the pharmaceutically acceptable salt is the hemisulfate. Non-limiting examples of compounds of formula IVf include:

[0592]

[0593]

[0594]

[0595]

[0596] The present invention also includes the use of compounds of formula V in the treatment or prevention of COVID-19 disease caused by the SARS-CoV-2 virus as described herein:

[0597]

[0598] or a pharmaceutically acceptable salt thereof, wherein:

[0599] Y and Y' are independently selected from Cl and F; and

[0600] R 1 、R 2 、R 3 、R 4a 、R 4b and R 5 are as defined herein.

[0601] In one embodiment of formula IV, Y' is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R5 is C 1 -C 6 alkyl group.

[0602] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl group.

[0603] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, and R 5 is C 1 -C 6 alkyl group.

[0604] In one embodiment of Formula IV, Y' is F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl group.

[0605] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, and R 5 is C 1 -C 6 alkyl group.

[0606] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C1 -C 6 alkyl

[0607] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl

[0608] In one embodiment of Formula IV, Y' is Cl, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl

[0609] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl

[0610] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl

[0611] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R5 is C 1 -C 6 alkyl group.

[0612] In one embodiment of Formula IV, Y' is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl group.

[0613] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, R 5 is C 1 -C 6 alkyl group.

[0614] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl group.

[0615] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, and R 5 is C 1 -C 6 alkyl group.

[0616] In one embodiment of Formula IV, Y' is F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C1 -C 6 alkyl

[0617] Non-limiting examples of the compound of Formula V include

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626] Non-limiting examples of the compound of Formula V include:

[0627]

[0628]

[0629] The present invention also includes the use of the compound of Formula VI for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0630]

[0631] wherein

[0632] R 6 is selected from hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1-6 alkyl and -CH 2 -O-R 6A , in an alternative embodiment, -C(O)NR 6B R 6C ;

[0633] R 6A is selected from hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl (e.g., -CHCl 2 , -CCl 3 , -CH 2 Cl, -CF 3 , -CHF2 , -CH 2 F), aryl and aryl(C 1-6 alkyl)-, where the aryl is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl. In an alternative embodiment, R 6A is selected from C 1-20 alkyl and C 2-20 alkenyl;

[0634] 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, where C 1-20 alkyl, C 2-20 alkenyl, aryl, aryl(C 1-6 alkyl)-, heteroaryl, and heteroarylalkyl may optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl;

[0635] R 7 is NH 2 , H, or -NR 8 R 9 ;

[0636] R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0637] Y is selected from F and Cl;

[0638] Z is selected from methyl, C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 hydroxyalkyl and halogen (including Cl and F), and in an alternative embodiment, Z is C 1-4 alkyl; and

[0639] R 1 R 2 R 3 R 4a R 4b R 5 as defined herein.

[0640] R 6 Non-limiting examples of

[0641]

[0642] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0643] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0644] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 。

[0645] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A 。

[0646] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A 。

[0647] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0648] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0649] In one embodiment of Formula VI, Z is CH 3 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0650] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0651] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0652] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6alkyl, and R 7 is NR 8 R 9 .

[0653] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A .

[0654] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A .

[0655] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0656] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0657] In one embodiment of Formula VI, Z is CF 3 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0658] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0659] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0660] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0661] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)R 6A .

[0662] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A .

[0663] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0664] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0665] In one embodiment of Formula VI, Z is Cl, Y is F, R 1 is cyclopropyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C6 Alkyl

[0666] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0667] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0668] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0669] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C6 Alkyl, R 7 is NHC(O)R 6A .

[0670] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A .

[0671] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0672] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0673] In one embodiment of Formula VI, Z is CH 2 F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl.

[0674] In one embodiment of Formula VI, Z is CHCH 2 , Y is F, R1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R7 is NH 2 .

[0675] In one embodiment of Formula VI, Z is CH 2 CH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0676] In one embodiment of Formula VI, Z is CH 2 CH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0677] In one embodiment of Formula VI, Z is CH 2 CH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)R 6A。

[0678] In one embodiment of Formula VI, Z is CH 2 CH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A 。

[0679] In one embodiment of Formula VI, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0680] In one embodiment of Formula VI, Z is CHCH 2 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0681] In one embodiment of Formula VI, Z is CHCH 2 , Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0682] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0683] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0684] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0685] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)R 6A .

[0686] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A .

[0687] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0688] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0689] In one embodiment of Formula VI, Z is CCH, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0690] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0691] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0692] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0693] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)R 6A .

[0694] In one embodiment of Formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A .

[0695] In one embodiment of formula VI, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0696] In one embodiment of formula VI, Z is F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0697] In one embodiment of formula VI, Z is F, Y is F, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0698] In one embodiment of formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0699] In one embodiment of formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R5 is C 1 -C 6 alkyl, and R 7 is H.

[0700] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0701] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A .

[0702] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A .

[0703] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0704] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl.

[0705] In one embodiment of Formula VI, Z is CH 3 , Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0706] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0707] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0708] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0709] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)R 6A .

[0710] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A .

[0711] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0712] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0713] In one embodiment of Formula VI, Z is CF 3 , Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0714] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0715] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0716] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0717] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A .

[0718] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A .

[0719] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0720] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0721] In one embodiment of Formula VI, Z is Cl, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0722] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0723] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0724] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR8 R 9 。

[0725] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A 。

[0726] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NHC(O)OR 6A 。

[0727] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0728] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl.

[0729] In one embodiment of Formula VI, Z is CH 2 F, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0730] In one embodiment of Formula VI, Z is CHCH 2 , Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0731] In one embodiment of Formula VI, Z is CH 2 CH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0732] In one embodiment of Formula VI, Z is CH 2 CH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0733] In one embodiment of Formula VI, Z is CH2 CH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)R 6A 。

[0734] In one embodiment of Formula VI, Z is CH 2 CH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is NHC(O)OR 6A 。

[0735] In one embodiment of Formula VI, Z is CHCH 2 ,Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, R 5 is C 1 -C 6 alkyl。

[0736] In one embodiment of Formula VI, Z is CHCH 2 ,Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, and R 5 is C 1 -C 6 alkyl。

[0737] In one embodiment of Formula VI, Z is CHCH 2 ,Y is Cl, R 1 is cyclopropyl, R2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl.

[0738] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NH 2 .

[0739] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 7 is H.

[0740] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, and R 7 is NR 8 R 9 .

[0741] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1-C 4 alkyl group, R 5 is C 1 -C 6 alkyl group, and R 7 is NHC(O)R 6A .

[0742] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, R 5 is C 1 -C 6 alkyl group, and R 7 is NHC(O)OR 6A .

[0743] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl group.

[0744] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl group, and R 5 is C 1 -C 6 alkyl group.

[0745] In one embodiment of Formula VI, Z is CCH, Y is Cl, R 1 is cyclopropyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is methyl, and R 5 is C 1 -C 6 alkyl group.

[0746] Non-limiting examples of the compounds of Formula VI include:

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753] Other non-limiting examples of the compound of formula VI include:

[0754]

[0755]

[0756]

[0757]

[0758] The present invention also includes the use of the compound of formula VII for treating or preventing COVID-19 in a host in need thereof, as described herein:

[0759]

[0760] wherein

[0761] B is selected from

[0762]

[0763] R 6 is selected from hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1-6 alkyl and -CH 2 -O-R 6A , in an alternative embodiment, -C(O)NR 6B R 6C ;

[0764] R 6A is selected from hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl (e.g., -CHCl 2 , -CCl 3 , -CH 2 Cl, -CF 3 , -CHF 2 , -CH2 F), aryl and aryl(C 1-6 alkyl)-, wherein the aryl is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl. In an alternative embodiment, R 6A is selected from C 1-20 alkyl and C 2-20 alkenyl;

[0765] 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 optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl;

[0766] R 7 is NH 2 , H or -NR 8 R 9 ;

[0767] R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, -C(O)R 6A and -C(O)OR 6A ;

[0768] Y is selected from F and Cl;

[0769] Z is selected from methyl, C 1 -C 3 haloalkyl (including C 1-3 fluoroalkyl and C 1-3 chloroalkyl, such as CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CF 2 CF 3 , and CH 2 Cl), C 2 -C4 Alkenyl, C 2 -C 4 Alkynyl, C 1 -C 3 Hydroxyalkyl and halogen (including Cl and F), and in an alternative embodiment, Z is C 1-4 Alkyl;

[0770] R 40 is selected from H, C 1-3 Alkoxy, C 1-3 Alkyl, N 3 , CN and halogen (including Cl and F);

[0771] R 41 is selected from H, C 1-3 Alkyl (including methyl) and halogen (including Cl, F and Br);

[0772] R 42a and R 42b are selected from C 1-3 Alkyl (including methyl), NH 2 , H, -NR 8 R 9 and -C(O)NR 8 R 9 ; and

[0773] R 1 R 2 R 3 R 4a R 4b and R 5 as defined herein.

[0774] Non-limiting examples of B include:

[0775]

[0776] In one embodiment, the present invention also includes compounds of Formula VIIa, Formula VIIb, Formula VIIc and Formula VIId:

[0777]

[0778] In one embodiment of Formula VII, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 Alkyl, R 5 is C 1 -C6 Alkyl, R 6 is hydrogen, R 40 is hydrogen; and B is

[0779] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 . In a further embodiment, R 1 is methyl and R 7 is NH 2 .

[0780] In one embodiment of formula VIIa, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and B is

[0781] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0782] In one embodiment of formula VIIb, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R6 is hydrogen, R 40 is hydrogen; and B is

[0783] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0784] In one embodiment of formula VIIc, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; and B is

[0785] In a further embodiment, R41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0786] In one embodiment of formula VIId, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0787] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R41 is a halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0788] In one embodiment of formula VII, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0789] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 . In a further embodiment, R 1 is methyl and R 7 is NH 2 .

[0790] In one embodiment of formula VIIa, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0791] In a further embodiment, R 41 is C 1-6 alkyl and R42a is H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is C 1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0792] In one embodiment of formula VIIb, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0793] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6An alkyl group or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0794] In one embodiment of formula VIIc, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0795] In a further embodiment, R 41 is H, R 42a is NH 2 and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH3 , and R 42b is NH 2 .

[0796] In one embodiment of formula VIId, Z is CH 3 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0797] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0798] In one embodiment of formula VII, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0799] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0800] In one embodiment of formula VIIa, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0801] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 。In a further embodiment, R 41 is methyl and R 42a is NH 2 。

[0802] In one embodiment of formula VIIb, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0803] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0804] In one embodiment of formula VIIc, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0805] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42ais NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0806] In one embodiment of formula VIId, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0807] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0808] In one embodiment of formula VII, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0809] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 . In a further embodiment, R 1 is methyl and R 7 is NH 2 .

[0810] In one embodiment of formula VIIa, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0811] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0812] In one embodiment of formula VIIb, Z is Cl, Y is F, R1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0813] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0814] In one embodiment of formula VIIc, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C4 Alkyl, R 5 is C 1 -C 6 Alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0815] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0816] In one embodiment of formula VIId, Z is Cl, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40is cyano or nitro; B is

[0817] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 。In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0818] In one embodiment of formula VII, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0819] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0820] In one embodiment of formula VIIa, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C6 Alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0821] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0822] In one embodiment of formula VIIb, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0823] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0824] In one embodiment of formula VIIc, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0825] In a further embodiment, R 41 is H, R 42a is NH 2 and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0826] In one embodiment of formula VIId, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0827] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0828] In one embodiment of formula VII, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6is hydrogen, R 40 is cyano or nitro; B is

[0829] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0830] In one embodiment of formula VIIa, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0831] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 。In a further embodiment, R 41 is methyl and R 42a is NH 2 。

[0832] In one embodiment of formula VIIb, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R40 is cyano or nitro; B is

[0833] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0834] In one embodiment of formula VIIc, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0835] In a further embodiment, R 41 is H, R42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0836] In one embodiment of formula VIId, Z is CH 2 F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0837] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41is a halogen and R 42a is -C(O)NHCH 3 。In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0838] In one embodiment of formula VII, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0839] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0840] In one embodiment of formula VIIa, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0841] In a further embodiment, R 41 is C 1-6 alkyl and R 42ais H. In a further embodiment, R 41 is methyl and R 42a is H. In a further embodiment, R 41 is C 1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0842] In one embodiment of formula VIIb, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0843] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0844] In one embodiment of Formula VIIc, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0845] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42bis NH 2 .

[0846] In one embodiment of formula VIId, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0847] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0848] In one embodiment of formula VII, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0849] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0850] In one embodiment of formula VIIa, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0851] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 。In a further embodiment, R 41 is methyl and R 42a is NH 2 。

[0852] In one embodiment of formula VIIb, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0853] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6Alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0854] In one embodiment of Formula VIIc, Z is CHCH 2 Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0855] In a further embodiment, R 41 is H, R 42a is NH 2 and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 and R 42bis H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0856] In one embodiment of formula VIId, Z is CHCH 2 , Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0857] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0858] In one embodiment of Formula VII, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0859] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0860] In one embodiment of Formula VIIa, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0861] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 。In a further embodiment, R 41 is methyl and R42a is NH 2 .

[0862] In one embodiment of formula VIIb, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0863] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or hydrogen. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0864] In one embodiment of formula VIIc, Z is CCH, Y is F, R 1 is methyl, R2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0865] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0866] In one embodiment of formula VIId, Z is CCH, Y is F, R 1 is methyl, R 2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4Alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0867] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 。In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0868] In one embodiment of formula VII, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0869] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0870] In one embodiment of formula VIIa, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1-C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0871] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0872] In one embodiment of formula VIIb, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0873] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0874] In one embodiment of Formula VIIc, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0875] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41is C 1-6 is alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 is alkyl or H. In a further embodiment, R 41 is C 1-6 is alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0876] In one embodiment of formula VIId, Z is CCH, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0877] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 . In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 .

[0878] In one embodiment of formula VII, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6Alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0879] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0880] In one embodiment of formula VIIa, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0881] In a further embodiment, R 41 is 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 is C 1-6 alkyl and R 42a is NH 2 。In a further embodiment, R 41 is methyl and R 42a is NH 2 。

[0882] In one embodiment of formula VIIb, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0883] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 and R 42b is NH 2 .

[0884] In one embodiment of formula VIIc, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0885] In a further embodiment, R 41 is H, R 42a is NH 2 and R42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0886] In one embodiment of formula VIId, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is hydrogen; B is

[0887] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 . In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3。In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0888] In one embodiment of formula VII, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0889] In a further embodiment, R 1 is C 1-6 alkyl and R 7 is NH 2 。In a further embodiment, R 1 is methyl and R 7 is NH 2 。

[0890] In one embodiment of formula VIIa, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0891] In a further embodiment, R 41 is 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 is C1-6 alkyl and R 42a is NH 2 . In a further embodiment, R 41 is methyl and R 42a is NH 2 .

