Diaryl hydantoin compounds and uses thereof

Abstract

Advantageous specific symmetric diaryl hydantoin compounds are provided that have surprising activity as protease inhibitors against the main protease of coronavirus (MPRO), and thus can be used to treat a host in need thereof with a coronavirus including the SARS CoV-2 virus or a seasonal coronavirus in a host.

Description

[0001] DIARYL HYDANTOIN COMPOUNDS AND USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention provides select diaryl hydantoin compounds and their pharmaceutically acceptable salts with advantageous activity for the treatment of coronaviruses, in a host, typically a human. The treatment is useful to treat a human with the SARS-CoV-2 virus that causes COVID-19, as well as other coronaviruses such as seasonal coronaviruses or other viruses that have a protease that is structurally similar to a coronavirus protease.

[0004] BACKGROUND OF THE INVENTION

[0005] In December 2019, a number of patients in Wuhan, China were diagnosed with pneumonia. These patients exhibited symptoms similar to those seen in the SARS (severe acute respiratory syndrome) outbreak in 2002-2003. In January 2020, the infectious cause was identified as a novel coronavirus that was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the resulting disease called coronavirus disease 2019 (COVID-19). This potentially severe and sometimes lethal disease quickly spread throughout the world. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic.

[0006] Patients infected with the SARS-CoV-2 virus exhibit a range of moderate to severe symptoms, including fever, cough, muscle aches, headaches, loss of taste and / or smell, fatigue, shortness of breath, gastrointestinal problems, ocular problems, conjunctivitis, or even blurred or loss of vision. Sometimes these symptoms resolve within a few weeks, however, the symptoms can persist for months. The Center for Disease Control defines long COVID as a chronic condition that occurs after the initial SARS-CoV-2 infection and lasts for at least three months. The virus may cause long-term damage to the lungs, heart, and brain. Furthermore, in some patients, especially older adults, immunocompromised individuals, or those with underlying conditions, the virus can cause severe symptoms that result in hospitalization and / or death.

[0007] Coronaviruses can be classified as alpha, beta, gamma or delta. They are enveloped, positive-strand RNA viruses and are typically zoonotic, which means the virus jumps from a nonhuman vertebrate to a human. Betacoronaviruses included OC43 and HKU1, which can cause the common cold.

[0008] SARS-CoV-2 is also a betacoronavirus (CoV), which is in the order Nidovirales, family Coronaviridae , subfamily Coronavirinae . SARS-CoV-2 is approximately 30 kilobases in size, which is among the largest known RNA genomes. Related coronaviruses include severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). SARS-CoV-2 shares 80-90% of its genome with SARS-CoV and is considered a new human-infecting betacoronavirus (Zhou et al. Nature 2020, 579, 270) Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster human-to-human transmission rate (Huang et al., Lancet 2000, 395, 497), making it particularly challenging to contain and dangerous.

[0009] In October of 2020, the FDA granted Emergency Use Authorization to the intravenous drug remdesivir, a nucleotide analog that is a polymerase inhibitor, as the first drug for the treatment of COVID-19 in hospitalized patients. In January 2022 the indication for remdesivir was expanded to include individuals with positive COVID-19 test results. However, an analysis of the SOLIDARITY trial run by the WHO concludes there is “no convincing evidence of remdesivir benefit” (Nevalainen, O. et al. Nature Communications, 2022, 13, 6152).

[0010] In December 2021, Pfizer received an Emergency Use Authorization from the FDA for Paxlovid, a combination of nirmatrelvir and ritonavir for COVID-19. Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease (MPro). Ritonavir is an inhibitor of cytochrome CYP3 A4, which prevents premature metabolism of nirmatrelvir. In contrast to remdesivir, Paxlovid can be administered orally. Paxlovid was fully approved by the FDA in May 2023 for the treatment of mild-to-moderate CO VID-19. Despite this, in a trial of 2,246 nonhospitalized high-risk patients, a subgroup analysis indicated minimal benefit for patients under 65 (Hammond, J. et al. New England Journal of Medicine, 2022, 386, 1397-1408).

[0011] In April 2023, Shionogi received a Fast Track Designation for Xocova (ensitrelvir fumatate). Xocova is a protease inhibitor taken once daily for five days for the treatment of SARS- CoV-2. In May 2024 Shionogi reported that Xocova missed the primary endpoint in a global Phase 3 trial of symptomatic non-hospitalized patients.

[0012] Additional protease inhibitors for SARS-CoV-2 have been disclosed in Luttens, A. et al. J. Am. Chem. Soc. 2022, 144, 2905-2920 and WO 2022 / 229458, that disclose certain hydantoin compounds.

[0013] While progress has been made in the treatment of the SARS-CoV-2 virus that causes CO VID-19, given the ability of the virus to mutate, more therapies are needed. Furthermore, there are currently no approved therapeutics for seasonal coronaviruses. Seasonal coronavirus infection can cause severe and potentially fatal complications even in healthy adults.

[0014] It is therefore an object of the present invention to provide compounds, compositions, and methods for the treatment of coronaviruses.

[0015] SUMMARY OF THE INVENTION

[0016] It has been discovered that the diaryl hydantoin protease inhibitor compounds of Formula I or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, are highly active against coronaviruses, for example SARS-CoV-2. The compounds are specific inhibitors of the main corona protease, MPRO, also referred to as 3CLPROor nsp5. By introducing the symmetrical biaryl structure into the hydantoin, substantial improvements in potency, hERG inhibition and stability are surprisingly achieved. Further, in certain embodiments, where the biaryl groups are identical, stereochemical complexities pertaining to activity and manufacturing are eliminated.

[0017] The protease inhibiting compounds of Formula I described herein or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, include compounds with sub-nanomolar activity against coronavirus (Example 6). As an illustrative embodiment, Compound 5 is from 9- to 75-fold more potent than comparator compounds that differ only at the hydantoin substitution (Example 12, Table 9). The unexpectedly advantageous features of the specific diaryl hydantoin framework compounds of Formula I have not been disclosed previously. Inhibitors of hERG can disrupt the coordinated beating of cardiac muscle cells and cause arrhythmias. In certain cases, hERG inhibitors can cause an arrhythmia known as torsades de pointes, which can lead to sudden cardiac death. It is very surprising that the presently disclosed compounds dramatically decrease hERG activity over other hydantoin protease inhibitor compounds (Example 12, Table 8).

[0018] Further, and importantly, the diaryl hydantoin protease inhibitor compounds of the present invention are slowly metabolized and therefore possess long half-lives (Examples 8 and 9). This surprising benefit enables advantageous dosing regimens. For example, a course of treatment may include a single pill per day. Mutant and drug-resistant forms of infectious diseases can be generated by patient non-compliance, for example forgetting to take some of the pills in a regimen or stopping treatment once their symptoms resolve and so minimizing the dosage regimen is helpful. This advantageous property may allow the compound of Formula I to be administered in an effective amount to treat a coronavirus without the concomitant administration of an inhibitor of a CYP3 A metabolic enzyme, as is currently required for Paxlovid (Pfizer’s combination of nirmatrelvir and ritonavir).

[0019] The compounds of Formula I or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, can be administered to a host, such as a human, in need thereof, using a simple solid oral dosage form that can be conveniently taken at home or outside of a medical facility. The therapy can be used to treat a mild, moderate or severe coronavirus disease.

[0020] Therefore, in certain aspects, the invention includes a treatment for a coronavirus in a host in need thereof, such as a human, comprising administering an effective amount of a diaryl hydantoin compound or a pharmaceutically acceptable salt thereof as further described herein. In certain embodiments, the coronavirus is SARS-CoV-2.

[0021] In certain aspects, the invention comprises a compound of Formula I: or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein: is a five- to eight-membered aryl or heteroaryl; R1and R2are each independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0022] R3is bound to carbon and independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0023] R33is bound to nitrogen as allowed by valence and independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, -C2-ealkynyl, -C(O)Ci-Cealkyl, -C(O)C2-Cealkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3. x, y, and z are independently selected from 0, 1, 2, and 3 as allowed by valence; p is selected from 0, 1, and 2, based on the number of nitrogen atoms that can be substituted based on valence;

[0024] R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;

[0025] R6is independently selected at each instance from hydrogen, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, -OR7and -N(R5)2;

[0026] R7is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-6 alkynyl, -Ci-6alkoxy, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;

[0027] R11and R12are each independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2; and

[0028] R13is selected from -H and -F.

[0029] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0030] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0031] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0032] In certain embodiments, Het is

[0033] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0034]

[0035] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0036] In certain embodiments, the compound of Formula I is administered once, twice, or three times or more a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once per day. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered once per day for 2, 3, 4, 5, or more days, optionally with the standard of care.

[0037] In certain embodiments, the coronavirus protease inhibitor provided herein may be administered in combination with ritonavir or another CYP3 A inhibitor to slow the metabolism of the compound of the present invention or its pharmaceutically acceptable salt. While ritonavir is an HIV-1 inhibitor, it does not have protease inhibiting activity against coronavirus. If ritonavir or another CYP3A inhibitor is administered in combination with the compound of the present invention, care should be taken to consider any other drugs that the patient is taking to eliminate an unwanted increase in exposure to these drugs by inhibiting their metabolism. In certain embodiments, the compound of Formula I of the present invention does not require the coadministration of ritonavir or other CYP3 A inhibitor to maintain an efficacious level of drug in the blood.

[0038] Compounds, compositions, dosage forms, and methods are provided for the treatment of coronaviruses in a host in need thereof via delivery of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be used for the treatment of COVID-19 caused by the SARS-CoV-2 virus. In certain embodiments, the compound of Formula I is administered once, twice or three times in a once a day dosage to achieve the desired treatment. The compound or its salt is provided to the patient in any amount that the healthcare provider determines to be appropriate under the circumstances, and may for example range from 50 mg to 500 mg, or 100-400 mg, or 150-350 mg, per dosage, including for example, 100, 150, 200, 250, 300, 350, 400 or 50 mg (measured as the active compound without regard to an accompanying salt).

[0039] The present invention thus includes one or more of the following features: (a) A compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

[0040] (b) A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient;

[0041] (c) A pharmaceutical composition that delivers an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a coronavirus such as SARS-CoV-2, in a host in need thereof, typically a human;

[0042] (d) The pharmaceutical composition of (b) or (c), wherein the pharmaceutically acceptable carrier is in a dosage form suitable for oral administration;

[0043] (e) A method for the treatment of a coronavirus in a host in need thereof comprising administering an effective amount of a compound of (a) or a pharmaceutical composition of any one of (b)-(d);

[0044] (f) The method of (e), wherein the coronavirus is SARS-CoV-2 or a seasonal coronavirus;

[0045] (g) A compound of (a), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of (b)-(d), for use in the treatment of a coronavirus infection such as a coronavirus infection in a host in need thereof, typically a human;

[0046] (h) The compound or pharmaceutical composition for use of (g), wherein the coronavirus is SARS-CoV-2 or a seasonal coronavirus;

[0047] (i) The use of a compound of (a) or a pharmaceutical composition of any one of (b)-(d), in the manufacture of a medicament for use in the treatment of a coronavirus infection, such as a coronavirus infection in a host in need thereof, typically a human;

[0048] (j) The use of (i), wherein the coronavirus is a seasonal coronavirus or SARS-CoV-2;

[0049] (k) Any of the above embodiments, wherein the compound is administered in combination with an additional therapeutic agent;

[0050] (l) A method of manufacture of a compound of (a), or a pharmaceutically acceptable salt thereof; and

[0051] (m) Compounds useful in the preparation of a compound of (a).

[0052] BRIEF DESCRIPTION OF THE FIGURES

[0053] FIG. 1 is a dose-response curve showing the antiviral activity of Compounds 1, 2, and 4 against the seasonal coronavirus HCoV-OC43, as described in Example 7. FIG. 2 is a dose-response curve showing the antiviral activity of Compounds 1, 2, and 4 against the coronavirus MERS-CoV, as described in Example 7.

[0054] FIG. 3 is a dose-response curve showing the antiviral activity of Compounds 1, 2, and 4 against the seasonal coronavirus HCoV-229E, as described in Example 7.

[0055] FIG. 4 is an illustration of Formula I, which can optionally be administered as a pharmaceutically acceptable salt.

[0056] DETAILED DESCRIPTION OF THE INVENTION

[0057] Compounds of the Invention

[0058] In certain aspects, the invention disclosed herein is compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0059] ( A ) is a five- to eight-membered aryl or heteroaryl;

[0060] R1and R2are each independently selected at each instance from -F, -Cl, -CF3, -CF2H, - CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0061] R3is bound to carbon and independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0062] R33is bound to nitrogen as allowed by valence and independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, -C2-ealkynyl, -C(O)Ci-Cealkyl, -C(O)C2-Cealkenyl, - C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, - CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3; x, y, and z are independently selected from 0, 1, 2, and 3 as allowed by valence; p is selected from 0, 1, and 2, based on the number of nitrogen atoms that can be substituted based on valence; R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3;

[0063] R6is independently selected at each instance from hydrogen, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, -OR7and -N(R5)2;

[0064] R7is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2.6alkenyl, -C2-6 alkynyl, -Ci-6alkoxy, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3;

[0065] R11and R12are each independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2; and

[0066] R13is selected from -H and -F.

[0067] In certain aspects, the invention disclosed herein includes a method for the treatment of an infection of a coronavirus in a host in need thereof comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0068] In certain aspects, the invention disclosed herein includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use to treat an infection of coronavirus in a host in need thereof.

[0069] In certain aspects, the invention disclosed herein includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament to treat an infection of coronavirus in a host in need thereof.

[0070] In certain embodiments, the coronavirus is an alphacoronavirus.

[0071] In certain embodiments, the coronavirus is a betacoronavirus.

[0072] In certain embodiments, the coronavirus is an alphacoronavirus or betacoronavirus.

[0073] In certain embodiments, the coronavirus is a seasonal coronavirus.

[0074] In certain embodiments, the coronavirus is HCoV-229E.

[0075] In certain embodiments, the coronavirus is HCoV-HKUl.

[0076] In certain embodiments, the coronavirus is HCoV-NL63.

[0077] In certain embodiments, the coronavirus is HCoV-OC43.

[0078] In certain embodiments, the coronavirus is severe acute respiratory syndrome virus (SARS-CoV2). In certain embodiments, the coronavirus is Middle East respiratory syndrome coronavirus (MERS-CoV).

[0079] Definitions

[0080] A “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of a coronavirus infection, for example an infection of SARS-CoV2 or a seasonal coronavirus. Typically, the host is a human. A “patient” or “host” or “subject” may refer to, if allowed by context, a mammal, primate (e.g., human), cow, horse, dog, cat, rabbit, rat, mice, bird, bat and the like.

[0081] The terms "coadminister,” "coadministration," or “in combination” are used to describe the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, according to the present invention in combination with at least one other antiviral active agent. The timing of the coadministration is best determined by the medical specialist treating the patient. It is sometimes desired that the agents be administered at the same time. Alternatively, the drugs selected for combination therapy may be administered at different times to the patient. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with other agents to treat that other infection or condition as required.

[0082] A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified to an inorganic and organic, acid or base addition salt thereof without undue toxicity. The salts of the present compounds can be synthesized from the parent compound with a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds may optionally be provided in the form of a solvate.

[0083] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional salts and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic acids that are not unduly toxic. For example, acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, H00C-(CH2)n-C00H where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). The compound can be delivered in any molar ratio of salt that delivers the desired result. For example, the compound can be provided with less than a molar equivalent of a counter ion, such as in the form of a hemi-sulfate salt. Alternatively, the compound can be provided with more than a molar equivalent of counter ion, such as in the form of a di-sulfate salt. Non-limiting examples of molar ratios of the compound to the counter ion include 1 : 0.25, 1 : 0.5, 1 : 1, and 1 : 2.

[0084] “Alkyl” is a straight chain, branched or cyclic saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or Ci-Ce (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with length of each member of the range described as an independent species. For example, Ci-Ce alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and Ci-C4alkyl as used herein indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tertpentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2-dimethylbutane and 2,3- dimethylbutane.

[0085] “Cycloalkyl” is a saturated mono-cycle hydrocarbon ring system. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. For clarity, when “alkyl” is used, cycloalkyl is intended to be included if the number of carbons allows.

[0086] "Alkenyl" refers to a non-aromatic hydrocarbon group which contains at least one double bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein. For example, an alkenyl group can have to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethenyl or vinyl (-CH=CH2), allyl (- CH2CH=CH2), 1-butenyl (-C=CH-CH2CH3) and 2-butenyl (-CH2CH=CHCH2).

[0087] The term "alkynyl" refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein. For example, an alkynyl group can have 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Examples of alkynyl groups include, but are not limited to ethynyl and propargyl. "Aryl" indicates aromatic groups containing only carbon in the aromatic ring or rings. In one embodiment, the aryl groups contain 1 to 3 separate or fused rings and is 6 to about 14 or 18 ring atoms, without heteroatoms as ring members. Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above. In one embodiment, aryl groups include, for example, dihydroindole, dihydrobenzofuran, isoindoline-l-one and indolin-2-one.

[0088] “Aryl(alkyl)-” is an alkyl group as described herein substituted with an aryl group as described herein. For example, aryl(CH2)- is benzyl. Examples of aryl(alkyl)- include benzyl, 2- phenyl (alkyl), 3-phenyl(alkyl), and napthyl(alkyl).

[0089] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 or 6 ring atoms. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2- hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4- hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[0090] The term "heteroalkyl" refers to an alkyl, alkenyl, alkynyl, or haloalkyl moiety as defined herein wherein a CEE group is either replaced by a heteroatom or a carbon atom is substituted with a heteroatom for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. In one embodiment, "heteroalkyl" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. Isotopic Substitution

[0091] The present invention includes the use of an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compounds have a desired isotopic substitutions of atoms at amounts above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures.

[0092] Alternatively or in addition, isotopes of carbon, e.g.,13C and14C, may be used. An example of an isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug. The deuterium can be bound in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a P-deuterium kinetic isotope effect). Achillion Pharmaceuticals, Inc. (WO / 2014 / 169278 and WO / 2014 / 169280) describes deuteration of nucleotides to improve their pharmacokinetic or pharmacodynamic, including at the 5-position of the molecule.

[0093] Substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Substitution of deuterium for hydrogen at a site of metabolic breakdown can reduce the rate of or eliminate the metabolism at that bond. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including protium (1H), deuterium (2H) and tritium (3H). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0094] The term "isotopically-labeled" analog refers to an analog that is a "deuterated analog", a "13C-labeled analog," or a "deuterated / 13C-labeled analog." The term "deuterated analog" means a compound described herein, whereby a H-isotope, i.e., hydrogen / protium (1H), is substituted by a H-isotope, i.e., deuterium (2H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.

[0095] In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location. Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results.

[0096] Stereochemistry

[0097] All racemic and stereospecific forms of the compounds of the present invention, such as Formula I, are included in the invention and can be used for therapeutic purposes as described herein as a protease inhibitor in an effective amount to treat a host such as a human with a coronavirus infection, such as SARS-CoV2 or a seasonal coronavirus.

[0098] If the diaryl groups of the compound of the present invention, such as Formula I, are identical, the carbon atom in the cyclobutane to which they are attached is not chiral. Alternatively, if the diaryl groups of the compound of the present invention are not identical, then the carbon atom of the cyclobutane to which they are attached is chiral, creating a stereocenter. In addition, the carbon atom in the hydantoin ring which is also part of the cyclobutane would also be chiral and create another stereocenter.

[0099] Further, if there are any chiral carbons in the substituent groups on the compound of Formula I of the present invention, these would also create stereocenters. In addition, if a chiral salt is used as a pharmaceutically acceptable salt, a stereocenter is likewise introduced. Examples are acid addition or base addition salts wherein the counterion is optically active, for example, a D-lactate or L-lysine or other chiral amino acid.

[0100] If the compound of the present invention is a racemate in the crystal form, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0101] Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience. One skilled in the art will recognize that pure enantiomers, enantiomerically enriched compounds and diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals - a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e. chirality) in the product, which may be achieved by chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reaction with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is place in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; xiv) simulated moving bed chromatography is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

[0102] Embodiments of the Compound of Formula I

[0103] In certain embodiments, the compound is of a formula selected from pharmaceutically acceptable salt thereof.

[0104] In certain embodiments, the compound is of a formula selected from pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the compound is of a formula selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of a formula selected from pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0107] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of the formula or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0110] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0111] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0112] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0113] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0114] Embodiments of Het

[0115] In certain embodiments, Het

[0116] In certain embodiments, Het i

[0117] Embodiments of R1

[0118] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -ci, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0119] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0120] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0121] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0122] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and -Ci-3alkyl.

[0123] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and methyl.

[0124] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, and -Cl.

[0125] In certain embodiments, R1is independently selected at each instance from -F, -ci, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0126] In certain embodiments, R1is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0127] In certain embodiments, R1is independently selected at each instance from -F,

[0128] -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0129] In certain embodiments, R1is independently selected at each instance from -F,

[0130] -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2. In certain embodiments, R1is independently selected at each instance from -F, -Cl, -CF3, and -Ci-3alkyl.

[0131] In certain embodiments, R1is hydrogen.

[0132] In certain embodiments, R1is -F.

[0133] In certain embodiments, R1is -Cl.

[0134] In certain embodiments, R1is -CF3.

[0135] In certain embodiments, R1is -Ci-3alkyl.

[0136] In certain embodiments, R1is -OR5.

[0137] In certain embodiments, R1is -N(R5)2.

[0138] Embodiments of R2

[0139] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -ci, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0140] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0141] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0142] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0143] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and -Ci-3alkyl.

[0144] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and methyl.

[0145] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, and -Cl.

[0146] In certain embodiments, R2is independently selected at each instance from -F, -ci, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3,

[0147] -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2. In certain embodiments, R2is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0148] In certain embodiments, R2is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0149] In certain embodiments, R2is independently selected at each instance from -F,

[0150] -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0151] In certain embodiments, R2is independently selected at each instance from -F,

[0152] -Cl, -CF3, and -Ci-3alkyl.

[0153] In certain embodiments, R2is hydrogen.

