WO2021194991A1

WO2021194991A1 - Use of losmapimod for treatment of covid-19

Info

Publication number: WO2021194991A1
Application number: PCT/US2021/023526
Authority: WO
Inventors: Owen Brendan Wallace; Diego CADAVID
Original assignee: Fulcrum Therapeutics, Inc.
Priority date: 2020-03-22
Filing date: 2021-03-22
Publication date: 2021-09-30

Abstract

Methods of using Losmapimod to treat SARS-CoV-2 infection and related diseases and disorders, including COVID-19, are disclosed.

Description

USE OF LOSMAPIMOD FOR TREATMENT OF COVID-19

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority to U.S.S.N. 62/993,013 filed March 22, 2020, which is incorporated herein by reference in its entirety.

BACKGROUND

[002] A new disease called coronavirus disease 2019 (C OVID- 19) has recently been reported globally. As of March 19, 2020, about 209,839 caseshad been confirmed with genetic testing, and 8778 deaths worldwide. Reported illnesses have ranged from mild symptoms to severe illness and death for confirmed C OVID- 19 cases. Primary symptoms of the disease often appear 2 - 14 days after exposure, which may include fever, cough, and shortness of breath. COVID-19 has been shown to affect all age groups, with higher fatality rates noted in elderly patients and those with comorbidities, highlighting the need for agents to address the novel virus.

[003] In late December 2019, local health facilities reported a cluster of patients with pneumonia that had been epidemioiogically finked to a seafood market in Wuhan, China. In response, the Chinese Center for Disease Control and Prevention (China CDC) conducted an epidemiological and etiologic investigation, which identified a novel coronavirus in the cluster of patients with pneumonia. Human airway epithelial cel Is were used to isolate the novel coronavirus, named SARS-CoV-2 or 2019-nCoV, which forms a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily.

[004] Current management of COVID-19 in patients is largel}^ supportive, with respiratory failure from acute respiratory distress syndrome (ARDS) as the leading cause of mortality. Reports on the clinical (fever, confusion) and laboratory (hyperferritinemia, lymphopenia, prolonged prothombin time, elevated lactate dehydrogenase, elevated interleukin (E_) 6, elevated C-reaetive protein, elevated soluble CD25) features of critically ill patients infected with CO VID-19 suggest the presence of a cytokine storm syndrom eresulting in adult respiratory distress syndrome (ARDS) and multi-organ failure. Indeed, many of the diagnostic criteria for cytokine storm syndrome are reported present in those COVID-19 infected individuals under intensive care. Secondary_' haemophagocytic lymphohistiocytosis (sHLH) is a hy perinfl ammatory syndrome characterized by sudden and fatal hypercytokinaemia with multiorgan failure. A cytokine profile resembling sHLH is associated with COVID-19 disease severity, which is characterized by increased interleukin (IL)-2, EL-7, granulocyte-colony stimulating factor (GCSF), interferon-g inducible protein 10 (IP 10), monocyte chemoattractant protein I (MCP-1), macrophage inflammatory protein 1-a (MIP-la), and tumor necrosis factor-a (TNF-a). Furthermore, predictors of fatality from a retrospective, multi center study of COVID-19 cases in Wuhan, China identified statistically significant elevated ferritin (p<0.001)and EL-6 (p<0.001), suggesting that mortality may be due to vira!ly driven hy peri nfl ammati on .

[005] Thus, there is urgent need for safe, novel treatments to address COVID-

19 infections. The only available means of control currently are public health measures, which include isolation of suspected cases, quarantine of contacts, and personal protective equipment for high-risk individuals and health care workers. As a result, there is critical need to find effective treatments to address viral replication, ARDS, and hyperinflammation associated with COVID-19. The present disclosure meets this need.

SUMMARY

[006] In one embodiment, the present disclosure provides methods for treating a subject having, or considered at risk of developing, a disease or disorder resulting from infection by a SARS-CoV-2 virus, comprising administering to the subject an effecti ve am ount of a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof. In particular embodiments, the subjecthas been diagnosed with or is considered at risk of developing COVTD-19. In certain embodiments, the disease or disorder is associated with, or comprises symptoms resulting from, an immune response or inflammatory response in the subject. For example, in some embodiments, the disease or disorder is associated with, or comprises symptoms resulting from, elevated levels of interleukin-6 (IL~6), C-reactive protein, troponin, myoglobin, and/or D-dimer in the subject, optionally in the subject’s serum. In certain embodiments of the methods disclosed herein, the compound inhibits repl ication of the vims in the subj ect. in some embodiments, the compound inhibits translation of one or more SARS-CoV-2 viral protein in the subject, optionally wherein the SARS- CoV viral protein is selected from the group consisting of: spike glycoprotein trimer (S), nucieoprotein (N), membrane protein (M), and envelope small membrane protein pen tamer (E),

[007] In certain embodiments of the methods disclosed herein, the compound inhibits or reduces an inflammatory response in the subject, e.g. cytokine storm syndrome. In some embodiments, the inflammatory response comprises expression and/or release of one or more cytokines or chemokines by ceils of the subject. In some embodiments, the one or more cytokines or chemokines are selected from the group consisting of: interleukin (IL)-2, IL-6, IL-7, granulocyte-colony stimulating factor, interferon-g inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-ct, and tumor necrosis factor-a. In some embodiments, the one or more cytokine or chemokine comprises IL-6.

[008] In certain embodiments of the methods disclosed herein, the method inhibits the development of acute respiratory' distress syndrome (ARDS), sepsis, septic shock, coagulopathy, or a secondary infection in the subject.

[009] In certain embodiments of the methods disclosed herein, the method increases the time from onset of the disease or disorder to dyspnea in the subject, or reduces the duration of dyspnea in the subject.

[0010] In certain embodiments of the methods disclosed herein, the method inhibits damage to a lung of the subject, and/or inhibits or prevents respiratory failure in the subject.

[0011] In certain embodiments of the methods disclosed herein, the method inhibits damage tothe heart of the subject, and/or inhibits or prevents heart failure in the subject. [0012] In certain embodiments of the methods disclosed herein, the method inhibits, prevents orslows the progression of the disease or disorder. In some embodiments, the disease or disorder associated with infection by the SARS-CoV-2 virus is of mild severity, and the method inhibits progression of the disease or disorder to moderate or severe severity. In some embodiments, the disease or disorder associated with infection by the SARS-CoV-2 virus is of moderate severity, and the method inhibits or reduces progression of the disease or disorder to severe or critical severity. In some embodiments, the disease or disorder associated with infection by the SARS- CoV-2 vims is of severe severity, and the method inhibits or reduces progression of the disease or disorder to critical severity. In some embodiments, the disease or disorder associated with infection by the SARS-CoV-2 virus is of critical severity. In certain embodiments of the methods disclosed herein, the method reduces the likelihood of the disease or disorder resulting in death of the subject.

[0013] In certain embodiments of the methods disclosed herein, the method reduces the likelihood of the subject being hospitalized or admitted to an intensive care unit, and/or reducesthe duration of the subject being hospitalized or admitted to an intensive care unit. In certain embodiments, the method reduces the likelihood of the subject requiring intubation and mechanical ventilation, in certain embodiments of the methods disclosed herein, the method reduces the duration of shedding of the SARS- CoV-2 vims by the subject. In related embodiments, the method reduces the duration of time of required physical isolation or quarantine of the subject, e.g., by at least 3 days, at least five days, at least one week, at least two weeks, or at least one month.

[0014] In certain embodiments of the methods disclosed herein, the compound or pharmaceutically acceptable salt or solvate thereof is orally or parenteraliy administered tothe subject. In some embodiments, between about 1 mg and about 100 mg of the compound or pharmaceutically acceptable salt or solvate thereof is administered to the subject. In certain embodiments, the compound or pharmaceutically acceptable salt or solvate thereof is administeredto the subject once per day, twice per day, or three times per day. In one embodiment, about 15 mg of the compound or pharmaceutically acceptable salt or solvate thereof is orally administered to the subject twice a day. In one embodiment, about 7.5 mg of the compound or pharmaceutically acceptable salt or solvate thereof is orally administered to the subject twice a day.

