Highly active compounds against covid-19

Abstract

To provide compounds and their pharmaceutically acceptable salts that are 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, for example a human, in need thereof.SOLUTION: The present invention provides a pharmaceutical composition for the treatment of coronavirus in a human host in need thereof, comprising a compound represented by the following structure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application is a continuation of U.S. Provisional Patent Application No. 62 / 982,670, filed February 27, 2020, U.S. Provisional Patent Application No. 62 / 994,206, filed March 24, 2020, U.S. Provisional Patent Application No. 63 / 032,247, filed May 29, 2020, U.S. Provisional Patent Application No. 63 / 039,352, filed June 15, 2020, and U.S. Provisional Patent Application No. 63 / 039,352, filed June 15, 2020. This application claims the benefit of U.S. Provisional Patent Application No. 63 / 040,985, filed June 18, 2000, U.S. Provisional Patent Application No. 63 / 054,680, filed July 21, 2020, U.S. Provisional Patent Application No. 63 / 073,328, filed September 1, 2020, and U.S. Provisional Patent Application No. 63 / 146,456, filed February 5, 2021, the entireties of which are incorporated herein by reference for all purposes.

[0002] The present invention relates to the use of selected purine nucleotides and their pharmaceutically acceptable salts that have advantageous activity and convenient dosing for the treatment or prevention of the SARS-CoV-2 virus that causes COVID-19 in a host, typically a human, in need of such treatment or prevention. [Background technology]

[0003] In December 2019, a large number of patients in Wuhan, China, 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 infectious agent was identified as a novel coronavirus, which was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the resulting illness was named coronavirus disease 2019 (COVID-19). This potentially severe and potentially fatal illness spread rapidly around the world. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic.

[0004] Most patients infected with the SARS-CoV-2 virus experience mild, flu-like symptoms, including fever, cough, fatigue, shortness of breath, muscle aches, and loss of taste and / or smell. These symptoms usually subside within a few weeks with minimal medical care. However, symptoms can persist for months. The virus can also cause long-term damage to the lungs, heart, and brain. Furthermore, in some patients, particularly the elderly, immunocompromised individuals, or those with underlying medical conditions, the virus can cause severe symptoms, leading to hospitalization, ventilation, and / or death.

[0005] SARS-CoV-2 is a coronavirus (CoV) belonging to the Coronaviridae family, Coronaviridae subfamily, of the Nidovirales order, which are enveloped viruses with a single-stranded, positive-sense RNA genome. SARS-CoV-2 is approximately 30 kilobases in size, making it one of the largest known RNA genomes. Closely 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 therefore considered a new betacoronavirus that infects humans (Non-Patent Document 1). Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster human-to-human transmission rate (Non-Patent Document 2), making it particularly difficult and dangerous to contain.

[0006] CoVs often occur as enzootic infectious diseases that cross the animal-human species barrier, leading to the establishment of zoonotic diseases in humans (Non-patent Document 3, Non-patent Document 4). By crossing the barrier, CoVs such as SARS-CoV and Middle East Respiratory Syndrome CoV (MERS) have emerged as virulent human viruses (Non-Patent Document 5). Similarly, genome sequencing has revealed that SARS-CoV-2 is 96% identical to bat coronaviruses at the whole genome level (Non-Patent Document 1), and therefore 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, followed by cleavage and activation of the spike protein by the human transmembrane protease serine 2, allowing SARS-CoV-2 to enter cells by endocytosis or direct fusion with the host membrane (Non-Patent Documents 6, 7, and 8).

[0008] After entry into the cell, transcription and replication of SARS-CoV-2 are mediated by a multisubunit polymerase complex. The catalytic subunit of the complex is an RNA-dependent RNA polymerase (RdRp) known as nsp12. While the isolated nsp12 subunit can carry out the polymerase reaction alone, the presence of cofactors nsp7 and nsp8 significantly enhances the efficiency of the polymerase reaction (Non-Patent Document 9, Non-Patent Document 10).

[0009] In April 2020, the crystal structure of SARS-CoV-2 nsp-12 in complex with nsp-7 and nsp-8 was elucidated (Non-Patent Document 11). The structure of nsp12 contains a polymerase C-terminal RdRp domain connected to an N-terminal extension domain termed the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. This NiRAN domain is conserved in all nidoviruses capable of exhibiting nucleotidylation activity and is characterized by an α- and β-fold composed of eight α-helices and a five-stranded β-sheet (Non-Patent Document 11). 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 has spread worldwide, it has exhibited a high mutation rate, resulting in numerous mutated forms of the virus circulating globally. These mutations can affect the virus's ability to cause infection and its transmissibility. For example, in the United Kingdom, the B.1.1.7 variant, designated Variant of Concern 202012 / 01 by Public Health England in the fall of 2020, was identified. This variant contains eight mutations in the spike region. This variant has been shown to spread more rapidly and 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 several mutations with the B.1.1.7 variant, including the N501Y mutation. A variant known as P.1 has also been identified in Brazil, which contains mutations that may affect the virus's ability to be recognized by antibodies. For this reason, it is important to develop therapies capable of treating mutated forms of the virus, particularly those with mutations in the spike protein.

[0011] The history of drug discovery for human coronavirus diseases illustrates the complexity and difficulty of this problem: despite the discovery of MERS-CoV and SARS-CoV in 2012 and 2003, respectively, there have been no licensed commercially available vaccines or drugs for these viruses.

[0012] The lack of licensed treatments, coupled with its high mortality rate and the ease and speed of its transmission, highlights the need to develop effective COVID-19 antivirals. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Zhou et al. Nature 2020, 579, 270 [Non-patent document 2] Huang et al., Lancet 2000, 395, 497 [Non-patent document 3] Lau et al., PNAS 2005, 102, 14040-5 [Non-patent document 4] Rest et al., Infect Genet Evol. 2003, 3, 219-25 [Non-Patent Document 5] Schoeman and Fielding, Virology 2019, 16, 69 [Non-patent document 6] Luan et al. Biochem. Biophys. Res. Commun. 2020: 527, 165 [Non-Patent Document 7] Hoffman, M. et al. Cell, 2020, 181, 271 [Non-patent document 8] Yang et al. Int. J. Biol. Sci. 2020, 16, 1724 [Non-Patent Document 9] Ahn et al. Arch Virol. 2012, 157, 2095 [Non-Patent Document 10] Subissi et al. Proc. Natl. Acad. Sci., 2014, 111, E3900 [Non-Patent Document 11] Gao et al. Science 2020, 368:779-782 Summary of the Invention [Problem to be solved by the invention]

[0014] It is therefore an object of the present invention to provide compounds, compositions and methods for the treatment and prevention of the SARS-CoV-2 virus that causes COVID-19. [Means for solving the problem]

[0015] The present invention relates to the use of active compounds as further described herein for the advantageous treatment, prevention or prophylaxis of the SARS-CoV-2 virus that causes COVID-19. The present invention provides a treatment for SARS-CoV-2 virus in a host in need thereof, comprising administering an amount of selected purine nucleotide compounds, which exhibit targeted activity against the virus.

[0016] Moreover, importantly, these compounds can be administered to a host, such as a human, in need thereof using a simple solid oral dosage form that can be conveniently taken at home or generally outside of a medical facility, without the need for parenteral administration or hospitalization. Where necessary or appropriate, the active compounds described herein may alternatively be administered parenterally or orally within a medical facility. Therapy can be used to treat mild, moderate, or severe disease.

[0017] In one embodiment of the present invention, a compound of formula I: [ka] (In the formula, R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl; 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 alternative In an embodiment, R 2 is aryl(C1-C4 alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1~6 alkyl (including methyl, ethyl, propyl and isopropyl); R 4a and R 4b are independently hydrogen, C1~6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3~7 cycloalkyl; 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 alternative embodiments, R 5 is aryl(C1-C4 alkyl)-, aryl, heteroaryl, or heteroalkyl), or a pharmaceutically acceptable salt thereof, is administered in an effective amount to a host, typically a human, with COVID-19 in need thereof, or to a host at risk of infection or reinfection with the SARS-CoV-2 virus, i.e., prophylactically (wherein the term prophylactically refers to the complete prevention or minimization of acquired infection compared to the disease in the absence of such prophylactic treatment).

[0018] Non-limiting examples of C1-C6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2. Non-limiting examples of C3-C6 cycloalkyl include cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl.

[0019] A non-limiting example of aryl(C1-C4 alkyl)- is benzyl. A non-limiting example of aryl is phenyl.

[0020] In one embodiment, the SARS-CoV-2 virus is wild-type. In another embodiment, the SARS-CoV-2 virus expresses a spontaneous or drug-induced mutation, such as, but not limited to, a mutation in a viral protein selected from envelope (E) protein, membrane (M) protein, spike (S) protein, nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15, nsp16, ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10.

[0021] A non-limiting example of a compound of Formula I is Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered to a host, such as a human infected with SARS-CoV-2 in need thereof or to a host at risk for infection by the SARS-CoV-2 virus, i.e., as a prophylactic. [ka]

[0022] Compound 1 is shown above without regard to the stereochemistry at the chiral phosphorus atom. Compound 1 may be prepared either without regard to the stereochemistry at the phosphorus, or in phosphoro-racemic form, or as an enantiomerically enriched material (i.e., Any desired ratio of phosphorus R- and S-enantiomers of compounds containing 1A is the S-enantiomer and compound 1B is the R-enantiomer. [ka]

[0023] Compound 1, including Compound 1A and Compound 1B, is a potent inhibitor of COVID-19 caused by the SARS-CoV-2 virus. As described in Examples 5 and 6, Compound 1A exhibited an EC of 0.64 μM against SARS-CoV-2 in HAE cells (human airway epithelial cells). 90 The HAE cell assay is an in vitro model of the lung and is representative of SARS-CoV-2 replication. Surprisingly, we also found that the active triphosphate metabolite of compound 1A is robustly formed upon exposure 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 exceeded 1.5 days in both bronchial and nasal epithelial cells. This was previously unpredictable and is particularly important for treating patients in the early stages of infection, when the virus is highly concentrated in nasal and bronchial cells.

[0024] The data presented herein demonstrate that the compounds concentrate in the lung relative to the liver, and previously reported data also confirm that the compounds selectively concentrate in the liver relative to the heart (see, e.g., Example 19 of International Application No. PCT / US2018 / 016301). Collectively, this data confirms that the compounds concentrate in the target organ, the lung, relative to the liver or heart, resulting in reduced toxicity.

[0025] In one embodiment, Compound 1, such as Compound 1A or Compound 1B, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host, e.g., a human, infected with the SARS-CoV-2 virus in need thereof, or to a host at risk of infection by the SARS-CoV-2 virus, i.e., as a prophylactic. In one embodiment, the pharmaceutically acceptable salt is a hemisulfate salt, shown below as Compound 2, Compound 2A, and Compound 2B: [ka] TIFF2024173929000005.tif107170

[0026] As described in Example 8, compound 2A was administered to non-human primates, and intracellular concentrations of the active triphosphate species were measured in lung, kidney, and liver cells. Surprisingly, the active triphosphate metabolite was concentrated in the lung compared to 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 manifests as a respiratory disease. Indeed, the concentration of the active triphosphate species was 1.6-fold higher in the lung than in the liver after twice-daily oral administration of 30 mg / kg of compound 2A.

[0027] Furthermore, the compounds of the present invention are able to inhibit SARS-CoV-2 infection through a unique mechanism of action that confers high selectivity. CoV viral replication is mediated by the cofactors nsp7 and ns This is achieved by the RNA-dependent RNA polymerase (RdRp) nsp12 subunit, which is activated by p8. As discussed in Example 6, a 30-fold difference in the activity of compound 1A against SARS-CoV-2 and MERS-CoV is observed, even though MERS-CoV and other CoVs, such as SARS-CoV-1 and SARS-CoV-2, do not exhibit significant structural differences in the RdRp active site. This suggests that polymerase inhibition is not the sole basis for the difference in activity against these viruses.

[0028] COVID-19 is an acute viral infection, and antiviral therapeutics may be effective during the early stages of infection, when viral load is highest and rapid viral replication occurs primarily in nasal, throat, and lung cells. The availability of potent, safe, oral antiviral drugs administered to SARS-CoV-2-infected individuals early in the disease process could potentially prevent clinical disease, minimize long-term damage, and mitigate the COVID-19 pandemic. As described above, select compounds of the present invention have been shown to be concentrated in the lungs relative to the liver. This is therapeutically beneficial when treating patients in the early stages of infection with the SARS-CoV-2 pathogen, when it is desirable to prevent or reduce viral damage at later stages. Higher concentrations in the lungs relative to the heart and liver are also therapeutically beneficial when treating patients in the later stages of infection.

[0029] The present invention also provides a compound of formula II: [ka] (In the formula, R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl; 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 alternative embodiments, R 2 is aryl(C1-C4 alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1~6 alkyl (including methyl, ethyl, propyl and isopropyl); R 4a and R 4b are independently hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3~7cycloalkyl; 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 alternative embodiments, R 5 includes the use of a compound of formula (I) wherein R is aryl(C1-C4 alkyl)-, aryl, heteroaryl, or heteroalkyl, or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, a compound of formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered to a host infected with the SARS-CoV-2 virus in need thereof, or to a host at risk of infection or re-infection with the SARS-CoV-2 virus. That is, it is administered in an effective amount as a prophylactic measure.

[0031] A non-limiting example of a compound of Formula II is Compound 3 or a pharmaceutically acceptable salt thereof. [ka]

[0032] 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 infected with the SARS-CoV-2 virus in need thereof or to a host at risk of infection by the SARS-CoV-2 virus, i.e., as a prophylactic. Compound 3 can be used in its phosphoro-racemic form or in any desired ratio of phosphorus R- and S-enantiomers of the compound, including materials enriched in one enantiomer up to pure enantiomers. Compound 3A is the S-enantiomer, and compound 3B is the R-enantiomer. [ka]

[0033] Additional non-limiting examples of compounds of Formula II include Compound 4. Alternative structures 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 infected with the SARS-CoV-2 virus in need thereof or at risk of infection, i.e., as a prophylactic. [ka]

[0034] The present invention also provides a compound of formula III: for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention as described herein. [ka] (In the formula, X is C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 (including chloroalkyl), C2-C4 alkenyl, C2-C4 alkyl selected from alkyl, alkynyl, and C1-C3 hydroxyalkyl; R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, the compound of formula III for treating or preventing COVID-19 disease is a compound of formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf, or a pharmaceutically acceptable salt thereof: [ka] TIFF2024173929000012.tif109170

[0036] The present invention also provides a compound of formula IV: [ka] (In the formula, X is C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0037] 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: [ka] TIFF2024173929000015.tif110170

[0038] The present invention also provides a compound of formula V: [ka] (In the formula, Y and Y' are independently selected from Cl and F; R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0039] Non-limiting examples of compounds of formula V include: [ka] Examples include:

[0040] The present invention also provides a method for the treatment or prevention of COVID-19 in a host in need thereof, comprising administering to said host a compound of formula VI: [ka] (In the formula, R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A In an alternative embodiment, —C(O)NR 6B R 6C is selected from R 6A is hydrogen, C 1~6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl(C 1~6 alkyl)-, wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; and in alternative embodiments, R 6A is C 1~20 Alkyl and C 2~20 alkenyl, R 6B and R 6C are independently hydrogen, C 1~20 Alkyl, C2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl, wherein C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl may be optionally substituted with at least one substituent selected from alkoxy (including, but not limited to, methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R 7 is NH2, H or -NR 8 R 9 and R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, -C(O)R 6A and -C(O)OR 6A is selected from Y is selected from F and Cl; Z is methyl, C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 In an alternative embodiment, Z is selected from C 1~4 is alkyl, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein).

[0041] R 6 Non-limiting examples of [ka] Examples include:

[0042] R 6 Additional non-limiting examples include: [ka] Examples include:

[0043] R 6 Additional non-limiting examples include: [ka] Examples include:

[0044] R 6 Additional non-limiting examples include: [ka] TIFF2024173929000023.tif84170 is an example.

[0045] Non-limiting examples of compounds of formula VI include: [ka] Examples include TIFF2024173929000025.tif231170TIFF2024173929000026.tif175170TIFF2024173929000027.tif218170TIFF2024173929000028.tif217170.

[0046] The present invention also provides a compound of formula VII: [ka] (In the formula, B is [ka] is selected from R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A In an alternative embodiment, —C(O)NR 6B R 6C is selected from R 6A is hydrogen, C 1~6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl(C 1~6 alkyl)-, wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; and in alternative embodiments, R 6A is C 1~20 Alkyl and C 2~20 alkenyl, R 6B and R 6C are independently hydrogen, C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl, wherein C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl may be optionally substituted with at least one substituent selected from alkoxy (including, but not limited to, methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R 7 is NH2, H or -NR 8 R 9 and R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, -C(O)R 6A and -C(O)OR 6A is selected from Y is selected from F and Cl; Z is methyl, C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 In an alternative embodiment, Z is selected from C 1~4 is alkyl, R 40 is H, C 1~3 Alkoxy, C 1~3 selected from alkyl, N, CN and halogen (including Cl and F); R 41 is H, C 1~3 selected from alkyl (including methyl) and halogen (including Cl, F and Br); R 42a and R 42b is independently C 1~3 Alkyl (including methyl), NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 is selected from R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) This includes the use of compounds.

[0047] In one embodiment, the present invention also provides compounds of formula VIIa, VIIb, VIIc, and VIId: [ka] This includes compounds of the formula:

[0048] Non-limiting examples of B include: [ka] Examples include:

[0049] Non-limiting examples of compounds of formula VII include: [ka] TIFF2024173929000034.tif188170 is an example.

[0050] The present invention also provides a method for treating or preventing COVID-19 disease in a host in need of the treatment or prevention described herein. 10 is monophosphate, diphosphate, triphosphate or R 10A and R 10A is a stabilized phosphate prodrug of Formula VIII, Formula IX or Formula X, which is metabolized in vivo to the monophosphate, diphosphate or triphosphate: [ka] (In the formula, R 10 teeth, [ka] and R 10A is selected from R 10A is a stabilized phosphate prodrug that is metabolized in vivo to the monophosphate, diphosphate, or triphosphate; R 11 is hydrogen and R 1 is selected from R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl.

[0051] Non-limiting examples of compounds of Formula VIII, Formula IX, or Formula X include: [ka] TIFF2024173929000038.tif222170 is an example.

[0052] Additional non-limiting examples of compounds of Formula VIII, Formula IX, or Formula X include: [ka] TIFF2024173929000040.tif69170 is an example.

[0053] The phosphorus in any of the formulas described herein may be chiral and thus may be provided as either 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 may 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, Compound 1 is shown without regard to the stereochemistry at the chiral phosphorus atom. Compound 1 may be provided as the phosphorus R of the compound in racemic form, or as a material enriched in one enantiomer up to a pure enantiomer. p - and S p 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 may be at least 98%, 99%, or even 100% free of the opposite enantiomer. For example, compound 1A has S-stereochemistry at phosphorus, and compound 1B has R-stereochemistry at phosphorus. p Alternatively, compound 1B may be at least 90%, 95%, 98%, 99% or even 100% free of the opposite S -enantiomer. p - may be at least 90%, 95%, 98%, 99% or even 100% free of an enantiomer.

[0054] Similarly, compound 2 is shown without regard to the stereochemistry at the chiral phosphorus atom. Compound 2 can be used in any desired ratio of phosphorus R- and S-enantiomers, including racemic or enantiomer-enriched compounds up to 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 may be at least 98%, 99%, or even 100% free of the opposite enantiomer. In one embodiment, compound 2A has S-stereochemistry at phosphorus and R-stereochemistry at phosphorus. p In one embodiment, compound 2B may be at least 90%, 95%, 98%, 99% or even 100% free of the opposite S -enantiomer. p - may be at least 90%, 95%, 98%, 99% or even 100% free of an enantiomer.

[0055] 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, drawn with respect to the stereochemistry at the phosphorus atom, are at least 90% free of the opposite enantiomer.

[0056] and administering to a host in need thereof a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII effective to treat COVID-19 caused by the SARS-CoV-2 virus. Compounds, compositions, dosage forms, and methods for treatment by 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, are provided. 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, can also be used prophylactically in an effective amount to prevent or limit the progression of COVID-19 in a host in need thereof that has been exposed to or is at risk of infection or re-infection with the virus.

[0057] The weight of the active compound in the dosage forms described herein refers to either the free form or the salt form of the compound unless otherwise specified. For example, approximately 600 mg of Compound 2 is equivalent to approximately 550 mg of Compound 1. In one non-limiting embodiment, the loading dose is 1100 mg / day (free base) (i.e., 1200 mg / day of the hemisulfate salt of Compound 1), and the maintenance dose is 550 mg / day (free base) (i.e., 600 mg / day of the hemisulfate salt). In one embodiment, the loading dose is administered once, and the maintenance dose is administered twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days.

[0058] 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 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, or 1700 mg. In certain embodiments, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered 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, at least 1400 mg, or at least 1500 mg.

[0059] 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, e.g., Compound 2, is administered once daily in a dosage form of about 550 mg.

[0060] 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, e.g., Compound 2, is administered once daily in a dosage form of about 600 mg.

[0061] 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.

[0062] 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.

[0063] 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 for at least five days in a dosage form of about 550 mg, optionally in conjunction with standard of care. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily for at least five days in a dosage form of about 550 mg, optionally in conjunction with standard of care. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound 1B.

[0064] 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 for at least days in a dosage form of about 600 mg, optionally in conjunction with standard of care. In one embodiment, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily for at least 5 days in a dosage form of about 600 mg, optionally in conjunction with standard of care. In one embodiment, compound 2 is compound 2A. In one embodiment, compound 2 is compound 2B.

[0065] 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 an about 550 mg dosage form for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally in conjunction with standard of care. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily in an about 550 mg dosage form for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally in conjunction with standard of care.

[0066] 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 an about 600 mg dosage form for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally in conjunction with standard of care. In one embodiment, Compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily in an about 600 mg dosage form for at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or more days, optionally in conjunction with standard of care.