[0154] In certain embodiments, R2is -F.

[0155] In certain embodiments, R2is -Cl.

[0156] In certain embodiments, R2is -CF3.

[0157] In certain embodiments, R2is -Ci-3alkyl.

[0158] In certain embodiments, R2is -OR5.

[0159] In certain embodiments, R2is -N(R5)2.

[0160] Embodiments of R1and R2

[0161] In certain embodiments R1and R2are the same.

[0162] In certain embodiments R1and R2are different.

[0163] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2; and R2is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2Fs, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0164] In certain embodiments, R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2; and R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2Fs, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0165] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2; and R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2Fs, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2 In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2; and R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0166] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and -Ci-3alkyl; and R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and -Ci-3alkyl.

[0167] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and methyl; and R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, and methyl

[0168] In certain embodiments, R2is independently selected at each instance from hydrogen, -F, and -Cl; and R2is independently selected at each instance from hydrogen, -F, and -Cl.

[0169] In certain embodiments R1and R2are -F.

[0170] In certain embodiments R1and R2are -Cl.

[0171] In certain embodiments R1and R2are -Ci-3alkyl.

[0172] In certain embodiments R1and R2are methyl.

[0173] In certain embodiments R1and R2are -CF3.

[0174] In certain embodiments R1is -F and R2is -F.

[0175] In certain embodiments R1is -F and R2is -Cl.

[0176] In certain embodiments R1is -F and R2is -Ci-3alkyl.

[0177] In certain embodiments R1is -F and R2is methyl.

[0178] In certain embodiments R1is -F and R2is -CF3.

[0179] In certain embodiments R1is -Cl and R2is -F.

[0180] In certain embodiments R1is -Cl and R2is -Cl.

[0181] In certain embodiments R1is -Cl and R2is -Ci-3alkyl.

[0182] In certain embodiments R1is -Cl and R2is methyl.

[0183] In certain embodiments R1is -Cl and R2is -CF3.

[0184] In certain embodiments R1is -CF3 and R2is -F.

[0185] In certain embodiments R1is -CF3 and R2is -Cl.

[0186] In certain embodiments R1is -CF3 and R2is -Ci-3alkyl.

[0187] In certain embodiments R1is -CF3 and R2is methyl.

[0188] In certain embodiments R1is -CF3 and R2is -CF3. Embodiments of R3

[0189] In certain embodiments, R3is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0190] In certain embodiments, R3is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -Ci-3alkyl, -OR5, -SR5, and -N(R5)2.

[0191] In certain embodiments, R3is independently selected at each instance from -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, and -Ci-3alkyl.

[0192] In certain embodiments, R3is independently selected at each instance from -F, -Cl, -CF3, -CF2H, and -CFH2.

[0193] In certain embodiments, R3is independently selected at each instance from -F, and -Cl.

[0194] In certain embodiments, R3is independently selected at each instance from -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0195] In certain embodiments, R3is independently selected at each instance from -CF3, -CF2H, -CFH2, -CH2CF3, and -C2F5.

[0196] In certain embodiments, R3is independently selected at each instance from -F, -Cl, -CF3, and -CH2CF3.

[0197] In certain embodiments, R3is -F.

[0198] In certain embodiments, R3is -Cl.

[0199] In certain embodiments, R3is -CF3.

[0200] In certain embodiments, R3is-CF2H

[0201] In certain embodiments, R3is-CFFF

[0202] In certain embodiments, R3is-CFFCFs

[0203] In certain embodiments, R3is-C2F5

[0204] In certain embodiments, R3is-CF2CH3

[0205] In certain embodiments, R3is -Ci-3alkyl.

[0206] In certain embodiments, R3is -OR5.

[0207] In certain embodiments, R3is -SR5.

[0208] In certain embodiments, R3is -N(R5)2.

[0209] In certain embodiments, R3is selected from -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2. Embodiments of R33

[0210] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-6alkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3.

[0211] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-6alkyl, -C2.6alkenyl, -C2.6alkynyl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0212] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-6alkyl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2FS.

[0213] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-6alkyl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2FS.

[0214] In certain embodiments, R33is independently selected at each instance from hydrogen, and -Ci-ealkyl.

[0215] In certain embodiments, R33is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0216] In certain embodiments, R33is independently selected at each instance from hydrogen, -CF3, -CF2H, and -CFH2.

[0217] In certain embodiments, R33is independently selected at each instance from hydrogen, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0218] In certain embodiments, R33is independently selected at each instance from hydrogen, -CH2CF3, and -C2F5.

[0219] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-6alkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0220] In certain embodiments, R33is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-ealkynyl, -C(O)Ci-Cealkyl, -C(O)C2-Cealkenyl, and -C(O)C2-C6alkynyl.

[0221] In certain embodiments, R33is independently selected at each instance from -Ci-ealkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, -CF2CF3; In certain embodiments, R33is independently selected at each instance from -Ci-ealkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0222] In certain embodiments, R33is hydrogen.

[0223] In certain embodiments, R33is -Ci-ealkyl.

[0224] In certain embodiments, R33is -CH3.

[0225] In certain embodiments, R33is -C2-6alkenyl.

[0226] In certain embodiments, R33is -C2-6alkynyl.

[0227] In certain embodiments, R33is -C(O)Ci-Cealkyl.

[0228] In certain embodiments, R33is -C(O)C2-Cealkenyl.

[0229] In certain embodiments, R33is -C(O)C2-Cealkynyl.

[0230] In certain embodiments, R33is -CF2CH3.

[0231] In certain embodiments, R33is -CH2CF2H.

[0232] In certain embodiments, R33is -CH2CFH2.

[0233] In certain embodiments, R33is -CH2CF3.

[0234] In certain embodiments, R33is -C2Fs.

[0235] Embodiments of x, y, z, and p

[0236] In certain embodiments, x is 0.

[0237] In certain embodiments, x is 1.

[0238] In certain embodiments, x is 2.

[0239] In certain embodiments, x is 3.

[0240] In certain embodiments, y is 0.

[0241] In certain embodiments, y is 1.

[0242] In certain embodiments, y is 2.

[0243] In certain embodiments, y is 3.

[0244] In certain embodiments, z is 0.

[0245] In certain embodiments, z is 1.

[0246] In certain embodiments, z is 2.

[0247] In certain embodiments, z is 3.

[0248] In certain embodiments, x and y are both 0.

[0249] In certain embodiments, x and y are both 1.

[0250] In certain embodiments, x and y are both 2.

[0251] In certain embodiments, x and y are both 3.

[0252] In certain embodiments, x is 0 and y is 1. In certain embodiments, x is 1 and y is 2.

[0253] In certain embodiments, x is 0 and y is 2.

[0254] In certain embodiments, y is 0 and x is 1.

[0255] In certain embodiments, y is 1 and x is 2.

[0256] In certain embodiments, y is 0 and x is 2.

[0257] In certain embodiments, p is 0.

[0258] In certain embodiments, p is 1.

[0259] In certain embodiments, p is 2.

[0260] Embodiments of R11

[0261] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0262] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -CN, -COR6, -N(R5)COR6, -OR5, -SR5, and -N(R5)2.

[0263] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -OR5, and -SR5.

[0264] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0265] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -OCH3, -OCH2CH3, -OCH(CH3)2, -0CF3, -OCF2H, -0CFH2, -OCH2CF3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCF3, -SCF2H, and -SCFH2.

[0266] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -OCH3, -OCH2CH3, -OCH(CH3)2, -0CF3, -OCF2H, -0CFH2, and -OCH2CF3.

[0267] In certain embodiments, R11is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -OCH3, -OCF3, -OCF2H, -OCFH2, and -OCH2CF3.

[0268] In certain embodiments, R11is hydrogen.

[0269] In certain embodiments, R11is -F.

[0270] In certain embodiments, R11is -Cl.

[0271] In certain embodiments, R11-CF3.

[0272] In certain embodiments, R11is -CF2H. In certain embodiments, R11is -CFH2.

[0273] In certain embodiments, R11is -CH2CF3.

[0274] In certain embodiments, R11is selected from -C2F5.

[0275] In certain embodiments, R11is -OCH3.

[0276] In certain embodiments, R11is -OCF2H.

[0277] In certain embodiments, R11is -OCFH2.

[0278] In certain embodiments, R11is -OCH2CF3.

[0279] Embodiments of R12

[0280] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0281] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -CN, -COR6, -N(R5)COR6, -OR5, -SR5, and -N(R5)2.

[0282] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -OR5, and -SR5.

[0283] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0284] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -OCH3, -OCH2CH3, -OCH(CH3)2, -0CF3, -OCF2H, -0CFH2, -OCH2CF3, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCF3, -SCF2H, and -SCFH2.

[0285] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -OCH3, -OCH2CH3, -OCH(CH3)2, -0CF3, -OCF2H, -0CFH2, and -OCH2CF3.

[0286] In certain embodiments, R12is selected from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, -OCH3, -OCF3, -OCF2H, -OCFH2, and -OCH2CF3.

[0287] In certain embodiments, R12is hydrogen.

[0288] In certain embodiments, R12is -F.

[0289] In certain embodiments, R12is -Cl.

[0290] In certain embodiments, R12-CF3.

[0291] In certain embodiments, R12is -CF2H. In certain embodiments, R12is -CFH2.

[0292] In certain embodiments, R12is -CH2CF3.

[0293] In certain embodiments, R12is selected from -C2F5.

[0294] In certain embodiments, R12is -OCH3.

[0295] In certain embodiments, R12is -OCF2H.

[0296] In certain embodiments, R12is -OCFH2.

[0297] In certain embodiments, R12is -OCH2CF3.

[0298] In certain embodiments, R11and R12are each independently selected at each instance from -F, -Cl, -CF3, -CF2H,

[0299] -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3,-NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2.

[0300] Embodiments of R13

[0301] In certain embodiments, R13is -H.

[0302] In certain embodiments, R13is -F.

[0303] Embodiments of R5, R6, and R7

[0304] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3.

[0305] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, -C2-ealkynyl, -C(O)Ci-Cealkyl, -C(O)C2-Cealkenyl, and -C(O)C2-C6alkynyl.

[0306] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, -C2-ealkynyl, -C(O)Ci-Cealkyl, -C(O)C2-Cealkenyl, and -C(O)C2-C6alkynyl.

[0307] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, and -C2-ealkynyl.

[0308] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-6alkynyl, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0309] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -CF3, -CF2H, and -CFH2. In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0310] In certain embodiments, R5is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2,

[0311] -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3.

[0312] In certain embodiments, R5is independently selected at each instance from hydrogen, -Ci-6alkyl, and -C(O)Ci-C6alkyl.

[0313] In certain embodiments, R5is independently selected at each instance from hydrogen, and -Ci-ealkyl.

[0314] In certain embodiments, R5is hydrogen.

[0315] In certain embodiments, R5is -Ci-ealkyl.

[0316] In certain embodiments, R6is independently selected at each instance from -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, -OR7and -N(R5)2.

[0317] In certain embodiments, R6is independently selected at each instance from -Ci-Cealkyl, -OR7and -N(R5)2.

[0318] In certain embodiments, R6is -Ci-Cealkyl.

[0319] In certain embodiments, R6is -OR7.

[0320] In certain embodiments, R6is -N(R5)2.

[0321] In certain embodiments, R7is independently selected at each instance from hydrogen,

[0322] -Ci-6alkyl, -C2-6alkenyl, -C2-6 alkynyl, -Ci-6alkoxy, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3,

[0323] -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0324] In certain embodiments, R7is independently selected at each instance from hydrogen,

[0325] -Ci-ealkyl, -C2-ealkenyl, -C2-6 alkynyl, -Ci-ealkoxy, -CF3, -CH2CF3, and -C2F5.

[0326] In certain embodiments, R7is independently selected at each instance from hydrogen,

[0327] -Ci-ealkyl, -C2-ealkenyl, -C2-6 alkynyl, -Ci-ealkoxy, -CF3, and -CH2CF3.

[0328] In certain embodiments, R7is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-ealkenyl, -C2-6 alkynyl, and -Ci-ealkoxy.

[0329] In certain embodiments, R7is independently selected at each instance from hydrogen, -Ci-ealkyl, and -Ci-ealkoxy.

[0330] In certain embodiments, R7is independently selected at each instance from hydrogen,

[0331] -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, -CH2CFH2, -CH2CF3, -CFHCF3, and -C2F5.

[0332] In certain embodiments, R7is hydrogen.

[0333] In certain embodiments, R7is -Ci-ealkyl.

[0334] In certain embodiments, R7is -Ci-ealkoxy.

[0335] In certain embodiments, R7is -CF3. In certain embodiments, R7is -CH2CF3.

[0336] Additional Embodiments of the Compound of Formula I

[0337] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0338] In certain embodiments, the compound is selected from a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from a pharmaceutically acceptable salt thereof.

[0339] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0340] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0341] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0342] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0343] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from acceptable salt thereof.

[0344] In certain embodiments, the compound is selected from acceptable salt thereof.

[0345] In certain embodiments, the compound is selected from cally acceptable salt thereof. In certain embodiments, the compound is selected from pharmaceuti- cally acceptable salt thereof.

[0346] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0347] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from

[0348] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from thereof.

[0349] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0350] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0351] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0352] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0353] In certain embodiments, the compound is selected from

[0354] pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof.

[0355] In certain embodiments, the compound is selected from , or a pharmaceutically acceptable salt thereof.

[0356] In certain embodiments, the compound is selected from , or a pharmaceutically acceptable salt thereof.

[0357] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0358] In certain embodiments, the compound is selected from thereof.

[0359] In certain embodiments, the compound is selected from acceptable salt thereof.

[0360] In certain embodiments, the compound is selected from acceptable salt thereof.

[0361] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0362] In certain embodiments, the compound is selected from acceptable salt thereof. In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0363] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0364] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from acceptable salt thereof.

[0365] In certain embodiments, the compound is selected from

[0366] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0367] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0368] In certain embodiments, the compound is selected from

[0369]

[0370] In certain embodiments, the compound is selected from

[0371] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0372] In certain embodiments, the compound is selected from

[0373] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0374] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from maceutically acceptable salt thereof.

[0375] In certain embodiments, the compound is selected from

[0376] pharmaceutically acceptable salt thereof.

[0377] In certain embodiments, the compound is selected from and , or a pharmaceutically acceptable salt thereof.

[0378] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from acceptable salt thereof. In certain embodiments, the compound is selected from

[0379] In certain embodiments, the compound is selected from maceutically acceptable salt thereof. In certain embodiments, the compound is selected from

[0380] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0381] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0382] In certain embodiments, the compound is selected from ,or a pharmaceuti- cally acceptable salt thereof.

[0383] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0384] In certain embodiments, the compound is selected from ,or a pharmaceu- tically acceptable salt thereof.

[0385] In certain embodiments, the compound is selected from ,or a pharmaceuti- cally acceptable salt thereof.

[0386] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0387] In certain embodiments, the compound is selected from cally acceptable salt thereof.

[0388] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof.

[0389] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from cally acceptable salt thereof.

[0390] In certain embodiments, the compound is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from cally acceptable salt thereof.

[0391] In certain embodiments, the compound is selected from maceutically acceptable salt thereof. In certain embodiments, the compound is selected from tically acceptable salt thereof.

[0392] In certain embodiments, the compound is selected from cally acceptable salt thereof. In certain embodiments, the compound is selected from ceptable salt thereof.

[0393] In certain embodiments, the compound is selected from ceptable salt thereof. In certain embodiments, the compound is selected from

[0394] In certain embodiments, the compound is selected from

[0395]

[0396] In certain embodiments, the compound is selected from acceptable salt thereof. In certain embodiments, the compound is selected from cally acceptable salt thereof.

[0397] In certain embodiments, the compound is selected from ceptable salt thereof.

[0398] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from thereof.

[0399] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from ceutically acceptable salt thereof.

[0400] In certain embodiments, the compound is selected from ceutically acceptable salt thereof. In certain embodiments, the compound is selected from thereof.

[0401] In certain embodiments, the compound is selected from In certain embodiments, the compound is selected from tically acceptable salt thereof.

[0402] In certain embodiments, the compound is selected from ceutically acceptable salt thereof. In certain embodiments, the compound is selected from thereof.

[0403] In certain embodiments, the compound is selected from pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from cally acceptable salt thereof.

[0404] In certain embodiments, the compound is selected from cally acceptable salt thereof. General Embodiments of the Present Invention

[0405] In certain embodiments, the invention includes

[0406] 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0407] Het is selected from is a five- to eight-membered aryl or heteroaryl ring, and wherein R3, when present, is only bound to carbon and R33, when present, is only bound to nitrogen; x, y, and z are independently selected from 0, 1, 2, and 3 as allowed by valence; p is selected from 0, 1, and 2, based on the number of nitrogen atoms that can be substituted based on valence;

[0408] R1and R2are each independently selected at each instance from hydrogen, -F, -Cl, -CF3,

[0409] -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0410] R3is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;

[0411] R33is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3,

[0412] -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;

[0413] R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, and -CF2CF3;

[0414] R6is independently selected at each instance from hydrogen, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, -OR7and -N(R5)2; R7is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-6 alkynyl, -Ci-6alkoxy, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;

[0415] R11and R12are each independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3,-NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2; and

[0416] R13is selected from -H and -F.

[0417] 2. The compound of embodiment 1, wherein x is 1.

[0418] 3. The compound of embodiment 1, wherein x is 2.

[0419] 4. The compound of embodiment 1, wherein x is 3.

[0420] 5. The compound of any one of embodiments 1-3, wherein y is 1.

[0421] 6. The compound of any one of embodiments 1-3, wherein y is 2.

[0422] 7. The compound of any one of embodiments 1-3, wherein y is 3.

[0423] 8. The compound of embodiment 1, selected from pharmaceutically acceptable salt thereof.

[0424] 9. The compound of any one of embodiments 1-8, wherein R13is -H.

[0425] 10. The compound of any one of embodiments 1-8, wherein R13is -F.

[0426] 11. The compound of any one of embodiments 1-10, wherein R1is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H,

[0427] -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2,

[0428] -CF2CF3, -F, -Cl, -O-Ci-6alkyl, -O-CF3, and -O-CH2CF3. 12. The compound of any one of embodiments 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, and -O-Ci- ealkyl.

[0429] 13. The compound of any one of embodiments 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, -O-Ci-ealkyl, -O-CF3, and -O-CH2CF3.

[0430] 14. The compound of any one of embodiments 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, and -O-Ci-ealkyl.

[0431] 15. The compound of any one of embodiments 1-10, wherein R1is F.

[0432] 16. The compound of any one of embodiments 1-15, wherein R2is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CHFCH3, -CF2CH3, -CH2CF2H, - CH2CFH2, -CH2CF3, -CFHCF3, -C2F5, -F, -Cl, -O-Ci-6alkyl, -O-CF3, and -O-CH2CF3.

[0433] 17. The compound of any one of embodiments 1-15, wherein R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, and -O-Ci- ealkyl.

[0434] 18. The compound of any one of embodiments 1-15, wherein R2is independently selected at each instance from hydrogen, -F, -Cl, and -O-Ci-ealkyl.

[0435] 19. The compound of any one of embodiments 1-15, wherein R2is F.

[0436] 20. The compound of any one of embodiments 1-19, wherein Het is

[0437] R13f3 A

[0438] (Bl R3A3) OA

[0439] ( A )

[0440] 21. The compound of any one of embodiments 1-20, wherein is a six membered heteroaryl.

[0441]

[0442] 23. The compound of any one of embodiments 1-20, wherein is a five membered heteroaryl.

[0443] 26. The compound of any one of embodiments 23-25, wherein from: 27. The compound of embodiment 23, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0444] 28. The compound of embodiment 27 wherein the compound is selected from or a pharmaceutically acceptable salt thereof. 29. The compound of embodiment 27, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0445] 30. The compound of embodiment 27, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0446] 31. The compound of embodiment 27, wherein the compound is selected from pharmaceutically acceptable salt thereof. 32. The compound of embodiment 24, wherein the compound is selected from

[0447] 33. The compound of embodiment 32, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0448] 34. The compound of embodiment 32, wherein the compound is selected from pharmaceutically acceptable salt thereof. 35. The compound of embodiment 32, wherein the compound is selected from acceptable salt thereof.

[0449] 36. The compound of embodiment 32, wherein the compound is selected from acceptable salt thereof.

[0450] 37. The compound of any one of embodiments 23-36, wherein R33is hydrogen

[0451] 38. The compound of any one of embodiments 23-36, wherein R33is Ci-ealkyl.

[0452] 39. The compound of any one of embodiments 23-36, wherein R33is -CH2CF3.

[0453] 40. The compound of embodiment 23, wherein selected from

[0454] 41. The compound of embodiment 40, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0455] 42. The compound of embodiment 40, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0456] 43. The compound of embodiment 40, wherein the compound is selected from pharmaceutically acceptable salt thereof.

[0457] 44. The compound of embodiment 40, wherein the compound is selected from

[0458] or a pharmaceutically acceptable salt thereof.

[0459] 45. The compound of embodiment 40, wherein the compound is selected from

[0460] pharmaceutically acceptable salt thereof.

[0461] 46. The compound of any one of embodiments 1-19, wherein Het i

[0462] 47. The compound of embodiment 46, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

[0463] 48. The compound of embodiment 47, wherein the compound is selected from

[0464] pharmaceutically acceptable salt thereof.

[0465] 50. The compound of embodiment 1, wherein the compound is selected from

[0466] 51. The compound of embodiment 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

[0467] 52. The compound of embodiment 1, wherein the compound is selected from pharmaceutically acceptable salt thereof. The compound of embodiment 53, selected from pharmaceutically acceptable salt thereof. The compound of embodiment 53, selected from pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of treating a coronavirus infection in a human in need thereof comprising administering an effective amount of a compound of any one of embodiments 1-55, or a pharma- ceutically acceptable salt thereof. The method of embodiment 57, wherein the coronavirus is SARS-CoV-2. A compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, for use in the treatment of a coronavirus infection. The compound for use of embodiment 60, wherein the coronavirus is SARS-CoV-2. 62. A use of a compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a coronavirus infection.

[0468] 63. The use of embodiment 62, wherein the coronavirus is SARS-CoV-2.