[0015] In some embodiments of the methods disclosed herein, the compound or pharmaceutically acceptable salt or solvate thereof is administered to the subject in combination with one or more therapeutic agent, optionally an agent used to treat an infection with SARS- CoV-2 or COVID-19. In some embodiments, the one or more therapeutic agent comprises an anti-viral agent. In some embodiments, the one or more therapeutic agent is selected from the group consisting of: sarilumab, tociiizumab, remdesivir, favipiravir, chloroquine and metabolites thereof (optionally, hydroxychloroquine), oseltamivir, camostat, molnupiravir (MK-4482), and immunoglobulin therapy. In some embodiments, immunoglobin therapy is selected from intravenous immunoglobulin (IVIG), COVID-19 sera, anti-COVID-19 monoclonal antibodies, or blood transfusions using blood from recovered COVID-19 patients). In some embodiments, COVID-19 sera is sera obtained from individuals who have recovered from COVID-19 (e.g., human convalescent sera). In some embodiments, the anti-COVID-19 monoclonal antibody is selected from the group consisting of bamlanivitnab, etesevimab, and combinations thereof.

[0016] In one embodiment, described herein is a method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula

or a pharmaceutically acceptable salt or prodrug thereof.

[00171 In another embodiment, described herein is a method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising orally administering to the patient about 10 mg to 20 mg, twice daily, of a compound represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

[0018] In some embodiments, the method comprises orally administering about 15 mg of the compound to the patient twice daily. In some embodiments, the disorder is an exaggerated acute inflammatory response, in some embodiments, the disorder is selected from the group consisting of COVID-19, cytokine storm syndrome, acute respiratory distress syndrome (ARDS), sepsis or septic shock, coagulopathy, respiratory failure, heart failure, dyspnea, and a secondary infection. In some embodiments, the patient is hospitalized having moderate or severe COVID-19 disease. In some embodiments, the patient is age 50 or older. In some embodiments, the method comprises administering one or more additional therapeutic agents to the patient. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: sarilumab, tocilizumah, remdesivir, favipiravir, chloroquine or metabolites thereof, oseltamivir, camostat, molnupiravir (MK-4482), and immunoglobulin therapy. In some embodiments, the immunoglobulin therapy is selected from the group consisting of intravenous immunoglobulin (IVIG), COVID-19 serum, anti-COVID-19 monoclonal antibody, and blood transfusions from recovered COVID-19 patients. In some embodiments, the anti-COVID-19 monoclonal antibody is selected from the group consisting of hamlanivimab, etesevimab, and combinations thereof.

DETAILED DESCRIPTION

[0019] The present disclosure is based, in part, on the discovery that the p38 kinase inhibitor, Losmapimod, is effective in treating diseases and disorders associated with SARS-CoV-2 infection, including but not limited to COVID-19. Accordingly, the disclosure provides methodsfor treating diseases and disorders associated with 8ARS- CoV-2 infection, such as COVID-19. Definitions

[0020] As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the content clearly dictates otherwise.

[0021] As used in this specification, the term "and/or" is used in this disclosure to either "and" or "or" unless indicated otherwise.

[0022] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, or integer or group of elements or integers but not the exclusion of any other element or integer or group of el ements or integers.

[0023] As used in this application, the terms "about" and "approximately" are used as equivalents. Any numerals used in this application with or without about/approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. In certain embodiments, the term "approximately" or "about" refers to a range of values that fail within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated referencevaiue unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0024] "Administration" refers herein to introducing an agent or composition into a sub_ject or contacting an agent or composition with a cell and/or tissue.

[0025] "Individual, " "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g, dogs, cats, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0026] A “combination therapy” is a treatment that includes the administration of two or more therapeutic agents, e.g., a compound of Formula I described herein and an antiviral agent. [0027] "Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may he exposed toor predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0028] "A therapeutically effective amount" means the amount of a compound that, whenadministered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0029] Certain compounds of the present disclosure may exist in stereo! som eric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). Some compounds may include more than one asymmetric carbon atoms. "Stereoisomer" refers to a compound that differ in orientation (R/S) about one or more asymmetric carbon atom(s), ordiffers in orientation (cis:trans) about a double bond. The term stereoisomer may also encompass atropisomers, which arise from hindered rotation about a single bond, e.g., in compounds having a substituted biphenyl moiety. An "enantiomer" is a compound that is a mirror image of another compound, i.e., all asymmetric carbon atoms of an enantiomer exist in opposite orientation (R/S) with respect to the other compound. A "diastereomer" is a compound that is not a mirror image of another compound, but includes one or more asymmetric carbon atoms existing in opposite orientation (R/S) with respect to the other compound. The embodiments of the present disclosure may include mixtures of stereoisomers, or may include a single stereoisomer. Single enantiomers or diastereomers may be prepared beginning with chiralreagents or by stereoselective or stereospeeific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographicor crystallization techniques.

[0030] "Isotopically-enriched" refers to a compound wherein one or more atoms is enrichedwith an isotope beyond its natural abundance. For example, the natural abundance of deuteriumis 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with aH atom, theH atom actually represents a mixture ofH and D, with about 0.015% being D. An isotopically-enriched compound may have one or more specific chemical sites wherein the H/D ratio is greater than 0.015%. An isotopically-enriched compound may be referred to as isotopicaily-labeied.

[0031] "Solvate" refers to an aggregate of a compound with one or more solvent molecules - a complex of variable stoichiometry formed by a solute and the solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. All such solvates are included within the scope of the present disclosure. For example, the solvent in any solvate described herein may include water,

[0032] "Prodrug" refers to a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.

[0033] "Pharmaceutically acceptable salt" is a salt that retains the biological effectiveness ofthe free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organi c bases, and inorganic and organic acids, to form a pharmaceutically acceptable sale. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present disclosure with a mineral or organic acid or an inorganic base. For example, salts of the present disclosure include, but are not limited to: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, deeanoat.es, caprylates, acrylates, formates, iso-butyrates, caproates, heptanoates, propiolates, oxalates, maionates, succinates, suberates, sebacates, fumarates, maleates, butyn-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitro~menzoat.es, hydroxybenzoates, methoxybenzoat.es, phthalates, sulfonates, xylenesulfonates, plieylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y- hydroxy butyrates, glycol fates, tartrates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and rnandelates. For example, salts of the present disclosure include, but are not limited to: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Esto!ate, Esylate, Fumarate, G!uceptate, Gluconate, Glutamate, Glycoilyiarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methyl sulfate, Monopotassium Maleate, Miicate, Napsylate, Nitrate, N-methylgiucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. For example, salts of the present disclosure include, but are not limited to: hydrochloric, sulfuric, phosphoric, diphosphoric, bydrobromic, and nitric or salts of organic adds such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxy ethyl sulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. For example, salts of the present disclosure include, but are not limited to: alkali metal salts: sodium salt, potassium salt and the like; alkaline earth metal salt: calcium salt, magnesium salt, barium salt, and the like; aluminum salt and the like. As a suitable example of a salt with an organic base, for example, there are salts with trimethy!amine, triethylamine, pyridine, picoline, 2,6-iutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethyienediamine and the like. As a suitableexample of a salt with an inorganic acid, for example, there are salts with hydrochloric acid, bydrobromic acid, nitric add, sulfuric acid, phosphoric acid and the like. As a suitable example of a salt with an organic acid, for example, there are salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. As a suitable example of a salt with a basic amino acid, for example, there are salts with alginine, lysine, ornithine and the like. As a suitable example of a salt with an acidic amino acid, for example, there are salts with aspartic acid, glutamic acid and the like.

