(S)-8-(BENZHYDRYL )-6-ISOPROPYL-3,5-DIOXO- 5, 6,7,8,-TETRAHYDRO-3H-PYRAZINO-[1 ,2-B]PYRIDAZIN-YL-ISOBUTYRATE

ANTIVIRAL AGENT FOR USE IN TREATING INFLUENZA

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.

Field

[0002] The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are methods of treating an influenza viral infection with one or more aza-pyridone compounds and pharmaceutical compositions thereof.

Description

[0003] Influenza viruses are negative-sense, single-stranded RNA viruses in the Orthomyxoviridae family which contains several genera including Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. Influenza viruses can be transmitted from person to person via direct contact with infected secretions and/or contaminated surfaces or objections and can cause respiratory viral infections, including upper and lower respiratory tract viral infections. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory system below the vocal cords, including the trachea, primary bronchi and lungs. Complications from an influenza viral infection include pneumonia, bronchitis, dehydration, and sinus and ear infections. Respiratory viral infections are a leading cause of death of millions of people each year. There is therefore a need for improved medications to treat respiratory viral infections such as influenza.

[0004] Food can affect the bioavailability of a drug which can have clinically significant consequences. Food can alter the bioavailability of a drug by various means, including, but not limited to, delaying gastric emptying, stimulating bile flow, changing gastrointestinal (GI) pH, increasing splanchnic blood flow, changing luminal metabolism of a drug substance, and/or physically or chemically interacting with a dosage form or a drug substance. These physiological changes in the GI tract can affect the transit time, luminal dissolution, drug permeability, and/or systemic availability of a drug and its metabolites. However, the relative direction and magnitude of food effects on formulation bioavailability are difficult, if not impossible, to predict. See Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2002. Accordingly, the presence of food in the GI tract at the time of administering certain drugs introduces an unpredictable variability in the exposure of the subject to that drug leading to unpredictable efficacy and safety of the drug.

SUMMARY

[0005] The present disclosure generally relates to methods for treating an influenza infection. Embodiments described herein relate to methods for treating an influenza infection that can include administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to methods for treating an influenza infection that involve administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with food.

[0006] Embodiments of the present disclosure also include methods of decreasing the dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for an effective amount of said compound to be administered to a subject being treated for an influenza infection.

[0007] Still yet other embodiments described herein generally relate to a method of increasing the oral bioavailability of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that can include administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with food. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 shows the mean plasma concentration over time after administration of a compound of Formula (I), wherein the dosage form was in the form of a suspension or a tablet and the subject had either fasted or been fed a standard meal.

[0009] Figure 2 shows the mean plasma concentration over time after administration of a compound of Formula (I), wherein the dosage form was in the form of a tablet and the subject had either fasted, been fed a standard meal or been fed a high-fat meal.

DETAILED DESCRIPTION

[0010] Influenza A has been further classified based the hemagglutinin (H or HA) and the neuramididase (N). There are approximately 16 H antigens (HI to HI 6) and 9 N antigens (Nl to N9). Influenza A includes several subtypes, including H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2 and H10N7. The influenza virus polymerase is a heterotrimer composed of three subunits, polymerase acid (PA), polymerase basic 1 (PB1) and polymerase basic 2 (PB2). This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells. The PA subunit contains the endonuclease active site. The endonuclease activity of the PA cleaves the cellular mRNA, which is then used by the PB1 subunit as a primer for the viral mRNA synthesis.

Definitions

[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, definitions in this section prevail unless stated otherwise.

[0012] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Ci-C alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0013] As used herein "with food" or "in the presence of food" means administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at the same time or at substantially the same time as consuming food. For example, administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may occur between 30 minutes prior to consuming food and 2 hours after consumption of food. In some embodiments, administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may occur at the same time or within 1 hour after consumption of food. In some embodiments, administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may occur at the same time or within 30 minutes after consumption of food. In embodiments, the food is a high calorie meal, a high fat meal, or both a high calorie and high fat meal.

