CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 18/243,812, filed Sep. 8, 2023, which claims the benefit of U.S. Provisional Application No. 63/405,221, filed on Sep. 9, 2022, U.S. Provisional Application No. 63/494,194, filed on Apr. 4, 2023, and U.S. Provisional Application No. 63/465,989, filed on May 12, 2023. The entire contents of these applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to methods for treating viral infections.

BACKGROUND

There is a need for compounds and methods for treating viral infections, for example paramyxoviridae, pneumoviridae, picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus, and coronaviridae infections.

SUMMARY

Provided herein is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is:

[Image Omitted]

a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of less than 1,600 mg/dose.

Also provided herein is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein the administering comprises determining an eGFR of the patient, selecting a standard dosage if the eGFR is at least 60 mL/min/1.73 m², and selecting an adjusted dosage that is less than the standard dosage if the eGFR is less than 60 mL/min/1.73 m².

Also provided herein is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound of Formula A:

[Image Omitted]

a deuterated compound of Formula A, a prodrug of the compound of Formula A, a prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein R¹, R², and Base are defined herein, wherein when the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted substantially to the compound of Formula A or the deuterated compound of Formula A, and wherein the administration results in a mean C_maxof the compound of Formula A, or the deuterated compound of Formula A, of less than 7,000 ng/mL.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a set of plots of PK exposures of compound 1 for dosing regimens of compound 16 including 350 mg BID, 700 mg loading with 350 mg BID maintenance, 500 mg BID, and 700 mg QD. Plotting was conducted using nonparametric superpositioning.

FIG. 2 is a set of plots comparing PK exposures of compound 1 for a 350 mg BID dosing regimen of compound 16 in patients with normal renal function (eGFR≥90 mL/min/1.73 m²) and in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²).

FIG. 3 is a graph showing agreement between PK exposure data for compound 1 after administration of compound 16, and a population-PK model described herein.

FIG. 4 is a plot comparing renal clearance values of compound 1 after administration of remdesivir and compound 16.

FIG. 5 is a plot showing a target exposure range of compound 1, based on simulated PK exposures after administration of 350 mg BID of compound 16 to patients with normal renal function (eGFR≥90 mL/min/1.73 m²).

FIG. 6 is a plot comparing simulated PK exposures of compound 1 after administration of 350 mg BID of compound 16 to patients with normal renal function (eGFR≥90 mL/min/1.73 m²) and patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²) with a target exposure range of compound 1.

FIG. 7 is a plot comparing simulated PK exposures of compound 1 after administration of 350 mg QD of compound 16 in patients with normal renal function (eGFR≥90 mL/min/1.73 m²), patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²), and patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m²) with a target exposure range of compound 1.

FIG. 8 is a plot showing the proportion of simulated PK exposures within a target exposure range of compound 1 for dosing regimens of compound 16 including 350 mg BID, 350 mg QD, 350 mg QOD, and 350 mg loading with 150 mg QD maintenance, in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m²).

FIG. 9A is a schematic for single-dose cohorts.

FIG. 9B is a schematic for multiple-dose cohorts.

FIG. 10A is a plot showing plasma concentration-time profiles of the compound 1 metabolite in healthy participants receiving compound 16 in for single-dose cohorts.

FIG. 10B is a plot showing plasma concentration-time profiles of the compound 1 metabolite in healthy participants receiving compound 16 in for multiple-dose cohorts.

FIG. 10C is a plot showing plasma concentration-time profiles of the compound 1 metabolite in healthy participants receiving compound 16 in for food-effect cohorts.

FIG. 11 is a plot showing regression analysis of plasma exposure of compound 1 vs. eGFR following IV administration of remdesivir in participants with varying levels of renal impairment and matched controls.

FIG. 12 is a plot showing quadratic relation between eGFR and renal clearance (CLr) of compound 1 following IV administration of remdesivir in participants with varying levels of renal impairment.

FIG. 13A is a plot showing the compound 1 predicted steady-state exposures following a fixed dose of 350 mg BID in participants with normal renal function and those with varying degrees of RI. The predicted 5th to 95th percentile of compound 1 exposures following 350 mg BID oral doses of compound 16 in participants with normal renal function was considered the Target Exposure Range.

FIG. 13B is plot showing the compound 1 predicted steady-state exposures following the recommended adjusted dosing regimen for each RI population. The predicted 5th to 95th percentile of compound 1 exposures following 350 mg BID oral doses of compound 16 in participants with normal renal function was considered the Target Exposure Range.

DETAILED DESCRIPTION

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈alkyl), 1 to 6 carbon atoms (i.e., C₁-C₆alkyl), or 1 to 3 carbon atoms (i.e., C₁-C₃alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), and 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C_2-20alkenyl), 2 to 8 carbon atoms (i.e., C_2-8alkenyl), 2 to 6 carbon atoms (i.e., C_2-6alkenyl), or 2 to 4 carbon atoms (i.e., C₂₄alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C_2-20alkynyl), 2 to 8 carbon atoms (i.e., C_2-8alkynyl), 2 to 6 carbon atoms (i.e., C_2-6alkynyl), or 2 to 4 carbon atoms (i.e., C₂₄alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

“Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂haloalkyl), 1 to 8 carbon atoms (i.e., C₁-C₈haloalkyl), 1 to 6 carbon atoms (i.e., C₁-C₆alkyl) or 1 to 3 carbon atoms (i.e., C₁-C₃alkyl). Examples of suitable haloalkyl groups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, and the like.

“Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20 membered heteroaryl), 3 to 12 ring atoms (i.e., 3 to 12 membered heteroaryl) or 3 to 8 carbon ring atoms (3 to 8 membered heteroaryl) or 5 to 6 ring atoms (5 to 6 membered heteroaryl). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

“Carbocyclyl” or “carbocyclic ring” refers to a non-aromatic hydrocarbon ring consisting of carbon and hydrogen atoms, having from three to twenty carbon atoms, in certain embodiments having from three to fifteen carbon atoms, in certain embodiments having from three to ten carbon atoms, from three to eight carbon atoms, from three to seven carbon atoms, or from 3 to 6 carbon atoms and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocyclic rings include cycloalkyl groups.

“Cycloalkyl” refers to a saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C_3-20cycloalkyl), 3 to 12 ring carbon atoms (i.e., C_3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C_3-10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C_3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C_3-6cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

“Heterocycle” or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. For example, “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). As used herein, heterocycle or heterocyclyl has from 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The terms “heterocycle” or “heterocyclyl” includes saturated rings and partially unsaturated rings. Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents described herein including carbonyl groups. A non-limiting example of a carbonyl substituted heterocyclyl is:

[Image Omitted]

Example heterocycles include, but are not limited to, tetrahydrofuranyl azetidinyl, and 2-oxo-1,3-dioxol-4-yl.

The term “optionally substituted” in reference to a particular moiety of a compound described herein such as the compound of Formula A or Formula I (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by the listed substituents.

Unless otherwise specified, the carbon atoms of the compounds of Formula and Formula I are intended to have a valence of four. If in some chemical structure representations, carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen.

Any reference to the compounds described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of the compounds described herein include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na⁺, Li⁺, K⁺, Ca⁺²and Mg⁺²), ammonium and NR₄⁺ (wherein R is defined herein). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na⁺ and NR₄⁺. In some embodiments, R₄is H, (C₁-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, C₆-C₂₀aryl, or C₂-C₂₀heterocyclyl.

For therapeutic use, salts of active ingredients of the compounds described herein will be pharmaceutically acceptable, i.e., they will be salts derived from a pharmaceutically acceptable acid or base. It is also to be understood that the compositions herein comprise compounds described herein in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. It is to be noted that all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of compounds described herein (e.g., compounds within the scope of Formula A or Formula I) and pharmaceutically acceptable salts thereof are embraced by the present disclosure. All mixtures of such enantiomers and diastereomers are within the scope of the present disclosure.

