Remdesivir treatment methods

Abstract

To provide remdesivir treatment methods.SOLUTION: Provided herein are methods of treating or preventing a viral infection in a subject, comprising administering a compound of Formula (I), Formula (la), or Formula (lb), or a pharmaceutically acceptable salt thereof, wherein the subject is not being treated with chloroquine, or an analog or salt thereof. Methods of treating a viral infection comprising the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human in need thereof should avoid other agents that decrease, retard, or attenuate antiviral activity of the compound.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 032,321, filed May 29, 2021, which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] Preventing or treating infections with some Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Pneumoviridae, and Paramyxoviridae viruses presents a challenge due to the lack of vaccines or post-exposure treatment modalities to prevent or manage infections caused by viruses from these families. In some cases, patients only receive supportive care such as electrolyte and fluid balance, oxygen, blood pressure maintenance, or treatment of secondary infections. The compound (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, referred to herein as the compound of formula Ia, is known to exhibit antiviral properties against several virus families, including Arenaviridae, Coronaviridae, Filoviridae, Paramyxoviridae, and Flaviviridae (see, e.g., Warren, T. et al., Nature (2016) 531:381-385; Lo MK, et al., Sci. Reports 2017;7:43395; Sheahan TP, et al., Nature (2016) 531:381-385; (see, for example, WO 2017 / 184668; Agostini ML, et al., MBio 2018; 9(2):e00221-18; Cell Research (2020) 30:269-271; and WO 2017 / 184668). There is a need for the development of methods for treating viral infections, comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof. In humans in need of such treatment, methods of treating viral infections that include a compound of formula Ia, or a pharma- ceutically acceptable salt thereof, should avoid other agents that reduce, delay, or attenuate the antiviral activity of the compound. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2017 / 184668 [Non-patent literature]

[0004] [Non-Patent Document 1] Warren, T. et al., Nature (2016) 531:381-385 [Non-Patent Document 2] Lo MK,et al.,Sci.Reports 2017;7:43395 [Non-Patent Document 3] Sheahan TP,et al.Sci.Transl.Med.2017;9:eaal3653 Summary of the Invention [Means for solving the problem]

[0005] In some embodiments, the disclosure provides a method of treating a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof; [ka] The human is not being treated with chloroquine, or an analogue or salt thereof, to treat the viral infection.

[0006] In some embodiments, the present disclosure provides a method of optimizing plasma or blood concentration of a compound of formula II, or a pharma- ceutically acceptable salt thereof, in a human in need thereof, comprising: [ka] The method includes administering an antiviral compound to a human, where the human is not administered chloroquine, or an analog or salt thereof, and where upon administration to the human, the antiviral compound is converted to a compound of formula II, and the concentration of the compound of formula II in the plasma or blood is optimized in the absence of chloroquine, or an analog or salt thereof.

[0007] In some embodiments, the disclosure provides a method of optimizing the plasma or blood concentration of a compound of formula II, or a pharma- ceutically acceptable salt thereof, in a human in need thereof, the method comprising: (a) administering to the human a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof; (b) measuring the plasma or blood concentration of the compound of formula II in the human; and (c) adjusting any remaining dose of the compound of formula I, formula Ia, or formula Ib to optimize the plasma or blood concentration of the compound of formula II in the human.

[0008] In some embodiments, the disclosure provides a method of determining a delivered dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, to treat a viral infection in a human in need thereof, the method comprising: (a) providing an original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof; (b) determining whether the human has been administered chloroquine, or an analog or salt thereof; and (c1) determining the delivered dose by increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, if the human has been administered chloroquine, or an analog or salt thereof; or (c2) selecting the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof as the delivered dose, if the human has not been administered chloroquine, or an analog or salt thereof.

[0009] In some embodiments, the disclosure provides a method of forming a compound of formula II in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of formula Ia; and instructing the human to avoid taking chloroquine, or an analog or salt thereof, wherein the compound of formula Ia is metabolized in the absence of chloroquine, or an analog or salt thereof, to a compound of formula II, the compound of formula II having the structure: [ka] The compound of formula Ia has the following structure: [ka]

[0010] In some embodiments, the disclosure provides a method for reducing the risk of reduced efficacy of a compound of formula Ia, or a pharma- ceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby reducing the risk of reduced efficacy of the compound of formula Ia, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the disclosure provides a method of preventing a contraindication in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of a compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, during treatment with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering a compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby preventing the contraindication in the human.

[0012] In some embodiments, the disclosure provides a method of maintaining the effectiveness of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining whether the human was taking chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human to not take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby maintaining the effectiveness of the compound of formula Ia, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the disclosure provides a method of reducing a risk of decreased plasma concentration of the compound of formula II in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby reducing the risk of decreased plasma concentration of the compound of formula II. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the effect of chloroquine (CQ) or hydroxychloroquine (HCQ) on formula Ia triphosphate (TP) formation in A549-hACE2 cells. [Diagram 2] FIG. 1 shows the effect of CQ or HCQ on formula Ia triphosphate (TP) formation in NHBE cultures. [Diagram 3] FIG. 1 shows the effect of CQ or HCQ on formula Ia triphosphate (TP) formation in HEp-2 cells. [Figure 4]FIG. 1 shows anti-SARS-CoV-2 viral data of compound of formula Ia in combination with either CQ or HCQ in A549-hACE2 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] I. Overview The disclosure provides a method of treating a viral infection in a subject, the method comprising administering a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, to the subject, where the subject is not being treated with chloroquine, or an analog or salt thereof. II. Definition

[0016] "Compound of the disclosure" refers to a compound administered to a subject in the methods described herein and includes a compound of Formula I, Formula Ia, Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0017] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0018] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0019] "Pharmaceutical composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, such as a human. Such a vehicle includes all pharma- ceutically acceptable excipients therefor.

[0020] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the present disclosure that is sufficient to provide treatment of a disease state, condition, or disorder for which the compound is useful when administered to a patient in need thereof. Such an amount will be sufficient to elicit a biological or medical response in a tissue system or patient that is desired by a researcher or clinician. The amount of a compound of the present disclosure that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in combination with or concurrently with the compound of the present disclosure, and the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can usually be determined by one of ordinary skill in the art having regard to his or her knowledge, the state of the art, and this disclosure.

[0021] The terms "treatment," "treating," or "treating" refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or attenuating the severity of a disease or condition); b) slowing or arresting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving a disease state, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0022] "Prevention" or "preventing" refers to any treatment of a disease or condition that results in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0023] "Subject" or "patient" refers to an animal, such as a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human, a domestic animal such as a dog or cat, a livestock animal such as a cow, horse, sheep, goat, or pig, or a laboratory animal such as a mouse, rat, hamster, guinea pig, pig, rabbit, dog, or monkey. In some embodiments, the subject or patient is a human.

[0024] "A human in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from a particular treatment, for example, a human being who is being treated with a compound disclosed herein in accordance with the present application to treat a viral infection. III.How to use

[0025] The disclosure also provides a method of treating or preventing a viral infection in a human in need thereof, the method comprising administering a compound described herein.

[0026] In some embodiments, the disclosure provides a method of treating a viral infection in a human in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula Ia, or Formula Ib, [ka] or a pharma- ceutically acceptable salt thereof to a human; The human is not being treated with chloroquine, or an analogue or salt thereof, to treat the viral infection.

[0027] In some embodiments, the disclosure provides a method for confirming administration of a compound of Formula I, Formula Ia, or Formula Ib to a human, the method comprising identifying a compound of Formula II or a salt thereof in a biological sample obtained from the human. In some embodiments, the human is not being treated with chloroquine, or an analog or salt thereof. In some embodiments, the human has not been previously treated with chloroquine, or an analog or salt thereof, prior to administration of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the biological sample is derived from plasma or blood.

[0028] In some embodiments, the disclosure provides a method for measuring the metabolic rate of a compound of formula I, formula Ia, or formula Ib in a human, the method comprising measuring the amount of a compound of formula II or a salt thereof in the human at one or more time points after administration of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been previously treated with chloroquine, or an analog or salt thereof, prior to administration of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a biological sample obtained from the human. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a blood sample. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a plasma sample.

[0029] In some embodiments, the disclosure provides a method for determining a prophylactic or therapeutic response of a human in the treatment of a viral infection, the method comprising measuring the amount of a compound of formula II or a salt thereof in the human at one or more time points after administration of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been previously treated with chloroquine, or an analog or salt thereof, prior to administration of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a biological sample obtained from the human. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a blood sample. In some embodiments, the amount of a compound of formula II or a salt thereof is measured from a plasma sample. A. Chloroquine administration

[0030] The methods provide for the treatment of a human having no appreciable systemic concentrations of chloroquine, or an analog or salt thereof, in some embodiments, the human in need thereof has not been previously treated with chloroquine, or an analog or salt thereof, prior to administration of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments, the human has been previously treated with chloroquine, or an analog or salt thereof. In some embodiments, the human in need thereof has not been treated with chloroquine, or an analog or salt thereof, for a period of time prior to administration of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure allows for a reduction in the systemic concentration of chloroquine, or an analog or salt thereof, such that the antiviral activity of the compound of the present disclosure is not reduced. For example, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure can allow for a reduction in the plasma concentration of chloroquine, or an analog or salt thereof, as a result of excretion or metabolism.

