Obeldesivir for the treatment of viral infections

Abstract

The present disclosure relates to methods for treating or preventing pneumoviridae infections in a patient comprising administering compound 1 a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof.

Description

Attorney Docket No. 1570-WO-PCTMETHODS FOR TREATMENT OF VIRAL INFECTIONSCROSS REFERENCE

[0001] This application claims priority to U.S Provisional Application No. 63 / 693,566 filed September 11, 2024. The entire contents of which application are incorporated herein in their entirety for all purposes.FIELD OF THE INVENTION

[0002] The present disclosure relates to methods for treating viral infections.BACKGROUND

[0003] There is a need for compounds and methods for treating viral infections, for example pneumoviridae infections.SUMMARY

[0004] Provide herein is a method of treating a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is:a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein compound 1, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice daily on a first day of administration, and a dosage of about 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.Attorney Docket No. 1570-WO-PCT

[0005] Provide herein is a method of preventing a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound which is:a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein compound 1, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice daily on a first day of administration, and a dosage of about 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.BRIEF DESCRIPTION OF DRAWINGS

[0006] FIG. 1 shows predicted intrinsic and extrinsic factors impacting PK.

[0007] FIG. 2 shows predicted RSV dosing regimen exposure.DETAILED DESCRIPTION

[0008] Obeldesivir (compound 1, ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate) is an antiviral agent,compound 1 and its methods of making it, as well as its salts and polymorph forms are described in WO 2022 / 047065 (Compound 15 of WO 2022 / 047065), which is incorporated herein by reference in its entirety.

[0009] Provided is a method of treating a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 1 :Attorney Docket No. 1570-WO-PCT(compound 1) a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein compound 1, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 700 mg / dose (on a free base basis) twice daily on a first day of administration, and a dosage of 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.

[0010] Alo provided is a method of preventing a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 1 :(compound 1) a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein compound 1, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 700 mg / dose (on a free base basis) twice daily on a first day of administration, and a dosage of 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.

[0011] In some embodiments, the method comprises administering to the patient a compound which is compound 1. In some embodiments, the method comprises administering to the patient a compound which is a pharmaceutically acceptable salt of compound 1. In some embodiments, the method comprises administering to the patient a compound which is a deuterated compound of compound 1. In some embodiments, the method comprises administering to the patient a compound which is a pharmaceutically acceptable salt of a deuterated compound of compound 1.Attorney Docket No. 1570-WO-PCT

[0012] Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the pneumoviridae infection is a respiratory syncytial virus infection or a human metapneumovirus infection. In some embodiments, the pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviridae virus infection is human metapneumovirus infection.

[0013] In some embodiments, the patient is suffering from a chronic respiratory syncytial viral infection. In some embodiments, the patient is acutely infected with RSV. In some embodiments, the present disclosure provides a method of inhibiting RSV replication. In some embodiments, the present disclosure provides a method for reducing the viral load associated with RSV infection.

[0014] In some embodiments, the patient has normal renal function. In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) of at least 90 mL / min / 1.73 m2. In some embodiments, the method further comprises determining that the patient has an eGFR of at least 90 mL / min / 1.73 m2prior to the administration.

[0015] In some embodiments, the patient has mild renal impairment. In some embodiments, the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2. In some embodiments, the method further comprises determining that the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2prior to the administration.

[0016] In some embodiments, compound 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof, is administered in a dosage of 700 mg / dose (on a free base basis) twice daily on a first day of administration, and in a dosage of 350 mg / dose (on a free base basis) twice daily on second to fifth day of administration. In some embodiments, compound 1 is administered in a dosage of 700 mg / dose twice daily on a first day of administration, and a dosage of 350 mg / dose twice daily on second to fifth day of administration.

[0017] In some embodiments, the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof is administered orally.

[0018] In some embodiments, the method comprises administering to the patient a tablet comprising(i) compound 1 in an amount of about 350 mg;(ii) microcrystalline cellulose in an amount of about 315 mg;(iii) crospovidone in an amount of about 28 mg; and(iv) magnesium stearate in an amount of about 7 mg.Attorney Docket No. 1570-WO-PCT

[0019] In some embodiments, the table comprises(i) compound 1 in an amount of 350 mg;(ii) microcrystalline cellulose in an amount of 315 mg;(iii) crospovidone in an amount of 28 mg; and(iv) magnesium stearate in an amount of 7 mg.

[0020] In some embodiments, two tablets are administered twice on the first day of administration, and one tablet is administered twice daily on each day of administration after the first day.

[0021] In some embodiments, the methods described herein comprise administering to the subject a loading dose or loading doses of compound 1 described herein, followed by administering a maintenance dose or maintenance doses of compound 1 on each subsequent day. The maintenance doses may be administered for as long as required, for example for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to a month or longer. In some embodiments, the maintenance doses is administered for about 6-12 days, for example for about example 8-10 days. In some embodiments, the maintenance doses are administered for about 4 days. In some embodiments, the once daily maintenance doses are administered for about 5 days. In some embodiments, the once daily maintenance doses are administered for about 9 days. In some embodiments, the once daily maintenance doses are administered for about 10 days.

[0022] In some embodiments, the administration of 700 mg of compound 1 results in a mean Cmax of about 1 gg / mL to about 50 gg / mL, about 1 gg / mL to about 40 gg / mL, about 1 gg / mL to about 30 gg / mL, about 1 gg / mL to about 20 gg / mL, about 1 gg / mL to about 10 gg / mL, about 1 gg / mL to about 8 gg / mL, about 2 gg / mL to about 6 gg / mL, about 3 gg / mL to about 5 gg / mL, or about 4 gg / mL to about 5 gg / mL. In some embodiments, the administration of 700 mg of compound 1 results in a mean Cmax of about 5 gg / mL. In some embodiments, the administration of 700 mg of compound 1 results in a mean Cmax of about 4.76 gg / mL. In some embodiments, the administration of 700 mg of compound 1 results in a AUC0-12 of about 10 h»gg / mL to about 30 h* gg / mL, about 15 h* gg / mL to about 25 h* gg / mL, about 20 h* gg / mL to about 25 h* gg / mL, about 20 h* gg / mL to about 22 h* gg / mL. In some embodiments, the administration of 700 mg of compound 1 results in a AUC0-12 of about 20 h* gg / mL. In some embodiments, the administration of 700 mg of compound 1 results in a AUC0-12 of about 20.41 h»gg / mL.

[0023] In some embodiments, the administration of 350 mg results in a mean Cmax of about 1 gg / mL to about 50 gg / mL, about 1 gg / mL to about 40 gg / mL, about 1 gg / mL to about 30 gg / mL, about 1 gg / mL to about 20 gg / mL, about 1 gg / mL to about 10 gg / mL, about 1 gg / mL toAttorney Docket No. 1570-WO-PCT about 8 gg / mL, about 2 gg / mL to about 6 gg / mL, about 2 gg / mL to about 5 gg / mL, or about 2 gg / mL to about 3 gg / mL. In some embodiments, the administration of 350 mg results in a mean Cmax of about 3 gg / mL. In some embodiments, the administration of 350 mg results in a mean Cmax of about 2.54 gg / mL. In some embodiments, the administration of 350 mg results in a AUCo-u of about 5 h»gg / mL to about 25 h»gg / mL, about 5 h»gg / mL to about 15 h»gg / mL, about 10 h»gg / mL to about 15 h»gg / mL, about 12 h»gg / mL to about 14 h»gg / mL.. In some embodiments, the administration of 350 mg results in a AUC0-12 of about 14 h»gg / mL. In some embodiments, the administration of 350 mg results in a AUC0-12 of about 13.68 h»gg / mL.