[0892] In one embodiment of formula VIIb, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0893] In a further embodiment, R 41 is H, R 42a is H, and R 42b is C 1-6 alkyl. In a further embodiment, R 41 is H, R 42a is H, and R 42b is methyl. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH2 .

[0894] In one embodiment of formula VIIc, Z is F, Y is F, R 1 is methyl, R 2 is aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0895] In a further embodiment, R 41 is H, R 42a is NH 2 , and R 42b is H. In a further embodiment, R 41 is H, R 42a is -NHCH 3 , and R 42b is H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is NH 2 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NR 8 R 9 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is C 1-6 alkyl or H. In a further embodiment, R 41 is C 1-6 alkyl or H, R 42a is -NHCH 3 , and R 42b is NH 2 .

[0896] In one embodiment of formula VIId, Z is F, Y is F, R 1 is methyl, R2 is an aryl, R 3 is hydrogen, R 4a is hydrogen, R 4a is C 1 -C 4 alkyl, R 5 is C 1 -C 6 alkyl, R 6 is hydrogen, R 40 is cyano or nitro; B is

[0897] In a further embodiment, R 41 is halogen and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is halogen and R 42a is -C(O)NHCH 3 。In a further embodiment, R 41 is Br and R 42a is -C(O)NR 8 R 9 。In a further embodiment, R 41 is Br and R 42a is -C(O)NHCH 3 。

[0898] Non-limiting examples of the compounds of formula VII include:

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907] The present invention also includes the use of the compounds of formula VIII, formula IX or formula X, wherein R 10 is a monophosphate, diphosphate, triphosphate or R 10A wherein R 10Ais a stable phosphate prodrug that is metabolized in vivo to a mono-phosphate, di-phosphate, or tri-phosphate to treat or prevent COVID-19 disease in a host in need thereof, as described herein:

[0908]

[0909] wherein

[0910] R 10 is selected from and R 10A ;

[0911] R 10A is a stable phosphate prodrug that can be metabolized in vivo to a mono-phosphate, di-phosphate, or tri-phosphate;

[0912] R 11 is selected from hydrogen and R 1 ; and

[0913] R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and -C(O)C 1 -C 6 alkyl;

[0914] The present invention also includes compounds of formula XI and formula XII:

[0915]

[0916] or a pharmaceutically acceptable salt thereof;

[0917] wherein

[0918] R 12a and R 12b are oxygen protecting groups and at least one of R 12a and R 12b is -C(O)OC 1-6 alkyl, such as -C(O)OtBu, or -C(O)O-benzyl, wherein the alkyl and benzyl may optionally be substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl.

[0919] In one embodiment, R 12a is -C(O)OC 1-6 alkyl or -C(O)O-benzyl and R 12b is an oxygen protecting group that is an ester, ether, or silyl ether moiety when attached to oxygen. In a further embodiment, R 12b is -C(O)OC 1-6an 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. In one embodiment, R 12a and R 12b are both -C(O)OC 1-6 alkyl, such as -C(O)OtBu. In one example, R 12a and R 12b are both -C(O)O-benzyl.

[0920] In one embodiment, the compound of formula XII is of formula XIIA:

[0921]

[0922] In one embodiment, the compound of formula XII is of formula XIIB:

[0923]

[0924] For example, the protecting group attached to oxygen can be an ester moiety, such as benzoic acetic acid ester. 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 set according to one of the methods described in Theodora W. Green, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons (1999), for protecting hydroxyl groups. For example, when the oxygen protecting group attached 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 on pages 149 - 178, and when the oxygen protecting group attached to oxygen is a silyl ether moiety, the compound of formula XI or formula XII can be prepared according to the conditions described in the text on pages 113 - 147. In one embodiment, the protecting group is a tert-butyldimethylsilyl (TBS) group. Using the conditions described in the text on page 128 and Ogilvie et al. Can. J. Chem. 1979, 57, 2230., the TBS group is selectively set on the primary alcohol rather than the secondary alcohol. These conditions include using TBSCl, DMAP, and NEt3 in DMF at 25 °C.

[0925] Non-limiting examples of additional protecting groups attached to oxygen also 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 ether, 2-methylpyridine ether, 4-methylpyridine ether, 1,3-benzodithiolan-2-yl ether, p-chlorophenoxyacetate, 3-phenylpropionate, p-phenylbenzoate, alkyl p-nitrophenylcarbonyl, alkyl benzylcarbonyl, alkyl p-methoxybenzylcarbonyl, alkyl o-nitrobenzylcarbonyl, and alkyl p-nitrobenzylcarbonyl.

[0926] R 12a and R 12b Non-limiting examples of include:

[0927]

[0928]

[0929] Non-limiting examples of the compounds of Formulas XI and XII include:

[0930]

[0931]

[0932]

[0933] In some embodiments, the compounds 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 are used in a form that is at least 90% free of the opposite phosphorus enantiomer and can be at least 98%, 99%, or 100% free of the opposite phosphorus enantiomer.

[0934] 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) has been previously described in U.S. Patent 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; as well as 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.

[0935] Compound 2 has been previously described in U.S. Patents 10,519,186; 10,906,928; 10,894,804; and 10,874,687 and PCT Applications WO2018 / 144640; WO2019 / 200005; and WO2020 / 117966 assigned to Atea Pharmaceuticals. By inhibiting the RNA-dependent RNA polymerase (RdRp) (Good, S.S. et al. PLoS ONE 15(1), e0227104 (2020)), Compound 2A has demonstrated potent in vitro activity against clinical isolates of hepatitis C virus (HCV) (Good, S.S. et 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 for up to 12 weeks in HCV-infected subjects and achieved a high rate of efficacy.

[0936] 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) is described in Example 1 below.

[0937] In one embodiment, Compound 2 is provided in its pharmaceutically acceptable composition or solid dosage form.

[0938] Non-limiting illustrative methods for preparing Compound 2 include

[0939] (i) In a first step, in a flask or container, dissolve Compound 1 in an organic solvent such as acetone, ethyl acetate, methanol, acetonitrile, or ether, etc.;

[0940] (ii) Add a second organic solvent, which may be the same as or different from the organic solvent in step (i), to a second flask or container. Optionally, cool the second solvent to 0 - 10 degrees Celsius and add H 2 SO 4 dropwise to the second organic solvent to produce an H 2 SO 4 / organic solvent mixture; and wherein the solvent can be, for example, methanol;

[0941] (iii) At ambient temperature or a slightly elevated or reduced temperature (e.g., 23 - 35 degrees Celsius), add the 0.5 / 1.0 molar ratio of H 2 SO 4 / solvent mixture from step (ii) dropwise to the solution of Compound 1 in step (i));

[0942] (iv) Stir the reaction in step (iii) until a precipitate of Compound 2 forms, for example, at ambient temperature or a slightly elevated or reduced temperature;

[0943] (v) Optionally, filter the precipitate obtained from step (iv) and wash it with an organic solvent; and

[0944] (vi) Optionally, dry the resulting Compound 2 in vacuo, optionally at an elevated temperature, such as 55, 56, 57, 58, 59, or 60 °C.

[0945] In one example, the solvent in step (iii) is an alcohol such as methanol, ethanol, or isopropanol. In one embodiment, the solvent in step (iii) is an alkyl ester such as ethyl acetate.

[0946] Scheme 1 provides the metabolic pathway of the compound of formula I, which involves the initial de-esterification of the aminophosphate (Compound 1) to form metabolite 1-1, which spontaneously decomposes to metabolite 1-2. Metabolite 1-2 is then converted to an N 6 -methyl-2,6-diaminopurine-5'-monophosphate derivative (metabolite 1-3), which is in turn metabolized to the free 5'-hydroxy-N 6-Methyl-2,6-diaminopurine riboside (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 ester (Metabolite 1-4). Metabolite 1-4 is anabolized to the corresponding diphosphate ester (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 thus a surrogate for the active triphosphate (1-6), which is not measurable in plasma).

[0947]

[0948]

[0949] Definitions

[0950] "Patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of COVID-19 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 (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, bats, and the like.

[0951] The terms "prophylactic" or "preventive" when used refer to the administration of an active compound to prevent, reduce the likelihood of occurrence or recurrence of COVID-19, or minimize new infections associated with the infection that would occur without such treatment. The present invention includes therapeutic and prophylactic or preventive treatment. In one embodiment, the active compound is administered to a host that has been exposed to COVID-19 and thus is at risk of contracting COVID-19. In another alternative embodiment, a method of preventing transmission is provided that includes administering to a human an effective amount of one of the compounds described herein for a sufficient length of time, prior to exposure to a population that may be infected, including during travel or public events or meetings, including, for example, up to 3, 5, 7, 10, 12, 14 days or longer before an infectious situation occurs.

[0952] The terms "co-administer", "co-administered", or "combination" are used to describe a combination of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII or a pharmaceutically acceptable salt thereof according to the invention with at least one other antiviral agent. The timing of co-administration is preferably determined by a medical expert treating the patient. Sometimes it is desirable to administer these agents simultaneously. Alternatively, the selected drugs for combination therapy can be administered to the patient at different times. Of course, when there is more than one virus or other infection or other condition, the compounds of the invention can be combined with other drugs as needed to treat other infections or conditions.

[0953] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified to its inorganic and organic, acid or base addition salts without undue toxicity. The salts of the compounds of the invention can be synthesized by conventional chemical methods from the parent compounds having basic or acidic moieties. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of the appropriate base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form with a stoichiometric amount of the appropriate acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used when feasible. The salts of the compounds of the invention can optionally be provided in the form of solvates.

[0954] Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues of mineral or organic acids such as amines; acidic residues of alkali metal or organic salts such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional salts and quaternary ammonium salts of the parent compounds formed, for example, from inorganic or organic acids without undue toxicity. For example, acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; 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, hydroxyethanesulfonic acid, HOOC-(CH 2 )n-COOH where n is 0-4, etc., or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0955] 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 counterion, such as in the form of a hemisulfate. Alternatively, the compound can be provided with more than a molar equivalent of counterion, such as in the form of a disulfate. Non-limiting examples of the molar ratio of the compound to the counterion include 1:0.25, 1:0.5, 1:1, and 1:2.

[0956] "Alkyl" is a straight-chain or branched-chain saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl is C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 or C 1 -C 6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbon atoms in length). As used herein, the specified range indicates an alkyl having a length of each member of the range described as an independent species. For example, C 1 -C 6 alkyl as used herein means an alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to represent each of these as an independent species, while C 1 -C 4 alkyl as described herein means an alkyl having 1, 2, 3, or 4 carbon atoms and is intended to represent each of these as an independent species. Examples of alkyl 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.

[0957] "Cycloalkyl" is a saturated monocyclic hydrocarbon ring system. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0958] "Alkenyl" refers to a non-aromatic hydrocarbon group that contains at least one double bond between adjacent carbon atoms and has a structure similar to the alkyl described elsewhere herein. For example, the alkenyl can have up to 4 carbon atoms (i.e., C 2 -C 4 alkenyl). Examples of suitable alkenyl include, but are not limited to, vinyl or ethenyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-butenyl (-C=CH-CH 2 CH 3) and 2-butenyl (-CH 2 CH=CHCH 2 ).

[0959] 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 may have 2 to 4 carbon atoms (i.e., C 2 -C 4 alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

[0960] "Aryl" denotes an aryl group containing only carbon in one or more aromatic rings. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and has 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 example, the aryl group is pendant. An example of a pendant ring is phenyl substituted with phenyl. In one embodiment, the aryl group is optionally substituted as described above. In one embodiment, aryl groups include, for example, dihydroindole, dihydrobenzofuran, isoindolin-1-one, and indolin-2-one.

[0961] "Aryl(alkyl)-" is an alkyl group as described herein substituted with an aryl group as described herein. For example, aryl(CH 2 )- is benzyl. Examples of aryl(alkyl)- include benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0962] "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), where the remaining ring atoms are carbon, or a stable bicyclic or tricyclic system containing at least one 5-, 6- or 7-membered aromatic ring, the 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 being 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 typically has 5 or 6 ring atoms. When the total number of S and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. Examples of heteroaryl include, but are not limited to, pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuryl and furanopyridyl.

[0963] The term "heteroalkyl" refers to an alkyl, alkenyl, alkynyl or haloalkyl moiety as defined herein, where a CH 2 group is replaced by a heteroatom or a carbon atom is substituted by a heteroatom, such as amine, carbonyl, carboxyl, oxo, thio, 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 denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

[0964] The term aminophosphate is used throughout the specification to describe a moiety at the 5'-position of the nucleoside furanose ring and forms a prodrug form of the nucleoside compound, where the phosphorus atom is linked by a 5'-O-bond, and where the phosphorus is also covalently bound to at least one nitrogen, forming a P-N bond. In some embodiments, the phosphorus is covalently linked to the amino moiety of a natural or synthetic amino acid (which may be in the form of an ester). Aminophosphate groups useful in the present invention include, for example, those having the following structures:

[0965]

[0966] Other aminophosphates for use in the present invention include those having the following structures:

[0967]

[0968] Wherein:

[0969] R P1 is an optionally substituted straight-chain, branched-chain or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a combination of their linkages; and

[0970] R P2 is a -NR N1 R N2 group or a B' group;

[0971] Wherein:

[0972] R N1 and R N2 are each independently H, C 1-8 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl-, (aryl)C 0 -C 4 alkyl-, (C 3 -C 6 heterocycle)C 0 -C 4 alkyl- or (heteroaryl)C 0 -C 4 alkyl-; which may be optionally substituted; or

[0973] R N1 and R N2 together with the attached nitrogen atom, form a 3- to 7-membered heterocycle;

[0974] B' is

[0975] Wherein:

[0976] R 13 is hydrogen, (C 1 -C 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl-, (aryl)C 0 -C 4 alkyl-, (C 3 -C6 heterocyclic)C 0 -C 4 alkyl-, (heteroaryl)C 0 -C 4 alkyl- or the side chain of an amino acid, e.g., the side chain of an amino acid usually 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 (as further described herein) (usually R 13 is hydrogen, methyl, isopropyl or isobutyl);

[0977] R 14 is hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl-, (aryl)C 0 -C 4 alkyl-, (C 3 -C 6 heterocyclic)C 0 -C 4 alkyl-, (heteroaryl)C 0 -C 4 alkyl- or the side chain of an amino acid, e.g., the side chain of an amino acid usually 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 (as further described herein) (usually R 14 is hydrogen, methyl, isopropyl or isobutyl);

[0978] R 15 is hydrogen or C 1 -C 3 alkyl; or

[0979] R 13 and R 14 can form a (C 3 -C 7 )cycloalkyl or a (C 3 -C 7 )heterocyclic group; or

[0980] R 13and R 14 or R 16 can form a (C 3 -C 6 ) heterocyclic group; and

[0981] R 16 is hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) alkenyl, (C 3 -C 6 ) alkynyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl-, (C 3 -C 6 heterocycle)C 0 -C 4 alkyl-, (heteroaryl)C 0 -C 4 alkyl-.