[0032] In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure is at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days. In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure is at least 14 days. In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure is at least 28 days. In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure is at least 40 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 50 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 60 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 90 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 120 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 180 days. In some embodiments, the period between treatment with chloroquine, or an analogue or salt thereof, and administration of a compound of the present disclosure is at least 365 days.

[0033] In some embodiments, the period between treatment with chloroquine, or an analog or salt thereof, and administration of a compound of the present disclosure is at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 20 hours, or at least 24 hours.

[0034] In some embodiments, the human is administered chloroquine, or an analog or salt thereof, about 1 day to about 365 days prior to receiving the first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, or about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 30 days, about 1 day to about 45 days, about 10 days to about 45 days, about 14 days to about 45 days, about 21 days to about 45 days, about 28 days to about 45 days, about 30 days to about 50 days, about 60 days to about 70 days, about 80 days to about 90 days, about 90 days to about 100 days, about 100 days to about 120 days, about 120 days to about 14 ... chloroquine, or an analog or salt thereof, was administered about 45 days, 10 days to about 60 days, about 14 days to about 60 days, about 21 days to about 60 days, about 28 days to about 60 days, about 30 days to about 60 days, about 40 days to about 60 days, about 10 days to about 90 days, about 14 days to about 90 days, about 21 days to about 90 days, about 28 days to about 90 days, about 30 days to about 90 days, about 40 days to about 90 days, about 10 days to about 365 days, about 14 days to about 365 days, about 21 days to about 365 days, about 28 days to about 365 days, about 30 days to about 365 days, or about 60 days to about 365 days prior to the administration of chloroquine, or an analog or salt thereof. In some embodiments, the human is administered chloroquine, or an analog or salt thereof, about 30 days to about 60 days prior to receiving the first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human is administered chloroquine, or an analog or salt thereof, about 21 days to about 45 days prior to receiving the first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0035] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days of receiving the first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 2 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 5 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 7 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 10 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 90 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 365 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments, the methods further include instructing the human to avoid taking chloroquine, or an analog or salt thereof, during treatment of the viral infection.

[0038] In some embodiments, the method further includes instructing the human to wait about 1 day to about 365 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, or to wait about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 10 days, about 1 day to about 14 days, about 10 days to about 45 days, about 14 days to about 45 days, about 14 days to about 45 days, or ... The method further includes instructing the human to wait for about 21 to about 45 days, about 28 to about 45 days, about 30 to about 45 days, 10 to about 60 days, about 14 to about 60 days, about 21 to about 60 days, about 28 to about 60 days, about 30 to about 60 days, about 40 to about 60 days, about 10 to about 90 days, about 14 to about 90 days, about 21 to about 90 days, about 28 to about 90 days, about 30 to about 90 days, about 40 to about 90 days, about 10 to about 365 days, about 14 to about 365 days, about 21 to about 365 days, about 28 to about 365 days, about 30 to about 365 days, or about 60 to about 365 days.

[0039] In some embodiments, the method further comprises instructing the human to wait after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the method further comprises instructing the human to wait at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0040] In some embodiments, the method further includes instructing the human to wait about 30 minutes to about 1 day after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, e.g., to wait at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 20 hours, or at least 24 hours before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0041] In some embodiments, the method further comprises instructing the human to wait after taking the chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the method further comprises instructing the human to wait at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days after taking the chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, the method further includes instructing the human to wait about 30 minutes to about 1 day after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia or a pharma- ceutically acceptable salt thereof, e.g., to wait at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 20 hours, or at least 24 hours before administering the compound of Formula Ia or a pharma- ceutically acceptable salt thereof.

[0043] In some embodiments, the human is not administered chloroquine, or an analog or salt thereof, during treatment of the viral infection. In some embodiments, the method further comprises instructing the human not to administer chloroquine, or an analog or salt thereof, during treatment of the viral infection.

[0044] In some embodiments, the method includes administering a therapeutically effective amount of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, to a human, thereby treating a viral infection, provided that the human has not been administered chloroquine, or an analog or salt thereof, prior to the initiation of treatment. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days prior to the initiation of treatment. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, for at least 1 day prior to the initiation of treatment. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, for at least 10 days prior to initiating treatment, hi some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, for at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 20 hours, or at least 24 hours prior to initiating treatment.

[0045] A variety of techniques can be used to determine whether a person in need thereof has previously taken chloroquine, or an analog or salt thereof, including, but not limited to, self-reporting, interviewing the person, reviewing the person's medical records, or measuring the concentration of chloroquine, or a metabolite, analog, or salt thereof, in the person's plasma or blood.

[0046] A human in need of treatment for a viral infection can also be evaluated for plasma or blood levels of chloroquine, or an analog or salt thereof, prior to administration of a compound of the present disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, a human in need of treatment for a viral infection has plasma or blood levels measured prior to administration of a compound of the present disclosure.

[0047] The concentration of chloroquine, or its analogs or salts, in human plasma or blood can be measured by any method known in the art.See, for example, Walker, O. et al., British Journal Clinical Pharmacology (1983), vol.16, pp.701-705; Kaewkhao, K. et al., Bioanalysis (2019), vol.11(5), pp.333-347; Durcan, L. et al., Journal of Rheumatology (2015), vol.42(11), pp.2092-2097; Munster, T. et al., Arthritis Rheumatology (2002), vol.46(6), pp.1460-1469.

[0048] In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of about 0.1 ng / mL to about 5000 ng / mL at the time the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to the human; or a plasma or blood concentration of chloroquine, or an analog or salt thereof, of about 0.1 ng / mL to about 4000 ng / mL, or about 0.1 ng / mL to about 5000 ng / mL at the time the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to the human. ng / mL~about 3000ng / mL, about 0.1ng / mL~about 2000ng / mL, about 0.1ng / mL~about 1000ng / mL, about 0.1ng / mL~about 500ng / mL, about 0.1ng / mL~about 400ng / mL, about 0.1 ng / mL~about 300ng / mL, about 0.1ng / mL~about 200ng / mL, about 0.1ng / mL~about 100ng / mL, about 0.1ng / mL~about 80ng / mL, about 0.1ng / mL~about 60ng / mL, about 0.1ng / mL about 50ng / mL, about 0.1ng / mL to about 40ng / mL, about 0.1ng / mL to about 30ng / mL, about 0.1ng / mL to about 20ng / mL, or about 0.1ng / mL to about 10ng / mL, about 5ng / mL to about 4000ng / mL, about 5ng / mL to about 3000ng / mL, about 5ng / mL to about 2000ng / mL, about 5ng / mL to about 1000ng / mL, about 5ng / mL to about 500ng / mL, about 5ng / mL to about 400ng / mL, about 5ng / mL to about 5 ... In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of about 0.1 ng / mL to about 50 ng / mL, about 5 ng / mL to about 300 ng / mL, about 5 ng / mL to about 200 ng / mL, about 5 ng / mL to about 100 ng / mL, about 5 ng / mL to about 80 ng / mL, about 5 ng / mL to about 60 ng / mL, about 5 ng / mL to about 50 ng / mL, about 5 ng / mL to about 40 ng / mL, about 5 ng / mL to about 30 ng / mL, about 5 ng / mL to about 20 ng / mL, or about 5 ng / mL to about 10 ng / mL. In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of about 0.1 ng / mL to about 50 ng / mL at the time the first dose of a compound of the disclosure is administered to the human.

[0049] In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of less than 5000 ng / mL at the time a first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to the human, or has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of less than 4000 ng / mL, 3000 ng / mL, 2000 ng / mL, 1000 ng / mL, 500 ng / mL, 400 ng / mL, 300 ng / mL, 200 ng / mL, 100 ng / mL, 80 ng / mL, 60 ng / mL, 50 ng / mL, 45 ng / mL, 40 ng / mL, 35 ng / mL, 30 ng / mL, 25 ng / mL, 20 ng / mL, 15 ng / mL, 10 ng / mL, or 5 ng / mL at the time a first dose of a compound of the present disclosure is administered to the human.

[0050] In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, less than 50 ng / mL at the time the first dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to the human.