[0024] In the methods described herein for the treatment of a pneumoviridae infection, compound 1, a pharmaceutically acceptable salt of compound 1, deuterated compound 1, or a pharmaceutically acceptable salt of deuterated compound 1 (hereinafter referred to as the compounds described herein) can be administered at any time to a patient who may come into contact with the virus or is already suffering from the viral infection. In some embodiments, the compounds described herein can be administered prophylactically to patients coming into contact with patients suffering from the viral infection or at risk of coming into contact with patients suffering from the viral infection, e.g., healthcare providers. In some embodiments, administration of the compounds described herein can be to patients testing positive for the viral infection but not yet showing symptoms of the viral infection. In some embodiments, the compounds described herein can be administered to the patient upon commencement of symptoms of the viral infection. In some embodiments, the compounds described herein are administered to the patient within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days of symptom commencement. In some embodiments, the compounds described herein are administered to the patient within 3 days of symptom commencement.

[0025] In some embodiments, the methods described herein comprise event driven administration of a compound described herein. As used herein, the terms “event driven” or “event driven administration” refer to administration of a compound described herein (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and / or (2) during an event (or more than one recurring event) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection); and / or (3) after an event (or after the final event in a series of recurring events) that would expose the individual to the virus (or that would otherwise increase the individual’s risk of acquiring the viral infection). In some embodiments, the event driven administration is performed pre-exposure of the subject to the virus. In some embodiments, theAttorney Docket No. 1570-WO-PCT event driven administration is performed post-exposure of the subject to the virus. In some embodiments, the event driven administration is performed pre-exposure of the subject to the virus and post-exposure of the subject to the virus.

[0026] In certain embodiments, the methods described herein involve administration prior to and / or after an event that would expose the individual to the virus or that would otherwise increase the individual’s risk of acquiring the viral infection, e.g., as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). In some embodiments, the methods described herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, methods described herein comprise post-exposure prophylaxis (PEP).

[0027] In some embodiments, a compound described herein is administered before exposure of the subject to the virus. In some embodiments, a compound described herein is administered before and after exposure of the subject to the virus. In some embodiments, a compound described herein is administered after exposure of the subject to the virus.

[0028] An example of event driven dosing regimen includes administration of a compound described herein within 24 to 2 hours prior to the virus, followed by administration of a compound described herein every 24 hours during the period of exposure, followed by a further administration of a compound described herein after the last exposure, and one last administration of a compound described herein 24 hours later.

[0029] A further example of an event driven dosing regimen includes administration of a compound described herein within 24 hours before the viral exposure, then daily administration during the period of exposure, followed by a last administration approximately 24 hours later after the last exposure (which may be an increased dose, such as a double dose).Pharmaceutical Formulations

[0030] The compounds described herein may be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations may optionally comprise excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxy alkylmethylcellulose, stearic acid and the like. In some embodiments, the formulations comprise one or more pharmaceutically acceptable excipients. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5, but is ordinarily about 3 to 4.Attorney Docket No. 1570-WO-PCT

[0031] While it is possible for the compounds of the disclosure (“the active ingredients”) to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0032] The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any appropriate method known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0033] In some embodiments, the formulations of the present invention are suitable for oral administration and may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[0034] In some embodiments, the formulation is a tablet and the tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0035] Pharmaceutical formulations according to the present invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups orAttorney Docket No. 1570-WO-PCT elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0036] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0037] Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally -occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptad ecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n -propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include Cyclodextrin. In some examples, the suspending agent is Sulfobutyl ether betacyclodextrin (SEB-beta-CD), for example Captisol®.

[0038] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hardAttorney Docket No. 1570-WO-PCT paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0039] Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0040] The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally -occurring gums, such as gum acacia and gum tragacanth, naturally -occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0041] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to patients may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight: weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 mg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0042] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w / w.Attorney Docket No. 1570-WO-PCT

[0043] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0044] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0045] In some embodiments, the compounds described herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and dosed as dry powder. In some embodiments, the compounds used herein are formulated and dosed as a nebulized formulation. In some embodiments, the compounds used herein are formulated for delivery by a face mask. In some embodiments, the compounds used herein are formulated for delivery by a face tent.

[0046] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0047] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0048] The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.Attorney Docket No. 1570-WO-PCT

[0049] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0050] The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

[0051] Compounds described herein are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds described herein (“controlled release formulations”) in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.Combination Therapy

[0052] In some embodiments, the compounds disclosed herein are used in combination with additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.

[0053] The additional therapeutic agents can be administered in any dosage amount, for example, from 1 mg to 1000 mg of compound. Amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose, or such as from about 1 mg per dose to about 1000 mg per dose.

[0054] In some embodiments, the additional therapeutic agent is active against Pneumovirinae virus infections, particularly respiratory syncytial virus infections. Non-limiting examples of these other active therapeutic agents include ribavirin, palivizumab, CMAB-813; motavizumab, ALN-RSV0, ALX-0171 and mixtures thereof.

[0055] In some embodiments, the additional agent is administered orally or by direct inhalation.Glucocorticoids

[0056] Glucocorticoids, which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effectiveAttorney Docket No. 1570-WO-PCT therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids. Non -limiting examples of corticosteroids that may be used in combinations with the compounds disclosed here are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21 -butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone , AZD-7594, ciclesonide; or a pharmaceutically acceptable salts thereof.Anti-inflammatory agents

[0057] Other anti-inflammatory agents working through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agent in combination with the compounds disclosed herein for the treatment of viral respiratory infections. Applying “anti-inflammatory signal transduction modulators” (referred to in this text as AISTM), like phosphodiesterase inhibitors (e.g. PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g. blocking NFKB through IKK inhibition), or kinase inhibitors (e.g. blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to switching off inflammation as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-l- isobutyl-lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY -797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4- difluorormethoxy -benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3 -cyclopentyloxy -4- methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-l -dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol- 3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-Methoxy-2-trifluoromethyl-quinoline- 5-carboxylic acid (3,5-dichloro-l-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-Attorney Docket No. 1570-WO-PCT(4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB- 203850); 4-[4-(4-Fluoro-phenyl)-l-(3-phenyl-propyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3- yn-l-ol (P38 inhibitor RWJ-67657); 4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)- cyclohexanecarboxylic acid 2 -diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl- propoxy)-quinazolin-4-yl]-amine (Gefitinib, EGFR inhibitor); and 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl] -benzamide (Imatinib, EGFR inhibitor).P2-adrenoreceptor agonist bronchodilators

[0058] Combinations comprising inhaled P2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds disclosed herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.