Methods of Use

[0034] In several embodiments, a method for treating a disease or disorder associated with or resulting from infection by SARS-CoV-2 is provided. The method may include administering to a subject in need thereof, an effective amount, e.g., therapeutically effective amount of the p38 kinase inhibitor of Formula I:

or a stereoisomer thereof, an isotopically-enriched compound thereof a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof,

[0035] In certain embodiments, the subject is a mammal, e.g., a human. In some embodiments, the subject has been diagnosed with or is considered at risk of having or developing COVTD-19. In certain embodiments, the subject has an elevated level of one or more of: interleukin-6 (IL-6), C-reactive protein, troponin, myoglobin, and/or D- dimer. In certain embodiments, the elevated level is an elevated serum level.

[0036] In some embodiments, the methods may be practiced to inhibit or reduce one or more symptoms of a disease or disorder associated with or resulting from infection by SARS-CoV-2. Such symptoms include, but are not limited to inflammatory and/or immune responses of the infected subject.

[0037] In certain embodiments, an infected subject has increased levels of one or more cytokines, e.g., one or more of IL-2, IL-6, 1L-7, IL-10, IL-17, G-CDF, IP 10, MCP1, MIPla, or TNF-a. In some embodiments, the subject has an increased level of IL-6 or IL-17. The increased levelsof the one or more cytokines may be present in the serum of the subject. The increased levels of the one or more cytokines may be due to increased expression of the one or more cytokines by animmune cell of the subject, e.g., a monocyte, or by another type of cell, e.g., an epithelial cell, such as a lung epithelial cell. In particular embodiments, the method results in a decrease in the level or amount of one or more of these cytokines in an infected subject, as compared to the level or amount prior to administration of the compound of Formula 1 or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, in particular embodiments, the method results in a decrease in the level or amount of one or more of these cytokines in an infected subject, as compared to a predetermined level or amount, e.g., an average obtained from untreated subjects infected with SARS-CoV-2. The methods disclosed herein may also have prophylactic effects, in some embodiments, the method results in a reduced or dampened increase in the level or amount of one or more of these cytokines in an infected subject, as compared to the increase in the level or amount of the one or more cytokines that occurs when the subject is not administeredthe compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a reduced or dampened increase in the level or amount of one or more of these cytokines in an infected subject, as compared to a predetermined increase in the level or amount, e.g., an average obtained from untreated subj ects infected with SARS-CoV-2.

[0038] In some embodiments, the disease or disorder, or associated symptom is cytokine storm syndrome. In some embodiments, the cytokine storm syndrome is associated with one or more clinical (e.g., fever, confusion) and/or laboratory (e.g., hyperferritinemia, lymphopenia, prolonged prothrombin time, elevated lactate dehydrogenase, elevated interleukin (IL)~6, elevated C-reactive protein, elevated soluble CD25) characteristic or symptom. In some embodiments, the cytokine storm syndrome is associated with increased levels of one or more or interleukin (lL)-2,IL-7, granulocyte- colony stimulating factor (GCSF), interferon-g inducible protein 10 (IP 10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein la (MIP-la), and/or tumor necrosis factor-a (TNF-a). In particular embodiments, the method results in a decrease in the characteristics or severity of cytokine storm syndrome in an infected subject, as compared to the characteristics or severity prior to administration of the compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the method results in a decrease in the characteristics or severity' of cytokine storm syndrome in an infected subject, as compared to a predetermined level or amount of such characteristics or severity, e.g., an average obtained from untreated subjects infected with SARS-CoV-2. The methods disclosed herein may also have prophylactic effects. In some embodiments, the methodresuits in a reduction in the characteristics or severity of cytokine storm syndrome, or preventionof cytokine storm syndrome, in an infected subject, as compared to the amount of characteristics or severity of cytokine storm syndrome that occurs when the subject is not administered the compound of Formula Ϊ or a stereoisomer thereof, an isotopical !y- enriched compound thereof, a prodrug thereof a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a reduction in the characteristics or severity of cytokine storm syndrome in an infected subject, as compared to a predetermined level of the characteristics or severity of cytokine storm syndrome, e.g., an average obtained from untreated subjects infected with SARS-CoV-2. [0039] In some embodiments, the disease or disorder, or associated symptom is secondary haemophagocytic lymphohistiocytosis (sHLH). In certain embodiments, the method results in a reduction of or a decrease in the severity of sHLH in an infected subject, as compared to the severity of sHLH prior to administration of the compound of Formula I or a stereoisomer thereof, an isotopically-emiched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a reduction of or a decrease in the severity of sHLH in an infected subject, as compared to a predetermined amount or severity' of sHLH, e.g., an average obtained from untreated subjects infected with SARS-CoV-2. The methods disclosed herein may also have prophylactic effects. In some embodiments, the method results in a reduction of or a decrease in the severity of sHLH in an infected subject, as compared to the amount or severity' of sHLH that occurs when the subject is not administered the compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a reduction of or a decrease in the severity' of sHLH in an infected subject, as compared to a predetermined amount, e.g., an average obtained from untreated subjects infected with SARS-CoV-2.

[0040] In certain embodiment, an infected subject has an increased level C- reactive protein. (CRP). Although CRP does not normally elevate significantly in mild viral respiratory infections, levels have shown to increase in severe cases, such as in avian influenza Hi M and H7N9, and during SAKS epidemics in 2003. A similar significant increase of CRP has also been reported inCOVID-19 patients. One possible explanation for this phenomenon is the overproduction of inflammatory cytokines that take part in the defense against the pathogen, but also cause more severe symptoms and damage in lung alveoli and stimulate CRP production. The increased levels of the one or snore cytokines may be present in the serum of the subject. The increased levels of the one or more cytokines may be due to increased expression of the one or more cytokines by an immune cell of the subject, e.g., a monocyte, or by another type of cell, e.g., an epithelial cells, such as a lung epithelial cell. In particular embodiments, the method results in a decrease in the level or amount of CRP in an infected subject, e.g., the serum of an infected subject, as compared to the level or amount prior to administration of the compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a decrease in the level or amount of CRP in an infected subject, as compared to a predetermined level or amount, e.g., an average obtained from untreated subjects infected with SARS-CoV-2. The methods disclosed herein may also have prophylactic effects. In some embodiments, the method results in a reduced or dampened increase in the level or amount of CRP in an infectedsubject, as compared to the increase in the level or amount of CRP that occurs when the subject is not administered the compound of Formula I or a stereoisomer thereof, an isotopically- enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. In particular embodiments, the method results in a reduced or dam pen edin crease in the level or amount of CRP in an infected subject, as compared to a predetermined increase in the level or amount, e.g., an average obtained from untreated subjects infected withSARS-CoV- 2

[0041] in some embodiments, the disease or disorder, or associated symptom is COVID-19, cytokine storm syndrome, CRP, acute respiratory distress syndrome (ARDS), sepsis or septic shock, coagulopathy, respiratory failure, heart failure, dyspnea, or a secondary infection. Each of these has been associated with infection by SARS- CoV-2 and/or with COVID-19, According to some embodiments, methods disclosed herein may be used to treat, inhibit, or reduce theseverity of any of these disorders, e.g., as compared to an untreated subject or a predetermined value, e.g., an average obtained from untreated subjects infected with SARS-CoV-2.

[0042] In certain embodiments, the methods disclosed herein may also be used to delay the onsetof or reduce the severity of any of the diseases, disorders, or symptoms disclosed herein. In certain embodiments, the delay of onset is at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, or at least ten days.