[0051] "Chloroquinone, or an analog or salt thereof" refers to chloroquine (CQ, also known as N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, which has a CAS number of 54-05-7), hydroxychloroquine (HCQ, also known as 2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol, which has a CAS number of 118-42-3), and its metabolites in plasma following administration to humans. Members include chloroquine, desethylchloroquine (DCQ, also known as 4-N-(7-chloroquinolin-4-yl)-1-N-ethylpentane-1,4-diamine, CAS number 1476-52-4), hydroxychloroquine, desethylhydroxychloroquine (DHCQ, also known as kletoquine, 2-[4-[(7-chloroquinolin-4-yl)amino]pentylamino]ethanol, CAS number 4298-15-1), and bidesethylhydroxychloroquine (also known as BDCQ), or a pharma- ceutically acceptable salt thereof. Illustrative examples include chloroquine, or a pharma- ceutically acceptable salt thereof. One example is chloroquine phosphate, commercially available as Aralen®. Chloroquine has the chemical structure: [ka] has. An alternative example is hydroxychloroquine, or a pharma- ceutically acceptable salt thereof. One example is hydroxychloroquine sulfate, commercially available as Plaquenil®. Hydroxychloroquine has the chemical structure: [ka] has.

[0052] In some embodiments, the chloroquine, or an analog or salt thereof, is chloroquine, desethylchloroquine, hydroxychloroquine, desethylhydroxychloroquine, or bidesethylhydroxychloroquine, or a pharmaceutically acceptable salt thereof. In some embodiments, the chloroquine, or an analog or salt thereof, is chloroquine, hydroxychloroquine, or a pharmaceutically acceptable salt thereof. In some embodiments, the chloroquine, or an analog or salt thereof, is chloroquine, or a pharmaceutically acceptable salt thereof. For example, the chloroquine, or an analog or salt thereof, can be chloroquine phosphate. In some embodiments, the chloroquine, or an analog or salt thereof, is hydroxychloroquine, or a pharmaceutically acceptable salt thereof. For example, the chloroquine, or an analog or salt thereof, can be hydroxychloroquine sulfate. B. Compound

[0053] The present disclosure includes methods of using antiviral compounds that, when administered to a human in need thereof, produce a compound of Formula II, or a pharma- ceutically acceptable salt thereof.

[0054] The disclosure also includes methods of using the compounds of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0055] The compound of formula I is described in WO 2012 / 012776. The IUPAC name of the compound of formula I is 2-ethylbutyl((((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)-L-alaninate. The compound of formula I, or a pharma- ceutically acceptable salt thereof, has the structure: [ka] has.

[0056] The compound of formula Ia is described in WO 2016 / 069826. 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 the CAS registry number is 1809249-37-3. The compound of formula Ia is also referred to as remdesivir and GS-5734. The compound of formula Ia, or a pharma- ceutically acceptable salt thereof, has the structure: [ka] has.

[0057] The compound of formula Ib is disclosed in WO 2016 / 069826. The IUPAC name of the compound of formula Ib is (S)-2-ethylbutyl 2-(((R)-(((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. The compound of formula Ib, or a pharma- ceutically acceptable salt thereof, has the structure: [ka] has.

[0058] In some embodiments, a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to a human in need thereof to produce a compound of formula II, [ka] or a pharma- ceutically acceptable salt thereof is produced.

[0059] The compound of formula I, formula Ia, or formula Ib can be used in any suitable form.For example, the compound of formula I, formula Ia, or formula Ib can be amorphous or crystalline.In some embodiments, the compound of formula I, formula Ia, or formula Ib is amorphous.In some embodiments, the compound of formula I, formula Ia, or formula Ib is crystalline.

[0060] Crystalline forms of the compound of formula Ia useful in the methods and compositions of the present disclosure are described in U.S. Patent Application Publication No. 2018 / 0346504. For example, the compound of formula Ia can be crystalline form I, form II, form III, or form IV, or a combination thereof, as described in U.S. Patent Application Publication No. 20180346504. In some embodiments, the compound of formula Ia is crystalline.

[0061] The compounds of formula I, formula Ia, and formula Ib, or pharma- ceutically acceptable salts thereof, can be combined with one or more pharma- ceutically acceptable excipients. In some embodiments, the pharma- ceutically acceptable excipients include an aqueous vehicle. In some embodiments, the pharmaceutical compositions provided herein include a compound of formula I, or a pharma- ceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical compositions provided herein include a compound of formula Ia, or a pharma- ceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical compositions provided herein include a compound of formula Ib, or a pharma- ceutically acceptable salt thereof, and an aqueous vehicle. The aqueous vehicle includes water, and optionally one or more components selected from a cosolvent, a surfactant, a suspending agent, a tonicity agent, a buffer, a cyclodextrin, and an antibacterial agent or a preservative. Exemplary formulations can be found in U.S. Patent Application Publication No. 2019 / 0083525.

[0062] In some embodiments, the method of treating a viral infection in a human in need thereof includes administering to the human a compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the methods include administering a compound of formula I.

[0063] In some embodiments, the method of treating a viral infection in a human in need thereof comprises administering to the human a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the methods include administering a compound of formula Ia.

[0064] In some embodiments, the method of treating a viral infection in a human in need thereof includes administering to the human an antibody of formula Ib: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the methods include administering a compound of formula Ib.

[0065] The compounds of the present disclosure can be administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal (including inhalation), pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), implantation, etc. It will be understood that the preferred route may vary, for example, depending on the condition of the human.

[0066] In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered by inhalation or intravenously. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered by inhalation.

[0067] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered once a day or twice a day. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered once a day.

[0068] In some embodiments, the human weighs at least 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following four days. In some embodiments, a second dose of 50-150 mg is administered for an additional 1-5 days. In some embodiments, the human weighs at least 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs at least 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following 9 days. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered once a day. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered over about 30 minutes to about 120 minutes.

[0069] In some embodiments, the human body weight is at least 40 kg and the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously in a first dose of 200 mg on day 1, and in a second dose of 100 mg on each of the following four days. In some embodiments, a second dose of 100 mg is administered for an additional 1-5 days. In some embodiments, the human body weight is at least 40 kg and the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously in a first dose of 200 mg on day 1, and in a second dose of 100 mg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human body weight is at least 40 kg, and the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at a first dose of 200 mg on day 1, and at a second dose of 100 mg on each of the following 9 days. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously once a day. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously over about 30 minutes to about 120 minutes.

[0070] In some embodiments, the human weighs at least 40 kg and the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following four days. In some embodiments, a second dose of 50-150 mg is administered for an additional 1-5 days. In some embodiments, the human weighs at least 40 kg and the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs at least 40 kg and the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, is administered in a first dose of 150-250 mg on day 1, and in a second dose of 50-150 mg on each of the following 9 days. In some embodiments, the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, is administered once daily. In some embodiments, the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, is administered over about 30 minutes to about 120 minutes.

[0071] In some embodiments, the human body weight is at least 40 kg and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously in a first dose of 200 mg on day 1, and in a second dose of 100 mg on each of the following four days. In some embodiments, a second dose of 100 mg is administered for an additional 1-5 days. In some embodiments, the human body weight is at least 40 kg and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously in a first dose of 200 mg on day 1, and in a second dose of 100 mg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human body weight is at least 40 kg and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously in a first dose of 200 mg on day 1, and in a second dose of 100 mg on each of the following nine days. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously once daily, hi some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously over about 30 to about 120 minutes.

[0072] In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered at a first dose of 2.5-10 mg / kg on day 1, and at a second dose of 1-5 mg / kg on each of the following four days. In some embodiments, a second dose of 1-5 mg / kg is administered for an additional 1-5 days. In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered at a first dose of 2.5-10 mg / kg on day 1, and at a second dose of 1-5 mg / kg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered at a first dose of 2.5 to 10 mg / kg on day 1, and at a second dose of 1 to 5 mg / kg on each of the following 9 days. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered once a day. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered over about 30 minutes to about 120 minutes.

[0073] In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following four days. In some embodiments, a second dose of 2.5 mg / kg is administered intravenously for an additional 1 to 5 days. In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following 9 days. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously once a day. In some embodiments, the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously over about 30 minutes to about 120 minutes.

[0074] In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered at a first dose of 2.5 to 10 mg / kg on day 1, and at a second dose of 1 to 5 mg / kg on each of the following four days. In some embodiments, a second dose of 1 to 5 mg / kg is administered for an additional 1 to 5 days. In some embodiments, the human weighs less than 3.5 kg to 40 kg and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered at a first dose of 2.5 to 10 mg / kg on day 1, and at a second dose of 1 to 5 mg / kg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered at a first dose of 2.5 to 10 mg / kg on day 1, and at a second dose of 1 to 5 mg / kg on each of the following 9 days. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered over about 30 minutes to about 120 minutes.

[0075] In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following four days. In some embodiments, a second dose of 2.5 mg / kg is administered intravenously for an additional 1 to 5 days. In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following four, five, six, seven, eight, or nine days. In some embodiments, the human weighs less than 3.5 kg to 40 kg, and the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously at a first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following 9 days. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously once a day. In some embodiments, the compound of formula Ia or a pharma- ceutically acceptable salt thereof is administered intravenously over about 30 to about 120 minutes. C. Viral infections

[0076] Any suitable viral infection can be treated by the methods of the present disclosure, hi some embodiments, the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Pneumoviridae, and Paramyxoviridae.

