How to Treat a Poxvirus Infection

Abstract

The present disclosure relates to methods for treating poxvirus infections using a compound of Formula I: Formula I, or a pharmaceutically acceptable salt or deuterated analog thereof. Methods are provided that include administering a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analog thereof. Also provided is a method of treating or preventing poxvirus infections in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analog thereof, and one or more pharmaceutically acceptable carriers. TIFF2025540572000022.tif42128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 426,536, filed November 18, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure relates to methods for treating poxvirus infections. [Background technology]

[0003] Poxviruses, members of the Poxviridae family, are found worldwide and can infect humans and many other types of animals. Poxvirus infections can result from contact with contaminated animals, humans, or materials and typically result in the formation of skin lesions. There is a need for compounds and methods for treating poxvirus infections, such as orthopoxviruses, parapoxviruses, morsipoxviruses, yatapoxviruses, capripoxviruses, suipoxviruses, leporipoxviruses, and avipoxviruses.

[0004] One such poxvirus, monkeypox virus, was first discovered in laboratory monkeys in 1958 and can infect both animals and humans. Monkeypox virus belongs to the orthopoxvirus genus, which also includes variola virus (which causes smallpox), vaccinia virus (used in smallpox vaccines), and cowpox virus. Since the first human case of monkeypox infection was recorded in 1970, the majority of reported cases have been in the Democratic Republic of the Congo and other Central and West African countries. Recently, multiple cases have been reported in countries that do not normally report monkeypox infections, such as Australia and countries in Europe and North America. Summary of the Invention

[0005] Methods are provided for the treatment or prevention of infections caused by poxviruses.

[0006] A method for treating or preventing a poxvirus infection in a patient in need thereof, the method comprising administering to the patient a compound of formula I: [ka] or a pharmaceutically acceptable salt or deuterated analog thereof.

[0007] Also provided is a method for treating or preventing a poxvirus infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, and one or more pharmaceutically acceptable carriers.

[0008] Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, for use in treating or preventing a poxvirus infection.

[0009] Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, in the preparation of a medicament for treating or preventing a poxvirus infection.

[0010] Also provided are kits comprising a compound of Formula I or a pharmaceutically acceptable salt or deuterated analogue thereof and instructions for their use in treating or preventing poxvirus infection. DETAILED DESCRIPTION OF THE INVENTION

[0011] Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:

[0012] When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

[0013] As used herein, the term "patient" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans.

[0014] The term "treating," as used herein, unless otherwise specified, means reversing, alleviating, or inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0015] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds and compositions disclosed herein, in some embodiments, can be administered to subjects (including humans) at risk of having a disease or condition. As used herein, the terms "preventing" and "prevention" encompass administering a compound, composition, or pharmaceutically acceptable salt according to embodiments disclosed herein before or after an individual is exposed to a virus, but before symptoms of viral infection appear and / or before the virus is detected in the blood. The term also refers to preventing disease symptoms from appearing and / or preventing the virus from reaching detectable levels in the blood. The term includes both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. These terms also refer to preventing perinatal transmission of a virus from mother to infant by administration to the mother before birth and to the child within the first few days of life. The term also refers to preventing transmission of the virus via blood transfusion.

[0016] As used herein, the term "therapeutically effective amount" refers to the amount of active ingredient required to provide a desired level of drug in the bloodstream of a treated subject to produce an expected physiological response or desired biological effect when such a formulation is administered by a selected route of administration. The exact amount will depend on numerous factors, including the particular compound, the specific activity of the compound, the delivery device used, the physical properties of the compound, its intended use, and patient considerations such as the severity of the disease state and patient interaction, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0017] Reference will now be made in detail to specific embodiments of the invention, examples of which are illustrated in the accompanying description. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention.

[0018] 1. A method of treating a poxvirus infection in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of formula I: [ka] or a pharmaceutically acceptable salt or deuterated analog thereof.

[0019] Also provided is a method for preventing poxvirus infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or deuterated analog thereof.

[0020] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharmaceutically acceptable salt or deuterated analog thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia:

[0021] The compound of Formula Ia is also known as remdesivir and GS-5734. The IUPAC name of the compound of Formula Ia is (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, and its CAS registry number is 1809249-37-3. The compound of Formula Ia is disclosed in International Publication Nos. 9,724,360, 10,065,958, and 10,695,361, the contents of each of which are incorporated herein in their entireties.

[0022] In some embodiments, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable salt or deuterated analog thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib:

[0023] In some embodiments, a compound of Formula I is administered. In some embodiments, a compound of Formula Ia is administered. In some embodiments, a compound of Formula Ib is administered.

[0024] The methods described herein can be used to treat or prevent a poxvirus infection. In some embodiments, the poxvirus infection is an orthopoxvirus infection. In some embodiments, the poxvirus infection is a camelpox virus infection, a cowpox virus infection, an ectromelia virus infection, a horsepox virus infection, a monkeypox virus infection, a raccoonpox virus infection, a skunkpox virus infection, a taterapox virus infection, a Uasin Gishu virus infection, a vaccinia virus infection, a variola virus infection, or a bolepovirus infection.

[0025] In some embodiments, the poxvirus infection is a vaccinia virus infection.

[0026] In some embodiments, the poxvirus infection is a monkeypox virus infection. The methods described herein can be used to treat or prevent infection caused by any strain of monkeypox virus. In some embodiments, the poxvirus infection is caused by a West African strain of monkeypox virus. In some embodiments, the poxvirus infection is caused by a Congo Basin strain of monkeypox virus.

[0027] In some embodiments, the poxvirus infection is a parapoxvirus infection. In some embodiments, the poxvirus infection is a bovine papular stomatitis virus infection, an orf virus infection, a pseudocowpox virus infection, a parapoxvirus of red deer infection, or a parapoxvirus of squirrels infection. In some embodiments, the poxvirus infection is a contagious pustular dermatitis of camels (Ausdyk) virus infection, a contagious pustular dermatitis of chamois virus infection, a parapoxvirus of reindeer infection, or a sealpox virus infection.

[0028] In some embodiments, the poxvirus infection is a molsipoxvirus infection. In some embodiments, the poxvirus infection is a molluscum contagiosum infection.

[0029] In some embodiments, the poxvirus infection is a Yatapoxvirus infection. In some embodiments, the poxvirus infection is a Tanapoxvirus, a Yaba-like disease virus infection, or a Yaba monkey tumor virus infection.

[0030] In some embodiments, the poxvirus infection is a capripoxvirus infection, hi some embodiments, the poxvirus infection is a sheeppoxvirus infection, a goatpoxvirus infection, or a lumpy skin disease virus infection.

[0031] In some embodiments, the poxvirus infection is a suipoxvirus infection. In some embodiments, the poxvirus infection is a swinepox virus infection.