[0014] The term "high-calorie meal" refers to a meal of food having at least 500 total calories in a single meal. In some embodiments, a high calorie meal constitutes approximately 500 to 2000 total calories in a single meal. In some embodiments, a high calorie meal constitutes approximately 800 to 1000 total calories in a single meal.

[0015] In some embodiments, at least 40% of the total calories in a single meal of food are derived from fat. For example, the food in a single meal may derive approximately 300-800 calories from fat or 500-600 calories from fat. The term "high fat meal" refers to calories in a single meal wherein the fat of such food on a calorie basis is in the range of 45% to 65% of the total caloric basis of the single meal. In some embodiments, the fat on a calorie basis is in the range of 50% to 60% of the total caloric basis of a single meal.

[0016] As used herein "without food" means that a subject has not consumed any food for at least 2 hours before administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a subject has not consumed any food for at least 1 hour before administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0017] As used herein, the term "fed" is following the Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2002. A subject undergoing "fed" treatment undergoes an overnight fast of at least 10 hours, and should start the recommended meal 30 minutes prior to administration of the drug product. Subjects should eat the mean in 30 minutes or less; however, the drug product should be administered 30 minutes after the start of the meal. The drug product should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration.

[0018] As used herein, the term "fasted" is following the Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2002. A subject undergoing "fasted" treatment undergoes an overnight fast of at least 10 hours, and should be administered the drug product with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration.

[0019] As used herein, the term "bioavailability" generally means the rate and extent to which the active ingredient, or active form thereof, is absorbed from a drug product and becomes available at the site of action. For oral dosage forms, bioavailability relates to the processes by which the active ingredient is released from the oral dosage form, e.g., a tablet, converted to the active form (if the active ingredient is not already the active form), and moved to the site of action, e.g., absorbed into the systemic circulation.

[0020] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean 'including, without limitation,' 'including but not limited to,' or the like; the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'having' should be interpreted as 'having at least;' the term 'includes' should be interpreted as 'includes but is not limited to;' the term 'example' is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably,' 'preferred,' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Similarly, a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.

[0021] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0022] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S -configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0023] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. Additionally, all tautomers of heterocyclic bases known in the art are intended to be included.

[0024] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

Compounds

[0025] The compounds of Formulae (I) include compounds of Formula (la), Formula (lb) and Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing. Compounds of Formula (I) are described in at least one of U.S. Publication Nos. 2015/0072982 and 2016/0264581 and International Publication Nos. WO 2015/038655 and WO 2016/145103, all of which are hereby incorporated by reference in their entireties.

[0026] A compound of Formula (la), or a pharmaceutically acceptable salt thereof, is BCS Class II compound as defined by the FDA (See Particle Sciences Drug Development Services Technical Brief 2011, Volume 9) and is a potent endonuclease inhibitor of influenza A and B including strains resistant to neuraminidase inhibitors. A compound of Formula (la) is an ester prodrug of a compound of Formula (lb), or a pharmaceutically acceptable salt thereof. A compound of Formula (la), or a pharmaceutically acceptable salt thereof, can be hydrolyzed by esterases to a compound of Formula (lb), or a pharmaceutically acceptable salt thereof. A compound of Formula (lb), or a pharmaceutically acceptable salt thereof, can undergo glucuronidation to a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof which undergoes enterohepatic circulation.

[0027] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 40 mg to 250 mg. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 50 mg to 200 mg. In still other embodiments, compound (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 100 mg to 200 mg. In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 50 mg to 100 mg. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 150 mg to 200 mg. In other embodiments, pharmaceutically acceptable salt a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount in the range of 50 mg to 500 mg. [0028] In a 24 hour time period, the total dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can vary. In some embodiments, the total dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be in the range of 100 mg to 400 mg in a 24 hour time period. In some embodiments, the total dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be in the range of 250 mg to 350 mg in a 24 hour time period. In some embodiments, the total dosage of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be 300 mg ± 10 mg in a 24 hour time period.