[0982] Preferred R P1 groups include optionally substituted phenyl, naphthyl and monocyclic heteroaryl, especially those that enhance the bioavailability of the compound in patient cells and exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (slower compound metabolism and excretion) (especially lipophilic groups).

[0983] Stable phosphate prodrug

[0984] Stable phosphate prodrugs are moieties that can deliver monophosphate, diphosphate, or triphosphate in vivo. For example, McGuigan disclosed aminophosphates 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 disclosed phosphorothioates in US 8,895,723 and 8,871,737 (incorporated herein by reference). Alios also disclosed cyclic nucleotides in U.S. Patent No. 8,772,474 (incorporated herein by reference). Idenix disclosed cyclic aminophosphates and aminophosphate / SATE derivatives in WO 2013 / 177219 (incorporated herein by reference). Idenix also disclosed substituted carbonyloxymethyl aminophosphate compounds in WO 2013 / 039920 (incorporated herein by reference). Hostetler disclosed lipid phosphate prodrugs, see for example US7,517,858. Hostetler also disclosed 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 disclosed nucleotide sphingosine and lipid derivatives in WO 2014 / 124430. RFS Pharma disclosed purine nucleoside monophosphate prodrugs in WO 2010 / 091386. Cocrystal Pharma Inc. also disclosed purine nucleoside monophosphate prodrugs in U.S. Patent No.: 9,173,893 (incorporated herein by reference). HepDirect TMThe technical disclosure is 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, phosphates, 3',5'-cyclic phosphates (including CycloSAL), SATE derivatives (S-acyl-2-thioesters), and DTE (dithiobisethyl) prodrugs. For a review of references on 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 Pro-nucleotide 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 literature can be used for the R 10A position of the compounds of the present invention.

[0985] 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 the preparation methods. For example, the 5'-prodrug can be represented by the following groups:

[0986]

[0987] where

[0988] Z is O or S;

[0989] R 17 and R 18Capable of providing nucleoside monophosphates, diphosphates or triphosphates upon in vivo administration. Representative R 12 and R 13 are independently selected from:

[0990] (a) OR 19 , wherein R 19 is selected from H, Li, Na, K, phenyl and pyridyl and wherein phenyl and pyridyl are optionally substituted with one to three substituents independently selected from (CH 2 ) 0-6 CO 2 R 20 and (CH 2 ) 0-6 CON(R 20 ) 2 ;

[0991] R 20 is independently H, C 1-20 alkyl, a carbon chain derived from a 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 C 3-10 alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C 1-5 alkyl substituted with cycloalkyl or cycloalkyl;

[0992] (b)

[0993] (c) an ester of a D-amino acid or an L-amino acid:

[0994]

[0995] wherein

[0996] R 21 is limited to those side chains that occur in natural L-amino acids, and

[0997] R 22 is H, C 1-20 alkyl, a carbon chain derived from a 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 C1-5 alkyl, or C substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl or cycloalkyl-substituted C 1-5 alkyl;

[0998] (d) R 17 and R 18 can together form a ring:

[0999]

[1000] wherein

[1001] R 23 is H, C 1-20 alkyl, C 1-20 alkenyl, a carbon chain derived from a 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, fluoro, 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 C substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl or cycloalkyl-substituted C 1-5 alkyl;

[1002] (e) R 17 and R 18 can together form a ring selected from

[1003]

[1004] wherein

[1005] R 24 is selected from H, C 1-20 alkyl, C 1-20 alkenyl, a carbon chain derived from a fatty acid (such as oleic acid, linoleic acid, etc.), and C substituted by lower alkyl 1-20 alkyl, alkoxy, di(lower alkyl)-amino, fluoro, 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 C substituted by lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl or cycloalkyl-substituted C 1-5 alkyl; and

[1006] R 25 is O or NH.

[1007] In an alternative embodiment, the 3',5'-prodrug can be represented as:

[1008]

[1009] wherein:

[1010] When the phosphorus center is chiral, it can be all or part Rp or Sp or any mixture thereof, and can be enantiomerically enriched;

[1011] R 26 is selected from OR 19 、 or is derived from a fatty alcohol (such as but not limited to linoleyl-O- and oleyl-O-);

[1012] R 11 is selected from R 1 and hydrogen; and

[1013] R 1 、R 21 、R 22 and R 19 as defined herein.

[1014] Isotopic substitution

[1015] The present invention includes compounds 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 said compounds have an amount of the desired atomic isotopic substitution that is higher 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 a limitation, isotopes of hydrogen, for example, deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the structure. Optionally or additionally, isotopes of carbon, such as 13 C and 14C. An example of isotope substitution is the replacement of hydrogen with deuterium at one or more positions of a molecule to improve the properties of a drug. Deuterium can be incorporated at positions where bonds break 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 the deuteration of nucleotides to improve their pharmacokinetics or pharmacodynamics, including at the 5-position of the molecule.

[1016] Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dose requirements. Replacing hydrogen with deuterium at the site of metabolic breakdown can lower the metabolic rate at that bond or eliminate the metabolism of that bond. At any position where a hydrogen atom may be present in a compound, the hydrogen atom can be any isotope of hydrogen, including protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Thus, unless the context clearly indicates otherwise, compounds referred to herein include all potential isotopic forms.

[1017] The term “isotopically labeled” analogue refers to a “deuterated analogue”, “ 13 C-labeled analogue” or “deuterated / 13 C-labeled analogue”. The term “deuterated analogue” refers to a compound as described herein in which the H-isotope, such as hydrogen / protium ( 1 H), is replaced by an H-isotope, such as deuterium ( 2 H). Deuteration can be partial or complete. Partial deuteration means that at least one hydrogen is replaced by at least one deuterium.

[1018] In certain embodiments, the isotope is enriched at 90, 95 or 99% or more at any position of interest. In some embodiments, deuterium is enriched at 90, 95 or 99% at the desired position. Unless otherwise stated, the deuteration rate at the selected position is at least 80%. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired result.

[1019] In one embodiment, a compound of formula XIII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical carrier, is used for treating or preventing COVID-19 disease caused by SARS-CoV-2 in a host in need thereof, as described herein:

[1020]

[1021] wherein

[1022] R 6 is selected from hydrogen, -C(O)R6A 、 -C(O)OR 6A 、 C 1-6 alkyl and -CH 2 -O-R 6A ;

[1023] R 6 is selected from hydrogen, -C(O)R 6A 、 -C(O)OR 6A 、 C 1-6 alkyl and -CH 2 -O-R 6A , in an alternative embodiment, -C(O)NR 6B R 6C ;

[1024] R 6A is selected from hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl (e.g., -CHCl 2 、 -CCl 3 、 -CH 2 Cl, -CF 3 、 -CHF 2 、 -CH 2 F), aryl and aryl(C 1-6 alkyl)-, wherein the aryl is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl, in an alternative embodiment, R 6A is selected from C 1-20 alkyl and C 2-20 alkenyl;

[1025] 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 may optionally be substituted with at least one substituent selected from alkoxy (including but not limited to methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido and haloalkyl;

[1026] R 30 is CH 3 、 CD 3 、 CHD 2 or CH 2 D;

[1027] R 31 is NH 2Or D or, in an alternative embodiment, CD 3 ;

[1028] R 32 is CH 3 、CD 3 、CHD 2 or CH 2 D; and

[1029] Y is selected from F and Cl; and

[1030] R 1 、R 2 、R 3 、R 4a 、R 4b and R 5 as defined herein.

[1031] For example, non-limiting examples of compounds of formula XIII include:

[1032]

[1033]

[1034]

[1035] Other examples of compounds of formula XIII include:

[1036]

[1037]

[1038]

[1039]

[1040] Treatment or prevention methods

[1041] As used herein, treatment refers to administering, to a host (e.g., a human), an effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X or formula XIII or a pharmaceutically acceptable salt thereof, wherein the host 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.

[1042] The present invention also includes prophylaxis 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 thus is at risk of infection or reinfection with the SARS-CoV-2 virus. For example, prophylactic treatment can be administered to a subject who has not been exposed to or infected with SARS-CoV-2, but is susceptible or at risk of exposure to or infection with COVID-19. 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 the risk of exposure no longer exists.

[1043] In another alternative embodiment, a method of preventing transmission is provided, the method comprising administering to a human an effective amount of one of the compounds described herein for a sufficient length of time prior to exposure to a population that may be infected, including during travel or public events or meetings, including, for example, up to 3, 5, 7, 10, 12, 14 days or longer before the onset of an infectious condition, either because the person is infected or to prevent an infected person from infecting others during an infectious condition.

[1044] 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 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.

[1045] The present invention relates to a method of treating COVID-19, including drug-resistant and multi-drug-resistant forms of the virus, as well as virus-infected related disease states, conditions or complications, including pneumonia, such as pneumonia caused by the 2019 novel coronavirus (NCIP), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Other non-limiting complications include hypoxic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, thrombosis, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis and cytokine storm.

[1046] The method further comprises administering to a host in need, typically a human, an effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X or formula XIII or a pharmaceutically acceptable salt thereof, optionally in combination with at least one additional bioactive agent, for example, an additional antiviral agent, further optionally in combination with a pharmaceutically acceptable carrier additive and / or excipient.

[1047] 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 to a patient in need results in a decrease in the incidence of progressive respiratory insufficiency (PRI), such as an increase in the level of respiratory support method greater than or equal to 1 level or even 2 levels or more required to maintain satisfactory oxygenation (SpO2≥93%) using the 6-level respiratory support method described below.

[1048] The levels of increasing the respiratory support level include:

[1049] Level 1: Normal oxygenation in room air (SpO 2 ≥93%) without supplemental O 2

[1050] Level 2: Persistent hypoxemia in room air (SpO2≥93) requiring low-level supplementation of O through nasal cannula or mask (up to 2 L / min) 2 to maintain SpO 2 ≥93

[1051] Level 3: Requiring higher-level passive supplementation of O through nasal cannula or mask (up to 2 L / min) 2 to maintain SpO 2 ≥93

[1052] Level 4: Requiring oxygenation through a positive pressure device, such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) or other non-invasive positive pressure respiratory support methods, to maintain satisfactory oxygenation and / or ventilation

[1053] Level 5: Requiring invasive respiratory support (intubation mechanical ventilation or ECMO)

[1054] Level 6: Death

[1055] In one example, 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 from level 4 to level 1. In one embodiment, the reduction in PRI is from level 3 to level 1.

[1056] 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, for at least 3, 4, 5 or more days reduces the median time to clinical recovery (status 6, 7 or 8 on the NIAID Clinical Status Scale, using the adapted National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status Ordinal Scale). 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, results in improvement as measured by the adapted ordinal scale of clinical status.

[1057] The stages of the adapted ordinal scale of overall clinical status, from the most severe disease to the progressively less severe disease, are defined as follows:

[1058] 1. Death

[1059] 2. Hospitalized, with invasive mechanical ventilation or ECMO

[1060] 3. Hospitalized, using non-invasive ventilation or high-flow oxygen device

[1061] 4. Hospitalized, requiring supplemental oxygen

[1062] 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (related to COVID-19 or otherwise)

[1063] 6. Hospitalized, not requiring supplemental oxygen; no longer requiring close medical care for COVID-19

[1064] 7. Not hospitalized, but with restricted activity and requiring close outpatient care due to COVID-19 manifestations

[1065] 8. Not requiring hospitalization, with unrestricted activity and no need for ongoing close medical care

[1066] 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, for 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 reduces the median time to clinical recovery (status 6, 7 or 8 on the NIAID Clinical Status Scale, using the adapted National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status Ordinal Scale).

[1067] 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 the length of hospital stay in patients infected with the SARS-CoV-2 virus.

[1068] 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 the time to achieve persistent undetectability of the SARS-CoV-2 virus in the nose and / or throat of patients infected with the SARS-CoV-2 virus.

[1069] 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.

[1070] 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 the proportion of patients who are SARS-CoV-2 positive in a hospital population after treatment for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[1071] In another embodiment, a method of treating or preventing SARS-CoV-2 infection in a host in need thereof (typically a human) is provided by administering to the host an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, wherein the SARS-CoV-2 infection is caused by a viral variant that has undergone a natural or drug-induced mutation on the wild type.

[1072] In some embodiments, the SARS-CoV-2 variant has a natural or drug-induced mutation in a viral protein selected from the 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, ORF 3 a, ORF6, ORF7a, ORF7b, ORF8, and ORF10. In some embodiments, the SARS-CoV-2 variant has a mutation that results in acquired resistance to one or more antiviral drugs.

[1073] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acids H69 and V70.

[1074] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acid D614G.

[1075] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acid Y144.

[1076] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N501Y.

[1077] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A570D.

[1078] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution P681H.

[1079] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution T716I.

[1080] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution S982A.

[1081] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D1118H.

[1082] In some embodiments, the SARS-CoV-2 variant has a premature stop codon mutation Q27stop in the protein product of ORF8.

[1083] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[1084] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution E484K.

[1085] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[1086] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D215G.

[1087] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A701V.

[1088] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution L18F.

[1089] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution R246I.

[1090] In some embodiments, the SARS-CoV-2 variant has a deletion at spike protein amino acids 242-244

[1091] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution Y453F.

[1092] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution I692V.

[1093] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution M1229I.

[1094] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N439K.

[1095] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A222V.

[1096] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution S477N.

[1097] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A376T.

[1098] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution P323L.

[1099] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution Y455I.

[1100] In some embodiments, the SARS-CoV-2 variant has an Orf8 protein amino acid substitution R52I.

[1101] In some embodiments, the SARS-CoV-2 variant has an ORF8 protein amino acid substitution Y73C.

[1102] In some embodiments, the SARS-CoV-2 variant has a nucleocapsid (N) protein amino acid substitution D3L.

[1103] In some embodiments, the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution S235F.

[1104] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution T1001I.

[1105] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution A1708D.

[1106] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid substitution I2230T.