[0077] In some embodiments, the viral infection is caused by an Arenaviridae virus. In some embodiments, a method of treating an Arenaviridae virus infection comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, such as an Allpahuayo virus (ALLV), Amapari virus (AMAV), Bear Canyon virus (BCV), or a combination thereof. Bear Canyon virus (BCNV), Catarina virus, Chapare virus, Cupixi virus (CPXV) ), Dandenong virus, Flexal virus , FLEV), Guanarito virus (GTOV), Ippy virus (IPPYV), Junin virus (JUNV), Kodoko virus Kodoko virus, Lassa virus (LASV), Latino virus Latino virus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus, Machupo virus (MACV), Mobala virus (MOBV), Morogo virus Morogoro virus, Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinhal virus, Pirital virus (PIRV), Sabia virus (Sabi virus), Skinner Tank virus, SABV, Tacaribe Tacaribe virus (TCRV), Tamiami virus (TAMV) ), and Whitewater Arroyo virus (WWAV) by administering a compound of the disclosure provided herein. In some embodiments, the Arenaviridae virus is a Lassa virus or a Junin virus. In some embodiments, the method includes treating a Lassa virus infection by administering a compound of the disclosure provided herein. In some embodiments, the method includes treating a Junin virus infection by administering a compound of the disclosure provided herein.

[0078] In some embodiments, the viral infection is caused by a Coronaviridae virus. In some embodiments, the method of treating a Coronaviridae virus infection comprises administering a compound of the present disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the Coronaviridae virus infection is selected from the group consisting of a Severe Acute Respiratory Syndrome (SARS) infection, a SARS-CoV-2 (also known as 2019-nCov and CoVID-19) infection, a Middle Eastern Respiratory Syndrome (MERS) infection, other human coronaviruses (229E, NL63, 0C43, HKU1, or WW1) infection, or a zoonotic coronavirus (PEDV, or an HKU CoV isolate (e.g., HKU3, HKU5, or HKU9)) infection. In some embodiments, the Coronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments, the Coronaviridae virus is SARS. In some embodiments, the Coronaviridae virus is SARS-CoV-2. In some embodiments, the Coronaviridae virus is MERS. In some embodiments, the viral infection is caused by a virus with at least 70% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. In some embodiments, the viral infection is caused by a virus with at least 80% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. In some embodiments, the viral infection is caused by a virus with at least 90% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase.In some embodiments, the viral infection is caused by a virus that has at least 95% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. In some embodiments, the viral infection is caused by a virus that has at least 97% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. In some embodiments, the viral infection is caused by a virus that has at least 99% sequence homology to a viral polymerase selected from SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase.

[0079] In some embodiments, the viral infection is caused by a Filoviridae virus. In some embodiments, a method of treating a Filoviridae virus infection comprises administering a compound of the present disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the Filoviridae virus is an Ebola virus or a Marburg virus. In some embodiments, the Filoviridae virus is an Ebola virus. In some embodiments, the Ebola virus is selected from the group consisting of Zaire virus (i.e., Ebola virus, EBOV), Sudan virus, Tai Forest virus, Bundibugyo virus, and Reston virus. In some embodiments, the Filoviridae virus is a genus of leukemia virus (LEV), ... In embodiments, the Filoviridae virus is a Marburg virus.

[0080] In some embodiments, the viral infection is caused by a Flaviviridae virus. In some embodiments, the method of treating a Flaviviridae virus infection comprises administering a compound of the present disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the Flaviviridae virus is selected from the group consisting of Dengue virus, Yellow Fever virus, West Nile virus, and Zika virus. In some embodiments, the method of treating a Dengue virus infection comprises administering a compound of the present disclosure provided herein. In some embodiments, the Flaviviridae virus is a Yellow Fever virus. In some embodiments, the method of treating a Yellow Fever virus infection comprises administering a compound of the present disclosure provided herein. In some embodiments, the method of treating a West Nile virus infection comprises administering a compound of the present disclosure provided herein. In some embodiments, the method of treating a Zika virus infection comprises administering a compound of the present disclosure provided herein. In some embodiments, the method of treating a Hepatitis C virus infection comprises administering a compound of the present disclosure provided herein.

[0081] In some embodiments, the viral infection is caused by a Pneumoviridae virus. In some embodiments, the method of treating a Pneumoviridae virus infection comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus or a human metapneumovirus. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is a human metapneumovirus.

[0082] In some embodiments, the viral infection is caused by a Paramyxoviridae virus. In some embodiments, a method of treating a Paramyxoviridae virus infection comprises administering a compound of the present disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus or parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus. In some embodiments, the Paramyxoviridae virus is parainfluenza virus.

[0083] In some embodiments, the present disclosure provides a compound of the present disclosure provided herein or a pharma- ceutically acceptable salt thereof for use in a method for treating an Arenaviridae virus infection. In some embodiments, the present disclosure provides a compound of the present disclosure provided herein for use in a method for treating an Arenaviridae virus infection. In some embodiments, the present disclosure provides a compound of the present disclosure for use in a method for treating an Arenaviridae virus infection. In some embodiments, the present disclosure provides a compound of the present disclosure for use in a method for treating an Arenaviridae virus infection. Provided herein is a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method of treating an Arenaviridae virus infection selected from the group consisting of Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinar virus, Piritar virus (PIRV), Sabia virus (SABV), Skinner tank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and Whitewater Arroyo virus (WWAV) by administering a compound of the present disclosure provided herein. In some embodiments, the Arenaviridae virus is Lassa virus or Junin virus. In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method of treating a Lassa virus infection. In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method of treating a Junin virus infection.

[0084] In some embodiments, the disclosure provides a compound of the disclosure provided herein for use in a method of treating a Coronaviridae virus infection. In some embodiments, the Coronaviridae virus infection is selected from the group consisting of a Severe Acute Respiratory Syndrome (SARS) infection, a SARS-CoV-2 (also known as 2019-nCov and CoVID-19) infection, a Middle East Respiratory Syndrome (MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, or WW1) infection, or a zoonotic coronavirus (PEDV, or an HKU CoV isolate (e.g., HKU3, HKU5, or HKU9)) infection. In some embodiments, the Coronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments, the Coronaviridae virus is SARS. In some embodiments, the disclosure provides a compound of the disclosure provided herein for use in a method of treating a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the Coronaviridae virus is SARS-CoV-2. In some embodiments, the present disclosure provides a compound of the present disclosure provided herein for use in a method for treating a SARS-nCoV-2 infection. In some embodiments, the Coronaviridae virus is MERS. In some embodiments, the present disclosure provides a compound of the present disclosure provided herein for use in a method for treating a Middle East Respiratory Syndrome (MERS) infection.

[0085] In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a Filoviridae virus infection. In some embodiments, the Filoviridae virus is an Ebola virus or a Marburg virus. In some embodiments, the Filoviridae virus is an Ebola virus. In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating an Ebola virus infection. In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating an Ebola virus infection selected from the group consisting of Zaire virus (i.e., Ebola virus, EBOV), Sudan virus, Tai Forest virus, Bundibugyo virus, and Reston virus. In some embodiments, the Filoviridae virus is a Marburg virus. In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a Marburg virus infection.

[0086] In some embodiments, the disclosure provides a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof for use in a method of treating a Flaviviridae virus infection. In some embodiments, the Flaviviridae virus is selected from the group consisting of Dengue virus, Yellow Fever virus, West Nile virus, and Zika virus. In some embodiments, the Flaviviridae virus is Dengue virus. In some embodiments, the Flaviviridae virus is Yellow Fever virus. In some embodiments, the Flaviviridae virus is West Nile virus. In some embodiments, the Flaviviridae virus is Zika virus. In some embodiments, the Flaviviridae virus is Hepatitis C virus.

[0087] In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharma- ceutically acceptable salt thereof, for use in a method for treating a Pneumoviridae virus infection. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus or a human metapneumovirus. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is a human metapneumovirus.

[0088] In some embodiments, the disclosure provides a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof for use in a method of treating a Paramyxoviridae virus infection. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus or parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus. In some embodiments, the Paramyxoviridae virus is parainfluenza virus.

[0089] In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating an Arenaviridae virus infection. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating an Arenaviridae virus infection. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating an Arenaviridae virus infection. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating an Arenaviridae virus infection. In some embodiments, the present disclosure provides a use of a compound of the present disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an Arenaviridae virus infection selected from the group consisting of BV), Morogoro virus, Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinar virus, Piritar virus (PIRV), Sabia virus (SABV), Skinner tank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and Whitewater Arroyo virus (WWAV). In some embodiments, the Arenaviridae virus is Lassa virus or Junin virus. In some embodiments, the present disclosure provides a use of a compound of the present disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Lassa virus infection. In some embodiments, the present disclosure provides a use of a compound of the present disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Junin virus infection.