The compounds described herein may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds described herein thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds described herein include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the disclosure. The racemic mixtures are separated into their individual, substantially optically pure isomers through appropriate techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (−), or 1 meaning that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The compounds described herein may also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.

Any formula or structure described herein, including Formula A and Formula I compounds, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²p, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

The disclosure also includes compounds (e.g., compounds of Formula A or Formula I) in which from 1 to x hydrogens attached to a carbon atom is/are replaced by deuterium, in which x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound described herein (e.g., compounds of Formula A or Formula I) when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compounds described herein.

For example, in the deuterated compound of Formula A, one or more hydrogen atoms attached to one or more carbon atoms of Formula A are replaced by deuterium. In some embodiments of the deuterated compound of Formula A, one hydrogen atom attached to one carbon atom of Formula A is replaced by deuterium. In some embodiments of the deuterated compound of Formula A, two hydrogen atoms attached to one carbon atom of Formula A are replaced by deuterium. In some embodiments of the deuterated compound of Formula A, two or more hydrogen atoms attached to two carbon atoms of Formula A are replaced by deuterium.

The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

Whenever a compound described herein is substituted with more than one of the same designated group, e.g., “R” or “R”, then it will be understood that the groups may be the same or different, i.e., each group is independently selected.

Wavy lines, [Image Omitted] , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms.

The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.

“Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. The compounds and compositions described herein may, in some embodiments, be administered to a subject (including a human) who is at risk of having the disease or condition. As used herein, the terms “preventing” and “prevention” encompass the administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments described herein pre- or post-exposure of the individual to a virus, but before the appearance of symptoms of the viral infection, and/or prior to the detection of the virus in the blood. The terms also refer to prevention of the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood. The terms include both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event driven or “on demand” prophylaxis. The terms also refer to prevention of perinatal transmission of a virus from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms also refer to prevention of transmission of a virus through blood transfusion.

The term “therapeutically effective amount”, as used herein, is the amount of a compound described herein (e.g., a compound of Formula A or Formula I) present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound described herein (e.g., the compound of Formula A or Formula I), the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.

The term “prodrug,” as used herein, refers to a biologically inactive derivative of a drug that, upon administration to the patient, can be converted to a parent drug according to some chemical or enzymatic pathway. For example, when a prodrug of the compound of Formula A, or a pharmaceutically acceptable salt thereof, is administered, the prodrug, or the pharmaceutically acceptable salt thereof, can be converted to the compound of Formula A. In another example, when a prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, is administered, the prodrug, or the pharmaceutically acceptable salt thereof, can be converted to the deuterated compound of Formula A.

The term “converted substantially,” as used herein in reference to a prodrug, refers to conversion of greater than 50% of a prodrug (e.g., a prodrug of the compound of Formula A, or a prodrug of the deuterated compound of Formula A) to a parent compound (e.g., the compound of Formula A, or the deuterated compound of Formula A). For example, the term “converted substantially” can refer to conversion of greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, or greater than 99% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof, to the compound of Formula A or the deuterated compound of Formula A.

The term “estimated glomerular filtration rate,” or “eGFR,” refers to an estimate of the glomerular filtration rate of a patient. Any suitable method for determining eGFR can be used. For example, eGFR can be calculated using the Cockcroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equation, the MDRD II equation, the Mayo Quadratic (Mayo) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. In some embodiments, eGFR values are determined using the Modification of Diet in Renal Disease (MDRD) formula. See, e.g., Levey et al., Ann. Intern. Med. 145(4):247-54 (2006).

As used herein, “normal renal function,” used in reference to a patient, means that the patient does not have renal impairment or chronic kidney disease (CKD). A patient can be classified as having normal renal function using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient's population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 90 mL/min/1.73 m²can indicate normal renal function.

As used herein, “mild renal impairment,” used in reference to a patient, means that the patient has mild kidney damage. Mild renal impairment can also be referred to as “mild CKD.” A patient can be classified as having mild renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient's population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 60 mL/min/1.73 m²to less than 90 mL/min/1.73 m²can indicate mild renal impairment.

As used herein, “moderate renal impairment,” used in reference to a patient, means that the patient has moderate kidney damage. Moderate renal impairment can also be referred to as “moderate CKD.” A patient can be classified as having moderate renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient's population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 30 mL/min/1.73 m²to less than 60 mL/min/1.73 m²can indicate moderate renal impairment.

As used herein, “severe renal impairment,” used in reference to a patient, means that the patient has severe kidney damage. Severe renal impairment can also be referred to as “severe CKD.” A patient can be classified as having severe renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient's population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and/or patient population). For example, an eGFR of at least 15 mL/min/1.73 m²to less than 30 mL/min/1.73 m²can indicate severe renal impairment.

As used herein, “mean,” when preceding a pharmacokinetic value (e.g. mean C_max) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified.

As used herein, “C_max” means the maximum observed plasma concentration. Unless specifically described, C_maxcan be calculated using standard methods.

As used herein, “AUC” refers to the area under the plasma concentration-time curve, which is a measure of total bioavailability. Unless specifically described, AUC can be calculated using standard methods.

As used herein, the term “AUC_0-24,” refers to the area under the plasma concentration-time curve from 0 time to 24 hours. Unless specifically described, AUC_0-24can be calculated using standard methods.

As used herein, and in the absence of a specific reference to a particular pharmaceutically acceptable salt of a compound described herein, any dosages (e.g., expressed in milligrams) should be taken as referring to the amount of the compound on a free base basis. For example, a reference to “administering to the patient a compound which is:

[Image Omitted]

a deuterated compound thereof, or a pharmaceutically acceptable salt thereof . . . in a dosage of less than 1,600 mg/dose” means administration of an amount of the compound, the deuterated compound thereof, or the pharmaceutically salt thereof which provides the same amount of compound as 1600 mg of

[Image Omitted]

or the deuterated compound thereof, i.e., the free base compound.

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying description. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention.

Provided is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is:

[Image Omitted]

In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of less than 1,500 mg/dose, less than 1,200 mg/dose, less than 1,000 mg/dose, less than 900 mg/dose, less than 800 mg/dose, less than 700 mg/dose, less than 600 mg/dose, or less than 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of less than 900 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of less than 600 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of less than 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered twice daily.

In some embodiments, the patient has mild renal impairment. In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m². In certain such embodiments, the method further includes determining that the patient has an eGFR of at least 60 mL/min/1.73 m²prior to the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an eGFR of 60 mL/min/1.73 m²to 89 mL/min/1.73 m². In certain such embodiments, the method further includes determining that the patient has an eGFR of 60 mL/min/1.73 m²to 89 mL/min/1.73 m²prior to the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the patient has normal renal function. In some embodiments, the patient has an eGFR of at least 90 mL/min/1.73 m². In certain such embodiments, the method further includes determining that the patient has an eGFR of at least 90 mL/min/1.73 m²prior to the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the determining includes classifying the patient as potentially having an eGFR of less than 90 mL/min/1.73 m², and administering a blood test to the patient potentially having an eGFR of less than 90 mL/min/1.73 m².

In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²twice daily. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 100 mg/dose to 1,600 mg/dose, 100 mg/dose to 900 mg/dose, 100 mg/dose to 700 mg/dose, 100 mg/dose to 500 mg/dose, 100 mg/dose to 400 mg/dose, 100 mg/dose to 200 mg/dose, 200 mg/dose to 1,600 mg/dose, 200 mg/dose to 900 mg/dose, 200 mg/dose to 800 mg/dose, 200 mg/dose to 700 mg/dose, 200 mg/dose to 500 mg/dose, or 200 mg/dose to 400 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 250 mg/dose to 800 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 250 mg/dose to 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 350 mg/dose, 500 mg/dose, or 700 mg/dose. For example, in some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 350 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of least 60 mL/min/1.73 m²in a dosage of 700 mg/dose.