[0067] In certain embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, such as Compound 1 or Compound 3, or a pharmaceutically acceptable salt thereof, including Compound 2 or Compound 4, is administered with an initial dose (i.e., a loading dose) followed by a maintenance dose, the loading dose being at the discretion of a physician based on the severity of the disease manifestation and the patient's physical condition. In certain embodiments, the loading dose is about 1.5-fold or at least 1.5-fold higher, about 2-fold or at least 2-fold higher, about 2.5-fold or at least 2.5-fold higher, or about 3-fold or at least 3-fold higher than the maintenance dose. In one embodiment, the loading dose is administered once, twice, three times, four times, or more times daily before the initial maintenance dose, and may be given once, twice, three times, or four times daily as directed by a physician.

[0068] 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 provided. Possible salts are administered in a daily loading dose of at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg, at least about 1200 mg, at least about 1300 mg, or at least about 1400 mg (which can be given in one or several doses throughout the day), followed by a maintenance dose of at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, or at least about 750 mg, with the maintenance dose given once, twice, or three times daily. In one embodiment, the maintenance dose is given twice daily, optionally over 1, 2, 3, or 4 days. In one embodiment, the maintenance dose is administered once, twice, or three times daily thereafter 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.

[0069] 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 mg, or at least about 750 mg, given once, twice, or three times daily.

[0070] In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, e.g., Compound 2, is administered at a dose of at least about 500 mg, at least about 550 mg, or at least 600 mg, given twice daily. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof, e.g., 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 embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B.

[0071] In one embodiment, Compound 1 is administered at a dose of about 550 mg, given twice daily. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound 1B.

[0072] In one embodiment, Compound 2 is administered at a dose of about 600 mg, given twice daily. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 2B.

[0073] In certain embodiments, the methods of the invention comprise administering a compound described herein, e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, e.g., Compound 1 or Compound 2, once, twice, three, four, or more times daily as needed to treat the infection. In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, e.g., Compound 1 or Compound 2, is administered for at least about 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more days, or for a period at the discretion of a healthcare provider. Alternatively, the compound can be administered for a period appropriate to prevent infection or reduce the severity of infection in a human or other animal at risk of infection with the virus.

[0074] In one embodiment, the compound of the invention is administered indefinitely until the risk of infection or reinfection no longer exists. In one embodiment, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months, or more. In certain embodiments, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or more times daily.

[0075] In another alternative embodiment, there is provided a method of preventing transmission comprising administering an effective amount of one of the compounds described herein to a human in need thereof prior to exposure to a high-risk situation, including when traveling or at a public event or meeting, or for a period of sufficient length if the host is in a high-risk group (e.g., including prior to and during the subsequent potential exposure to a contagious situation, and optionally for up to 3, 5, 7, 10, 12, 14, or more days thereafter). Alternatively, selected compounds described herein can be administered indefinitely at a maintenance dose to protect individuals in high-risk environments.

[0076] The present invention also relates to compounds of formula XI and formula XII: [ka] (In the formula, R 12a and R 12b is an oxygen protecting group, and R 12a and R 12b At least one of the following is -C(O)OC 1~6 or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, R 12a -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 alternative embodiments, R 12b -C(O)OC 1~6 alkyl or -C(O)O-benzyl, and R 12a is an oxygen protecting group that 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 1~6alkyl, for example, —C(O)OtBu. In one embodiment, R 12a and R 12b are both -C(O)O-benzyl.

[0078] In one embodiment, the compound of formula XII has formula XIIA: [ka] is.

[0079] In one embodiment, the compound of formula XII has formula XIIB: [ka] is.

[0080] To this end, the present invention includes the following features: (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; (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; (c) the method of (b) for preventing or minimizing reinfection with SARS-CoV-2 virus or COVID-19 in a host in need thereof; (d) The method of (a) to (c), wherein the compound is Compound 1; (e) The method of (a) to (c), wherein the compound is Compound 1A. (f) The method of (a) to (c), wherein the compound is Compound 1B. (g) The method of (a) to (c), wherein the compound is Compound 2; (h) The method of (a) to (c), wherein the compound is Compound 2A. (i) Methods (a) to (c) in which the compound is compound 2B; (j) The method of (a) to (c), wherein the compound is Compound 3; (k) The method of (a) to (c), wherein the compound is Compound 3A. (l) Method (a) to (c), wherein the compound is Compound 3B; (m) The method of (a) to (c), wherein the compound is Compound 4; (n) The method of (a) to (c), wherein the compound is compound 4A. (o) The method of (a) to (c), wherein the compound is compound 4B. (p) The process of (a)-(c), wherein the compound is a compound of formula IIIa; (q) The process of (a)-(c), wherein the compound is a compound of formula IIIb; (r) the process of (a)-(c), wherein the compound is a compound of formula IIIc; (s) the process of (a) to (c), wherein the compound is a compound of formula IIId; (t) the process of (a)-(c), wherein the compound is a compound of formula IIIe; (u) the process of (a)-(c), wherein the compound is a compound of formula IIIf; (v) The process of (a)-(c), wherein the compound is a compound of formula IVa; (w) the process of (a)-(c), wherein the compound is a compound of formula IVb; (x) The process of (a)-(c), wherein the compound is a compound of formula IVc; (y) The process of (a)-(c), wherein the compound is a compound of formula IVd; (z) the method of (a) to (c), wherein the compound is a compound of formula IVe; (aa) the process of (a) to (c), wherein the compound is a compound of formula IVf; (bb) the process of (a)-(c), wherein the compound is a compound of formula V; (cc) the process of (a)-(c), wherein the compound is a compound of formula VI; (dd) the process of (a)-(c), wherein the compound is a compound of formula VII; (ee) the process of (a) to (c), wherein the compound is a compound of formula VIII, formula IX or formula X; (ff) Any pharmaceutically acceptable carrier for use in treating COVID-19 infection caused by the SARS-CoV-2 virus in a host in need of treatment. 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 carrier; (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, optionally in a pharmaceutically acceptable carrier, for use in preventing or minimizing (compared to no treatment) infection caused by the SARS-CoV-2 virus in a host in need thereof; (hh) a compound (gg) for preventing reinfection caused by the SARS-CoV-2 virus in a host in need thereof; (ii) the use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus; (jj) use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in the manufacture of a medicament for the prevention of COVID-19 caused by the SARS-CoV-2 virus in a host in need thereof; (kk) Use of (jj) to prevent reinfection caused by the SARS-CoV-2 virus in a host in need of such prevention; (ll) Any of the above embodiments, wherein the pharmaceutically acceptable carrier is in a dosage form suitable for oral administration; (mm) the dosage form of (ll), wherein the dosage form is a solid dosage form; (nn) a dosage form of (mm) in the form of a tablet; (oo) a dosage form of (mm) in the form of a capsule; (pp) the dosage form of (ll), wherein the dosage form is a liquid dosage form; (qq) a dosage form of (pp) in the form of a solution or suspension; (rr) any of embodiments (a) through (kk), wherein the pharmaceutically acceptable carrier is in a form suitable for intravenous administration; (ss) any of embodiments (a) through (kk), wherein the pharmaceutically acceptable carrier is in a dosage form suitable for parenteral administration; (tt) any of the above embodiments wherein 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 daily; (uu) Any of the above embodiments, wherein the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered twice daily; (vv) Any of the above embodiments, wherein the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered three times per day; (ww) any of the above embodiments, wherein the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered for at least 1 week, 10 days, 2 weeks, 3 weeks, 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months, or more; (xx) Any of the above embodiments, wherein a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered at least once, at least twice, or at least three times daily indefinitely until the risk of infection no longer exists; (yy) 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, Any of the above embodiments administered in a dose of 400 mg; (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 in a dose of at least about 500 mg; (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 in a dose of at least about 550 mg; (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 in a dose of at least about 600 mg; (ccc) a method of 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 wherein said dose is administered twice daily; (ddd) A method of treating COVID-19 virus in a host in need thereof, comprising administering Compound 1, wherein Compound 1 is administered twice daily at a loading dose of at least about 1100 mg followed by a maintenance dose of at least about 550 mg; (eee) the embodiment (ccc or ddd) in which Compound 1 is Compound 1A; (fff) the embodiment (ccc or ddd) in which Compound 1 is Compound 1B; (ggg) A method of treating COVID-19 in a host in need thereof, comprising administering Compound 2, wherein Compound 2 is administered at a dose of at least about 600 mg, and wherein the dose is administered twice daily; (hhh) A method of treating COVID-19 in a host in need thereof, comprising administering Compound 2, wherein Compound 2 is administered twice daily at a loading dose of at least about 1200 mg followed by a maintenance dose of at least about 600 mg; (iii) the embodiment (ggg or hhh) in which Compound 2 is Compound 2A; (jjj) the embodiment (ggg or hhh) in which Compound 2 is Compound 2B; (kkk) a compound of formula II or a pharmaceutically acceptable salt thereof; (lll) Compound 4 described herein or a pharmaceutically acceptable salt thereof; (mmm) Compound 4A and Compound 4B described herein; (nnn) a pharmaceutical formulation comprising an effective amount of a compound of formula II, optionally in a pharmaceutically acceptable carrier; (ooo) a compound of formula XI or formula XII, (ppp) a compound of formula XIIA, (qqq) a compound of formula XIIB, (rrr) a compound of formula VII, (sss) a compound of formula VIIa, (ttt) a compound of formula VIIb, (uuu) a compound of formula VIIc, (vvv) a compound of formula VIId, and (www) A pharmaceutical composition comprising an effective amount of a compound of Formula VIIa, Formula VIIb, Formula VIIc, or Formula VIId. [Brief explanation of the drawings]

[0081] [Figure 1] 1 is a graph of the concentration of triphosphate Compound 1-6 in human bronchial and nasal epithelial cells after exposure to 10 μM Compound 1A as described in Example 7. The half-lives of Compound 1-6 in bronchial and nasal cells were 39 and 38 hours, respectively. The x-axis is time after washout measured in hours, and the y-axis is the concentration of Compound 1-6 in pmol / million cells. [Figure 2]FIG. 1 is a graph comparing the levels of triphosphate compound 1-6 in human bronchial epithelial cells after exposure to compound 1A (1A), ALS-8112 (ALS), and the 4′-Me-substituted prodrug isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-2,4-dimethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (4′-Me), as described in Example 7. The x-axis is time after washout measured in hours, and the y-axis is the concentration of compound 1-6 in pmol / million cells. [Figure 3] FIG. 1 is a 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 isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-2,4-dimethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (4′-Me), as described in Example 7. The x-axis is time after washout measured in hours, and the y-axis is the concentration of compounds 1-6 in pmol / million cells. [Figure 4] 1 is a graph of the mean plasma profile of Compound 1A in monkeys administered a 30 mg / kg oral dose of Compound 2A twice daily (BID) for 3 days as described in Example 8. The x-axis is time after administration measured in hours and the y-axis is plasma concentration of Compound 1A measured in ng / mL. [Figure 5] 1 is a graph of the mean plasma profile of the metabolite Compound 1-2 in monkeys administered a 30 mg / kg oral dose of Compound 2A twice daily (BID) for 3 days as described in Example 8. The x-axis is time after administration measured in hours and the y-axis is the plasma concentration of Compound 1-2 measured in ng / mL. [Figure 6]1 is a graph of the mean plasma profile of the triphosphate surrogate metabolite Compound 1-7 in monkeys administered a 30 mg / kg oral dose of Compound 2A twice daily (BID) for 3 days as described in Example 8. The x-axis is time after administration measured in hours and the y-axis is the plasma concentration of Compound 1-7 measured in ng / mL. [Figure 7A] 1 is a graph of the concentration of triphosphate Compound 1-6 in monkey lung, kidney, and liver tissues after administration of a 30 mg / kg oral dose of Compound 2A twice daily (BID) for 3 days as described in Example 8. The half-lives in lung, kidney, and liver were 9.4 hours, 8.0 hours, and 4.3 hours, respectively. The x-axis is time after administration measured in hours, and the y-axis is the tissue concentration of Compound 1-6 measured in ng / g. [Figure 7B] 1 is a graph of the concentration of triphosphate Compound 1-6 in lung, kidney, and liver tissues of monkeys after administration of a 30 mg / kg oral dose of Compound 2A twice daily (BID) for three days as described in Example 8. Tissue concentrations of Compound 1-6 are shown 2 hours, 12 hours, 24 hours, and 48 hours after the final dose. The x-axis is time after the final dose measured in hours, and the y-axis is tissue concentration measured in μM. [Figure 8] FIG. 1 is a graph of the levels of triphosphate compounds 1-6 in hepatocytes incubated with Compound 2A as described in Example 9 and previously described in Good, SS et al. 2020 PLoS ONE 15(1):e0227104. Concentrations were 7-fold higher in human hepatocytes than in monkeys. The x-axis is incubation time measured in hours, and the y-axis is the concentration of compounds 1-6 measured in pmol / 10 cells. [Figure 9]Figure 1 shows a simulation of intracellular concentrations of Compound 1-6 in human lung tissue as described in Example 10. The predicted lung concentrations are based on the predicted trough (Ch) steady state of plasma Compound 1-7, a plasma surrogate for the intracellular triphosphate Compound 1-6 in humans, multiplied by a ratio of 1.6 (as described in Example 8, triphosphate concentrations in the lung are 1.6-fold higher than in the liver at steady-state trough levels) (Berliba, e. et al. 2019 Antimicrob. Agents Chemother. 63(12):e01201-19). The x-axis is time, measured in days, and the y-axis is the simulated lung concentration of Compound 1-6, measured in μM. [Figure 10] Figure 1 shows simulations of intracellular concentrations of compound 1-6 in human lung tissue using two approaches as described in Example 10. The solid curve represents the predicted lung concentration of the active triphosphate compound 1-6 metabolite after correcting for the lung-to-liver concentration ratio of compound 1-6 of 1.6. The dotted curve represents the predicted lung concentration of the active triphosphate compound 1-6 metabolite after correcting for the lung compound 1-6 to plasma compound 1-7 ratio of 1.2. The horizontal line represents the EC90 of compound 1A against SARS-CoV-2 in HAE cells in vitro (0.47 μM). The x-axis is time measured in days, and the y-axis is the simulated lung compound 1-6 concentration measured in μM. [Figure 11] FIG. 1 shows compounds of formula I that can also be administered as pharmaceutically acceptable salts. DETAILED DESCRIPTION OF THE INVENTION

[0082] The invention disclosed herein comprises administering to a subject an effective amount of a compound of formula I: [ka] (In the formula, R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl; R2 is hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 3~7 cycloalkyl or aryl (including phenyl and naphthyl), and in alternative embodiments, R 2 is aryl(C1-C4 alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1~6 alkyl (including methyl, ethyl, propyl and isopropyl); R 4a and R 4b are independently hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3~7 cycloalkyl; 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 an aryl(C1-C4 alkyl)-, aryl, heteroaryl, or heteroalkyl) compound or a pharmaceutically acceptable salt thereof, for treating or preventing coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a host, e.g., a human, in need of such treatment or prevention.

[0083] Non-limiting examples of compounds of Formula I include Compound 1 and Compound 2. In one embodiment, the compound is administered as the S-enantiomer, 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. [ka] TIFF2024173929000046.tif165170

[0084] Alternative configurations of Compound 1 or a pharmaceutically acceptable salt thereof that can be used include: [ka] Contains TIFF2024173929000048.tif46170.

[0085] Alternative configurations of compound 2 that can be used include: [ka] Includes:

[0086] Alternative configurations of Compound 1 or a pharmaceutically acceptable salt thereof that can be used, such as Compound 2, include: [ka] Contains TIFF2024173929000051.tif45170.

[0087] Non-limiting examples of compounds of Formula I include: [ka] TIFF2024173929000053.tif254170TIFF2024173929000054.tif153170 or a pharmaceutically acceptable salt thereof.

[0088] Additional non-limiting examples of compounds of Formula I include: [ka] TIFF2024173929000056.tif231170TIFF2024173929000057.tif179170TIFF2024173929000058.tif91170 or a pharmaceutically acceptable salt thereof.

[0089] Additional non-limiting examples of compounds of Formula I include: [ka] TIFF2024173929000060.tif203170TIFF2024173929000061.tif254170 or a pharmaceutically acceptable salt thereof.

[0090] The present invention also provides a compound of formula II: [ka] (In the formula, R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl; 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 alternative embodiments, R 2 is aryl(C1-C4 alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1~6 alkyl (including methyl, ethyl, propyl and isopropyl); R 4a and R 4b are independently hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3~7 cycloalkyl; 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 includes the use of a compound of formula (I) wherein R is aryl(C1-C4 alkyl)-, aryl, heteroaryl, or heteroalkyl, or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the compound of formula II or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, is administered in an effective amount to a host in need thereof having COVID-19 or at risk for infection by the SARS-CoV-2 virus, i.e., as a prophylactic.

[0092] Non-limiting examples of compounds of Formula II include Compound 3 and Compound 4. In one embodiment, the compounds are administered as S-enantiomers, such as Compound 3A and Compound 4A. In one embodiment, the compounds are administered as R-enantiomers, such as Compound 3B and Compound 4B. [ka] TIFF2024173929000064.tif63170

[0093] Alternative configurations of compound 3 or a pharmaceutically acceptable salt thereof include: [ka] Includes:

[0094] Additional alternative configurations of compound 4 include: [ka] Contains TIFF2024173929000067.tif46170.

[0095] Additional alternative configurations of compound 3 or a pharmaceutically acceptable salt thereof that can be used, such as compound 4, include: [ka] Includes:

[0096] Non-limiting examples of compounds of Formula II include: [ka] TIFF2024173929000070.tif254170TIFF2024173929000071.tif254170 or a pharmaceutically acceptable salt thereof.

[0097] Additional non-limiting examples of compounds of Formula II include: [ka] TIFF2024173929000073.tif186170TIFF2024173929000074.tif144170 or a pharmaceutically acceptable salt thereof.

[0098] Additional non-limiting examples of compounds of Formula II include: [ka] TIFF2024173929000076.tif252170TIFF2024173929000077.tif219170TIFF2024173929000078.tif105170 or a pharmaceutically acceptable salt thereof.

[0099] The present invention also provides a compound of formula III: [ka] (In the formula, R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl; 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 alternative embodiments, R 2is aryl(C1-C4 alkyl)-, heteroaryl or heteroalkyl; R 3 is hydrogen or C 1~6 alkyl (including methyl, ethyl, propyl and isopropyl); R 4a and R 4b are independently hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl) and C 3~7 cycloalkyl; R 5 is hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl and isopropyl), C 1~6 Haloalkyl or C 3~7 cycloalkyl, and in an alternative embodiment, R 5 is aryl(C1-C4 alkyl)-, aryl, heteroaryl or heteroalkyl; X is C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 The present invention includes the use of a compound of the formula (I) selected from C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl, including chloroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0100] 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 has formula IIIa: [ka] or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment of Formula IIIa, R 1 is methyl.

[0102] In one embodiment of Formula IIIa, R1 is cyclopropyl.

[0103] In one embodiment of Formula IIIa, R 2 is phenyl.

[0104] In one embodiment of Formula IIIa, R 2 is naphthyl.

[0105] In one embodiment of Formula IIIa, R 4a is hydrogen and R 4b is methyl.

[0106] In one embodiment of Formula IIIa, R 5 is isopropyl.

[0107] In one embodiment of Formula IIIa, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0108] In one embodiment of Formula IIIa, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0109] In one Formula IIIa embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0110] Non-limiting examples of compounds of formula IIIa include: [ka] Examples include TIFF2024173929000082.tif236170TIFF2024173929000083.tif244170TIFF2024173929000084.tif254170TIFF2024173929000085.tif203170TIFF2024173929000086.tif242170TIFF2024173929000087.tif92170.

[0111] Additional non-limiting examples of compounds of Formula IIIa include: [ka] Examples include:

[0112] 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 represented by formula IIIb: [ka] or a pharmaceutically acceptable salt thereof.

[0113] In one embodiment of Formula IIIb, R 1 is methyl.

[0114] In one embodiment of Formula IIIb, R 1 is cyclopropyl.

[0115] In one embodiment of Formula IIIb, R 2 is phenyl.

[0116] In one embodiment of Formula IIIb, R 2 is naphthyl.

[0117] In one embodiment of Formula IIIb, R 4a is hydrogen and R 4b is methyl.

[0118] In one embodiment of Formula IIIb, R 5 is isopropyl.

[0119] In one embodiment of Formula IIIb, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0120] In one embodiment of Formula IIIb, the compound is R p-isomer, and the phosphoramidate is in the L-configuration.

[0121] In one Formula IIIb embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0122] Non-limiting examples of compounds of formula IIIb include: [ka] Examples include TIFF2024173929000091.tif230170TIFF2024173929000092.tif237170TIFF2024173929000093.tif250170TIFF2024173929000094.tif253170TIFF2024173929000095.tif252170TIFF2024173929000096.tif147170.

[0123] Additional non-limiting examples of compounds of Formula IIIb include: [ka] TIFF2024173929000098.tif48170 is an example.

[0124] 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 represented by formula IIIc: [ka] or a pharmaceutically acceptable salt thereof.

[0125] In one embodiment of Formula IIIc, R 1 is methyl.

[0126] In one embodiment of Formula IIIc, R 1 is cyclopropyl.

[0127] In one embodiment of Formula IIIc, R 2 is phenyl.

[0128] In one embodiment of Formula IIIc, R 2 is naphthyl.

[0129] In one embodiment of Formula IIIc, R 4a is hydrogen and R 4b is methyl.

[0130] In one embodiment of Formula IIIc, R 5 is isopropyl.

[0131] In one embodiment of Formula IIIc, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0132] In one embodiment of Formula IIIc, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0133] In one Formula IIIc embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0134] Non-limiting examples of compounds of formula IIIc include: [ka] Examples include TIFF2024173929000101.tif235170TIFF2024173929000102.tif244170TIFF2024173929000103.tif201170TIFF2024173929000104.tif252170TIFF2024173929000105.tif242170TIFF2024173929000106.tif91170.

[0135] Additional non-limiting examples of compounds of Formula IIIc include: [ka] Examples include:

[0136] 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 represented by formula IIId: [ka] or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment of Formula IIId, R 1 is methyl.

[0138] In one embodiment of Formula IIId, R 1 is cyclopropyl.

[0139] In one embodiment of Formula IIId, R 2 is phenyl.

[0140] In one embodiment of Formula IIId, R 2 is naphthyl.