[0029] The frequency and length of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be dosed once daily. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be dosed twice daily. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be given in a single dosage once daily. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be given in two dosages at different times in a 24 hour period. As an example, a first dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be given at a first time period and a second dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be given at a second time period, wherein the two time periods are separated by one or more hours (for example, separated by 8-14 hours) in a 24 hour period. In some embodiments, the two dosages of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are separated by approximately 12 hours in a 24 hour period. In other embodiments, the two dosages of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are separated by at least 8 hours in a 24 hour period.

[0030] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 50 ± 1 mg in each dosage form. In other embodiments a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 100 ± 5 mg in each dosage form. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 125 ± 10 mg in each dosage form. In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 150 ± 10 mg in each dosage form. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 175 ± 10 mg in each dosage form. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in an amount of 200 ± 10 mg in each dosage form.

[0031] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total number of at least 3 days. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total number of at least 5 days. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total number of at least 7 days. In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total number of at least 14 days. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total time period in the range of 3 days to 14 days. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total time period in the range of 5 days to 7 days. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided for a total time period in the range of 5 days to 14 days.

[0032] Examples of regimen embodiments described herein are provided in Table 1. The amounts in Table 1 are for a compound of Formula (I), or a pharmaceutically acceptable salt thereof, administered in an oral dosage form.

Table 1

[0033] Some embodiments described herein relate to a method for treating an influenza infection that can include administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, according to a regimen selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 in Table 1. Other embodiments described herein relate to using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an influenza infection in a subject suffering from the influenza infection, wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided according to a regimen selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 in Table 1. Still other embodiments described herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for treating an influenza infection in a subject suffering from the influenza infection, wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided according to a regimen selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 in Table 1.

Pharmaceutical Compositions

[0034] Various routes are suitable for providing a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided in a pharmaceutical composition, that can include an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0035] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0036] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

[0037] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0038] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0039] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.

[0040] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0041] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0042] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be administering orally.

[0043] When administered orally, one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to assist in simulating nasal secretions. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be formulated as tablet. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be formulated as suspension. Methods of Use

[0044] Embodiments described herein relate to a method of treating an influenza infection. Certain embodiments described herein relate to a method of treating an influenza infection, which can include administering an effective amount of a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) in a method, an amount and/or a regime described herein.

[0045] Other embodiments described herein relate to a method of inhibiting an influenza viral replication, which can include contacting a cell infected with an effective amount of a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) in a method, an amount and/or regime described herein.

[0046] In some embodiments, an effective amount of a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) can be used to inhibit the influenza polymerase complex. In some embodiments, an effective amount of a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) can be used for inhibiting and/or reducing the endonuclease activity of an influenza endonuclease that can include contacting the active site of the endonuclease with a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, one or more compounds described herein inhibits and/or reduces the ability of the endonuclease to cleave the mRNA.

[0047] In some embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza A viral infection. In other embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza B viral infection. In still other embodiments, including those embodiments in the previous paragraphs, the influenza viral infection can be an influenza C viral infection. In some embodiments, a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) can be used to treat one or more subtypes of influenza. For example, a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) can be used to treat H1N1 , H1N2, H2N2, H3N2, H5N1, H7N9, H8N4, and H9N2 for influenza A and/or Victoria and Yamagata strains for influenza B. In some embodiments, a compound selected from a compound of Formula (I)can be effective against more than 1 subtype of influenza. For example, a compound described herein (for example, a compound of Formula (la), a compound of Formula (lb) and/or a compound of Formula (Ic), or a pharmaceutically acceptable salt of any of the foregoing) can be effective against 2, 3, 4, and/or 5 or more subtypes of influenza.

[0048] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.

[0049] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.

[0050] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of a compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or the disease itself or to prolong the survival of the subject being treated. In embodiments, the effective amount is the amount needed to be effective while remaining safe or tolerable for the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0051] Various indicators for determining the effectiveness of a method for treating an influenza viral infection are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.