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or a deuterated compound thereof.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of at least 60 mL/min/1.73 m²results in a mean C_maxof 1,000 ng/mL to 6,500 ng/mL, 1,000 ng/mL to 6,000 ng/mL, 1,000 ng/mL to 5,500 ng/mL, 1,000 ng/mL to 5,000 ng/mL, 1,000 ng/mL to 4500 ng/mL, 2,000 ng/mL to 6,500 ng/mL, 2,000 ng/mL to 6,000 ng/mL, 2,000 ng/mL to 5,500 ng/mL, 2,000 ng/mL to 5,000 ng/mL, 2,000 ng/mL to 4500 ng/mL, 2,500 ng/mL to 6,500 ng/mL, 2,500 ng/mL to 6,000 ng/mL, 2,500 ng/mL to 5,500 ng/mL, 2,500 ng/mL to 5,000 ng/mL, or 2,500 ng/mL to 4500 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of at least 60 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of at least 60 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 4,900 ng/mL of compound 1, or a deuterated compound thereof.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of least 60 mL/min/1.73 m²results in a mean AUC_0-24of 12,000 ng/mL*h to 44,000 ng/mL*h, 12,000 ng/mL*h to 40,000 ng/mL*h, 12,000 ng/mL*h to 36,000 ng/mL*h, 12,000 ng/mL*h to 32,000 ng/mL*h, 16,000 ng/mL*h to 44,000 ng/mL*h, 16,000 ng/mL*h to 40,000 ng/mL*h, 16,000 ng/mL*h to 36,000 ng/mL*h, 16,000 ng/mL*h to 32,000 ng/mL*h, 20,000 ng/mL*h to 44,000 ng/mL*h, 20,000 ng/mL*h to 40,000 ng/mL*h, 20,000 ng/mL*h to 36,000 ng/mL*h, or 20,000 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of least 60 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of least 60 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has an eGFR of at least 60 mL/min/1.73 m², and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has normal renal function or mild kidney impairment, and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has normal renal function, and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has mild kidney impairment, and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has an eGFR of less than 60 mL/min/1.73 m². In some embodiments, the patient has moderate renal impairment. In some embodiments, the patient has an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m². In certain such embodiments, the method further includes determining that the patient has an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²prior to the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the determining includes classifying the patient as potentially having an eGFR of less than 60 mL/min/1.73 m², and administering a blood test to the patient potentially having an eGFR of less than 60 mL/min/1.73 m².

In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²once daily. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²in a dosage of 50 mg/dose to 900 mg/dose, 50 mg/dose to 700 mg/dose, 50 mg/dose to 500 mg/dose, 50 mg/dose to 400 mg/dose, 50 mg/dose to 200 mg/dose, 100 mg/dose to 900 mg/dose, 100 mg/dose to 800 mg/dose, 100 mg/dose to 700 mg/dose, 100 mg/dose to 500 mg/dose, 100 mg/dose to 400 mg/dose, or 100 mg/dose to 200 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²in a dosage of 50 mg/dose to 650 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²in a dosage of 150 mg/dose to 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²in a dosage of 350 mg/dose.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean C_maxof 1,000 ng/mL to 6,500 ng/mL, 1,000 ng/mL to 6,000 ng/mL, 1,000 ng/mL to 5,500 ng/mL, 1,000 ng/mL to 5,000 ng/mL, 1,000 ng/mL to 4500 ng/mL, 2,000 ng/mL to 6,500 ng/mL, 2,000 ng/mL to 6,000 ng/mL, 2,000 ng/mL to 5,500 ng/mL, 2,000 ng/mL to 5,000 ng/mL, 2,000 ng/mL to 4500 ng/mL, 2,500 ng/mL to 6,500 ng/mL, 2,500 ng/mL to 6,000 ng/mL, 2,500 ng/mL to 5,500 ng/mL, 2,500 ng/mL to 5,000 ng/mL, or 2,500 ng/mL to 4500 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 4,900 ng/mL of compound 1, or a deuterated compound thereof.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean AUC_0-24of 12,000 ng/mL*h to 44,000 ng/mL*h, 12,000 ng/mL*h to 40,000 ng/mL*h, 12,000 ng/mL*h to 36,000 ng/mL*h, 12,000 ng/mL*h to 32,000 ng/mL*h, 16,000 ng/mL*h to 44,000 ng/mL*h, 16,000 ng/mL*h to 40,000 ng/mL*h, 16,000 ng/mL*h to 36,000 ng/mL*h, 16,000 ng/mL*h to 32,000 ng/mL*h, 20,000 ng/mL*h to 44,000 ng/mL*h, 20,000 ng/mL*h to 40,000 ng/mL*h, 20,000 ng/mL*h to 36,000 ng/mL*h, or 20,000 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has an eGFR of 30 mL/min/1.73 m²to 59 mL/min/1.73 m², and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered once daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has moderate renal impairment, and compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered once daily in a dosage of 350 mg/dose. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has severe renal impairment. In some embodiments, the patient has an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m². In certain such embodiments, the method further includes determining that the patient has an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²prior to the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the determining includes classifying the patient as potentially having an eGFR of less than 60 mL/min/1.73 m², and administering a blood test to the patient potentially having an eGFR of less than 60 mL/min/1.73 m².

In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²once daily. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 50 mg/dose to 900 mg/dose, 50 mg/dose to 700 mg/dose, 50 mg/dose to 500 mg/dose, 50 mg/dose to 400 mg/dose, 50 mg/dose to 200 mg/dose, 100 mg/dose to 900 mg/dose, 100 mg/dose to 800 mg/dose, 100 mg/dose to 700 mg/dose, 100 mg/dose to 500 mg/dose, 100 mg/dose to 400 mg/dose, or 100 mg/dose to 200 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 50 mg/dose to 650 mg/dose, 50 mg/dose to 500 mg/dose, or 50 mg/dose to 400 mg/dose. In some embodiments, compound 16, the deuterated compound, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 50 mg/dose to 350 mg/dose, or 150 mg/dose to 500 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 350 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 150 mg/dose. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²in a dosage of 350 mg/dose on a first day of administration. In certain such embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 150 mg/dose on each day of administration after the first day.

In certain such embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 175 mg/dose on each day of administration after the first day. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 175 mg/dose on each day 2, 3, 4, and 5 of administration after the first day.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean C_maxof 1,000 ng/mL to 6,500 ng/mL, 1,000 ng/mL to 6,000 ng/mL, 1,000 ng/mL to 5,500 ng/mL, 1,000 ng/mL to 5,000 ng/mL, 1,000 ng/mL to 4500 ng/mL, 2,000 ng/mL to 6,500 ng/mL, 2,000 ng/mL to 6,000 ng/mL, 2,000 ng/mL to 5,500 ng/mL, 2,000 ng/mL to 5,000 ng/mL, 2,000 ng/mL to 4500 ng/mL, 2,500 ng/mL to 6,500 ng/mL, 2,500 ng/mL to 6,000 ng/mL, 2,500 ng/mL to 5,500 ng/mL, 2,500 ng/mL to 5,000 ng/mL, or 2,500 ng/mL to 4500 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean C_maxof 2,000 ng/mL to 4,900 ng/mL of compound 1, or a deuterated compound thereof.

In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean AUC_0-24of 12,000 ng/mL*h to 44,000 ng/mL*h, 12,000 ng/mL*h to 40,000 ng/mL*h, 12,000 ng/mL*h to 36,000 ng/mL*h, 12,000 ng/mL*h to 32,000 ng/mL*h, 16,000 ng/mL*h to 44,000 ng/mL*h, 16,000 ng/mL*h to 40,000 ng/mL*h, 16,000 ng/mL*h to 36,000 ng/mL*h, 16,000 ng/mL*h to 32,000 ng/mL*h, 20,000 ng/mL*h to 44,000 ng/mL*h, 20,000 ng/mL*h to 40,000 ng/mL*h, 20,000 ng/mL*h to 36,000 ng/mL*h, or 20,000 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof. In some embodiments, the administration of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient having an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m²results in a mean AUC_0-24of 18,200 ng/mL*h to 32,000 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m², and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 150 mg/dose on each day of administration after the first day. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m², and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 175 mg/dose on each day of administration after the first day. In some embodiments, the patient has an eGFR of 15 mL/min/1.73 m²to 29 mL/min/1.73 m², and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 175 mg/dose on each day 2, 3, 4, and 5 of administration after the first day.