[0141] In one embodiment of Formula IIId, R 4a is hydrogen and R 4b is methyl.

[0142] In one embodiment of Formula IIId, R 5 is isopropyl.

[0143] In one embodiment of formula IIId, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0144] In one embodiment of Formula IIId, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0145] In one Formula IIId embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0146] Non-limiting examples of compounds of formula IIId include: [ka] Examples include TIFF2024173929000110.tif229170TIFF2024173929000111.tif244170TIFF2024173929000112.tif252170TIFF2024173929000113.tif253170TIFF2024173929000114.tif251170TIFF2024173929000115.tif237170.

[0147] Additional non-limiting examples of compounds of formula IIId include: [ka] Examples include:

[0148] 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 represented by formula IIIe: [ka] or a pharmaceutically acceptable salt thereof.

[0149] In one embodiment of Formula IIIe, R 1 is methyl.

[0150] In one embodiment of Formula IIIe, R 1 is cyclopropyl.

[0151] In one embodiment of Formula IIIe, R 2 is phenyl.

[0152] In one embodiment of Formula IIIe, R2 is naphthyl.

[0153] In one embodiment of Formula IIIe, R 4a is hydrogen and R 4b is methyl.

[0154] In one embodiment of Formula IIIe, R 5 is isopropyl.

[0155] In one embodiment of Formula IIIe, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0156] In one embodiment of Formula IIIe, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0157] In one Formula IIIe embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0158] Non-limiting examples of compounds of formula IIIe include: [ka] Examples include TIFF2024173929000119.tif236170TIFF2024173929000120.tif242170TIFF2024173929000121.tif202170TIFF2024173929000122.tif252170TIFF2024173929000123.tif237170TIFF2024173929000124.tif46170.

[0159] Additional non-limiting examples of compounds of Formula IIIe include: [ka] Examples include:

[0160] 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 represented by formula IIIf: [ka] or a pharmaceutically acceptable salt thereof.

[0161] In one embodiment of Formula IIIf, R 1 is methyl.

[0162] In one embodiment of Formula IIIf, R 1 is cyclopropyl.

[0163] In one embodiment of Formula IIIf, R 2 is phenyl.

[0164] In one embodiment of Formula IIIf, R 2 is naphthyl.

[0165] In one embodiment of Formula IIIf, R 4a is hydrogen and R 4b is methyl.

[0166] In one embodiment of Formula IIIf, R 5 is isopropyl.

[0167] In one embodiment of Formula IIIf, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0168] In one embodiment of Formula IIIf, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0169] In one Formula IIIf embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0170] Non-limiting examples of compounds of formula IIIf include: [ka] Examples include TIFF2024173929000128.tif228170TIFF2024173929000129.tif242170TIFF2024173929000130.tif247170TIFF2024173929000131.tif203170TIFF2024173929000132.tif252170TIFF2024173929000133.tif200170.

[0171] Additional non-limiting examples of compounds of Formula IIIe include: [ka] TIFF2024173929000135.tif244170 is an example.

[0172] Non-limiting examples of compounds of formula III include: [ka] Examples include:

[0173] The present invention also provides a compound of formula IV: for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention as described herein. [ka] (In the formula, X is C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3C2-C4 alkenyl, C2-C4 alkynyl, and C1-C3 hydroxyalkyl; R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0174] 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: [ka] TIFF2024173929000139.tif223170

[0175] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus is represented by formula IVa: [ka] or a pharmaceutically acceptable salt thereof.

[0176] In one embodiment of Formula IVa, R 1 is methyl.

[0177] In one embodiment of Formula IVa, R 1 is cyclopropyl.

[0178] In one embodiment of Formula IVa, R 2 is phenyl.

[0179] In one embodiment of Formula IVa, R 2 is naphthyl.

[0180] In one embodiment of Formula IVa, R 4ais hydrogen and R 4b is methyl.

[0181] In one embodiment of Formula IVa, R 5 is isopropyl.

[0182] In one embodiment of Formula IVa, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0183] In one embodiment of Formula IVa, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0184] Non-limiting examples of compounds of formula IVa include: [ka] Examples include TIFF2024173929000142.tif230170TIFF2024173929000143.tif242170TIFF2024173929000144.tif200170TIFF2024173929000145.tif251170TIFF2024173929000146.tif202170TIFF2024173929000147.tif103170.

[0185] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus is represented by formula IVb: [ka] or a pharmaceutically acceptable salt thereof.

[0186] In one embodiment of Formula IVb, R 1 is methyl.

[0187] In one embodiment of Formula IVb, R 1is cyclopropyl.

[0188] In one embodiment of Formula IVb, R 2 is phenyl.

[0189] In one embodiment of Formula IVb, R 2 is naphthyl.

[0190] In one embodiment of Formula IVb, R 4a is hydrogen and R 4b is methyl.

[0191] In one embodiment of Formula IVb, R 5 is isopropyl.

[0192] In one embodiment of Formula IVb, the compound is S p -isomers and phosphoramides The ester is in the L-configuration.

[0193] In one embodiment of Formula IVb, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0194] Non-limiting examples of compounds of formula IVb include: [ka] Examples include TIFF2024173929000150.tif237170TIFF2024173929000151.tif244170TIFF2024173929000152.tif161170TIFF2024173929000153.tif211170TIFF2024173929000154.tif252170TIFF2024173929000155.tif51170.

[0195] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus is represented by formula IVc: [ka] or a pharmaceutically acceptable salt thereof.

[0196] In one embodiment of Formula IVc, R 1 is methyl.

[0197] In one embodiment of Formula IVc, R 1 is cyclopropyl.

[0198] In one embodiment of Formula IVc, R 2 is phenyl.

[0199] In one embodiment of Formula IVc, R 2 is naphthyl.

[0200] In one embodiment of Formula IVc, R 4a is hydrogen and R 4b is methyl.

[0201] In one embodiment of Formula IVc, R 5 is isopropyl.

[0202] In one embodiment of Formula IVc, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0203] In one embodiment of Formula IVc, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0204] In one Formula IVc embodiment, the pharmaceutically acceptable salt is a hemisulfate salt.

[0205] Non-limiting examples of compounds of formula IVc include: [ka] Examples include TIFF2024173929000158.tif228170TIFF2024173929000159.tif244170TIFF2024173929000160.tif247170TIFF2024173929000161.tif252170TIFF2024173929000162.tif202170.

[0206] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease is represented by formula IVd: [ka] or a pharmaceutically acceptable salt thereof.

[0207] In one embodiment of Formula IVd, R 1 is methyl.

[0208] In one embodiment of Formula IVd, R 1 is cyclopropyl.

[0209] In one embodiment of Formula IVd, R 2 is phenyl.

[0210] In one embodiment of Formula IVd, R 2 is naphthyl.

[0211] In one embodiment of Formula IVd, R 4a is hydrogen and R 4b is methyl.

[0212] In one embodiment of Formula IVd, R 5 is isopropyl.

[0213] In one embodiment of formula IVd, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0214] In one embodiment of formula IVd, the compound is R p-isomer, and the phosphoramidate is in the L-configuration.

[0215] In one embodiment of Formula IVd, the pharmaceutically acceptable salt is a hemisulfate salt.

[0216] Non-limiting examples of compounds of formula IVd include: [ka] Examples include TIFF2024173929000165.tif230170TIFF2024173929000166.tif243170TIFF2024173929000167.tif253170TIFF2024173929000168.tif101170.

[0217] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease has formula IVe: [ka] or a pharmaceutically acceptable salt thereof.

[0218] In one embodiment of Formula IVe, R 1 is methyl.

[0219] In one embodiment of Formula IVe, R 1 is cyclopropyl.

[0220] In one embodiment of Formula IVe, R 2 is phenyl.

[0221] In one embodiment of Formula IVe, R 2 is naphthyl.

[0222] In one embodiment of Formula IVe, R 4a is hydrogen and R 4b is methyl.

[0223] In one embodiment of Formula IVe, R 5is isopropyl.

[0224] In one embodiment of Formula IVe, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0225] In one embodiment of Formula IVe, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0226] In one embodiment of Formula IVe, the pharmaceutically acceptable salt is a hemisulfate salt.

[0227] Non-limiting examples of compounds of formula IVe include: [ka] Examples include TIFF2024173929000171.tif235170, TIFF2024173929000172.tif242170, and TIFF2024173929000173.tif251170.

[0228] In one embodiment, the compound of formula IV for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus is represented by formula IVf: [ka] or a pharmaceutically acceptable salt thereof.

[0229] In one embodiment of Formula IVf, R 1 is methyl.

[0230] In one embodiment of Formula IVf, R 1 is cyclopropyl.

[0231] In one embodiment of Formula IVf, R 2 is phenyl.

[0232] In one embodiment of Formula IVf, R2 is naphthyl.

[0233] In one embodiment of Formula IVf, R 4a is hydrogen and R 4b is methyl.

[0234] In one embodiment of Formula IVf, R 5 is isopropyl.

[0235] In one embodiment of formula IVf, the compound is S p -isomer, and the phosphoramidate is in the L-configuration.

[0236] In one embodiment of formula IVf, the compound is R p -isomer, and the phosphoramidate is in the L-configuration.

[0237] In one embodiment of Formula IVf, the pharmaceutically acceptable salt is a hemisulfate salt.

[0238] Non-limiting examples of compounds of formula IVf include: [ka] Examples include TIFF2024173929000176.tif227170TIFF2024173929000177.tif242170TIFF2024173929000178.tif202170TIFF2024173929000179.tif202170.

[0239] The present invention also provides a compound of formula V: for treating or preventing COVID-19 disease caused by the SARS-CoV-2 virus as described herein: [ka] (In the formula, Y and Y' are independently selected from Cl and F; R 1 , R 2 , R 3 , R4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof.

[0240] In one embodiment of Formula IV, Y' is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0241] In one embodiment of Formula IV, Y' is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0242] In one embodiment of Formula IV, Y' is F, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0243] In one embodiment of Formula IV, Y' is F, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0244] In one embodiment of Formula IV, Y' is Cl, Y is F, and R1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0245] In one embodiment of Formula IV, Y' is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0246] In one embodiment of Formula IV, Y' is Cl, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0247] In one embodiment of Formula IV, Y' is Cl, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0248] In one embodiment of Formula IV, Y' is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a C1~C4 Rukill and R 5is C1-C6 alkyl.

[0249] In one embodiment of Formula IV, Y' is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0250] In one embodiment of Formula IV, Y' is Cl, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0251] In one embodiment of Formula IV, Y' is Cl, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0252] In one embodiment of Formula IV, Y' is F, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0253] In one embodiment of Formula IV, Y' is F, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0254] In one embodiment of Formula IV, Y' is F, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0255] In one embodiment of Formula IV, Y' is F, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0256] Non-limiting examples of compounds of formula V include: [ka] Examples include TIFF2024173929000182.tif193170TIFF2024173929000183.tif241170TIFF2024173929000184.tif193170TIFF2024173929000185.tif242170TIFF2024173929000186.tif242170TIFF2024173929000187.tif242170TIFF2024173929000188.tif242170.

[0257] Additional non-limiting examples of Formula V include: [ka] TIFF2024173929000190.tif49170 is an example.

[0258] The present invention also provides a method for the treatment or prevention of COVID-19 in a host in need thereof, comprising administering to said host a compound of formula VI: [ka] (In the formula, R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A , in an alternative embodiment, —C(O)NR 6B R 6C is selected from R 6A is hydrogen, C 1~6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl(C 1~6 alkyl)-, wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; and in an alternative embodiment, R 6A is C 1~20 Alkyl and C 2~20 alkenyl, R 6B and R 6C are independently hydrogen, C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl, wherein C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6alkyl), heteroaryl, and heteroarylalkyl may be optionally substituted with at least one substituent selected from alkoxy (including, but not limited to, methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R 7 is NH2, H or -NR 8 R 9 and R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, -C(O)R 6A and -C(O)OR 6A is selected from Y is selected from F and Cl; Z is methyl, C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 (including chloroalkyl), C2-C4 alkenyl, C2 In an alternative embodiment, Z is selected from C 1~4 is alkyl, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein).

[0259] R 6 Non-limiting examples of [ka] Examples include:

[0260] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0261] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0262] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0263] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0264] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0265] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0266] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0267] In one embodiment of Formula VI, Z is CH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0268] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0269] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0270] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0271] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0272] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0273] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0274] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0275] In one embodiment of Formula VI, Z is CF, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0276] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0277] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4ais hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0278] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0279] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0280] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0281] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4ais hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0282] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0283] In one embodiment of Formula VI, Z is Cl, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0284] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0285] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0286] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0287] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0288] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0289] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0290] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0291] In one embodiment of Formula VI, Z is CHF, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0292] In one embodiment of Formula VI, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0293] In one embodiment of Formula VI, Z is CH2CH2, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0294] In one embodiment of Formula VI, Z is CH2CH2, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0295] In one embodiment of Formula VI, Z is CH2CH2, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0296] In one embodiment of Formula VI, Z is CH2CH2, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0297] In one embodiment of Formula VI, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0298] In one embodiment of Formula VI, Z is CHCH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4ais hydrogen and R 4a is C 1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0299] In one embodiment of Formula VI, Z is CHCH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0300] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0301] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0302] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8R 9 is.

[0303] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0304] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0305] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0306] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0307] In one embodiment of Formula VI, Z is CCH, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0308] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0309] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0310] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0311] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0312] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0313] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0314] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0315] In one embodiment of Formula VI, Z is F, Y is F, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4ais methyl and R 5 is C1-C6 alkyl.

[0316] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0317] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0318] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0319] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7is NHC(O)R 6A is.

[0320] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0321] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0322] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1 -C4 alkyl, and R 5 is C1-C6 alkyl.

[0323] In one embodiment of Formula VI, Z is CH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0324] In one embodiment of Formula VI, Z is CF, Y is Cl, and R1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0325] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0326] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0327] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0328] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0329] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0330] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0331] In one embodiment of Formula VI, Z is CF, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0332] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R5 is C1-C6 alkyl, and R 7 is NH2.

[0333] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0334] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a C1~C4 Al Kill and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0335] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0336] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0337] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0338] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0339] In one embodiment of Formula VI, Z is Cl, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0340] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0341] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0342] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0343] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0344] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0345] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0346] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0347] In one embodiment of Formula VI, Z is CHF, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0348] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0349] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4ais hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0350] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0351] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0352] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0353] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0354] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0355] In one embodiment of Formula VI, Z is CHCH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0356] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NH2.

[0357] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is H.

[0358] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NR 8 R 9 is.

[0359] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)R 6A is.

[0360] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 7 is NHC(O)OR 6A is.

[0361] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0362] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl.

[0363] In one embodiment of Formula VI, Z is CCH, Y is Cl, and R 1 is cyclopropyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is methyl and R 5 is C1-C6 alkyl.

[0364] Non-limiting examples of compounds of formula VI include: [ka] Examples include TIFF2024173929000194.tif224170TIFF2024173929000195.tif222170TIFF2024173929000196.tif228170TIFF2024173929000197.tif221170TIFF2024173929000198.tif227170.

[0365] Additional non-limiting examples of compounds of formula VI include: [ka] Examples include TIFF2024173929000200.tif234170 and TIFF2024173929000201.tif101170.

[0366] The present invention also provides a compound of formula VII: [ka] (In the formula, B is [ka] is selected from R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A , in an alternative embodiment, —C(O)NR 6B R 6C is selected from R 6A is hydrogen, C 1~6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl(C 1~6 alkyl)-, wherein the aryl group is optionally substituted with a substituent selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; and in an alternative embodiment, R 6A is C 1~20 Alkyl and C 2~20 Arke Selected from Nil, R 6B and R 6C are independently hydrogen, C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl, wherein C 1~20 Alkyl, C 2~20 Alkenyl, aryl, aryl(C 1~6 alkyl), heteroaryl, and heteroarylalkyl may be optionally substituted with at least one substituent selected from alkoxy (including, but not limited to, methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R 7is NH2, H or -NR 8 R 9 and R 8 and R 9 are independently hydrogen, C 1~6 Alkyl, -C(O)R 6A and -C(O)OR 6A is selected from Y is selected from F and Cl; Z is methyl, C1-C3 haloalkyl (C such as CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CF2CF3 and CH2Cl) 1~3 Fluoroalkyl and C 1~3 In an alternative embodiment, Z is selected from C 1~4 is alkyl, R 40 is H, C 1~3 Alkoxy, C 1~3 selected from alkyl, N, CN and halogen (including Cl and F); R 41 is H, C 1~3 selected from alkyl (including methyl) and halogen (including Cl, F and Br); R 42a and R 42b is C 1~3 Alkyl (including methyl), NH2, H, -NR 8 R 9 and -C(O)NR 8 R 9 is selected from R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein).

[0367] Non-limiting examples of B include: [ka] Examples include:

[0368] In one embodiment, the present invention also provides compounds of formula VIIa, VIIb, VIIc, and VIId: [ka] This includes compounds of the formula:

[0369] In one embodiment of Formula VII, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0370] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0371] In one embodiment of Formula VIIa, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0372] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0373] In one embodiment of Formula VIIb, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0374] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 and R 42b is C 1~6 alkyl or H. In a further embodiment, R 41 is C 1~6 alkyl or H, R42a Ha-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 -NHCH3, and R 42b is NH2.

[0375] In one embodiment of Formula VIIc, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0376] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 and R 42b is C 1~6 alkyl or H. In a further embodiment, R 41 is C 1~6 alkyl or H, R42a Ha-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 -NHCH3, and R 42b is NH2.

[0377] In one embodiment of Formula VIId, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0378] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0379] In one embodiment of Formula VII, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0380] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0381] In one embodiment of Formula VIIa, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0382] 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, R41 is C 1~6 alkyl, and R 42a is NH. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0383] In one embodiment of Formula VIIb, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0384] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 R42b 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 NH2.

[0385] In one embodiment of Formula VIIc, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0386] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 42ais -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 -NHCH3, and R 42b is NH2.

[0387] In one embodiment of Formula VIId, Z is CH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0388] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0389] In one embodiment of Formula VII, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4ais C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0390] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0391] In one embodiment of Formula VIIa, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0392] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0393] In one embodiment of Formula VIIb, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0394] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0395] In one embodiment of Formula VIIc, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0396] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0397] In one embodiment of Formula VIId, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0398] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0399] In one embodiment of Formula VII, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0400] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0401] In one embodiment of Formula VIIa, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0402] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0403] In one embodiment of Formula VIIb, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0404] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0405] In one embodiment of Formula VIIc, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0406] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0407] In one embodiment of Formula VIId, Z is Cl, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0408] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0409] In one embodiment of Formula VII, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0410] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0411] In one embodiment of Formula VIIa, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0412] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0413] In one embodiment of Formula VIIb, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0414] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0415] In one embodiment of Formula VIIc, Z is CHF, Y is F, and R 1 is methyl R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0416] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0417] In one embodiment of Formula VIId, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0418] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0419] In one embodiment of Formula VII, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0420] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0421] In one embodiment of Formula VIIa, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0422] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0423] In one embodiment of Formula VIIb, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0424] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and R 42a is H and R42b is methyl. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0425] In one embodiment of Formula VIIc, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0426] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42ais -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0427] In one embodiment of Formula VIId, Z is CHF, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0428] In a further embodiment, R 41 is a 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. 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)NHCH3.

[0429] In one embodiment of Formula VII, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0430] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0431] In one embodiment of Formula VIIa, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0432] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0433] In one embodiment of Formula VIIb, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0434] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 and R 42b is C 1~6 alkyl or H. In a further embodiment, R 41 is C1~6 alkyl or H, R 42a Ha-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 -NHCH3, and R 42b is NH2.

[0435] In one embodiment of Formula VIIc, Z is CHCH, Y is F, and R 1 is methyl Yes, R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0436] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 and R 42b is C 1~6 alkyl or H. In a further embodiment, R41 is C 1~6 alkyl or H, R 42a Ha-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 -NHCH3, and R 42b is NH2.

[0437] In one embodiment of Formula VIId, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0438] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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 R42a is -C(O)NHCH3.

[0439] In one embodiment of Formula VII, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0440] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0441] In one embodiment of Formula VIIa, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0442] In a further embodiment, R 41 is C 1~6 alkyl, and R 42a is H. In a further embodiment, R41 is methyl and R 42a is H. In a further embodiment, R 41 is C 1~6 alkyl, and R 42a is NH. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0443] In one embodiment of Formula VIIb, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0444] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-NR 8 R 9 and R 42b is C 1~6 alkyl or H. In a further embodiment, R 41 is C1~6 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 -NHCH3, and R 42b is NH2.

[0445] In one embodiment of Formula VIIc, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0446] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-NR 8 R 9 and R 42b is C 1~6 alkyl or H. In a further embodiment, R 41is 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 -NHCH3, and R 42b is NH2.

[0447] In one embodiment of Formula VIId, Z is CHCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0448] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0449] In one embodiment of Formula VII, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0450] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0451] In one embodiment of Formula VIIa, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0452] 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. In a further embodiment, R 41 is methyl and R 42ais NH2.

[0453] In one embodiment of Formula VIIb, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0454] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R42b is NH2.

[0455] In one embodiment of Formula VIIc, Z is CCH, Y is F, and R 1 is methyl , R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0456] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 42ais -NHCH3, and R 42b is NH2.

[0457] In one embodiment of Formula VIId, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0458] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0459] In one embodiment of Formula VII, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0460] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0461] In one embodiment of Formula VIIa, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0462] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0463] In one embodiment of Formula VIIb, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4ais hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0464] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0465] In one embodiment of Formula VIIc, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R 3is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0466] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0467] In one embodiment of Formula VIId, Z is CCH, Y is F, and R 1 is methyl and R 2 is aryl and R3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0468] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0469] In one embodiment of Formula VII, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0470] In a further embodiment, R 1 is C 1~6 alkyl, and R 7is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0471] In one embodiment of Formula VIIa, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0472] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0473] In one embodiment of Formula VIIb, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0474] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and 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 NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0475] In one embodiment of Formula VIIc, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0476] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R 42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0477] In one embodiment of Formula VIId, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is hydrogen and B is [ka] is.

[0478] In a further embodiment, R 41 is a halogen, and R 42a is -C(O)NR 8 R 9 In a further embodiment, R 41 is a halogen, and R 42a is —C(O)NHCH. 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)NHCH3.