[0090] In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a Coronaviridae virus infection. In some embodiments, the Coronaviridae virus infection is selected from the group consisting of a Severe Acute Respiratory Syndrome (SARS) infection, a SARS-CoV-2 (also known as 2019-nCov and CoVID-19) infection, a Middle East Respiratory Syndrome (MERS) infection, another human coronavirus (229E, NL63, 0C43, HKU1, or WW1) infection, or a zoonotic coronavirus (PEDV, or an HKU CoV isolate (e.g., HKU3, HKU5, or HKU9)) infection. In some embodiments, the Coronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments, the Coronaviridae virus is SARS. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a SARS infection. In some embodiments, the Coronaviridae virus is SARS-CoV-2. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a SARS-nCoV-2 infection. In some embodiments, the Coronaviridae virus is MERS. In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a MERS infection.

[0091] In some embodiments, the disclosure provides a method of using a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Filoviridae virus infection. In some embodiments, the Filoviridae virus is an Ebola virus or a Marburg virus. In some embodiments, the Filoviridae virus is an Ebola virus. In some embodiments, the disclosure provides a method of using a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an Ebola virus infection. In some embodiments, the disclosure provides a method of using a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an Ebola virus infection selected from the group consisting of Zaire virus (i.e., Ebola virus, EBOV), Sudan virus, Tai Forest virus, Bundibugyo virus, and Reston virus. In some embodiments, the disclosure provides a method of using a compound of the disclosure provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Marburg virus infection.

[0092] In some embodiments, the disclosure provides a use of a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a Flaviviridae infection. In some embodiments, the Flaviviridae virus is selected from the group consisting of Dengue virus, Yellow Fever virus, West Nile virus, and Zika virus. In some embodiments, the Flaviviridae virus is Dengue virus. In some embodiments, the Flaviviridae virus is Yellow Fever virus. In some embodiments, the Flaviviridae virus is West Nile virus. In some embodiments, the Flaviviridae virus is Zika virus. In some embodiments, the Flaviviridae virus is Hepatitis C virus.

[0093] In some embodiments, the disclosure provides a compound of the disclosure provided herein, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a Pneumoviridae virus infection. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus or a human metapneumovirus. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is a human metapneumovirus.

[0094] In some embodiments, the disclosure provides a compound of the disclosure provided herein or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for treating a Paramyxoviridae virus infection. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus or parainfluenza virus. In some embodiments, the Paramyxoviridae virus is Nipah virus. In some embodiments, the Paramyxoviridae virus is parainfluenza virus. D. Additional Uses

[0095] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof in a human in need thereof, the method comprising administering an antiviral compound to the human, the human not having been administered chloroquine, or an analog or salt thereof, the antiviral compound being converted to a compound of formula II upon administration to the human, and the concentration of the compound of formula II in the plasma or blood being optimized in the absence of chloroquine, or an analog or salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day of administering the antiviral compound to the human. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 10 days of administering the antiviral compound to the human.

[0096] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, or 24 hours of administration of the antiviral compound to the human. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days of administration of the antiviral compound to the human. In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of less than 50 ng / mL, such as less than 45 ng / mL, less than 40 ng / mL, less than 35 ng / mL, less than 30 ng / mL, less than 25 ng / mL, less than 20 ng / mL, less than 15 ng / mL, less than 10 ng / mL, or less than 5 ng / mL, at the time the first dose of the antiviral compound is administered to the human. In some embodiments, the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of less than 50 ng / mL at the time the first dose of the antiviral compound is administered to the human.

[0097] In some embodiments, the antiviral compound is a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the concentration of the compound of Formula II in the plasma or blood of the human is higher than a second concentration of the compound of Formula II in a reference human treated with chloroquine, or an analog or salt thereof, and the antiviral compound. In some embodiments, the concentration of the compound of Formula II in the plasma or blood of the human is about 1.1 to about 10 times higher, e.g., about 1.2 to about 5 times, about 1.3 to about 5 times, about 1.2 to about 4 times, about 1.3 to about 4 times, about 1.2 to about 3 times, about 1.3 to about 3 times, about 1.2 to about 2 times, or about 1.3 to about 2 times higher than a second concentration of the compound in a reference human treated with chloroquine, or an analog or salt thereof, and the antiviral compound. In some embodiments, the concentration of the compound of formula II in plasma or blood in the human is at least 1.1 times higher, e.g., at least 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times, 4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher than a second concentration of the compound in a reference human treated with chloroquine, or an analog or salt thereof, and an antiviral compound.

[0098] In some embodiments, the present disclosure provides a method for optimizing the plasma or blood concentration of a compound of formula II, or a pharma- ceutically acceptable salt thereof, in a human in need thereof, the method comprising: (a) administering to the human a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof; (b) measuring the plasma or blood concentration of the compound of formula II in the human; and (c) adjusting any remaining dose of the compound of formula I, formula Ia, or formula Ib to optimize the plasma or blood concentration of the compound of formula II in the human. In some embodiments, the method comprises administering a daily dose to the human. In some embodiments, the method comprises administering a 10-day dose to the human.

[0099] In some embodiments, the concentration of the compound of Formula II in plasma or blood in a human is about 1.1-fold to about 10-fold higher, e.g., about 1.2-fold to about 5-fold, about 1.3-fold to about 5-fold, about 1.2-fold to about 4-fold, about 1.3-fold to about 4-fold, about 1.2-fold to about 3-fold, about 1.3-fold to about 3-fold, about 1.2-fold to about 2-fold, or about 1.3-fold to about 2-fold higher than a second concentration of the compound in a reference human treated with chloroquine, or an analog or salt thereof, and a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the concentration of the compound of Formula II in plasma or blood in the human is at least 1.1-fold higher, e.g., at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.2-fold, 3.5-fold, 3.6-fold, 3.8-fold, 4-fold, 4.2-fold, 4.4-fold, 4.6-fold, 4.8-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher than a second concentration of the compound in a reference human treated with chloroquine, or an analog or salt thereof, and a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutical acceptable salt thereof.

[0100] In some embodiments, the disclosure provides a method of determining a delivered dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, for treating a viral infection in a human in need thereof, the method comprising: (a) providing an original dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof; (b) determining whether the human has been administered chloroquine, or an analog or salt thereof; and (c1) if the human has been administered chloroquine, or an analog or salt thereof, increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof to determine the delivered dose; or (c2) if the human has not been administered chloroquine, or an analog or salt thereof, selecting the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof as the delivered dose.

[0101] In some embodiments, the method of determining the delivered dose comprises determining whether the human was administered chloroquine or an analog thereof within 1 day prior to treatment of the viral infection. In some embodiments, the method comprises determining whether the human was administered chloroquine or an analog thereof within 10 days prior to treatment of the viral infection. In some embodiments, determining whether the human was administered chloroquine or an analog thereof comprises self-reporting, interviewing the human, reviewing the human's medical records, or measuring the concentration of chloroquine, or an analog or salt thereof, in the human's plasma or blood. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days prior to administration of the antiviral compound to the human.

[0102] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, if the human has been administered chloroquine, or an analog or salt thereof, prior to treating the viral infection, the method includes increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof by about 1.1-fold to about 10-fold higher to determine the delivered dose, or by increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof by about 1.2-fold to about 5-fold, about 1.3-fold to about 5-fold, about 1.2-fold to about 4-fold, about 1.3-fold to about 4-fold, about 1.2-fold to about 3-fold, about 1.3-fold to about 3-fold, about 1.2-fold to about 2-fold, or about 1.3-fold to about 2-fold higher to determine the delivered dose. In some embodiments, if the human has been administered chloroquine, or an analog or salt thereof, prior to treating the viral infection, the method includes increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof by at least 1.1 times higher to determine the delivered dose, or increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof by at least 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times, 4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times higher to determine the delivered dose. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days of administration of the antiviral compound to the human.

[0104] In some embodiments, the disclosure provides a method of forming a compound of formula II in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of formula Ia and instructing the human not to take chloroquine, or an analog or salt thereof, where the compound of formula Ia is metabolized to the compound of formula II in the absence of chloroquine, or an analog or salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receiving the first dose of the compound of formula Ia. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 28, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, 300, 330, or 365 days prior to administration of the compound of formula Ia. In some embodiments, after instructing the human not to take chloroquine, or an analog or salt thereof, the human waits at least one day before administering the compound of formula Ia.

[0105] In some embodiments, the disclosure provides a method of reducing a risk of reduced efficacy of a compound of formula Ia or a pharmaceutically acceptable salt thereof in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to being administered the compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human to not take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby reducing the risk of reduced efficacy of the compound of formula Ia, or a pharmaceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days of administration of the compound of Formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof.