[0059] Combinations of inhaled P2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS’s are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively). The combinations comprising these ICS and p2-adrenoreceptor agonist combinations along with the compounds disclosed herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.

[0060] Other examples of Beta 2 adrenoceptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.Anticholinergics

[0061] For the treatment or prophylaxis of pulmonary broncho-constriction, anticholinergics are of potential use and, therefore, useful as an additional therapeutic agent in combination with the compounds disclosed herein for the treatment of viral respiratory infections. These anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); l-{4-Hydroxy-l-[3,3,3-tris-(4-fluoro-phenyl)- propionyl]-pyrrolidine-2-carbonyl} -pyrrolidine-2 -carboxylic acid (l-methyl-piperidin-4- ylmethyl)-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl- 8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate); l-Cyclohexyl-3,4-dihydro- lH-isoquinoline-2-carboxylic acid l-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin); 2- Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid l-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate); 2-{ l-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-Attorney Docket No. 1570-WO-PCT acetamide (Darifenacin); 4-Azepan-l-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2- Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia- tricyclo[3.3.1 ,02,4]nonane (Oxitropium-N,N-diethylglycinate); 7-[2-(2-Diethylamino-acetoxy)- 2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (Tiotropium-N,N-diethylglycinate); Dimethylamino-acetic acid 2-(3-diisopropylamino-l- phenyl-propyl)-4-methyl-phenyl ester (Tolterodine-N,N-dimethylglycinate); 3-[4,4-Bis-(4- fluoro-phenyl)-2-oxo-imidazolidin-l-yl]-l-methyl-l -(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium; 1 -[ 1 -(3 -Fluoro-benzyl)-piperidin-4-y 1] -4,4-bi s-(4 -fluoro-pheny l)-imidazolidin-2-one; 1 - Cyclooctyl-3-(3-methoxy-l-aza-bicyclo[2.2.2]oct-3-yl)-l-phenyl-prop-2-yn-l-ol; 3-[2-(2- Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-l-(3-phenoxy-propyl)-l-azonia- bicyclo[2.2.2]octane (Aclidinium-N,N-diethylglycinate); or (2-Diethylamino-acetoxy)-di- thiophen-2-yl-acetic acid 1 -methyl- 1 -(2 -phenoxy -ethyl)-piperidin-4-yl ester; revefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencycloquidium bromide.

[0062] Additional agents for the treatment of COPD include anti-IL5 antibodies, such as benralizumab, mepolizumab; anti-IL33R antibodies, such as 9MW-1911; dipeptidyl peptidase I (DPP1) inhibitors, such as AZD-7986 (INS-1007); DNA gyrase inhibitor / topoisomerase IV inhibitors, such as ciprofloxacin hydrochloride; MDR associated protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors, such as RPL-554; CFTR stimulators, such as ivacaftor, QBW-251; MMP-9 / MMP-12 inhibitors, such as RBx-10017609; Adenosine Al receptor antagonists, such as PBF-680; GATA 3 transcription factor inhibitors, such as SB-010; Muscarinic receptor modulator / nicotinic acetylcholine receptor agonists, such as ASM-024; Muscarinic Ml receptor antagonists / Muscarinic M3 receptor antagonists / Muscarinic receptor antagonists, such as tiotropium (long-acting / spray, chronic obstructive pulmonary disease); MARCKS protein inhibitors, such as BIO-11006; Kit tyrosine kinase / PDGF inhibitors such as masitinib;Phosphodiesterase (PDE) 4 inhibitors, such as roflumilast, CHF-6001; Phosphoinositide-3 kinase delta inhibitors, such as nemiralisib; 5 -Lipoxygenase inhibitors, such as TA-270; Muscarinic receptor antagonist / beta 2 adrenoceptor agonist, such as batefenterol succinate, AZD-887, ipratropium bromide; TRN-157; beta 2 adrenoceptor agonists, such as formoterol fumarate; Elastase inhibitors, such as erdosteine; Metalloprotease-12 inhibitors such as FP-025; Interleukin 18 ligand inhibitors, such as tadekinig alfa; Interleukin 33 ligand inhibitors, such as QX-007-N; Skeletal muscle troponin activators, such as CK-2127107; p38 MAP kinase inhibitors, such as acumapimod; IL-17 receptor modulators, such as CNTO-6785; CXCR2 chemokine antagonists, such as danirixin; Leukocyte elastase inhibitors, such as POL-6014;Attorney Docket No. 1570-WO-PCTEpoxide hydrolase inhibitors, such as GSK -2256294; HNE inhibitors, such as CHF -6333; VIP agonists, such as aviptadil; Phosphoinositide-3 kinase delta / gamma inhibitors, such as RV-1729; Complement C3 inhibitors, such as APL-1; G-protein coupled receptor-44 antagonists, such as AM-211; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as RO-7486967; Phosphatidylinositol 4 kinase beta (PI4KB) inhibitors, such as CUR-N399, GSK-3923868; Muscarinic M3 receptor antagonists, such as aclidinium bromide (inhaled, dry prowder);

[0063] Further examples of additional include Budesonide, adipocell, CXF-11, AlloRx, allogeneic UC-MSC therapy, REGEND-001, HL-231, nitric oxide, PUR-1800, YLP-001, LT- 4001, azithromycin, gamunex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxofylline, TEV-46017, OligoG- COPD-5 / 20, Stempeucel®, ZP-051, lysine acetylsalicylate, PRP-PBMC autologous cellular therapy (COPD), cannabidiol (COPD), budesonide + arformoterol, RB-1000, RCD-405, NX-73, long-acting aerosolized peptide-based therapy, JK-0001, AB-255;

[0064] Further additional agents include vaccines for the treatment of COPD, such as MV - 130, GSK-2838497A.

[0065] Further additional agents include mucolytic agents. The compounds disclosed herein may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds disclosed herein may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0066] Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266). The compounds disclosed herein may also be combined with nebulized hypertonic saline particularly when the Pneumovirinae virus infection is complicated with bronchiolitis. The combination of the compounds disclosed herein with hypertonic saline may also comprise any of the additional agents discussed above. In one embodiment, nebulized about 3% hypertonic saline is used.

[0067] Additional agents for treatment or prevention of RSV include respiratory syncytial virus protein F inhibitors, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, presatovir, TP-0591816, NS-401; RNA polymerase inhibitors, such as lumicitabine, ALS-8112, EDP-323, AT-934, AT-889; anti-RSV G protein antibodies, such as anti -G-protein mAb; anti- RSV antibodies, such as RSM-01, TNM-001; Viral replication inhibitors, such as nitazoxanide; Angiotensin converting enzyme 2 modulators / Moesin modulators, such as Neumifil; TLR-4 agonists, such as REVTx-99; TLR-7 agonists, such as PRTX-007; Interleukin-29 ligands,. Such as XW-001;Attorney Docket No. 1570-WO-PCT

[0068] In some embodiments, the additional therapeutic agents is a vaccines for treatment or prevention of RSV, such as AlloStim vaccine, mRNA-1365, MVA-BN RSV, RSV-F, MEDI- 8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, RSV fusion glycoprotein subunit vaccine, IVX-A12, RSV vaccine, IVX-121, mRNA-1345, ADV-110, EC- RSV.