[0479] In one embodiment of Formula VII, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0480] In a further embodiment, R 1 is C 1~6 alkyl, and R 7 is NH. In a further embodiment, R 1 is methyl and R 7 is NH2.

[0481] In one embodiment of Formula VIIa, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0482] 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. In a further embodiment, R 41 is methyl and R 42a is NH2.

[0483] In one embodiment of Formula VIIb, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0484] In a further embodiment, R 41 is H and R 42a is H and R 42b is C 1~6 In a further embodiment, R 41 is H and R42a is H and R 42b is methyl. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0485] In one embodiment of Formula VIIc, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0486] In a further embodiment, R 41 is H and R 42a is NH2 and R 42b is H. In a further embodiment, R 41 is H and R42a is -NHCH3, and R 42b is H. In a further embodiment, R 41 is C 1~6 alkyl or H, R 42a is NH2 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 Ha-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 -NHCH3, and R 42b is NH2.

[0487] In one embodiment of Formula VIId, Z is F, Y is F, and R 1 is methyl and R 2 is aryl and R 3 is hydrogen and R 4a is hydrogen and R 4a is C1-C4 alkyl, and R 5 is C1-C6 alkyl, and R 6 is hydrogen and R 40 is cyano or nitro and B is [ka] is.

[0488] In a further embodiment, R 41 is a 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. 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)NHCH3.

[0489] Non-limiting examples of compounds of formula VII include: [ka] Examples include TIFF2024173929000267.tif226170, TIFF2024173929000268.tif231170, TIFF2024173929000269.tif224170, TIFF2024173929000270.tif232170, TIFF2024173929000271.tif216170, and TIFF2024173929000272.tif242170.

[0490] The present invention also provides a method for treating or preventing COVI in a host in need of the treatment or prevention described herein. R for treating or preventing D-19 disease 10 is monophosphate, diphosphate, triphosphate or R 10A and R 10A is a stabilized phosphate prodrug of Formula VIII, Formula IX or Formula X, which is metabolized in vivo to the monophosphate, diphosphate or triphosphate: [ka] (In the formula, R 10 teeth, [ka] and R 10A is selected from R 10A is a stabilized phosphate prodrug that is metabolized in vivo to the monophosphate, diphosphate, or triphosphate; R 11 is hydrogen and R 1 is selected from R 1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and —C(O)C1-C6 alkyl.

[0491] The present invention also relates to compounds of formula XI and formula XII: [ka] (In the formula, R 12a and R 12b is an oxygen protecting group, and R 12a and R 12b At least one of the following is -C(O)OC 1~6 or a pharmaceutically acceptable salt thereof.

[0492] In one embodiment, R 12a -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 an alternative embodiment, R 12b -C(O)OC 1~6 alkyl or -C(O)O-benzyl, and R 12a is an oxygen protecting group that 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, for example, —C(O)OtBu. In one embodiment, R 12a and R12b are both -C(O)O-benzyl.

[0493] In one embodiment, the compound of formula XII has formula XIIA: [ka] is.

[0494] In one embodiment, the compound of formula XII has formula XIIB: [ka] is.

[0495] For example, the protecting group when attached to oxygen can be an ester moiety, such as benzoate, acetate. In one embodiment, the oxygen protecting group when attached to oxygen is a silyl ether moiety (e.g., trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS or TBS), or tert-butyldiphenylsilyl (TBDPS)). In one embodiment, the oxygen protecting group when attached to oxygen is an ether moiety, such as a methyl ether, methoxymethyl ether, or benzyl ether. These protecting groups can be introduced for the protection of hydroxyls according to one of the procedures described in Theodora W. Green, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons (1999), incorporated herein by reference. For example, when the oxygen protecting group attached to the oxygen is an ester moiety, compounds 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 the oxygen is a silyl ether moiety, compounds 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. The TBS group is described in the text on page 128 and in Ogilvie et al. Can. J. Chem. 1979, 57, 2230. It is selectively introduced to primary versus secondary alcohols using the conditions described, which include the use of TBSCl, DMAP, and NEt in DMF at 25°C.

[0496] Non-limiting examples of additional protecting groups for attachment to oxygen include bromobenzoic acid, p-methoxybenzyloxymethyl ether (MPBM), o-nitrobenzyloxymethyl ether (NBOM), p-nitrobenzyloxymethyl ether, t-butoxymethyl ether, Also included are 2,2,2-trichloroethoxymethyl ether, 3-bromotetrahydropyranyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 1-methoxycyclohexyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, substituted phenyl ether, 2-picolyl ether, 4-picolyl ether, 1,3-benzodithiolan-2-yl ether, p-chlorophenoxyacetic acid ester, 3-phenylpropionic acid ester, p-phenylbenzoic acid ester, alkyl p-nitrophenylcarbonyl, alkylbenzylcarbonyl, alkyl p-methoxybenzylcarbonyl, alkyl o-nitrobenzylcarbonyl, and alkyl p-nitrobenzylcarbonyl.

[0497] R 12a and R 12b Non-limiting examples of [ka] Examples include:

[0498] Non-limiting examples of compounds of formula XI and formula XII include: [ka] TIFF2024173929000280.tif214170 is an example.

[0499] In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula IX, Formula X, or Formula XIII, e.g., Compound 1A, Compound 1B, Compound 2A, Compound 2B, Compound 3A, Compound 3B, Compound 4A, or Compound 4B, is used in a form that is at least 90% free of the opposite phosphorus enantiomer, and may be at least 98%, 99%, or even 100% free of the opposite phosphorus enantiomer.

[0500] Compound 1 (isopropyl((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-alaninate) was previously synthesized by Atea These compounds are described in U.S. Patent Nos. 9,828,410, 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, U.S. Patent Application Publication No. 2019-0201433 and U.S. Patent Application Publication No. 2020-0222442, and International Publication Nos. WO 2016 / 144918, WO 2018 / 048937, WO 2019 / 200005 and WO 2020 / 117966, all of which are assigned to the Pharmaceuticals Division of the Pharmaceuticals Corporation of America. The synthesis of Compound 1 is described in Example 1 below.

[0501] Compound 2 was previously disclosed in U.S. Patent Nos. 10,519,186, 10,906,928, 10,894,804, and 10,874,687, assigned to Atea Pharmaceuticals, and in International Publication Nos. 2018 / 144640, 2019 / 200005, and 2020 / 117966. Compound 2A demonstrated potent in vitro activity against clinical isolates of hepatitis C virus (HCV) by inhibiting RNA-dependent RNA polymerase (RdRp) (Good, SS 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 in HCV-infected subjects for up to 12 weeks, achieving a high efficacy rate.

[0502] The synthesis of compound 2 (isopropyl((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-alaninate hemisulfate salt) is described in Example 1 below.

[0503] In one embodiment, compound 2 is provided in a pharmaceutically acceptable composition or solid dosage form thereof.

[0504] A non-limiting example of a process for the preparation of compound 2 is: (i) a first step of dissolving Compound 1 in an organic solvent, such as acetone, ethyl acetate, methanol, acetonitrile, or ether, in a flask or container; (ii) charging a second flask or vessel with a second organic solvent, which may be the same as or different from the organic solvent in step (i), optionally cooling the second solvent to 0°C to 10°C, and adding HSO dropwise to the second organic solvent to create a HSO / organic solvent mixture (the solvent may be, for example, methanol); (iii) adding the H2SO4 / solvent mixture of step (ii) dropwise in a molar ratio of 0.5 / 1.0 to the solution of compound 1 of step (i) at ambient temperature or a slightly higher or lower temperature (e.g., 23°C to 35°C); (iv) stirring the reactants of step (iii), for example at ambient temperature or a slightly higher or lower temperature, until a precipitate of compound 2 forms; (v) optionally filtering and washing the precipitate obtained from step (iv) with an organic solvent; (vi) optionally drying the resulting compound 2 under vacuum, optionally at an elevated temperature, for example, 55°C, 56°C, 57°C, 58°C, 59°C or 60°C; Includes:

[0505] In one embodiment, the solvent in step (iii) is an alcohol, such as methanol, ethanol, or isopropyl alcohol. In one embodiment, the solvent in step (iii) is an alkyl ester, such as ethyl acetate.

[0506] Scheme 1 presents the metabolic pathway of compounds of Formula I. The metabolic pathway involves the initial deesterification of the phosphoramidate (compound 1) to form metabolite 1-1, which is then spontaneously degraded to metabolite 1-2. Metabolite 1-2 is then N 6 -methyl-2,6-diaminopurine-5'-monophosphate derivatives (metabolites 1-3), which are then converted to the free 5'-hydroxyl-N 6 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) 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 (1-8). Metabolite 1-7 is measurable in plasma and therefore serves as a surrogate for the active triphosphate (1-6), which is not measurable in plasma. [ka] TIFF2024173929000282.tif133170

[0507] definition A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of COVID-19, which is caused by the SARS-CoV-2 virus. Typically, the host is a human. "Patient" or "host" or "subject" also refers to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, bats, etc.

[0508] The terms "prophylactic" or "preventative," as used, refer to the administration of an active compound to prevent or reduce the likelihood of COVID-19 occurrence or recurrence, or to minimize new infections compared to infections that would occur in the absence of such treatment. The present invention includes both treatment and prophylactic or preventative therapy. In one embodiment, an active compound is administered to a host that has been exposed to COVID-19 and is therefore at risk for COVID-19 infection. In another alternative embodiment, a method of preventing transmission is provided, comprising administering an effective amount of one of the compounds described herein to a human for a sufficient period of time (including, for example, up to 3, 5, 7, 10, 12, 14, or more days before a contagious situation) prior to exposure to potentially infectious crowds, including when traveling or at a public event or conference.

[0509] The terms "co-administer", "co-administration" or "combination" refer to 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 according to the present invention, or a combination thereof, in combination with at least one other antiviral active agent. The term "co-administration" is used to describe the administration of a pharmaceutical acceptable salt. The timing of co-administration is best determined by the specialist who treats the patient. Sometimes it is preferable that the active substances are administered simultaneously. Alternatively, the drugs selected for combination therapy can be administered to the patient at different times. Of course, when two or more viruses or other infections or other pathologies exist, the compound of the present invention can be combined with other active substances to treat other infections or pathologies as needed.

[0510] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified into its inorganic and organic acid addition salts or base addition salts without undue toxicity. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the compounds of the present invention can optionally be provided in the form of a solvate.

[0511] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional salts of the parent compound formed, for example, from non-excessively toxic inorganic or organic acids, and quaternary ammonium salts. For example, acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts derived from 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, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nThese include salts prepared from organic acids such as -COOH (where n is 0 to 4) or using a different acid that produces the same counterion. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). It can be put out.

[0512] The compound can be delivered in any molar ratio of salt that gives the desired result.For example, the compound can be provided with less than the molar equivalent of counterion, for example, in the form of hemisulfate.Alternatively, the compound can be provided with more than the molar equivalent of counterion, for example, in the form of disulfate.Non-limiting examples of the molar ratio of compound to counterion include 1:0.25, 1:0.5, 1:1, and 1:2.

[0513] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. In certain embodiments, alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbon atoms long). As used herein, specified ranges refer to alkyl groups having the length of each member of the range described as a separate species. For example, as used herein, C1-C6 alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species, and as used herein, C1-C4 alkyl refers to alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n- Examples of dimethylbutane include, but are not limited to, hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0514] "Cycloalkyl" is a saturated monocyclic hydrocarbon ring system. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0515] "Alkenyl" refers to a non-aromatic hydrocarbon group containing at least one double bond between adjacent carbon atoms and a structure similar to an alkyl group, as described elsewhere herein. For example, an alkenyl group can have four carbon atoms (i.e., a C2-C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethenyl, i.e., vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-butenyl (-C=CH-CH2CH3), and 2-butenyl (-CH2CH=CHCH2).

[0516] 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 an alkyl group, as described elsewhere herein. For example, an alkynyl group can have from 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl and propargyl.

[0517] "Aryl" refers to an aromatic group containing only carbon in the aromatic ring(s). In one embodiment, an aryl group contains 1 to 3 separate or fused rings, has 6 to about 14 or 18 ring atoms, and does not contain heteroatoms as ring members. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above. In one embodiment, aryl groups include, for example, dihydroindole, dihydrobenzofuran, isoindolin-1-one, and indolin-2-one.

[0518] "Aryl(alkyl)-" refers to an alkyl group, as defined herein, substituted with an aryl group, as defined herein. For example, aryl(CH)- is benzyl. Examples of aryl(alkyl)- include benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0519] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing one to three, or in some embodiments one, two, or three, heteroatoms selected from N, O, S, B, and P (typically selected from N, O, and S), with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic ring system containing at least one 5-, 6-, or 7-membered aromatic ring containing one to three, or in some embodiments one or two heteroatoms selected from N, O, S, B, or P, with 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 groups typically have five or six ring atoms. When the total number of S and O atoms in the heteroaryl group exceeds one, these heteroatoms are not adjacent to one another. Examples of heteroaryl groups include pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, iso These include, but are not limited to, indolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[0520] The term "heteroalkyl" refers to an alkyl, alkenyl, alkynyl, or haloalkyl moiety, as defined herein, in which a CH group is replaced with a heteroatom, or a carbon atom is replaced with a heteroatom, such as an amine, carbonyl, carboxy, 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" refers to a heteroaliphatic group (cyclic, acyclic, or substituted) having 1 to 6 carbon atoms. It is used to indicate the type (substituted, unsubstituted, branched or unbranched).

[0521] The term phosphoramidate is used throughout this specification to describe the 5'-position portion of the furanose ring of a nucleoside, where the phosphorus atom is linked via a 5'-O-bond and the phosphorus is covalently linked to at least one nitrogen atom, forming a P-N bond, forming a prodrug form of the nucleoside compound. 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). Phosphoramidate groups for use in the present invention include, for example, those having the structure: [ka] Examples include:

[0522] Other phosphoramidates of use in the present invention include those having the structure: [ka] (In the formula, R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl, or heterocyclic group, or a linked combination thereof; R P2 Ha-NR N1 R N2group or B′ group, where: R N1 and R N2 are each independently H, C 1~8 alkyl, (C3-C7 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl- or (heteroaryl)C0-C4 alkyl-, optionally substituted; or R N1 and R N2 join with the nitrogen atom to which they are attached to form a 3- to 7-membered heterocycle, B' is [ka] It is the basis, where: R 13 is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, such as the side chain of an amino acid (as described elsewhere herein), often selected from the group consisting of 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 (often 13 is hydrogen, methyl, isopropyl or isobutyl), R 14is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, such as the side chain of an amino acid (as described elsewhere herein), often selected from the group consisting of 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 (often 14 is hydrogen, methyl, isopropyl or isobutyl), R 15 is hydrogen or C1-C3 alkyl, or R 13 and R 14 may form a (C3-C7)cycloalkyl or (C3-C7)heterocyclic group, or R 13 and R 14 or R 16 may form a (C3-C6) heterocyclic group, R 16 is hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-.

[0523] Preferred R P1 Groups include optionally substituted phenyl, naphthyl and monocyclic heteroaryl groups, particularly groups (especially lipophilic groups) that enhance the bioavailability of the compound in the patient's cells, and exhibit reduced toxicity, an enhanced therapeutic index and enhanced pharmacokinetics (the compound is metabolized and excreted more slowly).

[0524] Stabilized Phosphate Prodrugs The stabilized phosphate prodrug may be a monophosphate, diphosphate, or triphosphate. The phosphoramidates are moieties capable of delivering a phosphate in vivo. For example, McGuigan disclosed phosphoramidates in U.S. Patent Nos. 8,933,053, 8,759,318, 8,658,616, 8,263,575, 8,119,779, 7,951,787, and 7,115,590. Alios cites Alios also disclosed thiophosphoramidates in U.S. Patent Nos. 8,895,723 and 8,871,737, which are incorporated herein by reference. Thus, U.S. Patent No. 8,772,474, which is incorporated herein by reference, disclosed cyclic nucleotides. Idenix disclosed cyclic phosphoramidates and phosphoramidate / SATE derivatives in International Publication No. 2013 / 177219, which is incorporated herein by reference. Idenix also disclosed substituted carbonyloxymethyl phosphoramidate compounds in International Publication No. 2013 / 039920, which is incorporated herein by reference. Hostetler disclosed lipid phosphate prodrugs. For example, See U.S. Patent No. 7,517,858. Hostetler also discloses phosphonate protons. Lipid conjugates of drugs have been disclosed. See, e.g., U.S. Patent Nos. 8,889,658, 8,846,643, 8,710,030, 8,309,565, 8,008,308, and 7,790,703. Emory University disclosed nucleotide sphingoid and lipid derivatives in WO 2014 / 124430. RFS Pharma disclosed purine nucleoside monophosphate prodrugs in WO 2010 / 091386. Cocrystal Pharma Inc. also disclosed, citing Purine nucleoside monophosphate prodrugs were disclosed in US Pat. No. 9,173,893, the disclosure of which is incorporated herein by reference. HepDirect™ technology was disclosed in the article, "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver," J. Am. Chem. Soc. 126, 5154-5163 (2004). Additional phosphate prodrugs include, but are not limited to, phosphate esters, 3',5'-cyclic phosphates including CycloSAL, SATE derivative (S-acyl-2-thioester) prodrugs, and DTE (dithiodiethyl) prodrugs. For a literature review disclosing non-limiting examples, see A. Ray and K. Hostetler, "Application of kinase bypass strategies to nucleoside antivirals," Antiviral Research (2011) 277-291, M. Sofia, "Nucleotide prodrugs for HCV therapy," Antiviral Chemistry and Chemotherapy 2011; 22-23-49, and S. Peyrottes et al., "SATE Pronucleotide Approaches: An Overview," Mini Reviews in Medicinal Chemistry 2004, 4, 395. In one embodiment, a 5'-prodrug described in any of these patent applications or publications is used in the R 10A It can be used in the following positions.

[0525] In an alternative embodiment, stabilized phosphate prodrugs include, but are not limited to, those described in U.S. Patent Nos. 9,173,893 and 8,609,627 (incorporated herein by reference), including those describing the preparation process. For example, 5'-prodrugs may be prepared by adding a group: [ka] (In the formula, Z is O or S; R 17 and R 18 can be represented by the formula (which, when administered in vivo, can result in a nucleoside monophosphate, diphosphate, or triphosphate). 12 and R 13 are independently selected from: (a) OR 19 , where R 19 from H, Li, Na, K, phenyl and pyridinyl and wherein phenyl and pyridinyl are selected from (CH2) 0~6 CO2R 20 and (CH2) 0~6 CON(R 20 ) optionally substituted with 1 to 3 substituents independently selected from the group consisting of R 20 are independently H, C 1~20 Alkyl, carbon chain derived from fatty alcohol (oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C1~5 is alkyl; (b) [ka] (c) Esters of D- or L-amino acids: [ka] (In the formula, R 21 is limited to the side chains occurring in natural L-amino acids, R 22 is H, C 1~20 Alkyl, carbon chain derived from fatty alcohol (oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 alkyl); (d)R 17 and R 18 are both rings: [ka] (In the formula, R 23 is H, C 1~20 Alkyl, C 1~20 Alkenyl, fatty alcohols (oleyl Alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 alkyl); (e)R 17 and R 18 Both [ka] (In the formula, R 24 is H, C 1~20 Alkyl, C 1~20 Alkenyl, carbon chains derived from fatty acids (oleic acid, linoleic acid, etc.), and lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 is alkyl, R 25 may form a ring selected from:

[0526] In an alternative embodiment, the 3',5'-prodrug is [ka] (In the formula, When chirality is present at the phosphorus center, this can be fully or partially R p Or S por any mixture thereof, which may be enriched in one enantiomer, R 26 is OR 19 , [ka] and derived fatty alcohols (such as, but not limited to, linoleyl-O- and oleyl-O-); R 11 is R 1 and hydrogen; R 1 , R 21 , R 22 and R 19 is as defined herein).

[0527] isotope substitution The present invention includes the use of an effective amount of a compound of Formula I (e.g., including Compound 1, 1A, or 1B), Formula II (e.g., including Compound 3, 3A, or 3B), Formula III (e.g., including a compound of Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, or Formula IIIf), Formula IV (e.g., including a compound of Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, or Formula IVf), Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic substitution of a desired atom in an amount greater than the natural abundance of the isotope, i.e., is enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. By way of general example and not limitation, there is provided deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in the depicted structures. Alternatively, or in addition, isotopes of carbon, for example 13 C and 14C may also be used. An example of a typical isotope substitution is the substitution of hydrogen with deuterium at one or more positions on a molecule to improve drug performance. Deuterium can be attached at the position of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or adjacent to or near the site of bond cleavage (β-deuterium kinetic isotope effect). Achillion Pharmaceuticals, Inc. (WO 2014 / 169278 and WO 2014 / 1 No. 69280 describes the deuteration of nucleotides, including the 5-position of the molecule, to improve their pharmacokinetics or efficacy.

[0528] Substitution with isotopes such as deuterium can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution of hydrogen with deuterium at a site of metabolic degradation can reduce the rate of metabolism or eliminate metabolism at that bond. At any position in a compound where a hydrogen atom can be present, the hydrogen atom can be substituted with protium ( 1 H), deuterium ( 2 H) and tritium ( 3 Any isotope of hydrogen, including H. Accordingly, unless the context clearly dictates otherwise, reference herein to a compound includes all possible isotopic forms.

[0529] The term "isotopically labeled" analogues refers to "deuterated analogues," 13 C-labeled analogs" or "deuterated / 13 The term "deuterated analog" refers to an analog that is a "C labeled analog." The term "deuterated analog" refers to an analog that is a "C labeled analog" or a "C labeled analog." The term "deuterated analog" refers to an analog that is a deuterated analog of the compounds described herein, 1 H) is converted to the H-isotope, namely deuterium ( 2 H). The deuterium substitution may be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0530] In certain embodiments, the isotope is enriched to 90%, 95%, or 99% or more in the isotope at any desired position. In some embodiments, it is deuterium that is enriched to 90%, 95%, or 99% at the desired position. Unless specified to the contrary, deuteration is at least 80% at the selected position. Deuteration of nucleosides can occur at any substitutable hydrogen that provides the desired result.