[0032] In some embodiments, the poxvirus infection is a leporipoxvirus, hi some embodiments, the poxvirus infection is a myxoma virus infection, a Shope fibroma virus (rabbit fibroma) infection, a squirrel fibroma virus infection, or a hare fibroma virus infection.

[0033] In some embodiments, the poxvirus infection is an avipoxvirus infection. In some embodiments, the poxvirus infection is a canarypoxvirus infection, a fowlpoxvirus infection, a goldfinchpoxvirus infection, a minnowpoxvirus infection, a pigeonpoxvirus infection, a psittacoccuspoxvirus infection, a quailpoxvirus infection, a sparrowpoxvirus infection, a starlingpoxvirus infection, or a turkeypoxvirus infection. In some embodiments, the poxvirus infection is a cloudpoxvirus infection, a peacockpoxvirus infection, or a penguinpoxvirus infection.

[0034] Also provided is a method of treating a poxvirus infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, and one or more pharmaceutically acceptable carriers.

[0035] Also provided is a method of preventing a poxvirus infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, and one or more pharmaceutically acceptable carriers.

[0036] In some embodiments, the pharmaceutical composition comprises a compound of formula Ia, or a pharmaceutically acceptable salt or deuterated analog thereof. In some embodiments, the pharmaceutical composition comprises a compound of formula Ib, or a pharmaceutically acceptable salt or deuterated analog thereof.

[0037] Pharmaceutically acceptable carriers can be selected according to conventional practice. For example, tablets can contain excipients, lubricants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, if intended for delivery by a route other than oral administration, can generally be isotonic. The pharmaceutical compositions described herein can optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the pharmaceutical composition can range from 3 to 11, but is typically 7 to 10. In some embodiments, the pH of the pharmaceutical composition ranges from about 2 to about 5, but is typically about 3 to 4.

[0038] The pharmaceutical compositions described herein comprise at least one active ingredient (e.g., a compound of Formula I, Formula Ia, Formula Ib, or a pharmaceutically acceptable salt or deuterated analog thereof), together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients, e.g., one or more additional therapeutic ingredients described herein. The one or more carriers are pharmaceutically acceptable, i.e., the one or more carriers are compatible with the other ingredients of the pharmaceutical composition and physiologically non-toxic to the recipient thereof.

[0039] Pharmaceutical compositions may be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. General techniques and formulations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include, for example, bringing the active ingredient into association with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions described herein can be prepared, for example, by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0040] Pharmaceutical compositions suitable for oral administration may be presented in the form of 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 suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0041] For oral use, the pharmaceutical compositions described herein may be in the form of, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation.

[0042] For example, a pharmaceutical composition in the form of a tablet may contain the active ingredient in admixture with one or more pharmaceutically acceptable carriers suitable for the manufacture of acceptable tablets. These carriers may include, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc.

[0043] Tablets can be made by compression or molding with one or more pharmaceutically acceptable carriers. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with, for example, a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and can optionally be formulated to provide sustained or controlled release of the active ingredient therefrom. For example, tablets can be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax.

[0044] The pharmaceutical compositions described herein may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0045] Aqueous suspensions of the pharmaceutical compositions described herein may contain the active ingredient in admixture with one or more pharmaceutically acceptable carriers suitable for the manufacture of aqueous suspensions. Such carriers include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins and Captisol (= sulfobutyl ether beta-cyclodextrin, SEB-beta-CD).

[0046] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0047] Pharmaceutical compositions described herein in the form of dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can contain 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 mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0048] The pharmaceutical compositions described herein may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, 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. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, flavorings, or coloring agents.

[0049] The pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques, for example, using suitable dispersing or wetting agents and suspending agents described herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic mono- or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, may also be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0050] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the patient and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain about 1 to 1,000 mg of active ingredient, combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution, thereby allowing infusion of a suitable volume at a rate of 30 mL / hour.

[0051] Pharmaceutical compositions suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0052] The pharmaceutical compositions may be presented in unit-dose or multi-dose form, for example, in sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein recited, of the active ingredient, or an appropriate fraction thereof.

[0053] It will be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions described herein 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.

[0054] Further provided are veterinary compositions comprising at least one active ingredient described herein together with a veterinary carrier therefor. The veterinary carrier may be a solid, liquid, or gaseous substance useful for purposes of administering the composition and otherwise inert or acceptable in veterinary technology and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0055] The compounds and pharmaceutical compositions described herein can be administered by any route appropriate for the condition to be treated or prevented. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of the compounds described herein is that they are orally bioavailable and can be administered orally.

[0056] In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula Ia, or Formula Ib), or a pharmaceutically acceptable salt or deuterated analog thereof, is administered orally. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered parenterally.

[0057] In some embodiments, the pharmaceutical compositions described herein are administered orally. In some embodiments, the pharmaceutical compositions described herein are administered parenterally.

[0058] In some embodiments, the patient is a human. In the methods described herein, the compounds and pharmaceutical compositions described herein can be administered at any time to a human who may come into contact with a human suffering from a poxvirus infection or who already has a poxvirus infection. In some embodiments, the compounds described herein can be administered prophylactically to a human, such as a healthcare provider, who comes into contact with a human suffering from a poxvirus infection or is at risk of coming into contact with a human suffering from a poxvirus infection. In some embodiments, the compounds described herein can be administered to a human who has tested positive for a poxvirus infection but has not yet shown symptoms of the viral infection. In some embodiments, the compounds described herein can be administered to a human at the onset of symptoms of a poxvirus infection.

[0059] In some embodiments, the methods described herein involve event-driven administration of a compound or pharmaceutical composition described herein to a subject. As used herein, the term "event-driven" or "event-driven administration" refers to administration of a compound or pharmaceutical composition (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the individual to a poxvirus (or otherwise increases the individual's risk of becoming infected with a poxvirus), and / or (2) during an event (or two or more recurring events) that exposes the individual to a poxvirus (or otherwise increases the individual's risk of becoming infected with a poxvirus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the individual to a poxvirus (or otherwise increases the individual's risk of becoming infected with a poxvirus). In some embodiments, event-driven administration occurs before the subject's exposure to a poxvirus. In some embodiments, event-driven administration occurs after the subject's exposure to a poxvirus. In some embodiments, event-driven administration occurs before the subject's exposure to a poxvirus and after the subject's exposure to a poxvirus.

[0060] In some embodiments, the compound or pharmaceutical composition is administered before the subject's exposure to a poxvirus. In some embodiments, the compound or pharmaceutical composition is administered before or after the subject's exposure to a poxvirus. In some embodiments, the compound or pharmaceutical composition is administered after the subject's exposure to a poxvirus.