[0043] In certain embodiments, the methods disclosed herein are used to inhibit or prevent the progression of disease associated with SARS-CoV-2 infection (e.g., COVID- 19) from a less severe form to a more severe form. As used herein, mild form of the disease or disorder is defined as having systemic symptoms (e.g., fever, pain, fatigue, cough, sore throath) but without evidence of pulmonary_' involvement; moderate form of the disease or disorder is defined as having evidence of pulmonary involvement (e.g., cough or abnormalities visible on CXR examination or Chest CT examination) but without dyspnea or the need for supplemental oxygen; severe form of the disease or disorder is defined as having pulmonary' abnormalities with dyspnea and/or hypoxia requiring supplemental oxygen but not in need of intubation and mechanical ventilation; and critical form of the disease or disorder is defined as requiring admission to intensive care for mechanical ventilation and/or treatment of cardiomyopathy with low ejection fraction. In particular embodiments, methods disclosed herein may be practiced to prevent, inhibit, reduce, or delay the progression of the disease or disorder (e.g., COVID-19) from mild to moderate, severe, or critical; or from moderate to severe or critical; or from severe to critical. In related embodiments, the methods disclosed herein reduce the likelihood of the subject infected with SARS-CoV-2 from dying. Thus, any of the methods disclosed herein may be practiced to reduce morbidity and/or mortality of a subject infected with SARS-CoV-2, e.g., asubject having CO VID-19. Also, any of the methods disclosed herein may be practiced to enhance the longevity of a subject infected with SARS-CoV-2, e.g., a subject having COVID-19. In some embodiments, longevity is enhanced as compared to longevity in the absence of treatment with the compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0044] in related embodiments, the methods disclosed herein reduce the likelihood of the subject infected with SARS-CoV-2 from being hospitalized or admitted to an intensive care unit, in related embodiments, the methods disclosed herein reduce the duration of time that the subject infected with SARS-CoV-2 is hospitalized or admitted to an intensive care unit, in related embodiments, the methods disclosed herein reduce the likelihood of the subject infected with SARS-CoV-2 requiring intubation and m ech ani eal ventil ati on .

[0045] As discussed above, methods disclosed herein may be used to alter the response of an infected subject to the infection, e.g., the subject's inflammatory response to the infection. In other embodiments, methods disclosed herein may be practiced to inhibit or reduce the virulenceor amount of virus in an infected subject. In addition, methods disclosed herein may be practicedto reduce the duration of time that a subject is infected with SARS-CoV-2, or the duration of time that SARS-CoV-2 is measurably detected in the subj ect.

[0046] In some embodiments, methods disclosed herein comprising administering the compoundof Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof a prodrug thereof a solvate thereof or a pharmaceutically acceptable salt thereof to a subject infected with SARS-CoV-2, e.g., a patent diagnosed with or at risk of developing COVID-19, to inhibit one orrnore property or characteri stic of the virus, such as, e.g., viral replication, viral gene expression or viral shedding by the subject. [0047] Thus, in one embodiment, the disclosure provides a method of inhibiting replication of SARS-CoV-2 vims in a subject infected with SARS-CoV-2, comprising administering the compound of Formula I or a stereoisomer thereof an isotopically- enriched compound thereof, aprodrug thereof a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject.

[0048] In another embodiment, the disclosure provides a method of reducing or inhibiting expression of one or more SARS-CoV-2 proteins in a subject infected with SARS-CoV-2, comprising administering the compound of Formula Ϊ, or a stereoisomer thereof, an isotopically-enriched compound thereof a prodrug thereof a solvate thereof or a pharmaceutically acceptable salt thereof to a subject. In particular embodiments, the one or more SARS-CoV-2 proteins are selected from the group consisting of: the spike glycoprotein trimer (S), nucleoprotein (N), membrane protein (M), and envelope small membrane protein pentamer (E) of SARS-Co-V-2.

[0049] In another embodiment, the disclosure provides a method of reducing or inhibiting shedding of SARS-CoV-2 virus by a subject infected with SARS-CoV-2, comprising administering the compound of Formula I, or a stereoisomer thereof, an isotopically-enrichedcompound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject.

[0050] In particular embodiments of any of the methods disclosed herein related to inhibiting orreducing a value or characteristic, e.g., viral replication, viral shedding, viral gene expression levels, viral protein expression levels, or the amount or severity of a disease, disorder, or symptom, the reduction or inhibition is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0051] In particular embodiments of any of the methods disclosed herein related to a duration oftime, the duration of time may be, e.g., about 12 hours, one day, two days, three days, four days, five days, one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three montss,four months, six months, one year, or longer; and a reducti on in the duration of time may be, e.g., a reduction of at l east 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0052] In certain embodiments, any of the methods disclosed herein further comprising administering to the subject an additional therapeutic agent, e.g., an anti-viral agent. In certain embodiments, the therapeutic agent is any agent used to treat C OVID- 19 or to treat infection with a coronavirus, e.g,, SARS-CoV-2 vims. In particular embodiments, the additional therapeutic agent is selected from the group consisting of: sarilumab, tocilizumab, remdesivir,favipiravir, chloroquine and metabolites thereof (optionally, hydroxychloroquine), oseltamivirxamostat, molnupiravir (MK-4482), and immunoglobulin therapy (optionally, IVIG, COVED- 19 sera, anti-COVED-19 monoclonal antibodies, or blood transfusions using blood obtained from recovered COVID- 19 patients). In some embodiments, the anti-COVID-19 monoclonal antibody is selected from the group consisting of bamlanivimab, etesevimab, and combinations thereof, in some embodiments, intravenous immunoglobulin (IVIG) is a blood product prepared from the serum of human donors, e.g., between 1000 and 15,000 donors per batch. Inone embodiment, IVIG is used at a "replacement dose" of 200-400 mg/kg body weight, given approximately 3-weekly In particular embodiments, COVID-19 sera is sera obtained fromindividuals who have recovered from COVID-19 (e.g., human convalescent sera).

[0053] Furthermore, the di sclosure also provides, in part, methods of treating or ameliorating disorders resulting from infection by SARS-CoV-2 are disclosed. In one embodiment, described herein is a method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof,

[0054] In another embodiment, described herein is a method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising orally administering to the patient about 10 mg to 20 mg, twice daily, of a compound represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

[0055] In some embodiments, the method comprises orally administering about 15 mg of the compound to the patient twice daily. In some embodiments, the disorder is an exaggerated acute inflammatory' response. In some embodiments, the disorder is selected from the group consisting of COVID-19, cytokine storm syndrome, acute respiratory distress syndrome (ARDS), sepsis or septic shock, coagulopathy, respiratory_' failure, heart failure, dyspnea, and a secondary infection. In some embodiments, the patient is hospitalized having moderate or severe CQVID-19 disease. In some embodiments, the patient is age 50 or older, in some embodiments, the method comprises administering one or more additional therapeutic agents to the patient. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: sarilumab, tocilizumab, remdesivir, favipiravir, chloroquine or metabolites thereof, oseltamivir, camostat, molnupiravir (MK-4482), and immunoglobulin therapy. In some embodiments, the immunoglobulin therapy is selected from the group consisting of intravenous immunoglobulin (IVIG), COVID-19 serum, anti-CO VID- 19 monoclonal antibody, and blood transfusions from recovered COVID-19 patients. In some embodiments, the anti-COVHM9 monoclonal antibody is selected from the group consisting of bamlamvimab, etesevimab, and combinations thereof.

[0056] When the compound of Formula I, or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with the additional therapeutic agent, thetwo therapeutic agents may be administered at the same or different times, and either may be administered first. In certain embodiments, the compound of Formula I, or the stereoisomer thereof, isotopically- enriched compound thereof, prodrug thereof, solvate thereof, or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are present in the subject during an overlapping time period.