[0531] In one embodiment, a compound of Formula XIII: [ka] (In the formula, R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A is selected from R 6 is hydrogen, -C(O)R 6A , -C(O)OR 6A , C 1~6 Alkyl and -CH2-OR 6A , in an alternative embodiment, —C(O)NR 6B R 6C is selected from R 6A is hydrogen, C 1~6 Alkyl, C1-C6 haloalkyl (e.g., -CHCl2, -CCl3, -CH2Cl, -CF3, -CHF2, -CH2F), aryl and aryl(C 1~6 alkyl)-, wherein the aryl group is selected from alkoxy, hydroxy, nitro and optionally substituted with a substituent selected from chloro, bromo, chloro, fluoro, azido, and haloalkyl; in an alternative embodiment, R 6A is C 1~20 Alkyl and C 2~20 alkenyl, R 6B and R 6C are independently hydrogen, C 1~20 Alkyl, C 2~20selected from alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein C 1~20 Alkyl, C 2~20 The alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl may be optionally substituted with at least one substituent selected from alkoxy (including, but not limited to, methoxy and ethoxy), hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R 30 is CH3, CD3, CHD2 or CH2D, R 31 is NH2 or D, or in alternative embodiments, CD3; R 32 is CH3, CD3, CHD2 or CH2D, Y is selected from F and Cl; R 1 , R 2 , R 3 , R 4a , R 4b and R 5 is as defined herein) or a pharmaceutically acceptable salt thereof is used to treat or prevent COVID-19 disease caused by SARS-CoV-2 in a host in need of the treatment or prevention described herein.

[0532] For example, non-limiting examples of compounds of formula XIII include: [ka] Examples include TIFF2024173929000295.tif235170, TIFF2024173929000296.tif242170, and TIFF2024173929000297.tif44170.

[0533] Additional examples of compounds of formula XIII include: [ka] Examples include TIFF2024173929000299.tif240170 and TIFF2024173929000300.tif145170.

[0534] Treatment or prevention method Treatment, as used herein, refers to the administration of an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, to a host, e.g., a human, infected or susceptible to infection with the SARS-CoV-2 virus. In one embodiment, the method of treatment comprises the administration of an effective amount of Compound 1A or Compound 3A, or a pharmaceutically acceptable salt thereof, e.g., Compound 2A or Compound 4A. In one embodiment, the method of treatment comprises the administration of an effective amount of Compound 1B or Compound 3B, or a pharmaceutically acceptable salt thereof, e.g., Compound 2B or Compound 4B.

[0535] The present invention also encompasses prophylactic or preventative therapy. In one embodiment, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered to a host that has been exposed to the SARS-CoV-2 virus and is therefore at risk of infection or reinfection with the SARS-CoV-2 virus. Prophylactic treatment can be administered, for example, to subjects who have not yet been exposed to or infected with SARS-CoV-2 but who are susceptible to or otherwise at risk of exposure or infection with COVID-19. In one embodiment, a host at risk of infection or reinfection is administered a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, indefinitely until the risk of exposure no longer exists.

[0536] In another alternative embodiment, a method of inhibiting transmission is provided, comprising administering an effective amount of one of the compounds described herein to a human for a sufficient length of time (including, for example, up to 3, 5, 7, 10, 12, 14 or more days before a contagious situation) prior to exposure to potentially contagious crowds, including when traveling or at a public event or conference, to prevent the human from becoming infected or from an infected person in a contagious situation.

[0537] 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 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more after infection.

[0538] The present invention relates to methods for treating COVID-19, including drug-resistant and multi-drug resistant forms of the virus, and related pathologies, conditions, or complications of viral infection, including pneumonia such as 2019 novel coronavirus infection pneumonia (NCIP), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Additional non-limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, thrombosis, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis, and cytokine storm.

[0539] The method also includes administering to a host, typically a human, in need thereof 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, such as an additional antiviral agent, and optionally in combination with a pharmaceutically acceptable carrier additive and / or excipient.

[0540] 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 thereof results in a reduction in the incidence of progressive respiratory failure (PRI) as measured by an increase of one or more, or even two or more, levels in the respiratory support required to maintain adequate oxygenation (SpO2 > 93%) using the six-level hierarchy of respiratory support described below.

[0541] Measures of increasing levels of respiratory support include: Level 1: Normal oxygenation on room air (SpO2 ≥ 93%) without the need for supplemental O2 Level 2: Persistent hypoxemia on room air (SpO2 ≥ 93) requiring low levels of O2 supplementation (maximum 2 L / min) via nasal cannula or mask to maintain SpO2 ≥ 93. Level 3: Requires higher levels of passive O2 supplementation (maximum 2 L / min) via nasal cannula or mask to maintain SpO2 ≥ 93. Level 4: Requires oxygenation via 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, to maintain adequate oxygenation and / or ventilation. Level 5: Requires invasive respiratory support (intubated mechanical ventilation or ECMO) Level 6: Death

[0542] In one embodiment, the reduction in PRI is an increase 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 an increase from level 4 to level 2, or from level 4 to level 1. In one embodiment, the reduction in PRI is an increase from level 3 to level 1.

[0543] 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 mean time to clinical recovery (state 6, 7, or 8 on the National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status Scale using an adapted ordinal scale of clinical status) by at least 3, 4, 5, or more days. 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 an improvement as measured by an adapted ordinal scale of clinical status.

[0544] The stages of the adapted ordinal scale of global clinical status are defined as follows, from most severe disease to progressively less severe disease: 1. Death 2. Hospitalization with invasive mechanical ventilation or ECMO 3. Hospitalization with non-invasive ventilation or high-flow oxygen devices 4. Hospitalization requiring supplemental oxygen 5. Hospitalization requiring ongoing medical care (COVID-19 related or otherwise) without the need for supplemental oxygen 6. Hospitalization without needing supplemental oxygen or further careful medical care for COVID-19 7. Not hospitalized, but with restricted activity and careful outpatient care for signs of COVID-19 8. No hospitalization, no activity restrictions, and no need for continued careful medical care

[0545] 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 mean time to clinical recovery (state 6, 7, or 8 on the National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status Scale using the NIAID Adapted Ordinal Scale of Clinical Status) by at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days.

[0546] 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 a patient infected with the SARS-CoV-2 virus.

[0547] 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 persistent undetectable SARS-CoV-2 virus in the nose and / or throat of a patient infected with SARS-CoV-2 virus.

[0548] 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.

[0549] 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 SARS-CoV-2 positive patients in hospitalized patients after at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of treatment.

[0550] In another embodiment, an effective amount of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI Methods are provided for treating or preventing SARS-CoV-2 infection in a host, typically a human, in need thereof, by administering to the host a compound of Formula I, 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 mutant exhibiting a spontaneous or drug-induced mutation relative to the wild-type.

[0551] In some embodiments, the SARS-CoV-2 variants have a spontaneous or drug-induced mutation in a viral protein selected from envelope (E) protein, membrane (M) protein, spike (S) protein, nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15, nsp16, ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10. In some embodiments, the SARS-CoV-2 variants have a mutation that causes acquired resistance to one or more antiviral drugs.

[0552] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acids H69 and V70.

[0553] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acid D614G.

[0554] In some embodiments, the SARS-CoV-2 variant has a deletion of spike protein amino acid Y144.

[0555] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution N501Y.

[0556] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution A570D.

[0557] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution P681H.

[0558] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution T716I.

[0559] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution S982A.

[0560] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution D1118H.

[0561] In some embodiments, the SARS-CoV-2 variant has a premature stop codon mutation Q27STOP in the protein product of ORF8.

[0562] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution K417N.

[0563] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution E484K.

[0564] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution K417N.

[0565] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution D215G.

[0566] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution A701V.

[0567] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution L18F.

[0568] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution R246I.

[0569] In some embodiments, the SARS-CoV-2 variant has a deletion of the spike protein at amino acids 242-244.

[0570] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution Y453F.

[0571] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution I692V.

[0572] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution M1229I.

[0573] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution N439K.

[0574] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution A222V.

[0575] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution S477N.

[0576] In some embodiments, the SARS-CoV-2 variant has the spike protein amino acid substitution A376T.

[0577] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution P323L.

[0578] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution Y455I.

[0579] In some embodiments, the SARS-CoV-2 variant has the ORF8 protein amino acid substitution R52I.

[0580] In some embodiments, the SARS-CoV-2 variant comprises the ORF8 protein amino acid sequence It has the substitution Y73C.

[0581] In some embodiments, the SARS-CoV-2 variant has the nucleoside (N) protein amino acid substitution D3L.

[0582] In some embodiments, the SARS-CoV-2 variant has the nucleoside (N) protein amino acid substitution S235F.

[0583] In some embodiments, the SARS-CoV-2 variant has the ORF1ab protein amino acid substitution T1001I.

[0584] In some embodiments, the SARS-CoV-2 variant has the ORF1ab protein amino acid substitution A1708D.

[0585] In some embodiments, the SARS-CoV-2 variant has the ORF1ab protein amino acid substitution I2230T.

[0586] In some embodiments, the SARS-CoV-2 variant has a deletion of ORF1ab protein amino acids SGF3675-3677.

[0587] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution S861X, where X is any amino acid.

[0588] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution F480V.

[0589] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution V557L.

[0590] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution D484Y.

[0591] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution F480X, where X is any amino acid.

[0592] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution V557X, where X is any amino acid.

[0593] In some embodiments, the SARS-CoV-2 variant has the nsp12 protein amino acid substitution D484X, where X is any amino acid.

[0594] In some embodiments, the SARS-CoV-2 variant comprises a deletion of spike protein amino acids 69-70, a 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 in the protein product of ORF8 (STOP Q27).

[0595] In some embodiments, the SARS-CoV-2 variant comprises a variant of the SARS-CoV-2 variant in the spike protein. The spike protein contains amino acid substitutions of N501Y, K417N, E484K, D80A, D215G, L18F, and R246I, as well as an amino acid deletion at amino acids 242 to 244 of the spike protein.

[0596] In some embodiments, the SARS-CoV-2 variant is selected from the SARS-CoV-2 clades O, S, L, V, G, GH, or GR as described in Alm et al., "Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020". Euro Surveillance: Bulletin European Sur les Maladies Transmissibles = European Communicable Disease Bulletin. 25 (32).

[0597] In some embodiments, SARS-CoV-2 variants are identified using the method described in Guan et al., A genetic barcode of SARS-CoV-2 for monitoring global distribution of different clades during The virus is selected from SARS-CoV-2 clades G614, S84, V251, I378 or D392 as described in the COVID-19 pandemic. Int J Infect Dis. 2020 Nov; 100: 216-223.

[0598] In some embodiments, SARS-CoV-2 variants are identified using Nextstrain: Genomic epidemiology of novel coronavirus - Global sub-sampling. (https: / / nextstrain.org / ncov The antibody may be selected from SARS-CoV-2 clades 19A, 19B, 20A, or 20C as described in the SARS-CoV-2 antibody kits (available from CDC).

[0599] In some embodiments, the SARS-CoV-2 variants are those described in Rambaut et al., Phylogenetic Assignment of Named Global Outbreak LINeages (pangolin). San Francisco: GitHub. Nov;5(11):1403-1407, Rambaut et al. SARS-CoV-2 lineages. SARS-CoV-2 as described in (available at https: / / cov-lineages.org / ) Selected from lineages A, B, B.1, B.1.1 or B.1.177.

[0600] In some embodiments, the SARS-CoV-2 variant is a "Cluster 5" variant that contains the spike protein amino acid substitution D614G.

[0601] In some embodiments, the SARS-CoV-2 variant is VUI 202012 / 01 (Variant Under Investigation, December 2020, variant 01) (also known as B.1.1.7 lineage and 20B / 501Y.V1) defined by multiple spike protein alterations including a deletion of spike protein amino acids 69-70, a 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 (Q27 stop) in the protein product of ORF8.

[0602] In some embodiments, the SARS-CoV-2 variant is a B.1.351 strain containing several mutations in the receptor binding domain (RBD) of the spike protein that allow the virus to more easily attach to human cells: N501Y, K417N, and E484K, as well as the amino acid substitution D80A in the spike protein, the amino acid substitution D215G in the spike protein, the amino acid substitution A701V in the spike protein, the amino acid substitution L18F in the spike protein, the amino acid substitution R246I in the spike protein, and an amino acid deletion at amino acids 242-244 in the spike protein. It is a phylogenetic variant (501.V2, also known as 20C / 501Y.V2).

[0603] In some embodiments, the SARS-CoV-2 variant is the 501Y.V2 lineage variant (501Y.V2, also known as 20C / 20H / 501Y.V2), which also contains the spike protein mutations N501Y, K417N, and E484K.

[0604] In some embodiments, the SARS-CoV-2 variant is the P.1 lineage variant (also known as the brazil(ian) variant), which contains 10 mutations in the spike protein, including N501Y and E484K.

[0605] In some embodiments, the SARS-CoV-2 variant is a B.1.1.207 lineage variant that contains the P681H mutation in the spike protein.

[0606] In some embodiments, the SARS-CoV-2 variant is the Danish mink variant, which contains the amino acid deletions H69 and V70 in the spike protein and the amino acid substitution Y453F in the spike protein.

[0607] In some embodiments, the SARS-CoV-2 variant is a Danish mink cluster 5 variant that includes the amino acid deletions H69 and V70 in the spike protein, the amino acid substitution Y453F in the spike protein, the amino acid substitution I692V in the spike protein, and the amino acid substitution M1229I in the spike protein.

[0608] In some embodiments, the SARS-CoV-2 variant comprises an amino acid deletion of H69 and V70 in the spike protein and an amino acid substitution of N439K in the spike protein.

[0609] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU1 variant, which contains the amino acid substitution A222V in the spike protein.

[0610] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU2 variant, which contains the amino acid substitution S477N in the spike protein and the amino acid substitution A376T in the nucleocapsid protein.

[0611] In some embodiments, the SARS-CoV-2 variant comprises one or more mutations selected from the following: an amino acid substitution T1001I in the protein product of ORF1ab, an amino acid substitution A1708D in the protein product of ORF1a, an amino acid substitution I2230T in the protein product of ORF1ab, a deletion of amino acids SGF at 3675-3677 in the protein product of ORF1ab, an amino acid substitution G251V in the protein product of ORF3a, an amino acid substitution S24L in the protein product of ORF8, an amino acid substitution R52I in the protein product of ORF8, an amino acid substitution Y73C in the protein product of ORF8, an amino acid substitution Y73C in the protein product of ORF8, an amino acid substitution Y73D in the protein product of ORF8, an amino acid substitution Y73E in the protein product of ORF8, an amino acid substitution Y73F ... Amino acid substitution L84S in the protein product of RF8, amino acid substitution P323L in the nsp12 domain, amino acid substitution Y455I in the nsp12 domain, amino acid substitution Q57H in the protein product of ORF3a, amino acid substitution R27C in nsp2, amino acid substitution V198I in nsp2, amino acid substitution T85I in nsp2, amino acid substitution P585S in nsp2, amino acid substitution I559V in nsp2, amino acid substitution M33I in nsp4, amino acid substitution G15S in nsp5, amino acid substitution L37F in nsp6, amino acid substitution Y541C in nsp13, amino acid substitution P50 in nsp13 4L, amino acid substitution S477N in the spike protein, amino acid substitution N439K in the spike protein, amino acid substitution N501Y in the spike protein, amino acid substitution Y453F in the spike protein, amino acid substitution K417N in the spike protein, amino acid substitution E484K in the spike protein, amino acid substitution A222V in the spike protein, amino acid substitution S98F in the spike protein, amino acid substitution D80Y in the spike protein, amino acid substitution A626S in the spike protein, amino acid substitution V1122L in the spike protein, amino acid substitution A570D in the spike protein, amino acid substitution P681H in the spike protein, amino acid substitution V1122L in the spike protein, amino acid substitution T716I in the spike protein, amino acid substitution S982A in the spike protein, amino acid substitution D1118H in the spike protein, amino acid substitution E583D in the spike protein, amino acid substitution V483A in the spike protein, amino acid substitution Q675R in spike protein, amino acid substitution A344S in spike protein, amino acid substitution T345S in spike protein, amino acid substitution R346K in spike protein, amino acid substitution A348S in spike protein, amino acid substitution A348T in spike protein, amino acid substitution N354K in spike protein, amino acid substitution S359N in spike protein, amino acid substitution V367F in spike protein, amino acid substitution V382L in spike protein, amino acid substitution P384L in spike protein, amino acid substitution P384S in spike protein, amino acid substitution T385S in spike protein, amino acid substitution V395I in spike protein, amino acid substitution R403K in spike protein, amino acid substitution D405V in spike protein, amino acid substitution Q414P in spike protein, amino acid substitution Q414E in spike protein, amino acid substitution I418V in spike protein, amino acid substitution L441I in spike protein,Amino acid substitution R457K in spike protein, amino acid substitution K458Q in spike protein, amino acid substitution P463S in spike protein, amino acid substitution A475V in spike protein, amino acid substitution G476S in spike protein, amino acid substitution T478A in spike protein, amino acid substitution P479L in spike protein, amino acid substitution V483A in spike protein, amino acid substitution F490L in spike protein, amino acid substitution Q493L in spike protein, amino acid substitution A520S in spike protein, amino acid substitution L5F in spike protein, amino acid substitution P521R in spike protein, amino acid substitution A522S in spike protein, amino acid substitution A831V in spike protein, amino acid substitution D839Y in spike protein, an amino acid substitution D839N in the spike protein, an amino acid substitution D839E in the spike protein, an amino acid substitution L8V in the spike protein, an amino acid substitution L8W in the spike protein, an amino acid substitution H49Y in the spike protein, a deletion of amino acid H69 in the spike protein, a deletion of amino acid V70 in the spike protein, a deletion of amino acid Y144 in the spike protein, an amino acid substitution D3L in the nucleocapsid protein, an amino acid substitution S253F in the nucleocapsid protein, an amino acid substitution RG203KR in the nucleocapsid protein, an amino acid substitution G214C in the nucleocapsid protein, an amino acid substitution S194L in the nucleocapsid protein, an amino acid substitution F377L in the nsp14 protein, an amino acid substitution K1186R in nsp3, or an amino acid substitution A58T in nsp3.

[0612] 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.

[0613] 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.

[0614] 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; A15 6S;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;D340 N;K373N;P168Q;A211V;D3L;G212V;K370N;P151L;T334I;A359S;G34W;P67T;R203M;D144N;R191L;S232I;D402Y;P168 S;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.

[0615] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp1 protein: M85; D75E; G82 deletion; V84 deletion; P80 deletion; H83 deletion; V86 deletion; H81 deletion; E87 deletion; L88 deletion; K141 deletion; A79 deletion; V89 deletion; V56I; R124C. ;D75G;A90 deletion;Y118C;D139N;Y136 deletion;G30D;R24C;D139Y;E37K;H45Y;H110Y;G52S;I71V;D156 deletion;A76T;E37D;S135 deletion;S166G;A138T;F157 deletion;G49C;M85I;or D144A;and combinations thereof.

[0616] 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.

[0617] 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; A 423V;M463I;T26I;A656T;M668I;T806I;T276M;T801N;V588L;K267N;V880I;K718R;L514F;F415 S;T252N;Y38H;E744D;H752Q;I171V;S913L;A526V;A382V;G228C;P94L;E84K;K59N;P830S;T908 I;P21S;D879Y;G108D;K780N;R279S;D258Y;T259I;K263N;D284Y;Q292H;T293I;N297S;V299F;D304Y;T3 19I;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;K4 78N;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;A6 99S;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.

[0618] In some embodiments, the SARS-CoV-2 variant contains 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; P78 S;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.

[0619] 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; V 290F;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.

[0620] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp15 protein: V320L; A217V; V22L; V172L; D219N; P205S; V127F; Q19H; M218 deletion; A92V; D282G; I252V; T33I; G129S; L331F; A81V; V69L; S312F; T325I; A171V; R206S; D272Y; D87N; S288F; K109R; P270S; P65S; D267Y; D128Y; E215I; T144I; S2 61L; S287L; T112I; E260K; P205L; S161I; V66L; D39Y; or T114A; or combinations thereof.

[0621] 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.

[0622] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp2 protein: T85I; P585S; I559V; D268; G212D; V198I; H237R; F10L; G339S; T166I; R27C; L271F; S211F; P91S; G199E; T371I; A336V; I120F; S122F; A476V; S138L; V480A; T388I; T6 34I;P129S;R218C;I188T;T170I;P568L;E574A;I367V;H208Y;S99F;T429I;A306V;M405V;P129L;R222C;T44I;Q275 H;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;T590 I;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.

[0623] 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; A 1311V;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;T1 269I;T779I;V1315I;V1795F;V325F;A1892V;A579V;E493G;H1274Y;S1467F;T1063I;T350I;V61F;A1736V;K1804N;R646W;T583I;T611 I;V1243I;V190I;A41V;H290Y;H295Y;H342Y;L1244F;Q128H;V1673I;A1305V;A1526S;E948K;L72F;P125S;P402T;A1766V;D1214N;E12 71D;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;I181 6T;L956I;N1369T;N506S;P153S;P2L;T1275I;T1459I;V1234M;E595D;F90L;G1585S;H1307Y;I1409V;L1034V;L1328F;L292F;N1264;P1 326T;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 combinations thereof.

[0624] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp4 protein: F308Y; T295I; M33I; A307V; A457V; G309C; L360F; A231V; H313Y; K399E; V20F; S137L; S34F; A380V; H470Y; T204I; S336L; L264F; L438F; M33L; S209F; C296S; L475I; G79V; T327N; T350I; L206F; M324I; E230G; L436 deletion; T237I; T492I; A260V; A446V; M458I; S395G; S481L; H36Y; T73I; L323F; L349F; S59F; T214I; or T60I; and combinations thereof.

[0625] 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.

[0626] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp6 protein: L37F; G277S; A46V; L75F; F37 deletion; T10I; V149F; L260F; Q208H; M83I; A136V; V145I; N156D; M86I; Y153C; G188V; L230I; F34 deletion; I189V; R233H; V114A; L33F; A287V; H11Y; A287T; A51V; G188S; I162T; M126V; M183I; N40Y; S104; F35L; M58L; or V84F; and combinations thereof.

[0627] 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.

[0628] 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.

[0629] 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.

[0630] 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.