In some embodiments, the patient has severe renal impairment, and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 150 mg/dose on each day of administration after the first day. In certain such embodiments, the administration results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL and a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of compound 1, or a deuterated compound thereof.

In some embodiments, the patient has severe renal impairment, and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 175 mg/dose on each day of administration after the first day. In some embodiments, the patient has severe renal impairment, and compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered once in a dosage of 350 mg/dose, on a first day of administration, and once daily in a dosage of 175 mg/dose on each day 2, 3, 4, and 5 of administration after the first day.

In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered for three consecutive days, or for five consecutive days. For example, in some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered for five consecutive days. In some embodiments, compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered for three consecutive days.

Also provided herein is a method for treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein the administering comprises determining an eGFR of the patient, selecting a standard dosage if the eGFR is at least 60 mL/min/1.73 m², and selecting an adjusted dosage that is less than the standard dosage if the eGFR is less than 60 mL/min/1.73 m².

In some embodiments, the standard dosage is 100 mg/dose to 1,600 mg/dose, 100 mg/dose to 900 mg/dose, 100 mg/dose to 700 mg/dose, 100 mg/dose to 500 mg/dose, 100 mg/dose to 400 mg/dose, 100 mg/dose to 200 mg/dose, 200 mg/dose to 1,600 mg/dose, 200 mg/dose to 900 mg/dose, 200 mg/dose to 800 mg/dose, 200 mg/dose to 700 mg/dose, 200 mg/dose to 500 mg/dose, or 200 mg/dose to 400 mg/dose. In some embodiments, the standard dosage is 250 mg/dose to 800 mg/dose. In some embodiments, the standard dosage is 350 mg/dose, 500 mg/dose, or 700 mg/dose. In some embodiments, the standard dosage is 700 mg/dose. In some embodiments, the standard dosage is 500 mg/dose. In some embodiments, the standard dosage is 350 mg/dose. In some embodiments, the standard dosage is administered twice daily. In some embodiments, the standard dosage is administered once daily.

In some embodiments, the adjusted dosage is 50 mg/dose to 900 mg/dose, 50 mg/dose to 700 mg/dose, 50 mg/dose to 500 mg/dose, 50 mg/dose to 400 mg/dose, 50 mg/dose to 200 mg/dose, 100 mg/dose to 900 mg/dose, 100 mg/dose to 800 mg/dose, 100 mg/dose to 700 mg/dose, 100 mg/dose to 500 mg/dose, 100 mg/dose to 400 mg/dose, or 100 mg/dose to 200 mg/dose. In some embodiments, the adjusted dosage is 50 mg/dose to 650 mg/dose. In some embodiments, the adjusted dosage is 350 mg/dose. In some embodiments, the adjusted dosage is 150 mg/dose. In some embodiments, the adjusted dosage is 350 mg/dose on a first day of administration, and 150 mg/dose on each day of administration after the first day. In some embodiments, the adjusted dosage is administered once daily.

In some embodiments, the adjusted dosage is 175 mg/dose.

In some embodiments, the adjusted dosage is 350 mg/dose on a first day of administration, and 175 mg/dose on each day of administration after the first day. In some embodiments, the adjusted dosage is 350 mg/dose on a first day of administration, and 175 mg/dose on each day of administration after the first day. In some embodiments, the adjusted dosage is 350 mg/dose on a first day of administration, and 175 mg/dose on each day of administration after the first day. In some embodiments, the adjusted dosage is 350 mg/dose on a first day of administration, and 175 mg/dose on each day 2, 3, 4, and 5 of administration after the first day.

In some embodiments, a deuterated compound of compound 16 is administered. In certain such embodiments, the deuterated compound is

[Image Omitted]

In some embodiments, a pharmaceutically acceptable salt of compound 16 is administered.

In some embodiments, compound 16 is administered.

Also provided herein is a compound which is compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, to the patient in a dosage of less than 1,600 mg/dose.

Also provided herein is a compound which is compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for use in a method for treating a viral infection in a patient in need thereof, wherein the method comprises determining an eGFR of the patient, selecting a standard dosage of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, if the eGFR is at least 60 mL/min/1.73 m², and selecting an adjusted dosage of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, that is less than the standard dosage if the eGFR is less than 60 mL/min/1.73 m².

Also provided herein is the use of a compound which is compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a viral infection in a patient in need thereof, wherein the treatment comprises determining an eGFR of the patient, selecting a standard dosage of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, if the eGFR is at least 60 mL/min/1.73 m², and selecting an adjusted dosage of compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, that is less than the standard dosage if the eGFR is less than 60 mL/min/1.73 m².

Also provided herein is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound of Formula A:

[Image Omitted]

a deuterated compound of Formula A, a prodrug of the compound of Formula A, a prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or —OCHR⁶O—;
- R⁴and R⁵are each independently H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl, and 5 to 6 membered heteroaryl of R⁴and R⁵is independently, optionally substituted with one, two, or three R^asubstituents;
- R⁶is H, C₁-C₆alkyl, C₁-C₆alkoxy, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl; wherein each 5 to 6 membered heteroaryl and C₆-C₁₀aryl of R⁶is independently, optionally substituted with one, two, or three R^bsubstituents;
- Base is,

[Image Omitted]

- R¹¹is C₁-C₆alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);
- R¹²is H, C₁-C₆alkyl, —C(═O)R¹³or —C(═O)OR¹³;
- each R¹³is independently H, C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, or —O—C₁-C₁₀alkyl; wherein each C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, and —O—C₁-C₁₀alkyl of R¹³is independently, optionally substituted with one, two, or three R^csubstituents;
- each R^ais independently halo, cyano, C₁-C₆alkyl, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or phenyl; wherein each 4 to 6 membered heterocyclyl of R^ais independently, optionally substituted with one, two, or three R^dsubstituents; wherein each phenyl of R^ais independently, optionally substituted with one, two or three R^esubstituents;
- R⁸, R⁹, and R¹⁰are each independently H, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₃-C₆cycloalkyl
- each R^bis independently halo, cyano, C₁-C₆alkoxy, or C₁-C₆alkyl;
- each R^cis independently halo, cyano, —OP(═O)(OH)(OR¹⁴) or phenyl; wherein each phenyl of R^cis optionally substituted with —OP(═O)(OH)(OR¹⁴);
- each R¹⁴is independently H, C₁-C₈alkyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl of R¹⁴is independently, optionally substituted with one, two or three R^fsubstituents;
- each R^dis independently carbonyl or C₁-C₆alkyl;
- each R^eis independently halo, cyano, or C₁-C₆alkyl; and
- each R^fis independently halo, cyano, or phenyl;
- wherein when the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted substantially to the compound of Formula A or the deuterated compound of Formula A; and
- wherein the administration results in a mean C_maxof less than 7,000 ng/mL of the compound of Formula A, or the deuterated compound of Formula A.