[0061] An example of an event-driven dosing regimen includes administering the compound or pharmaceutical composition within 24 hours to 2 hours before exposure to the poxvirus, followed by administering the compound or pharmaceutical composition every 24 hours during the exposure period, followed by another dose of the compound or pharmaceutical composition after the final exposure, and finally administering the compound or pharmaceutical composition 24 hours later.

[0062] A further example of an event-driven dosing regimen includes administering the compound or pharmaceutical composition within 24 hours before exposure to a poxvirus, then daily for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0063] The effective dose of the active ingredients described herein will depend, at least, on the nature of the condition being treated or prevented, toxicity, whether the compound is being used prophylactically or against an active viral infection, the delivery method, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose-escalation studies. This can be expected to be about 0.0001 to about 100 mg / kg body weight per day, typically 0.01 to 10 mg / kg body weight per day, more typically about 0.01 to about 5 mg / kg body weight per day, and most typically about 0.05 to about 0.5 mg / kg body weight per day. For example, the daily candidate dose for an adult weighing approximately 70 kg will range from 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can take the form of single or multiple doses.

[0064] The effective dose of a compound described herein for treating or preventing a poxvirus infection may depend on whether the dose is used prophylactically or to treat a person already suffering from a poxvirus infection. Furthermore, the dose may depend on whether the person suffering from a poxvirus infection has not yet shown symptoms of poxvirus infection or is already showing symptoms. Compared to people receiving prophylactic treatment, larger doses may be required to treat people who test positive for a poxvirus infection and people who show symptoms of a poxvirus infection.

[0065] Any suitable period for administering the compounds and pharmaceutical compositions described herein is contemplated. For example, administration can be for 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also be for 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer administration periods are also contemplated. The duration of administration can depend on whether the compound is being administered prophylactically or to treat a human suffering from a poxvirus infection. For example, prophylactic administration can be during the period in which a human regularly comes into contact with other humans suffering from a poxvirus infection, and for a suitable period after the last contact with a human suffering from a poxvirus infection. For humans already suffering from a poxvirus infection, the administration period can be any time necessary to treat the patient and a suitable period after testing negative for the poxvirus infection to ensure that the poxvirus infection does not recur.

[0066] In some embodiments, a compound described herein (e.g., a compound of Formula I, Formula Ia, or Formula Ib), or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once daily. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once every other day. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once every three days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once weekly. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered twice weekly.

[0067] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once daily for 5 days, hi some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered once daily for 10 days.

[0068] In some embodiments, the pharmaceutical compositions described herein are administered once daily. In some embodiments, the pharmaceutical compositions described herein are administered once every other day. In some embodiments, the pharmaceutical compositions described herein are administered once every three days. In some embodiments, the pharmaceutical compositions described herein are administered once weekly. In some embodiments, the pharmaceutical compositions described herein are administered twice weekly.

[0069] In some embodiments, the pharmaceutical compositions described herein are administered once daily for 5 days, hi some embodiments, the pharmaceutical compositions described herein are administered once daily for 10 days.

[0070] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered in a dosage of 5 mg to 500 mg. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered in a dosage of 5 mg to 300 mg. In some embodiments, 5 to 300 mg of a compound described herein is administered once daily, for example, for 6 to 12 days. In some embodiments, 5 to 300 mg of a compound described herein is administered once daily, for example, for 5 or 10 days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered in a dosage of 100 mg or 200 mg. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered in a dosage of 100 mg. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, is administered in a dosage of 200 mg. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analogue thereof, is administered at a dosage of 0.1 mg / kg to 15 mg / kg, e.g., 0.1 mg / kg to 10 mg / kg. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or deuterated analogue thereof, is administered at a dosage of 0.1 mg / kg to 15 mg / kg.

[0071] The compounds and pharmaceutical compositions described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein is a method for treating a poxvirus infection in a patient in need thereof, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, and further comprising administering to the patient a therapeutically effective amount of an additional therapeutic agent. Also provided herein is a method for treating a poxvirus infection in a patient in need thereof, comprising administering to the patient a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound described herein, or a pharmaceutically acceptable salt or deuterated analog thereof, and further comprises an additional therapeutic agent.

[0072] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the additional therapeutic agent is selected from a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a polymerase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A / NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, or any combination thereof.

[0073] In some embodiments, the additional therapeutic agent is one or more 5-substituted 2'-deoxyuridine analogs, hi some embodiments, the one or more additional therapeutic agents comprise idoxuridine, trifluridine, brivudine [BVDU], or any combination thereof.

[0074] In some embodiments, the additional therapeutic agent comprises one or more nucleoside analogs. In some embodiments, the additional therapeutic agent comprises vidarabine, entecavir (ETV), telbivudine, lamivudine, famciclovir, clevudine, or any combination thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, or a combination thereof. In some embodiments, the additional therapeutic agent is β-D-N4-hydroxycytidine.

[0075] In some embodiments, the additional therapeutic agent comprises one or more pyrophosphate analogs. In some embodiments, the additional therapeutic agent comprises foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent comprises foscarnet.

[0076] In some embodiments, the additional therapeutic agent comprises one or more polymerase inhibitors. In some embodiments, the additional therapeutic agent comprises one or more DNA polymerase inhibitors. In some embodiments, the additional therapeutic agent comprises cidofovir. In some embodiments, the additional therapeutic agent comprises lamivudine.

[0077] In some embodiments, the additional therapeutic agent comprises one or more nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent comprises zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, or any combination thereof. In some embodiments, the additional therapeutic agent comprises sangivamycin, β-d-N4-hydroxycytidine (NHC), EIDD-2801, EIDD-1931, or any combination thereof. In some embodiments, the additional therapeutic agent comprises MK-4482 (EIDD-2801).

[0078] In some embodiments, the additional therapeutic agent comprises one or more non-nucleoside reverse transcriptase inhibitors, hi some embodiments, the additional therapeutic agent comprises nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, doravirine, or any combination thereof.

[0079] In some embodiments, the additional therapeutic agent comprises one or more nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is islatravir.

[0080] In some embodiments, the additional therapeutic agent comprises one or more protease inhibitors. In some embodiments, the additional therapeutic agent comprises an HIV protease inhibitor. In some embodiments, the additional therapeutic agent comprises saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, or any combination thereof. In some embodiments, the additional therapeutic agent comprises saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises an HCV NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent comprises voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, or any combination thereof.

[0081] In some embodiments, the additional therapeutic agent comprises one or more integrase inhibitors. For example, in some embodiments, the additional therapeutic agent comprises raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, or any combination thereof. In some embodiments, the additional therapeutic agent comprises bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises bictegravir, dolutegravir, and cabotegravir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises bictegravir.