Compounds

[0057] Methods disclosed herein include administering to a subject in need thereof, an effective amount of the p38 kinase inhibitor of Formula I:

or a stereoi somer thereof, an i sot opi cal I y -enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The compound of Formula I is also referred to as Losmapimod. [0058] The methods disclosed herein may also be practiced using a modified compound of anyone of such compounds, e.g., the compound of Formula L including a modification having an improved, e.g., enhanced, greater, pharmaceutical solubility, stability, bioavailability and/or therapeutic index as a compared to the unmodified compound is also contemplated. The examples of modifications include but are not limited to the prodrug derivatives, and isotopicaliy-labeled compounds, e.g., deuterium-enriched compounds,

[0059] In certain embodiments, the modified compound is a prodrug form of the Compound ofFormuia I or any other compounds disclosed herein. Prodrugs, upon administration to a subject, will converted in vivo into active compounds of the present disclosure (Nature Reviews of Drug Discovery, 2008, 7:255). It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present disclosure. The prodrugs ofthe compounds of the present disclosure can be prepared by standard organic reaction, for example, by reacting with a carbamylating agent (e.g., 1,1 -acyl oxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further exampl es of methods and strategies of making prodrugs are described in Bioorganic and Medicinal Chemistry Leters, 1994, 4: 1985.

[0060] Certain isotopicaily-labelied compounds of Formula I (e.g., those labeled with ¾ and ¹⁴C) are useful in compound and/or substrate tissue distribution assays.

Tritiated (i.e., Ή) and carbon- 14 (i.e., ⁱ⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, Isotopicaily labelled compounds of the various Formulae can generally be prepared by followingprocedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopicaily labelled reagent for a non-isotopicaliy labelled reagent.

[0061] Deuterium-enriched compounds: deuterium (D or Ί I) is a stable, non- radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes H (hydrogen or protium), D (¾ or deuterium), and T (Ί f or tritium). The natural abundance of deuterium is 0.015%. One of ordinary' skill in the art. recognizes that, in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonemiched counterparts.

[0062] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In particular one, some, or all hydrogens may be deuterium. Radioactive isotopesmay be used, for instance for structural analysis or to facilitate tracing the fate of the compounds or their metabolic products after administration. By^¬ way of general example and without limitation, isotopes of hydrogen include deuterium and tritium and isotopes of carbon include C-13 and C-14.

[0063] It should be recognized that the compounds of the present disclosure may^¬ be present, and optionally administered in the form of salts, and solvates. For example, it is within the scope of the present disclosure to convert the compounds of the present disclosure into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acidsand bases in accordance with procedures well known in the art.

[0064] When the compounds of the present disclosure possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptabl e inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present disclosure include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, di gluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galacterate (from rnucic acid), gaiacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemi succinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesuifonate, iodide, isethionate, iso- butyrate, lactate, laetohionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility_' in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present disclosure.

[0065] When the compounds of the present disclosure possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of suchbases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkalineearth metal hydroxides such as barium and calcium hydroxides; alkali metal aikoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine. Also included are the aluminum salts of the compounds of the present disclosure. Further base salts of the present disclosure include, but are not limited to; copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chi oroprocaine, choline, N,N' -dibenzylethylenediamine (benzathine), di cyclohexyl amine, diethanolamine, 2-diethylaminoethanol, 2-dimethyiaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, iidocaine, lysine, meglumine, N~ methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethyl amine, tripropylamine and tris-(hydroxymethyl)-methyl amine (tromethamine). it should be recognized that the free acid formswill typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present disclosure. [0066] In one aspect, a pharmaceutically acceptable salt is a hydrochloride salt, hydrobromidesalt, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maieate, nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or mixtures thereof.

[0067] Compounds of the present disclosure that comprise tertiary nitrogen- containing groups may be quatemized with such agents as (Cl -4) alkyl halides, e.g., methyl, ethyl, iso-propyl andtert-butyl chlorides, bromides and iodides; di-(Cl~4) alky! sulfates, e.g., dimethyl, diethyl anddiamyl sulfates; alkyl halides, e.g., decyl, dodecyl, iauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (Cl -4) alkyl halides, e.g,, benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water- and oil-soluble compounds of the disclosure.

[0068] Amine oxides, also known as amine-N-oxide and N-oxide, of anti-cancer agents with tertiary nitrogen atoms have been developed as prodrugs (Mai. Cancer Therapy, 2004 Mar; 3(3):233-244). Compounds of the present disclosure that comprise tertiary nitrogen atoms may be oxidized by such agents as hydrogen peroxide (H202), Caro's acid or peracids like meta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.

[0069] Additional therapeutic agents that may be administered to a subject in combination with thecompound of Formula I include, but are not limited to, sarilumab, tocilizumab, remdesivir, favipiravir, chloroquine and metabolites thereof (optionally, hydroxychloroquine), oseltamivir, camostat, molnupiravir (MK-4482), and immunoglobulin therapy (optionally, IVIG, C OVID- 19 sera, anti-COVID-19 monoclonal antibodies, or blood transfusions from recovered COVID-19 patients), or prodrugs or pharmaceutically acceptable salts thereof. In some embodiments, the anti- COVTD-19 monoclonal antibody is selected from the group consisting of bamlanivimab, etesevimab, and combinations thereof.

[0070] Sarilumab is a human monoclonal antibody against the interleukin-6 receptor, and thesequences of the heavy and light chains present in sarilumab are known in the art.

[0071] Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R), and the sequences of the heavy and light chains present in sarilumab are known in the art.

[0072] in one embodiment, Remdesivir is a nucleoside analog having the structure shown below:

[0073] In one embodiment, Favipiravir is a pyrazinecarboxamide derivative having the structure shown below:

[0074] In one embodiment, Ch!oroquine has the structure shown below:

[0075] In one embodiment, Hydroxychloroquine has the structure shown below:

[0076] In one embodiment, Oseltamivir has the structure shown below:

[0077] in one embodiment, Camostat has the structure shown below:

Pharmaceutical Compositions

[0078] The disclosure encompasses pharmaceutical compositions comprising a compound of Formula I or a stereoisomer thereof, an isotopically-enriched compound thereof, a prodrug thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients, as well as other conventional pharmaceutically inactive agents. Any inert excipient that is commonly used as a carrier or diluent may be used in compositions of thepresent disclosure, such as sugars, polyalcohols, soluble polymers, salts and lipids. Sugars and polyalcohols which may be employed include, without limitation, lactose, sucrose, mannitol, andsorbitol. illustrative of the soluble polymers which may be employed are polyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran. Useful salts include, without limitation, sodium chloride, magnesium chloride, and calcium chloride. Lipids which may be employed include, without limitation, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.

[0079] In addition, the pharmaceutical compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxy-propyl cellulose, hydroxypropylmethyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch giycolate, Primogel), buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, ^’Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol, cyclodextrins), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabi sulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, bydroxypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium iauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyi cellulose, sodium Iauryl sulfate, methyl cellulose, hydroxy ethyl cellulose, carboxymethylcellulose sodium), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g,, ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

[0080] In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglyeoiic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc, Liposomal suspensions (including liposomes targeted to infected ceils with monoclonal antibodies to viral antigens) canaiso be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.8. Pat. No. 4,522,811.

[0081] Additionally, the disclosure encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the disclosure. For example, the compounds canbe in a crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.

[0082] When compounds according to the present disclosure exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skiliin this art, and include, but are not limited to, pH adjustment and salt formation, using co-solvents, such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA( 10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, such as polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), Solutol HS15 (20-50%), Vitamin E TPGS, and d-a-tocopheryl PEG 1000 succinate (20-50%), and using advanced approaches such as micelle, addition of a polymer, nanoparticle suspensions, and liposome formation,

[0083] A wide variety of administration methods may be used in conjunction with the compounds of the present disclosure. Compounds of the present disclosure may be administeredor coadministered topically, orally, parenteral!y, intraperitoneally, intravenously, intraarterially, transdermaliy, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery' (for example by catheter or stent), subcutaneously, intraadiposaily, intraarticularly, intrathecally, transmucosally, pulmonary, or parenterally, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly .In some embodiments, compounds of the present disclosure, e.g., a compound of Formula Ϊ, is administered directly into the stomach via a nasogastric tube, e.g., to a subject who is intubated.