[0052] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to a lower level, for example, from about 10 ⁴ TCIDso/mL (TCID = tissue culture infectious dose) to about 10 TCIDso/mL, or to about 100 TCIDso/mL, or to about 10 TCID ₅ o/mL. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, wherein the viral load is measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after initiation of the treatment regime with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 10 days after initiation of treatment). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be an amount that is effective to reduce viral load to lower than about 10 ⁴ TCIDso/mL. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective to achieve a reduction in viral titer in a nasal/pharyngeal swab or nasal wash sample of the subject in the range of about 1.5 -log to about a 2.5 -log reduction or about a 3 -log to about a 4-log reduction compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, wherein the viral load is measured before administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and again after initiation of the treatment regimen with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (for example, 10 days after initiation of treatment).

[0053] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in one or more overall quality of life health, such as reduced illness duration, reduced illness severity, reduced time to return to normal health and normal activity, and reduced time to alleviation of one or more symptoms of influenza infection, compared to a subject who is untreated. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in a reduction in the length and/or severity of one or more symptoms associated with an influenza infection compared to an untreated subject. Symptoms of an influenza infection are described herein and include but not limited to cough, myalgia (muscle pain), nasal obstruction, sore throat, fatigue, headache and fever. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the thereof, can result in a reduction in one or more secondary complications associated with an influenza infection, including but not limited to otitis media (ear inflammation), sinusitis, bronchitis and pneumonia compared to an untreated subject.

[0054] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of an influenza relative to pre-treatment levels in a subject, as determined after initiation of the treatment regime (for example, 10 days after initiation of treatment). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt of the foregoing, can result in a reduction of the replication of an influenza relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of influenza replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, or 3 to 3.5 log reduction of influenza replication compared to the reduction of influenza reduction achieved by oseltamivir (Tamiflu®), or may achieve the same reduction as that of oseltamivir (Tamiflu®) therapy in a shorter period of time, for example, in one day, two days, three days, or four days as compared to the reduction achieved after 5 days of oseltamivir (Tamiflu®) therapy.

[0055] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term "resistance" as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with an influenza virus that is resistant to one or more different anti- influenza agents (for example, amantadine, rimantadine and/or oseltamivir). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with an influenza virus that is resistant to a M2 protein inhibitor such as those described herein. In some embodiments, the influenza virus is resistant to a neuraminidase inhibitor. Examples of neuraminidase inhibitor include those described herein, such as Relenza® (zanamivir), Tamiflu® (oseltamivir), Inavir (laninamivir) and Rapivab (peramivir). In some embodiments, development of resistant influenza strains is delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of influenza strains resistant to other influenza drugs.

[0056] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can decrease the percentage of subjects that experience complications from an influenza viral infection compared to the percentage of subjects that experience complication being treated with oseltamivir. For example, the percentage of subjects being treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that experience complications can be 10%, 25%, 40%, 50%, 60%, 70%, 80% and 90% less compared to subjects being treated with oseltamivir.

[0057] Bioavailability of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be significantly increased when administered with food or at substantially the same time as consuming food. In some embodiments, a method of increasing the bioavailability of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof), in a subject being administered the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can include administering an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition to a subject infected with an influenza with food, wherein the food is not part of the pharmaceutical composition. In some embodiments, the maximum plasma concentration (C _max ) of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food. In some embodiments, the maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 2-fold. In some embodiments, the maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 3-fold. In some embodiments, the maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 1-fold to 2-fold. In some embodiments, the maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 2-fold to 4-fold.

[0058] In some embodiments, the time to maximum plasma concentration (T _max ) of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food. In some embodiments, the time to maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 2- fold. In some embodiments, the time to maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 3- fold. In some embodiments, the time to maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 1-fold to 2-fold. In some embodiments, the time to maximum plasma concentration of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 2-fold to 4-fold.