[0069] In some embodiments, the additional therapeutic agent is an agent for treatment of RSV, such as VN-0200, antiviral MicroQuin therapeutics, L-rmAb, IE -4308, AK-0702.

[0070] It is also possible to combine any compound described herein with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0071] Co-administration of a compound described herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.

[0072] Co-administration includes administration of unit dosages of the compounds described herein before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound described herein first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound described herein.KitsAttorney Docket No. 1570-WO-PCT

[0073] Also provided herein are kits that include a compound described herein. In some embodiments the kits described herein may comprise a label and / or instructions for use of the compound in the treatment of a pneumoviridae infection

[0074] In some embodiments, the kit may also comprise one or more additional therapeutic agents and / or instructions for use of additional therapeutic agents in combination with a compound described herein in the treatment of the pneumoviridae infection (e.g., patient) in need thereof.

[0075] In some embodiments, the kits provided herein comprises individual dose units of a compound described herein. Examples of individual dosage units may include pills, tablets, capsules, prefilled syringes or syringe cartridges, inhalers, nebulizers etc., each comprising a therapeutically effective amount of a compound described herein. In some embodiments, the kit may contain a single dosage unit and in others, multiple dosage units are present, such as the number of dosage units required for a specified regimen or period.Definitions

[0076] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

[0077] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 100 includes a range of from 90 to 110.

[0078] The phrase “on a free base basis” indicates that the amount of compound 1 or salt thereof in the dosage form is measured based on the molecular weight of compound 1 free base only, even when the actual active ingredient is a salt of compound 1, deuterated compound 1, a salt of deuterated compound 1 having a different molecular weight than the free base.

[0079] The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.

[0080] The term “estimated glomerular filtration rate,” or “eGFR,” refers to an estimate of the glomerular filtration rate of a patient. Any suitable method for determining eGFR can be used. For example, eGFR can be calculated using the Cockcroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equation, the MDRD II equation, the Mayo Quadratic (Mayo) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. In some embodiments, eGFR values are determined using the Modification of Diet in Renal Disease (MDRD) formula. See, e.g., Levey et al., Ann. Intern. Med. 145(4)247-54 (2006).Attorney Docket No. 1570-WO-PCT

[0081] As used herein, “normal renal function,” used in reference to a patient, means that the patient does not have renal impairment or chronic kidney disease (CKD). A patient can be classified as having normal renal function using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient’s population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and / or patient population). For example, an eGFR of at least 90 mL / min / 1.73 m2can indicate normal renal function.

[0082] As used herein, “mild renal impairment,” used in reference to a patient, means that the patient has mild kidney damage. Mild renal impairment can also be referred to as “mild CKD.” A patient can be classified as having mild renal impairment using known methods, such as determining an eGFR of the patient (e.g., using an equation suitable for the patient’s population) and comparing the eGFR to suitable guidelines (e.g., current medical guidelines for a given eGFR calculation equation and / or patient population). For example, an eGFR of at least 60 mL / min / 1.73 m2to less than 90 mL / min / 1.73 m2can indicate mild renal impairment.

[0083] As used herein, "Cmax" means the maximum observed plasma concentration. Unless specifically described, Cmax can be calculated using standard methods.

[0084] As used herein, "AUC" refers to the area under the plasma concentration -time curve, which is a measure of total bioavailability. Unless specifically described, AUC can be calculated using standard methods.

[0085] As used herein, the term “AUCo-24,” refers to the area under the plasma concentration-time curve from 0 time to 24 hours. Unless specifically described, AUCo-24 can be calculated using standard methods.

[0086] Symptoms of coronavirus infections include stuffy or runny nose, sore throat, shortness of breath, difficulty breathing, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, or diarrhea or combinations thereof.

[0087] Any formula or structure described herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),nC,13C,14C,15N,18F,31P,32P,35S,36C1 and125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such asAttorney Docket No. 1570-WO-PCT3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0088] The disclosure also includes compounds in which from 1 to x hydrogens attached to a carbon atom is / are replaced by deuterium, in which x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of a compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0089] Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (AD ME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compounds described herein.

[0090] For example, in the deuterated compound 1, one or more hydrogen atoms attached to one or more carbon atoms of compound 1 are replaced by deuterium. In some embodiments of the deuterated compound 1, one hydrogen atom attached to one carbon atom of compound 1 is replaced by deuterium. In some embodiments of the deuterated compound of compound 1, two hydrogen atoms attached to one carbon atom of compound 1 are replaced by deuterium. In some embodiments of the deuterated compound of compound 1, two or more hydrogen atoms attached to two carbon atoms of compound 1 are replaced by deuterium.

[0091] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position isAttorney Docket No. 1570-WO-PCT understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0092] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters, which can be changed or modified to yield essentially the same results.EXAMPLESExample 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 1)Compound 1

[0093] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxole-4-carbonitrile (2000 mg, 6.0 mmol) (Siegel et. al. J. Med. Chem. 2017, 60, 1648-1661) and isobutyric acid (638 ng, 7.2 mmol) in DMF (5 mL), N,N' -diisopropylcarbodiimide (914 mg, 7.2 mmol) was added slowly followed by 4-dimethylaminopyridine (737 mg, 6.0 mmol) at r.t and stirred for 4 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated . The resulting product was purified by flash chromatography using DCM / Methanol (20% methanol / DCM) as eluent to get the intermediate ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)methyl isobutyrate. MS m / z = 402.2 (M+l).

[0094] To a solution of intermediate acetonide (1500 mg) in THF (10 mL), cone. HC1 (2 mL) was added and stirred at r.t for 4 h. LC-MS shows the product formation along with SM. Reaction stopped after 4 h, diluted the reaction mixture with dichloromethane, washed with water, saturated bicarbonate, and brine, dried over sodium sulphate, concentrated and purified by flash chromatography using DCM / Methanol (30% methanol / DCM) as eluent to get the title compound.XH NMR (400 MHz, Methanol-d4) 5 7.88 (s, 1H), 6.96 - 6.85 (m, 2H), 4.50 - 4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H). MS m / z: 362.1 (M+l).Attorney Docket No. 1570-WO-PCTExample !. Alternative Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 1)Compound 1

[0095] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxole-4-carbonitrile (2000 mg, 6.0 mmol) in THF, N,N-dimethyl aminopyridine (0.03 eq) was added. To the reaction mixture isobutyric anhydride (1.1 eq) was added slowly. After the completion of the staring material, the reaction mixture was concentrated and purified by flash chromatography using DCM / Methanol (20% methanol / DCM) as eluent to get the intermediate ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)methyl isobutyrate. MS m / z = 402.2 (M+l).