[0084] The compounds according to the disclosure may also be administered or coadministered in slow release dosage forms. Compounds may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, syrups, emulsions, oils and the like. For parenteral administration, reconstitution of a [yophilized powder is typically used.

[0085] Suitable doses of the compounds for use in treating the di seases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary? evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.

[0086] in some embodiments, a compound of Formula I described herein may be administered ata dosage from about 1 mg to about 60 mg, or more. For example, the compound may be administered to a subject at a dosage of about 5, 10, 15, 20, 25, 40,

35, 40, 45, 50, 55, or 60 mg, or within a range between any of the proceeding values, for example, between about 30 mg and about 40 mg, between about 5 mg and about 20 mg, and the like. In another embodiment, a compound, e.g., a compound of Formula I, described herein may be administered at a dosage from about 1 mg to about 20 mg. For example, the compound may be administered to a subject at a dosage of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg, or within a range between any of the proceeding values, for example, between about 10 mg and about 15 mg, between about 6 mg and about 12 mg, and the like. In another embodiment, a compound described herein, e.g., a compound of Formula I, is administered at a dosage of about <15 mg. For example, a compound, e.g., a compound of Formula I may be administered at about 15 mg per day for 7 days for a total of 105 mg per week. For example, a compound, e.g,, a compound of Formula I, may be administered at about 10 mg twice per day for 7 days for a total of 140 mg per week. For example, a compound of Formula I may be administered at about 15 mg twice per day, optionally for about 7 days for a total of about 210 mg per week. In some embodiments, a compound of Formula I may be administered at about 15 mg twice per day for two weeks, optionally by oral administration. In some embodiments, a compound of Formula I may be administered at about 15 rng twice per day for three weeks, optionally by oral administration. In some embodiments, a compound of Formula 1 may be administered at about 15 mg twice per day for four weeks, optionally by oral administration. In some embodiments, a compound of Formula I may be administered at about 7.5 mg twice per day for about one week, two weeks, three weeks, or four weeks, optionally by oral administration. In some embodiments, a compound of Formula I may be administered at about 20 mg twice per day for about one week, two weeks, three weeks, or four weeks, optionally by oral administration. In some embodiments, a compound of Formula I described herein may be administered at a dosage from about 1 mg to about 100 mg, or more, e.g., once a day, twice a day, or three times a day, for about 5 days, about one week, about two weeks, about three weeks, about four weeks, or longer. In certain embodiments, a compound of Formula I is administered via a tapering dosing regimen, wherein the compound of Formula I is initially administered at a higher dosage (e g., 10-20 mg twice a day) for about one to two weeks, and is then subsequently administered at a lower dosage(e.g,,

2.5-7.5 mg twice a day) for about one to two weeks. In some embodiments, a subject is administered about 15 mg of a compound of Formula I twice a day for about 2 weeks, and then administered about 7.5 mg of a compound of Formula I twice a day for about the next 2 weeks. In some embodiments, the compound is administered orally.

[0087] In some embodiments, a method described herein comprises orally administering one or more tablets to the subject daily, wherein each tablet comprises about 5 mg to about 20 mg of the compound of Formula I In some embodiments, a method described herein comprises orally administering two tablets to the subject twice daily, wherein each tablet comprises about 5 mg to about 20 mg of the compound of Formula I. In some embodiments, a method described herein comprises orally administering two tablets to the subject twice daily, wherein each tablet comprises about 7.5 mg of the compound of Formula I.

[0088] In some embodiments, the dosages described herein may refer to a single dosage, a daily dosage, or a weekly dosage.

[0089] In some embodiment, a compound may be administered up to 120 mg per day.

[0090] In some embodiment, a compound may be administered up to 840 mg per week.

[0091] In some embodiment, a compound may be administered once per day. In anotherembodiment, a compound may be administered twice per day. In some embodiments, a compound may be administered three times per day. In some embodiments, a compound may befour times per day.

[0092] In some embodiments, a compound described herein may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times per week. In other embodiments, the compound is administered once biweekly.

[0093] In some embodiments, a compound described herein may be administered orally.

[0094] In some embodiments, a compound described herein may be administered orally at adosage of <15 mg once per day.

[0095] in some embodiments, the compound of Formula I may be administered orally at a dosage of <15 mg once per day.

[0096] In some embodiments, a compound described herein is administered orally at <15 mg twice per day.

[0097] In some embodiments, the compound of Formula I may be administered orally at adosage of <15 mg twice per day.

[0098] Other compounds disclosed herein may be administered at their routinely administereddosages, or at a lower dose, in some embodiments.

[0099] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the ait. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[00100] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors i ncluding type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the pati ent; and the parti cul ar disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effecti ve amount of the drug required to prevent, counter or arrest the progress of the condition,

[00101] The amount and frequency of administration of the compounds of the disclosure and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of theattending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.

Combination Therapy [00102] Compounds described herein, e.g., a compound of Formula I as defined herein, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as a SARS-CoV-2 viral infection or disorder resulting from a SARS-CoV-2 viral infection. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I as defined herein and one additional therapeutic agent is administered. In some embodiments, a compound of Formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by- administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula I as one therapeutic agent and one or more additional therapeutic agents such as an antiviral agent. For example, a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[00103] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. [00104] Non-limiting examples of additional therapeutic agents that can be used in combination with the compound of Formula I, or pharmaceutically acceptable salts, prodrugs, or solvates thereof, as described herein include sarilumab, tocilizumab, remdesivir, favipiravir, chloroquine and metabolites thereof (optionally, hydroxychloroquine), ose!tamivir, carnostat, molnupiravir (MK-4482), and immunoglobulin therapy (e.g., intravenous immunoglobulin (IVIG), COVID-19 sera, anti-CO VID-19 monoclonal antibodies, or blood transfusions using blood from recovered COVID-19 patients). In some embodiments, COVID-19 sera is sera obtained from individuals who have recovered from COVID-19 (e.g., human convalescent sera). In some embodiments, the anti-COVID-19 monoclonal antibody is selected from the group consisting of bamianivimab, etesevimab, and combinations thereof.

EXAMPLES

[00105] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described.it is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby, it is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure.

EXAMPLE 1. INHIBITION OF IL-6 PROTEIN EXPRESSION IN H UMAN MONOCYTES.

[00106] The ability of the compound of Formula I to inhibit expression of inflammatory cytokinesis demonstrated by quantifying protein expression levels of various inflammatory cytokines in mock-infected primary human monocyte-derived macrophage cells as compared to SARS-CoV- 2-infected primary human monocyte- derived macrophage cells, incubated in the presence of either DMSO or the compound of Formula I (Losmapimod). The expression levels of various cytokines, including IL- 2, IL-6, IL-7, IL-10, IL-17, G-CDF, IP 10, MCP1, MIPla, and TNF-a are determined utilizing ELISA, e.g., Human ELISA kit (Thermo Fisher Scientific, Waltham, MA, USA). It is expected that protein levels of these inflammatory cytokines, or a subset thereof, will be reduced in SARS-CoV-2-infected primary human monocyte-derived macrophage cells treated with the compound of Formula 1 (Losmapimod) as compared to those treated with DMSO, which demonstrates that the compound of Formula I is effective in inhibiting or reducing inflammation and/or an immune response in subjects infected with SARS-CoV-2.

EXAMPLE 2. INHIBITION OF VIRAL REPLICATION IN HUMAN EPITHELIAL CELLS.

[00107] The ability of the compound of Formula I to inhibit replication of the SARS-CoV-2 virus! s demonstrated using vims plaque assay kit (VIRAPUR, San Diego, CA, USA). The amount of SARS-CoV-2 viral replication is determined in mock- infected human lung epithelial cells and SARS-CoV-2 infected human lung epithelial cells, i ncubated in the presence of either DMSO or the compound of Formula I (Losmapimod). It is expected that the amount of viral replication willbe reduced in SARS-CoV-2 infected human lung epithelial cells treated with the compound of Formula I as compared to those treated with DMSO, which demonstrates that the compound of Formula I is effective in inhibiting or reducing SARS-CoV-2 replication in human cells.