[1107] In some embodiments, the SARS-CoV-2 variant has an ORF1ab protein amino acid deletion SGF3675-3677.

[1108] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution S861X, where X is any amino acid.

[1109] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution F480V.

[1110] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution V557L.

[1111] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution D484Y.

[1112] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution F480X, where X = any amino acid.

[1113] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution V557X, where X = any amino acid.

[1114] In some embodiments, the SARS-CoV-2 variant has an nsp12 protein amino acid substitution D484X, where X = any amino acid.

[1115] In some embodiments, the SARS-CoV-2 variant includes a deletion of amino acids 69-70 in the spike protein, a deletion of amino acid Y144 in the spike protein, an amino acid substitution N501Y in the spike protein, an amino acid substitution A570D in the spike protein, an amino acid substitution D614G in the spike protein, an amino acid substitution P681H in the spike protein, an amino acid substitution T716I in the spike protein, an amino acid substitution S982A in the spike protein, an amino acid substitution D1118H in the spike protein, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.

[1116] In some embodiments, the SARS-CoV-2 variant includes amino acid substitutions 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.

[1117] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clades O, S, L, V, G, GH, or GR, as described by Alm et al. in "Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020". Euro Surveillance: Bulletin European Sur les Maladies Transmissibles = European Communicable Disease Bulletin. 25(32).

[1118] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clades G614, S84, V251, I378, or D392, as described by Guan et al. in 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.

[1119] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clades 19A, 19B, 20A, or 20C, as described in Nextstrain: Genomic epidemiology of novel coronavirus-Global sub-sampling. Available from: https: / / nextstrain.org / ncov.

[1120] 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 / .

[1121] In some embodiments, the SARS-CoV-2 variant is a "cluster 5" variant that includes the spike protein amino acid substitution D614G.

[1122] In some embodiments, the SARS-CoV-2 variant is VUI202012 / 01 (Variant Under Investigation, December 2020, Variant 01) (also known as lineage B.1.1.7 and 20B / 501Y.V1), which is defined 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.

[1123] In some embodiments, the SARS-CoV-2 variant is a lineage B.1.351 variant (also known as 501.V2, 20C / 501Y.V2), which includes several mutations in the receptor binding domain (RBD) of the spike protein: N501Y, K417N, and E484K, which make the virus more likely 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 an amino acid deletion at amino acids 242-244 of the spike protein.

[1124] 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.

[1125] In some embodiments, the SARS-CoV-2 variant is a lineage P.1 variant (also known as the Brazil(ian) variant), which includes ten mutations in the spike protein mutations, including N501Y and E484K.

[1126] In some embodiments, the SARS-CoV-2 variant is a lineage B.1.1.207 variant, which includes the P681H mutation in the spike protein.

[1127] In some embodiments, the SARS-CoV-2 variant is the Danish mink variant, which includes deletion of the amino acids H69 and V70 in the spike protein, and amino acid substitution Y453F in the spike protein.

[1128] In some embodiments, the SARS-CoV-2 variant is the Danish mink cluster 5 variant, which includes amino acid deletions of H69 and V70 in the spike protein, amino acid substitution Y453F in the spike protein, amino acid substitution I692V in the spike protein, and amino acid substitution M1229I in the spike protein.

[1129] In some embodiments, the SARS-CoV-2 variant includes amino acid deletions of H69 and V70 in the spike protein, and amino acid substitution N439K in the spike protein.

[1130] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU1 variant, which includes amino acid substitution A222V in the spike protein.

[1131] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU2 variant, which includes amino acid substitution S477N in the spike protein and amino acid substitution A376T in the nucleocapsid protein.

[1132] In some embodiments, the SARS-CoV-2 variant has one or more mutations selected from the following: the amino acid substitution T1001I in the ORF1ab protein product; the amino acid substitution A1708D in the ORF1a protein product; the amino acid substitution I2230T in the ORF1ab protein product; the deletion of amino acids SGF at positions 3675 - 3677 in the ORF1ab protein product; the amino acid substitution G251V in the protein product of ORF3a; the amino acid substitution S24L in the protein product of ORF8; the amino acid substitution R52I in the protein product of ORF8; the amino acid substitution Y73C in the protein product of ORF8; the amino acid substitution L84S in the protein product of ORF8; the amino acid substitution P323L in the nsp12 domain; the amino acid substitution Y455I in the nsp12 domain; the amino acid substitution Q57H in the protein product of ORF3a; the amino acid substitution R27C in nsp2; the amino acid substitution V198I in nsp2; the amino acid substitution T85I in nsp2; the amino acid substitution P585S in nsp2; the amino acid substitution I559V in nsp2; the amino acid substitution M33I in nsp4; the amino acid substitution G15S in nsp5; the amino acid substitution L37F in nsp6; the amino acid substitution Y541C in nsp13; the amino acid substitution P504L in nsp13; the amino acid substitution S477N in the spike protein; the amino acid substitution N439K in the spike protein; the amino acid substitution N501Y in the spike protein; the amino acid substitution Y453F in the spike protein; the amino acid substitution K417N in the spike protein; the amino acid substitution E484K in the spike protein; the amino acid substitution A222V in the spike protein; the amino acid substitution S98F in the spike protein; the amino acid substitution D80Y in the spike protein; the amino acid substitution A626S in the spike protein; the amino acid substitution V1122L in the spike protein; the amino acid substitution A570D in the spike protein; the amino acid substitution P681H in the spike protein; the amino acid substitution V1122L in the spike protein; the amino acid substitution T716I in the spike protein; the amino acid substitution S982A in the spike protein; the amino acid substitution D1118H in the spike protein; the amino acid substitution E583D in the spike protein; the amino acid substitution V483A in the spike protein; the amino acid substitution Q675R in the spike protein; the amino acid substitution A344S in the spike protein; the amino acid substitution T345S in the spike protein; the amino acid substitution R346K in the spike protein; the amino acid substitution A348S in the spike protein; the amino acid substitution A348T in the spike protein; the amino acid substitution N354K in the spike protein; the amino acid substitution S359N in the spike protein; the amino acid substitution V367F in the spike protein; the amino acid substitution V382L in the spike protein; the 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; amino acid substitution K458Q in the spike protein; amino acid substitution P463S in the spike protein; amino acid substitution A475V in the spike protein; amino acid substitution G476S in the spike protein; amino acid substitution T478A in the spike protein; amino acid substitution P479L in the spike protein; amino acid substitution V483A in the spike protein; amino acid substitution F490L in the spike protein; amino acid substitution Q493L in the spike protein; amino acid substitution 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 spike 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.;

[1133] 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.

[1134] 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.

[1135] 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; A35V; K387N; P122L; R191C; R195K; T391I; A252S; Q418L; T271I; T325I; G18V; L161F; Q289H; R203S; P162L; D340N; K373N; 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.

[1136] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp1 protein: M85; D75E; deletion of G82; deletion of V84; deletion of P80; deletion of H83; deletion of V86; deletion of H81; deletion of E87; deletion of L88; deletion of K141; deletion of A79; deletion of V89; V56I; R124C; D75G; deletion of A90; Y118C; D139N; deletion of Y136; G30D; R24C; D139Y; E37K; H45Y; H110Y; G52S; I71V; deletion of D156; A76T; E37D; deletion of S135; S166G; A138T; deletion of F157; G49C; M85I; or D144A; and combinations thereof.

[1137] 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.

[1138] 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; N297S; V299F; D304Y; T319I; F321L; P328S; V330E; I333T; G337C; T344I; Y346H; L351P; V354L; Q357H; E370G; L372F; A400S; T402I; V405F; V410I; D418N; K426N; K430N; V435F; Q444H; D445G; A448V; R457C; P461T; C464F; I466V; V473F; K478N; D481G; D517G; D523N; A529V; P537S; S549N; A555V; C563F; M566I; A581T; G584V; A585T; G596S; T604I; S607I; D608G; V609I; M615V; W617L; M629V; I632V; L636F; L638F; A639V; T643I; T644M; L648F; V667I; A699S; N713S; H725; N734T; D736N; V737F; T739I; V742M; N743S; M756I; L758I; A771V; L775V; A777T; K780T; F793L; T801I; T803A; H810Y; G823C; D825Y; V827A; Y828H; V848L; T870I; K871R; N874D; Q875R; E876D; H882Y; H892Y; D901Y; M906I; N909D; T912N; P918S; E919D; A923T; F480V; V557L; D484Y; or S433G; and combinations thereof.

[1139] 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; S80G; V496L; A4V; T413I; A296S; A368S; K460R; L297F; P172S; A302S; P402S; T530I; 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.

[1140] 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.

[1141] 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; deletion of M218; 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.

[1142] 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.

[1143] 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; R218C; I188T; T170I; P568L; E574A; I367V; H208Y; S99F; T429I; A306V; M405V; P129L; R222C; T44I; Q275H; R380C; A360V; A361V; G115C; L353F; H237Y; L462F; E261G; R4C; S263F; T573I; A318V; G262V; P624L; S430L; T422I; A357S; I100V; E272G; L400F; A192V; D464A; E172D; G262S; L501F; S369F; E172K; G465S; K219R; A411V; A522V; H194Y; S32L; F437L; P181S; P446L; G115V; H532Y; N92H; P13S; A159V; A184S; A306S; I273T; L274F; P13L; R370H; T223I; T590I; 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.

[1144] 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; T1335I; A1711V; K19R; A994D; K1325R; P822L; K412N; A465V; T1004I; T808I; G489D; S1699F; M1436V; S1265R; V1768G; A231V; M951I; K384N; T1288I; Q966H; R1614K; T1036I; T1306I; A1179V; P395L; N1785D; P679L; S166G; A1769V; T181I; L1718F; P822S; T1022I; A1381V; A602T; I1720V; K837N; T73I; A1033V; S1204; C1223Y; P389L; T398A; M1441I; M494I; T1303I; T181A; P1228L; R1135K; V267F; A1883V; A655V; S1296F; T686I; L198I; P1403S; L781F; T1046A; A1215V; E374D; I205 deletion; V477F; E324K; I707V; P109L; P1558L; P74S; S1212L; S1807F; T819I; T864I; H1000Y; P340L; S697F; T1189I; A480V; D729Y; K1771R; S1717L; T749I; M829I; Q172R; T1482I; A1395V; I385T; M560I; S1206L; S1699P; T1269I; T779I; V1315I; V1795F; V325F; A1892V; A579V; E493G; H1274Y; S1467F; 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; K945N; L1839S; L312F; N1263S; P1292S; S1670F; S743A; T771I; V1936I; A1262V; A1321V; A358V; A41T; C55Y; G1273S; K463E; K497Q; P1044S; R30K; S1375F; S1682F; T133I; T1348I; 465I; T1830I; T237I; V1248L; A225V; A496V; G1217R; I1816T; L956I; N1369T; N506S; P153S; P2L; T1275I; T1459I; V1234M; E595D; F90L; G1585S; H1307Y; I1409V; L1034V; L1328F; L292F; N1264; P1326T; S1197G; T1456I; T64I; T703I; T720I; T820I; V1229F; V234I; A1279V; A333V; A54S; 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.;

[1145] 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; deletion of L436; T237I; T492I; A260V; A446V; M458I; S395G; S481L; H36Y; T73I; L323F; L349F; S59F; T214I; or T60I; and combinations thereof.

[1146] 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.

[1147] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp6 protein: L37F; G277S; A46V; L75F; deletion of F37; T10I; V149F; L260F; Q208H; M83I; A136V; V145I; N156D; M86I; Y153C; G188V; L230I; deletion of F34; I189V; R233H; V114A; L33F; A287V; H11Y; A287T; A51V; G188S; I162T; M126V; M183I; N40Y; S104; F35L; M58L; or V84F; and combinations thereof.

[1148] 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.

[1149] 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.

[1150] 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.

[1151] 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; Q29 stop; Y14C; R20I; or A8V; and combinations thereof.

[1152] 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; S253P; 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.

[1153] 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 combinations thereof.

[1154] 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; Q62stop; S83L; E16D; T14I; T28I; V93F; G38V; H47Y; T39I; T120S; Q62del; Q62L; S37T; V104; P34S; P99L; T120I; V108L; H73Y; V24F; V29L; A13T; or L5F; or a combination thereof.

[1155] 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; C41del; H42; H42L; S5L; L20F; L32F; E33stop; A15S; or F13del; and combinations thereof.

[1156] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF8: E110stop; G66del; S69L; T11I; F104L; F120L; G8R; P38S; D119E; I10S; or I39V; and combinations thereof.

[1157] 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; deletion of Y145; E583D; R214L; A1020V; Q1208H; D215G; H146Y; S98F; T95I; G1219C; A846V; I197V; R102I; V367F; T572I; A1078S; A831V; P1162L; T73I; A845S; G1219V; H245Y; L8V; Q675R; S254F; V483A; Q677H; D138H; D80Y; M1237T; D1146H; E654D; 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; T323I; V826L; E1202Q; L1203F; L611F; V615I; A262S; A522V; A688V; A706V; A892S; E554D; Q836H; T1027I; T22I; A222V; A27S; A626V; C1247F; K1191N; M731I; P26L; S1147L; S1252F; S255F; V1264L; V308L; D80A; I670L; P251L; P631S; *1274Q; A344S; A771S; A879T; D1084Y; D253G; H1101Y; L1200F; Q14H; Q239K; A623V; D215Y; E1150D; G476S; K77M; M177I; P812S; S704L; T51I; T547I; T791I; V1122L; Y145H; D574Y; G142D; G181V; I834T; N370S; P812L; S12F; T791P; 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.;

[1158] Drug Compositions and Dosage Forms

[1159] 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 coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a host in need thereof (typically a human). 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.

[1160] The compound or its salt can be provided as a pure chemical, but is more typically administered as a drug composition that contains an effective amount for a host (typically a human) in need of treatment for COVID-19. Thus, in one embodiment, the drug composition provided by the present disclosure contains 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 treating COVID-19. The drug composition can 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 alternative embodiments, in combination with at least one additional active agent.

[1161] Compounds of 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, or a pharmaceutically acceptable salt thereof, can be formulated with one or more pharmaceutically acceptable carriers. An oral dosage form is sometimes chosen 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 a pharmaceutically acceptable salt thereof, are provided in a solid dosage form, 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 compounds via the oral route of administration. The pharmaceutical composition (formulation) can be administered orally, parenterally, intravenously, by inhalation, intramuscularly, topically, transdermally, orally, sublingually, locally, by suppository or by other routes, including intranasal spray delivery routes.