[0631] 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; S 195Y;V112F;W131L;G44V;D27H;G174C;K21N;S165F;L65F;T229I;T89I;S74F;A99S ;G254R;H204N;K75N;F43L;L53F;Q38P;S26L;S40L;M260I;V256 deletion;K16N;Q218R;S2 53P;V163L;W69C;A23V;L41F;L106F;V55F;V88A;A99D;E239D;L52F;T24I;A31T;D27Y;I186V;L73F;P104L;D22Y;F114V;L95F;P240S;P42L;T268M;or T32I;and combinations thereof.

[0632] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF6: I33T; W27L; D53G; F22 deletion; P57L; D61Y; D61L; K42N; D53Y; H3Y; I32T; or R20S; or a combination thereof.

[0633] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7a: S81L; A8T; L96F; A50V; V104F; Q62 stop; S83L; E16D; T14I; T28I; V93F; G38V; H47Y; T39I; T120S; Q62 deletion; Q62L; S37T; V104; P34S; P99L; T120I; V108L; H73Y; V24F; V29L; A13T; or L5F; or a combination thereof.

[0634] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7b: C41F; T40I; A43V; L11F; S31L; C41 deletion; H42; H42L; S5L; L20F; L32F; E33 stop; A15S; or F13 deletion; and combinations thereof.

[0635] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF8: E110 stop; G66 deletion; S69L; T11I; F104L; F120L; G8R; P38S; D119E; I10S; or I39V; and combinations thereof.

[0636] 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; P479 S;S1252P;Y145 deletion;E583D;R214L;A1020V;Q1208H;D215G;H146Y;S98F;T95I;G1219C;A846V;I197V;R102I;V367F;T 572I;A1078S;A831V;P1162L;T73I;A845S;G1219V;H245Y;L8V;Q675R;S254F;V483A;Q677H;D138H;D80Y;M1237T;D 1146H;E654D;H655Y;S50L;S939F;S943P;G485R;Q613H;T76I;V341I;M153I;S221L;T859I;W258L;L242F;P681L;V 289I;A520S;V1104L;V1228L;L176F;M1237I;T307I;T716I;L141;M1229I;A1087S;P26S;P330S;P384L;R765L;S940 F;T323I;V826L;E1202Q;L1203F;L611F;V615I;A262S;A522V;A688V;A706V;A892S;E554D;Q836H;T1027I;T22I;A2 22V;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;P8 12L;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.

[0637] Pharmaceutical Compositions and Dosage Forms A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, can be administered in an effective amount for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a host, typically a human, in need thereof. In one embodiment, the compound is Compound 1A or Compound 3A, or a pharmaceutically acceptable salt thereof, e.g., Compound 2A or Compound 4A. In one embodiment, the compound is Compound 1B or Compound 3B, or a pharmaceutically acceptable salt thereof, e.g., Compound 2B or Compound 4B.

[0638] The compounds or salts thereof may be provided as neat chemicals, but are more commonly administered as pharmaceutical compositions containing an effective amount to a host, typically a human, in need of treatment for COVID-19. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, and at least one other compound or salt thereof, for the treatment of COVID-19. and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, as the sole active agent, or in alternative embodiments, in combination with at least one additional active agent.

[0639] A compound 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 optionally selected for ease of administration and the likelihood of favorable patient compliance. 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 provided in a solid dosage form, such as a tablet or pill, as known in the art and further described below. Enteric coated oral tablets may also be used to increase the bioavailability of the compound via the oral route of administration. The pharmaceutical compositions (formulations) may be administered by other routes, including oral, parenteral, intravenous, inhalation, intramuscular, topical, transdermal, buccal, subcutaneous, suppository, or nasal spray delivery routes.

[0640] 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 intravenously. In one non-limiting embodiment, the compound of the invention is 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 one non-limiting embodiment, the intravenous loading dose is 550 mg / day of Compound 1 (i.e., 600 mg / day of the hemisulfate salt of Compound 1) and the maintenance dose is 275 mg / day (i.e., 300 mg / day of the hemisulfate salt).

[0641] An effective dosage form will depend on the bioavailability / pharmacokinetics of the particular agent selected and the severity of the disease in the patient. A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, may be administered in the form of, for example, one or more tablets, capsules, injectables, intravenous formulations, suspensions, solutions, emulsions, implants, particles, spheres, creams, ointments, or the like. The compositions can be administered as suppositories, inhalants, transdermal, buccal, sublingual, topical, gel, mucosal, and the like.

[0642] Intravenous and intramuscular formulations are often administered in sterile saline. One skilled in the art can modify the formulation to make it more soluble in water or another vehicle; for example, this can be easily accomplished by minor modifications (salt formulations, esterification, etc.).

[0643] The pharmaceutical compositions contemplated herein optionally contain a carrier, as further described below. The carrier must have sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert or have its own medicinal effect. The amount of carrier used with the compound is sufficient to provide a practical amount of the substance to be administered per unit dose of the compound. Typical carriers include solvents, diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, isotonicity agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier.

[0644] One or more viscosity agents can be added to pharmaceutical compositions to increase the viscosity of compositions as needed.The examples of useful viscosity agents 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, their derivatives and their mixtures.

[0645] The solution, suspension, or emulsion for administration may be buffered with an effective amount of a buffering agent required to maintain a suitable pH for the selected administration. Suitable buffering agents are known to those skilled in the art. Some examples of useful buffering agents are acetate, borate, carbonate, citrate, and phosphate buffers.

[0646] To prepare pharmaceutical compositions according to the invention, a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically acceptable carrier by conventional pharmaceutical compounding techniques to produce a single dosage. The carrier may take a variety of forms depending on the form of preparation desired, e.g., for oral or parenteral administration.

[0647] Any conventional pharmaceutical medium may be used in preparing pharmaceutical compositions into oral dosage forms. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives may be used, including water, glycols, oils, alcohols, flavorings, preservatives, coloring agents, etc. For solid oral preparations such as powders, tablets, and capsules, and for solid preparations such as suppositories, suitable carriers and additives may be used, including sugar carriers such as starch, dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. If desired, tablets or capsules may be enterically coated or sustained-release by standard techniques. The use of these dosage forms can significantly enhance the bioavailability of the compound in patients.

[0648] For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, although other ingredients, including those that aid dispersion, may be included. Where sterile water is to be used and maintained as sterile, the composition and carrier must, of course, also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be utilized.

[0649] Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers, which may be suitable for delivery of the free nucleoside, acyl / alkyl nucleoside, or phosphate ester prodrug forms of the nucleoside compounds according to the present invention.

[0650] The amounts and weights recited in this disclosure typically refer to the free form (i.e., non-salt, hydrated, or solvated form). The typical values ​​described herein represent the equivalent of the free form, i.e., the same amount as when the free form is administered. When a salt is administered, the amount must be calculated based on the molecular weight ratio between the salt and the free form.

[0651] 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 invention is an amount effective to achieve the desired result of treating COVID-19, reducing the likelihood of COVID-19, or preventing, reducing, and / or eliminating COVID-19 or its secondary effects, including pathologies, conditions, and / or complications secondary to the virus. In a non-limiting embodiment, a therapeutically effective amount of the compound in a pharmaceutical dosage form is, for example, Amounts can range from about 0.001 mg / kg to about 100 mg / kg or more per day. For example, in a non-limiting 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, can be administered in an amount ranging from about 0.1 mg / kg to about 15 mg / kg of patient per day, depending on the pharmacokinetics of the agent in the patient.

[0652] The weight of active compound in the dosage forms described herein refers to either the free form or the salt form of the compound unless otherwise specified. For example, approximately 600 mg of Compound 2 corresponds to approximately 550 mg of Compound 1.

[0653] In certain embodiments, the pharmaceutical composition is a dosage form containing about 1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, about 200 mg to about 600 mg, about 300 mg to about 500 mg, or about 400 mg to about 450 mg of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, per unit dosage form.

[0654] In certain embodiments, the pharmaceutical composition may contain up to about 10 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 ... and the like. In some embodiments, the dosage form is a solid dosage form containing about 0 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg or more of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X or Formula XIII, or a pharmaceutically acceptable salt thereof.

[0655] 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 (i.e., a 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, given once or twice daily. In one embodiment, the loading dose is about 1.5-fold higher, about 2-fold higher, about 2.5-fold higher, or about 3-fold higher than the maintenance dose. In one embodiment, one, two, three, four, or more loading doses are administered prior to the initial maintenance dose.

[0656] In one embodiment, the pharmaceutical composition is a dosage form, e.g., a solid dosage form, containing at least 500 mg, at least 550 mg, 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, 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, per unit dosage form.

[0657] In certain embodiments, the pharmaceutical composition, e.g., 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 (i.e., loading dose) of at least about 900 mg, 1000 mg, 1100 mg, 1100 mg, or 1200 mg of Compound 1, followed by a dose of at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, or at least about 650 mg of Compound 1, administered twice daily. In one embodiment, the pharmaceutical composition is administered at an initial dose (i.e., loading dose) of at least about 1100 mg of Compound 1, followed by a dose of at least about 450 mg, 550 mg, 650 mg, 750 mg, or 850 mg of Compound 1, administered twice daily. In one embodiment, the pharmaceutical composition is administered at an initial dose (i.e., loading dose) of at least about 1100 mg of Compound 1, followed by a dose of at least about 550 mg of Compound 1 twice daily. In one embodiment, a maintenance dose is administered for about 4, 5, 6, 7, 8, 9, 10 or more days. In one embodiment, Compound 1 is Compound 1A. In one embodiment, Compound 1 is Compound 1B.

[0658] In one embodiment, an effective amount of a compound of Formula I: [ka] or a pharmaceutically acceptable salt thereof is administered for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof, wherein the compound is administered according to the following schedule: (i) A single loading dose of 1100 mg of the free base on one day, followed by (ii) A maintenance dose of 550 mg of the free base per day.

[0659] In one embodiment, an effective amount of a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof is administered for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof, wherein the compound is administered according to the following schedule: (i) A single loading dose of 1100 mg of the free base on one day, followed by (ii) A maintenance dose of 550 mg of the free base per day.

[0660] In one embodiment, an effective amount of a compound of the formula: [ka] is administered for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus in a human in need of treatment, wherein the compound is administered according to the following schedule: (i) Following a single loading dose of 1200 mg of salt on 1 day, (ii) A maintenance dose of 600 mg of salt per day.

[0661] In certain embodiments, the pharmaceutical composition, e.g., 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 dose (i.e., loading dose) of at least about 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1300 mg of Compound 2, followed by doses of at least about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of Compound 2 once, twice, or three times daily. In one embodiment, the pharmaceutical composition is administered at an initial dose (i.e., 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 dose (i.e., 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 daily. In one embodiment, the pharmaceutical composition is administered at an initial dose (i.e., 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 daily. In one embodiment, the maintenance dose is administered for about 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or more. In one embodiment, Compound 2 is Compound 2A. In one embodiment, Compound 2 is Compound 1B.

[0662] 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 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more. 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.

[0663] For purposes of this invention, a prophylactically or preventatively effective amount of a composition according to the invention will generally fall within the ranges described above and can be determined using the best judgment of a healthcare provider. In one embodiment, the compounds of the invention can be administered only during seasons when there is an increased risk of the virus to prevent infection, or can be administered before, during, and / or after, for example, travel or exposure.

[0664] A therapeutically effective amount will depend on the infection or condition to be treated, its severity, the treatment regimen used, and the Those skilled in the art will recognize that such therapeutic amounts will vary depending on the pharmacokinetics of the agent being administered and the patient or subject (animal or human) being treated, and can be determined by the attending physician or specialist.

[0665] solid dosage form One aspect of the 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.

[0666] 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 delivery. In another embodiment, the solid dosage form is a granulo-layered solid dispersion of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral delivery.

[0667] In yet another embodiment, the solid dispersion comprises at least one excipient selected from copovidone, poloxamer, and HPMC-AS. In one embodiment, the poloxamer is poloxamer 407 or a mixture of poloxamers that may include poloxamer 407. In one embodiment, the HPMC-AS is HPMC-AS-L.

[0668] In yet other embodiments, solid dosage forms made 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, comprise one or more of the following excipients: phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleoylphosphatidylethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; Diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexanedecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate (Span™ 85) glycocholate; sorbitan monolaurate (Span™ 20); polysorbate 20 (Tween™ 20); polysorbates Polysorbate 60 (Tween™ 60); Polysorbate 65 (Tween™ 65); Polysorbate 80 (Tween™ 80); Polysorbate 85 (Tween™ 85); Polyoxyethylene monostearate; Surfactin; Poloxamer; Sorbitan fatty acid esters such as sorbitan trioleate; Lecithin; Lysolecithin; Phosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiolipin; Phosphatidic acid; Cerebrosides; Dicetidinyl phosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; hexadecyl stearate; isopropyl myristate; tyloxapol; poly(ethylene glycol) 5000-phosphatidylethanolamine; poly(ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents with high surfactant properties; deoxycholate; cyclodextrin; chaotropic salts; ion pairing agents;Glucose, fu; Lactose, galactose, ribose, lactose, sucrose, maltose, trehalose sugar, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid; pullulan, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycone, amylose, chitosan, N,O-carboxymethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pastulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, Pluronic polysaccharides. mers, polyethylene, polycarbonates (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-hydroxyalkanoates))), poly(orthoesters), polycyanoacrylates, polyvinyl alcohol, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines, polylysine, polylysine-PEG copolymers, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monocaprylocaprate, 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 copolymer of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0669] In other embodiments, solid dosage forms made from a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, comprise one or more of the following surfactants: polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl esters, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, and poloxamer. Examples of poloxamers include poloxamers 188, 237, 338, and 407. These poloxamers are available under the trade name Pluronic™ (available from BASF, Mount Olive, New Jersey), and correspond to Pluronic™ F-68, F-87, F-108, and F-127, respectively. Poloxamer 188 (corresponding to Pluronic™ F-68) is a block copolymer having an average molecular weight of about 7,000 Da to about 10,000 Da, or about 8,000 Da to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic™ F-87) is a block copolymer having an average molecular weight of about 6,000 Da to about 9,000 Da, or about 6,500 Da to about 8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to Pluronic™ F-108) is a block copolymer having an average molecular weight of about 12,000 Da to about 18,000 Da, or about 13,000 Da to about 15,000 Da, or about 14,600 Da. Poloxamer 407 (corresponding to Pluronic™ F-127) is a polyoxyethylene-polyoxypropylene triblock copolymer having an average molecular weight of about 10,000 Da to about 15,000 Da, or about 12,000 Da to about 14,000 Da, or about 12,000 Da to about 13,000 Da, or about 12,600 Da, in a ratio of about E101 P56 E101 to about E106 P70 E106, or about E101 P56 E101, or about E106 P70 E106.

[0670] In still other embodiments, the solid dosage form made 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, comprises one or more of the following surfactants: polyvinyl acetate, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethylammonium bromide, saponin, sugar ester, Triton X series, sorbitan trioleate, sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, oxyethylene and oxypropylene block copolymer, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil, and sunflower seed oil.

[0671] In an alternative embodiment, solid dosage forms made 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, are made by a process comprising solvent or dry granulation, optionally followed by compression or consolidation, spray drying, nanosuspension processing, hot melt extrusion, extrusion / spheronization, molding, spheronization, layering (e.g., spray layering suspension or solution), and the like. Examples of such techniques include direct compression using suitable punches and dies (e.g., where the punches and dies are adapted to a suitable tablet press); wet granulation using suitable granulation equipment such as a high shear granulator to form wet particles that are dried into granules; granulation followed by compression using suitable punches and dies (where the punches and dies are adapted to a suitable tablet press); extrusion of the wet mass to form a cylindrical extrudate that is cut to the desired length or broken to length under gravity and attrition; extrusion / spheronization (where the extrudate is rolled into spherical particles and densified by spheronization); precipitation of a suspension or solution over an inert core using techniques such as a convention pan or Wurster column. spray lamination; injection molding or compression molding using a suitable mold adapted to a compression unit; and the like.

[0672] Exemplary disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), powdered cellulose, chitosan, croscarmellose sodium, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch , sodium carboxymethyl starch, etc., or Combinations of these are possible.

[0673] Exemplary lubricants include calcium stearate, magnesium stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, light mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, silicon dioxide, colloidal silicon dioxide, dimethyldichlorosilane treated with silica, talc, or combinations thereof.

[0674] The dosage cores described herein may be coated to provide coated tablets. The dosage cores may be coated with a functional or non-functional coating, or a combination of functional and non-functional coatings. A "functional coating" refers to a coating that enhances the release of the overall composition. Tablet coatings include those that modify the release characteristics, such as sustained- or delayed-release coatings. "Non-functional coatings" include coatings that are not functional, such as cosmetic coatings. Non-functional coatings may have some effect on the release of the active agent due to initial dissolution, hydration, perforation of the coating, etc., but are not considered to deviate significantly from the uncoated composition. Non-functional coatings can also mask the taste of uncoated compositions containing active pharmaceutical ingredients. The coating may include a light-blocking material, a light-absorbing material, or a combination of a light-blocking material and a light-absorbing material.

[0675] Exemplary polymethacrylates include copolymers of acrylic and methacrylic acid esters, such as: a. amino methacrylate copolymers USP / NF, such as poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1 (e.g., EUDRAGIT E 100, EUDRAGIT EPO, and EUDRAGIT E 12.5; CAS No. 24938-16-7); b. poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., EUDRAGIT L30 D-55, EUDRAGIT L100-55, EASTACRYL 30D, KOLLICOAT MAE 30D AND 30DP; CAS No. 25212-88-8); c. poly(methacrylic acid, methyl methacrylate) 1:1 (e.g., EUDRAGIT L 100, EUDRAGIT L 12.5, and 12.5P; also known as methacrylic acid copolymers, Type A NF; CAS No. 25806-15-1; d. Poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., EUDRAGIT S 100, EUDRAGIT S 12.5 and 12.5P; CAS No. 25086-15-1; e. Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 (e.g., Eudragit FS 30 D; 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 30 D, RL 12.5, RS 100, RS PO, RS 30 D, or RS 12.5; CAS No. 33434-24-1; g. poly(ethyl acrylate, methyl methacrylate) 2:1 (e.g., EUDRAGIT NE 30 D, Eudragit NE 40D, Eudragit NM 30D; CAS No. 9010-88-2), and the like, or combinations thereof.

[0676] Suitable alkylcelluloses include, for example, methylcellulose, ethylcellulose, and the like, or combinations thereof. An exemplary water-based ethylcellulose coating agent is sodium lauryl sulfate, available from FMC, Philadelphia, Pennsylvania. Examples include AQUACOAT, a 30% dispersion further containing ammonium oleate and cetyl alcohol; SURELEASE, a 25% dispersion further containing stabilizers or other coating ingredients (e.g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.) available from Colorcon, West Point, Pennsylvania; and ethyl cellulose (Ethocel), available from Aqualon or Dow Chemical Co, Midland, Michigan. Those skilled in the art will appreciate that other cellulose polymers, including other alkyl cellulose polymers, can be substituted for some or all of the ethyl cellulose.

[0677] Other suitable materials that can be used to make functional coatings include hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate phthalate (CAP); polyvinyl acetate phthalate; neutral or synthetic waxes, fatty alcohols (lauryl, myristyl, stearyl, cetyl, etc., or specifically cetostearyl alcohol), fatty acid esters, fatty acids including fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fats and oils, hydrocarbons, conventional waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials with a hydrocarbon backbone, or combinations thereof. Suitable waxes include beeswax, glycowax, castor wax, and the like. Examples of waxes that can be used include castor wax, carnauba wax, microcrystalline wax, candelilla, and wax-like substances, such as materials that are normally solid at room temperature and have a melting point of about 30° C. to about 100° C., or combinations thereof.

[0678] In other embodiments, the functional coating comprises a digestible long chain (e.g., C8-C 50 , specifically C12 ~C 40 The hydrocarbon may include substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils and vegetable oils, waxes, or combinations thereof. Hydrocarbons having a melting point of about 25°C to about 90°C may be used. Specifically, fatty (aliphatic) alcohols, which are long-chain hydrocarbon materials, may be used.

[0679] The coating may optionally include additional pharmaceutically acceptable excipients such as plasticizers, stabilizers, water-soluble components (e.g., pore-forming agents), anti-tacking agents (e.g., talc), surfactants, etc., or combinations thereof.

[0680] The functional coating may include a release modifier that affects the release characteristics of the functional coating. The release modifier may function, for example, as a pore-forming agent or matrix disintegrating agent. The release modifier may be organic or inorganic and include materials that can be dissolved, extracted, or leached from the coating in the environment of use. The release modifier may include one or more hydrophilic polymers, including cellulose ethers and other cellulose compounds such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; acrylic polymers such as gastrosoluble Eudragit FS 30D, pH-sensitive Eudragit L30D 55, L 100, S 100, or L 100-55; or combinations thereof. Other exemplary release-modifying agents include povidone; saccharides (e.g., lactose, etc.); metal stearates; inorganic salts (e.g., dibasic calcium phosphate, sodium chloride, etc.); polyethylene glycols (e.g., polyethylene glycol (PEG) 1450, etc.); sugar alcohols (e.g., sorbitol, mannitol, etc.); alkali alkyl sulfates (e.g., sodium lauryl sulfate); polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates); or combinations thereof. Exemplary matrix disintegrants include water-insoluble organic or inorganic materials. Organic polymers, including but not limited to, cellulose, cellulose ethers such as ethyl cellulose, cellulose esters such as cellulose acetate, cellulose acetate butyrate, and cellulose acetate propionate, and starch, can function as matrix disintegrants. Examples of inorganic disintegrants include many calcium salts, such as monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate, silica, and talc.

[0681] The coating agent may optionally contain a plasticizer to improve the physical properties of the coating. For example, because 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 the ethyl cellulose before use as a coating material. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the polymer, and may be, for example, from about 1% to about 200% depending on the polymer, but is often from about 1% to about 100% by weight of the polymer. However, the concentration of the plasticizer can be determined by routine experimentation.