EXAMPLE 3. INHIBITION OF VIRUS-SPECIFIC TRANSLATION IN H UMAN EPITHELIAL CELLS.

[00108] The ability' of the compound of Formula I to i nhibit virus-specific translation is demonstrated by labeling neosynthesized proteins in SARS-CoV-2 infected human lung epithelial ceils utilizing Easy Tag EXPRESS ³⁵S (Perkin Elmer, Waltham, MA, USA), and then identifying SARS-CoV-2 viral proteins using antibodies specific for the spike glycoprotein trimer (S), nucleoprotein (N), membrane protein (M), and envelope small membrane protein pentamer (E) of SARS-Co-V-2. The levels of neosynthesized viral proteins is determined in SARS-CoV-2 infected human lung epithelial cells, incubated in the presence of either DMSO orthe compound of Formula I (Losmapimod). It is expected that the amount of neosynthesized viral proteins will be reduced in SARS-CoV-2 infected human lung epithelial cells treated with the compound of Formula I as compared to those treated with DMSO, which demonstrates that the compound of Formula I is effective in inhibiting or reducing SARS-CoV-2 translation in human cells.

EXAMPLE 4. REDUCED SARS-CoV-2 SPECIFIC GENE EXPRESSION IN HUMAN EPITHELIAL CELLS.

[00109] The ability of the compound of Formula I to inhibit virus-specific gene expression is demonstrated using the real-time PCR assay panel for coronavirus (BIORAD, Hercules, CA, USA) to assess changes in gene expression in SARS-CoV-2 infected human lung epithelial cells. Viral gene expression levels measured include those of the genes encoding spike glycoprotein trirner (S), nucleoprotein (N), membrane protein (M), and envelope small membrane protein pentamer (E) of SARS-Co-V-2. The levels of viral gene expression is determined in SARS-CoV-2 infected human lung epithelial cells, incubated in the presence of either DMSO or the compound of Formula I (Losmapimod). It is expected that the gene expression levels will be reduced in SARS- CoV-2 infected human lung epithel ial ceils treated with the compound of Formula I as compared to those treated with DMSO, which demonstrates that the compound of Formula I Is effective in inhibiting or reducing SARS-CoV-2 gene expression in human cells,

EXAMPLE 5. INCREASED SURVIVAL IN MICE INFECTED WITH SARS- CoV-2.

[00110] The ability of the compound of Formula I to increase survival of mice infected with SARS-CoV-2 is demonstrated in 16-week old B ALB/c mice infected with SARS-CoV-2 (e.g., as described in Jiminez-Guardeno et al. PLoS Pathog 10(8): el004320). Mice are treated with the compound of Formula I or a vehicle control (untreated), and output of the study is quantified as percentage survival based on time post-infection (days). It is expected that percentage survival at various times post-infection will be higher for mice treated with the compound of Formula 1 as compared to those untreated or treated with vehicle control, thus demonstrating the compound of Formula i is effective in treating infection with SARS-CoV-2, such as COVED- 19, EXAMPLE 6. CYTOKINE ANALYSIS OF HUMAN BLOOD SAMPLES.

[00111] The ability of the compound of Formula 1 to inhibit or reduce pro- inflammatory cytokinelevels is demonstrated using the lymphocyte test kit (Beckman Coulter Inc_·., FL, USA) for lymphocyte subset analysis by flow cytometry. Plasma cytokines (IL-2, IL-4, IL-6, tumor necrosis factor (TNF)-a and interferon (IFN)-y) are detected by ELISA with human Thl/2 cytokine kit II (BD Ltd., Franklin Lakes, NJ, USA) in blood samples obtained from healthy human volunteers or patients infected with SARS-CoV-2, either treated with the compound of Formula I or untreated. It is expected that plasma cytokine levels will be reduced in samples obtained from patients treated with the compound of Formula I as compared to the plasma cytokine levels present in samples obtained from untreated patients, thus demonstrating that the compound of Formula I is effective in reducing or inhibiting an increase in cytokine levels and associated cytokine storm.

EXAMPLE 7. C-REACTIVE PROTEIN (CRP) ANALYSIS OF HUMAN BLOOD SAMPLES.

[00112] The ability of the compound of Formula I to inhibit or reduce C-reactive protein (CRP) levels is demonstrated using various analytical methods, such as ELISA, immunoturbidimetry, rapid immunodiffusion and visual agglutination. C-reactive protein (CRP) levels in blood samples obtained from healthy human volunteers or patients infected with SARS-CoV-2, either treated with the compound of Formula I or untreated, are measured using a HITACHI 7600-020 automated biochemistry' analyzer. It is expected that CRP levels will be reduced in samples obtained from patients treated with the compound of Formula I as compared to the plasma cytokine levels present in samples obtained from untreated patients, thus demonstrating that the compound of Formula I is effective in reducing or inhibiting CRP expression or stability.

EXAMPLE 8. INHIBITION OF CYTOPATHIC EFFECT OF SARS-CoV-2.

[00113] The ability of the compound of Formula I to inhibit or reduce the cytopathic effect(CPE) of infection by SARS-CoV-2 is demonstrated in L132 cells treated with various concentrations of the compound of Formula I or untreated, and subsequently adsorbed with SARS-CoV-2. At 72 h post-infection, the cells are stained with crystal violet and cell viability is measured. The absorbance of untreated ceils is calculated as 100%. It is expected that cells treated with the compound of Formula I will have a higher percentage viability than untreated ceils, thus demonstrating that the compound of Formula I is effective in reducing cell death due to infection with SARS-CoV-2.

EXAMPLE 9. LOSMAPIMOD EFFICACY IN COVID-19.

[00114] This study is a Phase 3, multicenter, randomized, double-blind, placebo- controlled study that evaluates the safety and efficacy of losmapimod versus placebo in subjects with C OVID- 19 disease.

[00115] Patients participate in this study for approximately 34 days. The total treatment duration is 14 days. Subjects are evaluated during a 3 day pre-treatment period (Screening and Baseline Visits) to establish pre-treatment baseline assessments and eligibility. Subjects are then randomized to treatment with losmapimod or placebo for 14 days and assessed frequently for changes from pre-treatment in various clinical outcome assessments. Patients must have a confirmed diagnosis of COV1D-19 by viral PCR prior to randomization and first dosing. Patients receive 15 mg of Losmapimod, or placebo twice daily given as two 7.5 mg tablets per dose by mouth: for a total of 4 pills or 30 mg daily for 14 consecutive days. Ail study visits during the first week of treatment are anticipated to he conducted in the inpatient setting while later visits are anticipated to be conducted as outpatient.

[00116] The primary endpoint of the study is to assess the efficacy of losmapimod tablets compared with placebo for the treatment of CQVID-19 when administered concurrently with the local standard of care. Secondary endpoints include evaluating the effect of losmapimod compared with placebo on clinical outcomes, clinical status, effect on survival, safety, and tolerability and to characterize changes in the levels of SARS-CoV-2 infection.

Equivalents

[00117] While the present disclosure has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. Ail such alternatives, modifications and variations are intended to fall within the spirit and scope of the present disclosure.

[00118] Furthermore, it is intended any method described herein may be rewritten into Swiss-type format for the use of any agent described herein, for the manufacture of a medicament, in treating any of the disorders described herein. Likewise, it is intended for anymethod described herein to be rewritten as a compound for use claim. [00119] For example, the disclosure encompasses use of a p38 kinase inhibitor, for themanufacture of a medicament, for treating or preventing COVED- 19, wherein the p38 kinase inhibitor is characterized by Formula I:

or a stereoisomer thereof, an isotopicaliy-emiched compound thereof, a prodmg thereof, asolvate thereof, or a pharmaceutically acceptable salt thereof [00120] All publications and patent applications described herein are hereby incorporatedby reference in their entireties.