[0096] To a solution of intermediate acetonide (1000 mg) in acetonitrile (10 mL), cone. HC1 (5 eq, ImL) was added and stirred at r.t for 2 h. LC-MS shows the product formation. Reaction was stopped after 4 h, the reaction mixture was diluted with ethyl acetate, quenched with saturated bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulphate, and concentrated . The residue was purified by flash chromatography using DCM / Methanol (30% methanol / DCM) as eluent, concentrated the factions to get the title compound.XH NMR (400 MHz, Methanol-d4) 5 7.88 (s, 1H), 6.96 - 6.85 (m, 2H), 4.50 - 4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H); MS m / z: 362.1 (M+l).Example 3: Compound 1 Tablets

[0097] Compound 1 tablets evaluated were manufactured using a dry granulation / tablet compression / film-coating process train. Dry granulation by roller compaction was selected as the means of combining 350 mg compound 1 with inactive excipients including microcrystalline cellulose, crospovidone, and magnesium stearate in order to minimize exposure of compound 1 to moisture during the granulation process. The overall manufacturing process consisted of coblending and lubricating compound 1 with intragranular excipients, followed by roller compaction and milling. The resulting compound 1 granules were then blended and lubricated with extragranular magnesium stearate to produce the compound 1 final powder blend, which was compressed into core tablets that were subsequently film-coated.Attorney Docket No. 1570-WO-PCTExample 4. Obeldesivir (ODV) Safety and Pharmacokinetic Evaluation

[0098] The ODV safety and PK were evaluated in a Phase 1 single and multiple ascending dose study (GS-US-611-6248) in healthy participants. Single ODV doses up to 1600 mg and multiple doses of ODV 500 mg twice daily and ODV 900 mg once daily for 5 days were generally safe and well tolerated. A graded laboratory abnormality of decreased creatinine clearance (CLcr) was observed across all cohorts, although there was a disproportionately higher number of participants with decreased CLcr at the highest dose evaluated (single ODV 1600 mg dose).

[0099] Following oral administration of ODV, GS-441524 (parent nucleoside that can enter cells where it is anabolized to the active triphosphate metabolite GS -443902, see both structures below) was the only circulating species. The plasma half-life of this metabolite was approximately 6 hours, supporting twice daily dosing. The twice daily dosing regimen also provided higher daily exposure (AUCo-24h), higher Ctau concentrations, and lower Cmax as compared with once daily dosing. ODV builds on the already proven mechanism of action of RDV that is inhibition of SARS-CoV-2 RNA polymerase by the active triphosphate metabolite, GS-443902. The major metabolic pathways leading to formation of the GS-443902 metabolite are different between RDV and ODV. For ODV, the major metabolic pathway is through phosphorylation of the GS-441524 metabolite by cellular kinases, a pathway that is believed to play a minor role in activation of RDV to GS-443902 metabolite. In order to overcome the less efficient conversion to GS-443902, the levels of GS-441524 need to be approximately 14-fold higher, as compared with what is observed after RDV, in order to result in the similar levels of intracellular active metabolite. Robust intracellular formation of active metabolite was observed in the GS-US-611-6248 clinical study in PBMCs (e.g., ODV 500 mg administered twice daily achieved GS-443902 levels comparable with IV RDV on Day 1 and exceeded those on later days by approximately 4-fold). The intracellular formation of GS-443902 was dose-proportional and significant accumulation was observed following twice daily dosing (approximately 6 -fold accumulation by Day 5).GS-441524Attorney Docket No. 1570-WO-PCTGS-443902

[0100] ODV showed therapeutic efficacy in multiple SARS-CoV-2 animal models (i.e., mouse, ferret, and African green monkeys [AGMs]). Administration of ODV to SARS-CoV-2- infected mice (10 mg / kg twice daily; AUC0-24h = 10,500 h»ng / mL), ferrets (20 mg / kg once daily; AUCo-24h = 28,500 h»ng / mL) and AGM (60 mg / kg once daily; AUCo-24h = 25,700 h»ng / mL) for 5 days resulted in a significant reduction of clinical signs of respiratory disease, infectious virus titers in lungs, and genomic RNA compared with vehicle -treated animals. Similarly, in the AGM model, IV delivery of parent nucleoside (20 mg / kg once daily; AUCo-24h = 42,800 h»ng / mL) and oral administration of GS-621763, a tri-isobutyryl ester tool prodrug of GS-441524 (60 mg / kg once daily; AUCo-24h = 18,200 h»ng / mL); (120 mg / kg once daily; AUCo- 24h = 36,400 h»ng / mL) significantly reduced SARS-CoV-2 levels in the lower airways, as early as 1 to 2 days after infusion.Example 5. ODV Dose Selection for Treating RSV

[0101] Obeldesivir (ODV) is an ester prodrug of the parent nucleoside, GS-441524. Following oral administration, ODV is extensively hydrolyzed presystemically to the parent nucleoside GS-441524, which can then enter cells where it is subsequently anabolized to the active nucleoside triphosphate metabolite (GS-443902).

[0102] The proposed ODV dosing regimen for evaluation in this Phase 2 study titled A Phase 2 Randomized, Placebo-controlled Study of the Safety and Efficacy of Obeldesivir to Treat Nonhospitalized Adults With Acute Respiratory Syncytial Virus (RSV) Infection is 700 mg twice daily on Day 1 followed by 350 mg twice daily on Days 2 to 5. This dosing regimen was selected based on the totality of available clinical and nonclinical data and with careful consideration of the overall benefit -risk profile. Additionally, due to the approximately 7-hour half-life of GS-441524, the twice-daily regimen on Day 1 as well as Days 2 to 5 maintains plasma GS-441524 exposure above the efficacy target during the course of treatment.

[0103] Pharmacokinetic and safety of ODV were evaluated in a comprehensive clinical program with 6 Phase 1 studies in healthy adult participants (first -in-human study GS-US-611- 6248, drug-drug interaction studies GS-US-611-6409 and GS-US-611-6469, Japanese bridging study (GS-US-611-6586), and renal impairment study GS-US-611-6472 [interim data]) and 2Attorney Docket No. 1570-WO-PCT pivotal Phase 3 studies in adult and adolescent participants with COVID-19 (GS-US-611-6549 and GS-US-611-6273). ODV was generally safe and well tolerated in healthy volunteers following single ODV doses up to 1600 mg and multiple doses of ODV 350 mg twice daily, 500 mg twice daily, and ODV 900 mg once daily for 5 days in healthy volunteers and ODV 350 mg twice-daily doses for 5 days in COVID-19 patients.

[0104] A preliminary GS-441524 population PK (PopPK) model incorporating weight -based allometric scaling on clearance and volume parameters was developed using nonlinear mixed effects modeling. Available GS-441524 plasma concentration data following oral administration of ODV in the above-listed studies (except the ADME study GS-US-611-6408) were used for model development. The developed PopPK model was used to evaluate intrinsic and extrinsic factors impacting the ODV PK. Body weight, estimated glomerular filtration rate (eGFR), and presence of CO VID-19 disease were found to have an impact on the PK of GS-441524 (FIG. 1).

[0105] Utilizing the PopPK estimated plasma exposures, a logistic regression PK / pharmacodynamics (PK / PD) analysis was conducted to characterize the exposure -safety relationship with asymptomatic Grade 3 or higher creatinine clearance (CLcr) treatment- emergent laboratory abnormalities (TELA; Division of AIDS [DAIDS] grading). The established relationship was used to predict the rate of Grade 3 or higher CLcr TEL As associated with exposures following various dosing regimens.