[0106] In the case of the disclosed methods that require instructing a human not to take chloroquine, or an analog or salt thereof, while being treated with a compound of formula Ia or a pharma- ceutically acceptable salt thereof, if the human is administered chloroquine, or an analog or salt thereof, after receiving the above instruction and after receiving a compound of formula Ia or a pharma- ceutically acceptable salt thereof, any number of countermeasures can be implemented, alone or in combination. In some embodiments, the human stops taking chloroquine, or an analog or salt thereof. In some embodiments, the human waits at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours after the last dose of chloroquine, or an analog or salt thereof, before receiving the first dose of a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human waits at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days after the last dose of chloroquine, or an analog or salt thereof, before receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, after instructing the human not to take chloroquine, or an analog or salt thereof, the human waits at least one day before administering the compound of Formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the human is dosed with 1 additional dose, 2 additional doses, 3 additional doses, 4 additional doses, 5 additional doses, 6 additional doses, 7 additional doses, 8 additional doses, 9 additional doses, or 10 additional doses of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, compared to a reference human who has not received chloroquine, or an analog or salt thereof.In some embodiments, the human is administered a higher dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, as compared to a reference human not administered chloroquine, or an analog or salt thereof, or ... as compared to a reference human not administered chloroquine, or an analog or salt thereof, as compared to a reference human not administered chloroquine, or an analog or salt thereof, as compared to a reference human not administered chloroquine, or an analog or salt thereof, In one embodiment, the patient is administered a 0.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.2-fold, 3.5-fold, 3.6-fold, 3.8-fold, 4-fold, 4.2-fold, 4.4-fold, 4.6-fold, 4.8-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the disclosure provides a method of preventing a contraindication in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby preventing the contraindication in the human. In some embodiments, if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, preventing a contraindication in a human is by comparison with a second human who has taken chloroquine, or an analog or salt thereof, or has not been instructed not to take chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof. In some embodiments, a second human who has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof is more likely to have a contraindication after administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof than the human. In some embodiments, a second human who has not been instructed not to take chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof is more likely to have a contraindication after administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof than the human. In some embodiments, the second human is at least 1.1 times, e.g., 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times, 4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times more likely to have a contraindication following administration of a compound of Formula Ia or a pharma- ceutically acceptable salt thereof, than the second human.

[0109] In some embodiments, the disclosure provides a method of maintaining efficacy of a compound of Formula Ia or a pharmaceutically acceptable salt thereof in a human suffering from a viral infection, the method comprising: (a) determining whether the human was taking chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of Formula Ia or a pharmaceutically acceptable salt thereof; and (c) administering the compound of Formula Ia or a pharmaceutically acceptable salt thereof to the human, thereby maintaining efficacy of the compound of Formula Ia or a pharmaceutically acceptable salt thereof. In some embodiments, maintaining efficacy comprises maintaining a sufficient plasma or blood concentration of the compound of Formula II in the human after administration compared to a second human not taking chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia or a pharmaceutically acceptable salt thereof. In some embodiments, the concentration of the compound of formula II in the plasma or blood of the human after administration is about 50% to about 100% of the second concentration of the compound of formula II in the plasma or blood of a second human who has not taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof, or is about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 90% to about 100% of the second concentration of the compound of formula II in the plasma or blood of a second human who has not taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof. In some embodiments, if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the disclosure provides a method of reducing the risk of decreased plasma concentration of a compound of formula II in a human suffering from a viral infection, the method comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of a compound of formula Ia, or a pharmaceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharmaceutically acceptable salt thereof; and (c) administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof, to the human, thereby reducing the risk of decreased plasma concentration of the compound of formula II. In some embodiments, if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharmaceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, reducing the risk of a decrease in the concentration of the compound of formula II in the plasma comprises maintaining a sufficient concentration of the compound of formula II in the plasma of the human after administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, compared to a second human who is not taking chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the concentration of the compound of Formula II in plasma in the human after administration is about 50% to about 100% of the second concentration of the compound of Formula II in a second human not taking chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, or is about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 90% to about 100% of the second concentration of the compound of Formula II in a second human not taking chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

[0112] For methods of the present disclosure that require determining whether a human has taken chloroquine, or an analog or salt thereof, prior to administration of a compound of formula Ia or a pharma- ceutically acceptable salt thereof, the determination can be performed by any suitable means. For example, non-limiting techniques include self-reporting, interviewing the human, reviewing the human's medical records, or measuring the concentration of chloroquine, or an analog or salt thereof, in the human's plasma or blood. In some embodiments, determining includes measuring the concentration of chloroquine, or a metabolite, analog, or salt thereof, in the human's plasma or blood. IV. Kit

[0113] In some embodiments, the present disclosure provides a method of using a kit comprising a compound or composition disclosed herein. In some embodiments, the kit further comprises a label and / or instructions for using the compound or pharmaceutical composition in the method of the present disclosure. For example, in some embodiments, the kit further comprises instructing the human not to take chloroquine, or an analog or salt thereof, during the treatment of a viral infection.

[0114] In some embodiments, the kit comprises instructions to instruct the human to wait at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit comprises instructing the human to wait after taking chloroquine, or an analog or salt thereof, for example, to wait at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit further comprises instructing the human to wait at least 1 day after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit further comprises instructing the human to wait at least 10 days after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises instructing the human to wait at least 14 days after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises instructing the human to wait at least 21 days after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the kit comprises instructions to instruct the human to wait at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours after taking the chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit comprises instructing the human to wait after taking chloroquine, or an analog or salt thereof, for example, to wait at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days after taking chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit comprises instructing the human to wait at least 10 days after taking chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit includes instructions to the human to wait at least 14 days after taking chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, hi some embodiments, the kit includes instructions to the human to wait at least 21 days after taking chloroquine, or an analog or salt thereof, before administering the compound of formula Ia, or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments, the kit further comprises a nebulizer. Any suitable nebulizer may be used. In some embodiments, the nebulizer is a glass nebulizer. In some embodiments, the nebulizer is a hand valve nebulizer. In some embodiments, the nebulizer is a jet nebulizer or a vibrating mesh nebulizer. In some embodiments, the nebulizer is a jet nebulizer (e.g., VixOne™, AeroEclipse®, Pari LC® Plus). In some examples, the nebulizer is a vibrating mesh nebulizer (e.g., eFlow® rapid). In some embodiments, the nebulizer is an ultrasonic nebulizer. In some embodiments, the nebulizer is an adaptive aerosol delivery nebulizer. In some embodiments, the nebulizer is a metered dose inhaler (e.g., a metered dose liquid inhaler). EXAMPLES

[0117] V. Working Examples Example 1. Effect of chloroquine on compounds of formula Ia in cells Antivirals of formula Ia against respiratory syncytial virus (RSV) The antiviral potency of the compounds was determined in HEp2 cells in the following manner. HEp2 cells (3x103 / well) were suspended in DMEM medium + GlutaMAX (supplemented with 10% FBS and 1% penicillin / streptomycin) and seeded in a 96-well plate. After 4 hours of incubation at 37°C + 5% CO2, 3-fold serial dilutions of the compounds (final RDV concentrations from 9.28nM to 2000nM) were added to each well using a HP D300e digital dispenser. To determine the effect of chloroquine (CQ) on the antiviral activity of Formula Ia, the serial dilutions of Formula Ia were further spiked with DMSO or 4-fold increasing concentrations of CQ (final concentrations: 10nM, 40nM, 160nM, 640nM, and 2560nM). The cells were then infected with RSV A2 virus diluted in DMEM medium + GlutaMAX at MOI = 4 and incubated at 37 ° C and 5% CO2 for 4 days. The final volume in each well was 200 μL. Uninfected and untreated wells were included as controls for 100% cell viability. After incubation, 100 μL of culture supernatant was removed from each well and replaced with 100 μL of CellTiter-Glo reagent (Promega). The plate was then rocked for 2 minutes, followed by incubation at 25 ° C for 10 minutes. Cell viability was then assessed by measuring the luminescence signal using an Envision plate reader. Values ​​were normalized to uninfected DMSO controls and infected DMSO controls (100% and 0% infection, respectively), and the data were fitted using nonlinear regression analysis in XLfit software. EC 50 Values ​​were determined as the point of 50% infection on the nonlinear regression curve. Data collected were generated using three biological replicates, each containing a technical replicate of each CQ concentration.

[0118] The effect of the combination of the compound of formula Ia with chloroquine (CQ) concentrations on RSV replication in HEp2 cells was measured. The results showed that the EC 50 As demonstrated by the values ​​(Table 1), CQ neutralizes the anti-RSV activity of the compound of Formula Ia in a dose-dependent manner. [Table 1] Example 2: Metabolic Data

[0119] A549-hACE2 cells and NHBE cells were placed in a 6-well plate at 4 × 10 5 pcs / well and 2.5 x 10 5 HEp-2 cells were seeded at 2.5 × 10 cells / well in a 12-well plate. 5 Cells were seeded at 1000 cells / well. After 24 hours, the cell culture medium was replaced with medium containing 1 μM Formula Ia alone or in combination with 1 μM or 10 μM CQ or HCQ and incubated at 37°C. At 2, 8, 24, and 48 hours after drug addition, cells were washed three times with ice-cold Tris-buffered saline, scraped into 0.5 mL of ice-cold 70% methanol, and stored at -80°C. Extracts were centrifuged at 15,000 g for 15 minutes, and the supernatant was transferred to a clean tube and evaporated in a miVac Duo concentrate (Genevac). Dried samples were reconstituted with 10 mM dimethylhexylamine (DMHA) in water in mobile phase A containing 3 mM ammonium formate (pH 5) and analyzed by LC-MS / MS using a multi-step linear gradient of 10% to 50% acetonitrile in mobile phase A at a flow rate of 360 μL / min. Analytes were separated using a 50 x 2 mm, 2.5 μm Luna C18(2) HST column (Phenomenex) connected to an LC-20ADXR (Shimadzu) ternary pump system and an HTS PAL autosampler (LEAP Technologies). Detection was performed on a Qtrap (6500+, AB Sciex) mass spectrometer operated in positive ion and multiple reaction monitoring mode. Analytes were quantified using a 7-point standard curve ranging from 0.624 to 160 pmol per million cells prepared in extracts from untreated cells. For normalization by cell number, multiple untreated culture wells were counted at each time point.