[0059] In some embodiments, the total drug exposure over time (AUC) of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food. In some embodiments, the total drug exposure over time of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 2-fold. In some embodiments, the total drug exposure over time of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food at least 3-fold. In some embodiments, the total drug exposure over time of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 1-fold to 2-fold. In some embodiments, the total drug exposure over time of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is increased as compared to the administration of the pharmaceutical composition without food in the range of 2-fold to 4-fold. In some embodiments of this paragraph, the AUC can be AUCi _ast . In some embodiments of this paragraph, the AUC can be AUCoo.

[0060] As described herein, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with food. In some embodiments, a meal can be consumed prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a high-fat meal can be consumed at least 30 minutes prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered within 2 hours of the consumption of food. In some embodiments, including those of this paragraph, the food can be a high-fat meal.

[0061] By administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with food, the effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that needs to be administered in a 24 hour time period can be less compared to the effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that needs to be administered in a 24 hour time period when the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt thereof, without food. As a result, the total dosage of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be decreased from the total dosage needed to achieve an effective amount comparing the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with food to the administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, without food.

[0062] In some embodiments, the amount the total dosage needed to achieve an effective amount of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is decreased as compared to the total dosage needed to achieve an effective amount without food is at least 2-fold. In some embodiments, the amount the total dosage needed to achieve an effective amount of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is decreased as compared to the total dosage needed to achieve an effective amount without food is at least 3 -fold. In some embodiments, the amount the total dosage needed to achieve an effective amount of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is decreased as compared to the total dosage needed to achieve an effective amount without food is in the range of 1-fold to 2-fold. In some embodiments, the amount the total dosage needed to achieve an effective amount of an active form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (such as a compound of Formula (la), or a pharmaceutically acceptable salt thereof) is decreased as compared to the total dosage needed to achieve an effective amount without food is in the range of 2-fold to 4-fold.

[0063] In embodiments, the total dosage over a 24 hour time period of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the presence of food is in the range of 100 mg to 400 mg. In some embodiments, the total dosage in a 24 hour time period is in the range of 250 mg to 350 mg. In some embodiments, the total dosage in a 24 hour time period is 300 mg ± 10 mg in a 24 hour time period.

[0064] A pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be part of a pharmaceutical package that can include further materials. A subject may be informed via printed material that administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with food results in an increase of the bioavailability of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to administration without food. In some embodiments, a package pharmaceutical composition can include a pharmaceutical composition that can include compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a label and/or insert advising that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is to be administered with food. As used herein, "label and/or insert" includes, but is not limited to, written, electronic and/or spoken communication with the subject or with any person substantially responsible for the care of the subject.

EXAMPLES

EXAMPLE 1

FORMULATIONS

[0065] The respective qualitative compositions of the active and placebo tablets are given in Tables 2A and 2B.

Table 2A: Qualitative Composition of the Active Tablets

Table 2B: Qualitative Composition of the Placebo Tablets

[0066] The respective qualitative compositions of the reconstituted suspensions and of the placebo solution are provided in Table 3A and 3B. Table 3A: Qualitative Composition of the Active Drug Product Reconstituted Oral Suspension

Table 3B: Qualitative Composition of the Placebo Oral Solution

EXAMPLE 2

[0067] A Phase 1 , multi-Part, first-in-human study of Formula (I) was conducted in 89 healthy volunteers (HVs).

[0068] Dosing commenced 12 hours after confirmed infection by qualitative PCR or on Day 4 post-innoculation. In all Parts, serial sampling for plasma concentrations of Formula (la) and its metabolite Formula (lb) were collected; Pharmacokinetics (PK) were calculated using non-compartmental analysis. ECGs, laboratory and other safety parameters were routinely collected. In Part 4, nasopharyngeal swabs were collected 2-3 times/day post- inoculation for viral load as determined by quantitative PCR and symptoms were recorded.

[0069] A compound of Formula (I) was well tolerated in all Parts with mostly mild treatment-emergent adverse events (TEAEs). There were no SAEs (serious adverse events). The most common TEAEs reported were headache and lightheadedness; these occurred at high exposures of Formula (la). Lightheadedness was not observed in any subjects receiving 50 or 150 mg BID in Part 4. There were no clinically significant ECG or laboratory abnormalities across all Parts.