[0106] The clinical PK efficacy target for RSV infection in adults is based on preclinical data obtained from PK and efficacy studies in African green monkeys (AGMs). In AGM efficacy studies, once-daily oral administration of ODV at 30 and 90 mg / kg reduced RNA viral loads of RSV A2 in bronchiolar lavage fluid (BALF) and throat swabs. In BALF, a > 2 loglO mean reduction in viral load of ODV-treated animals receiving doses of both 30 mg / kg and 90 mg / kg was observed on Day 5, the time of peak viral load in vehicle -treated control animals.Since the planned clinical RSV dosing regimens are twice-daily treatments, plasma exposures of GS-441524 obtained from AGM PK studies were estimated for 30 mg / kg in AGM twice daily for five days using the Nonparametric Superposition function in Phoenix® WinNonlin®. The estimated exposure (Cmax or AUC) for 30 mg / kg in AGM twice daily was selected as the PK efficacy target when evaluating different clinical ODV dosing regimens for the treatment of RSV.

[0107] Preliminary PK simulations were performed to evaluate different dosing regimens in adult patients (>18 years) with normal kidney function and those with mild renal impairment. The simulated population was based on the latest NHANES database, with 1000 participants included in each dosing regimen evaluated. Based on the performed simulations, following aAttorney Docket No. 1570-WO-PCT dosing regimen of 700 mg twice on Day 1 and 350 mg twice daily on Days 2 to 5, GS-441524 exposures are predicted and listed in Table 1.Table 1. Preliminary predicted mean plasma exposures of GS-441524 following the proposed RSV adult dosing regimen.

[0108] Note that the predicted mean Cmax is the highest Cmax of the two doses on Days 1 and 5 and predicted mean AUC0-12 corresponds to the morning dose on Days 1 and 5. Days 1 and 5 predicted Cmax values are below those observed in Study GS -US-611-6248 (first-in-human) in participants who received 900 mg once daily for 5 days (6.23 pg / mL and 5.18 pg / mL, respectively) and Days 1 and 5 predicted AUC0-12 values are below the observed AUC0-12 in Study GS-US-611-6248 (first -in-human) in participants who received 500 mg twice daily for 5 days (Day 5 AUC0-12: 21.48 h»pg / mL). Both these regimens were generally safe and well tolerated and thus, the above proposed dosing regimen is anticipated to be safe and well tolerated.

[0109] The outlined approach allowed an informed dose selection to ensure clinical exposures of GS-441524 will be above the AGM RSV efficacy target (FIG. 2) and below the exposure predicted to have an acceptable rate of Grade 3 or higher CLcr TELA in participants with normal kidney function or those with mild renal impairment.

[0110] Following ODV administration, intracellular GS-443902 PK in peripheral blood mononuclear cells (PBMCs) was dose-proportional and accumulation was observed following twice-daily dosing in Phase 1 studies. Levels of the circulating GS-441524 nucleoside metabolite are a surrogate for the antiviral effect of the intracellular active nucleoside triphosphate (GS-443902) in the lungs. The selected RSV dosing regimen for adults (700 mg twice on Day 1, 350 mg twice daily on Days 2 to 5) is expected to provide plasma concentrations of GS-441524 sufficient to support high intracellular exposures of GS-443902 in PBMCs on Days 1 through 5.Example 6. Clinical Study Protocol[OlH] This is a Phase 2, randomized, double-blind, placebo-controlled study comparing the safety and efficacy of oral ODV with placebo for the treatment of acute RSV infection in nonhospitalized adult participants with > 1 risk factors for severe RSV disease.Attorney Docket No. 1570-WO-PCT

[0112] A total of approximately 240 participants is planned for this study. Up to approximately 25% of total enrollment may consist of participants who qualify for inclusion by the age criterion (i.e., MH1 risk factor a) alone and with no other risk factors for severe RSV disease. Up to approximately 50% of total enrollment may consist of participants who qualify for inclusion by the presence of chronic cardiovascular disease (i.e., MH1 risk factor e) without additional medical comorbidity risk factors (i.e., MH1 risk factors b, c, or d). Note that the 50% cap applies to both those participants with MH1 risk factor e alone or those participants with MH1 risk factors a and e. No caps are present for participants with medical history of COPD, asthma or specified chronic lung disease. All the enrolled participants will be randomized 1 :1 to receive ODV or placebo-to-match for 5 days. Randomization will be stratified by vaccination status (ever vs never).

[0113] A total of approximately 240 participants is planned for this study. The target population is non-hospitalized participants 18 years of age or older with acute RSV infection and at least 1 risk factor for severe RSV disease.Inclusion Criteria

[0114] Moreover, to ensure a diversity of age range and medical comorbidities studied, enrollment caps will be placed on participants enrolled meeting the risk factor criterion of 60 years of age or older alone (i.e., only MHl.a.) and on participants qualifying for inclusion by the cardiovascular disease criterion without other risk factors (i.e., only MHl.e. without other risk factors).

[0115] MH1. Exhibits at least 1 of the following risk factors for severe RSV disease: a) Age > 60 years. b) Moderate or severe COPD by 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and documented history of high exacerbation risk (exacerbation history Category E by GOLD ABE Assessment Tool) during the preceding 12 months. c) Asthma meeting the following 2 criteria: i) Diagnosed by 1 of either the 2023 Global Initiative for Asthma guidelines or the 2007 National Asthma Education and Prevention Program guidelines.AND ii) Documented history < 12 months before screening of > 1 exacerbation requiring treatment with systemic corticosteroids and / or hospital or emergency department visit. d) One or more of the following chronic lung diseases: i) BronchiectasisAttorney Docket No. 1570-WO-PCT ii) Interstitial lung disease (eg, idiopathic pulmonary fibrosis) iii) Pulmonary hypertension e) Chronic cardiovascular disease exclusive of treated or untreated hypertension: i) CHF ii) Past or present history of coronary artery disease (including stable angina) AND receiving 1 or more medications for its treatment (eg, nitrates, beta-blockers, and angiotensin converting enzyme inhibitors)

[0116] MH2. RSV infection confirmed < 3 days before randomization by a locally available approved or authorized polymerase chain reaction (PCR) assay or alternative nucleic acid -based detection, including a respiratory viral panel, or respiratory pathogen panel. Serologic tests will not be accepted.

[0117] MH3. Acute RSV infection defined as RSV infection (criterion MH2) plus new onset or increased from baseline of > 2 of the following signs and / or symptoms, and at least 1 sign / symptom of moderate severity within 3 days prior to randomization: a) Nasal congestion. b) Sore throat. c) Cough. d) Wheezing. e) Shortness of breath (ie, dyspnea). f) Expectoration (ie, sputum production).

[0118] MH4. RSV vaccine status: a) Participants whose only risk factor is age > 60 years (ie, risk factor a) must not have received, at any time, any doses of investigational or licensed vaccine for RSV.

[0119] b) For all other participants, receipt of > 1 dose(s) of investigational or licensed RSV vaccine, at any time prior to randomization, is allowed.Exclusion Criteria

[0120] Participants who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

[0121] MH1. Currently requiring or expected to require hospitalization within 48 hours after

[0122] randomization.