[1162] 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 a pharmaceutically acceptable salt thereof, are administered intravenously. In a non-limiting embodiment, the compounds of the present invention are administered intravenously at a loading dose of 550 mg / day and a maintenance dose of 275 mg / day. 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 of Compound 1 (i.e., 600 mg / day of the hemisulfate of Compound 1), and the maintenance dose is 275 mg / day (i.e., 300 mg / day of the hemisulfate of Compound 1).

[1163] 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 a pharmaceutically acceptable salt thereof, can be administered in one or more forms, such as tablets, capsules, injections, intravenous preparations, suspensions, liquids, emulsions, implants, granules, microspheres, creams, ointments, suppositories, inhalable forms, transdermal forms, orally, sublingually, locally, gels, mucosal, etc.

[1164] Intravenous and intramuscular preparations are usually administered in sterile saline. One of ordinary skill in the art can modify the preparation to make it more water-soluble or soluble in another carrier, for example, this can be easily achieved by minor modifications (salt preparation, esterification, etc.).

[1165] The pharmaceutical compositions contemplated herein optionally include a carrier, as further described below. The carrier must have a sufficiently high purity and a sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier can be inert or can have its own pharmaceutical benefit. The amount of carrier used in combination with the compound is sufficient to provide an actual amount of material for administration per unit dose of the compound. Representative carriers include solvents, diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, tonicity agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier.

[1166] One or more binders can be added to the pharmaceutical composition to increase the viscosity of the composition as needed. Examples of useful binders include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof, and mixtures thereof.

[1167] Solutions, suspensions, or emulsions for administration can be buffered with an effective amount of a buffer to maintain a pH value suitable for the selected route of administration. Suitable buffers are well known to those skilled in the art. Some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers.

[1168] To prepare the pharmaceutical compositions according to the 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. Depending on the form of the preparation required for administration, e.g., oral or parenteral, the carrier can take a variety of forms.

[1169] When preparing a pharmaceutical composition in an oral dosage form, any commonly used pharmaceutical vehicle can be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives can be used, including water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. For solid oral preparations such as powders, tablets, capsules, and solid dosage forms such as suppositories, suitable carriers and additives include starches, sugar carriers such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used. If desired, tablets or capsules can be enteric-coated or sustained-release by standard techniques. The use of these dosage forms can significantly improve the bioavailability of the compound in the patient's body.

[1170] For parenteral preparations, the vehicle generally includes sterile water or an aqueous sodium chloride solution, but can also include other components, including components that aid in dispersion. Of course, when using sterile water and maintaining sterility, the composition and the vehicle must also be sterilized. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents, etc. can be used.

[1171] Liposome suspensions (including liposomes targeting viral antigens) can also be prepared by conventional methods to produce a pharmaceutically acceptable vehicle. This may be suitable for delivering the free nucleoside, acyl / alkyl nucleoside, or phosphate prodrug form of the nucleoside compound according to the present invention.

[1172] The amounts and weights mentioned in this disclosure generally refer to the free form (i.e., the non-salt, hydrate, or solvate form). The typical values described herein represent the equivalents of the free form, i.e., as if the amount of the free form were being 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.

[1173] 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 to achieve the desired result of treating COVID-19, reducing the likelihood 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 a pharmaceutical dosage form can be in the range of, for example, 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, can be administered, for example, in a non-limiting embodiment, 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's body.

[1174] 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.

[1175] In certain embodiments, the dosage form of the pharmaceutical composition comprises from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, or from about 400 mg to about 450 mg of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or a compound of Formula XIII, or a pharmaceutically acceptable salt thereof, in a unit dosage form.

[1176] In certain embodiments, the pharmaceutical composition is a dosage form, such as a solid dosage form, which contains in a unit dosage form up to about 10, about 50, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, about 675, about 700, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 900, about 925, about 950, about 975, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg or more of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or a compound of Formula XIII, or a pharmaceutically acceptable salt thereof.

[1177] 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 at an initial dose (or loading dose), followed by a maintenance dose of at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 650 mg or at least about 750 mg, and the dose is taken once or twice daily. In one embodiment, the loading dose is about 1.5-fold, about 2-fold, about 2.5-fold or 3-fold the maintenance dose. In one embodiment, the loading dose is administered one, two, three, four or more times before the first maintenance dose.

[1178] In one embodiment, the pharmaceutical composition is a dosage form, such as a solid dosage form, which contains at least 500 mg, at least 550 mg, 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200, at least 1300 mg, at least 1400 mg or at least 1500 mg of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, in a unit dosage form.

[1179] In certain embodiments, a 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 daily. In one embodiment, the pharmaceutical composition contains at least about 550 mg of Compound 1 and the pharmaceutical composition is administered twice daily. In one embodiment, the pharmaceutical composition is administered at an initial dose (or loading dose) of at least about 900 mg, 1000 mg, 1100 mg, 1100 mg, or 1200 mg of Compound 1, followed by 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 doses of Compound 1 twice daily. 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 at least about 450 mg, 550 mg, 650 mg, 750 mg, or 850 mg doses of Compound 1 twice daily. 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 at least about 550 mg doses of Compound 1 twice daily. In one embodiment, the maintenance dose is administered for about 4, 5, 6, 7, 8, 9, 10, or more days. In one example, Compound 1 is Compound 1A. In one example, Compound 1 is Compound 1B.

[1180] In one embodiment, an effective amount of a compound of Formula I:

[1181]

[1182] or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for treating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a person in need, wherein the compound is administered according to the following schedule:

[1183] (i) A single loading dose of 1100 mg free base in one day; followed by

[1184] (ii) A maintenance dose of 550 mg free base daily.

[1185] In one example, an effective amount of a compound of the following formula:

[1186]

[1187] Or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for treating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a person in need thereof, wherein the compound is administered according to the following schedule:

[1188] (i) A single loading dose of 1100 mg of the free base in one day; followed by

[1189] (ii) A maintenance dose of 550 mg of the free base per day.

[1190] In one embodiment, an effective amount of a compound of the following formula:

[1191]

[1192] Optionally in a pharmaceutically acceptable carrier, is administered for treating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a person in need thereof, wherein the compound is administered according to the following schedule:

[1193] (i) A single loading dose of 1200 mg of the salt in one day; followed by

[1194] (ii) A maintenance dose of 600 mg of the salt per day.

[1195] In certain embodiments, a 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 daily. In one embodiment, the pharmaceutical composition contains at least about 600 mg of Compound 2 and the pharmaceutical composition is administered twice daily. In one embodiment, the pharmaceutical composition is administered at an initial (or loading) dose of at least about 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1300 mg of Compound 2, followed by a dose of at least about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of Compound 2 once, twice, or three times a day. In one embodiment, the pharmaceutical composition is administered at an initial (or loading) dose of at least about 1000 mg, 1200 mg, or 1400 mg of Compound 2, followed by a dose of at least about 600 mg of Compound 2 twice daily. In one embodiment, the pharmaceutical composition is administered at an initial (or loading) dose of at least about 1200 mg of Compound 2, followed by a dose of at least about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of Compound 2 twice a day. In one embodiment, the pharmaceutical composition is administered at an initial (or loading) dose of at least about 1200 mg of Compound 2, followed by a dose of at least about 600 mg of Compound 2 twice a day. In one embodiment, the maintenance dose is administered for about 4, 5, 6, 7, 8, 9, 10, or more days. In one example, Compound 2 is Compound 2A. In one example, Compound 2 is Compound 1B.

[1196] 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, 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, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, or more times daily. In one embodiment, it is administered orally twice daily.

[1197] For the purposes of the present invention, a prophylactic or prophylactically effective amount of the compositions according to the present invention will generally fall within the ranges described above 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 virus is increased, or can be administered, for example, before, during, and / or after travel or exposure.

[1198] One 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 employed, the pharmacokinetics of the agent to be used, and the patient or subject to be treated (animal or human). Such therapeutic amounts can be determined by the attending physician or specialist.

[1199] Solid dosage forms

[1200] 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.

[1201] In one embodiment, the solid dosage form comprises a spray-dried solid dispersion of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral administration. In another embodiment, the solid dosage form is a particulate layered solid dispersion of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral administration.

[1202] In other embodiments, the solid dispersion further contains at least one excipient selected from copovidone, poloxamer, and HPMC-AS. In one example, the poloxamer is poloxamer 407 or a mixture of poloxamers including poloxamer 407. In one embodiment, the HPMC-AS is HPMC-AS-L.

[1203] In other embodiments, the solid dosage form prepared from a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII or a pharmaceutically acceptable salt thereof further comprises one or more of the following excipients: glycerophosphates; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleoyl phosphatidylethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoyl phosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; diacylglycerol succinate; dipalmitoyl phosphatidylglycerol (DPPG); cetyl alcohol; 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; lysophosphatidylcholine; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidylglycerol; stearylamine; dodecylamine; cetylamine; acetyl palmitate; glyceryl ricinoleate; 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; deoxycholates; 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; amylopectin, cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextrin, glycogen, hydroxyethyl starch, carrageenan, glycoside, amylose, chitosan, N,O-carboxymethyl chitosan, alginate and alginic acid, starch, chitin, inulin, konjac, glucomannan, bacillus pyocyaneus, heparin, hyaluronic acid, gellan gum and xanthan gum, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, pluronic polymers, polyethylene, polycarbonate (e.g., poly(1,3-dioxan-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(ortho esters), polycyanoacrylates, polyvinyl alcohol, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes and polyamines, polylysine, poly(ethylene glycol)lysine-PEG copolymer and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glyceryl monocaprylate, propylene glycol, vitamin E TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethyl cellulose (NaCMC) or hydroxypropyl methylcellulose acetate succinate cellulose (HPMCAS).

[1204] In other embodiments, the solid dosage forms prepared from 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 their pharmaceutically acceptable salts further comprise one or more of the following surfactants: polyethylene glycol, polypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyethylene glycol octylphenol, Triton X-100, glycerol alkyl esters, glyceryl laurate, coconut oil amide MEA, coconut oil amide DEA, dodecyl dimethylamine oxide, and poloxamers. Examples of poloxamers include poloxamer 188, 237, 338, and 407. These poloxamers are available under the trade name (available from BASF, Mount Olive, NJ) and correspond respectively to F-68, F-87, F-108, and F-127. Poloxamer 188 (corresponding to F-68) is a block copolymer with 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 with 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 with 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 with a ratio between about E101 P56 E101 and about E106 P70E106, or between about E101 P56E101 or about E106 P70 E106, having 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.

[1205] In other embodiments, the solid dosage forms prepared from the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XIII or pharmaceutically acceptable salts thereof further comprise one or more of the following surfactants: polyvinyl acetate, sodium cholate, sodium dioctyl sulfosuccinate, cetyltrimethylammonium bromide, saponins, sugar esters, 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 copolymers of ethylene oxide and propylene oxide, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monocastor oilate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil, and sunflower oil.

[1206] In alternative embodiments, the solid dosage forms prepared from the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or XIII or pharmaceutically acceptable salts thereof are prepared by methods including solvent or dry granulation, optionally followed by compression or compaction, spray drying, nano-suspension treatment, hot melt extrusion, extrusion / spheronization, molding, spheronization, layering (such as spray layering of suspensions or solutions), etc. Examples of such techniques include direct compression using suitable punches and dies, such as where the punches and dies are mounted on a suitable tablet press; wet granulation using a suitable granulation device such as a high shear granulator to form wet granules, which are then dried into granules; granulation followed by pressing using suitable punches and dies, where the punches and dies are mounted on a suitable tablet press; extruding the wet mass into cylindrical extrudates and cutting or breaking into desired lengths under gravity and abrasion; extrusion / spheronization, where the extrudates are rounded into spherical granules and densified by spheronization; spraying suspensions or solutions onto an inert core using techniques such as a conventional pan or Wurster column; injection or compression molding using suitable dies mounted on a compression unit; and similar methods.

[1207] Exemplary disintegrants include alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium (croscarmellose sodium), powdered cellulose, chitosan, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, sodium methyl cellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch, sodium carboxymethyl starch, etc., or combinations thereof.

[1208] 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 silica, talc, or combinations thereof.

[1209] The cores of the dosage forms 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 alter 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, the non-functional coating may have some effect on the release of the active agent, but it is not considered a significant deviation from the uncoated 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 a combination of light-blocking and light-absorbing materials.

[1210] Exemplary polymethacrylates include copolymers of acrylates and methacrylates, such as, 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 Registry Number 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 Number 25806-15-1); d. poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., EUDRAGIT S100, EUDRAGIT S12.5, and 12.5P; CAS Number 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, trimethylammonioethyl 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, EudragitNE 40D, Eudragit NM 30D; CAS No. 9010-88-2); and so on, or combinations thereof.

[1211] Suitable alkyl celluloses include, for example, methylcellulose, ethylcellulose, etc., or combinations thereof. Exemplary aqueous ethylcellulose coatings include AQUACOAT, a 30% dispersion, further containing sodium lauryl sulfate and cetyl alcohol, available from FMC, Philadelphia, PA; SURELEASE 25% dispersion further containing stabilizers or other coating components (such as ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium-chain triglycerides, etc.), purchased from Colorcon, West Point, PA; ethylcellulose can be obtained from Aqualon or Dow Chemical Co (Ethocel), Midland, MI. Those skilled in the art will understand that other cellulose polymers, including other alkyl cellulose polymers, can replace some or all of the ethylcellulose.

[1212] Other suitable materials for preparing functional coatings include hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate phthalate (CAP); polyvinyl acetate phthalate; neutral or synthetic waxes, fatty alcohols (such as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or especially cetostearyl alcohol), fatty acids, including fatty acid esters, fatty acid glycerides (monoglycerides, diglycerides and triglycerides), hydrogenated fats, hydrocarbons, common waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials having a hydrocarbon backbone, or combinations thereof. Suitable waxes include beeswax, sugar wax, castor wax, carnauba wax, microcrystalline wax, candelilla wax and wax-like 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.

[1213] In other embodiments, the functional coating may include digestible, long-chain (e.g., C 8 -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. Specifically, long-chain hydrocarbon materials, fatty (aliphatic) alcohols can be used.

[1214] The coating may optionally contain additional pharmaceutically acceptable excipients, such as plasticizers, stabilizers, water-soluble components (e.g., pore formers), anti-adhesives (e.g., talc), surfactants, etc., or combinations thereof.