[0469] Methods of Treatment or Prophylaxis

[0470] Treatment, as used herein, refers to the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, in an effective amount to a host, for example a human, that is or may become infected with a coronavirus. In one embodiment the method of treatment comprises administration of an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a coronavirus, for example SARS-CoV-2.

[0471] In certain embodiments, the coronavirus is an alphacoronavirus.

[0472] In certain embodiments, the coronavirus is a betacoronavirus.

[0473] In certain embodiments, the coronavirus is a gammacoronavirus.

[0474] In certain embodiments, the coronavirus is a deltacoronavirus.

[0475] In certain embodiments, the coronavirus is an alphacoronavirus or betacoronavirus.

[0476] In certain embodiments, the coronavirus is a seasonal coronavirus.

[0477] In certain embodiments, the coronavirus is HCoV-229E.

[0478] In certain embodiments, the coronavirus is HCoV-HKUl.

[0479] In certain embodiments, the coronavirus is HCoV-NL63.

[0480] In certain embodiments, the coronavirus is HCoV-OC43.

[0481] In certain embodiments, the coronavirus is severe acute respiratory syndrome virus (SARS-CoV).

[0482] In certain embodiments, the coronavirus is Middle East respiratory syndrome coronavirus (MERS-CoV).

[0483] The present invention also includes prophylactic or preventative therapies. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered to a host who has been exposed to and thus is at risk of infection or at risk of reinfection with a coronavirus, for example the SARS-CoV-2 virus. Prophylactic treatment may be administered, for example, to a subject not yet exposed to or infected a coronavirus, but who is susceptible to, or otherwise at risk of exposure or infection. In one embodiment, a host at risk for infection or reinfection is administered a compound of Formula I or a pharmaceutically acceptable salt thereof indefinitely until the risk of exposure no longer exists.

[0484] In another alternative embodiment, a method to prevent transmission is provided that includes administering an effective amount of one of the compounds described herein to humans for a sufficient length of time prior to exposure to crowds that can be infected, including during travel or public events or meetings, including for example, up to 2, 3, 5, 7, 10, 12, 14 or more days prior to a communicable situation, either because the human is infected or to prevent infection from an infected person in the communicable situation.

[0485] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an effective amount for at least 1, 2, 3, 4, 5 or 6 days, one week, two weeks, three weeks, one month, two months, three months, four months, five months, or six months or more after identification or diagnosis of the infection.

[0486] In certain embodiments, the invention is directed to a method of treatment of COVID-19, including drug resistant and multidrug resistant forms of the virus and related disease states, conditions, or complications of the viral infection, including pneumonia, such as 2019 novel coronavirus-infected pneumonia (NCIP), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Additional non-limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, blood clots, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis, and cytokine storm.

[0487] The method also comprises administering to a host in need thereof, typically a human, an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in combination with at least one additional bioactive agent, for example, an additional anti-viral agent, further optionally in combination with a pharmaceutically acceptable carrier additive and / or excipient.

[0488] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof results in a reduction in the incidence of progressive respiratory insufficiency (PRI) as measured by greater than or equal to a 1 -tier or even a 2-tier or more increase in respiratory support methods required to maintain satisfactory oxygenation (SpCh > 93%) using the 6-tier hierarchical levels of respiratory support methods described below.

[0489] The scale of increasing respiratory support levels includes:

[0490] Level 1 : Normal oxygenation on room air (SpCh >_93%), no need for supplemental O2

[0491] Level 2: Persistent hypoxemia on room air (SpCh > 93) with requirement for low-level supplemental O2 by nasal cannular or mask (up to 2L / min) to maintain SpCh > 93

[0492] Level 3: Requirement for higher levels of passive supplemental O2 by nasal cannular or mask (up to 2L / min) to maintain SpCh > 93

[0493] Level 4: Requirement for oxygenation by positive-pressure devices, e.g., Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) or other non- invasive positive-pressure respiratory support methods to main satisfactory oxygenation and / or ventilation

[0494] Level 5: Requires invasive respiratory support (intubated mechanical ventilation or ECMO) Level 6: Death

[0495] In one embodiment, the reduction in PRI is an increase from level 5 to level 3, level 5 to level 2, or level 5 to level 1. In one embodiment, the reduction in PRI is an increase from level 4 to level 2 or level 4 to level 1. In one embodiment, the reduction in PRI is an increase from level 3 to level 1.

[0496] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces the median time to Clinical Recovery (status 6, 7, or 8 in the NIAID Clinical Status scale using an adapted National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of Clinical Status) by at least 3, 4, 5, or more days. In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof results in an improvement as measured by the adapted ordinal scale of Clinical Status.

[0497] From most severe disease to progressively less severe disease, the stages of the adapted ordinal scale of overall Clinical Status are defined as follows:

[0498] 1. Death

[0499] 2. Hospitalized, on invasive mechanical ventilation or ECMO

[0500] 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices

[0501] 4. Hospitalized, requiring supplemental oxygen

[0502] 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)

[0503] 6. Hospitalized, not requiring supplemental oxygen; no longer requires close medical care for COVID-19

[0504] 7. Not hospitalized, but with limitation on activities and needing close outpatient care for COVID-19 manifestations

[0505] 8. Not hospitalized, no limitations on activities, no need for continued close medical care

[0506] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces the median time to Clinical Recovery (status 6, 7, or 8 in the NIAID Clinical Status scale using an adapted National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of Clinical Status) by at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days. In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces the duration of hospitalization for a patient infected with the SARS- CoV-2 virus.

[0507] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces the time to sustained non-detectable SARS-CoV-2 virus in the nose and / or throat in a patient infected with the SARS-CoV-2 virus.

[0508] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces respiratory failure or death.

[0509] In one embodiment, the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof reduces the proportion of patients in a hospital population who are SARS- CoV-2 positive after at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of treatment.

[0510] In another embodiment, a method of treating or preventing a SARS-CoV-2 infection in a host, typically a human, in need thereof is provided by administering to the host an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the SARS-CoV- 2 infection is caused by a viral variant that has developed a natural or drug-induced mutation over the wild-type.

[0511] In some embodiments, the SARS-CoV-2 variant has a natural mutation or drug-induced mutation in a viral protein selected from an envelope (E) protein, membrane (M) protein, spike (S) protein, nspl, nsp2, nsp3, nsp4, nsp5, nsp 6, nsp7, nsp8, nsp9, nsplO, nspl2, nspl3, nspl4, nspl5, nspl6, ORFlab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORFIO. In some embodiments, the SARS-CoV-2 variant has a mutation which results in the acquired resistance to one or more antiviral drugs.

[0512] In some embodiments, the SARS-CoV-2 variant has a deletion of the spike protein amino acids H69 and V70.

[0513] In some embodiments, the SARS-CoV-2 variant has a deletion of the spike protein amino acids D614G.

[0514] In some embodiments, the SARS-CoV-2 variant has a deletion of the spike protein amino acid Y144.

[0515] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N501Y.

[0516] In some embodiments, the SARS-CoV-2 variant which has a spike protein amino acid substitution A570D.

[0517] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution

[0518] P681H. In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution

[0519] T716I.

[0520] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution S982A.

[0521] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D1118H.

[0522] In some embodiments, the SARS-CoV-2 variant has a premature stop codon mutation Q27stop in the protein product of ORF 8.

[0523] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[0524] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution E484K.

[0525] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution K417N.

[0526] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution D215G.

[0527] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A701V.

[0528] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution L18F.

[0529] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution R246I.

[0530] In some embodiments, the SARS-CoV-2 variant has a spike protein deletion at amino acids 242-244

[0531] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution Y453F.

[0532] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution I692V.

[0533] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution Ml 2291.

[0534] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution N439K.

[0535] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A222V. In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution

[0536] S477N.

[0537] In some embodiments, the SARS-CoV-2 variant has a spike protein amino acid substitution A376T.

[0538] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution P323L.

[0539] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution Y455I.

[0540] In some embodiments, the SARS-CoV-2 variant has a Orf8 protein amino acid substitution R52I.

[0541] In some embodiments, the SARS-CoV-2 variant has an ORF8 protein amino acid substitution Y73C.

[0542] In some embodiments, the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution D3L.

[0543] In some embodiments, the SARS-CoV-2 variant has a nucleoside (N) protein amino acid substitution S235F.

[0544] In some embodiments, the SARS-CoV-2 variant has a ORF lab protein amino acid substitution T1001I.

[0545] In some embodiments, the SARS-CoV-2 variant has a ORF lab protein amino acid substitution A1708D.

[0546] In some embodiments, the SARS-CoV-2 variant has a ORF lab protein amino acid substitution I2230T.

[0547] In some embodiments, the SARS-CoV-2 variant has a ORF lab protein amino acid SGF 3675-3677 deletion.

[0548] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution S861X, wherein X is any amino acid.

[0549] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution F480V.

[0550] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution V557L.

[0551] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution D484Y.

[0552] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution F480X, wherein X=any amino acid. In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution V557X, wherein X=any amino acid.

[0553] In some embodiments, the SARS-CoV-2 variant has a nspl2 protein amino acid substitution D484X, wherein X=any amino acid.

[0554] In some embodiments, the SARS-CoV-2 variant includes a deletion of the spike protein amino acids 69-70, deletion of the spike protein amino acid Y144, the spike protein amino acid substitution N501 Y, the spike protein amino acid substitution A570D, the spike protein amino acid substitution D614G, the spike protein amino acid substitution P681H, the spike protein amino acid substitution T716I, the spike protein amino acid substitution S982A, the spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.

[0555] In some embodiments, the SARS-CoV-2 variant includes amino acid substitutions in the spike protein of N501 Y, K417N, E484K, D80A, D215G, L18F, and R246I in the spike protein, and amino acid deletion at amino acids 242-244 of the spike protein.

[0556] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clade O, S, L, V, G, GH, or GR as described by Alm et al., "Geographical and temporal distribution of SARS- CoV-2 clades in the WHO European Region, January to June 2020". Euro Surveillance: Bulletin European Sur les Maladies Transmissibles = European Communicable Disease Bulletin. 25 (32).

[0557] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clade G614, S84, V251, 1378 or D392 as described by Guan et al., A genetic barcode of SARS-CoV-2 for monitoring global distribution of different clades during the COVID-19 pandemic. Int J Infect Dis. 2020 Nov; 100: 216-223.

[0558] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 clade 19 A, 19B, 20A, or 20C as described by Nextstrain: Genomic epidemiology of novel coronavirus - Global sub-sampling. Available from: https: / / nextstrain.org / ncov.

[0559] In some embodiments, the SARS-CoV-2 variant is selected from SARS-CoV-2 lineage A, B, B.l, B.1.1, or B.1.177 as described by Rambaut et al., Phylogenetic Assignment of Named Global Outbreak LINeages (pangolin). San Francisco: GitHub. Available from: https: / / github.com / cov-lineages / pangolin; Rambaut et al. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol. 2020 Nov;5(l 1): 1403-1407; Rambaut et al. SARS-CoV-2 lineages. Available from: https: / / cov-lineages.org / .

[0560] In some embodiments, the SARS-CoV-2 variant is the “Cluster 5” variant, which includes the spike protein amino acid substitution D614G.

[0561] I l l SARS-CoV-2 B Lineage

[0562] In some embodiments, the SARS-CoV-2 variant is from the B lineage.

[0563] In some embodiments, the SARS-CoV-2 variant is from the B. l lineage.

[0564] In certain embodiments, the SARS-CoV-2 variant is from the B.1.1 lineage.

[0565] In certain embodiments, the SARS-CoV-2 variant is from the B. l.1.7 lineage.

[0566] In certain embodiments, the SARS-CoV-2 variant is from the B. l.1.28 (also referred to as P. l) lineage.

[0567] In certain embodiments, the SARS-CoV-2 variant is from the B.1.1.94 or B.1.1.143 lineage.

[0568] In certain embodiments, the SARS-CoV-2 variant is from the B. l.1.142 lineage.

[0569] In certain embodiments, the SARS-CoV-2 variant is from the B. l.1.529 lineage.

[0570] In some embodiments, the SARS-CoV-2 variant is VUI 202012 / 01 (Variant Under Investigation, year 2020, month 12, variant 01) (also known as B.l.1.7 lineage and 20B / 501Y.V1), which has been defined by multiple spike protein changes including deletion of the spike protein amino acids 69-70, deletion of the spike protein amino acid Y144, the spike protein amino acid substitution N501Y, the spike protein amino acid substitution A570D, the spike protein amino acid substitution D614G, the spike protein amino acid substitution P681H, the spike protein amino acid substitution T716I, the spike protein amino acid substitution S982A, the spike protein amino acid substitution D1118H, and a premature stop codon mutation (Q27stop) in the protein product of ORF8.

[0571] In some embodiments, the SARS-CoV-2 variant is the B. l.351 lineage variant (also known as 501. V2, 20C / 501 Y. V2), which includes several mutations in the receptor-binding domain (RBD) in the spike protein: N501Y, K417N, and E484K, which allows the virus to attach more easily to human cells, as well as amino acid substitution D80A in the spike protein, an amino acid substitution D215G in the spike protein, an amino acid substitution A701 V in the spike protein, an amino acid substitution L18F in the spike protein, an amino acid substitution R246I in the spike protein, and amino acid deletion at amino acids 242-244 of the spike protein.

[0572] In some embodiments, the SARS-CoV-2 variant is the 501 Y. V2 lineage variant (also known as 501 Y.V2, 20C / 20H / 501 Y.V2), which also includes the spike protein mutations N501 Y, K417N, and E484K.

[0573] In some embodiments, the SARS-CoV-2 variant is the P. l lineage variant (also known as the Brazil(ian) variant), which includes ten mutations in the spike protein mutations, including N501Y and E484K.

[0574] In some embodiments, the SARS-CoV-2 variant is the B. l.1.207 lineage variant, which includes a P681H mutation in the spike protein.

[0575] In certain embodiments, the SARS-CoV-2 variant is from the B.1.617.2 In certain embodiments, the SARS-CoV-2 variant is from the B.1.1.529

[0576] SARS-CoV-2 BA Lineage

[0577] In certain embodiments, the SARS-CoV-2 variant is from the BA. l lineage.

[0578] In certain embodiments, the SARS-CoV-2 variant is from the BA.1.1 lineage.

[0579] In certain embodiments, the SARS-CoV-2 variant is from the BA.2 lineage.

[0580] In certain embodiments, the SARS-CoV-2 variant is from the BA.2.12.1 lineage.

[0581] In certain embodiments, the SARS-CoV-2 variant is from the BA.2.86 lineage.

[0582] In certain embodiments, the SARS-CoV-2 variant is from the BA.2.86.1 lineage.

[0583] In certain embodiments, the SARS-CoV-2 variant is from the BA.4.6 lineage.

[0584] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.1 lineage.

[0585] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.1.14 lineage.

[0586] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.1.17 lineage.

[0587] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.2 lineage.

[0588] In certain embodiments, the SARS-CoV-2 variant is from the BA.2.75 lineage.

[0589] In certain embodiments, the SARS-CoV-2 variant is from the BA.2.75.2 lineage.

[0590] In certain embodiments, the SARS-CoV-2 variant is from the BA.4 lineage.

[0591] In certain embodiments, the SARS-CoV-2 variant is from the BA.5 lineage.

[0592] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.2.6 lineage.

[0593] SARS-CoV-2 KP Lineage

[0594] In certain embodiments, the SARS-CoV-2 variant is from the KP lineage.

[0595] In certain embodiments, the SARS-CoV-2 variant is from the KP. l lineage.

[0596] In certain embodiments, the SARS-CoV-2 variant is from the KP.1.1 lineage.

[0597] In certain embodiments, the SARS-CoV-2 variant is from the KP.l.1.3 lineage.

[0598] In certain embodiments, the SARS-CoV-2 variant is from the KP1.1 lineage.

[0599] In certain embodiments, the SARS-CoV-2 variant is from the KP.2 lineage.

[0600] In certain embodiments, the SARS-CoV-2 variant is from the KP.2.15 lineage.

[0601] In certain embodiments, the SARS-CoV-2 variant is from the KP.2.3 lineage.

[0602] In certain embodiments, the SARS-CoV-2 variant is from the KP.3 lineage.

[0603] In some embodiments, the SARS-CoV-2 variant is from the KP.3.1.1 lineage.

[0604] In certain embodiments, the SARS-CoV-2 variant is from the KP.4.1 lineage.

[0605] SARS-CoV-2 JN Lineage

[0606] In certain embodiments, the SARS-CoV-2 variant is from the JN.l lineage. In certain embodiments, the SARS-CoV-2 variant is from the JN.1.1 lineage.

[0607] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.1.1 lineage.

[0608] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.1.3 lineage.

[0609] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.1.5 lineage.

[0610] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.2 lineage.

[0611] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.3 lineage.

[0612] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.4 lineage.

[0613] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.4.2 lineage.

[0614] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.4.3 lineage.

[0615] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.5 lineage.

[0616] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.6 lineage.

[0617] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.6.1 lineage.

[0618] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.7 lineage.

[0619] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.7.1 lineage.

[0620] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.7.2 lineage.

[0621] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.8 lineage.

[0622] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.8.1 lineage.

[0623] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.9 lineage.

[0624] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.10 lineage.

[0625] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.11 lineage.

[0626] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.11.1 lineage

[0627] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.12 lineage.

[0628] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.13 lineage.

[0629] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.13.1 lineage

[0630] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.15 lineage.

[0631] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.16 lineage.

[0632] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.18 lineage.

[0633] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.19 lineage.

[0634] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.20 lineage.

[0635] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.21 lineage.

[0636] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.22 lineage.

[0637] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.23 lineage.

[0638] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.24 lineage.

[0639] In certain embodiments, the SARS-CoV-2 variant is from the JN.1.25.1 lineage

[0640] In certain embodiments, the SARS-CoV-2 variant is from the JN.2 lineage. In certain embodiments, the SARS-CoV-2 variant is from the JN.2.2 lineage.

[0641] In certain embodiments, the SARS-CoV-2 variant is from the JN.6 lineage.

[0642] In certain embodiments, the SARS-CoV-2 variant is from the JN.11 lineage.

[0643] In certain embodiments, the SARS-CoV-2 variant is from the JN.2 lineage.

[0644] In certain embodiments, the SARS-CoV-2 variant is from the JN.2 lineage.

[0645] In certain embodiments, the SARS-CoV-2 variant is from the JN.2 lineage.

[0646] SARS-CoV-2 XBB Lineage

[0647] In certain embodiments, the SARS-CoV-2 variant is from the XBB lineage.

[0648] In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5 lineage.

[0649] In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.1 lineage.

[0650] In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.10 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.59 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.68 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.70 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.5.72 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.9.1 lineage.

[0651] In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.9.2 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.16 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.16.1 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.16.6 lineage. In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.16.11 lineage In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.16.15 lineage In certain embodiments, the SARS-CoV-2 variant is from the XBB.1.42.2 lineage.

[0652] In certain embodiments, the SARS-CoV-2 variant is from the XBB.2.3 lineage.

[0653] In certain embodiments, the SARS-CoV-2 variant is from the XBB.2.3.8 lineage.

[0654] Other SARS-CoV-2 Variants

[0655] In certain embodiments, the SARS-CoV-2 variant is from the JQ.2 lineage.

[0656] In certain embodiments, the SARS-CoV-2 variant is from the BF.7.21 lineage.

[0657] In certain embodiments, the SARS-CoV-2 variant is from the BF.13 lineage.

[0658] In certain embodiments, the SARS-CoV-2 variant is from the BF.31.1 lineage.

[0659] In certain embodiments, the SARS-CoV-2 variant is from the BQ.1.1.32 lineage.

[0660] In certain embodiments, the SARS-CoV-2 variant is from the DT.3 lineage.

[0661] In certain embodiments, the SARS-CoV-2 variant is from the BQ.1.3.2 lineage. In certain embodiments, the SARS-CoV-2 variant is from the BQ.1.22 lineage.

[0662] In certain embodiments, the SARS-CoV-2 variant is from the BA.5.9 lineage.

[0663] In certain embodiments, the SARS-CoV-2 variant is from the XEC lineage.

[0664] In certain embodiments, the SARS-CoV-2 variant is from the KR.l lineage.

[0665] In certain embodiments, the SARS-CoV-2 variant is from the KQ.l lineage.

[0666] In certain embodiments, the SARS-CoV-2 variant is from the MC.l lineage.

[0667] In certain embodiments, the SARS-CoV-2 variant is from the LB.l lineage.

[0668] In certain embodiments, the SARS-CoV-2 variant is from the LB.1.3.1 lineage.

[0669] In certain embodiments, the SARS-CoV-2 variant is from the JN.l lineage.

[0670] In certain embodiments, the SARS-CoV-2 variant is from the KS.l lineage.

[0671] In certain embodiments, the SARS-CoV-2 variant is from the LP.l lineage.

[0672] In certain embodiments, the SARS-CoV-2 variant is from the LF.l lineage.

[0673] In certain embodiments, the SARS-CoV-2 variant is from the LF.3 lineage.

[0674] In certain embodiments, the SARS-CoV-2 variant is from the BN.l lineage.

[0675] In certain embodiments, the SARS-CoV-2 variant is from the CH.1.1 lineage.

[0676] In certain embodiments, the SARS-CoV-2 variant is from the LP.l lineage.

[0677] In certain embodiments, the SARS-CoV-2 variant is from the LF.3.1 lineage.

[0678] In certain embodiments, the SARS-CoV-2 variant is from the KQ.l lineage.

[0679] In certain embodiments, the SARS-CoV-2 variant is from the XEC lineage.

[0680] In certain embodiments, the SARS-CoV-2 variant is from the LB.l lineage.

[0681] In certain embodiments, the SARS-CoV-2 variant is from the BF.7 lineage.

[0682] In certain embodiments, the SARS-CoV-2 variant is from the BF.l 1 lineage.

[0683] In certain embodiments, the SARS-CoV-2 variant is from the BQ.l lineage.

[0684] In certain embodiments, the SARS-CoV-2 variant is from the BQ.1.1 lineage.