In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean C_maxof 1,000 ng/mL to 6,500 ng/mL, 1,000 ng/mL to 6,000 ng/mL, 1,000 ng/mL to 5,500 ng/mL, 1,000 ng/mL to 5,000 ng/mL, 1,000 ng/mL to 4500 ng/mL, 2,000 ng/mL to 6,500 ng/mL, 2,000 ng/mL to 6,000 ng/mL, 2,000 ng/mL to 5,500 ng/mL, 2,000 ng/mL to 5,000 ng/mL, 2,000 ng/mL to 4500 ng/mL, 2,500 ng/mL to 6,500 ng/mL, 2,500 ng/mL to 6,000 ng/mL, 2,500 ng/mL to 5,500 ng/mL, 2,500 ng/mL to 5,000 ng/mL, or 2,500 ng/mL to 4500 ng/mL of the compound of Formula A, or the deuterated compound of Formula A. In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean C_maxof 2,000 ng/mL to 6,200 ng/mL of the compound of Formula A, or the deuterated compound of Formula A. In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean C_maxof 2,000 ng/mL to 4,900 ng/mL of the compound of Formula A, or the deuterated compound of Formula A.

In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean AUC_0-24of less than 44,000 ng/mL*h the compound of Formula A, or the deuterated compound of Formula A. In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean AUC_0-24of 12,000 ng/mL*h to 44,000 ng/mL*h, 12,000 ng/mL*h to 40,000 ng/mL*h, 12,000 ng/mL*h to 36,000 ng/mL*h, 12,000 ng/mL*h to 32,000 ng/mL*h, 16,000 ng/mL*h to 44,000 ng/mL*h, 16,000 ng/mL*h to 40,000 ng/mL*h, 16,000 ng/mL*h to 36,000 ng/mL*h, 16,000 ng/mL*h to 32,000 ng/mL*h, 20,000 ng/mL*h to 44,000 ng/mL*h, 20,000 ng/mL*h to 40,000 ng/mL*h, 20,000 ng/mL*h to 36,000 ng/mL*h, or 20,000 ng/mL*h to 32,000 ng/mL*h of the compound of Formula A, or the deuterated compound of Formula A. In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean AUC_0-24of 18,200 ng/mL*h to 36,400 ng/mL*h of the compound of Formula A, or the deuterated compound of Formula A. In some embodiments, the administration of the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, results in a mean AUC_0-24of 18,200 ng/mL*h to 32,000 ng/mL*h of the compound of Formula A, or the deuterated compound of Formula A.

In some embodiments, upon administration to the patient, greater than 60% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A. In some embodiments, upon administration to the patient, greater than 70% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A. In some embodiments, upon administration to the patient, greater than 80% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A. In some embodiments, upon administration to the patient, greater than 90% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A. In some embodiments, upon administration to the patient, greater than 95% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A. In some embodiments, upon administration to the patient, greater than 95% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted to the compound of Formula A or the deuterated compound of Formula A.

In some embodiments, the carbon bonded to the 5 position on the tetrahydrofuranyl ring of the deuterated compound of Formula A is substituted with one or two deuterium atoms. In some embodiments, the deuterated compound of Formula A is

[Image Omitted]

In some embodiments, the deuterated compound of Formula A is

[Image Omitted]

In some embodiments, a carbon of the Base of the deuterated compound of Formula A is substituted with one or more deuterium atoms. In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, a carbon of R¹²of the Base of the deuterated compound of Formula A is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms. In some embodiments, a carbon on R¹¹of the Base of the deuterated compound of Formula A is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms.

In some embodiments, a carbon of R¹of the deuterated compound of Formula A is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms. In some embodiments, a carbon of R²of the deuterated compound of Formula A is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms.

In some embodiments, the compound of Formula A is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

In some embodiments, the deuterated compound of Formula A is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

In some embodiments, the method comprises administering to the patient a prodrug of Formula A having Formula I:

[Image Omitted]

or a deuterated compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

- R³is —C(═O)OR⁷, or —C(═O)R⁷; and
- R⁷is H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl, and 5 to 6 membered heteroaryl of R⁷are optionally substituted with one, two, or three R^asubstituents.

In some embodiments, a carbon of R³of the deuterated compound of Formula I is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms. In some embodiments, a carbon of R⁷of the deuterated compound of Formula I is substituted with one or more deuterium atoms, e.g., one or two deuterium atoms.

In some embodiments, R¹is —OH. In some embodiments, R¹is —OC(═O)R⁴. In some embodiments, R¹is —OC(═O)OR⁴.

In some embodiments, R²is —OH. In some embodiments, R²is —OC(═O)R⁵. In some embodiments, R²is —OC(═O)OR⁵.

In some embodiments, R¹and R²are both —OH. In some embodiments, R¹is —OC(═O)R⁴and R²is —OC(═O)R⁵. In some embodiments, R¹is OH, and R²is —OC(═O)R⁵or —OC(═O)OR⁵. In some embodiments, R¹is —OC(═O)R⁴or —OC(═O)OR⁴, and R²is OH. In some embodiments, R¹and R²are taken together to form —OC(═O)O— In some embodiments, R¹and R²are taken together to form —OP(═O)(OH)O—. In some embodiments, R¹and R²are taken together to form —OCHR⁶O—.

In some embodiments,

- R¹is OH, OC(O)CH(CH₃)₂, or OC(O)CH₃,
- R²is OH, OC(O)CH(CH₃)₂, or OC(O)CH₃, or
- R¹and R²are taken together to form —OC(═O)O—.

In some embodiments, R⁴is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl. In some embodiments, R⁴is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, each optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁴is C₁-C₈alkyl. In some embodiments, R⁴is C₁-C₈alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁴is unsubstituted C₁-C₈alkyl. In some embodiments, R⁴is unsubstituted C₁-C₆alkyl. In some embodiments, R⁴is unsubstituted C₁-C₃alkyl. In some embodiments, R⁴is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁴is —CH₃or —CH(CH₃)₂.

In some embodiments, R⁵is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl. In some embodiments, R⁵is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, each optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁵is C₁-C₈alkyl. In some embodiments, R⁵is C₁-C₈alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁵is unsubstituted C₁-C₈alkyl. In some embodiments, R⁵is unsubstituted C₁-C₆alkyl. In some embodiments, R⁵is unsubstituted C₁-C₃alkyl. In some embodiments, R⁵is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁵is —CH₃or —CH(CH₃)₂.

In some embodiments, R⁴and R⁵are the same. In some embodiments, R⁴and R⁵are different. In some embodiments, R⁴is C₁-C₈alkyl and R⁵is C₁-C₈alkyl. In some embodiments, R⁴is unsubstituted C₁-C₈alkyl and R⁵is unsubstituted C₁-C₈alkyl. In some embodiments, R⁴is —CH₃or —CH(CH₃)₂and R⁵is —CH₃or —CH(CH₃)₂. In some embodiments, R⁴is —CH₃and R⁵is —CH₃. In some embodiments, R⁴is —CH(CH₃)₂and R⁵is —CH(CH₃)₂.

In some embodiments, R⁶is H. In some embodiments, R⁶is C₁-C₆alkyl. In some embodiments, R⁶is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁶is C₁-C₆alkoxy.

In some embodiments, R⁶is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁶is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S substituted with one, two, or three R^bsubstitutents. In some embodiments, R⁶is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁶is unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, R⁶is C₆-C₁₀aryl. In some embodiments, R⁶is C₆-C₁₀aryl substituted with one, two, or three R^bsubstituents. In some embodiments, R⁶is unsubstituted C₆-C₁₀aryl. In some embodiments, R⁶is phenyl. In some embodiments, R⁶is unsubstituted phenyl.

In some embodiments, R³is —C(═O)OR⁷. In some embodiments, R³is —C(═O)R⁷.

In some embodiments, R⁷is C₁-C₈alkyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is C₁-C₈alkyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, each optionally substituted with one, two, or three R^asubstituents independently selected from —OR⁸, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl. In some embodiments, R⁷is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, each optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, each optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, and phenyl.

In some embodiments, R⁷is C₁-C₈alkyl. In some embodiments, R⁷is C₁-C₈alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is C₁-C₈alkyl optionally substituted with one R^asubstituent selected from —OR⁸, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is C₁-C₈alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, and phenyl. In some embodiments, R⁷is C₁-C₈alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, and unsubstituted phenyl. In some embodiments, R⁷is C₁-C₈alkyl substituted with —OR⁸. In some embodiments, R⁷is C₁-C₈alkyl substituted with phenyl. In some embodiments, R⁷is C₁-C₈alkyl substituted with C₃-C₈carbocyclyl. In some embodiments, R⁷is C₁-C₈alkyl substituted with —OP(═O)(OH)₂.