[1215] The functional coating may include release modifiers that affect the release characteristics of the functional coating. For example, release regulators can be used as pore formers or matrix disruptors. Release modifiers can be organic or inorganic and include materials that can be dissolved, extracted, or leached from the coating in the use environment. Sustained-release agents can include one or more hydrophilic polymers, including cellulose ethers and other celluloses, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; acrylic polymers, such as the gastric-soluble Eudragit FS 30D, the pH-sensitive Eudragit L30D 55, L 100, S100, or L 100-55; or combinations thereof. Other exemplary release modifiers include povidone; sugars (such as lactose, etc.); metal stearates; inorganic salts (such as calcium hydrogen phosphate, sodium chloride, etc.); polyethylene glycols (such as polyethylene glycol (PEG) 1450, etc.); sugar alcohols (such as sorbitol, mannitol, etc.); alkali metal alkyl sulfates (such as sodium lauryl sulfate); polyoxyethylene sorbitan fatty acid esters (such as 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 be used as a matrix disruptor. Examples of inorganic disruptors include various calcium salts, such as monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate; silica, and talc.

[1216] The coating may optionally contain a plasticizer to improve the physical properties of the coating. For example, since ethyl cellulose 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 ethyl cellulose before using it as a coating material. Generally, the amount of plasticizer contained in the coating solution is based on the concentration of the polymer. For example, depending on the polymer, it can be from about 1% to about 200%, but most commonly it is about 1 wt% to about 100% of the polymer. However, the concentration of the plasticizer can be determined by routine experimentation.

[1217] 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 (such as acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[1218] Examples of plasticizers for acrylic polymers include citrate esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2 - propanediol, polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, triacetin, or combinations thereof, although other plasticizers (such as acetylated monoglycerides, phthalates, castor oil, etc.) can also be used.

[1219] A suitable method can be used to apply the coating material to the surface of the dosage form core. 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.

[1220] In certain embodiments, an optional intermediate coating is used between the dosage form core and the outer coating. This intermediate coating can be used to protect the active agent or other components of the core subunit from 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 methylcellulose, polyethylene glycol, poly(ethylene oxide), etc., 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.

[1221] Combination and alternate therapies

[1222] The compounds or their pharmaceutically acceptable salts described herein can be administered on the basis of the current COVID patient care standard or in combination or alternation with any other compounds or therapies that a healthcare provider deems beneficial to the patient. The combination and / or alternate therapies can be therapeutic, adjuvant, or palliative.

[1223] It has been observed that COVID patients may experience different disease stages, and the standard of care may vary depending on the disease stage the patient presents or progresses to. Notably in COVID, there is the development of "crosstalk" between the immune system and the coagulation system. As the disease progresses, the patient's immune system may overreact, which can lead to many serious consequences, including cytokine storms. Through the interaction between the immune system and the coagulation system, the patient can start to form clots in various parts of the body, including the respiratory system, brain, heart, and other organs. Multiple clots have been observed throughout the body in COVID patients, requiring anticoagulant therapy. It is believed that if the disease is not treated and alleviated, these clots may cause long - term or even permanent damage.

[1224] More specifically, COVID - 19 is described as going through three general disease stages: Stage 1 (early infection), Stage 2 (lung stage), and Stage 3 (hyper - inflammatory stage / cytokine storm).

[1225] The characteristics of the first stage are non-specific and usually mild symptoms. Viral replication is occurring, making it suitable to immediately initiate treatment with the compounds described herein, and it may be combined with or alternated with another antiviral therapy. Interferon-β can also be administered to enhance the innate immune response to the virus. Thus, 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 or alternated with interferon-β and / or an additional antiviral agent. Zinc supplements and / or vitamin C are sometimes also taken at this stage or as the disease progresses.

[1226] The second stage of COVID-19 is the pulmonary stage, and patients may develop acute hypoxemic respiratory failure. In fact, the main organ failure in COVID-19 is hypoxemic respiratory failure. It has been shown that moderate immunosuppression with steroids (such as dexamethasone) is beneficial for patients with acute hypoxemic 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 which 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 days, DexPak 13 days, DexPak 6 days).

[1227] 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 the form of being combined with or alternated with remdesivir to enhance the overall antiviral effect.

[1228] The third stage is the final stage of the disease, characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small blood clots form throughout the bloodstream. This stage may also include multiple organ failure (e.g., vasodilatory shock, myocarditis). It has also been observed that many patients respond with a "cytokine storm" to this severe stage of COVID-19 infection. There does indeed appear to be a two-way synergistic relationship between DIC and the cytokine storm. To combat DIC, patients are often administered anticoagulants, which can be, for example, 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 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 a pharmaceutically acceptable salt thereof, are administered in the following form: in combination with or alternating with anticoagulant therapy. In some severe coagulation cases in COVID patients, TPA (tissue plasminogen activator) can be used.

[1229] It has been observed that high levels of the cytokine interleukin-6 (IL-6) are precursors of respiratory failure and death in COVID-19 patients. To treat this potentially cytokine storm-forming surge in immune response, monoclonal antibodies, drug inhibitors, or proteolysis targeting IL-6 can be administered to patients, such as bispecific compounds that bind IL-6 and a protein mediating 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 the following form: in combination with or alternating with tocilizumab or sarilumab. Other non-limiting examples of immunosuppressive drugs for treating an overactive 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 (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).

[1230] IL-1 blocks the production of IL-6 and other pro-inflammatory cytokines. COVID patients are sometimes also treated with anti-IL-1 to reduce excessive inflammatory responses, such as intravenous anakinra. Anti-IL-1 therapies can generally be, for example, targeted monoclonal antibodies, drug inhibitors, or proteolysis agents, such as bispecific compounds that bind IL-1 and a protein mediating degradation.

[1231] 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". The 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, therefore, 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 with or alternately with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such drugs can be used both as anti-inflammatory drugs in COVID patients and have a therapeutic effect on secondary bacterial infections.

[1232] 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 the treatment, analgesics can be added sequentially, and for persistent anxiety, sedatives can be added sequentially. 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 predominance properties (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 form of: in combination with or alternately with an analgesic, such as acetaminophen, ketamine, hydromorphone, fentanyl or morphine. 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 form of: in combination with or alternately with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol or phenobarbital.

[1233] Investigational drugs for COVID-19 include chloroquine and hydroxychloroquine. 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 form of: in combination with or alternately with chloroquine or hydroxychloroquine.

[1234] Protease inhibitors, such as lopinavir or ritonavir, which have been previously approved for HIV treatment, can also be used.

[1235] Other drugs that can be used to treat COVID patients include, but are not limited to, favipiravir, fingolimod (Gilenya), methylprednisolone, bevacizumab (Avastin), Actemra (tocilizumab), umifenovir, losartan, and monoclonal antibody combinations of REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines can be used in combination with or alternately with the active compounds provided herein to treat virus infections sensitive to them.

[1236] In one embodiment, the compounds of the present invention are used in combination with an anti-coronavirus vaccine therapy in an effective amount, 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 (Novavax), 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 combination with a passive antibody therapy or a convalescent plasma therapy in an effective amount.

[1237] SARS-CoV-2 is constantly mutating, and many mutations increase virulence and transmission rates. After long-term treatment with antiviral drugs, drug-resistant virus variants may emerge. Resistance may occur through mutations in the genes encoding the enzymes used in viral replication. In some cases, the efficacy of a drug against an RNA virus infection can be extended, enhanced, or restored by combining or alternately administering the compound with another, and possibly even two or three other antiviral compounds, which can induce different mutations or act through a different pathway, different from that of the main drug.

[1238] Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameters of the drug can be altered by this combination therapy (which may include alternate therapy if synergistic 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:

[1239] (1) protease inhibitors;

[1240] (2) another polymerase inhibitor;

[1241] (3) allosteric polymerase inhibitors;

[1242] (4) Interferon alfa-2a, which may be pegylated or otherwise modified, and / or ribavirin;

[1243] (5) Substrate-unbased inhibitors;

[1244] (6) Helicase inhibitors;

[1245] (7) Antisense oligodeoxynucleotides (S-ODN);

[1246] (8) Aptamers;

[1247] (9) Nuclease-resistant ribozymes;

[1248] (10) iRNA, including microRNA and SiRNA;

[1249] (11) Antibodies, partial antibodies or domain antibodies against the virus; or

[1250] (12) Viral antigens or partial antigens that induce a host antibody response. Examples

[1251] General methods

[1252] 1 H, 19 F and 31 P NMR spectra were recorded on a 400 MHz Fourier transform Brücker spectrometer. Unless otherwise stated, the spectra were DMSO-d 6 . Spin multiplicities are denoted by the symbols s (singlet), d (doublet), t (triplet), m (multiplet) and Br (broad peak). Coupling constants (J) are reported in Hz. Reactions were generally carried out under a dry nitrogen atmosphere using Sigma-Aldrich anhydrous solvents. All common chemicals were purchased from commercial sources.

[1253] The following abbreviations were used in the examples:

[1254] BID: Twice a day

[1255] DCM: Dichloromethane

[1256] EtOAc: Ethyl acetate

[1257] EtOH: Ethanol

[1258] GT: Genotype

[1259] HPLC: High performance liquid chromatography

[1260] LD: Loading dose

[1261] NaOH: Sodium hydroxide

[1262] Na 2 SO 4 : Sodium sulfate (anhydrous)

[1263] MeOH: Methanol

[1264] Na 2 SO 4 : Sodium sulfate

[1265] NH 4 Cl: Ammonium chloride

[1266] PE: Petroleum ether

[1267] Silica gel (230 to 400 mesh, Sorbent)

[1268] t-BuMgCl: tert-Butylmagnesium chloride

[1269] THF: Tetrahydrofuran (THF), anhydrous

[1270] TP: Triphosphate

[1271] Example 1. Synthesis of Compound 1A and Compound 2A

[1272] 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)

[1273]

[1274]

[1275] In Step 1, Compound 1-1 was dissolved in DCM and the reaction was cooled to 10 °C, then benzyl chloroformate was added, and then NEt 3Cool the reaction to room temperature and stir for 12 - 14 hours. Thereafter, under appropriate work-up and purification conditions, Compound 1-2 is isolated. In Step 2, before adding Morpho DAST, dissolve Compound 1-2 in acetonitrile and cool to -15 to 5 °C. Stir the reaction for 6 hours. Thereafter, under appropriate work-up and purification conditions, Compound 1-3 is isolated. In Step 3, dissolve Compound 1-3 in toluene and cool the reaction to 0 - 10 °C, then add reduced aluminum. Then, under appropriate work-up and purification conditions, Compound 1-4 is isolated as a diastereomer having (R)-stereochemistry at the hydroxy position. In Step 4, dissolve Compound 1-4 in acetonitrile and cool to -15 to 5 °C, then add CBr4 and PPh3. Then, under appropriate work-up and purification conditions, Compound 1-5 is isolated. In Step 5, dissolve Compound 1-5 in acetonitrile and add t-BuOH, t-BuOK, and 6-chloro-9H-purin-2-amine. Heat the reaction to 40 - 50 °C. Then, under appropriate work-up and purification conditions, Compound 1-6 is isolated. In Step 6, dissolve Compound 1-6 in MeOH and add MeNH 2 Heat the reaction to 20 - 30 °C. Under appropriate work-up and purification conditions, Compound 1-7 is isolated.

[1276] Part B: Synthesis of dihydroquinine salt (1-12) of (hydroxy(phenoxy)phosphoryl)-L-alanine isopropyl ester

[1277]

[1278] Add phenyl dichlorophosphate (1-8, 150 g, 1.0 eq.) to 1300 mL of isopropyl acetate. Cool the solution to -10 °C ± 5 °C, then add benzyl alcohol (1-9, 80.6 g, 1.05 eq.) and a solution of Et 3 N (86.3 g, 1.2 eq.). Stir the mixture at -10 ± 5 °C for 3 hours. Monitor the reaction endpoint by TLC.

[1279] At -10 °C ± 5 °C, add L-alanine isopropyl ester hydrochloride (1-10, 125 g, 1.05 eq.) and Et 3 N (152 g, 2.1 eq.). Stir the reaction mixture at -10 ± 5 °C for 2 hours. Monitor the reaction endpoint by TLC.

[1280] Filter the reaction mixture and wash the filter cake with 20 mL of isopropyl acetate. Wash the filtrate with 1N HCl, water, and aqueous sodium bicarbonate. Wash the separated organic layer with anhydrous Na 2 SO 4Dry, then concentrate to dryness under vacuum at 40 °C - 50 °C to obtain 240 g of crude product 1-11, which is a mixture of diastereomers (approx. 1:1). (Pale yellow oil; yield: 89.6% mol / mol; HPLC purity: 83.4% area; HPLC analysis: 86.2% w / w). This product contains approximately 6% - 7% residual benzyl alcohol. The crude product 1-4 was directly used in the next step.

[1281] Add compound 1-11 (135 g, 1.0 eq., 86.2% analysis) and quinine (100 g, 1.0 eq.) to 650 mL of isopropanol. After adding 5% Pd / C (19.2 g, 60% water, according to KF), hydrogenate at 20 °C - 25 °C for 8 hours using a hydrogen gas bag in a closed system. After the reaction is complete, filter the mixture through a Buchner funnel. Concentrate the filtrate under vacuum to remove the solvent.

[1282] Add 300 mL of TBME to the above residue. Concentrate the mixture under vacuum at 40 °C - 45 °C to remove the solvent, and then repeat this step with another 300 mL of MTBE. Add 600 mL of MTBE to it, stir the mixture at 40 °C - 45 °C for 1 hour, and then stir at 0 °C - 5 °C for another 1 hour. Filter the mixture, and wash the filter cake with 100 mL of MTBE. Dry the filter cake at 45 °C under non-vacuum for 16 hours to obtain 152 g of the dihydroquinine salt of (hydroxy(phenoxy)phosphoryl)-L-alanine isopropyl ester (1-12, white solid; yield: 69.5% mol / mol; HPLC purity: 97.91%).

[1283] Part C: Synthesis of Compound 1A

[1284]

[1285] (Hydroxy(phenoxy)phosphoryl)-L-alanine isopropyl ester dihydroquinine salt (1-12, 5.9 g, 1.5 eq.), compound 1-7 (2.0 g, 1.0 eq), DIPEA (0.83 g, 1.0 eq), and HATU (3.65 g, 1.5 eq) are added to 100 mL of dichloromethane. Heat the mixture to 40 °C and stir for 18 hours. Monitor the reaction by TLC and HPLC.

[1286] After the reaction is complete, cool the reaction mixture to room temperature and wash it with 1N hydrochloric acid (100 mL x 2), water (100 mL x 2), and 5% aqueous sodium bicarbonate solution 15 mL x 1. The separated organic phase is dried with 2 g of anhydrous sodium sulfate, filtered, and concentrated under vacuum at 40 °C - 45 °C to obtain a yellow oil.