[0685] In certain embodiments, the SARS-CoV-2 variant is from the GK.1.1 lineage.

[0686] In certain embodiments, the SARS-CoV-2 variant is from the GK.2 lineage.

[0687] In certain embodiments, the SARS-CoV-2 variant is from the EU.1.1 lineage.

[0688] In certain embodiments, the SARS-CoV-2 variant is from the FD.1.1 lineage.

[0689] In certain embodiments, the SARS-CoV-2 variant is from the FD.2 lineage.

[0690] In certain embodiments, the SARS-CoV-2 variant is from the JD.1.1 lineage.

[0691] In certain embodiments, the SARS-CoV-2 variant is from the FL.1.5.1 lineage.

[0692] In certain embodiments, the SARS-CoV-2 variant is from the EG.5 lineage.

[0693] In certain embodiments, the SARS-CoV-2 variant is from the HK.3 lineage.

[0694] In certain embodiments, the SARS-CoV-2 variant is from the HV.l lineage.

[0695] In certain embodiments, the SARS-CoV-2 variant is from the EG.6.1 lineage. In certain embodiments, the SARS-CoV-2 variant is from the JF.l lineage.

[0696] In certain embodiments, the SARS-CoV-2 variant is from the HF. l lineage.

[0697] In certain embodiments, the SARS-CoV-2 variant is from the FE.1.1 lineage.

[0698] In certain embodiments, the SARS-CoV-2 variant is from the GE. l lineage.

[0699] In certain embodiments, the SARS-CoV-2 variant is from the BM.4 lineage.

[0700] In certain embodiments, the SARS-CoV-2 variant is from the BM.4.1.1 lineage.

[0701] In certain embodiments, the SARS-CoV-2 variant is from the DV.7.1 lineage.

[0702] In some embodiments, the SARS-CoV-2 variant is the danish mink variant which includes an amino acid deletion of H69 and V70 in the spike protein, and an amino acid substitution Y453F in the spike protein.

[0703] In some embodiments, the SARS-CoV-2 variant is the danish mink cluster 5 variant, which includes an amino acid deletion of H69 and V70 in the spike protein, an amino acid substitution Y453F in the spike protein, an amino acid substitution I692V in the spike protein, and an amino acid substitution M1229I in the spike protein.

[0704] In some embodiments, the SARS-CoV-2 variant includes an amino acid deletion of H69 and V70 in the spike protein, and an amino acid substitution N439K in the spike protein.

[0705] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU1 variant, which includes an amino acid substitution A222V in the spike protein.

[0706] In some embodiments, the SARS-CoV-2 variant is the Nexstrain cluster 20A.EU2 variant, which includes an amino acid substitution S477N in the spike protein, and an amino acid substitution A376T in the nucleocapsid protein.

[0707] In some embodiments, the SARS-CoV-2 variant has one or more of the following mutations selected from: an amino acid substitution T1001I in the protein product of ORFlab; an amino acid substitution A1708D in the protein product of ORFla; an amino acid substitution I2230T in the protein product of ORFlab; a deletion of amino acids SGF at 3675-3677 in the protein product of ORFlab; an amino acid substitution G251V in the protein product of ORF3a; an amino acid substitution S24L in the protein product of ORF8; an amino acid substitution R52I in the protein product of ORF8; an amino acid substitution Y73C in the protein product of ORF8; an amino acid substitution L84S in the protein product of ORF8; an amino acid substitution P323L in the nspl2 domain; an amino acid substitution Y455I in the nspl2 domain; an amino acid substitution Q57H in the protein product of ORF3a; an amino acid substitution R27C in nsp2; an amino acid substitution VI 981 in nsp2; an amino acid substitution T85I in nsp2; an amino acid substitution P585S in nsp2; an amino acid substitution I559V in nsp2; an amino acid substitution M33I in nsp4; an amino acid substitution G15S in nsp5; an amino acid substitution L37F in nsp6; an amino acid substitution Y541C in nspl3; an amino acid substitution P504L in nspl3; an amino acid substitution S477N in the spike protein; an amino acid substitution N439K in the spike protein; an amino acid substitution N501 Y in the spike protein; an amino acid substitution Y453F in the spike protein; an amino acid substitution K417N in the spike protein; an amino acid substitution E484K in the spike protein; an amino acid substitution A222V in the spike protein; an amino acid substitution S98F in the spike protein; an amino acid substitution D80Y in the spike protein; an amino acid substitution A626S in the spike protein; an amino acid substitution VI 122L in the spike protein; an amino acid substitution A570D in the spike protein; an amino acid substitution P681H in the spike protein; an amino acid substitution VI 122L in the spike protein; an amino acid substitution T716I in the spike protein; an amino acid substitution S982A in the spike protein; an amino acid substitution DI 118H in the spike protein; an amino acid substitution E583D in the spike protein; an amino acid substitution V483 A in the spike protein; an amino acid substitution Q675R in the spike protein; an amino acid substitution A344S in the spike protein; an amino acid substitution T345S in the spike protein; an amino acid substitution R346K in the spike protein; an amino acid substitution A348S in the spike protein; an amino acid substitution A348T in the spike protein; an amino acid substitution N354K in the spike protein; an amino acid substitution S359N in the spike protein; an amino acid substitution V367F in the spike protein; an amino acid substitution V382L in the spike protein; an amino acid substitution P384L in the spike protein; an amino acid substitution P384S in the spike protein; an amino acid substitution T385S in the spike protein; an amino acid substitution V395I in the spike protein; an amino acid substitution R403K in the spike protein; an amino acid substitution D405V in the spike protein; an amino acid substitution Q414P in the spike protein; an amino acid substitution Q414E in the spike protein; an amino acid substitution I418V in the spike protein; an amino acid substitution L441I in the spike protein; an amino acid substitution R457K in the spike protein; an amino acid substitution K458Q in the spike protein; an amino acid substitution P463S in the spike protein; an amino acid substitution A475V in the spike protein; an amino acid substitution G476S in the spike protein; an amino acid substitution T478A in the spike protein; an amino acid substitution P479L in the spike protein; an amino acid substitution V483 A in the spike protein; an amino acid substitution F490L in the spike protein; an amino acid substitution Q493L in the spike protein; an amino acid substitution A520S in the spike protein; an amino acid substitution L5F in the spike protein; an amino acid substitution P521R in the spike protein; an amino acid substitution A522S in the spike protein; an amino acid substitution A831V in the spike protein; an amino acid substitution D839Y in the spike protein; an amino acid substitution D839N in the spike protein; an amino acid substitution D839E in the spike protein; an amino acid substitution L8V in the spike protein; an amino acid substitution L8W in the spike protein; an amino acid substitution H49Y in the spike protein; a deletion of amino acid H69 in the spike protein; a deletion of amino acid V70 in the spike protein; a deletion of amino acid Y144 in the spike protein; an amino acid substitution D3L in the nucleocapsid protein; an amino acid substitution S253F in the nucleocapsid protein; an amino acid substitution RG203KR in the nucleocapsid protein; an amino acid substitution G214C in the nucleocapsid protein; an amino acid substitution S194L in the nucleocapsid protein; an amino acid substitution F377L in the nspl4 protein; an amino acid substitution KI 186R in nsp3; or an amino acid substitution A58T in nsp3.

[0708] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the envelope (E) protein: S68F; L73F; P71L; S55F; R69I; T9I; V24M; D72H; T30I; S68C; V75L; V58F; V75F; or L21F; and combinations thereof.

[0709] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the membrane (M) protein: T175M; D3G; V23L; W31C; A2V; V70F; W75L; M109I; I52T; L46F; V70I; D3Y; K162N; H125Y; K15R; D209Y; R146H; R158C; L87F; A2S; A69S; S214I; T208I; L124F; or S4F; and combinations thereof.

[0710] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nucleocapsid (N) protein: RG203KR; S194L; S197L; P13L; D103Y; SI 931; S188L; I292T; S202N; D401Y; S190I; D22G; A208G; T205I; S183Y; S33I; D81Y; T393I; Al 19S; D377Y; S37P; T247I; A156S; D128Y; P199L; R195I; P207L; E62V; R209T; T362I; G18C; T24N; R185C; S180I; M234I; Q9H; P383L; A35S; P383S; D348H; K374N; R32H; S327L; G179C; G238C; A55S; S190G; H300Y; Al 19V; D144Y; L139F; P199S; P344S; P6L; R203K; P364L; R209I; S188P; A35V; K387N; P122L; R191C; R195K; T391I; A252S; Q418L; T271I; T325I; G18V; L161F; Q289H; R203S; P162L; D340N; K373N; P168Q; A211V; D3L; G212V; K370N; P151L; T334I; A359S; G34W; P67T; R203M; D144N; R191L; S232I; D402Y; P168S; S187L; T366I; A152S; A381T; N140T; T198I; A251V; A398V; A90S; D348Y; D377G; G204R; G243C; G34E; Q229H; R185L; T24I; T379I; A134V; N196I; P365S; Q384H; R276I; S235F; D216A; M2 101; M3221; P20S; Q389H; R209 deletion; or V246I; and combinations thereof.

[0711] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nspl protein: M85; D75E; G82 deletion; V84 deletion; P80 deletion; H83 deletion; V86 deletion; H81 deletion; E87 deletion; L88 deletion; K141 deletion;A79 deletion;V89 deletion; V56I; R124C; D75G; A90 deletion; Y118C; D139N; Y136 deletion; G30D; R24C; D139Y; E37K; H45Y; H110Y; G52S; 171 V; D156 deletion; A76T; E37D; S135 deletion; S166G; A138T; F157 deletion; G49C; M85I; or D144A; and combinations thereof.

[0712] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsplO protein: D64E; P136S; A104V; A32V; T12I; Ti l II; P84S; T51I; I55V; T102I; or T51A; and combinations thereof. In some embodiments, the SARS-CoV2 variant contains one or more of the following mutations in the nspl2 protein: P323L; T141I; A449V; S434F; M666I; H613Y; S647I; M380I; E922D; M629I; G774S; M601I; E436G; N491S; Q822H; A443V; T85I; A423V; M463I; T26I; A656T; M668I; T806I; T276M; T801N; V588L; K267N; V880I; K718R; L514F; F415S; T252N; Y38H; E744D; H752Q; I171V; S913L; A526V; A382V; G228C; P94L; E84K; K59N; P830S; T908I; P21S; D879Y; G108D; K780N; R279S; D258Y; T259I; K263N; D284Y; Q292H; T293I; N297S; V299F; D304Y; T319I; F321L; P328S; V330E; I333T; G337C; T344I; Y346H; L351P; V354L; Q357H; E370G; L372F; A400S; T402I; V405F; V410I; D418N; K426N; K430N; V435F; Q444H; D445G; A448V; R457C; P461T; C464F; I466V; V473F; K478N; D481G; D517G; D523N; A529V; P537S; S549N; A555V; C563F; M566I; A581T; G584V; A585T; G596S; T604I; S607I; D608G; V609I; M615V; W617L; M629V; I632V; L636F; L638F; A639V; T643I; T644M; L648F; V667I; A699S; N713S; H725; N734T; D736N; V737F; T739I; V742M; N743S; M756I; L758I; A771V; L775V; A777T; K780T; F793L; T801I; T803A; H810Y; G823C; D825Y; V827A; Y828H; V848L; T870I; K871R; N874D; Q875R; E876D; H882Y; H892Y; D901Y; M906I; N909D; T912N; P918S; E919D; A923T; F480V; V557L; D484Y; or S433G; and combinations thereof.

[0713] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nspl3 protein: Y541C; P504L; A18V; R392C; P47L; S485L; L297P; H290Y; T127I; L176F; V193I; V570L; D260Y; V49I; Q518H; S468L; A598V; D204Y; S74L; T588I; G206C; V226L; V348L; M576I; A302D; P53S; T481M; K524N; A338V; P419S; V479F; P77L; V169F; N124S; P78S; S80G; V496L; A4V; T413I; A296S; A368S; K460R; L297F; P172S; A302S; P402S; T530I; L428F; P504S; A368V; D458Y; P364S; S74P; T416A; A568V; M474I; S166L; S350L; D344N; E341D; I432T; L581F; S38L; T250I; Y253H; A509V; E244D; H164Y; S74A; T141I; V356F; E319D; E365D; G170S; L526F; R155C; or Y396C; and combinations thereof.

[0714] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nspl4 protein: A320V; F233L; T250I; V182L; A225V; R289C; A274S; P24L; I150T; S374A; H26Y; L177F; L157F; T16I; A482V; P297S; V120A; S255I; P203L; A23 deletion; K311N; M72I; V290F; F431L; K349N; M58I; P140S; R205C; T193A; L409F; P443S; Y260C; D345G; E204D; R163C; R81K; T524I; T113I; T31I; L493F; Al 19V; D345Y; M501I; A360V; A371V; T206I; V287F; A360S; I74T; M3151; P142L; or Q343K; and combinations thereof.

[0715] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nspl5 protein: V320L; A217V; V22L; V172L; D219N; P205S; V127F; Q19H; M218 deletion; A92V; D282G; I252V; T33I; G129S; L331F; A81V; V69L; S312F; T325I; A171V; R206S; D272Y; D87N; S288F; K109R; P270S; P65S; D267Y; D128Y; E215I; T144I; S261L; S287L; T1121; E260K; P205L; S 16 II; V66L; D39Y; or T114 A; or combinations thereof.

[0716] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nspl6 protein: S33R; K160R; P134S; Q28K; T195I; V78G; T35I; G265V; K249N; A204S; K182N; R287I; A188S; Al 16V; T140I; Lil IF; M270T; R216N; A188V; A34V; D108N; L163F; L163H; M17I; T91M; A226S; G77R; L126F; N298L; R216S; T48I; Q238H; or R279K; and combinations thereof.

[0717] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp2 protein: T85I P585S; I559V; D268; G212D; V198I; H237R; F10L; G339S; T166I; R27C; L271F; S211F; P91S; G199E; T371I; A336V; I120F; S122F; A476V; S138L; V480A; T388I; T634I; P129S; R218C; I188T; T170I; P568L; E574A; I367V; H208Y; S99F; T429I; A306V; M405V; P129L; R222C; T44I; Q275H; R380C; A360V; A361V; G115C; L353F; H237Y; L462F; E261G; R4C; S263F; T573I; A318V; G262V; P624L; S430L; T422I; A357S; I100V; E272G; L400F; A192V; D464A; E172D; G262S; L501F; S369F; E172K; G465S; K219R; A411V; A522V; H194Y; S32L; F437L; P181S; P446L; G115V; H532Y; N92H; P I3S; A159V; A184S; A306S; I273T; L274F; P13L; R370H; T223I; T590I; E453D; H145Y; K618N; S301F; T153M; V244I; V530I; A127V; L24F; P191L; Q182L; S196L; S248G; S378F; T139I; T434I; A205V; A375V; A411S; C51Y; F300L; M135T; P568S; Q496H; S348P; T412I; T528I; T547I; V447F; or V577I; and combinations thereof.

[0718] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp3 protein: A58T; T1198K; T428I; P153L; S1197R; D218E; S1424F; A1431V; S1285F; P74L; Q1884H; P1326L; L1221F; P141S; P1103S; S126L; Y916H; L557F; E391D; A1311V; S650F; P1103L; Y952H; P340S; A534V; P1787S; L1791F; N1587S; S371N; K1693N; G282V; P278S; T1335I; A1711V; K19R; A994D; K1325R; P822L; K412N; A465V; T1004I; T808I; G489D; S1699F; M1436V; S1265R; V1768G; A231V; M951I; K384N; T1288I; Q966H; R1614K; T1036I; T1306I; Al 179V; P395L; N1785D; P679L; S166G; A1769V; T181I; L1718F; P822S; T1022I; A1381V; A602T; I1720V; K837N; T73I; A1033V; S1204; C1223Y; P389L; T398A; M1441I; M494I; T1303I; T181A; P1228L; R1135K; V267F; A1883V; A655V; S1296F; T686I; L198I; P1403S; L781F; T1046A; A1215V; E374D; 1205 deletion; V477F; E324K; I707V; P109L; P1558L; P74S; S1212L; S1807F; T819I; T864I; H1000Y; P340L; S697F; T11891; A480V; D729Y; K1771R; S1717L; T749I; M829I; Q172R; T1482I; A1395V; I385T; M560I; S1206L; S1699P; T1269I; T779I; V1315I; V1795F; V325F; A1892V; A579V; E493G; H1274Y; S1467F; T1063I; T350I; V61F; A1736V; K1804N; R646W; T583I; T611I; V1243I; V190I; A41V; H290Y; H295Y; H342Y; L1244F; Q128H; V1673I; A1305V; A1526S; E948K; L72F; P125S; P402T; A1766V; D1214N; E1271D; G1440D; G283D; K1211N; K902N; K945N; L1839S; L312F; N1263S; P1292S; S1670F; S743A; T771I; V1936I; A1262V; A1321V; A358V; A41T; C55Y; G1273S; K463E; K497Q; P1044S; R30K; S1375F; S1682F; T133I; T1348I; 4651; T1830I; T237I; V1248L; A225V; A496V; G1217R; I1816T; L956I; N1369T; N506S; P153S; P2L; T1275I; T1459I; V1234M; E595D; F90L; G1585S; H1307Y; I1409V; L1034V; L1328F; L292F; N1264; P1326T; S1197G; T1456I; T64I; T703I; T720I; T820I; V1229F; V234I; A1279V; A333V; A54S; D1121G; D1761N; E731D; I1672T; I789V; K1037R; K487N; L142F; N1177H; P1228S; P723S; Q180H; Q474R; Q940L; S370L; T1180I; T275I; T422I; T526I; T724I; V1434G; or V207L; or combinations thereof.

[0719] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp4 protein: F308Y; T295I; M33I; A307V; A457V; G309C; L360F; A231V; H313Y; K399E; V20F; S137L; S34F; A380V; H470Y; T204I; S336L; L264F; L438F; M33L; S209F; C296S; L475I; G79V; T327N; T350I; L206F; M324I; E230G; L436 deletion; T237I; T492I; A260V; A446V; M458I; S395G; S481L; H36Y; T73I; L323F; L349F; S59F; T214I; or T60I; and combinations thereof.

[0720] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp5 protein: G15S; D248E; K90R; L89F; A266V; P108S; A70T; A129V; T45I; G71S; L75F; A191V; L220F; N274D; L67F; P241L; K236R; V157L; K61R; P184S; S62Y; T21I; L50F; P108L; S254F; T93I; A255V; A94V; P132S; A234V; A260V; R60C; P96L; V247F; or T199I; and combinations thereof.

[0721] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp6 protein: L37F; G277S; A46V; L75F; F37 deletion; T10I; V149F; L260F; Q208H; M83I; A136V; V145I; N156D; M86I; Y153C; G188V; L230I; F34 deletion; I189V; R233H; V114A; L33F; A287V; H11Y; A287T; A51V; G188S; I162T; M126V; M183I; N40Y; SI 04; F35L; M58L; or V84F; and combinations thereof.

[0722] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp7 protein: S25L; S26F; L71F; S15T; M75I; or N78S; and combinations thereof.

[0723] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp8 protein: M129I; I156V; T145I; R51C; T123I; L95F; T89I; P133S; S41F; K37N; T141M; V34F; R51L; A14T; A74V; I107V; A16V; PIOS; A194V; D30G; A152V; or T187I; and combinations thereof.

[0724] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the nsp9 protein: T77I; T109I; L42F; T34I; T19I; M101V; T62I; or T19K; and combinations thereof. In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF 10: L17P; A28V; PIOS; I4L; S23F; R24C; *39Q; Q29 stop; Y14C; R20I; orA8V; and combinations thereof.

[0725] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF3a: Q57H; G251V; V13L; G196V; A54S; A99V; H93Y; T14I; L46F; Q185H; T175I; Q213K; L108F; K61N; Y264C; A72S; T151I; A23S; G224C; K67N; S171L; W69L; H78Y; K136E; L86F; W131C; L147F; S58N; Y91H; I63T; D155Y; G172C; P240L; Y189C; W131R; KN136NY; T223I; G100C; S195Y; V112F; W131L; G44V; D27H; G174C; K21N; S165F; L65F; T229I; T89I; S74F; A99S; G254R; H204N; K75N; F43L; L53F; Q38P; S26L; S40L; M260I; V256 deletion; K16N; Q218R; S253P; V163L; W69C; A23V; L41F; L106F; V55F; V88A; A99D; E239D; L52F; T24I; A3 IT; D27Y; I186V; L73F; P104L; D22Y; Fl 14V; L95F; P240S; P42L; T268M; or T32I; and combinations thereof

[0726] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF6: I33T; W27L; D53G; F22 deletion; P57L; D61 Y; D61L; K42N; D53 Y; H3 Y; I32T; or R20S; or combinations thereof

[0727] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7a: S81L; A8T; L96F; A50V; V104F; Q62 stop; S83L; E16D; T14I; T28I; V93F; G38V; H47Y; T39I; T120S; Q62 deletion; Q62L; S37T; V104; P34S; P99L; T120I; V108L; H73Y; V24F; V29L; ABT; or L5F; or combinations thereof

[0728] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF7b: C41F; T40I; A43V; LI IF; S3 IL; C41 deletion; H42; H42L; S5L; L20F; L32F; E33 stop; A15S; or F13 deletion; and combinations thereof.

[0729] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the protein product of ORF8: El 10 stop; G66 deletion; S69L; Ti ll; F104L; F120L; G8R; P38S; DI 19E; Il OS; or I39V; and combinations thereof.