[0082] In some embodiments, the additional therapeutic agent comprises one or more entry inhibitors. In some embodiments, the additional therapeutic agent comprises docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), varicella-zoster immunoglobulin (VariZIG), varicella-zoster immune globulin (VZIG), or any combination thereof.

[0083] In some embodiments, the additional therapeutic agent comprises one or more acyclic guanosine analogs, hi some embodiments, the additional therapeutic agent comprises acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, or any combination thereof.

[0084] In some embodiments, the additional therapeutic agent comprises one or more acyclic nucleoside phosphonate analogs. In some embodiments, the additional therapeutic agent comprises cidofovir, emtricitabine, efavirenz, rilpivirine, elvitegravir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises cidofovir.

[0085] In some embodiments, the additional therapeutic agent comprises one or more HCV NS5A or NS5B inhibitors. In some embodiments, the additional therapeutic agent comprises one or more chemotherapeutic NS3 / 4A protease inhibitors. In some embodiments, the additional therapeutic agent comprises one or more NS5A protein inhibitors. In some embodiments, the additional therapeutic agent comprises one or more nucleoside / nucleotide NS5B polymerase inhibitors. In some embodiments, the additional therapeutic agent comprises one or more non-nucleoside NS5B polymerase inhibitors. In some embodiments, the additional therapeutic agent comprises daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, bemnifosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, bemnifosbuvir, dasabuvir, or any combination thereof.

[0086] In some embodiments, the additional therapeutic agent is molnupiravir (EIDD-2801), ASC-10, or any combination thereof.

[0087] In some embodiments, the additional therapeutic agent comprises one or more influenza virus inhibitors. In some embodiments, the additional therapeutic agent comprises one or more matrix 2 inhibitors. In some embodiments, the additional therapeutic agent comprises amantadine, rimantadine, or any combination thereof. In some embodiments, the additional therapeutic agent comprises one or more neuraminidase inhibitors. For example, in some embodiments, the additional therapeutic agent comprises zanamivir, oseltamivir, peramivir, laninamivir octanoate, or any combination thereof. In some embodiments, the additional therapeutic agent comprises one or more polymerase inhibitors. In some embodiments, the additional therapeutic agent comprises ribavirin, favipiravir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent comprises amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, or any combination thereof. In some embodiments, the additional therapeutic agent comprises DAS-181 or XC-221.

[0088] In some embodiments, the additional therapeutic agent comprises one or more interferons. In some embodiments, the additional therapeutic agent comprises interferon alfacon-1, interferon alfa-1b, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfacon-1, pegylated interferon alfa-1b, pegylated interferon alfa-2a (PegIFN-α-2a), and PegIFN-α-2b, or any combination thereof. In some embodiments, the additional therapeutic agent comprises interferon alfacon-1, interferon alfa-1b, interferon alfa-2a, interferon alfa-2b, pegylated interferon alfa-2a (PegIFN-α-2a), PegIFN-α-2b, or any combination thereof. In some embodiments, the additional therapeutic agent comprises interferon alfacon-1, pegylated interferon alfa-2a (PegIFN-α-2a), PegIFN-α-2b, ribavirin, or any combination thereof. In some embodiments, the additional therapeutic agent comprises pegylated interferon alpha-2a, pegylated interferon alpha-2b, or any combination thereof. In some examples, the additional therapeutic agent comprises interferon beta. For example, the additional therapeutic agent comprises interferon beta-1a, such as SNG-001. In some embodiments, the additional therapeutic agent comprises one or more interferon inducers, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent comprises an IL-17 antagonist, such as ixekizumab. In some embodiments, the additional therapeutic agent comprises an interferon alpha 2 ligand, secukinumab, IMU-838, or bidofludimus, or any combination thereof.

[0089] In some embodiments, the additional therapeutic agent comprises one or more immunostimulants. In some embodiments, the additional therapeutic agent comprises one or more oligonucleotides. In some embodiments, the additional therapeutic agent comprises one or more antimitotic agents. For example, in some embodiments, the additional therapeutic agent comprises fomivirsen, podofilox, imiquimod, sinecatechin, or any combination thereof. In some embodiments, the additional therapeutic agent comprises azeoximer bromide or IMM-101.

[0090] In some embodiments, the one or more additional therapeutic agents include one or more antiviral agents. Any suitable antiviral agent can be used in the methods described herein. For example, in some embodiments, the additional therapeutic agent includes Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent comprises (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, or any combination thereof. In some embodiments, the additional therapeutic agent comprises tirabrutinib, ibrutinib, acalabrutinib, or any combination thereof. In some embodiments, the additional therapeutic agent comprises tirabrutinib, ibrutinib, or any combination thereof. In some embodiments, the additional therapeutic agent comprises one or more receptor tyrosine kinase inhibitors (RTKIs). In some embodiments, the additional therapeutic agent comprises tyrphostin A9 (A9). In some embodiments, the additional therapeutic agent comprises one or more TEK receptor tyrosine kinase inhibitors. In some embodiments, the additional therapeutic agent comprises abivertinib maleate (STI-5656). In some embodiments, the additional therapeutic agent comprises one or more tyrosine kinase inhibitors, such as masitinib.

[0091] In some embodiments, the additional therapeutic agent comprises one or more sphingosine kinase-2 (sk2) inhibitors, such as opaganib. In some embodiments, the additional therapeutic agent comprises one or more kinase inhibitors, such as pacritinib. In some embodiments, the additional therapeutic agent comprises one or more Axl tyrosine kinase receptor inhibitors, such as bemcentinib. In some embodiments, the additional therapeutic agent comprises one or more FYVE finger phosphoinositide kinase inhibitors. In some embodiments, the additional therapeutic agent comprises one or more checkpoint kinase inhibitors, such as prexasertib. In some embodiments, the additional therapeutic agent comprises one or more MAP kinase inhibitors, such as KTH-222 and ATI-450. In some embodiments, the additional therapeutic agent comprises one or more mTOR inhibitors, such as sirolimus. In some embodiments, the additional therapeutic agent comprises one or more pi3k / mTOR inhibitors, such as dactolisib. In some embodiments, the additional therapeutic agent comprises one or more Hsp90 inhibitors, such as ganetespib and ADX-1612. In some embodiments, the additional therapeutic agent comprises one or more MEK inhibitors, such as ATR-002. In some embodiments, the additional therapeutic agent comprises one or more topoisomerase II inhibitors, such as etoposide. In some embodiments, the additional therapeutic agent comprises one or more exportin 1 inhibitors, such as selinexor or veldinexor. In some embodiments, the additional therapeutic agent comprises one or more dual inhibitors of PARP1 / 2 and tankyrase1 / 2, such as 2X-121. In some embodiments, the additional therapeutic agent comprises one or more cyclin-dependent kinase inhibitors, such as CYC-065 or CYC-202. In some embodiments, the additional therapeutic agent comprises one or more cytosine DNA methyltransferase inhibitors, such as decitabine. In some embodiments, the additional therapeutic agent comprises one or more DHFR inhibitors, such as methotrexate. In some embodiments, the additional therapeutic agent comprises one or more small ubiquitin-related modifier inhibitors, such as TAK-981. In some embodiments, the additional therapeutic agent comprises one or more integrin agonists, such as 7HP-349.In some embodiments, the additional therapeutic agent comprises one or more sBET inhibitors, such as apabetalone. In some embodiments, the additional therapeutic agent comprises one or more BRD4 inhibitors, such as CPI-0610, ABBV-744. In some embodiments, the additional therapeutic agent comprises one or more ER1 inhibitors, such as toremifene.