In some embodiments, R⁷is C₁-C₆alkyl. In some embodiments, R⁷is C₁-C₆alkyl optionally substituted with one, two, or three R^asubstituents independently selected from halo, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is C₁-C₆alkyl optionally substituted with one R^asubstituent selected from —OR⁸, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is C₁-C₄alkyl substituted with phenyl. In some embodiments, R⁷is C₁-C₄alkyl substituted with phenyl. R⁷is C₁-C₄alkyl substituted with —OP(═O)(OH)₂.

In some embodiments, R⁷is C₂-C₄alkyl. In some embodiments, R⁷is C₂-C₄alkyl substituted with —OR⁸. In some embodiments, R⁷is C₂-C₄alkyl substituted with —OCH₃. In some embodiments, R⁷is C₂-C₄alkyl substituted with C₄-C₇carbocyclyl. In some embodiments, R⁷is C₂-C₄alkyl substituted with

[Image Omitted]

In some embodiments, R⁷is —CH₃, —CH₂CH₃,

[Image Omitted]

In some embodiments, R⁷—CH₃, —CH₂CH₃,

[Image Omitted]

In some embodiments, R⁷is —CH₃, —CH₂CH₃,

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is C₃-C₈carbocyclyl. In some embodiments, R⁷is C₃-C₈carbocyclyl optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is C₃-C₈carbocyclyl optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is C₃-C₈carbocyclyl optionally substituted with one, two, or three substituents independently selected from —OR⁸, —NR⁹R¹⁰, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is C₆-C₁₀aryl. In some embodiments, R⁷is C₆-C₁₀aryl optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is C₆-C₁₀aryl optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is phenyl or naphthyl. In some embodiments, R⁷is phenyl or naphthyl, each optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is phenyl. In some embodiments, R⁷is phenyl optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is 5 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 5 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is unsubstituted 5 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is 4 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is unsubstituted 4 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁷is 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl.

In some embodiments, R⁷is 5 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 5 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is unsubstituted 5 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, R⁷is 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R⁷is 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and unsubstituted phenyl. In some embodiments, R⁷is 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with one, two, or three R^asubstituents independently selected from halogen, cyano, and —NR⁹R¹⁰. In some embodiments, R⁷is unsubstituted 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments R⁷is

[Image Omitted]

In some embodiments, R⁷is

[Image Omitted]

In some embodiments, R⁸is H. In some embodiments, R⁸is C₁-C₆alkyl. In some embodiments, R⁸is —CH₃. In some embodiments, R⁸is C₁-C₆haloalkyl. In some embodiments, R⁸is C₃-C₆cycloalkyl.

In some embodiments, R⁹is H. In some embodiments, R⁹is C₁-C₆alkyl. In some embodiments, R⁹is —CH₃. In some embodiments, R⁹is C₁-C₆haloalkyl. In some embodiments, R⁹is C₃-C₆cycloalkyl.

In some embodiments, R¹⁰is H. In some embodiments, R¹⁰is C₁-C₆alkyl. In some embodiments, R¹⁰is —CH₃. In some embodiments, R¹⁰is C₁-C₆haloalkyl. In some embodiments, R¹⁰is C₃-C₆cycloalkyl.

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, R¹¹is C₁-C₃alkyl substituted with —OP(═O)(OH)(OR¹⁴). In some embodiments, R¹¹is —(CH₂)OP(═O)(OH)(OR¹⁴).

In some embodiments, R¹⁴is H.

In some embodiments, R¹⁴is H or C₁-C₈alkyl; wherein C₁-C₈alkyl of R¹⁴is optionally substituted with one, two or three substituents independently selected from halogen, cyano, and phenyl.

In some embodiments, R¹⁴is C₁-C₈alkyl optionally substituted with one, two or three substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R¹⁴is C₁-C₃alkyl optionally substituted with one, two or three substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R¹⁴is C₁-C₃alkyl substituted with one phenyl. In some embodiments, R¹⁴is

[Image Omitted]

In some embodiments, R¹¹is —(CH₂)OP(═O)(OH)₂. In some embodiments, R¹¹is

[Image Omitted]

In some embodiments, R¹²is H. In some embodiments, R¹²is C₁-C₆alkyl. In some embodiments, R¹²is —C(═O)R¹³. In some embodiments, R¹²is —C(═O)(CH₂)₂CH₃. In some embodiments, R¹²is —C(═O)OR¹³. In some embodiments, R¹²is —C(═O)OCH₂CH(CH₃)₂. In some embodiments, R¹²is —C(═O)OCH₂CH(CH₃)₂or —C(═O)(CH₂)₂CH₃. In some embodiments, R¹²is

[Image Omitted]

In some embodiments, R¹³is H. In some embodiments, R¹³is C₁-C₁₀alkyl. In some embodiments, R¹³is C₁-C₈alkyl. In some embodiments, R¹³is C₁-C₈alkyl optionally substituted with one, two, or three R^csubstituents independently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴) and phenyl. In some embodiments, R¹³is C₁-C₈alkyl optionally substituted with one, two, or three R^csubstituents independently selected from halogen, cyano, and phenyl. In some embodiments, R¹³is C₁-C₈alkyl optionally substituted with one, two, or three R^csubstituents independently selected from halogen, cyano, and unsubstituted phenyl. In some embodiments, R¹³is C₁-C₈alkyl. In some embodiments, R¹³is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R¹³is —CH₂CH(CH₃)₂or —(CH₂)₂CH₃. In some embodiments, R¹³is —(CH₂)OP(═O)(OH)₂. In some embodiments, R¹³is C₆-C₁₀aryl. In some embodiments, R¹³is phenyl. In some embodiments, R¹³is —O—C₆-C₁₀aryl. In some embodiments, R¹³is —O-phenyl. In some embodiments, R¹³is —O—C₁-C₁₀alkyl. In some embodiments, R¹³is —O—CH₃, —O—CH₂CH₃, —O—(CH₂)₂CH₃, —O—(CH₂)₄CH₃, or —O—(CH₂)₆CH₃.

In some embodiments, R¹³is

[Image Omitted]

In some embodiments, Base is

[Image Omitted]

In some embodiments, the method comprises administering to the patient a compound of Formula A or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—; and
- R⁴, and R⁵are each independently unsubstituted C₁-C₈alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, Base is

[Image Omitted]

In some embodiments, R⁴and R⁵are each independently unsubstituted C₁-C₈alkyl. In some embodiments, R⁴and R⁵are each independently unsubstituted C₁-C₆alkyl. In some embodiments, R¹is —OH or —OC(═O)R⁴and R²is —OH or —OC(═O)R⁵. In some embodiments, R¹and R²are each independently —OH, OC(═O)CH(CH₃)₂, or OC(═O)CH₃. In some embodiments, R¹and R²are taken together to form —OC(═O)O—.

In some embodiments, the method comprises administering to the patient a deuterated compound of Formula A which has Formula A1

[Image Omitted]

or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—; and
- R⁴, and R⁵are each independently unsubstituted C₁-C₇alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, the method comprises administering to the patient a deuterated compound of Formula A which has Formula A2

[Image Omitted]

or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—; and
- R⁴, and R⁵are each independently unsubstituted C₁-C₈alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, the method comprises administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—;
- R³is —C(═O)OR⁷or —C(═O)R⁷; and
- R⁴, R⁵, and R⁷are each independently unsubstituted C₁-C₈alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, Base is

[Image Omitted]

In some embodiments, R⁴, R⁵, and R⁷are each independently unsubstituted C₁-C₈alkyl. In some embodiments, R⁴, R⁵, and R⁷are each independently unsubstituted C₁-C₆alkyl. In some embodiments, R¹is —OH or —OC(═O)R⁴, R²is —OH or —OC(═O)R⁵, and R³is —C(═O)R⁷. In some embodiments, R¹and R²are each independently —OH, OC(═O)CH(CH₃)₂, or OC(═O)CH₃, and R⁷is —CH(CH₃)₂or —CH₃. In some embodiments, R¹and R²are taken together to form —OC(═O)O—, and R⁷is —CH(CH₃)₂or —CH₃.