[0730] In some embodiments, the SARS-CoV-2 variant contains one or more of the following mutations in the spike protein: D614G; D936Y; P1263L; L5F; N439K; R21I; D839Y; L54F; A879S; L18F; F1121L; R847K; T478I; A829T; Q675H; S477N; H49Y; T29I; G769V; G1124V; V1176F; K1073N; P479S; S1252P; Y145 deletion; E583D; R214L; A1020V; Q1208H; D215G; H146Y; S98F; T95I; G1219C; A846V; I197V; R102I; V367F; T572I; A1078S; A831V; P1162L; T73I; A845S; G1219V; H245Y; L8V; Q675R; S254F; V483A; Q677H; D138H; D80Y; M1237T; D1146H; E654D; H655Y; S50L; S939F; S943P; G485R; Q613H; T76I; V341I; M153I; S221L; T859I; W258L; L242F; P681L; V289I; A520S; VI 104L; V1228L; L176F; M1237I; T307I; T716I; L141; M1229I; A1087S; P26S; P330S; P384L; R765L; S940F; T323I; V826L; E1202Q; L1203F; L611F; V615I; A262S; A522V; A688V; A706V; A892S; E554D; Q836H; T1027I; T22I; A222V; A27S; A626V; C1247F; K1191N; M731I; P26L; S1147L; S1252F; S255F; V1264L; V308L; D80A; I670L; P251L; P631S; *1274Q; A344S; A771S; A879T; D1084Y; D253G; Hl 101 Y; L1200F; Q14H; Q239K; A623V; D215Y; E1150D; G476S; K77M; M177I; P812S; S704L; T51I; T547I; T791I; V1122L; Y145H; D574Y; G142D; G181V; I834T; N370S; P812L; S12F; T791P; V90F; W152L; A292S; A570V; A647S; A845V; D1163Y; G181R; L84I; L938F; P1143L; P809S; R78M; T1160I; V1133F; V213L; V615F; A831V; D839Y; D839N; D839E; S943P; P1263L; or V622F; and combinations thereof.

[0731] Pharmaceutical Compositions and Dosage Forms

[0732] A compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered in an effective amount for the treatment of a coronavirus in a host, typically a human, in need thereof. In certain embodiments, the coronavirus is the 2019 coronavirus disease (COVID- 19) caused by the SARS-CoV-2 virus.

[0733] The compound or its salt can be provided as the neat chemical but is more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need thereof. Thus, in one embodiment, the disclosure provides pharmaceutical compositions comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier for the treatment of a coronavirus infection. The pharmaceutical composition may contain a compound of Formula I or a pharmaceutically acceptable salt thereof, as the only active agent, or, in an alternative embodiment, in combination with at least one additional active agent.

[0734] A compound of Formula I or a pharmaceutically acceptable salt thereof, can be formulated with one or more pharmaceutically acceptable carriers. Oral dosage forms are typical. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is provided in a solid dosage form, such as a tablet or pill, which are well known in the art and described further below. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds for an oral route of administration. Pharmaceutical compositions (formulations) may be administered via oral, parenteral, intravenous, inhalation, intramuscular, topical, transdermal, buccal, subcutaneous, suppository, or other route, including intranasal spray routes of delivery.

[0735] Effective dosage form will depend upon the bioavailability / pharmacokinetic of the particular agent chosen as well as the severity of disease in the patient. A compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered, for example, in one or more tablets, capsules, injections, intravenous formulations, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, bccal, sublingual, topical, gel, mucosal, and the like. Intravenous and intramuscular formulations are often administered in sterile saline. One of ordinary skill in the art may modify the formulations to render them more soluble in water or another vehicle, for example, this can be easily accomplished by minor modifications (salt formulation, esterification, etc.).

[0736] The pharmaceutical compositions contemplated herein optionally include a carrier, as described further below. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Representative carriers include solvents, diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agent, viscosity agents, tonicity agents, stabilizing agents, and combinations thereof. In some embodiments, the carrier is an aqueous carrier.

[0737] One or more viscosity agents may be added to the pharmaceutical composition to increase the viscosity of the composition as desired. Examples of useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof and mixtures thereof.

[0738] Solutions, suspensions, or emulsions for administration may be buffered with an effective amount of buffer necessary to maintain a pH suitable for the selected administration. Suitable buffers are well known by those skilled in the art. Some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers.

[0739] To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof may be admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.

[0740] In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.

[0741] For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.

[0742] Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl / alkyl nucleosides or phosphate ester pro-drug forms of the nucleoside compounds according to the present invention.

[0743] Amounts and weights mentioned in this disclosure typically refer to the free form (i.e., nonsalt, hydrate or solvate form). The typically values described herein represent free-form equivalents, i.e., quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.

[0744] The amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the pharmaceutically acceptable formulation according to the present invention is an effective amount to achieve the desired outcome of treating a coronavirus infection, reducing the likelihood of a coronavirus infection, or the inhibition, reduction, and / or elimination of a coronavirus infection or its secondary effects, including disease states, conditions, and / or complications which occur secondary to the virus.

[0745] As non-limiting embodiments, a therapeutically effective amount of the present compounds in a pharmaceutical dosage form may range, for example, from about 0.001 mg / kg to about 100 mg / kg per day or more. A compound of Formula I or a pharmaceutically acceptable salt thereof, may for example in non-limiting embodiments be administered in amounts ranging from about 0.1 mg / kg to about 15 mg / kg per day of the patient, depending upon the pharmacokinetics of the agent in the patient.

[0746] In certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, or from about 400 mg to about 450 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, in a unit dosage form.

[0747] In certain embodiments, the pharmaceutical composition is in a dosage form, for example in a solid dosage form, that contains up to about 250, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, about 675, about 700, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 900, about 925, about 950, about 975, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg or about 1300 mg, or more of a compound of Formula I or a pharmaceutically acceptable salt thereof, in a unit dosage form.

[0748] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered at an initial dose (or loading dose) followed by a maintenance dose. In one embodiment, the loading dose is about 1.5 times greater, about 2 times greater, about 2.5 times greater, or 3 -fold times greater than the maintenance dose. In one embodiment, the loading dose is administered once, twice, three, four, or more times before the first maintenance dose.

[0749] In one embodiment, the pharmaceutical composition is in a dosage form, for example in a solid dosage form, that contains at least 50 mg, at least 100 mg, 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450, at least 500 mg, at least 600 mg, or at least 700 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, in a unit dosage form.

[0750] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered one time. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered two times. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered three times.

[0751] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered once per week. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered once, twice, or three times or more per week. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered once per day. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered twice or three or more times per day.

[0752] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered for at least one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, two weeks, three weeks, one month, at least two months, at least three months, at least four months, at least five months, at least six months or more. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered once, twice, three, or more times a day. In one embodiment, it is administered orally twice a day.

[0753] For purposes of the present invention, a prophylactically or preventive effective amount of the compositions according to the present invention may generally fall within the ranges set out above, and can be determined in the best judgement of the health care provider. In one embodiment, a compound of the present invention is administered seasonally as the risk of the virus increases to prevent infection, or can be administered, for example, before, during and / or after travel or exposure.

[0754] One of ordinary skill in the art will recognize that a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetic of the agent used, as well as the patient or subject (animal or human) to be treated, and such therapeutic amount can be determined by the attending physician or specialist.

[0755] Solid Dosage Forms

[0756] An aspect of the invention is a solid dosage form that includes an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0757] In one embodiment, the solid dosage form includes a spray dried solid dispersion of a compound of Formula I or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral delivery. In another embodiment, the solid dosage form is a granule layered solid dispersion of a compound of Formula I or a pharmaceutically acceptable salt thereof, and the composition is suitable for oral delivery.

[0758] In other embodiments, the solid dispersion also contains at least one excipient selected from copovidone, poloxamer and HPMC-AS. In one embodiment the poloxamer is Poloxamer 407 or a mixture of poloxamers that may include Poloxamer 407. In one embodiment HPMC-AS is HPMC- AS-L.

[0759] In other embodiments, a solid dosage form prepared from a compound of Formula I or a pharmaceutically acceptable salt thereof, also comprises one or more of the following excipients: a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60); polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerol ricinoleate; hexadecyl stearate; isopropyl myristate; tyloxapol; polyethylene glycol)5000-phosphatidylethanolamine; poly(ethylene glycol)400-monostearate; phospholipid; synthetic and / or natural detergent having high surfactant properties; deoxycholate; cyclodextrin; chaotropic salt; ion pairing agent; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuramic acid; pullulan, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxy ethyl starch, carageenan, glycon, amylose, chitosan, N,O- carboxylmethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g., poly(l,3-dioxan- 2one)), polyanhydride (e.g., poly(sebacic anhydride)), polypropylfumerate, polyamide (e.g. poly caprolactam), polyacetal, poly ether, polyester (e.g., polylactide, polyglycolide, polylactide-co- glycolide, polycaprolactone, polyhydroxyacid (e.g., poly((P-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene, and polyamine, polylysine, polylysine-PEG copolymer, and poly(ethyleneimine), polyethylene imine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, Vitamin E TPGS (also known as d-a-Tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

[0760] In other embodiments, a solid dosage form prepared from a compound of Formula I or a pharmaceutically acceptable salt thereof, also comprises one or more of the following surfactants: polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and poloxamers. Examples of poloxamers include, poloxamers 188, 237, 338 and 407. These poloxamers are available under the trade name Pluronic® (available from BASF, Mount Olive, N.J.) and correspond to Pluronic® F- 68, F-87, F-108 and F-127, respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic® F-87) is a block copolymer with an average molecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to Pluronic® F-108) is a block copolymer with an average molecular mass of about 12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da. Poloxamer 407 (corresponding to Pluronic® F-127) is a polyoxy ethylene-polyoxypropylene triblock copolymer in a ratio of between about E101 P56 E101 to about E106 P70 E106, or about E101 P56E101, or about E106 P70 E106, with an average molecular mass of about 10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 to about 13,000 Da, or about 12,600 Da.

[0761] In yet other embodiments, a solid dosage form prepared from a compound of Formula I or a pharmaceutically acceptable salt thereof, also comprises one or more of the following surfactants: polyvinyl acetate, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethyl ammonium bromide, saponin, sugar esters, Triton X series, sorbitan trioleate, sorbitan mono-oleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, and sunflower seed oil.

[0762] In alternative embodiments, a solid dosage form prepared from a compound of Formula I or a pharmaceutically acceptable salt thereof, is prepared by a process that includes solvent or dry granulation optionally followed by compression or compaction, spray drying, nano-suspension processing, hot melt extrusion, extrusion / spheronization, molding, spheronization, layering (e.g., spray layering suspension or solution), or the like. Examples of such techniques include direct compression, using appropriate punches and dies, for example wherein the punches and dies are fitted to a suitable tableting press; wet granulation using suitable granulating equipment such as a high shear granulator to form wetted particles to be dried into granules; granulation followed by compression using appropriate punches and dies, wherein the punches and dies are fitted to a suitable tableting press; extrusion of a wet mass to form a cylindrical extrudate to be cut into desire lengths or break into lengths under gravity and attrition; extrusion / spheronization where the extrudate is rounded into spherical particles and densified by spheronization; spray layering of a suspension or solution onto an inert core using a technique such as a convention pan or Wurster column; injection or compression molding using suitable molds fitted to a compression unit; and the like.

[0763] Exemplary disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), powdered cellulose, chitosan, croscarmellose sodium, crospovidone, guar gum, low substituted hydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch, sodium carboxymethyl starch, and the like, or a combination thereof.

[0764] Exemplary lubricants include calcium stearate, magnesium stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, light mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, silicon dioxide, colloidal silicon dioxide, dimethyldichlorosilane treated with silica, talc, or a combination thereof.

[0765] The dosage form cores described herein may be coated to result in coated tablets. The dosage from cores can be coated with a functional or non-functional coating, or a combination of functional and non-functional coatings. “Functional coating” includes tablet coatings that modify the release properties of the total composition, for example, a sustained-release or delayed-release coating. “Non-functional coating” includes a coating that is not a functional coating, for example, a cosmetic coating. A non-functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition. A non-functional coating can also mask the taste of the uncoated composition including the active pharmaceutical ingredient. A coating may comprise a light blocking material, a light absorbing material, or a light blocking material and a light absorbing material.

[0766] Exemplary polymethacrylates include copolymers of acrylic and methacrylic acid esters, such as a. an aminomethacrylate copolymer USP / NF such as a poly(butyl methacrylate, (2-dimethyl aminoethyl)methacrylate, methyl methacrylate) 1 :2: 1 (e.g., EUDRAGIT E 100, EUDRAGIT EPO, and EUDRAGIT E 12.5; CAS No. 24938-16-7); b. a poly(methacrylic acid, ethyl acrylate) 1 : 1 (e.g., EUDRAGIT L30 D-55, EUDRAGIT L100-55, EASTACRYL 30D, KOLLICOAT MAE 30D AND 30DP; CAS No. 25212-88-8); c. a poly(methacrylic acid, methyl methacrylate) 1 : 1 (e.g., EUDRAGIT L 100, EUDRAGIT L 12.5 and 12.5 P; also known as methacrylic acid copolymer, type A NF; CAS No. 25806-15-1); d. a poly(methacrylic acid, methyl methacrylate) 1 :2 (e.g., EUDRAGIT S 100, EUDRAGIT S 12.5 and 12.5P; CAS No. 25086-15-1); e. a poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3: 1 (e.g., Eudragit FS 30 D; CAS No. 26936- 24-3); f. a poly(ethyl acrylate, methylmethacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 or 1 :2:0.1 (e g., EUDRAGITS RL 100, RL PO, RL 30 D, RL 12.5, RS 100, RS PO, RS 30 D, or RS 12.5; CAS No. 33434-24-1); g. a poly(ethyl acrylate, methyl methacrylate) 2: 1 (e.g., EUDRAGIT NE 30 D, Eudragit NE 40D, Eudragit NM 30D; CAS No. 9010-88-2); and the like, or a combination thereof.

[0767] Suitable alkylcelluloses include, for example, methylcellulose, ethylcellulose, and the like, or a combination thereof. Exemplary water based ethylcellulose coatings include AQUACOAT, a 30% dispersion further containing sodium lauryl sulfate and cetyl alcohol, available from FMC, Philadelphia, PA; SURELEASE a 25% dispersion further containing a stabilizer or other coating component (e.g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.) available from Colorcon, West Point, PA; ethyl cellulose available from Aquaion or Dow Chemical Co (Ethocel), Midland, MI. Those skilled in the art will appreciate that other cellulosic polymers, including other alkyl cellulosic polymers, can be substituted for part or all of the ethylcellulose.

[0768] Other suitable materials that can be used to prepare a functional coating include hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate phthalate (CAP); a polyvinylacetate phthalate; neutral or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or specifically cetostearyl alcohol), fatty acids, including fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials having hydrocarbon backbones, or a combination thereof. Suitable waxes include beeswax, glycowax, castor wax, carnauba wax, microcrystalline wax, candelilla, and wax-like substances, e.g., material normally solid at room temperature and having a melting point of from about 30°C to about 100°C, or a combination thereof.

[0769] In other embodiments, a functional coating may include digestible, long chain (e.g., C8- C50, specifically C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, waxes, or a combination thereof. Hydrocarbons having a melting point of between about 25 °C and about 90 °C may be used. Specifically, long chain hydrocarbon materials, fatty (aliphatic) alcohols can be used.

[0770] The coatings can optionally contain additional pharmaceutically acceptable excipients such as a plasticizer, a stabilizer, a water-soluble component (e.g., pore formers), an anti-tacking agent (e.g., talc), a surfactant, and the like, or a combination thereof.

[0771] A functional coating may include a release-modifying agent, which affects the release properties of the functional coating. The release-modifying agent can, for example, function as a pore-former or a matrix disrupter. The release-modifying agent can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The release-modifying agent can comprise one or more hydrophilic polymers including cellulose ethers and other cellulosics, such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methyl cellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; an acrylic polymer, such as gastric soluble Eudragit FS 30D, pH sensitive Eudragit L30D 55, L 100, S 100, or L 100- 55; or a combination thereof. Other exemplary release-modifying agents include a povidone; a saccharide (e.g., lactose, and the like); a metal stearate; an inorganic salt (e.g., dibasic calcium phosphate, sodium chloride, and the like); a polyethylene glycol (e.g., polyethylene glycol (PEG) 1450, and the like); a sugar alcohol (e.g., sorbitol, mannitol, and the like); an alkali alkyl sulfate (e.g., sodium lauryl sulfate); a polyoxyethylene sorbitan fatty acid ester (e.g., polysorbate); or a combination thereof. Exemplary matrix disrupters include water insoluble organic or inorganic material. Organic polymers including but not limited to cellulose, cellulose ethers such as ethylcellulose, cellulose esters such as cellulose acetate, cellulose acetate butyrate and cellulose acetate propionate; and starch can function as matrix disrupters. Examples or inorganic disrupters include many calcium salts such as mono-, di- and tri calcium phosphate; silica and, talc.

[0772] The coating may optionally contain a plasticizer to improve the physical properties of the coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it may be advantageous to add plasticizer to the ethylcellulose before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the polymer, e.g., can be from about 1% to about 200% depending on the polymer but is most often from about 1 wt% to about 100 wt% of the polymer. Concentrations of the plasticizer, however, can be determined by routine experimentation.

[0773] Examples of plasticizers for ethylcellulose and other celluloses include plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, or a combination thereof, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.

[0774] Examples of plasticizers for acrylic polymers include citric acid esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, triacetin, or a combination thereof, although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.

[0775] Suitable methods can be used to apply the coating material to the surface of the dosage form cores. Processes such as simple or complex coacervation, interfacial polymerization, liquid drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, or electrostatic deposition may be used.

[0776] In certain embodiments, an optional intermediate coating is used between the dosage form core and an exterior coating. Such an intermediate coating can be used to protect the active agent or other component of the core subunit from the material used in the exterior coating or to provide other properties. Exemplary intermediate coatings typically include water-soluble film forming polymers. Such intermediate coatings may include film forming polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, hydroxypropyl methylcellulose, polyethylene glycol, polyethylene oxide, and the like, or a combination thereof; and a plasticizer. Plasticizers can be used to reduce brittleness and increase tensile strength and elasticity. Exemplary plasticizers include polyethylene glycol propylene glycol and glycerin.

[0777] Combination and Alternation Therapy

[0778] The compounds or their pharmaceutically acceptable salts as described herein can be administered on top of the current standard of care for patients with a coronavirus infection, where such standard of care exists, or in combination or alternation with any other compound or therapy that the healthcare provider deems beneficial for the patient. The combination and / or alternation therapy can be therapeutic, adjunctive, or palliative.

[0779] Since the disclosed diaryl hydantoin compound described herein is a protease inhibitor, it may be useful to administer the compound to a host in combination with an effective amount, of one or more of the following or its pharmaceutically acceptable salt, and as discussed in more detail below:

[0780] (1) Bemnifosbuvir (or AT-511, AT-281, or AT-752 or mixture thereof)

[0781] (2) Paxlovid

[0782] (3) Remdesivir

[0783] (4) Molnupiravir

[0784] (5) Another 3 CL Protease (MPro) inhibitor;

[0785] (6) A papain-like protease (PLPro) inhibitor;

[0786] (7) A polymerase inhibitor;

[0787] (8) An allosteric polymerase inhibitor;

[0788] (9) An interferon alfa-2a, which may be pegylated or otherwise modified, and / or ribavirin;

[0789] (10) A non-substrate-based inhibitor;

[0790] (11) A heli case inhibitor;

[0791] (12) An antisense oligodeoxynucleotide (S-ODN);

[0792] (13) An aptamer;

[0793] (14) A nuclease-resistant ribozyme;

[0794] (15) An iRNA, including microRNA and SiRNA;

[0795] (16) An antibody, partial antibody or domain antibody to the virus; or

[0796] (17) A viral antigen or partial antigen that induces a host antibody response.

[0797] It has been observed that COVID patients can pass through various stages of disease, and that the standard of care can differ based on what stage of illness the patient presents with or advances to. COVID is noteworthy for the development of “cross-talk” between the immune system and the coagulation system. As the disease progresses, the patient can mount an overreaction by the immune system, which can lead to a number of serious implications, including a cytokine storm. Via the cross-talk between the immune system and the coagulation system, the patient can begin clotting in various areas of the body, including the respiratory system, brain, heart and other organs. Multiple clots throughout the body have been observed in COVID patients, requiring anticoagulant therapy. It is considered that these clots may cause long term, or even permanent damage if not treated and disease alleviated.

[0798] More specifically, COVID-19 has been described as progressing through three general stages of illness: stage 1 (early infection), stage 2 (pulmonary phase), and stage 3 (hyperinflammation phase / cytokine storm).

[0799] Stage 1 is characterized by non-specific, and often mild, symptoms. Viral replication is occurring, and it is appropriate to begin immediate treatment with the compounds described herein and perhaps in combination or alternation with another anti-viral therapy. Interferon-P may also be administered to augment the innate immune response to the virus. In one embodiment, therefore, a compound of Formula I or a pharmaceutically acceptable salt thereof is used in an effective amount in combination or alternation with interferon-P and or an additional anti-viral drug.

[0800] Stage 2 of COVID-19 is the pulmonary phase where patients may experience acute hypoxemic respiratory failure. In fact, the primary organ failure of COVID-19 is hypoxemic respiratory failure. It has been shown that moderate immunosuppression via a steroid, for example, dexamethasone, can be beneficial to patients with acute hypoxemic respiratory failure and / or patients on mechanical ventilation. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is used in an effective amount in combination with a corticosteroid which may be a glucocorticoid. Non-limiting examples are budesonide (Entocort EC), bethamethasone, (Celestone), prednisone (Prednisone Intensol), prednisolone (Orapred, Prelone), triamcinolone (Aristospan Intra-Articular, Aristospan Intralesional, Kenalog), methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol), hydrocortisone, or dexamethasone (Dexamethasone Intensol, DexPak 10 Day, DexPak 13 Day, DexPak 6 Day).

[0801] The RdRp inhibitor Remdesivir has provided mixed results when given to COVID-19 patients. It can only be administered in a hospital setting, and only by intravenous injection, typically three times a day, which makes it inappropriate for mild to moderate COVID-19 patients. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with Remdesivir to amplify the overall antiviral effect.

[0802] Stage 3, the final stage of the disease, is characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small blood clots develop throughout the bloodstream. This stage also can include multi -organ failure (e.g. vasodilatory shock, myocarditis). It has also been observed that many patients respond to this severe stage of COVID-19 infection with a “cytokine storm.” There does appear to be a bi-directional, synergistic relationship between DIC and cytokine storm. To combat DIC, patients are often administered an anti -coagulant agent, which may, for example, be an indirect thrombin inhibitor or a direct oral anticoagulant (“DOAC”). Non-limiting examples are low-molecular weight heparin, warfarin, bivalirudin (Angiomax), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), or edoxaban (Lixiana). In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with anti-coagulant therapy. In some severe cases of clotting in COVTD patients, TPA can be administered (tissue plasminogen activator).