[0092] In some embodiments, the additional therapeutic agent comprises one or more KRAS inhibitors. In some embodiments, the additional therapeutic agent comprises MRTX-849(G12C) and K-Ras(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), or any combination thereof.

[0093] In some embodiments, the additional therapeutic agent comprises one or more inflammation inhibitors, such as pirfenidone. In some embodiments, the additional therapeutic agent comprises LYT-100.

[0094] In some embodiments, the additional therapeutic agent comprises dosiparstat sodium. In some embodiments, the additional therapeutic agent comprises one or more agents used to treat septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent comprises one or more CCR1 antagonists, such as MLN-3897. In some embodiments, the additional therapeutic agent comprises one or more agents that target IKKβ and NFκβ, such as OP-101. In some embodiments, the additional therapeutic agent comprises one or more glucocorticoid receptor agonists, such as hydrocortisone or dexamethasone. In some embodiments, the additional therapeutic agent comprises one or more immunosuppressants, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, or M-5049. In some embodiments, the additional therapeutic agent comprises one or more RIP-1 kinase inhibitors, such as DNL-758. In some embodiments, the additional therapeutic agent comprises one or more IL-8 receptor antagonists, such as BMS-986253 (HuMax-IL8). In some embodiments, the additional therapeutic agent comprises one or more CD14 inhibitors, such as IC-14. In some embodiments, the additional therapeutic agent comprises one or more dihydroorotate dehydrogenase (DHODH) inhibitors, such as brequinar or PCT-299. In some embodiments, the additional therapeutic agent comprises one or more antifibrotic agents, such as RT-1840, nintedanib, GB-0139, nintedanib, or pamrevlumab. In some embodiments, the additional therapeutic agent comprises one or more hepatocyte growth factor (HGF) mimetics, such as SNV-003 (ANG-3777).

[0095] In some embodiments, the additional therapeutic agent comprises one or more vaccines. For example, in some embodiments, the additional therapeutic agent comprises a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent comprises a DNA vaccine. In some embodiments, the additional therapeutic agent comprises an RNA vaccine. In some embodiments, the additional therapeutic agent comprises a live attenuated vaccine. In some embodiments, the additional therapeutic agent comprises a therapeutic vaccine. In some embodiments, the additional therapeutic agent comprises a prophylactic vaccine. In some embodiments, the additional therapeutic agent comprises a protein-based vaccine.

[0096] In some embodiments, the additional therapeutic agent comprises one or more poxvirus vaccines. In some embodiments, the additional therapeutic agent comprises one or more vaccinia virus vaccines. In some embodiments, the additional therapeutic agent comprises one or more vaccines effective against variola virus (smallpox), monkeypox virus, or both. In some embodiments, the additional therapeutic agent comprises one or more vaccines effective against variola virus (smallpox). In some embodiments, the additional therapeutic agent comprises JYNNEOS (also known as Imvamune or Imvanex), ACAM2000, Aventis Pasteur smallpox vaccine (APSV), or a combination thereof. In some embodiments, the additional therapeutic agent comprises one or more vaccines effective against monkeypox virus. In some embodiments, the additional therapeutic agent comprises ACAM2000, MVA-BN, or both. In some embodiments, the additional therapeutic agent comprises JYNNEOS. In some embodiments, the additional therapeutic agent comprises ACAM2000. In some embodiments, the additional therapeutic agent comprises MVA-BN.

[0097] In some embodiments, the additional therapeutic agent comprises one or more antibodies, e.g., one or more monoclonal antibodies. In some embodiments, the additional therapeutic agent comprises one or more antibodies that bind to a poxvirus. In some embodiments, the additional therapeutic agent comprises an anti-CD147 antibody. In some embodiments, the additional therapeutic agent comprises meplasmab.

[0098] In some embodiments, the additional therapeutic agent comprises one or more immunomodulatory agents. Examples of immune system therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13, programmed cell death protein 1 (Pd-1) modulators, programmed death-ligand 1 (Pd-L1) modulators, IL-15 modulators, DermaVir, interleukin-7, Plaquenil (hydroxychloroquine), Proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MPA). mofetil, MMF), ribavirin, polymer polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent comprises fingolimod, leflunomide, or any combination thereof. In some embodiments, the additional therapeutic agent comprises thalidomide. In some embodiments, the additional therapeutic agent comprises CD24Fc. In some embodiments, the additional therapeutic agent comprises one or more type I IL-1 receptor antagonists, such as anakinra.In some embodiments, the additional therapeutic agent comprises one or more TLR4 antagonists, such as EB-05.

[0099] In some embodiments, the additional therapeutic agent comprises one or more agents for treating a poxvirus infection. In some embodiments, the poxvirus is smallpox virus, vaccinia virus, cowpox virus, rabbitpox virus, orf virus, pseudocowpox virus, bovine papular stomatitis virus, tanapox virus, yaba monkey tumor virus, molluscum contagiosum virus, or monkeypox virus. In some embodiments, the poxvirus is variola virus. In some embodiments, the additional therapeutic agent comprises cidofovir, brincidofovir (tembexa), tecovirimat, or ST-246 (TPOXX), intravenous vaccinia immune globulin (VIGIV), or any combination thereof. In some embodiments, the additional therapeutic agent is tecovirimat, brincidofovir, or cidofovir. In some embodiments, the additional therapeutic agent comprises brincidofovir, tecovirimat, or both. In some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is brincidofovir. In some embodiments, the additional therapeutic agent is tecovirimat. In some embodiments, the additional therapeutic agent is intravenous vaccinia immune globulin.

[0100] In some embodiments, the additional therapeutic agent comprises one or more agents for treating molluscum contagiosum virus infection. In some embodiments, the additional therapeutic agent is cimetidine. In some embodiments, the additional therapeutic agent comprises podophyllotoxin, iodine and salicylic acid, potassium hydroxide, tretinoin, cantharidin, imiquimod, or a combination thereof.