In some embodiments, the method comprises administering to the patient a deuterated compound of Formula I which has Formula Ia

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—;
- R³is —C(═O)OR⁷or —C(═O)R⁷; and
- R⁴, R⁵, and R⁷are each independently unsubstituted C₁-C₈alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, the method comprises administering to the patient a deuterated compound of Formula I which has Formula Ib

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—;
- R³is —C(═O)OR⁷or —C(═O)R⁷; and
- R⁴, R⁵, and R⁷are each independently unsubstituted C₁-C₈alkyl, unsubstituted C₃-C₈carbocyclyl, unsubstituted C₆-C₁₀aryl, unsubstituted 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or unsubstituted 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

Also provided herein is a compound of Formula A:

[Image Omitted]

a deuterated compound of Formula A, a prodrug of the compound of Formula A, a prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, for use in a method of treating a viral infection in a patient in need thereof, wherein:

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or —OCHR⁶O—;
- R⁴and R⁵are each independently H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl, and 5 to 6 membered heteroaryl of R⁴and R⁵is independently, optionally substituted with one, two, or three R^asubstituents;
- R⁶is H, C₁-C₆alkyl, C₁-C₆alkoxy, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl; wherein each 5 to 6 membered heteroaryl and C₆-C₁₀aryl of R⁶is independently, optionally substituted with one, two, or three R^bsubstituents;
- Base is

[Image Omitted]

- R¹¹is C₁-C₆alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);
- R¹²is H, C₁-C₆alkyl, —C(═O)R¹³or —C(═O)OR³;
- each R¹³is independently H, C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, or —O—C₁-C₁₀alkyl; wherein each C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, and —O—C₁-C₁₀alkyl of R¹³is independently, optionally substituted with one, two, or three R^csubstituents;
- each R^ais independently halo, cyano, C₁-C₆alkyl, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or phenyl; wherein each 4 to 6 membered heterocyclyl of R^ais independently, optionally substituted with one, two, or three R^dsubstituents; wherein each phenyl of R^ais independently, optionally substituted with one, two or three R^esubstituents;
- R⁸, R⁹, and R¹⁰are each independently H, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₃-C₆cycloalkyl
- each R^bis independently halo, cyano, C₁-C₆alkoxy, or C₁-C₆alkyl;
- each R^cis independently halo, cyano, —OP(═O)(OH)(OR¹⁴) or phenyl; wherein each phenyl of R^cis optionally substituted with —OP(═O)(OH)(OR¹⁴);
- each R¹⁴is independently H, C₁-C₈alkyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl of R¹⁴is independently, optionally substituted with one, two or three R^fsubstituents;
- each R^dis independently carbonyl or C₁-C₆alkyl;
- each R^eis independently halo, cyano, or C₁-C₆alkyl; and
- each R^fis independently halo, cyano, or phenyl;
- wherein when the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted substantially to the compound of Formula A or the deuterated compound of Formula A; and
- wherein administering the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, to the patient results in a mean C_maxof less than 7,000 ng/mL of the compound of Formula A, or the deuterated compound of Formula A.

Also provided herein is the use of a compound of Formula A:

[Image Omitted]

a deuterated compound of Formula A, a prodrug of the compound of Formula A, a prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment a viral infection in a patient in need thereof, wherein:

- R¹is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;
- R²is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or
- R¹and R²are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or —OCHR⁶O—;
- R⁴and R⁵are each independently H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, 4 to 6 membered heterocyclyl, and 5 to 6 membered heteroaryl of R⁴and R⁵is independently, optionally substituted with one, two, or three R^asubstituents;
- R⁶is H, C₁-C₆alkyl, C₁-C₆alkoxy, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl; wherein each 5 to 6 membered heteroaryl and C₆-C₁₀aryl of R⁶is independently, optionally substituted with one, two, or three R^bsubstituents;
- Base is

[Image Omitted]

- R¹¹is C₁-C₆alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);
- R¹²is H, C₁-C₆alkyl, —C(═O)R¹³or —C(═O)OR³; each R¹³is independently H, C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, or —O—C₁-C₁₀alkyl; wherein each C₁-C₁₀alkyl, C₆-C₁₀aryl, —O—C₆-C₁₀aryl, and —O—C₁-C₁₀alkyl of R¹³is independently, optionally substituted with one, two, or three R^csubstituents;
- each R^ais independently halo, cyano, C₁-C₆alkyl, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or phenyl; wherein each 4 to 6 membered heterocyclyl of R^ais independently, optionally substituted with one, two, or three R^dsubstituents; wherein each phenyl of R^ais independently, optionally substituted with one, two or three R^esubstituents;
- R⁸, R⁹, and R¹⁰are each independently H, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₃-C₆cycloalkyl
- each R^bis independently halo, cyano, C₁-C₆alkoxy, or C₁-C₆alkyl;
- each R^cis independently halo, cyano, —OP(═O)(OH)(OR¹⁴) or phenyl; wherein each phenyl of R^cis optionally substituted with —OP(═O)(OH)(OR¹⁴);
- each R¹⁴is independently H, C₁-C₈alkyl, C₃-C₈carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each C₁-C₈alkyl of R¹⁴is independently, optionally substituted with one, two or three R^fsubstituents;
- each R^dis independently carbonyl or C₁-C₆alkyl;
- each R^eis independently halo, cyano, or C₁-C₆alkyl; and
- each R^fis independently halo, cyano, or phenyl;
- wherein when the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salt thereof is converted substantially to the compound of Formula A or the deuterated compound of Formula A; and
- wherein administering the compound of Formula A, the deuterated compound of Formula A, the prodrug of Formula A, the prodrug of the deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, to the patient results in a mean C_maxof less than 7,000 ng/mL of the compound of Formula A, or the deuterated compound of Formula A.

In some embodiments, the compound of Formula A or the prodrug of the compound of Formula A is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

TABLE 1

Compound 1

[Image Omitted]

Compound 2

[Image Omitted]

Compound 3

[Image Omitted]

In some embodiments, the compound of Formula I is a compound of Table 2, or a pharmaceutically acceptable salt thereof.

TABLE 2

Compound 4

[Image Omitted]

Compound 5

[Image Omitted]

Compound 6

[Image Omitted]

Compound 7

[Image Omitted]

Compound 8

[Image Omitted]

Compound 9

[Image Omitted]

Compound 10

[Image Omitted]

Compound 11

[Image Omitted]

Compound 12

[Image Omitted]

Compound 13

[Image Omitted]

Compound 14

[Image Omitted]

Compound 15

[Image Omitted]

Compound 16

[Image Omitted]

Compound 17

[Image Omitted]

Compound 18

[Image Omitted]

Compound 19

[Image Omitted]

Compound 20

[Image Omitted]

Compound 21

[Image Omitted]

Compound 22

[Image Omitted]

Compound 23

[Image Omitted]

Compound 24

[Image Omitted]

Compound 25

[Image Omitted]

Compound 26

[Image Omitted]

Compound 27

[Image Omitted]

Compound 28

[Image Omitted]

Compound 29

[Image Omitted]

Compound 30

[Image Omitted]

Compound 31

[Image Omitted]

Compound 32

[Image Omitted]

Compound 33

[Image Omitted]

Compound 34

[Image Omitted]

Compound 35

[Image Omitted]

Compound 36

[Image Omitted]

Compound 37

[Image Omitted]

Compound 38

[Image Omitted]

Compound 39

[Image Omitted]