Claims

What is claimed is:

L A method for treating a subject having, or at risk of developing, a disease ordisorder resulting from infection by a SARS-CoV-2 virus, comprising administering to the subject a therapeutical ly effective amount of a compound of Formula I:

2. The method of claim 1, wherein the subject has been diagnosed with or is considered at risk of developing COVID-19.

3. The method of claim 1 or claim 2, wherein the disease or disorder is associated with, orcomprises symptoms resulting from, an immune response or inflammatory response in thesubj ect.

4. The method of any of claims 1-3, wherein the disease or disorder is associated with, or comprises symptoms resulting from, elevated levels of interleukin-6 (IL-6), C-reactive protein, troponin, myoglobin, and/or D-dimer in the subject, optionally in the subject's serum.

5. The method of claim 4, wherein the disease or disorder is associated with, or comprises symptoms resulting from, elevated levels of P_-ό or C-reactive protein in the subject.

6. The method of any one of claims 1-5, wherein the compound inhibits replication of the virusin the subject.

7. The method of any one of claims 1-6, wherein the compound inhibits translation of one or more SARS-CoV-2 viral protein in the subject, optionally wherein the SARS-CoV viral protein is seiected from the group consisting of: spike glycoprotein trimer (S), nudeoprotein (N), membrane protein (M), and envelope small membrane protein pentamer (E).

8. The method of any one of claims 1-7, wherein the compound inhibits or reduces an inflammatory response in the subject.

9. The method of claim 8, wherein the inflammatory response is cytokine storm syndrome.

10. The method of claim 8 or claim 9, wherein the inflammatory response comprises expression and/or release of one or more cytokines or chemokines by cells of the subject.

11. The method of claim 10, wherein the one or more cytokines or chemokines are selected from the group consisting of: interleukin (IL,)~2, IL-6, IL-7, granulocyte-colony stimulating factor, interferon-g inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-a, and tumor necrosis factor-a.

12. The method of claim 11, wherein the one or more cytokines or chemokines comprises IL-6.

13. The method of any one of cl aims 1-11, wherein the method inhibits the devel opment of acute respiratory' distress syndrome (ARDS) in the subject.

14. The method of any one of claims 1-13, wherein the method inhibits the development ofsepsis, septic shock, and/or coagulopathy in the subject.

15. The method of any one of claims 1-14, wherein the method inhibits the development of a secondary_' infection in the subject.

16. The method of any one of claims 1-15, wherein the method increases the time from onset ofthe disease or disorder to dyspnea in the subject, or reduces the duration of dyspnea in the subject.

17. The method of any one of claims 1-16, wherein the method inhibits damage to a lung of thesuhject, optionally wherein the method inhibits or prevents respiratory failure in the subject.

18. The method of any one of claims 1-17, wherein the method inhibits damage to the heart ofthe subject, optionally wherein the method inhibits or prevents heart failure in the subj eel

19. The method of any one of claims 1-5, wherein the di sease or disorder associated with infection by the SARS-CoV-2 vims is of mild severity, and the method inhibits progression ofthe disease or disorder to moderate or severe severity.

20. The method of any one of claims 1-5, w^rherein the disease or disorder associated with infection by the SARS-CoV-2 virus is of moderate severity, and the method inhibits or reduces progression of the disease or disorder to severe or critical severity.

21. The method of any one of claims 1-5, wherein the disease or disorder associated with infection by the SARS-CoV-2 virus is of severe severity, and the method inhibits or reducesprogression ofthe disease or disorder to critical severity.

22. The method of any one of claims 1 -5, wherein the disease or disorder associated withinfection by the SARS-CoV-2 virus is of critical severity.

23. The method of any one of claims 1-5, wherein the method reduces the likelihood of the subject being hospitalized or admitted to an intensive care unit, and/or reduces the duration of the subject being hospitalized or admitted to an intensive care unit.

24. The method of any one of claims 1-5, wherein the method reduces the likelihood of thesuhject requiring intubation and mechanical ventilation.

25. The method of any one of claims 1-24, wherein the method reduces the likelihood of thedisease or disorder resulting in death of the subject,

26. The method of claim 1 or claim 2, wherein the method reduces the duration of shedding ofthe SARS-CoV-2 virus by the subject.

27. The method of claim 1 or claim 2, wherein the method reduces the duration of time of required physical isolation ofthe subject.

28. The method of any one of claims 1-27, wherein the compound or pharmaceuti cally acceptable salt thereof is orally administered to the subject.

29. The method of any one of claims 1-27, wherein the compound or pharmaceutical ly acceptable salt thereof is parenteral ly administered to the subject.

30. The method of any one of claims 1-29, wherein between 1 mg and 100 mg of the compound or pharmaceutically acceptable salt thereof is administered to the subject.

31. The method of any one of claims 28-30, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject once per day, twice per day, or three times per day.

32. The method of claim 30 or claim 31, wherein about 15 mg of the compound or pharmaceutically acceptable salt thereof is orally administered to the subject twice a day.

33. The method of claim 30 or claim 31, wherein about 7.5 mg of the compound or pharmaceutically acceptable salt thereof is orally administered to the subject twice a day.

34. The method of any one of claims 1-33, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subj ect in combination with one or more therapeutic agents.

35. The method of claim 34, wherein the one or more therapeutic agents is an antiviral agent.

36. The method of claim 34, wherein the one or more therapeutic agents is selected from the group consisting of: sarilumab, tociiizumab, remdesivir, favipiravir, chloroquine or metabolites thereof, oseltamivir, eamostat, molnupiravir (MK-4482), and i m mun og! obulin therapy .

37. The method of claim 36, wherein the immunoglobulin therapy is selected from the group consisting of intravenous immunoglobulin (IVIG), COVID-19 serum, anti-CQVID- 19 monoclonal antibody, and blood transfusions from recovered COVTD-19 patients.

38. The method of claim 37, wherein the anti-COVID-19 monoclonal antibody is selected from the group consisting of bamlanivimab, etesevimab, and combinations thereof.

39. A method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

40. A method of ameliorating or treating a disorder resulting from an infection caused by SARS-CoV-2 in a patient in need thereof, comprising orally administering to the patient about 10 mg to 20 mg, twice daily, of a compound represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

41. The method of claim 39 or 40, comprising orally administering about 15 rng of the compound to the patient twice daily.

42. The method of any one of claims 39-41, wherein the disorder is an exaggerated acute inflammatory response.

43. The method of any one of claims 39-42, wherein the disorder is selected from the group consisting of COVID-19, cytokine storm syndrome, acute respiratory distress syndrome (ARDS), sepsis or septic shock, coagulopathy, respiratory failure, heart failure, dyspnea, and a secondary infection.

44. The method of any one of claims 39-43, wherein the patient is hospitalized having moderate or severe COVID-19 disease.

45. The method of any one of claims 39-44, wherein the patient is age 50 or older.

46. The method of any one of claims 39-45, comprising administering one or more additional therapeutic agents to the patient.

47. The method of any one of claims 39-46, wherein the one or more additional therapeutic agents is selected from the group consisting of: sarilumab, tocilizumab, remdesivir, favipiravir, chloroquine or metabolites thereof, oseitamivir, camostat, molnupiravir (MK-4482), and immunoglobulin therapy.

48. The method of claim 47, wherein the immunoglobulin therapy is selected from the group consisting of intravenous immunoglobulin (IVIG), COVID-19 serum, anti-COVID- 19 monoclonal antibody, and blood transfusions from recovered COVID-19 patients.

49. The method of claim 48, wherein the anti-COVID-19 monoclonal antibody is selected from the group consisting of bamlanivimab, etesevimab, and combinations thereof.