[0123] MH2. Documented previous infection and / or hospitalization for RSV during the current respiratory virus season.

[0124] MH3. Documented respiratory tract infection < 28 days before randomization.Attorney Docket No. 1570-WO-PCT

[0125] MH4. Documented to be positive for influenza A or B virus, and / or SARS-CoV-2 < 7 days prior to randomization.

[0126] MH5. Concurrent infections requiring treatment with any systemic antiviral, antibacterial, antifungal, or antimycobacterial therapy < 7 days prior to randomization.

[0127] MH6. Active acute exacerbations of any chronic illnesses within the inclusion criteria including acute coronary syndrome within 4 weeks of randomization or percutaneous coronary intervention planned within 4 weeks of randomization.

[0128] MH7. Participants with a history of cystic fibrosis.

[0129] MH8. Meets criteria for protocol -defined RSV LRU at screening or enrollment.

[0130] MH9. Participants who are immunocompromised, i.e., fulfill 1 or more of the criteria listed below. a) Have a history of cancer (except for nonmelanoma cancer) and who have received 1 or more doses of chemotherapy or immunotherapy or undergone surgical resection < 12 months prior to randomization. b) Have received solid organ or hematopoietic stem cell transplant and on immunosuppressive therapy at randomization. c) Have chronic use of high-dose corticosteroids (i.e., > 20 mg of prednisone or equivalent per day administered for > 2 weeks at randomization). d) Have untreated HIV infection or on active treatment for HIV infection with a CD4 count< 200 cells / mm3or CD4 percentage < 15% in the last 6 months.

[0131] MH 10. Breastfeeding (nursing). If willing to discontinue breastfeeding during 5 days of treatment, participant can be enrolled.

[0132] MH11. Unwilling to use protocol -mandated contraception.

[0133] MH12. Known hypersensitivity to the study drug, its metabolites, or formulation excipient. MH13. Decompensated cirrhosis (Child-Pugh Class C) or acute liver injury / failure.

[0134] LAI. Undergoing dialysis, known history of moderate or severe renal impairment, known CLcr< 60 mL / min (as calculated by Cockroft-Gault), or eGFR < 60 mL / min / 1.73 m2 within the preceding 6 months prior to randomization. Potential participants meeting laboratory criterion LAI may be enrolled if test results available before dosing show that renal function no longer meets this criterion.

[0135] LA2. Known history of any of the following abnormal laboratory results (< 6 months prior to randomization) unless confirmed as resolved at screening. a)ALT > 5 x ULN.Attorney Docket No. 1570-WO-PCT b) Positive urine or serum pregnancy test (Appendix 11.3) or pregnant at screening.

[0136] PT1. Received any approved or authorized, direct -acting antiviral drug or monoclonal antibody against RSV < 28 days or < 5 half -lives, whichever is longer, before randomization.

[0137] PT2. Received an investigational product < 28 days or < 5 half -lives, whichever is longer, before randomization.

[0138] OEC 1. Any inability to take study drug or comply with study procedures that, in the opinion of the investigator, would make the participant unsuitable for the study.Rational for Dose Selection

[0139] The dosing regimen of 700 mg twice daily on Day 1 followed by 350 mg twice daily on Days 2 to 5 was selected based on the totality of available clinical and nonclinical data and with careful consideration of the overall benefit -risk profile.

[0140] Pharmacokinetic and safety of ODV were evaluated in a comprehensive clinical program with 6 Phase 1 studies in healthy adult participants (first -in-human Study GS-US-611- 6248, absorption, distribution, metabolism, and excretion [ADME] Study GS-US-611-6408, DDI studies GS-US-611-6409 and GS-US-611-6469, Japanese bridging study GS-US-611-6586, and renal impairment study GS-US-611-6472 [interim data]) and 2 pivotal Phase 3 studies in adult and adolescent participants with COVID-19 (Studies GS-US-611-6549 and GS-US-611- 6273). Obeldesivir was generally safe and well tolerated (most adverse events (AEs) were Grade 1 in severity) following single dose up to 1600 mg and multiple doses of 350 mg twice daily, 500 mg twice daily, and 900 mg once daily for 5 days in healthy participants and ODV 350 mg twice-daily doses for 5 days in COVID-19 participants.

[0141] A GS-441524 population PK (PopPK) model incorporating weight -based allometric scaling on clearance and volume parameters was developed using nonlinear mixed effects modeling and data obtained from the above listed studies (except the ADME study GS-US-611- 6408). The developed PopPK model was used to evaluate intrinsic and extrinsic factors impacting the ODV PK. Body weight, estimated glomerular filtration rate (eGFR), and presence of COVID-19 disease were found to have a significant impact on the PK of GS-441524. Utilizing the PopPK estimated plasma exposures, a logistic regression PK / pharmacodynamics (PD) analysis was conducted to characterize the exposure-safety relationship with Grade 3 or higher CL cr treatment -emergent laboratory abnormalities (TELA; Division of AIDS [DAIDS] grading). The established relationship was used to predict the rate of Grade 3 or higher CLcr TELAs associated with exposures following various dosing regimens.Attorney Docket No. 1570-WO-PCT

[0142] The clinical PK efficacy target for RSV infection is based on nonclinical data obtained from PK and efficacy studies in African green monkeys (AGMs). In an AGM efficacy study, once-daily oral administration of ODV at 30 mg / kg and 90 mg / kg reduced RNA viral loads of RSV A2 in bronchoalveolar lavage (BAL) fluid and throat swabs. In BAL fluid, a > 2 logio mean reduction in RNA viral load of ODV-treated animals receiving doses of both 30 mg / kg and 90 mg / kg was observed on Day 5, the time of peak viral load in vehicle-treated control animals. Since the planned clinical RSV dosing regimens are twice-daily treatments, plasma exposures of GS-441524 obtained from AGM PK studies were estimated for 30 mg / kg in AGM twice daily for 5 days using the nonparametric superposition function in Phoenix® WinNonlin®. The estimated exposure (Cmax or AUC) for 30 mg / kg in AGM twice daily was selected as the PK efficacy target when evaluating different clinical ODV dosing regimens for the treatment of RSV.

[0143] Pharmacokinetic simulations were performed to evaluate different dosing regimens in adult patients (> 18 years) with normal kidney function and those with mild renal impairment. The simulated population was based on the latest National Health and Nutrition Examination Survey (NHANES) database, with 1000 participants included in each dosing regimen evaluated. Based on the performed simulations, following a dosing regimen of 700 mg twice daily on Day 1 and 350 mg twice daily on Days 2 to 5, Day 1 predicted mean Cmax and AUC0-12 are 4.76 pg / mL and 20.41 h»pg / mL, respectively, and Day 5 predicted mean Cmax and AUC0-12 are 2.54 pg / mL and 13.68 h»pg / mL, respectively. Note that the predicted mean Cmax is the highest Cmax on Days 1 and 5 and predicted mean AUC0-12 corresponds to a morning dose on Days 1 and 5. Days 1 and 5 predicted Cmax values are below those observed in Study GS-US-611-6248 (first- in-human) in participants who received 900 mg once daily for 5 days (6.23 pg / mL and 5.18 pg / mL, respectively) and Days 1 and 5 predicted AUC0-12 values are below the observed AUCo- 12 in Study GS-US-611-6248 (first-in-human) in participants who received 500 mg twice daily for 5 days (Day 5 AUCO-12: 21.48 h»pg / mL). Both these regimens were generally safe and well tolerated and thus the above proposed dosing regimen is anticipated to be safe and well tolerated.