[0803] It has been observed that high levels of the cytokine interleukin-6 (IL-6) are a precursor to respiratory failure and death in COVID-19 patients. To treat this surge of an immune response, which may constitute a cytokine storm, patients can be administered an IL-6-targeting monoclonal antibody, pharmaceutical inhibitor or protein degrader such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation. Examples of antibodies include tocilizumab, sarilumab, siltuximab, olokizumab and clazakizumab. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with tocilizumab or sarilumab. Additional nonlimiting examples of immunosuppressant drugs used to treat the overreacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and, IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolate (CellCept, Myfortic)). Additional antibodies and biologies include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta)).

[0804] IL-1 blocks the production of IL-6 and other proinflammatory cytokines. COVID patients are also sometimes treated with anti -IL- 1 therapy to reduce a hyperinflammatory response, for example, an intravenous administration of anakinra. Anti -IL- 1 therapy generally may be for example, a targeting monoclonal antibody, pharmaceutical inhibitor or protein degrader such as a bispecific compound that binds to IL-1 and also to a protein that mediates degradation.

[0805] Patients with COVID can develop viral pneumonia, which can lead to bacterial pneumonia. Patients with severe COVID-19 can also be affected by sepsis or “septic shock”. Treatment for bacterial pneumonia secondary to COVID or for sepsis includes the administration of antibiotics, for example a macrolide antibiotic, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin. In one embodiment, thus a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with an antibiotic, for example, azithromycin. Some of these antibiotics such as azithromycin have independent anti-inflammatory properties. Such drugs may be used both as anti-inflammatory agents for COVID patients and have a treatment effect on secondary bacterial infections.

[0806] A unique challenge in treating patients infected with severe COVID-19 is the relatively long-term need for sedation if patients require mechanical ventilation which might last up to or greater than 5, 10 or even 14 days. For ongoing pain during this treatment, analgesics can be added sequentially, and for ongoing anxiety, sedatives can be added sequentially. Non-limiting examples of analgesics include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with sedative-predominant properties (olanzapine, quetiapine), propofol or dexmedetomidine, haloperidol, and phenobarbital. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with a pain reliever, such as acetaminophen, ketamine, hydromorphone, fentanyl, or morphine. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination or in alternation with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital.

[0807] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination with another protease inhibitor, including but not limited to Paxlovid. Paxlovid is a combination of two protease inhibitors. Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease (MPro). Ritonavir is an inhibitor of cytochrome CYP3A4, which prevents premature metabolism of nirmatrelvir. Paxlovid is recommended as the first line therapeutic for COVID-19 by the National Institute of Health. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered in combination or alternation with a protease inhibitor such as Paxlovid, nirmatrelvir, PF-00835231, lopinavir or ritonavir. The SARS-CoV-2 genome also encodes for a second protease, the papain-like protease (PLPro). Inhibition of the PLPromay also inhibit the ability of the virus to replicate. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof

[0808] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered in combination with a polymerase inhibitor, including but not limited to remdesivir or bemnifosbuvir. Additional drugs that may be used in the treatment of a COVID patient include, but are not limited to favipiravir, fingolimod (Gilenya), methylprednisolone, bevacizumab (Avastin), Actemra (tocilizumab), umifenovir, losartan and the monoclonal antibody combination of REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with an active compound provided herein to treat a viral infection susceptible to such.

[0809] In one embodiment, a compound of the present invention is used in an effective amount in combination with anti-coronavirus vaccine therapy, including but not limited to mRNA-1273 (Moderna, Inc.), AZD-1222 (AstraZeneca and University of Oxford), BNT162 (Pfizer and BioNTech), CoronaVac (Sinovac), NVX-CoV 2372 (NovoVax), SCB-2019 (Sanofi and GSK), ZyCoV-D (Zydus Cadila), and CoVaxin(Bharat Biotech). In another embodiment, a compound of the present invention is used in an effective amount in combination with passive antibody therapy or convalescent plasma therapy.

[0810] SARS-CoV-2 is constantly mutating, which many increase virulence and transmission rates. Drug-resistant variants of viruses may emerge after prolonged treatment with an antiviral agent. Drug reszistance may occur by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against a coronavirus infection in certain cases can be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the principal drug.

[0811] Alternatively, the pharmacokinetics, bio distribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted).

[0812] The SARS-CoV-2 coronavirus infects cells which express P-glycoprotein. Some of the SARS-CoV-2 coronavirus 3CL protease inhibitors of the invention are P-glycoprotein substrates. Compounds which inhibit the SARS-CoV-2 coronavirus which are also P-glycoprotein substrates may be dosed with a P-glycoprotein inhibitor. Examples of P-glycoprotein inhibitors are verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir or cyclosporine. Dosing a coronavirus such as SARS-CoV-2-infected patient with the compound of Formula I of the present invention may lower the amount of SARS-CoV-2 coronavirus 3CL protease inhibitor required to achieve an efficacious dose by increasing the intracellular concentration of the SARS-CoV-2 coronavirus 3 CL protease inhibitor.

[0813] In certain embodiments, a compound of the present invention can be administered in combination an inhibitor of a cytochrome P450 (CYP450) enzyme. The isoforms of CYP450 that may be beneficially inhibited include, but are not limited to CYP1 A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. The compounds used in the methods of the invention include compounds that may be CYP3 A4 substrates and are metabolized by CYP3 A4. Dosing a coronavirus infected patient with a coronavirus inhibitor which is a CYP3 A4 substrate and a CYP3 A4 inhibitor, such as ritonavir, nelfinavir or delavirdine, will reduce the metabolism of the compound of the present invention. This will result in reduced clearance of the compound of the present invention and increased plasma concentrations. This reduced clearance and higher plasma concentrations may allow a lower efficacious dose of the SARS-CoV-2 coronavirus inhibitor.

[0814] Specific examples of therapeutic agents that can be used in combination with the compounds of Formula I of the present invention include the following:

[0815] PLpro inhibitors: Apilomod, EIDD-2801, Ribavirin, Valganciclovir, P-Thymidine, Aspartame, Oxprenolol, Doxycycline, Acetophenazine, lopromide, Riboflavin, Reproterol, 2,2'- Cyclocytidine, Chloramphenicol, Chlorphenesin carbamate, Levodropropizine, Cefamandole, Floxuridine, Tigecycline, Pemetrexed, L(+)-Ascorbic acid, Glutathione, Hesperetin, Ademetionine, Masoprocol, Isotretinoin, Dantrolene, Sulfasalazine Anti-bacterial, Silybin, Nicardipine, Sildenafil, Platycodin, Chrysin, Neohesperidin, Baicalin, Sugetriol-3,9-diacetate, (-)-Epigallocatechin gallate, Phaitanthrin D, 2-(3,4-Dihydroxyphenyl)-2-[[2-(3,4- dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2H-l-benzopyran-3-yl]oxy]-3,4-dihydro-2H-l- benzopyran-3,4,5,7-tetrol, 2,2-di(3-indolyl)-3 -indoIone, (S)-(l S,2R,4aS,5R,8aS)-l-Formamido- l,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen- 2-yl-2-amino-3-phenylpropanoate, Piceatannol, Rosmarinic acid, and Magnolol.

[0816] 3CLpro inhibitors: Nirmatrelvir, Lymecycline, Chlorhexidine, Alfuzosin, Cilastatin, Famotidine, Almitrine, Progabide, Nepafenac, Carvedilol, Amprenavir, Tigecycline, Montelukast, Carminic acid, Mimosine, Flavin, Lutein, Cefpiramide, Phenethicillin, Candoxatril, Nicardipine, Estradiol valerate, Pioglitazone, Conivaptan, Telmisartan, Doxycycline, Oxytetracycline, (1 S,2R,4aS,5R,8aS)-l-Formamido-l,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3- yl)ethenyl)decahydronaphthalen-2-yl5-((R)-l,2-dithiolan-3-yl) pentanoate, Betulonal, Chrysin-7- O-P-glucuronide, Andrographiside, (1 S,2R,4aS,5R,8aS)-l-Formamido-l,4a-dimethyl-6- methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 2- nitrobenzoate, 2P-Hydroxy-3,4-seco-friedelolactone-27-oic acid (S)-(l S,2R,4aS,5R,8aS)-l- Formamido-l,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl) decahydronaphthalen-2-yl-2-amino-3-phenylpropanoate, Isodecortinol, Cerevisterol, Hesperidin, Neohesperidin, Andrograpanin, 2-((lR,5R,6R,8aS)-6-Hydroxy-5-(hydroxymethyl)-5,8a-dimethyl- 2-methylenedecahydronaphthalen-l-yl)ethyl benzoate, Cosmosiin, Cleistocaltone A, 2,2-Di(3- indolyl)-3 -indoIone, Biorobin, Gnidicin, Phyllaemblinol, Theaflavin 3,3'-di-O-gallate, Rosmarinic acid, Kouitchenside I, Oleanolic acid, Stigmast-5-en-3-ol, Deacetylcentapicrin, and Berchemol. RNA dependent RNA inhibitors: Valganciclovir, Chlorhexidine, Ceftibuten, Fenoterol, Fludarabine, Itraconazole, Cefuroxime, Atovaquone, Chenodeoxycholic acid, Cromolyn, Pancuronium bromide, Cortisone, Tibolone, Novobiocin, Silybin, Idarubicin Bromocriptine, Diphenoxylate, Benzylpenicilloyl G, Dabigatran etexilate, Betulonal, Gnidicin, 2,6,30,6- Dihydroxy-3,4-seco-friedelolactone-27-Iactone, 14-Deoxy-l 1, 12-didehydroandrographolide, Gniditrin, Theaflavin 3,3'-di-O-gallate, (R)-((lR,5aS,6R,9aS)-l,5a-Dimethyl-7-methylene-3-oxo- 6-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydro-lH-benzo[c]azepin-l-yl)methyl2- amino-3-phenylpropanoate, 2P-Hydroxy-3,4-seco-friedelolactone-27-oic acid, 2-(3,4- Dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2H-l-benzopyran-3- yl]oxy]-3,4-dihydro-2H-l-benzopyran-3,4,5,7-tetrol, Phyllaemblicin B, 14- hydroxycyperotundone, Andrographiside, 2-((lR,5R,6R,8aS)-6-Hydroxy-5-(hydroxymethyl)- 5,8a-dimethyl-2-methylenedecahydro naphthalen-l-yl)ethyl benzoate, Andrographolide, Sugetriol-3,9-diacetate, Baicalin, (1 S,2R,4aS,5R,8aS)-l-Formamido-l,4a-dimethyl-6-methylene- 5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 5-((R)-l,2-dithiolan-3- yl)pentanoate, l,7-Dihydroxy-3 -methoxyxanthone, l,2,6-Trimethoxy-8-[(6-O-P-D- xylopyranosyl-P-D-glucopyranosyl)oxy]-9H-xanthen-9-one, and l,8-Dihydroxy-6-methoxy-2-[(6- O-P-D-xylopyranosyl-P-D-glucopyranosyl)oxy]-9H-xanthen-9-one, 8-(P-D-Glucopyranosyloxy)- l,3,5-trihydroxy-9H-xanthen-9-one,

[0817] Additional therapeutic agents that can be used in combination in the methods of the invention include Diosmin, Hesperidin, MK-3207, Venetoclax, Dihydroergocri stine, Bolazine, R428, Ditercalinium, Etoposide, Teniposide, UK-432097, Irinotecan, Lumacaftor, Velpatasvir, Eluxadoline, Ledipasvir, Lopinavir / Ritonavir+Ribavirin, Alferon, and prednisone. Other additional agents useful in the methods of the present invention include dexamethasone, azithromycin and remdesivir as well as boceprevir, umifenovir and favipiravir.

[0818] Methods of Manufacture and Intermediates

[0819] The compounds described herein may be prepared using methods known in the art and / or methods described in this document. Certain aspects of the invention include a method for preparing a diaryl hydantoin compound of Intermediate I comprising:

[0820] (a) reacting a suitably substituted benzophenone with a methyl Wittig reagent in the presence of a base to provide a 1,1 -diaryl styrene;

[0821] (b) treating the 1,1 -diaryl styrene with di chloroketene to provide diaryl dichlorocyclobutanone of the formula 1-3:

[0822] (c) reducing 1-3 to provide diaryl cyclobutanone 1-4:

[0823] (d) reacting 1-4 with a cyanide salt and a carbonate salt to form hydantoin Intermediate I:

[0824] Intermediate 1 or a salt thereof.

[0825] In certain embodiments, the invention includes a compound of Intermediate 1 :

[0826] Intermediate 1 or a salt thereof.

[0827] In certain embodiments, the invention includes a compound of Intermediate 2:

[0828] Intermediate 2 or a salt thereof. In certain embodiments, the invention includes a compound of the formula: or a salt thereof, for example the hydrochloride salt 1-5:

[0829] 1-5

[0830] Certain aspects of the invention include a method for preparing a diaryl hydantoin compound of Formula I comprising reacting Intermediate 1 with a Het-Cl, Het-Br, or Het-I in the presence of a transition metal, for example copper, palladium or nickel.

[0831] In certain embodiments, the compound of Formula I is prepared by reacting Intermediate I with a Het-Br or Het-I in the presence of a copper salt.

[0832] In certain embodiments, compound of Formula I is prepared by reacting Intermediate I with a Het-Cl, Het-Br, or Het-I in the presence of palladium, and optionally further reacted with a pharmaceutically acceptable acid or base. In certain embodiments, the palladium is aPd(0)complex. In certain embodiments, the Pd(0)complex comprises a phosphine ligand, for example a dialkylbiaryl phosphine ligand.

[0833] Certain aspects of the invention include a method for preparing a diaryl hydantoin compound of Formula I comprising:

[0834] (a) reacting Intermediate 1 with a hydroxide base to hydrolyze the hydantoin ring;

[0835] (b) forming an ester of the free acid, for example a methyl ester; and

[0836] (c) reacting the ester of (b) with triphosgene and Het-NH2 to form a urea;

[0837] (d) reacting the urea of (c) with a strong base, for example sodium hydride to form the hydantoin of Formula I; and

[0838] (e) optionally forming a pharmaceutically acceptable salt by reacting the compound of Formula I with a suitable pharmaceutically acceptable acid or base. EXAMPLES

[0839] General Methods

[0840] 'H,19F and31P NMR spectra were recorded on a 400 MHz Fourier transform Briicker spectrometer. Spectra were obtained DMSO-de unless stated otherwise. The spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), m (multiplet) and, br (broad). Coupling constants (J) are reported in Hz. The reactions were generally carried out under a dry nitrogen atmosphere using Sigma-Aldrich anhydrous solvents. All common chemicals were purchased from commercial sources.

[0841] The following abbreviations are used in the Examples:

[0842] BID: Twice a day

[0843] DCM: Dichloromethane

[0844] DMSO: dimethyl sulfoxideEDTA: ethylenediaminetetraacetic acid

[0845] ELSD: Evaporative Light Scattering Detector

[0846] ESI: electrospray ionisationEtOAc: Ethyl acetate

[0847] EtOH: Ethanol

[0848] FRET: Fluorescence Resonance Energy Transfer

[0849] GT: Genotype

[0850] HPLC: High pressure liquid chromatography

[0851] LC: liquid chromatography

[0852] LD: Loading dose

[0853] MHz: Mega Hertz

[0854] MS: Mass Spectroscopy

[0855] NADPH: Nicotinamide Adenine Dinucleotide Phosphate

[0856] NaOH: Sodium hydroxide

[0857] Na2SO4: Sodium sulphate (anhydrous)

[0858] NMR: Nuclear Magnetic Resonance

[0859] MeOH: Methanol

[0860] Na2SO4: Sodium sulfate

[0861] NH4CI: Ammonium chloride

[0862] PBS: phosphate buffered saline

[0863] PE: Petroleum ether

[0864] Silica gel (230 to 400 mesh, Sorbent) t-BuMgCl: / -Butyl magnesium chloride

[0865] THF: Tetrahydrofuran (THF), anhydrous TP: Triphosphate

[0866] UDPG: Uridine Diphosphate Glucose

[0867] UHPLC: Ultra High Performance Liquid Chromatography

[0868] Example 1. General Synthesis of Diaryl Hydantoin Compounds of Formula I

[0869] Intermediate 1

[0870] Heteroarylation Method 1: Aryl bromides as substrates.

[0871] General Product-1

[0872] To a degassed solution of Intermediate 1 (1.5 eq.) in 7V,7V-dimethylacetamide (1.5 eq.) is added copper(I) oxide (1 eq.) followed by aryl bromide ( leq.). The mixture is sparged with argon and stirred at 165 °C sealed for 17 h. The mixture is cooled, filtered through diatomaceous earth and washed with ethyl acetate (4 x 20 mL). The filtrate is concentrated in vacuo to dryness. The residue is purified by chromatography (silica gel, 40 g, dry loading, 0-15% methanol / dichloromethane, gradient elution, ELSD detection). The product is dissolved in methanol (8.0 mL) and is purified by reverse phase chromatography (C18, 150 g, methanol loading, 0-100% acetonitrile with 0.05% v / v trifluoroacetic acid / water with 0.05% v / v trifluoroacetic acid, gradient elution, UV detection) and lyophilized from acetonitrile (8.0 mL) and water (6.0 mL). The product is purified by chromatography (silica gel, 40 g, dry loading, 0-100% ethyl acetate / hexanes, gradient elution, ELSD detection) to afford General Product-1. Typical yields are 10% - 30% depending on the substrate. In certain embodiments, the reaction is performed in the microwave reactor for at least about 17 hours, for example about 24 hours, about 36 hours or about 40 hours.

[0873] If direct N-arylation does not work, or gives very low conversion, then a second method is employed using Ar-NEE as substrate.

[0874] Heteroarylation Method 2: Aryl amines as substrates. Intermediate 2 General Product-1

[0875] To a mixture of Intermediate 2 (1 eq.) in dichloromethane and saturated aqueous sodium bicarbonate (9 eq.) is added sodium bicarbonate (3.5 eq.) and the mixture is stirred for 15 min. Triphosgene (0.32 eq.) is added and the mixture is stirred for 30 min. Aryl amine (Het-NHi, 1 eq.) is added and the mixture was stirred at room temperature for 18 h. Dichloromethane (40 mL) and water (2 mL) are added and the organic layer, containing the precipitate, is separated and concentrated in vacuo. Dichloromethane (20 mL) is added, and the product is collected by filtration and washed with dichloromethane (2 mL) and diethyl ether (2 x 2 mL) to afford 1-6, typically as a white solid, which is used directly in the next step.

[0876] To a suspension of 1-6 (1 eq.) in THF (18.8 mL) at 0 °C is added sodium hydride (6 eq., 60 wt% in mineral oil) and the mixture is stirred at 0 °C for 20 min. Trifluoroacetic acid (50 eq.) is added and the mixture stirred at 0 °C for 15 min and concentrated in vacuo to dryness. To the residue is added acetonitrile (5 mL) and the solution is washed with heptane (25 mL). The acetonitrile layer is separated and purified by reverse phase chromatography (Cl 8, 50 g, acetonitrile 2.5 mL loading, 2 injections, 0-95% acetonitrile with 0.05% v / v trifluoroacetic acid / water with 0.05% v / v trifluoroacetic acid, non-linear ramp, UV detection). The product is lyophilized from acetonitrile (2 mL) and water (2 mL) to afford General Product-1. Typically, the yields vary between 50-70% depending on the substrate. Example 2. Synthesis of methyl l-amino-3,3-bis(3-fluorophenyl)cyclobutane-l-carboxylate (2-7)

[0877] Step 1. Synthesis of 3, 3'-(Ethene-l , l-diyl)bis(fluorobenzene) (2-2)

[0878] 2-1 2-2

[0879] To a mixture of methyltriphenylphosphonium bromide (14.7 g, 41.2 mmol) in THF (324 mL) was added / / -butyl lithium (16.5 mL, 41.2 mmol, 2.5 M in hexanes) dropwise and the red- orange mixture was stirred for 20 min. A solution of bis(3-fluorophenyl)methanone (2-1, 7.50 g, 34.4 mmol) in THF (28.2 mL) was added and the yellow-orange mixture was stirred for 2.5 h. Saturated aqueous ammonium chloride (214 mL) was slowly added and the mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 120 g, dichloromethane loading, 100% pentane, isocratic elution, ELSD detection) to afford 3,3'-(ethene-l,l-diyl)bis(fhiorobenzene) (2-2, 5.69 g, 77%) as a clear colorless oil: 'H NMR (500 MHz, CDC13) 8 7.32-7.28 (m, 2H), 7.10 (dt, J= 8.0, 1.0 Hz, 2H), 7.04-7.00 (m, 4H), 5.51 (s, 2H);19F NMR (471 MHZ, CDCI3) 6 -113.37. Step 2. Synthesis of 2, 2-Dichloro-3,3-bis(3-fluorophenyl)cyclobutan-l -one. (2-3)

[0880] To a mixture of 3,3'-(ethene-l,l-diyl)bis(fluorobenzene) (2-2, 5.69 g, 26.3 mmol) and zinccopper couple (5.16 g, 79.0 mmol) in diethyl ether (52.6 mL) was added a solution of tri chloroacetyl chloride (5.87 mL, 52.6 mmol) and phosphorous oxychloride (2.70 mL, 28.9 mmol) in diethyl ether (26.3 mL) via syringe pump over 48 min (1.33 min / mL) at room temperature. The mixture was heated to 40 °C for 16 h. The mixture was cooled, filtered through diatomaceous earth and washed with diethyl ether (100 mL). The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 120 g, di chloromethane loading, 0-30% ethyl acetate / pentane, gradient elution, ELSD detection) to afford 2,2-dichloro-3,3-bis(3-fhiorophenyl)cyclobutan-l-one (2-3, 2.95 g, 34%) as a pale yellow oil:JH NMR (500 MHz, CDC13) 8 7.41-7.36 (m, 2H), 7.08-7.04 (m, 4H), 6.92 (dt, J= 10.5, 2.0 Hz, 2H), 4.04 (s, 2H);19F NMR (471 MHz, CDCI3) 6 -111.34.