[0101] In some embodiments, the additional therapeutic agent comprises a compound selected from adefovir, tenofovir, adefovir dipivoxil, tenofovir disoproxil, tenofovir disoproxil hemifumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and tenofovir alafenamide fumarate. In some embodiments, the additional therapeutic agent is adefovir. In some embodiments, the additional therapeutic agent is tenofovir. In some embodiments, the additional therapeutic agent is adefovir dipivoxil. In some embodiments, the additional therapeutic agent is tenofovir disoproxil. In some embodiments, the additional therapeutic agent is tenofovir disoproxil hemifumarate. In some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate. In some embodiments, the additional therapeutic agent is tenofovir alafenamide. In some embodiments, the additional therapeutic agent is tenofovir alafenamide hemifumarate. In some embodiments, the additional therapeutic agent is tenofovir alafenamide fumarate.

[0102] The compounds and pharmaceutical compositions described herein can also be used in combination with the general care provided to patients with poxvirus infections, which may include parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients (including metronidazole and cephalosporin antibiotics (e.g., ceftriaxone and cefuroxime) and / or antifungal prophylaxis), fever and pain medications (e.g., acetaminophen), topical steroids or anesthetics (e.g., lidocaine), antiemetics (e.g., metoclopramide) and / or antidiarrheal medications, stool softeners, oral antiseptics (e.g., chlorhexidine mouthwash), analgesic mouthwashes (e.g., those containing antihistamines and / or anesthetics), oral antihistamines, , topical medications to prevent itching (e.g., calamine lotion, petrolatum, or colloidal oatmeal), vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory drugs (e.g., ibuprofen or steroids), corticosteroids (e.g., methylprednisolone), pain medications (e.g., gabapentin or opioids), and medications for other common illnesses in the patient population (e.g., malaria (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin).

[0103] Co-administration of a compound or pharmaceutical composition described herein with one or more other additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound or pharmaceutical composition described herein with one or more other additional therapeutic agents such that therapeutically effective amounts of both the compound or pharmaceutical composition of the invention and the one or more other active therapeutic agents are present in the patient's body.

[0104] In some embodiments, the compound or a pharmaceutically acceptable salt or deuterated analog thereof and the additional therapeutic agent are administered simultaneously. In some embodiments, the pharmaceutical composition and the additional therapeutic agent are administered simultaneously. In some embodiments, the compound or a pharmaceutically acceptable salt or deuterated analog thereof and the additional therapeutic agent are administered sequentially. In some embodiments, the pharmaceutical composition and the additional therapeutic agent are administered sequentially.

[0105] Co-administration includes administration of a unit dose of a compound or pharmaceutical composition described herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound or pharmaceutical composition described herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, a unit dose of a compound or pharmaceutical composition described herein can be administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound or pharmaceutical composition described herein. In some cases, it may be desirable to administer a unit dose of a compound or pharmaceutical composition described herein first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other additional therapeutic agents. In other embodiments, it may be desirable to administer a unit dose of one or more additional therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound or pharmaceutical composition described herein.

[0106] The combination therapies described herein may provide "synergy" or "synergistic effects," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the compounds described herein and one or more additional therapeutic agents are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds or pharmaceutical compositions described herein are administered or delivered sequentially, for example, by separate injections in separate tablets, pills, capsules, or separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination.

[0107] Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, for use in treating a poxvirus infection.

[0108] Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, for use in the prevention of poxvirus infection.

[0109] In some embodiments, the compound for use is a compound of formula Ia: In some embodiments, the compound for use is a compound of formula Ib:

[0110] Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, in the preparation of a medicament for treating a poxvirus infection.

[0111] Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or deuterated analogue thereof, in the preparation of a medicament for preventing poxvirus infection.

[0112] In some embodiments, the compound for use is a compound of formula Ia: In some embodiments, the compound for use is a compound of formula Ib:

[0113] Also provided are kits comprising a compound of Formula I or a pharmaceutically acceptable salt or deuterated analogue thereof and instructions for their use in treating poxvirus infection.

[0114] Also provided are kits comprising a compound of Formula I or a pharmaceutically acceptable salt or deuterated analogue thereof and instructions for their use in preventing poxvirus infection.

[0115] In some embodiments, the kit comprises a compound of formula Ia. In some embodiments, the kit comprises a compound of formula Ib.

[0116] In some embodiments, the kit may contain a single dosage unit and other multiple dosage units, such as the number of dosage units required for a particular regimen or time period.

[0117] Any formula or structure provided herein, including compounds of Formula I, Formula Ia, and Formula Ib, is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients.

[0118] The present disclosure also includes compounds (e.g., compounds of Formula I, Formula Ia, and Formula Ib) in which 1 to x hydrogens bonded to a carbon atom are replaced by deuterium, where x is the number of hydrogens in the molecule. In some embodiments, deuterated analogs of compounds disclosed herein are compounds in which one or more hydrogens bonded to a carbon of the compound are replaced by deuterium. In some embodiments, deuterated analogs are compounds of Formula I in which one or more hydrogens bonded to a carbon of the compound of Formula I are replaced by deuterium. In some embodiments, deuterated analogs are compounds of Formula Ia in which one or more hydrogens bonded to a carbon of the compound of Formula Ia are replaced by deuterium. In some embodiments, deuterated analogs are compounds of Formula Ib in which one or more hydrogens bonded to a carbon of the compound of Formula Ib are replaced by deuterium. In some embodiments, deuterated analogs of compounds disclosed herein are compounds in which one hydrogen bonded to a carbon of the compound is replaced by deuterium.

[0119] Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound described herein when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). In light of the present disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0120] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below. It is understood that deuterium in this context is considered a substituent in the compounds of Formula I, Formula Ia, and Formula Ib. [Example]

[0121] Example 1. In vitro antiviral activity against vaccinia virus

[0122] Compounds of Formula Ia were tested for in vitro antiviral activity against vaccinia virus (modified vaccinia virus Ankara; MVA) in BHK-21 baby hamster kidney cells. Compounds of Formula Ia were serially diluted using eight half-log dilutions in test medium (MEM + 5% fetal bovine serum and 50 μg / mL). Each dilution was added to five wells of a 96-well plate containing 80-100% confluent cells. Three wells of each dilution were infected with virus, and two wells were left uninfected as toxicity controls. Six wells were infected and untreated as virus controls, and six wells were uninfected and untreated as cell controls. Virus was prepared to achieve an MOI of 0.02. Cidofovir was tested in parallel as a positive control. Assay plates were incubated at 37 ± 2°C and 5% CO2 for 3 days. On day 3 post-infection, untreated virus control wells reached maximum CPE, and plates were stained with neutral red dye for approximately 2 hours (±15 minutes). The supernatant dye was removed, and wells were rinsed with phosphate-buffered saline (PBS). The incorporated dye was extracted in 50:50 Sorensen citrate buffer / ethanol for 30 minutes, and optical density was read at 540 nm on a spectrophotometer. Optical density was converted to a percent of the cell control and normalized to the virus control. The concentration of compound of Formula Ia required to inhibit CPE by 50% (EC 50 ) was calculated by regression analysis. The concentration of the compound of formula Ia that causes 50% cell death in the absence of virus (CC 50 ) was calculated in the same way. The selectivity index (SI) was calculated by 50 EC 50 It is divided by .