[0682] Examples of plasticizers for ethyl cellulose and other celluloses include dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, or combinations thereof, although other water-insoluble plasticizers (acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[0683] Examples of plasticizers for acrylic polymers include triethyl citrate NF, triethyl citrate Examples of suitable plasticizers include citric acid esters such as dibutyl phthalate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, triacetin, or combinations thereof, although other plasticizers (acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[0684] The coating material can be applied to the surface of the dosage form core using any suitable method, including processes such as simple or complex coacervation, interfacial polymerization, submerged drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, or electrostatic deposition.

[0685] In certain embodiments, an optional intermediate coating is used between the dosage form core and the outer coating. Such intermediate coatings 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 typically include water-soluble film-forming polymers. Such intermediate coatings may include film-forming polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene 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 glycerin.

[0686] Combination and Alternation Therapy The compounds described herein, or pharmaceutically acceptable salts thereof, can be administered in addition to the current standard of care for COVID patients, or in combination or alternation with any other compound or therapy that a healthcare provider deems beneficial to the patient. The combination and / or alternation therapy can be curative, adjunctive, or palliative.

[0687] It is recognized that COVID patients may progress through various stages of the disease, and standard treatments may differ based on the stage of disease a patient presents with or progresses to. COVID is notable for the occurrence of "crosstalk" between the immune and coagulation systems. As the disease progresses, patients may begin to overreact with their immune system, which can lead to numerous serious consequences, including a cytokine storm. Crosstalk between the immune and coagulation systems can lead to clots in various parts of the body, including the patient's respiratory system, brain, heart, and other organs. Numerous blood clots have been observed throughout the body of COVID patients, requiring anticoagulant therapy. These clots may cause long-term or even permanent damage if left untreated and the disease is not alleviated.

[0688] More specifically, COVID-19 has been described as progressing through three general disease stages: Stage 1 (initial infection), Stage 2 (pulmonary stage), and Stage 3 (hyperinflammatory stage / cytokine storm).

[0689] Stage 1 is characterized by nonspecific, often mild symptoms. Viral replication occurs, and immediate treatment with the compounds described herein, possibly in combination or alternating with another antiviral therapy, is appropriate. Interferon-β may 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 or alternation with interferon-β and / or an additional antiviral agent. Zinc supplements and / or vitamin C may be administered at this stage or once the disease has progressed. There are cases like this.

[0690] Stage 2 of COVID-19 is the pulmonary stage in which patients may experience acute hypoxemic respiratory failure. Indeed, hypoxemic respiratory failure is the primary organ failure of COVID-19. Moderate immunosuppression with steroids, such as dexamethasone, has been shown to be beneficial for patients with acute hypoxemic respiratory failure and / or patients on mechanical ventilation. In one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is used in an effective amount in combination with a corticosteroid, which may be a glucocorticoid. Non-limiting examples are budesonide (Entocort EC), betamethasone (Celestone), prednisone (Prednisone Intensol), prednisolone (Orapred, Prelone), triamcinolone (Aristospan Intra-Articular, Aristospan Intralesional, Kenalog), methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol), hydrocortisone, or dexamethasone (Dexamethasone Intensol, DexPak 10 Day, DexPak 13 Day, DexPak 6 Day).

[0691] The NS5B inhibitor remdesivir has produced mixed results when given to COVID-19 patients. Remdesivir can only be administered intravenously in a hospital, typically three times daily, making it unsuitable for patients with mild to moderate 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 in combination or alternation with remdesivir to enhance the overall antiviral effect.

[0692] The final stage of the disease, stage 3, is characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small blood clots develop in the bloodstream. This stage may also include multiple organ failure (e.g., vasodilatory shock, myocarditis). Many patients have also been observed to respond to this severe stage of COVID-19 infection with a "cytokine storm." There appears to be a bidirectional synergistic relationship between DIC and cytokine storm. To address DIC, patients are often administered anticoagulants, which may be indirect thrombin inhibitors or direct oral anticoagulants (DOACs). Non-limiting examples include low-molecular-weight heparin, warfarin, bivalirudin (Angiomax), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), or edoxaban (Lixiana). In one embodiment, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with anticoagulant therapy. In some severe cases of clotting in COVID patients, TPA (tissue plasminogen activator) can be administered.

[0693] High levels of the cytokine interleukin-6 (IL-6) have been recognized as a precursor to respiratory failure and death in COVID-19 patients. To treat this surge in immune response, which can lead to a cytokine storm, patients can be administered protein degraders, such as monoclonal antibodies targeting IL-6, pharmaceutical inhibitors, or bispecific compounds that bind both IL-6 and proteins 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 combination or alternation with tocilizumab or sarilumab. The additional use of immunosuppressants used to treat an overactive immune system is also beneficial. Non-limiting examples 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), mycophenolic acid (CellCept, Myfortic)). Additional 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).

[0694] IL-1 blocks the production of IL-6 and other inflammatory cytokines. COVID patients may also be treated with anti-IL-1 therapy, such as intravenous administration of anakinra, to reduce the excessive inflammatory response. Anti-IL-1 therapy generally can be a targeted monoclonal antibody, a pharmaceutical inhibitor, or a proteolytic inducer, such as a bispecific compound that binds both IL-1 and a protein that mediates degradation.

[0695] COVID patients often develop viral pneumonia, which can lead to bacterial pneumonia. Patients with severe COVID-19 may also suffer from sepsis or "septic shock." Treatment of bacterial pneumonia or sepsis secondary to COVID includes the administration of antibiotics, such as macrolide antibiotics, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanic acid, or levofloxacin. Thus, in one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination with or alternating with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such drugs can be used as anti-inflammatory agents for COVID patients and may also have therapeutic effects against secondary bacterial infections.

[0696] A unique challenge in treating patients infected with COVID-19 is the need for relatively long-term sedation, as patients may require mechanical ventilation for up to five, ten, or even fourteen days or longer. Pain medications can be added continuously for persistent pain during this treatment, and sedatives can be added continuously for persistent anxiety. 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 predominantly sedative 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 combination or alternation 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 combination or alternation with an analgesic, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital. It is administered in combination with or alternating with sedatives such as Vithal.

[0697] Test drugs for COVID-19 include chloroquine and hydroxychloroquine. In one embodiment, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XIII, or a pharmaceutically acceptable salt thereof, is administered in combination or alternation with chloroquine or hydroxychloroquine.

[0698] Protease inhibitors previously approved for HIV, such as lopinavir or ritonavir, can also be administered.

[0699] Additional 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 the monoclonal antibody combination REGN3048 and REGN3051, or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with the active compounds presented herein to treat viral infections susceptible to such compounds.

[0700] In one embodiment, the compound of the present invention is mRNA-1273 (Moderna, Inc.), AZD -1222 (AstraZeneca and University of Oxford), BNT162 (Pfizer and BioNTech), CoronaVac (Sinovac), NVX-CoV 2372 (NovoVax), SC B-2019 (Sanofi and GSK), ZyCoV-D (Zydus Cadila) and CoVaxin (Bharat Biotech). In another embodiment, the compounds of the invention are used in effective amounts in combination with passive antibody therapy or convalescent plasma therapy.

[0701] SARS-CoV-2 is constantly mutating, potentially increasing its virulence and rate of spread. Drug-resistant mutant strains of the virus may emerge after prolonged antiviral treatment. Drug resistance can arise through mutations in genes that encode enzymes used in viral replication. The effectiveness of a drug against RNA virus infections can, in certain cases, be extended, enhanced, or restored by administering the compound in combination or alternation with another, possibly two or three, other antiviral compounds that induce different mutations or act by a different pathway than the base drug.

[0702] Alternatively, the pharmacokinetics, biodistribution, half-life or other parameters of the drug may be altered by such combination therapy (which may include alternation therapy when considered coordinated). Because the disclosed purine nucleotides are polymerase inhibitors, the compounds may be used in combination with, for example, (1) protease inhibitors, (2) another polymerase inhibitor, (3) allosteric polymerase inhibitors, (4) interferon alpha-2a, which may be pegylated or otherwise modified, and / or ribavirin; (5) non-substrate-based inhibitors (6) helicase inhibitors, (7) antisense oligodeoxynucleotide (S-ODN), (8) aptamers, (9) nuclease-resistant ribozymes, (10) iRNA, including microRNA and siRNA; (11) Antibodies, partial antibodies, or domain antibodies against viruses, or (12) A viral antigen or partial antigen that induces a host antibody response; It may be useful to administer to a host in combination with [Example]

[0703] General method 1 H, 19 F and 31 P NMR spectra were recorded on a 400 MHz Fourier transform Bruker spectrometer. Spectra were obtained in DMSO-d6 unless otherwise specified. Spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J) are reported in Hz. The reactions were typically carried out under a dry nitrogen atmosphere using anhydrous solvents from Sigma-Aldrich. All common chemicals were purchased from commercial sources.

[0704] The following abbreviations are used in the examples: BID: Twice a day DCM: dichloromethane EtOAc: ethyl acetate EtOH: ethanol GT: genotype HPLC: High-pressure liquid chromatography LD:Loading dose NaOH: Sodium hydroxide Na2SO4: Sodium sulfate (anhydrous) MeOH: Methanol Na2SO4: Sodium sulfate NH4Cl: Ammonium chloride PE: Petroleum ether Silica gel (230-400 mesh, Sorbent) t-BuMgCl: t-butylmagnesium chloride THF: tetrahydrofuran (THF), anhydrous TP: Triphosphate

[0705] Example 1. Synthesis of Compound 1A and Compound 2A 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) [ka] In step 1, compound 1-1 is dissolved in DCM, the reaction is cooled to 10°C, and then benzyl chloroformate is added, followed by NEt3. The reaction is cooled to room temperature and stirred for 12 to 14 hours. Compound 1-2 is isolated following appropriate workup and purification conditions. In step 2, compound 1-2 is dissolved in acetonitrile, cooled to -15 to 5°C, and then added with Morpho DAST is added. The reaction is stirred for 6 hours. Compound 1-3 is isolated following appropriate workup and purification. In step 3, compound 1-3 is dissolved in toluene, the reaction is cooled to 0°C to 10°C, and Red Al is added. Compound 1-4 is isolated following appropriate workup and purification as a diastereomer with (R)-stereochemistry at the hydroxyl position. In step 4, compound 1-4 is dissolved in acetonitrile, cooled to -15°C to 5°C, and CBr4 and PPh3 are added. Compound 1-5 is isolated following appropriate workup and purification. In step 5, compound 1-5 is dissolved in acetonitrile and t-BuOH, and t-BuOK and 6-chloro-9H-purin-2-amine are added. The reaction is heated to 40°C to 50°C. Compound 1-6 is isolated following appropriate workup and purification. In step 6, compound 1-6 is dissolved in MeOH, and MeNH2 is added. The reaction is heated to 20° C.-30° C. Compounds 1-7 are isolated following appropriate workup and purification conditions.

[0706] Part B: Synthesis of dihydroquinine salts of isopropyl(hydroxy(phenoxy)phosphoryl)-L-alaninate (1-12) [ka] Phenyl dichlorophosphate (1-8, 150 g, 1.0 equiv.) was added to 1300 mL of isopropyl acetate. After the solution was cooled to -10°C ± 5°C, a solution of benzyl alcohol (1-9, 80.6 g, 1.05 equiv.) and EtN (86.3 g, 1.2 equiv.) was added. The mixture was stirred at -10°C ± 5°C for 3 hours. The reaction endpoint was monitored by TLC.

[0707] L-alanine isopropyl ester hydrochloride (1-10, 125 g, 1.05 eq.) and EtN (152 g, 2.1 eq.) were added at −10° C.±5° C. The reaction mixture was stirred at −10° C.±5° C. for 2 hours. The end point of the reaction was monitored by TLC.

[0708] The reaction mixture was filtered, and the filter cake was washed with 20 mL of isopropyl acetate. The filtrate was washed with 1 N HCl, water, and aqueous sodium bicarbonate. The separated organic layer was dried over anhydrous Na2SO4 and then concentrated to dryness under vacuum at 40-50 °C to give 240 g of crude product 1-11 as a diastereomeric mixture (approximately 1:1) (pale yellow oil; yield: 89.6% (mol / mol); HPLC purity: 83.4 area%; HPLC assay: 86.2% (w / w)). The product contained approximately 6%-7% residual benzyl alcohol. Crude 1-4 was used directly in the next step.

[0709] Compound 1-11 (135 g, 1.0 equiv., 86.2% assay) and quinine (100 g, 1.0 equiv.) were added to 650 mL of i-PrOH. After adding 5% Pd / C (19.2 g, 60% water by KF), hydrogenation was carried out in a closed system using a hydrogen bag at 20-25 °C for 8 h. After completion of the reaction, the mixture was filtered through a Buchner funnel. The filtrate was concentrated under vacuum to remove the solvent.

[0710] To the residue was added 300 mL of TBME. The mixture was concentrated under vacuum at 40-45°C to remove the solvent, and this process was repeated with an additional 300 mL of MTBE. To the above, 600 mL of MTBE was added, and the mixture was stirred at 40-45°C for 1 hour, followed by another 1 hour at 0-5°C. The mixture was filtered, and the filter cake was washed with 100 mL of MTBE. The cake was dried at 45°C for 16 hours without vacuum to give 152 g of the dihydroquinine salt of isopropyl(hydroxy(phenoxy)phosphoryl)-L-alaninate (1-12, white solid; yield: 69.5% (mol / mol); HPLC purity: 97.91%).

[0711] Part C: Synthesis of Compound 1A [ka] The dihydroquinine salt of isopropyl(hydroxy(phenoxy)phosphoryl)-L-alaninate (1-12, 5.9 g, 1.5 equiv.), compound 1-7 (2.0 g, 1.0 equiv.), DIPEA (0.83 g, 1.0 equiv.), and HATU (3.65 g, 1.5 equiv.) were added to 100 mL of dichloromethane. The mixture was heated to 40° C. and stirred for 18 hours. The reaction was monitored by TLC and HPLC.

[0712] After the reaction was completed, the reaction mixture was cooled to room temperature and washed with 1N hydrochloric acid (100 mL × 2), water (100 mL × 2), and 5% aqueous sodium bicarbonate solution (15 mL × 1). The separated organic phase was dried over 2 g of anhydrous sodium sulfate, filtered, and concentrated under vacuum at 40 °C to 45 °C to give a yellow oil.

[0713] Isopropyl acetate (10 mL) was added. After stirring, the mixture was concentrated under vacuum. Then, 25 mL of isopropyl acetate was added. The mixture was heated to 45° C. to obtain a clear solution. After stirring at room temperature for 2 hours, the solid precipitate was filtered and dried at 45° C. for 15 hours without vacuum to obtain 2.0 g of crude Compound 1A (yield: 53.8% (mol / mol); HPLC purity: 93.1 area % (3.7% R p -containing compound 1B)) was obtained.

[0714] A mixture of crude compound 1A (2.0 g) and 15 mL of isopropyl acetate was heated to 80-85°C to obtain a solution. The solution was cooled to 20-25°C and stirred for 1 h. The precipitated solid was filtered, washed with isopropyl acetate (1 mL), and dried at 50°C for 16 h without vacuum to obtain 1.7 g of compound 1A (yield: 45.7% (mol / mol); HPLC purity: 98.99%). 1 H NMR, 19 F NMR and 31 The structure of compound 1A was confirmed by P NMR spectroscopy.

[0715] Part D. Synthesis of the hemisulfate salt of compound 2A [ka] A 250 mL flask was charged with MeOH (151 mL) and the solution was cooled to 0-5°C. Concentrated HSO solution was added dropwise over 10 minutes. Compound 1A (151 g) and acetone (910 mL) were charged into a separate flask, and a HSO / MeOH solution was added dropwise over 2.5 hours at 25-30°C. A large amount of solid precipitated. After stirring the solution at 25-30°C for 12-15 hours, the mixture was filtered, washed with MeOH / acetone (25 mL / 150 mL), and dried in vacuo at 55-60°C to give compound 2A (121 g, 74%). 1 HNMR: (400 MHz, DMSO-d6): δ 8.41 (br, 1H), 7.97 (s, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H ), 7.17 (t, J=8.0 Hz, 1H), 6.73 (s, 2H), 6.07 (d, J=8.0 Hz, 1H), 6.00 (dd, J=12.0, 8.0 Hz, 1H), 5.81(br, 1H), 4.84-4.73 (m, 1H), 4.44-4.28 (m, 3H), 4.10 (t, J=8.0 Hz, 2H), 3.85-3.74 (m, 1H), 2.95 (s, 3H), 1.21 (s, J=4.0 Hz, 3H), 1.15-1.10 (m, 9H).

[0716] Example 2. Synthesis of selected compounds of the present invention NMR spectra were recorded on a 400 MHz Fourier transform Bruker spectrometer. Spectra were obtained from samples prepared in 5 mm diameter tubes in CDCl3, CD3OD, or DMSO-d6. Spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J) are reported in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS instrument. The reactions were typically carried out under a dry nitrogen atmosphere using anhydrous solvents from Sigma-Aldrich. All common Chemicals were purchased from commercial sources.

[0717] Synthesis 2. Isopropyl ((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-alaninate (Compound 5) [ka] 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]trioxadisilosin-8-yl)-9H-purin-2-yl)acetamide: To a solution of intermediate 2-1 (50.2 g, 92.25 mmol) in DCM (500 mL) and pyridine (75 ml) was added TMSCl (30.1 g, 276.74 mmol) at 0° C. and stirred at 0° C. for 0.5 h. To the solution was added acetic anhydride (28.2 g, 276.74 mmol) and the reaction was stirred at 0° C. for 0.5 h and then at room temperature for 1 h. To the reaction mixture was added HO and EtOAc. The organic phase was washed with saturated brine, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography (silica gel, EA / PE=0→10%) to give intermediate 2-2 (53 g, 51%) as a yellow solid.

[0718] 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]trioxadisirosin-8-yl)-9H-purin-2-yl)acetamide: To a solution of intermediate 2-2 (53 g, 82.25 mmol) in THF (530 mL) was added p-toluenesulfonic acid monohydrate (5.9 g, 36.67 mmol) at room temperature. The solution was stirred at room temperature for 1 hour. 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% → 20%) to give Intermediate 2-3 (47 g, 99.5%) as a white solid.

[0719] 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]trioxadisirosin-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 azeotropically concentrated with toluene (200 mL). The residue was purified by column chromatography (silica gel, EA / PE=33%→100%) to give intermediate 2-4 (34.8 g, 94%) as a white solid.

[0720] 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]trioxadisirosin-8-yl)-9H-purin-2-yl)acetamide: Magnesium chips (6.7 g, 278.66 mmol) were dispersed in anhydrous ether (380 mL) and deuterated methyl iodide (9.2 g, 63.33 mmol) was added and the reaction stirred at room temperature for 0.5 hours before allowing to reach room temperature. Deuterated methyl iodide (27.5 g, 190.00 mmol) was added dropwise and the reaction stirred for 1 hour before allowing to reach below 10° C. and intermediate 2-4 (37 g, 63.33 mmol) in DCM (380 ml) was added. The reaction mixture was stirred for 1 hour, then quenched with saturated NaHCO and extracted with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 33% to 50%) to give intermediate 2-5 (22 g, 57.9%) as a solid.

[0721] Step 5: N-(6-chloro-9-((2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-9H-purin-2-yl)acetamide: To a solution of intermediate 2-5 (22 g, 36.65 mmol) in THF (150 mL) was added tetrabutylammonium fluoride (23.12 g, 73.30 mmol) in THF (70 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 give intermediate 2-6 (20 g, >100%) as a solid.

[0722] Step 6: (2R,3R,4S,5R)-5-(2-acetamido-6-chloro-9H-purin-9-yl)-2-(acetoxymethyl)-4-hydroxy-4-methyltetrahydrofuran-3-yl acetate: To a solution of intermediate 2-6 (20 g, 55.90 mmol) in dry DCM (400 mL) and pyridine (8 ml) was added acetic anhydride (22.8 g, 223.62 mmol). The solution was stirred at 0 °C overnight. EtOAc was then added, and the suspension was filtered. The solution was washed with brine, dried over anhydrous Na SO , and concentrated. The residue was purified by column chromatography to give intermediate 2-7 (8.4 g, 29.8% yield over three steps) as a solid.

[0723] Step 7: (2R,3R,4R,5R)-5-(2-acetamido-6-chloro-9H-purin-9-yl)-2-(acetoxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate: Preparation of intermediate 2-7 (5.4 g, 1 To a solution of 2-(2.22 mmol) DAST (5.9 g, 36.67 mmol) was added dropwise at -65 °C, and the reaction was stirred for 0.5 h. The reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated NaHCO and separated. The organic phase was washed with saturated brine, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography (silica gel, EA / PE = 50% → 100%) to give intermediate 2-8 (1.54 g, 30%) as a solid.

[0724] 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 vessel and concentrated. Additional sodium methoxide (325.0 mg, 6.02 mmol) was then added, and the solution was stirred for an additional hour at room temperature. The pH was adjusted to 7 by adding acetic acid, and the solution was concentrated. The residue was purified by column chromatography (silica gel, MeOH / DCM = 0 → 2%) to give intermediate 2-9 (400 mg, 64.5%) as a solid. 1 H NMR (400 MHz, CD3OD) δ8.057(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, CD3OD) δ 164.351(s). C 12 H 14 D3FN6O3[M+H] + MS (ESI) m / z calculated for 316.13, found 316.4.

[0725] Step 9: Isopropyl ((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-alaninate: To a solution of intermediate 2-9 (230 mg, 0.736 mmol) and isopropyl ((R)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (334 mg, 0.736 mmol) in THF (4 mL) was added t-BuMgCl (1.7 N in THF) (912 μL, 1.55 mmol) dropwise at −5° C. The solution was stirred at 0° C. for 0.5 h. The reaction mixture was then quenched with saturated aqueous NH4Cl. The residue was purified by column chromatography (silica gel, MeOH / DCM=0→3.3%) to give compound 5 (130 mg, 30.5%) as a solid. 1 H NMR (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). C 24 H 30 D3FN7O7P [M+H] + MS (ESI) m / z calculated for 585.22, found 585.5.

[0726] Synthesis 3. Isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-4-(fluoromethyl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Compound 6) [ka] TIFF2024173929000310.tif56170 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]trioxadisirosin-9-ol: To a solution of intermediate 3-1 (81.8 g, 0.27 mol) in pyridine (330 mL) was added TPDSCl (102.6 g, 0.32 mol) dropwise at 0 ± 5 °C. The solution was stirred at 0 °C for 2 h and quenched with water. EtOAc was then added, the phases were separated, and dried over anhydrous NaSO. The solution was azeotropically concentrated with toluene three times to remove pyridine. The residue was purified by column chromatography (DCM / MeOH=200:1→100:1) to obtain an intermediate Compound 3-2 (123.3 g, yield 83.6%) was obtained as an oil.