[1287] Add isopropyl acetate (10 mL). After stirring, the mixture was concentrated under vacuum. Then, 25 mL of isopropyl acetate was added. The mixture was heated to 45 °C to give a clear solution. After stirring at room temperature for 2 h, the solid precipitate was filtered and dried under non-vacuum conditions at 45 °C for 15 h to give 2.0 g of crude compound 1A (yield: 53.8% mol / mol; HPLC purity: 93.1% area (containing 3.7% of Rp-compound 1B)).

[1288] A mixture of crude compound 1A (2.0 g) and 15 mL of isopropyl acetate was heated to 80 °C - 85 °C to give a solution. The solution was cooled to 20 °C - 25 °C and stirred for 1 h. The precipitated solid was filtered, washed with isopropyl acetate (1 mL), and dried under non-vacuum conditions at 50 °C for 16 h to give 1.7 g of compound 1A (yield: 45.7% mol / mol; HPLC purity: 98.99%). 1 HNMR, 19 FNMR and 31 PNMR spectra confirmed the structure of compound 1A.

[1289] Part D: Synthesis of hemisulfate compound 2A

[1290]

[1291] Charge methanol (151 mL) into a 250 mL flask and cool the solution to 0 - 5 °C. Add a concentrated solution of H 2 SO 4 dropwise over 10 min. Charge compound 1A (151 g) and acetone (910 mL) into a separate flask and add the H 2 SO 4 / MeOH solution dropwise over 2.5 h at 25 - 30 °C. A large amount of solid precipitated out. After stirring the solution at 25 - 30 °C for 12 - 15 h, the mixture was filtered, washed with methanol / acetone (25 mL / 150 mL), and dried under vacuum at 55 - 60 °C to give compound 2A (121 g, 74%). 1 HNMR: (400 MHz, DMSO-d 6):δ8.41(br, 1H), 7.97(s, 1H), 7.36(t, J = 8.0Hz, 2H), 7.22(d, J = 8.0Hz, 2H), 7.17(t, J = 8.0Hz, 1H), 6.73(s, 2H), 6.07(d, J = 8.0Hz, 1H), 6.00(dd, J = 12.0, 8.0Hz, 1H), 5.81(br, 1H), 4.84 - 4.73(m, 1H), 4.44 - 4.28(m, 3H), 4.10(t, J = 8.0Hz, 2H), 3.85 - 3.74(m, 1H), 2.95(s, 3H), 1.21(s, J = 4.0Hz, 3H), 1.15 - 1.10(m, 9H)

[1292] Example 2. Synthesis of the selected compounds of the present invention

[1293] The nuclear magnetic resonance spectra were recorded on a 400 MHz Fourier transform Brücker spectrometer. The spectra were obtained from samples prepared in a 5 mm diameter tube in CDCl 3 、CD 3 OD or DMSO-d 6 6. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), m (multiplet), and Br (broad peak). Coupling constants (J) are reported in Hz. The MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS instrument. Reactions were generally carried out under a dry nitrogen atmosphere using Sigma-Aldrich anhydrous solvents. All common chemicals were purchased from commercial sources.

[1294] Synthesis of 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 (Compound 5)

[1295]

[1296]

[1297] Step 1: N-(6-chloro-9-((6aR,8R,9R,9aR)-2,2,4,4-tetraisopropyl-9-((trimethylsilyl)oxy)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-9H-purin-2-yl)acetamide: A solution of Intermediate 2-1 (50.2 g, 92.25 mmol) in DCM (500 mL) and pyridine (75 mL) was added to TMSCl (30.1 g, 276.74 mmol) at 0 °C and stirred at 0 °C for 0.5 h. Acetic anhydride (28.2 g, 276.74 mmol) was added to the solution and the reaction was stirred at 0 °C for 0.5 h and then at room temperature for 1 h. H 2 O and EtOAc were added to the reaction mixture. The organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 0 to 10%) to give Intermediate 2-2 (53 g, 51%) as a yellow solid.

[1298] Step 2: N-(6-chloro-9-((6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-9H-purin-2-yl)acetamide: p-Toluenesulfonic acid monohydrate (5.9 g, 36.67 mmol) was added to a solution of Intermediate 2-2 (53 g, 82.25 mmol) in THF (530 mL) at room temperature. The solution was stirred at room temperature for 1 h. Then, TEA (8.3 g, 82.25 mmol) was added and the reaction mixture was concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 10% to 20%) to give Intermediate 2-3 (47 g, 99.5%) as a white solid.

[1299] Step 3: N-(6-Chloro-9-((6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)acetamide: Chromium trioxide (18.9 g, 189.36 mmol) was dispersed in DCM (280 mL), and pyridine (15.0 g, 189.36 mmol) and acetic anhydride (19.3 g, 189.36 mmol) were added dropwise. The reaction mixture turned black. Intermediate 2-3 (37 g, 63.12 mmol) in DCM (380 ml) was added at room temperature and the reaction was stirred for 0.5 h. EtOAc (1200 mL) was added. The reaction mixture was filtered and concentrated, and azeotroped with toluene (200 mL). The residue was purified by column chromatography (silica gel, EA / PE = 33% to 100%) to give intermediate 2-4 (34.8 g, 94%) as a white solid.

[1300] Step 4: N-(6-Chloro-9-((6aR,8R,9S,9aR)-9-hydroxy-2,2,4,4-tetraisopropyl-9-methyltetrahydro-6H-furo[3,2-f)[1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)acetamide: Magnesium powder (6.7 g, 278.66 mmol) was dispersed in anhydrous ether (380 mL), deuterated methyl iodide (9.2 g, 63.33 mmol) was added, and the reaction was stirred at room temperature for 0.5 h and then warmed to room temperature. Deuterated methyl iodide (27.5 g, 190.00 mmol) was added dropwise and the reaction was stirred for 1 h, then the temperature was lowered below 10 °C and a solution of intermediate 2-4 (37 g, 63.33 mmol) in DCM (380 ml) was added. The reaction was stirred for 1 h, then quenched with saturated NaHCO 3 and extracted with EtOAc. The organic phase was washed with saturated brine and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 33% to 50%) to afford intermediate 2-5 (22 g, 57.9%) in solid form.

[1301] Step 5: N-(6-chloro-9-((2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-9H-purin-2-yl)acetamide: A solution of tetrabutylammonium fluoride (23.12 g, 73.30 mmol) in THF (70 ml) was added to a solution of intermediate 2-5 (22 g, 36.65 mmol) in THF (150 mL). The solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by column chromatography (silica gel, MeOH / DCM = 2% to 5%) to afford intermediate 2-6 (20 g, >100%) as a solid.

[1302] Step 6: (2R,3R,4S,5R)-5-(2-acetamido-6-chloro-9H-purin-9-yl)-2-(acetoxymethyl)-4-hydroxy-4-methyltetrahydrofuran-3-yl acetate: Acetic anhydride (22.8 g, 223.62 mmol) was added to a solution of intermediate 2-6 (20 g, 55.90 mmol) in anhydrous DCM (400 mL) and pyridine (8 ml). The solution was stirred at 0 °C overnight. Then, EtOAc was added and the suspension was filtered. The solution was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to give intermediate 2-7 (8.4 g, 29.8% yield over 3 steps) as a solid.

[1303] Step 7: (2R,3R,4R,5R)-5-(2-acetamido-6-chloro-9H-purin-9-yl)-2-(acetoxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate: DAST (5.9 g, 36.67 mmol) was added dropwise to a solution of intermediate 2-7 (5.4 g, 12.22 mmol) in DCM (220 mL) at -65 °C and the reaction was stirred for 0.5 hour. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate and separated. The organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 50% to 100%) to afford intermediate 2-8 (1.54 g, 30%) as a solid.

[1304] Step 8: (2R,3R,4R,5R)-5-(2-Amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol: A solution of intermediate 2-8 (890 mg, 2.01 mmol) in methylamine (18% in EtOH) (36 mL) was stirred overnight at room temperature in a sealed container and concentrated. Then additional sodium methoxide (325.0 mg, 6.02 mmol) was added and the solution was stirred for an additional 1 hour at room temperature. Acetic acid was added to adjust the pH to 7 and the solution was concentrated. The residue was purified by column chromatography (silica gel, MeOH / DCM = 0 to 2%) to afford the solid intermediate 2-9 (400 mg, 64.5%). 1 H NMR (400 MHz, CD 3 OD) δ 8.057 (s, 1H), 6.103 (d, J = 18.4 Hz, 1H), 4.047 - 4.015 (m, 2H), 3.878 - 3.845 (m, 1H), 3.030 (s, 3H). 19 F NMR (400 MHz, CD 3 OD) δ 164.351 (s). MS (ESI) m / z C 12 H 14 D 3 FN 6 O 3 [M + H] + Theoretical value for 316.13; found 316.4.

[1305] Step 9: ((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: To a solution of intermediate 2-9 (230 mg, 0.736 mmol) and ((R)-(perfluorophenoxy)(phenoxy)phosphoryl))-L-alanine isopropyl ester (334 mg, 0.736 mmol) in THF (4 ml) at -5 °C was added dropwise t-BuMgCl (1.7 N in THF) (912 μL, 1.55 mmol). The solution was stirred at 0 °C for 0.5 hour. Then the reaction mixture was quenched with saturated NH 4 Cl aqueous solution. The residue was purified by column chromatography (silica gel, MeOH / DCM = 0 to 3.3%) to afford the compound 5 in solid form (130 mg, 30.5%). 1HNMR (400 MHz, DMSO) δ 7.81 (s, 1H), 7.32 - 7.16 (m, 5H), 6.13 - 6.08 (d, J = 18.8, 8.0 Hz, 1H), 4.87 (s, 1H), 4.50 (m, 3H), 4.19 (m, 1H), 3.89 (m, 1H), 3.02 (s, 1H), 1.30 - 1.27 (m, 3H), 1.17 - 1.13 (m, 9H). 19 F NMR (400 MHz, DMSO) δ -163.42 (s). MS (ESI) m / z C 24 H 30 D 3 FN 7 O 7 P[M + H] + The theoretical value of 585.22; the measured value of 585.5.

[1306] Synthesis of 3.((S)-(((2R,3R,4R,5R)-5-(2-Amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-4-(fluoromethyl)-3-hydroxyoxolan-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 6)

[1307]

[1308] Step 1: (6aR,8R,9R,9aS)-8-(2-Amino-6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-9-ol: To a solution of intermediate 3-1 (81.8 g, 0.27 mol) in pyridine (330 mL) at 0 ± 5 °C was added dropwise TPDSCl 2 (102.6 g, 0.32 mol). The solution was stirred at 0 °C for 2 hours and quenched with water. Then, EtOAc was added, the phases were separated and dried over anhydrous Na 2 SO 4 The solution was concentrated and azeotroped with toluene three times to remove pyridine. The residue was purified by column chromatography (DCM / MeOH = 200∶1 - 100∶1) to give the oily intermediate 3-2 (123.3 g, 83.6% yield).

[1309] Step 2: N-(6-chloro-9-((6aR,8R,9R,9aR)-2,2,4,4-tetraisopropyl-9-((trimethylsilyl)oxy)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)isobutyramide: To a solution of intermediate 3-2 (122.6 g, 0.225 mol) in DCM (1300 mL) and pyridine (184 mL) at 0 - 5 °C, TMSCl (48.7 g, 0.45 mol) was added dropwise. The reaction mixture was stirred at 0 °C for 10 minutes. Then isobutyryl chloride (36 g, 0.337 mol) was added and the reaction was stirred for another 10 minutes at 0 °C. Water was added, and the phases were separated and washed with an aqueous CuSO 4 aqueous solution. The organic phase was washed with brine and dried over anhydrous Na 2 SO 4 and concentrated to obtain crude intermediate 3-3 (151.7 g).

[1310] Step 3: N-(6-chloro-9-((6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)isobutyramide: To a solution of intermediate 3-3 (151.7 g, 0.22 mol) in THF (1500 mL) was added p-toluenesulfonic acid monohydrate (29 g, 0.155 mol). The mixture was stirred at room temperature for 10 minutes and then quenched with triethylamine (35 ml). The solution was concentrated and purified by column chromatography (DCM / MeOH = 200∶1 - 100∶1) to obtain intermediate 3-4 (81 g, 58.5% yield over 2 steps).

[1311] Step 4: N-(6-chloro-9-((6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)isobutyramide: At 0 °C, DMP (56 g, 0.13 mol) was added to a solution of intermediate 3-4 (40 g, 0.065 mol) in DCM (300 mL). The reaction mixture was stirred at room temperature overnight. Then, diethyl ether (2000 mL) was added and the suspension was filtered. The solution was washed successively with saturated NaHCO 3 aqueous solution, saturated Na 2 S 2 O 3 aqueous solution and brine. The organic phase was dried over anhydrous Na 2 SO 4 dried, concentrated, and azeotroped with toluene to obtain intermediate 3-5, which was directly used in the next step.

[1312] Step 5: N-(6-chloro-9-((6aR,8R,9S,9aR)-9-hydroxy-2,2,4,4-tetraisopropyl-9-((trimethylsilyl)ethynyl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)isobutyramide: At -15 to -20 °C, n-butyllithium (204 ml, 0.51 mol) (350 ml) was added dropwise to an anhydrous THF solution of trimethylsilylacetylene (52 g, 0.529 mol). The solution was stirred at -15 to -20 °C for 30 minutes. Then, the reaction mixture was cooled to -70 °C and an anhydrous DMF (200 mL) solution of intermediate 3-5 (54 g, 0.088 mol) was added dropwise. The solution was stirred at -70 °C for 20 minutes. The resulting solution was slowly warmed to 0 °C and quenched by adding saturated NH 4 Cl aqueous solution. EtOAc was added, the organic phase was separated and washed with brine, and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to give yellow solid intermediate 3-6 (35.1 g, 56% yield over 2 steps).

[1313] Step 6: N-(6-chloro-9-((6aR,8R,9R,9aR)-9-fluoro-2,2,4,4-tetraisopropyl-9-((trimethylsilyl)ethynyl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-9H-purin-2-yl)isobutyramide: At -70 °C, DAST (2.27 g, 14.05 mmol) was added to a solution of intermediate 3-6 (2 g, 2.81 mmol) in DCM (20 mL) and pyridine (0.703 g, 8.85 mmol). The reaction mixture was slowly warmed to -30 °C and stirred at -30 °C for 5 minutes. Then, the solution was slowly added to saturated NaHCO 3 aqueous solution and DCM was added. The organic phase was separated and washed with brine, and dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to afford white solid intermediate 3-7 (1.257 g, 62.85% yield).