[0123] The in vitro antiviral results of the compound of formula Ia against vaccinia virus are shown in Table 1. The in vitro antiviral results of the compound of formula Ia against vaccinia virus for tests 1-3 are shown in Table 1A. [Table 1] [Table 1A]

[0124] Example 2. Vaccinia virus cellomics assay

[0125] Compounds of Formula Ia were tested for their ability to inhibit vaccinia virus replication by monitoring levels of vaccinia virus fusion protein A27L using a high-throughput image-based Cellomics assay.

[0126] BHK-21 cells (Baby Hamster Kidney Cell Line 21, ATCC, CCL-10) were maintained in EMEM medium (ATCC, 30-2003) supplemented with 10% FBS (Corning, 35-011-CV) and 1% penicillin-streptomycin (Corning, 30-002-CI). Prior to confluence, BHK21 cells were removed with 0.25% trypsin (Gibco, 25200-056), neutralized with culture medium, and resuspended in assay medium (EMEM, 2% FBS, 1% penicillin-streptomycin). The cell density was adjusted to 450,000 cells / mL, and 20 μl / well of the cell suspension was added to a 384-well microplate (cellomics plate: Greiner, 781946; cytotoxicity plate: Corning, 3765) and incubated overnight at 37°C and 5% CO .

[0127] Ten doses of three-fold serial dilutions of the compound of Formula Ia were prepared at a starting concentration of 10 mM in 100% DMSO. 150 nL of compound was spotted onto the plate in quadruplicate using an HP D300e dispenser. The final starting concentration in the assay was 50 μM DMSO (no compound, negative control), and brincidofovir and / or tecovirimat (positive control) were included in each microplate. Vaccinia virus (MVA strain: ATCC, VR1508) was diluted in assay medium and added to the Cellomics plate at 10 μL / well to achieve an MOI of 0.04. For the cytotoxicity plate, 10 μL / well of assay medium (without virus) was added to all wells. The plate was then incubated at 37°C, 5% CO2 for 2 days.

[0128] The cell culture medium was aspirated, and the cells were fixed with 40 μL / well of paraformaldehyde solution (Electron Microscopy Sciences, 15712-S) diluted to 4% in DPBS (Corning, 21-031-CM). After 30 minutes of incubation at room temperature, the plate was washed once with 80 μL / well of DPBS. 7.5 μg / mL of anti-vaccinia antibody (Abcam, 35219) was prepared in staining buffer (PBS + 0.1% Triton® X-100 + 0.2% gelatin), and 25 μL / well was added to each well. The plate was incubated at room temperature for 1 hour. After washing the plate with 80 μL / well of PBS, 25 μL / well of a 1:1000 solution of secondary antibody (Alexa Fluor 488 goat anti-rabbit: Jackson Immuno Research, 711-095-152) and DAPI (Thermo Fisher Scientific, 62248) in staining buffer was added to the wells, and the plate was incubated in the dark at room temperature for 1 hour. The plate was washed once with 80 μL / well of PBS and then sealed with a black adhesive seal. Fluorescence was measured using a Cellomics plate reader. For cytotoxicity plates, 30 μL / well of CellTiter-Glo (Promega, G7570) was added to the plate, followed by a 15-minute incubation at room temperature, after which luminescence was quantified using an Envision plate reader.

[0129] Data analysis was performed using Thermo Scientific HCS Studio software. Cells were identified using DAPI nuclear staining, and a threshold was set to exclude cells based on shape and size. A second threshold based on green fluorescence intensity (detection of the vaccinia virus fusion protein A27L) was set to identify vaccinia-infected cells. Data were reported as the mean fluorescent area of ​​vaccinia-infected cells per object. EC 50 The CC value was defined as the compound concentration that reduced the mean fluorescent area by 50% and was calculated using a sigmoidal dose-response model to generate a curve fit. 50Values ​​were calculated similarly using luminescence signals normalized by the DMSO control.

[0130] The assay results for compounds of formula Ia (n=3) are shown in Table 2. [Table 2]

[0131] Assay results for compounds of Formula Ia (n=4) are shown in Table 2A. [Table 2A]

[0132] All references, including publications, patents, and patent documents, are incorporated herein by reference, as if individually incorporated by reference. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the disclosure. The description is to be considered as exemplary of the claimed subject matter, with the understanding that it is not intended to limit the scope of the appended claims to the specific embodiments illustrated.

Claims

1. 1. A method of treating a poxvirus infection in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound of formula I: 【Transformation 5】 or a pharmaceutically acceptable salt or deuterated analog thereof.

2. The compound is a compound of formula Ia, 【Transformation 6】 or a pharmaceutically acceptable salt thereof or a deuterated analog thereof.

3. 3. The method of claim 2, wherein the compound is a compound of formula Ia.

4. The compound is a compound of formula Ib, 【Transformation 7】 or a pharmaceutically acceptable salt or deuterated analog thereof.

5. 5. The method of claim 4, wherein the compound is a compound of formula Ib.

6. 10. The method of claim 1, wherein the compound of formula I is administered.

7. 5. The method of any one of claims 1, 2, and 4, wherein the deuterated analog is a compound in which one or more hydrogens bonded to a carbon of the compound are replaced by deuterium.

8. 8. The method of any one of claims 1, 2, 4, and 7, wherein the deuterated analog is a compound in which one hydrogen bonded to a carbon of the compound is replaced with deuterium.

9. 9. The method of any one of claims 1 to 8, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered orally.

10. 9. The method of any one of claims 1 to 8, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered parenterally.

11. 11. The method of any one of claims 1 to 10, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered once daily.

12. 12. The method of any one of claims 1 to 11, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered once daily for five days.

13. 12. The method of any one of claims 1 to 11, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered once daily for 10 days.

14. 14. The method of any one of claims 1 to 13, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered at a dosage of 5 mg to 300 mg.

15. 15. The method of any one of claims 1 to 14, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered in a dosage of 100 mg or 200 mg.

16. 15. The method of any one of claims 1 to 14, wherein the compound or the pharmaceutically acceptable salt or deuterated analogue thereof is administered at a dosage of about 0.1 mg / kg to 15 mg / kg.