[0881] Step 3. Synthesis of 3, 3-Bis(3-fluorophenyl)cyclobutan-l-one. (2-4)

[0882] A mixture of 2,2-dichloro-3,3-bis(3-fluorophenyl)cyclobutan-l-one (2-3, 1.50 g, 4.58 mmol) and zinc (1.20 g, 18.3 mmol) in acetic acid (11.8 mL) was stirred at room temperature for 2 h and 80 °C for 1 h. The mixture was cooled, filtered through diatomaceous earth and washed with diethyl ether (50 mL) and water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford 3,3-bis(3-fluorophenyl)cyclobutan-l-one (2-4, 1.14 g, 96%) as a pale yellow solid: 'H NMR (500 MHz, CDCI3) 6 7.34-7.30 (m, 2H), 7.09-7.07 (m, 2H), 6.97-6.93 (m, 4H), 3.78 (s, 4H);19F NMR (471 MHz, CDCI3) 6 -111.80. Step 4. Synthesis of 2, 2-Bis(3-fluorophenyl)-5, 7 -diazaspiro[3.4loctane-6,8-dione. (2-5)

[0883] To a solution of 3,3-bis(3-fluorophenyl)cyclobutan-l-one (2-4, 0.650 g, 2.52 mmol) in ethanol (2.0 mL) and water (2.0 mL) was added a solution of ammonium carbonate (1.21 g, 12.6 mmol) and potassium cyanide (0.213 g, 3.27 mmol) in water (5.6 mL). The mixture was irritated in the microwave at 105 °C for 30 min. Ethyl acetate (15 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (15 mL), brine (15 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was combined with 2 other batches of the same scale and recrystallized from dichloromethane to afford 2,2-bis(3- fluorophenyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (2-5, 2.08 g, 84%) as a white solid:JH NMR (500 MHz, DMSO-t / e) 8 10.53 (s, 1H), 8.27 (s, 1H), 7.35-7.19 (m, 6H), 6.98-6.93 (m, 2H), 3.40 (d, J= 14.0 Hz, 2H), 3.05 (d, J= 14.0 Hz, 2H).

[0884] Step 5. Synthesis of l-Amino-3,3-bis(3-fhiorophenyl)cyclobutane-l -carboxylic acid hydrochloride.

[0885] ( l

[0886] A mixture of 2, 2-bis(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (2-5, 0.927 g, 2.82 mmol) and sodium hydroxide (9.88 mL, 19.8 mmol, 2.0 M) was irradiated in the microwave at 140 °C for 40 min. Concentrated hydrochloric acid was added (pH 1-2) and the solid that formed was collected by filtration, washed with heptane (15 mL) and dried in vacuo to afford l-amino-3,3- bis(3-fluorophenyl)cyclobutane-l-carboxylic acid hydrochloride (2-6, 0.656 g, 68%) as a white solid: 'H NMR (500 MHz, DMSO-t / 6) 6 8.13 (br s, 2H), 7.35-7.20 (m, 6H), 6.98-6.90 (m, 2H), 3.46 (d, J= 13.5 Hz, 2H), 3.01 (d, J= 13.0 Hz, 2H);19F NMR (471 MHz, DMSO-t / 6) 6 -112.95, -

[0887] 113.33. Step 6. Synthesis of Methyl l-amino-3,3-bis(3-fhiorophenyl)cyclobutane-l -carboxylate hydrochloride (2-7)

[0888] To a suspension of l-amino-3,3-bis(3-fluorophenyl)cyclobutane-l-carboxylic acid hydrochloride (2-6, 0.656 g, 1.93 mmol) in methanol (17.8 mL) was carefully added thionyl chloride (0.423 mL, 5.79 mmol) and the mixture was sealed and heated at 65 °C for 2 h. The mixture was cooled and concentrated in vacuo to afford methyl l-amino-3,3-bis(3- fluorophenyl)cyclobutane-l -carboxylate hydrochloride (2-7, 0.640 g, 94%) as a white solid:JH NMR (500 MHz, DMSO-t / 6) 8 8.69 (br s, 3H), 7.43-7.40 (m, 1H), 7.36-7.30 (m, 4H), 7.21 (d, J= 8.0 Hz, 1H), 6.99-6.95 (m, 2H), 3.55 (dd, J= 12.5, 2.5 Hz, 2H), 3.46 (s, 3H), 3.16 (d, J= 12.5 Hz, 2H);19F NMR (471 MHZ, DMSO-t / 6) 6 -112.75, -113.04.

[0889] Example 3: Synthesis of 2,2-bis(3-fluorophenyl)-7-(l,6-naphthyridin-8-yl)-5,7- diazaspiro [3.4] octane-6, 8-dione (Compound 1)

[0890] Compound 1

[0891] To a degassed solution of 2, 2-bis(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (5, 0.100 g, 0.305 mmol) in 7V,7V-dimethylacetamide (1.0 mL) was added 8-bromo-l,6-naphthyridine (0.0637 g, 0.305 mmol) followed by copper(I) oxide (0.0436 g, 0.305 mmol). The mixture was sparged with argon and stirred at 165 °C sealed for 18 h. The mixture was cooled and ethyl acetate (25 mL) was added. The mixture was filtered through diatomaceous earth, washed with ethyl acetate (50 mL) and the filtrate was concentrated in vacuo to dryness. The residue was purified by chromatography (silica gel, 40 g, dry loading, 0-25% 90:9: 1 dichloromethane:methanol:concentrated aqueous ammonium hydroxide / dichloromethane, gradient elution, ELSD detection). The product was purified by chromatography (silica gel, 24 g, di chloromethane loading, 0-100% ethyl acetate / hexanes, gradient elution, ELSD detection). The product was purified by reverse phase chromatography (C18, 50 g, 1 : 1 acetonitrile: water loading, 0-100% acetonitrile with 0.05% vlv trifluoroacetic acid / water with 0.05% vlv trifluoroacetic acid, gradient elution, UV detection). The product was lyophilized from acetonitrile (3.0 mL) and water (4.0 mL) to afford 2,2-bis(3-fluorophenyl)-7-(l,6-naphthyridin-8-yl)-5,7-diazaspiro[3.4]octane- 6, 8-dione 2,2,2-trifluoroacetate (0.0177 g, 10%) as a pale yellow solid:JH NMR (500 MHz, DMSO-t / e) 8 9.50 (s, 1H), 9.15 (dd, J= 4.0, 1.5 Hz, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 8.69 (dd, J = 8.5, 2.0 Hz, 1H), 7.79 (dd, J= 8.5, 4.5 Hz, 1H), 7.39-7.35 (m, 3H), 7.31-7.26 (m, 3H), 7.02-6.98 (m, 1H), 6.94-6.89 (m, 1H), 3.62 (ddd, J = 32.0, 13.0, 3.0 Hz, 2H), 3.28 (dd, J= 22.5, 13.0 Hz, 2H);19F NMR (471 MHz, DMSO-t / 6) 6 -74.51, -112.67, -113.36; MS (ESI) m / z 457 [M + H]+; UHPLC: fe = 4.19 min, 98.8% (AUC) at 254 and fe = 4.18 min, 98.4% (AUC) at 215 nm.

[0892] Example 4: Synthesis of 2.2-Bis(3-fliioroplienyl)-7-(2-(2.2.2-trifliioroethyl)-2 / / -pyrazolo|4.3- c]pyridin-7-yl)-5,7-diazaspiro [3.4] octane-6, 8-dione 2,2,2-trifluoroacetate (Compound 2) To a suspension of 7-bromo-U / -pyrazolo[4,3-c]pyridine (4-1, 0.940 g, 4.75 mmol) in DMF (22.1 mL) at 0 °C was added cesium carbonate (1.55 g, 4.75 mmol). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.752 mL, 5.22 mmol) was added dropwise over 10 min and the mixture was stirred at room temperature for 18 h. The mixture was poured into ethyl acetate (50 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to dryness. The residue was purified by chromatography (silica gel, 80 g HP, dichloromethane loading, 0-80% ethyl acetate / heptane, gradient elution, ELSD detection) to afford 7-bromo-2-(2,2,2-trifluoroethyl)-2JT- pyrazolo[4,3-c]pyridine (4-3, 0.514 g, 39%) as the product: 'HNMR (500 MHz, CDCh) 8 9.13 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 5.14 (q, J= 8.5 Hz, 2H);19F NMR (471 MHz, DMSO-t / 6) 6 -70.65.

[0893] Step 2. Synthesis of l,l-Diphenyl-N-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo[4,3-c]pyridin-7- yDmethanimine. (4-4)

[0894] A suspension of 7-bromo-2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3-c]pyridine (4-3, 0.510 g, 1.82 mmol), benzophenone imine (0.456 mL, 2.73 mmol), palladium (II) acetate trimer (0.0410 g, 0.182 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.211 g, 0.364 mmol) and cesium carbonate (0.712 g, 2.19 mmol) in 1,4-dioxane (12.1 mL) was sparged with argon for 15 minutes and heated at 100 °C for 16 h. The mixture was cooled, filtered through diatomaceous earth, washed with ethyl acetate (2 x 2 mL) and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 40 g HP, dichloromethane loading, 0-100% ethyl acetate / heptane, gradient elution, ELSD detection) to afford l,l-diphenyl-A-(2-(2,2,2-trifluoroethyl)-2J7- pyrazolo[4,3-c]pyridin-7-yl)methanimine (4-4, 0.547 g, 79%) as a viscous yellow oil: 'H NMR (500 MHz, CDCh) 6 8.79 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.24-7.17 (m, 6H), 5.05 (q, J= 8.5 Hz, 2H). Step 3. Synthesis of 2-(2,2,2-Trifluoroethyl)-2H-pyrazolo[4,3-clpyridin-7-amine (4-5)

[0895] To a suspension of l,l-diphenyl-7V-(2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3-c]pyridin-7- yl)methanimine (11, 0.518 g, 1.36 mmol) in 2-methyltetrahydrofuran (13.6 mL) was added hydrochloric acid (4.14 mL, 8.28 mmol, 2.0 N) and the mixture was stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added, the aqueous layer was separated and concentrated in vacuo to dryness. The residue was triturated with diethyl ether (20 mL) for 20 min. The solid that formed was collected by filtration, washed with diethyl ether (2 x 4 mL) and dried in vacuo at 45 °C for 16 h to afford 2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3-c]pyridin-7-amine (4-5, 0.283 g, 82%) as an off-white solid: *H NMR (500 MHz, DMSO-t / 6) 8 15.24 (br s, 1H), 9.27 (s, 1H), 8.92 (s, 1H), 7.45 (s, 1H), 6.87 (br s, 2H), 5.76 (d, J= 8.5 Hz, 2H).

[0896] Step 4. Synthesis of Methyl 3,3-bis(3-fluorophenyl)-l-(3-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo[4,3- cjpyridin- 7 -yl)ureido)cyclobutane-l -carboxylate ( 4-6)

[0897] To a mixture of methyl l-amino-3,3-bis(3-fluorophenyl)cyclobutane-l-carboxylate hydrochloride (7, 0.250 g, 0.707 mmol) in dichloromethane (6.4 mL) and saturated aqueous sodium bicarbonate (6.36 mL, 6.36 mmol) was added sodium bicarbonate (0.416 g, 4.95 mmol) and the mixture was stirred for 15 min. Triphosgene (0.0690 g, 0.233 mmol) was added and the mixture was stirred for 30 min. 2-(2,2,2-Trifluoroethyl)-2J / -pyrazolo[4,3-c]pyridin-7-amine hydrochloride (12, 0.179 g, 0.707 mmol) was added and the mixture was stirred at room temperature for 18 h. Dichloromethane (40 mL) and water (2 mL) were added and the organic layer, containing the precipitate, was separated and concentrated in vacuo. Dichloromethane (20 mL) was added and the product was collected by filtration and washed with dichloromethane (2 mL) and diethyl ether (2 x 2 mL) to afford methyl 3,3-bis(3-fluorophenyl)-l-(3-(2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3- c]pyridin-7-yl)ureido)cyclobutane-l -carboxylate (13, 0.160 g, 41%) as a white solid which was used directly in the next step.

[0898] Step 5. Synthesis of2,2-Bis(3-fluorophenyl)-7-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo]4,3-c]pyridin- 7-yl)-5, 7-diazaspiro [3.4] octane-6,8-dione 2,2,2-trifluoroacetate (Compound 1)

[0899] To a suspension of 3,3-bis(3-fluorophenyl)-l-(3-(2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3- c]pyridin-7-yl)ureido)cyclobutane-l -carboxylate (4-6, 0.160 g, 0.286 mmol) in THF (18.8 mL) at 0 °C was added sodium hydride (0.0690 g, 1.72 mmol, 60 wt% in mineral oil) and the mixture was stirred at 0 °C for 20 min. Trifluoroacetic acid (1.10 mL, 14.3 mmol) was added and the mixture stirred at 0 °C for 15 min and concentrated in vacuo to dryness. To the residue was added acetonitrile (5 mL) and the solution was washed with heptane (25 mL). The acetonitrile layer was separated and purified by reverse phase chromatography (Cl 8, 50 g, acetonitrile 2.5 mL loading, 2 injections, 0-95% acetonitrile with 0.05% v / v trifluoroacetic acid / water with 0.05% v / v trifluoroacetic acid, non-linear ramp, UV detection). The product was lyophilized from acetonitrile (2 mL) and water (2 mL) to afford 2,2-bis(3-fluorophenyl)-7-(2-(2,2,2-trifluoroethyl)-2J / -pyrazolo[4,3-c]pyridin-7-yl)- 5, 7-diazaspiro[3.4]octane-6, 8-dione 2,2,2-trifluoroacetate (Compound 2) (0.120 g, 66%) as a white solid: 'H NMR (500 MHz, DMSO-t / 6) 8 9.45 (br s, 1H), 9.13-9.12 (m, 1H), 8.99 (s, 1H), 8.28 (d, J= 2.5 Hz, 1H), 7.39-7.27 (m, 6H), 7.00 (td, J= 8.5, 2.5 Hz, 1H), 6.95-6.91 (m, 1H), 5.69 (q, J= 8.5 Hz, 2H), 3.58 (d, J = 13.5 Hz, 2H), 3.25 (d, J= 14.0 Hz, 2H);19F NMR (471 MHz, DMSO-tfc) 6 -69.29, -74.56, -112.67, -113.34; MS (ESI) m / z 528 [M + H]+and 526 [M - H]"; HPLC: fe = 5.85 min, >99% (AUC) at 254 and at 220 nm, fe = 5.93 min, >99% (AUC) ELSD. Example 5: Synthesis of 2,2-Bis(3-fluorophenyl)-7-(2-(trifluoromethyl)-lH-pyrrolo[2,3- c]pyridin-4-yl)-5,7-diazaspiro [3.4] octane-6, 8-dione 2,2,2-trifluoroacetate (Compound 3)

[0900] 5-4 Compound 3

[0901] Step 1. Synthesis of l-(4-Bromo-2-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridin-3-yl)-2,2,2- trifluoroethan-l-one. (5-2)

[0902] To a solution of 5 -bromo-4-methylpyri din-3 -amine (5-1, 5.00 g, 26.7 mmol) in pyridine (134 mL) at 0 °C was added trifluoroacetic anhydride (12.3 mL, 88.0 mmol) dropwise over 3-4 min. The mixture was stirred at 0 °C for 10 min and at room temperature for 40 h. The solvent was removed in vacuo and water (150 mL) was added. The mixture was extracted with dichloromethane (2 x 200 mL) and the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 220 g, dry loading, 0-100% ethyl acetate / hexanes, gradient elution, ELSD detection) to afford l-(4-bromo-2-(trifluorom ethyl)- 17 / -pyrrolo[2, 3 -c]pyri din-3 -yl)-2, 2,2- trifhioroethan-l-one (5-2, 3.40 g, 35%) as a brown solid:JH NMR (500 MHz, DMSO-ifc) 5 14.63 (br s, 1H), 9.24 (s, 1H), 8.48 (s, 1H);19F NMR (471 MHz, DMSO-t / 6) 8 -59.36, -74.66. Step 2. Synthesis of l-(4-Bromo-2-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridin-3-yl)-2,2,2- trifluoroethan-l-one. (5-3)

[0903] A mixture of l-(4-bromo-2-(trifluoromethyl)-U / -pyrrolo[2,3-c]pyridin-3-yl)-2,2,2- trifluoroethan-l-one (5-2, 1.00 g, 2.77 mmol) and sodium carbonate (1.76 g, 16.6 mmol) in water (27.7 mL) was stirred at 80 °C for 18 h. To the mixture was added sodium carbonate (1.76 g, 16.6 mmol) and the mixture was stirred at 80 °C for 24 h. To the mixture was added sodium carbonate (1.76 g, 16.6 mmol) and the mixture was stirred at 80 °C for 72 h. The mixture was cooled and then extracted with dichloromethane (3 x 125 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford l-(4-bromo-2-(trifluoromethyl)- U / -pyrrolo[2,3-c]pyridin-3-yl)-2,2,2-trifluoroethan-l-one (5-3, 0.488 g, 67%) as a tan solid:JH NMR (500 MHz, DMSO-t / 6) 8 13.36 (br s, 1H), 8.89 (s, 1H), 8.40 (s, 1H), 7.10 (s, 1H);19F NMR (471 MHz, DMSO-ifc) 6 -59.66.

[0904] Step 3. Synthesis of 2, 2-Bis(3-fluorophenyl)-7-(2-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridin-4-yl)- 5, 7-diazaspiro[3.4]octane-6,8-dione. (5-4)

[0905] 5-4

[0906] To a degassed solution of 2, 2-bis(3-fhiorophenyl)-5,7-diazaspiro[3.4]octane-6, 8-dione (2- 5, 0.269 g, 0.821 mmol) in A'A -di methyl acetamide (2.1 mL) was added copper(I) oxide (0.078 g, 0.55 mmol) followed by 4-bromo-2-(trifluorom ethyl)- U / -pyrrolo[2, 3 -c]pyri dine (5-3, 0.145 g, 0.547 mmol). The mixture was sparged with argon and stirred at 165 °C sealed for 17 h. The mixture was cooled, filtered through diatomaceous earth and washed with ethyl acetate (4 x 20 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by chromatography (silica gel, 40 g, dry loading, 0-15% methanol / dichloromethane, gradient elution, ELSD detection). The product was dissolved in methanol (8.0 mL) and purified by reverse phase chromatography (C18, 150 g, methanol loading, 0-100% acetonitrile with 0.05% v / v trifluoroacetic acid / water with 0.05% v / v trifluoroacetic acid, gradient elution, UV detection) and lyophilized from acetonitrile (8.0 mL) and water (6.0 mL). The product was purified by chromatography (silica gel, 40 g, dry loading, 0- 100% ethyl acetate / hexanes, gradient elution, ELSD detection) to afford 2,2-bis(3-fhiorophenyl)- 7-(2-(trifluoromethyl)-U / -pyrrolo[2,3-c]pyridin-4-yl)-5,7-diazaspiro[3.4]octane-6, 8-dione (5-4, 0.087 g, 31%) as an off-white solid: 'H NMR (500 MHz, DMSO-t / 6) 6 13.13 (br s, 1H), 8.96 (s, 1H), 8.91 (br s, 1H), 8.18 (br s, 1H), 7.39-7.25 (m, 6H), 7.02-6.92 (m, 3H), 3.63 (d, J= 14.5 Hz, 2H), 3.22 (d, J = 14.5 Hz, 2H);19F NMR (471 MHz, DMSO-t / 6) 6 -59.58, -112.68, -113.31; MS (ESI) m / z 513 [M + H]+and 511 [M - H]"; UHPLC: fe = 4.33 min, >99% (AUC) at 254 and at 215 nm.

[0907] Step 4. Synthesis of 2, 2-Bis(3-fluorophenyl)-7-(2-(trifluoromethyl)-lH-pyrrolo [2, 3-c]pyridin-4-yl)-

[0908] 5, 7 -diazaspirol 3.4 loclane-6, 8-dione 2,2,2-trifluoroacetate (Compound 3)

[0909] 5-4 Compound 3

[0910] To a solution of 2,2-bis(3-fluorophenyl)-7-(2-(trifluoromethyl)-lJ / -pyrrolo[2,3-c]pyridin-4-yl)- 5, 7-diazaspiro[3.4]octane-6, 8-dione (5-4, 0.087 g, 0.17 mmol) in dichloromethane (3.0 mL) was added a solution of trifluoroacetic acid (0.026 mL, 0.34 mmol) in dichloromethane (3.0 mL). The solution was concentrated to dryness in vacuo and solvent exchanged with dichloromethane (5 mL) and acetonitrile (5 mL). The product was lyophilized from acetonitrile (8 mL) and water (6 mL) to afford 2,2-bis(3-fluorophenyl)-7-(2-(trifluoromethyl)-U / -pyrrolo[2,3-c]pyridin-4-yl)-5,7- diazaspiro[3.4]octane-6, 8-dione 2,2,2-trifluoroacetate (Compound 3, 0.120 g, >99%) as an off- white solid: 'HNMR (500 MHz, DMSO-t / 6) 8 13.60 (br s, 1H), 9.05 (br s, 1H), 9.02 (s, 1H), 8.29 (br s, 1H), 7.39-7.25 (m, 6H), 7.14 (s, 1H), 7.02-6.92 (m, 2H), 3.63 (d, J= 14.5 Hz, 2H), 3.23 (d, J= 14.0 Hz, 2H);19F NMR (471 MHz, DMSO-6 / 6) 5 -59.83, -74.52, -112.67, -113.31; MS (ESI) m / z 513 [M + H]+and 511 [M - H]"; UHPLC: fe = 4.29 min, >99% (AUC) at 254 and fe = 4.28 min, >99% (AUC) at 215 nm.