[1314] Step 7: N-(9-((6aR,8R,9R,9aR)-9-Ethynyl-9-fluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-6-(methylamino)-9H-purin-2-yl)isobutyramide: To a solution of intermediate 3-7 (14 g, 19.65 mmol) in methanol (30 mL) at 0 °C was added 30% methylamine methanol solution (30 ml) and the reaction was stirred at room temperature for 5 minutes. Then the solution was concentrated at room temperature to remove methylamine. Thereafter, the resulting solution was concentrated and purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to afford intermediate 3-8 as a white solid (8.8 g, 70.4% yield).

[1315] Step 8: N-(9-((6aR,8R,9R,9aR)-9-Fluoro-2,2,4,4-tetraisopropyl-9-vinyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocane-8-yl)-6-(methylamino)-9H-purin-2-yl)isobutyramide. To a solution of intermediate 3-8 (8.8 g, 13.86 mmol) in EtOAc (88 mL) was added Lindlar catalyst (3.52 g). Then, the solution was stirred overnight at room temperature under a hydrogen atmosphere (0.8 MPa). The reaction mixture was filtered to remove the catalyst, concentrated and purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to afford intermediate 3-9 as a solid (7.5 g, 85.2% yield).

[1316] Step 9: N-(9-((2R,3R,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-vinyltetrahydrofuran-2-yl)-6-(methylamino)-9H-purin-2-yl)isobutyramide. At 0 °C, to a solution of intermediate 3-9 (7.5 g, 11.77 mmol) in THF (40 ml) was added a solution of TBAF (5.56 g, 17.65 mmol) in THF (35 ml). When TLC indicated complete conversion of the starting material, the solution was concentrated and purified by column chromatography (DCM / MeOH = 200:1 - 10:1) to afford intermediate 3-10 as a solid (3.8 g, 82.6% yield).

[1317] Step 10: ((2R,3R,4R,5R)-3-(Benzoyloxy)-4-fluoro-5-(2-isobutyramido-6-(methylamino)-9H-purin-9-yl)-4-ethenyltetrahydrofuran-2-yl)methyl benzoate. At 0 °C, BzCl (2.9 g, 20.64 mmol) was added to a solution of compound intermediate 3-10 (3.7 g, 9.38 mmol) in pyridine (19 ml). The reaction mixture was stirred overnight at room temperature. Then, the reaction mixture was quenched with methanol and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to afford intermediate 3-11 as a white solid (4.68 g, 82.8% yield).

[1318] Step 11: ((2R,3R,4R,5R)-3-(Benzoyloxy)-4-((S)-1,2-dihydroxyethyl)-4-fluoro-5-(2-isobutyramido-6-(methylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl benzoate. To a solution of intermediate 3-11 (4.68 g, 7.77 mmol) in THF (46.8 ml) and H 2 O (9.36 ml) was added NMO (1.82 g, 15.53 mmol) and Os0 4 (0.65 g, 2.56 mmol). The reaction mixture was stirred overnight at room temperature. Then, the reaction mixture was quenched with saturated Na 2 S 2 O 3 aqueous solution and EtOAc was added. The organic phase was separated, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200∶1 - 50∶1) to give intermediate 3-12 as a white solid (4 g, 82% yield).

[1319] Step 12: ((2R,3R,4R,5R)-3-(Benzoyloxy)-4-fluoro-4-(hydroxymethyl)-5-(2-isobutyramido-6-(methylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl benzoate. Intermediate 3-12 (4 g, 6.28 mmol) was dissolved in methanol (40 ml), THF (11.7 ml) and water (7 ml). Then, sodium periodate (2 g, 9.42 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with methanol and THF. NaBH 4 (0.382 g, 10.05 mmol) was added portionwise to the resulting solution and the reaction was stirred for 10 minutes. The reaction mixture was quenched with ice water and EtOAc was added. The organic phase was separated, washed with brine, dried over anhydrous Na2 SO 4 Dry and concentrate. The residue was purified by column chromatography (DCM / MeOH = 200:1 - 50:1) to give the white solid intermediate 3-13 (3.17 g, 83.2% yield).

[1320] Step 13: ((2R,3R,4R,5R)-3-(Benzoyloxy)-4-fluoro-4-(fluoromethyl)-5-(2-isobutyramido-6-(methylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl benzoate. At -15 to -20 °C, trifluoromethanesulfonic anhydride (838 mg, 2.97 mmol) was added to a solution of intermediate 3-13 (1000 mg, 1.65 mmol) in DCM (10 ml) and pyridine (650 mg, 8.24 mmol). The reaction mixture was stirred at -15 to -20 °C for 10 minutes. The solution was quenched with saturated NaHCO 3 aqueous solution and washed with CuSO 4 aqueous solution. Then, the organic phase was washed with brine and dried over anhydrous Na 2 SO 4 and concentrated. The crude product was dissolved in acetonitrile (10 ml) and a solution of TBAF (1 M, 8.25 ml) in THF was added to the resulting solution. The reaction mixture was stirred for 5 minutes and monitored by TLC. Then the reaction was diluted with EtOAc and water. The phases were separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 - 100:1) to give the white solid intermediate 3-14 (113 mg, 37.7% yield).

[1321] Step 14: (2R,3R,4R,5R)-5-(2-Amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-4-(fluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3-ol. Intermediate 3-14 (0.51 g, 0.84 mmol) was dissolved in 20% methylamine in methanol solution and stirred overnight at 100 °C in a sealed steel reactor. The reaction mixture was concentrated and purified by column chromatography (DCM / MeOH = 200:1 - 10:1) to give the white solid intermediate 3-15 (241 mg, 87.6% yield). 1 H NMR (400 MHz, CD 3OD) δ 7.94 (s, 1H), 6.28 (d, J = 20.0 Hz, 1H), 4.84 - 4.56 (m, 1H), 4.46 (t, J = 24.0 Hz, 1H), 4.35 - 3.89 (m, 1H), 3.86 (m, 2H), 3.30 (d, J = 20.0 Hz, 1H), 3.03 (s, 3H). 19 F NMR (400 MHz, CD 3 OD) δ 179.67 (s), 80.15 (s).

[1322] Step 15: ((S)-(((2R, 3R, 4R, 5R)-5-(2-Amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-4-(fluoromethyl)-3-hydroxyoxolan-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester. Intermediate 3-15 (150 mg, 0.45 mmol) was dissolved in acetonitrile (6 mL), and NMI (895.6 mg, 10.80 mmol) was added at room temperature. The solution was cooled to 0 °C, and a solution of (chloro(phenoxy)phosphoryl)-L-alanine isopropyl ester (1247.7 mg, 4.05 mmol) in acetonitrile (2 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 5 minutes and monitored by TLC. Then, the resulting solution was quenched with water and diluted with EtOAc. The phases were separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200∶1 - 30∶1) to give the white solid compound 6 (111 mg, 40.8% yield).

[1323] 1 H NMR (400 MHz, CD 3 OD) δ 7.78 (s, 1H), 7.31 - 7.16 (m, 5H), 6.27 (dd, J = 20.0, 8.0 Hz, 1H), 4.91 - 4.84 (m, 1H), 4.56 (m, 1H), 4.51 (m, 4H), 4.50 (m, 1H), 3.87 (dd, J = 20.0, 8.0 Hz, 1H), 3.03 (s, 3H), 1.27 - 1.13 (m, 9H). 19 F NMR (400 MHz, CD 3 OD) δ 179.09 (s). 31 P NMR (400 MHz, CD 3 OD) δ 3.86, 3.79 (d). MS (ESI) m / z C 24 H 32 F 2 N 7O 7 P[M + H] + Theoretical value 600.2; measured value 600.2.

[1324] Synthesis of 4.((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-ethynyl-4-fluoro-3-hydroxyoxolan-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 7)

[1325]

[1326] Step 1: To a solution of intermediate 4-1 (30 mg, 0.09 mmol) in anhydrous THF (2 mL) at 0 °C was added dropwise tert-butylmagnesium chloride (1 M in THF) (112 μL, 0.11 mmol). The solution was stirred at 0 °C for 15 minutes and at room temperature for 45 minutes. Then, the reaction mixture was cooled to 0 °C, and a solution of ((R,S)-(pentafluorophenoxy)-phenoxy-phosphoryl)-L-alanine isopropyl ester (51 mg, 0.11 mmol) in anhydrous THF (1 mL) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 15 hours. Then the reaction mixture was diluted with EtOAc (10 mL) and saturated aqueous NH 4 Cl (8 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (silica gel, DCM / MeOH 0 to 10%) and reverse-phase column chromatography (C-18 silica, H 2 O / MeOH 0 to 100%). Compound 7 (9 mg, 16%) was obtained as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ 7.81, 7.79 (s + s, 1H), 7.36 - 7.14 (m, 5H), 6.26 (d, J = 17.4 Hz, 0.1H), 6.24 (d, J = 17.4 Hz, 0.9H), 4.93 - 4.89 (overlapping with H 2 O, m, 1H), 4.80 - 4.78 (m, 1H), 4.53 - 4.49 (m, 2H), 4.21 - 4.18 (m, 1H), 3.95 - 3.84 (m, 1H), 3.23 - 3.20 (m, 1H), 3.04 (bs, 1H), 1.31 - 1.14 (m, 9H). 31 P NMR (121 MHz, CD3 OD) δ 4.06 (s), 3.97 (s). MS(ESI) m / z C 25 H 32 FN 7 O 7 P[M + H] + Theoretical value 592.2; Measured value 592.2.

[1327] Synthesis of 5.((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy)-4-ethenyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 8)

[1328]

[1329] Step 1: (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-ethenyltetrahydrofuran-3-ol (3).

[1330] To a solution of intermediate 4-1 (255 mg, 0.79 mmol) in EtOH (4 mL) was added palladium (BaSO4 5%) (60 mg) and quinoline (2 drops). The solution was placed under H 2 atmosphere and stirred at room temperature for 1 hour. Then, the mixture was filtered through diatomaceous earth and concentrated. The residue was purified by column chromatography (silica gel, DCM / MeOH 0 to 10%). Intermediate 5-1 (177 mg, 70%) was obtained as a white solid. 1 1H NMR (400 MHz, CD 3 OD) δ 7.98 (s, 1H), 6.12 (d, J = 18.6 Hz, 1H), 5.52 - 5.35 (m, 2H), 5.25 - 5.19 (m, 1H), 4.86 - 4.70 (m, 1H, and H 2 O overlapped), 4.13 - 3.86 (m, 3H), 3.03 (br.s, 3H). MS(ESI) m / z C 13 H 18 FN 6 O 3 [M + H] + Theoretical value 325.1; Measured value 325.2.

[1331] Step 2: (2S)-isopropyl 2-(((((2R,3′R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-ethenyl-4-fluoro-3-hydroxyoxolan-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate. To a solution of intermediate 5-1 (150 mg, 0.47 mmol) in anhydrous THF (10 mL) at 0 °C was added dropwise tert-butylmagnesium chloride (1 M in THF) (560 μL, 0.55 mmol). The solution was stirred at 0 °C for 15 minutes and at room temperature for 45 minutes. Then, the reaction mixture was cooled to 0 °C and a solution of ((R,S)-(pentafluorophenoxy)-phenoxy-phosphoryl)-L-alanine isopropyl ester (250 mg, 0.55 mmol) in anhydrous THF (5 mL) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 15 hours. Then the reaction mixture was diluted with EtOAc (50 mL) and saturated NH 4 Cl aqueous solution (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with saturated NH 4 Cl aqueous solution (50 mL) and brine (50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (silica gel, DCM / MeOH 0 to 10%) and reverse-phase column chromatography (C-18 silica, H 2 O / MeOH 0 to 100%). Compound 8 (45 mg, 16%) was obtained as a white solid. 1 1H NMR (400 MHz, CD 3 OD) δ 7.81 (s, 1H), 7.36 - 7.14 (m, 5H), 6.12 (d, J = 19.1 Hz, 1H), 5.54 - 5.547 (m, 2H), 5.28 - 5.23 (m, 1H), 4.91 - 4.81 (m, 1H, overlapping with H 2 O), 4.58 - 4.47 (m, 2H), 4.28 - 4.22 (m, 1H), 3.95 - 3.85 (m, 1H), 3.05 (br.s, 3H...

Claims

1. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof: The compound or its pharmaceutically acceptable salt is optionally in a pharmaceutically acceptable carrier.

2. The use according to claim 1, wherein the compound has the following formula:

3. The use according to any one of claims 1-2, wherein the pharmaceutically acceptable carrier is a carrier suitable for preparing an oral dosage form.

4. The use according to claim 3, wherein the dosage form is a solid dosage form.

5. The use according to claim 4, wherein the solid dosage form is a tablet or a capsule.

6. The use according to any one of claims 1-2, wherein the pharmaceutically acceptable carrier is a carrier suitable for preparing an intravenous dosage form.

7. The use according to any one of claims 1-2, wherein the pharmaceutically acceptable carrier is a carrier suitable for preparing a parenteral dosage form.

8. The use according to any one of claims 1-2, wherein the compound is administered for at least one week.

9. The use according to any one of claims 1-2, wherein the compound is administered for at least two weeks.

10. The use according to any one of claims 1-2, wherein the compound is administered once, twice, three times or four times a day.

11. The use according to claim 10, wherein the compound is administered twice a day.

12. The use according to claim 10, wherein the compound is administered four times a day.

13. The use according to any one of claims 1-2, wherein the compound is administered in a single dosage form of at least 550 mg.

14. The use according to any one of claims 1-2, wherein the compound is administered in a single dosage form of at least 600 mg.

15. The use according to any one of claims 1-2, wherein the compound is administered in a single dosage form of at least 1100 mg.

16. The use according to claim 1, wherein the compound is administered twice a day at least 550 mg.

17. The use according to claim 1, wherein the compound is administered four times a day at least 550 mg.

18. The use according to claim 2, wherein the compound is administered twice a day at least 600 mg.

19. The use according to claim 2, wherein the compound is administered four times a day at least 600 mg.

20. The use according to claim 2, wherein the host is a human.

21. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need thereof: The compound or its pharmaceutically acceptable salt is optionally in a pharmaceutically acceptable carrier, wherein the medicament is administered in a single dosage form at an oral dose of 550 mg.

22. Use of a compound of the following formula in the preparation of a medicament for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need thereof: The compound is optionally in a pharmaceutically acceptable carrier, wherein the medicament is administered as a single dosage form at an oral dose of 600 mg.

23. The use according to claim 21 or 22, wherein the dosage form is a tablet or a capsule.

24. The use according to claim 21 or 22, wherein the compound is administered for at least one week.

25. The use according to claim 21 or 22, wherein the compound is administered for at least two weeks.

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