[0120] A549-hACE2, NHBE, and HEp-2 cell cultures were incubated with the compound of formula Ia alone and in combination with CQ or HCQ to assess the metabolism of the compound of formula Ia to the active triphosphate species (formula Ia-TP). The concentrations of CQ and HCQ used in these in vitro assays correspond to the systemic and pulmonary exposures resulting from doses recommended under previous EUA guidance for COVID-19. The mean systemic exposures ranged from 610-760 nM for CQ and approximately 1.7 μM for HCQ, amounts that can achieve lung concentrations of >20 μM for either drug {Salman 2017, Zhao 2014}. In A549-hACE2 cells, co-incubation of the compound of formula Ia with 1 μM CQ or HCQ did not significantly reduce the concentration of formula Ia-TP compared to formula Ia-TP in the absence of CQ or HCQ. However, incubation with 10 μM CQ or HCQ significantly reduced the production of formula Ia-TP (Table 2, Figure 1). For both concentrations of CQ, or for 1 μM HCQ, the formula Ia-TP concentrations of NHBE cultures treated with them tended to be lower, but these differences were not statistically significant. Conversely, treatment of NHBE cultures with 10 μM HCQ significantly reduced formula Ia-TP concentrations (Table 3, Figure 2). In HEp-2 cervical cancer cells, treatment with 1 μM and 10 μM CQ or HCQ showed a dose-dependent decrease in the formation of formula Ia-TP in cells (Table 4, Figure 3). Significant CQ or HCQ neutralization of formula Ia-TP formation in HEp-2 cells was observed 8 hours after treatment and persisted for 48 hours. The observed decrease in formula Ia-TP in the presence of CQ or HCQ indicates a potential neutralizing effect of the compound of formula Ia on the metabolism to its active triphosphate. [Table 2] a Values ​​are the mean ± SEM of replicate samples collected at each time point from two separate experiments. bThe average Formula Ia-TP concentration was determined at 0, 2, 8, 24, and 48 hours using GraphPad Prism 8.1.2 from the total area under the curve of the concentration of Formula Ia-TP detected by LC-MS and divided by the total time of the assay (48 hours). c P values ​​are determined using one-way ANOVA with Dunnett's multiple comparison analysis of Formula Ia+DMSO compared to various concentrations of CQ or HCQ using GraphPad Prism 8.1.2. [Table 3] a Values ​​are the mean ± SEM of replicate samples collected at each time point from two separate experiments. b The average concentration of Formula Ia was determined at 0, 2, 8, 24, and 48 hours using GraphPad Prism 8.1.2 from the total area under the curve of the concentration of Formula Ia-TP detected by LC-MS and divided by the total time of the assay (48 hours). c P values ​​are determined using one-way ANOVA with Dunnett's multiple comparison analysis of Formula Ia+DMSO compared to various concentrations of CQ or HCQ using GraphPad Prism 8.1.2. [Table 4] a Values ​​are the mean ± SEM of replicate samples collected at each time point from two separate experiments. b The average Formula Ia-TP concentration was determined at 0, 2, 8, 24, and 48 hours using GraphPad Prism 8.1.2 from the total area under the curve of the concentration of Formula Ia-TP detected by LC-MS and divided by the total time of the assay (48 hours). c P values ​​are determined using one-way ANOVA with Dunnett's multiple comparison analysis of Formula Ia+DMSO compared to various concentrations of CQ or HCQ using GraphPad Prism 8.1.2. Example 3. Anti-SARS-CoV-2 virus data

[0121] The anti-SARS-CoV-2 activity of the compound of formula Ia and either CQ or HCQ was evaluated in A549-hACE2-transduced airway epithelial cells. The compound of formula Ia, CQ, and HCQ alone showed potent in vitro antiviral activity against SARS-CoV-2, with EC 50 The EC values ​​for the compound of formula Ia in combination with CQ or HCQ at concentrations up to 2.5 μM are approximately 59.5 nM, 451 nM, and 365 nM, respectively (Table 5). 50 The values ​​were not observably different (Table 5). However, the overall Nluc signal in the assay was dose-dependently decreased in the presence of CQ or HCQ (Figure 4). As shown in Figure 4A, the Nluc signal at 0 μM Formula Ia (DMSO) + CQ corresponds to the Nluc signal at a particular CQ concentration in that treatment condition. The baseline Nluc signal for each Formula Ia titration curve drops to a level corresponding to the CQ concentration in that treatment condition. A similar effect is observed in the HCQ treatment condition in Figure 4B. At 10 μM CQ or HCQ alone, the Nluc signal was completely suppressed, indicating complete inhibition of SARS-CoV-2 replication by either CQ or HCQ alone. The potent antiviral activity of CQ and HCQ at a concentration of 10 μM allows the standard EC 50 Comparison of values ​​fails to reveal a potential decrease in the activity of Formula Ia against SARS-CoV-2 when combined with CQ or HCQ. No cytotoxicity was observed at the combined Formula Ia and HCQ concentrations analyzed (data not shown). [Table 5] a n=1 b EC 50Values ​​are expressed as the concentration at which there is a 50% reduction in counts per second (CPS) of Nluc compared to DMSO vehicle alone (0% virus inhibition) and uninfected control cultures (100% virus inhibition) using GraphPad Prism 8. Defined in 1.2. c ND inhibited EC by completely inhibiting Nluc signaling with CQ or HCQ. 50 Indicates that the value could not be calculated.