17. The method of any one of claims 1 to 16, further comprising administering a therapeutically effective amount of an additional therapeutic agent.

18. 18. The method of claim 17, wherein the additional therapeutic agent is an antiviral agent.

19. 19. The method of claim 17 or 18, wherein the additional therapeutic agent is tecovirimat or ST-246 (TPOXX), brincidofovir (tembexa), or cidofovir.

20. 19. The method of claim 17 or 18, wherein the additional therapeutic agent is intravenous vaccinia immune globulin (VIGIV).

21. 1. A method of treating a poxvirus infection in a patient in need thereof, said method comprising administering to said patient a compound of formula I: 【Transformation 8】 or a pharmaceutically acceptable salt or deuterated analog thereof, and one or more pharmaceutically acceptable carriers.

22. The pharmaceutical composition comprises a compound of formula Ia: 【Chemistry 9】 or a pharmaceutically acceptable salt or deuterated analog thereof.

23. The pharmaceutical composition comprises a compound of formula Ib, 【Chemistry 10】 or a pharmaceutically acceptable salt or deuterated analog thereof.

24. 24. The method of any one of claims 21 to 23, wherein the deuterated analog is a compound in which one or more hydrogens bonded to a carbon of the compound are replaced by deuterium.

25. 25. The method of any one of claims 21 to 24, wherein the deuterated analog is a compound in which one hydrogen bonded to a carbon of the compound is replaced by deuterium.

26. The method of any one of claims 21 to 25, wherein the pharmaceutical composition is administered orally.

27. The method of any one of claims 21 to 25, wherein the pharmaceutical composition is administered parenterally.

28. 28. The method of any one of claims 21 to 27, wherein the pharmaceutical composition is administered once daily.

29. 29. The method of any one of claims 21 to 28, wherein the pharmaceutical composition is administered once daily for five days.

30. 29. The method of any one of claims 21 to 28, wherein the pharmaceutical composition is administered once daily for 10 days.

31. The method of any one of claims 21 to 30, wherein the pharmaceutical composition further comprises an additional therapeutic agent.

32. 32. The method of claim 31 , wherein the additional therapeutic agent is an antiviral agent.

33. 33. The method of claim 31 or 32, wherein the additional therapeutic agent is tecovirimat or ST-246 (TPOXX), brincidofovir (tembexa), or cidofovir.

34. 33. The method of claim 31 or 32, wherein the additional therapeutic agent is intravenous vaccinia immune globulin (VIGIV).

35. The method of any one of claims 1 to 34, wherein the poxvirus infection is an orthopoxvirus infection.

36. 36. The method of any one of claims 1 to 35, wherein the poxvirus infection is a camelpox virus infection, a cowpox virus infection, an ectromelia virus infection, a horsepox virus infection, a monkeypox virus infection, a raccoonpox virus infection, a skunkpox virus infection, a taterapox virus infection, a Uasin Gishu virus infection, a vaccinia virus infection, a variola virus infection, or a bolepovirus infection.

37. The method of any one of claims 1 to 36, wherein the poxvirus infection is a vaccinia virus infection.

38. 37. The method of any one of claims 1 to 36, wherein the poxvirus infection is a monkeypox virus infection.

39. 39. The method of claim 38, wherein the poxvirus infection is caused by a West African strain of monkeypox virus.

40. 39. The method of claim 38, wherein the poxvirus infection is caused by the Congo Basin strain of monkeypox virus.

41. The method of any one of claims 1 to 34, wherein the poxvirus infection is a parapoxvirus infection.

42. 42. The method of claim 41, wherein the poxvirus infection is a bovine papular stomatitis virus infection, an orf virus infection, a pseudocowpox virus infection, a red deer-infected parapoxvirus, or a squirrel parapoxvirus infection.

43. 42. The method of claim 41, wherein the poxvirus infection is a contagious pustular dermatitis of camels (Ausdyk) virus infection, a contagious pustular dermatitis of chamois virus infection, a parapoxvirus of reindeer virus infection, or a sealpox virus infection.

44. The method of any one of claims 1 to 34, wherein the poxvirus infection is a morsipoxvirus infection.

45. 45. The method of claim 44, wherein the poxvirus infection is a molluscum contagiosum infection.

46. The method of any one of claims 1 to 34, wherein the poxvirus infection is a Yatapoxvirus infection.

47. 47. The method of claim 46, wherein the poxvirus infection is tanapoxvirus, yaba-like disease virus infection, or yaba monkey tumor virus infection.

48. The method of any one of claims 1 to 34, wherein the poxvirus infection is a capripoxvirus infection.

49. 49. The method of claim 48, wherein the poxvirus infection is a sheeppox virus infection, a goatpox virus infection, or a lumpy skin disease virus infection.

50. The method of any one of claims 1 to 34, wherein the poxvirus infection is a suipoxvirus infection.

51. 51. The method of claim 50, wherein the poxvirus infection is a swinepox virus infection.

52. The method of any one of claims 1 to 34, wherein the poxvirus infection is a leporipoxvirus infection.

53. 53. The method of claim 52, wherein the poxvirus infection is a myxoma virus infection, a Shope fibroma virus (rabbit fibroma) infection, a squirrel fibroma virus infection, or a hare fibroma virus infection.

54. The method of any one of claims 1 to 34, wherein the poxvirus infection is an avipoxvirus infection.

55. 55. The method of claim 54, wherein the poxvirus infection is a canarypox virus infection, a fowlpox virus infection, a goldfinch pox virus infection, a minnow pox virus infection, a pigeon pox virus infection, a psittacoccus virus infection, a quailpox virus infection, a sparrowpox virus infection, a starling pox virus infection, or a turkeypox virus infection.

56. 55. The method of claim 54, wherein the poxvirus infection is a cloudpox virus infection, a peacockpox virus infection, or a penguinpox virus infection.

57. 57. The method of any one of claims 1 to 56, wherein the patient is a human.

58. A compound of formula I for use in the treatment of poxvirus infections, 【Chemistry 11】 or the compound or a pharmaceutically acceptable salt or deuterated analogue thereof.

59. The compound is a compound of formula Ia, 【Chemistry 12】 59. The compound for use according to claim 58, wherein:

60. A compound of formula I, 【Chemistry 13】 or a pharmaceutically acceptable salt or deuterated analogue thereof in the preparation of a medicament for treating poxvirus infection.

61. The compound is a compound of formula Ia, 【Chemistry 14】 61. The use according to claim 60, wherein the compound is

62. A compound of formula I, 【Chemistry 15】 or a pharmaceutically acceptable salt or deuterated analogue thereof and instructions for their use in the treatment of poxvirus infection.

63. The compound is a compound of formula Ia, 【Chemistry 16】 63. The kit of claim 62, wherein:

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