[0911] Example 6. Synthesis of 2,2-bis(3-fluorophenyl)-7-(2-fluoropyridin-3-yl)-5,7-dia- zaspiro[3.4]octane-6, 8-dione (Compound 13)

[0912] Step 1. Synthesis of Methyl 3,3-bis(3-fluorophenyl)-l-(3-(2-fluoropyridin-3-yl)ureido)cyclobutane- 1 -carboxylate (6-2)

[0913] In a round bottom flask, under nitrogen atmosphere, to a solution of triphosgene (998 mg, 3.36 mmol) in dry DCM (100 mL) was added dropwise a solution of 3-amino-2-fluoropyridine (6- 1) (889 pL, 9.61 mmol) and A,A-diisopropylethylamine (1.84 mL, 10.6 mmol) in dry DCM (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then a solution of 7 (3.05 g, 9.61 mmol) and MA-diisopropylethylamine (1.84 mL, 10.6 mmol) in dry DCM (100 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h 15 (LCMS monitoring indicated 38% conversion to desired product). The reaction mixture was heated at 40 °C for 1 h resulting in no evolution of the reaction. The mixture was cooled to room temperature then MA-diisopropylethylamine (1.84 mL, 10.6 mmol) was added and the solution was stirred at room temperature for 16 h. Aqueous saturated NH4CI (150 mL) was added to the reaction mixture. The layers were separated then the aqueous layer was extracted with DCM (2x). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness affording 6-2 (4.38 g, yield assumed to be quantitative) as a brown solid which was used without further purification in next step. LCMS analysis: Rt= 3.500 min, [M+H]+= 456

[0914] Step 2. Synthesis of 2,2-bis(3-fluorophenyl)-7-(2-fluoropyridin-3-yl)-5, 7-diazaspiro[3.4]octane-

[0915] 6,8-dione (Compound 13)

[0916] In a round bottom flask, under nitrogen atmosphere, to a solution of 6-2 was added sodium hydride (1.32 g, 32.9 mmol) portion wise at 0 °C. The reaction mixture was stirred at room temperature for 2 h (LCMS monitoring indicated 55% conversion). Sodium hydride (1.32 g, 32.9 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 20 h. To the reaction mixture was added slowly saturated aqueous NH4CI (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluent: 0 / 100 to 10 / 90 CH3CN / DCM) affording a white solid which was purified by Cl 8 flash column chromatography (eluent: 0 / 100 to 100 / 0 CHsCN / water) to provide Compound 13 (2.59 g, 59% yield) as a white solid. LCMS analysis: Rt= 3.450 min, [M+H]+= 424, [M-H]’= 422. 'H NMR (400 MHz, DMSO-4 8 ppm, JHz) 5 9.04 (s, 1H), 8.29 (ddd, J= 4.9, 1.8, 1.1 Hz, 1H), 8.03 (ddd, J = 9.6, 7.7, 1.9 Hz, 1H), 7.49 (ddd, = 7.7, 4.9, 1.2 Hz, 1H), 7.41-7.26 (m, 5H), 7.24 (dt, J= 8.0, 1.1 Hz, 1H), 7.03-6.90 (m, 2H), 3.56-3.52 (m, 2H), 3.24-3.16 (m, 2H).

[0917] The compounds in Table 1 were prepared according to the General Procedure:

[0918] Table 1. Example Non-limiting Compounds of Formula I

[0919] Example 7. Antiviral Activity

[0920] SARS-CoV-2 Mpro Inhibition Assay

[0921] SARS-CoV-2 Mpro inhibition assay was conducted by Reaction Biology Corporation. The assay was carried out in 50 mM Tris-HCl pH 7.3, 1 mM EDTA, 0.005% Triton X-100, 1% DMSO, 1 mM DTT in the presence of recombinant SARS-CoV-2 Mpro protein (GenBank accession: QHD43415, aa3264-3569) and 5 pM FRET peptide substrate [NH2-

[0922] C(EDANS)VNSTQSGLRK(DABCYL)M-COOH], Compounds were evaluated at 10 concentrations with a series of 3 -fold dilutions. In brief, the enzyme solution was added to the reaction wells, followed by the addition of test compounds in DMSO; the reaction mixture was preincubated at room temperature for 20 minutes, then the substrate solution was added to initiate the reaction; subsequently, enzyme activity was monitored by measuring the fluorescence signal generated from the fluorescently labeled peptide substrate every 5 minutes over a 120-minute period at room temperature; data were analyzed by calculating the slope (signal / time) of linear portion of measurement, slopes were determined using Microsoft Excel, and IC50 values were calculating by GraphPad Prism software.

[0923] Cellular Antiviral Activity Assays

[0924] Compounds were tested at 9 concentrations with a series of 3 -fold dilutions in all cellular antiviral activity assays.

[0925] The antiviral activity against SARS-CoV-2 was evaluated using SARS-CoV-2-NLuc (Nano-Luciferase reporter virus) (Xie et al., 2020) and A549-hACE2 cells in a biosafety level 3 (BSL-3) laboratory. In brief, A549-hACE2 cells were seed in white 96-well plates at a density of 1.0* 104cells per well; one day later, the compound and SARS-CoV-2 -NLuc virus were pre-mixed and added to the wells to infect the cells at a multiplicity of infection (MOI) of 0.1; after 48 hours of incubation at 37°C with 5% CO2, Nano-Gio substrate was directly added to the wells to detect Nano-Luciferase signals; EC50 values were calculating by GraphPad Prism software. Dose-response curves are provided for HCoV-OC43 (Figure 1), MERS-CoV (Figure 2), and HCoV-229E (Figure 3).

[0926] The antiviral assays for human coronavirus OC43 (HCoV-OC43) and Middle East respiratory syndrome coronavirus (MERS-CoV) were conducted using HCoV-OC43-NLuc (Nanoluciferase reporter virus with insertion in NS2 region) / A549-hACE2 cells and MERS-CoV-NLuc (Nano-luciferase reporter virus) (Sheahan et al., 2017) / A549-DPP4 cells, respectively. The procedures were similar to those described for the SARS-CoV-2-NLuc assay, with some modifications: the assay for HCoV-OC43 was conducted in a BSL-2 laboratory, while the assay for MERS-CoV was conducted in a BSL-3 laboratory.

[0927] The antiviral activity against human coronavirus 229E (HCoV-229E) was evaluated using HCoV-229E obtained from ATCC (Cat#: VR-740) and Huh7 cells in a BSL-2 laboratory. In brief, Huh7 cells were seed in clear black flat-bottom 96-well plates at a density of 1.0* 104cells per well; one day later, the compound and HCoV-229E virus were pre-mixed and added to the wells to infect the cells, achieving an infection rate of approximately 30% at 48 hours post-infection; after 48 hours of incubation at 33°C with 5% CO2, infected cells were stained with an anti-HCoV-229E Nucleocapsid primary antibody (Sino Biological, Cat#: 40640-T62) and a secondary Fluor™ Plus 488 antibody (Invitrogen, Cat#: A32731), while all cells were counterstained by Hoechst 33342 (Thermo Scientific, Cat#: 62249); images of each well were acquired by Celllnsight CX7, and the infection rate in each well was calculated as the ratio of the number of infected cells to the total cell number; EC50 values for reduction of the infection rate were determined by GraphPad Prism software.

[0928] For information on the assays, see generally: Sheahan, T. P., Sims, A. C., Graham, R. L., Menachery, V. D., Gralinski, L. E., Case, J. B., Leist, S. R., Pyre, K., Feng, J. Y., Trantcheva, I., Bannister, R., Park, Y., Babusis, D., Clarke, M. O., Mackman, R. L., Spahn, J. E., Palmiotti, C. A., Siegel, D., Ray, A. S., ... Baric, R. S. (2017). Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine, 9(396), eaal3653; and Xie, X., Muruato, A. E., Zhang, X., Lokugamage, K. G., Fontes-Garfias, C. R., Zou, J., Liu, J., Ren, P., Balakrishnan, M., Cihlar, T., Tseng, C.-T. K., Makino, S., Menachery, V. D., Bilello, J. P., & Shi, P.-Y. (2020). A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti- infective drugs for COVID-19. Nature Communications, 77(1), 5214. Table 2. Antiviral Activity of Compounds of Formula I against SARS-CoV-2

[0929] Table 3. Anti-coronavirus Activity of Compounds of Formula I

[0930] Example 8. hERG Inhibition Assay

[0931] Test articles were run in the FASTPatch® hERG Assay at Charles River Laboratories Cleveland, Ohio site. The assay consists of treating HEK293 cells stably expressing hERG potassium ion channels with test / control articles formulated in 0.3% dimethyl sulfoxide (DMSO) and analyzing on the QPatch II®, an automatic parallel patch clamp instrument.

[0932] Test articles are prepared to achieve a stock concentration of 10 mM in DMSO. Test articles are exposed to ion channels at 10 pM in 0.3% DMSO for a single concentration assessment, or 5 different concentrations (values of which are determined by single concentration hERG inhibition %) for an IC50 determination. Cisapride serves as a positive control in the assay and is exposed to ion channels at 0.05 pM, 0.3% DMSO. All experiments are performed at room temperature.

[0933] Using the QPatch robot pipetting system, vehicle is applied to naive cells in a QPlate for 5- 10 minutes prior to treatment with control / test article. Afterwards, test articles are applied to the QPlate in at least three intervals (n > 3) or two intervals (n > 2) for the positive control. The QPlate is prepared for a recording session and the onset and blocking of hERG currents are evaluated by using a stimulus voltage pattern consisting of a 500 ms prepulse to -40 mV (leakage subtraction), a 2-second activating pulse to +40 mV followed by a 2-second test pulse to 40 mV. In addition to measuring ion channel blockage, a TurboSol evaluation is performed to assess solubility of test articles.

[0934] Table 4. hERG Inhibition of Hydantoin Antiviral Compounds

[0935] Example 9. Microsomal Stability Assay

[0936] The assay is carried out in 96-well microtiter plates at 37°C. Reaction mixtures (25 pL) contain a final concentration of 0.1 pM test compound, 0.5 mg / mL liver microsomes protein, and 1 mM NADPH and / or 1 mM UDPGA (with alamethicin) in 100 mM potassium phosphate, pH 7.4 buffer with 3 mM MgCh. The incubation is performed in duplicate at each time point. At each of the time points (for example, 0, 15, 30, and 60 minutes), 150 pL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard is transferred to each well. Besides the zero minute controls, mixtures containing the same components except the NADPH can also be prepared as the negative control. Propranolol and Ensitrelvir are included as positive controls to verify assay performance. Plates are sealed, vortexed, and centrifuged at 4°C for 15 minutes at 4000 rpm. The supernatant is transferred to fresh plates for LC / MS / MS analysis.

[0937] All samples are analyzed on LC / MS / MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples are separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consists of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B).

[0938] The extent of metabolism is calculated as the disappearance of the test compound, compared to the 0-min time incubation. Initial rates are calculated for the compound concentration and used to determine ti / 2 values and subsequently, the intrinsic clearance, CLint = (0.693)(l / ti / 2 (min))(g of liver / kg of body weight)(mL incubation / mg of microsomal protein)(45mg of microsomal protein / g of liver weight).

[0939] Summarized conditions:

[0940] [Compound] = 0.1 pM

[0941] [LM] = 0.5 mg / mL

[0942] [NADPH] = 1 mM

[0943] Buffer = 100 mM Potassium Phosphate, pH 7.4 with 3 mM MgCh

[0944] Time = 0, 15, 30, and 60 min

[0945] Temperature = 37°C

[0946] Table 5. Microsomal Stability

[0947] Example 10. Plasma Stability Assay

[0948] Human or animal plasmas (by default K2 EDTA) are obtained from Bioreclamation. The assay is carried in 96-well microtiter plates. Compounds are incubated in duplicate at 37°C in the presence of plasma. Reaction mixtures (50 pL) contain a final concentration of 0.1 pM test compound. The extent of metabolism is calculated as the disappearance of the test compound, compared to the 0-min control reaction incubations. Propantheline is included as a positive control to verify assay performance.

[0949] At each of the four time points, 300 pL of quench solution (50% acetonitrile, 50% methanol, and 0.05% formic acid, warmed up at 37°C) containing internal standards is added to each well. Plates are sealed, vortexed, and centrifuged at 4°C for 15 minutes at 4000 rpm. The supernatant is transferred to fresh plates for LC / MS / MS analysis.

[0950] All samples are analyzed on LC / MS / MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples are separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (10 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consists of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B).

[0951] The extent of metabolism is calculated as the disappearance of the test compound, compared to the 0-min control reaction incubations. Initial rates are calculated for the compound concentration and used to determine ti / 2 values.

[0952] Summarized conditions'.

[0953] [Compound] = 0.1 pM

[0954] Time = 0, 0.5, 1, and 4 hours

[0955] Temperature = 37°C

[0956] Table 6. Plasma Stability

[0957] Example 11. Plasma Protein Binding Assay

[0958] The rapid equilibrium dialysis (RED) device inserts along with a Teflon base plate (Pierce, Rockford, IL) are used for the binding studies. Human or animal plasma is obtained commercially. The pH of the plasma is adjusted to 7.4 prior to the experiment.

[0959] DMSO stocks (0.5 mM) are spiked into the plasma to make a final concentration of 1 pM. If the recovery determination is requested, aliquots (100 pL) are transferred to a fresh 96-well deep-well plate as the T4 (recovery) samples. An equal volume of blank PBS buffer is added to the plate to make the matrix as 50:50 plasma:buffer. The T4 recovery samples are incubated at 37°C for 4 hours.

[0960] The spiked plasma solutions (300 pL) are placed into the sample chamber (indicated by the red ring); and 500 pL of PBS buffer, pH 7.4, is placed into the adjacent chamber. The plate is sealed with a self-adhesive lid and incubated at 37°C on an orbital shaker (250 rpm) for 4 hours. After 4 hours, from the RED plate, aliquots (100 pL) are removed from each side of the insert (plasma and buffer) and dispensed into the 96-well plate. Subsequently, 100 pL of blank plasma is added to the buffer samples and 100 pL of blank buffer is added to all the collected plasma samples. At last, 300 pL of quench solution (50% acetonitrile, 50% methanol, and 0.05% formic acid, warmed up at 37°C) containing internal standards is added to each well. Plates are sealed, vortexed, and centrifuged at 4°C for 15 minutes at 4000 rpm. The supernatant is transferred to fresh plates for LC / MS / MS analysis. Reference compound propranolol is included in every experiment.

[0961] All samples are analyzed on LC / MS / MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples are separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B).

[0962] The percentage of test compound bound to protein is calculated by the following equation: % Free = (Concentration in buffer chamber / Concentration in plasma chamber) x 100% % Bound = 100% - % Free

[0963] If requested, the percentage of test compound recovered can be calculated by the following equation:

[0964] % Recovery = (Concentration in buffer chamber*500 + Concentration in plasma chamber*300) / (Concentration in T4 sample*300) x 100%

[0965] In screen mode, no calibration curve is needed. Ratios of the peak areas of analytes over internal standard, instead of concentrations, are used for calculation. All the samples are diluted by quench solution to around 400 nM to be within compounds’ linear ranges.

[0966] Summarized conditions:

[0967] [Compound] = 1 pM

[0968] Time = 4 hours

[0969] Temperature = 37°C Table 7. Plasma Protein Binding

[0970] Example 12. Comparative Data

[0971] Comparative hERG Inhibition

[0972] Compounds of Formula I were tested against comparator compounds for inhibition of the ion channel hERG. The results are presented in Table 8, below.

[0973] Table 8. Comparative hERG Inhibition Data

[0974] Comparative Anti-coronavirus Activity

[0975] Compound 5 was tested against four comparator compounds which differ only at the substitution of the hydantoin. Relative Activity is the fold superiority of Compound 5 over the comparative compounds. Table 9. Comparative Activity of Diaryl-substituted Hydantoin Compounds

[0976]

[0977] Table 10. 3-Chloropyridine Substituted Hydantoin Compounds

[0978] Table 11. 1,6-Napthyridine Substituted Hydantoin Compounds

[0979] This specification has been described with reference to embodiments of the invention. Given the teaching herein, one of ordinary skill in the art will be able to modify the invention for a desired purpose and such variations are considered within the scope of the invention.

Claims

1. CLAIMSWhat is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Het is selected fromis a five- to eight-membered aryl or heteroaryl ring, and wherein R3, when present, is only bound to carbon and R33, when present, is only bound to nitrogen; x, y, and z are independently selected from 0, 1, 2, and 3 as allowed by valence; p is selected from 0, 1, and 2, based on the number of nitrogen atoms that can be substituted based on valence;R1and R2are each independently selected at each instance from hydrogen, -F, -Cl, -CF3,-CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;R3is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -Ci-3alkyl, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2;R33is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;R5is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2.6alkenyl, -C2.6alkynyl, -C(O)Ci-C6alkyl, -C(O)C2-C6alkenyl, -C(O)C2-C6alkynyl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3J-CF2CF2H, -CF2CFH2, and -CF2CF3;R6is independently selected at each instance from hydrogen, -Ci-Cealkyl, -C2-Cealkenyl, -C2-C6alkynyl, -OR7and -N(R5)2;R7is independently selected at each instance from hydrogen, -Ci-ealkyl, -C2-6alkenyl, -C2-6 alkynyl, -Ci-6alkoxy, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, and -CF2CF3;R11and R12are each independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -NO2, -CN, -COR6, -N(R5)COR6, -SOR6, -SO2R6, -N(R5)SOR6, -N(R5)SO2R6, -OSOR6, -OSO2R6, -OR5, -SR5, and -N(R5)2; andR13is selected from -H and -F.

2. The compound of claim 1, wherein x is 1.

3. The compound of claim 1, wherein x is 2.

4. The compound of claim 1, wherein x is 3.

5. The compound of any one of claims 1-3, wherein y is 1.

6. The compound of any one of claims 1-3, wherein y is 2.

7. The compound of any one of claims 1-3, wherein y is 3.

8. The compound of claim 1, selected frompharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8, wherein R13is -H.

10. The compound of any one of claims 1-8, wherein R13is -F.

11. The compound of any one of claims 1-10, wherein R1is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3,-CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -F, -Cl,-O-Ci-6alkyl, -O-CF3, and -O-CH2CF3.

12. The compound of any one of claims 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, and -O-Ci-ealkyl.

13. The compound of any one of claims 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, -O-Ci-ealkyl, -O-CF3, and -O-CH2CF3.

14. The compound of any one of claims 1-10, wherein R1is independently selected at each instance from hydrogen, -F, -Cl, and -O-Ci-ealkyl.

15. The compound of any one of claims 1-10, wherein R1is F.

16. The compound of any one of claims 1-15, wherein R2is independently selected at each instance from hydrogen, -CF3, -CF2H, -CFH2, -CH2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, -CHFCH3, -CHFCFH2, -CHFCF2H, -CHFCF3, -CH2CF3, -CF2CF2H, -CF2CFH2, -CF2CF3, -F, -Cl,-O-Ci-6alkyl, -O-CF3, and -O-CH2CF3.

17. The compound of any one of claims 1-15, wherein R2is independently selected at each instance from hydrogen, -F, -Cl, -CF3, -CF2H, -CFH2, -CH2CF3, -C2F5, and -O-Ci-ealkyl.

18. The compound of any one of claims 1-15, wherein R2is independently selected at each instance from hydrogen, -F, -Cl, and -O-Ci-ealkyl.

19. The compound of any one of claims 1-15, wherein R2is F.

20. The compound of any one of claims 1-19, wherein Het21. The compound of any one of claims 1-20, whereinis a six membered het- eroaryl.17723. The compound of any one of claims 1-20, wherein is a five membered het- eroaryl.

25. The compound of claim 23 or 24, wherein17827. The compound of claim 23, wherein the compound is selected frompharmaceutically acceptable salt thereof.

28. The compound of claim 27 wherein the compound is selected frompharmaceutically acceptable salt thereof.17929. The compound of claim 27, wherein the compound is selected frompharmaceutically acceptable salt thereof.

30. The compound of claim 27, wherein the compound is selected frompharmaceutically acceptable salt thereof.

31. The compound of claim 27, wherein the compound is selected frompharmaceutically acceptable salt thereof.

32. The compound of claim 24, wherein the compound is selected from33. The compound of claim 32, wherein the compound is selected frompharmaceutically acceptable salt thereof.

34. The compound of claim 32, wherein the compound is selected frompharmaceutically acceptable salt thereof.18135. The compound of claim 32, wherein the compound is selected fromacceptable salt thereof.

36. The compound of claim 32, wherein the compound is selected fromacceptable salt thereof.

37. The compound of any one of claims 23-36, wherein R33is hydrogen38. The compound of any one of claims 23-36, wherein R33is Ci-ealkyl.

39. The compound of any one of claims 23-36, wherein R33is -CH2CF3.

41. The compound of claim 40, wherein the compound is selected frompharmaceutically acceptable salt thereof.

42. The compound of claim 40, wherein the compound is selected frompharmaceutically acceptable salt thereof.

43. The compound of claim 40, wherein the compound is selected frompharmaceutically acceptable salt thereof.

44. The compound of claim 40, wherein the compound is selected from184or a pharmaceutically acceptable salt thereof.

45. The compound of claim 40, wherein the compound is selected from47. The compound of claim 46, wherein the compound is selected fromor a pharmaceutically acceptable salt thereof.

48. The compound of claim 47, wherein the compound is selected from186pharmaceutically acceptable salt thereof.

50. The compound of claim 1, wherein the compound is selected from18751. The compound of claim 1, wherein the compound is selected fromor a pharmaceutically acceptable salt thereof.

52. The compound of claim 1, wherein the compound is selected from188pharmaceutically acceptable salt thereof.

53. The compound of claim 1, selected frompharmaceutically acceptable salt thereof.

54. The compound of claim 53, selected from189pharmaceutically acceptable salt thereof.

55. The compound of claim 53, selected frompharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

57. A method of treating a coronavirus infection in a human in need thereof comprising administering an effective amount of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the coronavirus is SARS-CoV-2.

59. A compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, for use as a medicament.

60. A compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, for use in the treatment of a coronavirus infection.

61. The compound for use of claim 60, wherein the coronavirus is SARS-CoV-2.19062. A use of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a coronavirus infection.

63. The use of claim 62, wherein the coronavirus is SARS-CoV-2.191

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