Compound 40

[Image Omitted]

Compound 41

[Image Omitted]

Compound 42

[Image Omitted]

Compound 43

[Image Omitted]

Compound 44

[Image Omitted]

Compound 45

[Image Omitted]

Compound 46

[Image Omitted]

Compound 47

[Image Omitted]

Compound 48

[Image Omitted]

Compound 49

[Image Omitted]

Compound 50

[Image Omitted]

Compound 51

[Image Omitted]

Compound 52

[Image Omitted]

Compound 53

[Image Omitted]

Compound 54

[Image Omitted]

Compound 55

[Image Omitted]

Compound 56

[Image Omitted]

Compound 57

[Image Omitted]

Compound 58

[Image Omitted]

Compound 59

[Image Omitted]

Compound 60

[Image Omitted]

Compound 61

[Image Omitted]

Compound 62

[Image Omitted]

Compound 63

[Image Omitted]

Compound 64

[Image Omitted]

Compound 65

[Image Omitted]

Compound 66

[Image Omitted]

Compound 67

[Image Omitted]

Compound 68

[Image Omitted]

Compound 69

[Image Omitted]

Compound 70

[Image Omitted]

Compound 71

[Image Omitted]

Compound 72

[Image Omitted]

Compound 73

[Image Omitted]

Compound 74

[Image Omitted]

Compound 75

[Image Omitted]

Compound 76

[Image Omitted]

Compound 77

[Image Omitted]

Compound 78

[Image Omitted]

Compound 79

[Image Omitted]

Compound 80

[Image Omitted]

Compound 81

[Image Omitted]

Compound 82

[Image Omitted]

Compound 83

[Image Omitted]

Compound 84

[Image Omitted]

Compound 85

[Image Omitted]

Compound 86

[Image Omitted]

Compound 87

[Image Omitted]

Compound 88

[Image Omitted]

Compound 89

[Image Omitted]

Compound 90

[Image Omitted]

Compound 91

[Image Omitted]

In some embodiments, the deuterated compound of Formula A, the prodrug of the compound of Formula A, or the prodrug of the deuterated compound of Formula A is a compound of Table 3, or a pharmaceutically acceptable salt thereof.

TABLE 3

Compound 92

[Image Omitted]

Compound 93

[Image Omitted]

Compound 94

[Image Omitted]

Compound 95

[Image Omitted]

Compound 96

[Image Omitted]

Compound 97

[Image Omitted]

Compound 98

[Image Omitted]

Compound 99

[Image Omitted]

Compound 100

[Image Omitted]

Compound 101

[Image Omitted]

Compound 102

[Image Omitted]

Compound 103

[Image Omitted]

Compound 104

[Image Omitted]

Compound 105

[Image Omitted]

Compound 106

[Image Omitted]

Compound 107

[Image Omitted]

Compound 108

[Image Omitted]

Compound 109

[Image Omitted]

Compound 110

[Image Omitted]

Compound 111

[Image Omitted]

Compound 112

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Compound 113

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Compound 114

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Compound 115

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Compound 116

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Compound 117

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Compound 118

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Compound 119

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Compound 120

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Compound 121

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Compound 122

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Compound 123

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Compound 124

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Compound 125

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Compound 126

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Compound 127

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Compound 128

[Image Omitted]

Compound 129

[Image Omitted]

Compound 130

[Image Omitted]

Compound 131

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Compound 132

[Image Omitted]

Compound 133

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Compound 134

[Image Omitted]

Compound 135

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Compound 136

[Image Omitted]

Compound 137

[Image Omitted]

Compound 138

[Image Omitted]

Compound 139

[Image Omitted]

Compound 140

[Image Omitted]

Compound 141

[Image Omitted]

Compound 142

[Image Omitted]

Compound 143

[Image Omitted]

Compound 144

[Image Omitted]

Compound 145

[Image Omitted]

Compound 146

[Image Omitted]

Compound 147

[Image Omitted]

Compound 148

[Image Omitted]

Compound 149

[Image Omitted]

Compound 150

[Image Omitted]

Compound 151

[Image Omitted]

Compound 152

[Image Omitted]

Compound 153

[Image Omitted]

Compound 154

[Image Omitted]

Compound 155

[Image Omitted]

Compound 156

[Image Omitted]

Compound 157

[Image Omitted]

Compound 158

[Image Omitted]

Compound 159

[Image Omitted]

Compound 160

[Image Omitted]

Compound 161

[Image Omitted]

Compound 162

[Image Omitted]

Compound 163

[Image Omitted]

Compound 164

[Image Omitted]

Compound 165

[Image Omitted]

Compound 166

[Image Omitted]

Compound 167

[Image Omitted]

Compound 168

[Image Omitted]

Compound 169

[Image Omitted]

Compound 170

[Image Omitted]

Compound 171

[Image Omitted]

Compound 172

[Image Omitted]

Compound 173

[Image Omitted]

Compound 174

[Image Omitted]

Compound 175

[Image Omitted]

Compound 176

[Image Omitted]

Compound 177

[Image Omitted]

Compound 178

[Image Omitted]

Compound 179

[Image Omitted]

Compound 180

[Image Omitted]

Compound 181

[Image Omitted]

Compound 182

[Image Omitted]

Compound 183

[Image Omitted]

Compound 184

[Image Omitted]

Compound 185

[Image Omitted]

Compound 186

[Image Omitted]

Compound 187

[Image Omitted]

Compound 188

[Image Omitted]

Compound 189

[Image Omitted]

Compound 190

[Image Omitted]

Compound 191

[Image Omitted]

Compound 192

[Image Omitted]

Compound 193

[Image Omitted]

Compound 194

[Image Omitted]

Compound 195

[Image Omitted]

Compound 196

[Image Omitted]

Compound 197

[Image Omitted]

Compound 198

[Image Omitted]

Compound 199

[Image Omitted]

Compound 200

[Image Omitted]

In some embodiments, the deuterated compound of Formula A, the prodrug of the compound of Formula A, or the prodrug of the deuterated compound of Formula A is a compound of Table 3A, or a pharmaceutically acceptable salt thereof.

TABLE 3A

Compound 201

[Image Omitted]

Compound 202

[Image Omitted]

Compound 203

[Image Omitted]

Compound 204

[Image Omitted]

Compounds 2-33 and their syntheses are disclosed in WO/2022/047065 and incorporated herein by reference in its entireties. Compounds 34-54, 59, 60, 62, 64, 68, 70, 73, and 201-204 and their syntheses are disclosed in PCT/US2023/014299 and incorporated herein by reference in its entireties. Compounds 55-58, 61, 63, 65-67, 69, 71, 72, and 74-78 are disclosed in PCT/US2023/014299 and incorporated herein by reference in its entireties. Compounds 79, 80, and 82-88 and their syntheses are disclosed in PCT/US2023/014293 and incorporated herein by reference in its entireties. Compounds 81 and 89-91 are disclosed in PCT/US2023/014293 and incorporated herein by reference in its entireties. Compounds 92-200 are disclosed in PCT/US2023/024473 and incorporated herein by reference in its entireties.

In some embodiments, the compound of Formula I is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

In some embodiments, the deuterated compound of Formula I is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

Compounds for Use in Treating Viral Infections

The application provides a compound which is:

[Image Omitted]

a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating a viral infection in a patient in need thereof, wherein the method comprises:

- administering compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof at a dose of 100 mg/dose to 1600 mg/dose if the patient's eGFR is at least 60 mL/min/1.73 m²; and
- administering compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof at a dose of 50 mg/dose to 900 mg/dose if the patient's eGFR is less than 60 mL/min/1.73 m².

In some embodiments, the method further comprises the step of determining an eGFR of the patient.

In some embodiments, if the patient has an eGFR which is at least 60 mL/min/1.73 m², the compound is administered twice daily and if the patient has an eGFR which is less than 60 mL/min/1.73 m², the compound is administered once daily.