[0144] The outlined approach allowed an informed dose selection to ensure clinical exposures of GS-441524 will be above the AGM efficacy target and below the exposure predicted to have an acceptable rate of Grade 3 or higher CLcr TELA in participants with normal kidney function or mild renal impairment.

[0145] Obeldesivir and RDV generate the same active triphosphate metabolite (GS -443902) through different metabolic pathways. Following ODV administration, GS-443902 PK wasAttorney Docket No. 1570-WO-PCT dose-proportional and accumulation was observed following twice-daily dosing. The proposed RSV dosing regimen (700 mg twice daily on Day 1, 350 mg twice daily on Days 2 to 5) is expected to provide plasma concentrations of GS-441524 sufficient to support higher intracellular exposures of the active metabolite (GS -443902) in peripheral blood mononuclear cell than RDV on Days 1 through 5.

[0146] All references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

1. Attorney Docket No. 1570-WO-PCTCLAIMS1. A method of treating a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 1 :(compound 1) a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein the compound 1, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice on a first day of administration, and a dosage of about 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.

2. The method of claim 1, wherein the pneumoviridae infection is a respiratory syncytial virus infection or a human metapneumovirus infection.

3. The method of claim 1 or 2, wherein the pneumoviridae infection is a respiratory syncytial virus infection.

4. The method of any one of claims 1-3, wherein the patient has normal renal function.

5. The method of claim 4, wherein the patient has an estimated glomerular filtration rate (eGFR) of at least 90 mL / min / 1.73 m2.

6. The method of claim 4 or 5, further comprising determining that the patient has an eGFR of at least 90 mL / min / 1.73 m2prior to the administration.

7. The method of any one of claims 1-3, wherein the patient has mild renal impairment.

8. The method of claim 7, wherein the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2.

9. The method of claim 7 or 8, further comprising determining that the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2prior to the administration.

10. The method of any one of claims 1-9, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice on the first day of administration, and in a dosage of about 350 mg / dose (on a free base basis) twice daily on second to fifth day of administration.Attorney Docket No. 1570-WO-PCT11. The method of any one of claims 1-10, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof, is administered in a dosage of 700 mg / dose (on a free base basis) twice on the first day of administration, and in a dosage of 350 mg / dose (on a free base basis) twice daily on second to fifth day of administration.

12. The method of any one of claims 1-11, wherein the method comprises administering to the patient the compound 1.

13. The method of any one of claims 1-9, wherein the compound 1 is administered in a dosage of about 700 mg / dose twice daily on a first day of administration, and a dosage of about 350 mg / dose twice daily on second to fifth day of administration.

14. The method of any one of claims 1-9 and 13, wherein the compound 1 is administered in a dosage of 700 mg / dose twice daily on a first day of administration, and a dosage of 350 mg / dose twice daily on second to fifth day of administration.

15. The method of any one of claims 1-14, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof is administered orally.

16. The method of any one of claims 1-15, wherein the method comprises administering to the patient a tablet comprising(i) compound 1 in an amount of about 350 mg;(ii) microcrystalline cellulose in an amount of about 315 mg;(iii) crospovidone in an amount of about 28 mg; and(iv) magnesium stearate in an amount of about 7 mg.

17. The method of claim 16, wherein the table comprises(i) compound 1 in an amount of 350 mg;(ii) microcrystalline cellulose in an amount of 315 mg;(iii) crospovidone in an amount of 28 mg; and(iv) magnesium stearate in an amount of 7 mg.

18. The method of claim 16 or 17, wherein two tablets are administered twice on the first day of administration, and one tablet is administered twice daily on each day of administration after the first day.

19. A method of preventing a pneumoviridae infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 1 :Attorney Docket No. 1570-WO-PCT(compound 1) a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt of a deuterated compound thereof; wherein the compound 1, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice on a first day of administration, and a dosage of about 350 mg / dose (on a free base basis) twice daily on each day of administration after the first day.

20. The method of claim 19, wherein the pneumoviridae infection is a respiratory syncytial virus infection or a human metapneumovirus infection.

21. The method of claim 19 or 20, wherein the pneumoviridae infection is a respiratory syncytial virus infection.

22. The method of any one of claims 19-21, wherein the patient has normal renal function.

23. The method of claim 22, wherein the patient has an estimated glomerular filtration rate (eGFR) of at least 90 mL / min / 1.73 m2.

24. The method of claim 22 or 23, further comprising determining that the patient has an eGFR of at least 90 mL / min / 1.73 m2prior to the administration.

25. The method of any one of claims 19-21, wherein the patient has mild renal impairment.

26. The method of claim 25, wherein the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2.

27. The method of claim 25 or 26, further comprising determining that the patient has an eGFR of 60 mL / min / 1.73 m2to 89 mL / min / 1.73 m2prior to the administration.

28. The method of any one of claims 19-27, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof, is administered in a dosage of about 700 mg / dose (on a free base basis) twice on the first day of administration, and in a dosage of about 350 mg / dose (on a free base basis) twice daily on second to fifth day of administration.

29. The method of any one of claims 19-28, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof, is administered in a dosage of 700 mg / dose (on a free baseAttorney Docket No. 1570-WO-PCT basis) twice on the first day of administration, and in a dosage of 350 mg / dose (on a free base basis) twice daily on second to fifth day of administration.

30. The method of any one of claims 19-29, wherein the method comprises administering to the patient the compound 1.

31. The method of any one of claims 19-27, wherein the compound 1 is administered in a dosage of about 700 mg / dose twice daily on a first day of administration, and a dosage of about 350 mg / dose twice daily on second to fifth day of administration.

32. The method of any one of claims 19-27 and 31, wherein the compound 1 is administered in a dosage of 700 mg / dose twice daily on a first day of administration, and a dosage of 350 mg / dose twice daily on second to fifth day of administration.

33. The method of any one of claims 19-32, wherein the compound 1, the pharmaceutically acceptable salt thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt of the deuterated compound thereof is administered orally.

34. The method of any one of claims 19-33, wherein the method comprises administering to the patient a tablet comprising(i) compound 1 in an amount of about 350 mg;(ii) microcrystalline cellulose in an amount of about 315 mg;(iii) crospovidone in an amount of about 28 mg; and(iv) magnesium stearate in an amount of about 7 mg.

35. The method of claim 34, wherein the table comprises(i) compound 1 in an amount of 350 mg;(ii) microcrystalline cellulose in an amount of 315 mg;(iii) crospovidone in an amount of 28 mg; and(iv) magnesium stearate in an amount of 7 mg.

36. The method of claim 34 or 35, wherein two tablets are administered twice on the first day of administration, and one tablet is administered twice daily on each day of administration after the first day.

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