[0727] 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]trioxadisirosin-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) was added TMSCl (48.7 g, 0.45 mol) dropwise at 0°C-5°C. The reaction mixture was stirred at 0°C for 10 minutes. Isobutyryl chloride (36 g, 0.337 mol) was then added and the reaction was stirred at 0°C for an additional 10 minutes. Water was added, the phases were separated, and washed with aqueous CuSO4. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude intermediate 3-3 (151.7 g).

[0728] 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]trioxadisirosin-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 by the addition of triethylamine (35 ml). The solution was concentrated and purified by column chromatography (DCM / MeOH=200:1→100:1) to give intermediate 3-4 (81 g, 58.5% yield over two steps).

[0729] 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]trioxadisirosin-8-yl)-9H-purin-2-yl)isobutyramide: To a solution of intermediate 3-4 (40 g, 0.065 mol) in DCM (300 mL) was added DMP (56 g, 0.13 mol) at 0 °C. The reaction mixture was stirred at room temperature overnight. Ether (2000 mL) was then added, and the suspension was filtered. The solution was washed successively with saturated aqueous NaHCO, saturated aqueous NaSO, and brine. The organic phase was dried over anhydrous NaSO and azeotropically concentrated with toluene to give intermediate 3-5, which was used directly in the next step.

[0730] 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]trioxadisirosin-8-yl)-9H-purin-2-yl)isobutyramide: To a solution of trimethylsilylacetylene (52 g, 0.529 mol) in dry THF (350 ml) was added n-butyllithium (204 ml, 0.51 mol) dropwise at −15° C. to −20° C. The solution was stirred at −15° C. to −20° C. for 30 minutes. The reaction mixture was then cooled to −70° C., and a solution of intermediate 3-5 (54 g, 0.088 mol) in dry DMF (200 mL) 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 the addition of saturated aqueous NH Cl. EtOAc was added, and the organic phase was separated, washed with brine, dried over anhydrous Na SO and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 to 100:1) to give intermediate 3-6 (35.1 g, 56% yield over two steps) as a yellow solid.

[0731] 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]trioxadisilosin-8-yl) (Il)-9H-purin-2-yl)isobutyramide: To a solution of intermediate 3-6 (2 g, 2.81 mmol) in DCM (20 mL) and pyridine (0.703 g, 8.85 mmol) was added DAST (2.27 g, 14.05 mmol) at -70 °C. The reaction mixture was slowly warmed to -30 °C and stirred at -30 °C for 5 min. The solution was then slowly added to saturated aqueous NaHCO3, and DCM was added. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 to 100:1) to give intermediate 3-7 (1.257 g, 62.85% yield) as a white solid.

[0732] 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]trioxadisirosin-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) was added 30% methylamine methanol solution (30 ml) at 0 °C, and the reaction was stirred at room temperature for 5 minutes. The solution was then concentrated at room temperature to remove methylamine. The resulting solution was then concentrated and purified by column chromatography (DCM / MeOH = 200:1 → 100:1) to give intermediate 3-8 (8.8 g, 70.4% yield) as a white solid.

[0733] 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]trioxadisirosin-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's catalyst (3.52 g). The solution was then 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 give intermediate 3-9 (7.5 g, 85.2% yield) as a solid.

[0734] 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. 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) at 0 °C. When TLC showed complete conversion of the starting material, the solution was concentrated and purified by column chromatography (DCM / MeOH = 200:1 → 10:1) to give intermediate 3-10 (3.8 g, 82.6% yield) as a solid.

[0735] Step 10: ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-(2-isobutylamido-6-(methylamino)-9H-purin-9-yl)-4-vinyltetrahydrofuran-2-yl)methyl benzoate. To a solution of compound intermediate 3-10 (3.7 g, 9.38 mmol) in pyridine (19 ml), BzCl (2.9 g, 20.64 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was quenched with methanol and concentrated. The residue was purified by column chromatography (DCM / MeOH = 200:1 → 100:1) to obtain intermediate 3-11 (4.68 g, yield 82.8%) as a white solid.

[0736] 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. Intermediate 3-11 (4 To a solution of 3-(2 ...

[0737] 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). Sodium metaperiodate (2 g, 9.42 mmol) was then 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 (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 NaSO, and concentrated. The residue was purified by column chromatography (DCM / MeOH=200:1→50:1) to give intermediate 3-13 (3.17 g, yield 83.2%) as a white solid.

[0738] 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. To a solution of intermediate 3-13 (1000 mg, 1.65 mmol) in DCM (10 ml) and pyridine (650 mg...

Claims

1. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to the host an effective amount of a compound of formula I: [Formula 1] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ The method comprises administering a compound of formula (I)-, (II)-, (III)-, (IV)-, (IV)-, (V)-, (VI)-, (VII ...

2. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to the host an effective amount of a compound of formula II: [chemical 2] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ The method comprises administering a compound of formula (I)-, (II)-, (III)-, (IV)-, (IV)-, (V)-, (VI)-, (VII ...

3. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to said host an effective amount of a compound represented by formula III or formula IV: [C3] (In the formula, X is C １ ~C ３ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl and C １ ~C ３ hydroxyalkyl; R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ The method comprises administering a compound of formula (I)-, (II)-, (III)-, (IV)-, (IV)-, (V)-, (VI)-, (VII ...

4. The compound is represented by formula IIIa, IIIb, IIIc, IIId, IIIe, and IIIf: [C4] [ka] or a pharma- ceutically acceptable salt thereof.

5. The compound is represented by formula IVa, IVb, IVc, IVd, IVe, and IVf: [C5] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

6. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to the host an effective amount of a compound of formula V: [C6] (In the formula, Y and Y' are independently selected from F and Cl; R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ The method comprises administering a compound of formula (I)-, (II)-, (III)-, (IV)-, (IV)-, (V)-, (VI)-, (VII ...

7. The compound has the formula: [C7] or a pharma- ceutically acceptable salt thereof.

8. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to the host an effective amount of a compound of formula VI: [C8] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl)-, aryl, heteroaryl or heteroalkyl; R ６ is hydrogen, -C(O)R ６Ａ , -C(O)OR ６Ａ , C １～６ Alkyl, -CH ２ -O-R ６Ａ is selected from R ６Ａ is hydrogen, C １～６ Alkyl, C １ ~C ６ Haloalkyl, aryl, aryl(C １～６alkyl)-, wherein the aryl group is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R ７ NH ２ , H or -NR ８ R ９ and R ８ and R ９ are independently hydrogen, C １～６ Alkyl, -C(O)R ６Ａ and -C(O)OR ６Ａ is selected from Y is selected from F and Cl; Z is methyl, C １ ~C ３ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C １ ~C ３ hydroxyalkyl and halogen), or a pharma- ceutically acceptable salt thereof.

9. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to the host an effective amount of a compound of formula VII: [C9] (In the formula, B is, [C10] is selected from R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl)-, aryl, heteroaryl or heteroalkyl; R ６ is hydrogen, -C(O)R ６Ａ , -C(O)OR ６Ａ , C １～６ Alkyl, -CH ２ -O-R ６Ａ and -C(O)NR ６Ｂ R ６Ｃ is selected from R ６Ａ is hydrogen, C １～６ Alkyl, C １ ~C ６ Haloalkyl, C １～２０ Alkyl and C ２～２０ alkenyl, R ６Ｂ and R ６Ｃ are independently hydrogen, C １～２０ Alkyl, C ２～２０ selected from alkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R ７ NH ２ , H or -NR ８ R ９ and R ８ and R ９ are independently hydrogen, C １～６ Alkyl, -C(O)R ６Ａ and -C(O)OR ６Ａ is selected from Y is selected from F and Cl; Z is methyl, C １ ~C ３ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C １ ~C ３ selected from hydroxyalkyl and halogen; R ４０ is H, C １～３ Alkoxy, C １～３ Alkyl, N ３ , CN and halogen; R ４１ is H, C １～３ selected from alkyl and halogen; R ４２ａ and R ４２ｂ is C １～３ Alkyl, NH ２ , H, -NR ８ R ９ and -C(O)NR ８ R ９ or a pharma- ceutically acceptable salt thereof.

10. B, [C11] The method of claim 9 , wherein the compound is selected from the group consisting of

11. R ２ The method of any one of claims 1 to 10, wherein is aryl.

12. R ２ The method of claim 11 , wherein is phenyl.

13. R ３ The method of any one of claims 1 to 12, wherein is hydrogen.

14. R ３ The method of any one of claims 1 to 12, wherein is methyl.

15. R ４ａis methyl and R ４ｂ The method of any one of claims 1 to 13, wherein is hydrogen.

16. R ４ａ is methyl and R ４ｂ The method of any one of claims 1 to 13, wherein is methyl.

17. R ５ C １ ~C ６ The method of any one of claims 1 to 16, wherein the alkyl group is an alkyl group.

18. R ５ 18. The method of claim 17, wherein is selected from methyl, ethyl, and isopropyl.

19. R ５ The method of claim 18 , wherein is isopropyl.

20. R ２ is phenyl, R ３ is hydrogen, R ４ａ is methyl, R ４ｂ is hydrogen, and R ５ is isopropyl; The method according to any one of claims 1 to 10.

21. R ２ is phenyl, R ３ is hydrogen, R ４ａ is methyl, R ４ｂ is hydrogen, R ５ is isopropyl, and Phosphoramidate is S ｐ is a type configuration, The method according to any one of claims 1 to 10.

22. R ２is phenyl, R ３ is hydrogen, R ４ａ is methyl, R ４ｂ is hydrogen, R ５ is isopropyl, and Phosphoramidate is R ｐ is a type configuration, The method according to any one of claims 1 to 10.

23. The compound has the formula: [C12] or a pharma- ceutically acceptable salt thereof.

24. The compound has the formula: [C13] or a pharma- ceutically acceptable salt thereof.

25. The compound has the formula: [C14] or a pharma- ceutically acceptable salt thereof.

26. The compound has the formula: [C15] or a pharma- ceutically acceptable salt thereof.

27. The compound has the formula: [C16] or a pharma- ceutically acceptable salt thereof.

28. The compound has the formula: [C17] [ka] or a pharma- ceutically acceptable salt thereof.

29. The compound has the formula: [C18] The method of claim 23, wherein the compound is

30. The compound has the formula: [C19] 24. The method of claim 23, wherein said compound is selected from the group consisting of

31. The compound has the formula: [C20] The method of claim 23, wherein the compound is

32. The compound has the formula: [C21] The method of claim 23, wherein the compound is

33. The compound has the formula: [C22] The method of claim 23, wherein the compound is

34. The compound has the formula: [C23] [ka] 24. The method of claim 23, wherein said compound is selected from the group consisting of

35. The compound is [C24] [ka] or a pharma- ceutically acceptable salt thereof.

36. The compound has the formula: [C25] or a pharma- ceutically acceptable salt thereof.

37. The compound has the formula: [C26] or a pharma- ceutically acceptable salt thereof.

38. A method for treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a host in need of such treatment or prevention, comprising administering to said host an effective amount of a compound of Formula VIII, Formula IX or Formula X, optionally in a pharmaceutically acceptable carrier: [C27] (In the formula, R １０ teeth, [C28] and R １０Ａ is selected from R １０Ａ is a stabilized phosphate prodrug that is metabolized in vivo to the monophosphate, diphosphate or triphosphate; R １１ is hydrogen and R １ is selected from R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ or a pharma- ceutically acceptable salt thereof.

39. The compound is [C29] or a pharma- ceutically acceptable salt thereof.

40. 2. The compound of formula: [C30] (In the formula, R １０ａThe method of claim 38, wherein:

41. The method of any one of claims 1 to 40, wherein the pharma- ceutically acceptable carrier is in a form suitable for oral administration.

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

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

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

45. 42. The method of claim 41, wherein the dosage form is a liquid dosage form.

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

47. The method of any one of claims 1 to 40, wherein the pharma- ceutically acceptable carrier is in a form suitable for intravenous administration.

48. The method of any one of claims 1 to 40, wherein the pharma- ceutically acceptable carrier is in a form suitable for parenteral administration.

49. 49. The method according to claim 1, wherein the compound is administered for at least one week. The method described.

50. The method of any one of claims 1 to 48, wherein the compound is administered for at least two weeks.

51. 49. The method of any one of claims 1 to 48, wherein the compound is administered for at least one month.

52. The method of any one of claims 1 to 48, wherein the compound is administered for at least 6 weeks.

53. 49. The method of any one of claims 1 to 48, wherein the compound is administered for at least two months.

54. 54. The method of any one of claims 1 to 53, wherein the compound is administered once daily.

55. 54. The method of any one of claims 1 to 53, wherein the compound is administered twice daily.

56. 54. The method of any one of claims 1 to 53, wherein the compound is administered three times daily.

57. 57. The method of any one of claims 1 to 56, wherein at least about 500 mg of the compound is administered.

58. 57. The method of any one of claims 1 to 56, wherein at least about 600 mg of the compound is administered.

59. 57. The method of any one of claims 1 to 56, wherein at least about 700 mg of the compound is administered.

60. 57. The method of any one of claims 1 to 56, wherein at least about 800 mg of the compound is administered.

61. 57. The method of any one of claims 1 to 56, wherein at least about 1000 mg of the compound is administered.

62. 57. The method of any one of claims 1 to 56, wherein at least 1200 mg of the compound is administered.

63. 57. The method of any one of claims 1 to 56, wherein at least about 1500 mg of the compound is administered.

64. 57. The method of any one of claims 1-56, wherein at least about 550 mg of the compound is administered once a day.

65. 57. The method of any one of claims 1-56, wherein at least about 550 mg of the compound is administered twice daily.

66. 57. The method of any one of claims 1-56, wherein at least about 600 mg of the compound is administered once a day.

67. 57. The method of any one of claims 1-56, wherein at least about 600 mg of the compound is administered twice daily.

68. The method of any one of claims 1 to 67, wherein the host is a human.

69. 1. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need of such treatment or prevention, comprising administering to a subject a compound of the formula: [C31] or a pharma- ceutically acceptable salt thereof, wherein the compound is administered in an oral dosage of about 550 mg twice daily.

70. 1. A method of treating or preventing COVID-19 caused by the SARS-CoV-2 virus in a human in need of such treatment or prevention, comprising administering to a subject a compound of the formula: [C32] wherein the compound is administered in an oral dosage of about 600 mg twice daily.

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

72. 71. The method of claim 69 or 70, wherein the oral dosage is via a capsule.

73. 73. The method of any one of claims 69 to 72, wherein the compound is administered for at least one week.

74. 73. The method of any one of claims 69 to 72, wherein the compound is administered for at least two weeks.

75. 73. The method of any one of claims 69 to 72, wherein the compound is administered for at least one month.

76. 76. The method of any one of claims 1 to 75, wherein the SARS-CoV-2 virus expresses natural or drug-induced mutations.

77. 77. The method of claim 76, wherein the spontaneous or drug-induced mutation is in a viral protein selected from an envelope (E) protein, a membrane (M) protein, and a spike (S) protein.

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

79. 77. The method of claim 76, wherein the spontaneous or drug-induced mutation is in a viral protein selected from nsp1, nsp2, nsp3, nsp4, nsp5, nsp6, nsp7, nsp8, nsp9, nsp10, nsp12, nsp13, nsp14, nsp15 and nsp16.

80. 77. The method of claim 76, wherein the spontaneous or drug-induced mutation is in a viral protein selected from ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10.

81. A compound of Formula I or Formula II, optionally in a pharma- ceutical carrier, in an amount effective for use in treating or preventing coronavirus disease 2019 (COVID-19) in a host in need of such treatment or prevention: [C33] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl), aryl, heteroaryl or heteroalkyl or a pharma- ceutically acceptable salt thereof.

82. formula: [C34] or a pharma- ceutically acceptable salt thereof.

83. formula: [C35] or a pharma- ceutically acceptable salt thereof.

84. formula: [C36] or a pharma- ceutically acceptable salt thereof.

85. formula: [C37] 83. The compound of claim 82,

86. formula: [C38] 86. The compound of claim 85,

87. formula: [C39] 87. The compound of claim 86,

88. A compound represented by the formula III or formula IV, optionally in a pharma- ceutical carrier, in an amount effective for use in treating or preventing coronavirus disease 2019 (COVID-19) in a host in need of such treatment or prevention. [C40] [ka] (In the formula, X is C １ ~C ３ Haloalkyl (CH ２ F, C.H.F. ２ , C.F. ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.F. ２ CH ３ , C.F. ２ CF ３ and C.H. ２ C such as Cl １～３ Fluoroalkyl and C １～３ (including chloroalkyl), C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl and C １ ~C ３ hydroxyalkyl; R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl)-, aryl, heteroaryl or heteroalkyl) or a pharma- ceutically acceptable salt thereof.

89. Formula IIIa, IIIb, IIIc, IIId, or IIIe: [C41] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

90. Formula IVa, Formula IVb, Formula IVc, Formula IVd, or Formula VIe: [C42] [ka] or a pharma- ceutically acceptable salt thereof.

91. Formula V, Formula VI or Formula VII, optionally in a pharma- ceutically acceptable carrier: [C43] [ka] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl)-, aryl, heteroaryl or heteroalkyl; R ６ is hydrogen, -C(O)R ６Ａ , -C(O)OR ６Ａ , C １～６ Alkyl, -CH ２ -O-R ６Ａ is selected from R ６Ａ is hydrogen, C １～６ Alkyl, C １ ~C ６ Haloalkyl, aryl, aryl(C １～６ alkyl)-, wherein the aryl group is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R ７ NH ２ , H or -NR ８ R ９ and R ８ and R ９ are independently hydrogen, C １～６ Alkyl, -C(O)R ６Ａand -C(O)OR ６Ａ is selected from Y and Y' are independently selected from F and Cl; Z is methyl, C １ ~C ３ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C １ ~C ３ selected from hydroxyalkyl and halogen; B is, [C44] is selected from R ４０ is H, C １～３ Alkoxy, C １～３ Alkyl, N ３ , CN and halogen; R ４１ is H, C １～３ selected from alkyl and halogen; R ４２ａ and R ４２ｂ is C １～３ Alkyl, NH ２ , H, -NR ８ R ９ and -C(O)NR ８ R ９ or a pharma- ceutically acceptable salt thereof.

92. 92. The method of any one of claims 81 to 91, wherein the pharma- ceutically acceptable carrier is in a form suitable for oral administration.

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

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

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

96. 93. The compound of claim 92, wherein the dosage form is a liquid dosage form.

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

98. For the manufacture of a medicament for the treatment or prevention of coronavirus disease 2019 (COVID-19) in a host in need of such treatment or prevention, a compound represented by the formula I, formula II, formula III or formula IV: [C45] [ka] (In the formula, X is C １ ~C ３ Haloalkyl (CH ２ F, C.H.F. ２ , C.F. ３ , C.H. ２ CF ３ , C.H. ２ CHF ２ , C.H. ２ CH ２ F, C.F. ２ CH ３ , C.F. ２ CF ３ and C.H. ２ C such as Cl １～３ Fluoroalkyl and C １～３ (including chloroalkyl), C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl and C １ ~C ３ hydroxyalkyl; R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ The use of a compound of formula (I)-, (II)-, (III)-, (IV ...)-, (IV)-)-, (IV)-)-, (IV)-)-, (IV)-)-, (IV)-

99. The compound has the formula: [C46] or a pharma- ceutically acceptable salt thereof.

100. The compound has the formula: [C47] or a pharma- ceutically acceptable salt thereof.

101. The compound has the formula: [C48] or a pharma- ceutically acceptable salt thereof.

102. The compound has the formula: [C49] The use according to claim 99, wherein the compound is

103. The compound has the formula: [50] The use according to claim 102, wherein the compound is

104. The compound has the formula: [C51] The use according to claim 103, wherein the compound is

105. For the manufacture of a medicament for the treatment or prevention of coronavirus disease 2019 (COVID-19) in a host in need of such treatment or prevention, a compound of Formula V, Formula VI or Formula VII, optionally in a pharma- ceutical acceptable carrier: [C52] [ka] (In the formula, R １ is C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -C(O)C １ ~C ６ alkyl, R ２ is hydrogen, C １～６ Alkyl, C ３～７ Cycloalkyl, aryl, aryl (C １ ~C ４ alkyl)-, heteroaryl or heteroalkyl; R ３ is hydrogen or C １～６ is alkyl, R ４ａ and R ４ｂ are independently hydrogen, C １～６ Alkyl and C ３～７ cycloalkyl; R ５ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, aryl (C １ ~C ４ alkyl)-, aryl, heteroaryl or heteroalkyl; R ６ is hydrogen, -C(O)R ６Ａ , -C(O)OR ６Ａ , C １～６ Alkyl, -CH ２ -O-R ６Ａ is selected from R ６Ａ is hydrogen, C １～６Alkyl, C １ ~C ６ Haloalkyl, aryl, aryl(C １～６ alkyl)-, wherein the aryl group is optionally substituted with substituents selected from alkoxy, hydroxy, nitro, bromo, chloro, fluoro, azido, and haloalkyl; R ７ NH ２ , H or -NR ８ R ９ and R ８ and R ９ are independently hydrogen, C １～６ Alkyl, -C(O)R ６Ａ and -C(O)OR ６Ａ is selected from Y is selected from F and Cl; Z is methyl, C １ ~C ３ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C １ ~C ３ selected from hydroxyalkyl and halogen; B is, [C53] is selected from R ４０ is H, C １～３ Alkoxy, C １～３ Alkyl, N ３ , CN and halogen; R ４１ is H, C １～３ selected from alkyl and halogen; R ４２ａ and R ４２ｂ is C １～３ Alkyl, NH ２ , H, -NR ８ R ９ and -C(O)NR ８ R ９ or a pharma- ceutically acceptable salt thereof.

106. The use according to any one of claims 98 to 105, wherein the pharma- ceutically acceptable carrier is in a form suitable for oral administration.

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

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

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

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

111. The use of claim 110, wherein the liquid dosage form is a solution or a suspension.

Images