[0122] Although the foregoing disclosure has been described in some detail by way of illustration and example for clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety as if each reference were individually incorporated by reference. In the event of any conflict between this application and a reference provided herein, this application shall control. The present invention provides, for example, the following items. (Item 1) 1. A method of treating a viral infection in a human in need of such treatment, said method comprising administering to said human a therapeutically effective amount of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof; [ka] The human is not being treated with chloroquine, or an analog or salt thereof, thereby treating the viral infection. (Item 2) 2. The method of claim 1, wherein the human has not been administered chloroquine, or an analog or salt thereof, within 1 day of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 3) 3. The method of claim 2, wherein the human has not been administered chloroquine, or an analog or salt thereof, within 10 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 4) 4. The method of claim 3, wherein the human has not been administered chloroquine, or an analog or salt thereof, within 90 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 5) 5. The method of any one of items 1 to 4, wherein the human has not been administered chloroquine, or an analog or salt thereof, within 365 days of receiving the first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 6) 6. The method of any one of items 1 to 5, further comprising instructing the human to avoid taking chloroquine, or an analogue or salt thereof, during said treatment of said viral infection. (Item 7) 7. The method of any one of items 1 to 6, further comprising instructing the human to wait at least 10 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 8) 8. The method of any one of items 1 to 7, wherein the human is not administered chloroquine, or an analogue or salt thereof, during said treatment of said viral infection. (Item 9) 9. The method of any one of items 1 to 8, wherein the human has a plasma or blood concentration of chloroquine, or an analogue or salt thereof, of less than 50 ng / mL at the time a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered to the human. (Item 10) 10. The method according to any one of items 1 to 9, wherein the chloroquine, or an analogue or salt thereof is chloroquine, desethylchloroquine, hydroxychloroquine, desethylhydroxychloroquine, or bidesethylhydroxychloroquine, or a pharma- ceutically acceptable salt thereof. (Item 11) 11. The method of claim 10, wherein the chloroquine, or an analogue or salt thereof, is chloroquine, or a pharma- ceutically acceptable salt thereof. (Item 12) 12. The method of claim 11, wherein the chloroquine, or an analogue or salt thereof, is chloroquine phosphate. (Item 13) 11. The method of claim 10, wherein the chloroquine, or an analogue or salt thereof, is hydroxychloroquine, or a pharma- ceutically acceptable salt thereof. (Item 14) Item 14. The method of item 13, wherein the chloroquine, or an analogue or salt thereof, is hydroxychloroquine sulfate. (Item 15) administering to said human a therapeutically effective amount of said compound of formula I, or a pharma- ceutically acceptable salt thereof; [ka] The method according to any one of items 1 to 14, comprising: (Item 16) administering to said human a therapeutically effective amount of said compound of formula Ia, or a pharma- ceutically acceptable salt thereof; [ka] 16. The method according to any one of items 1 to 15, comprising: (Item 17) administering to said human said therapeutically effective amount of said compound of formula Ia; [ka] 17. The method according to any one of items 1 to 16, comprising: (Item 18) 18. The method according to any one of items 1 to 17, wherein the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered by inhalation or intravenously. (Item 19) 19. The method of claim 18, wherein the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously. (Item 20) 19. The method of item 18, wherein the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof, is administered by inhalation. (Item 21) 20. The method of any one of items 1-19, wherein the human body weight is at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at the first dose of 200 mg on day 1, and at a second dose of 100 mg on each of four days thereafter. (Item 22) 22. The method of claim 21, wherein the second dose of 100 mg is administered for an additional 1 to 5 days. (Item 23) 23. The method of item 21 or 22, wherein the human body weight is at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at the first dose of 200 mg on day 1, and at second doses of 100 mg on each of the following 9 days. (Item 24) 20. The method of any one of items 1-19, wherein the human body weight is between 3.5 kg and less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at the first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the four days thereafter. (Item 25) 25. The method of claim 24, wherein the second dose of 2.5 mg / kg is administered for an additional 1 to 5 days. (Item 26) 26. The method of item 24 or 25, wherein the human weighs between 3.5 kg and less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously at the first dose of 5 mg / kg on day 1, and at a second dose of 2.5 mg / kg on each of the following 9 days. (Item 27) 27. The method according to any one of items 1 to 26, wherein the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Pneumoviridae, and Paramyxoviridae. (Item 28) 28. The method of claim 27, wherein the viral infection is caused by an Arenaviridae virus. (Item 29) 29. The method of claim 28, wherein the Arenaviridae virus is a Lassa virus or a Junin virus. (Item 30) 28. The method according to item 27, wherein the viral infection is caused by a Coronaviridae virus. (Item 31) 31. The method of claim 30, wherein the Coronaviridae virus is a SARS virus, a SARS-CoV-2 virus, a MERS virus, a 229E virus, a NL63 virus, an OC43 virus, or a HKU1 virus. (Item 32) 31. The method according to item 30, wherein the Coronaviridae virus is a SARS virus, a SARS-CoV-2 virus, or a MERS virus. (Item 33) 33. The method according to claim 32, wherein the coronavirus family virus is a SARS-CoV-2 virus. (Item 34) 33. The method according to any one of items 30 to 32, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. (Item 35) 35. The method according to any one of items 30 to 32 or 34, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. (Item 36) 36. The method of any one of items 30 to 32, 34, or 35, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. (Item 37) 37. The method according to any one of items 30 to 32 and 34 to 36, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. (Item 38) 28. The method of claim 27, wherein the viral infection is caused by a Filoviridae virus. (Item 39) 39. The method of claim 38, wherein the Filoviridae virus is an Ebola virus or a Marburg virus. (Item 40) 28. The method of claim 27, wherein the viral infection is caused by a Flaviviridae virus. (Item 41) 41. The method of claim 40, wherein the Flaviviridae virus is a Dengue virus, a Yellow Fever virus, a West Nile virus, or a Zika virus. (Item 42) 42. The method of claim 41, wherein the Flaviviridae virus is a yellow fever virus. (Item 43) 28. The method of claim 27, wherein the viral infection is caused by a Pneumoviridae virus. (Item 44) 44. The method of claim 43, wherein the Pneumoviridae virus is a respiratory syncytial virus or a human metapneumovirus. (Item 45) 45. The method of claim 44, wherein the Pneumoviridae virus is a respiratory syncytial virus. (Item 46) 28. The method according to item 27, wherein the viral infection is caused by a Paramyxoviridae virus. (Item 47) 47. The method according to item 46, wherein the Paramyxoviridae virus is a Nipah virus or a Parainfluenza virus. (Item 48) 1. A method of optimizing plasma or blood concentration of a compound of formula II, or a pharma- ceutically acceptable salt thereof, in a human in need thereof, comprising: [ka] The method includes administering to the human an antiviral compound; the human has not been administered chloroquine, or an analog or salt thereof; When the antiviral compound is administered to the human, it is converted to the compound of formula II, The method, wherein the concentration of the compound of formula II in plasma or blood is optimized in the absence of chloroquine, or an analog or salt thereof. (Item 49) 49. The method of claim 48, wherein the human has not been administered chloroquine or an analog thereof within one day prior to treatment of the viral infection. (Item 50) 49. The method of claim 48, wherein the human has not been administered chloroquine or an analog thereof within 10 days prior to treatment of the viral infection. (Item 51) 49. The method of claim 48, wherein the human has a plasma or blood concentration of chloroquine, or an analog or salt thereof, of less than 50 ng / mL at the time a first dose of the antiviral compound is administered to the human. (Item 52) 52. The method of claim 48 or 51, wherein the concentration of the compound of formula II in plasma or blood in the human is greater than a second concentration of the compound of formula II in a reference human treated with chloroquine, or an analogue or salt thereof. (Item 53) 53. The method according to any one of items 48 to 52, wherein the antiviral compound is a compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 54) 1. A method of optimizing plasma or blood concentration of a compound of formula II, or a pharma- ceutically acceptable salt thereof, in a human in need thereof, comprising: [ka] The method comprises: (a) administering to said human a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof; [ka] (b) measuring the concentration of the compound of formula II in plasma or blood in the human; and (c) adjusting any remaining doses of said compound of Formula I, Formula Ia, or Formula Ib to optimize said concentration of said compound of Formula II in plasma or blood in said human. (Item 55) 55. The method of claim 54, comprising administering a daily dose to the human. (Item 56) 55. The method of claim 54, comprising administering to the human a 10 day dose. (Item 57) 1. A method for determining a delivered dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, for treating a viral infection in a human in need of such treatment, comprising: [ka] The method comprises: (a) providing an original dose of the compound of formula I, formula Ia, or formula Ib, or a pharma- ceutically acceptable salt thereof; (b) determining whether the human has been administered chloroquine, or an analog or salt thereof; (c1) determining the delivered dose by increasing the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, if the human was administered chloroquine, or an analog or salt thereof; or (c2) if the human has not been administered chloroquine, or an analog or salt thereof, selecting as the delivered dose the original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof. (Item 58) 58. The method of claim 57, wherein the method comprises determining whether the human was administered chloroquine, or an analog thereof, within one day prior to the treatment of the viral infection. (Item 59) 58. The method of claim 57, wherein the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 10 days prior to said treating the viral infection. (Item 60) A method of forming a compound of formula II in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of formula Ia and instructing the human to avoid taking chloroquine, or an analog or salt thereof, wherein the compound of formula Ia is metabolized to the compound of formula II in the absence of chloroquine, or an analog or salt thereof; The compound of formula II has the structure: [ka] The compound of formula Ia has the following structure: [ka] method. (Item 61) 61. The method of item 60, wherein if the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia. (Item 62) 1. A method for reducing the risk of reduced efficacy of a compound of formula Ia, or a pharma- ceutically acceptable salt thereof, in a human suffering from a viral infection, comprising: [ka] The method comprises: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; and (c) administering to the human a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; Thereby reducing the risk of reduced efficacy of said compound of formula Ia, or a pharma- ceutically acceptable salt thereof. (Item 63) 63. The method of claim 62, wherein if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia or a pharma- ceutically acceptable salt thereof. (Item 64) 1. A method for preventing a contraindication in a human suffering from a viral infection, comprising: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; [ka] (b) instructing the human not to take chloroquine, or an analog or salt thereof, during treatment with the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; and (c) administering to the human a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; Thereby preventing contraindications in said human. (Item 65) 65. The method of claim 64, wherein if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia or a pharma- ceutically acceptable salt thereof. (Item 66) 1. A method of maintaining the availability of a compound of formula Ia, or a pharma- ceutically acceptable salt thereof, in a human suffering from a viral infection, comprising: [ka] The method comprises: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; and (c) administering to the human a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; thereby maintaining the efficacy of said compound of formula Ia, or a pharma- ceutically acceptable salt thereof. (Item 67) 62. The method of claim 61, wherein if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia or a pharma- ceutically acceptable salt thereof. (Item 68) 1. A method for reducing the risk of reduced plasma concentration of a compound of formula II in a human suffering from a viral infection, comprising: [ka] The method comprises: (a) determining whether the human has taken chloroquine, or an analog or salt thereof, prior to administration of a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; (b) instructing the human not to take chloroquine, or an analog or salt thereof, while being treated with the compound of formula Ia, or a pharma- ceutically acceptable salt thereof; and (c) administering to the human a compound of formula Ia, or a pharma- ceutically acceptable salt thereof; [ka] Thereby reducing the risk of a decrease in the concentration of said compound of formula II in plasma. (Item 69) 69. The method of item 68, wherein if it is determined that the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of formula Ia or a pharma- ceutically acceptable salt thereof, the human waits at least one day before administering the compound of formula Ia or a pharma- ceutically acceptable salt thereof.

Claims

[Claim 1] The invention described in the specification.

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