[0070] In Part 4, the anti-viral activity was evaluated in the human influenza A (A/Perth/16/2009) challenge model. Of the 60 randomized subjects, 42 (70%) were positively infected. Subjects receiving the 150 mg BID x 5 days regime demonstrated a reduction in viral AUCi _as t of 87.5 log io TCIDso/mL.h compared to subject receiving the placebo who had a viral AUCi _as t of 142 log io TCIDso/mL.h. The time to viral negativity was

75.3 hours compared 108 hours comparing subject receiving the 150 mg BID x 5 days regime versus placebo. Also the time to symptom resolution for 150 mg BID x 5 days regime was

26.4 hours compared to 49.1 hours for the subject receiving the placebo. These results demonstrate that subjects receiving Formula (I) at 50 or 150 mg BID had a more rapid decline in viral load and became PCR undetectable earlier compared to placebo.

EXAMPLE 3

[0071] A two-part, randomized, open-label, single-dose crossover study in healthy volunteers was conducted to assess the bioavailability of a compound Formula (I), or a pharmaceutically acceptable salt thereof, according to the Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2002. In Part 1, the following dosage regimes were provided. Study

Dosing Regimen

Part

150 mg suspension, fasted

1

150 mg tablet, fasted

(n=15)

150 mg tablet, standard meal

100 mg tablet, fasted

2 100 mg tablet, fasted

(n=16) 100 mg tablet, standard meal

100 mg tablet, high-fat meal

[0072] After a single dose of a compound Formula (I) (150 mg (fasted)), C _max and AUCo _o were 3.0 and 2.4-fold, respectively, higher for the compound of Formula (la) with the tablet than with the suspension. A standard meal administered with a single dose of a compound Formula (I) (150 mg) as a tablet significantly increased exposure to a compound Formula (I), about 2-fold relative to the same dose as a tablet under fasted conditions. The PK parameters of a compound Formula (I) are provided in Table 4.

Table 4

Mean+SD ^b

c tmax AUC _last AUC _ro tl/2

Dose (mg), Condition" (ng/niL) (h) (ng.h/mL) (ng.h/mL) (h)

Compound (I)

150 - Suspension, 83+28 2.0 (2.0-3.0) 855+254 877+259 8.0+1.4

Fasted

150 - Tablet, Fasted 256+109 2.0 (2.0-3.0) 2,070+608 2,090+608 6.7+0.5

150 - Tablet, Fed 458+108 4.0 (2.0-6.0) 4,046+740 4,070+746 6.2+0.5

AUCiast: area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration; AUC _oo : AUC extrapolated to infinite time; C _max : maximum plasma concentration; ty ₂ - terminal elimination half-life; t^: time of maximum plasma concentration

a n=15 for suspension, n=14 for tablet

b Median (range) for t _max .

[0073] In Part 2, repeated doses of a compound Formula (I) (50 mg) were administered after consumption of a standard (normal fat) breakfast. In Part 3 of the study, a single dose of a compound Formula (I) (450 mg) was administered shortly after consumption of a high-fat breakfast.

[0074] A high-fat meal administered with a single dose of a compound Formula (I) significantly increased both the C _max and AUC 3.6- and 3.0-fold, respectively, relative to same dose fasted. The PK parameters of a compound Formula (I) are provided in Table

Table 5

Mean+SD ^b

c tmax AUC _last AUC _ro tl/2

Dose (mg), Condition" (ng/niL) (h) (ng.h/mL) (ng.h/mL) (h)

Compound (I)

450, Fasted 562+93 2.0 (1.0-3.0) 5,637+1,364 5,671+1,356 7.6+1.6

450, Fed 2,052+428 3.0 (2.0-4.0) 16,464+2,882 16,489+2,884 10.3+3.0

AUCi _ast : area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration; AUC _oo i AUC extrapolated to infinite time; C _max : maximum plasma concentration; ty ₂ - terminal elimination half-life; t _max : time of maximum plasma concentration

a n=6

b Median (range) for t _max .

[0075] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.