Remdesivir treatment methods

Abstract

Provided herein are methods of treating or preventing a viral infection in a subject comprising administering a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, wherein the subject is not being treated with chloroquine, or an analog or salt thereof.

Description

(19) *EP004748374A1* (11) EP 4 748 374 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 27.05.2026 Bulletin 2026 / 22 (21) Application number: 25185294.3 (22) Date of filing: 28.05.2021 (51) International Patent Classification (IPC): A61K 31 / 4706 (2006.01) A61K 31 / 706 (2006.01) A61P 31 / 14 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 31 / 706; A61K 31 / 4706; A61P 31 / 14; Y02A 50 / 30 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 29.05.2020 US 202063032321 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 21733348.3 / 4 157 272 (71) Applicant: Gilead Sciences, Inc. Foster City, CA 94404 (US) (72) Inventor: CIHLAR, Tomas Foster City, 94404 (US) (74) Representative: Marks & Clerk LLP 15 Fetter Lane London EC4A 1BW (GB) Remarks: •This application was filed on 25‑06‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of receipt of the application (Rule 68(4) EPC). •The references to parts of the description (originally filed page 52 ) are deemed to be deleted (Rule 56(4) (6) EPC). (54) REMDESIVIR TREATMENT METHODS (57) Provided herein are methods of treating or pre- venting a viral infection in a subject comprising adminis- tering a compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof,wherein the subject is not being treated with chloroquine, or an analog or salt thereof. EP 4 74 8 37 4 A 1 Processed by Luminess, 75001 PARIS (FR) Description CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to the U.S. Provisional Patent Application No. 63 / 032,321, filed May 29, 2021, which is incorporated herein in its entirety for all purposes. Theapplication is adivisional application fromEuropeanPatent Application No. 21733348.3. BACKGROUND

[0002] Preventing or treating some Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxovirus, Pneumo- viridae, and Paramyxoviridae viral infections present challenges due to a lack of vaccine or post-exposure treatment modality for preventingormanaging infections causedbyviruses from these families. In somecases, patients only receive supportive therapy such as electrolyte and fluid balancing, oxygen, blood pressure maintenance, or treatment for secondary infections.

[0003] The compound (S)‑2-ethylbutyl 2‑(((S)‑(((2R,3S,4R,5R)‑5‑(4-aminopyrrolo[2,1-f][1,2,4]triazin‑7-yl)‑5-cya- no‑3,4-dihydroxytetrahydrofuran‑2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, referred to herein as the com- pound of Formula Ia, is known to exhibit antiviral properties against several viral families, including Arenaviridae, Coronaviridae, Filoviridae, Paramyxoviridae, and Flaviviridae viruses (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. Sci. Transl. Med. 2017;9:eaal3653; Agostini ML, et al. MBio 2018;9(2):e00221‑18; Cell Research (2020) 30:269‑271, and WO 2017 / 184668). There is a need to developmethods of treating viral infections comprising the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof.

[0004] 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 theantiviral activity of the compound. BRIEF SUMMARY

[0005] In some embodiments, the present disclosure provides a method of treating a viral infection in a human in need thereof, themethodcomprisingadministering to thehumana therapeutically effectiveamount of a compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof: 2 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 wherein the human is not being treated with chloroquine, or an analog or salt thereof, thereby treating the viral infection.

[0006] In some embodiments, the present disclosure provides a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: themethod comprising administering to the human an antiviral compound, wherein the human has not been administered chloroquine, or an analog or salt thereof, the antiviral compound is converted to the compound of Formula II upon administration to the human, and the plasma or blood concentration of the compound of Formula II is optimized in the absence of chloroquine, or an analog or salt thereof.

[0007] In some embodiments, the present disclosure provides a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically 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 pharmaceutically acceptable salt thereof; (b)measuring the plasmaor blood concentration of the compound of Formula II in the human; and (c) adjustingany remainingdosesof the compoundofFormula I, Formula Ia, orFormula Ib, to optimize theplasmaor blood concentration of the compound of Formula II in the human.

[0008] In someembodiments, thepresentdisclosureprovidesamethodofdeterminingadeliverydoseofacompoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, for treating 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, to determine the delivery 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 pharmaceutically acceptable salt thereof, as the delivery dose.

[0009] In someembodiments, thepresent disclosureprovidesamethodof formingacompoundofFormula II in ahuman in need thereof, 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, 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, wherein the compound of Formula II has the structure: 3 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 and wherein the compound of Formula Ia has the structure:

[0010] In some embodiments, the present disclosure provides is a method of reducing the risk of decreased efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining if the humanhas taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or apharmaceutically acceptable salt thereof, (b) instructing thehumannot to takechloroquine, or ananalogor 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 efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a method of preventing a contraindication in a human suffering froma viral infection, themethod comprising: (a) determining if the humanhas 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 a contraindication in the human.

[0012] In some embodiments, the present 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 if 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 maintaining efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a method of reducing the risk of a reduced plasma concentration of a compound of Formula II, in a human suffering from a viral infection, the method comprising: (a) determining if the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or apharmaceutically acceptable salt thereof, (b) instructing thehumannot to takechloroquine, or ananalogor 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 a reduced plasma concentration of the compound of Formula II. 4 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1. Shows the effect of chloroquine (CQ) or hydroxychloroquine (HCQ) on the Formula Ia triphosphate (TP) formation in A549-hACE2 cells. Figure 2. Shows the effect of CQ or HCQ on the Formula Ia triphosphate (TP) formation in NHBE cultures. Figure 3. Shows the effect of CQ or HCQ on the Formula Ia triphosphate (TP) formation in HEp‑2 cells. Figure 4.ShowsSARS-CoV‑2 antiviral data for the compound of Formula Ia in combination with either CQor HCQ in A549-hACE2 cells. DETAILED DESCRIPTION I. GENERAL

[0015] Thepresent disclosure providesamethodof treatinga viral infection in a subject, comprising administering to the subject a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, wherein the subject is not being treated with chloroquine, or an analog or salt thereof. II. DEFINITIONS

[0016] A "compound of the disclosure" refers to a compound that is administered to a subject in a method as described herein, and includes compounds of Formula I, Formula Ia, Formula Ib, or a pharmaceutically acceptable salt thereof.

[0017] "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0018] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0019] "Pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound tomammals, for example, humans. Such amedium includes all pharmaceutically acceptable excipients therefor.

[0020] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound of the disclosure, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound of the disclosure which constitutes a therapeutically effective amount will vary depending on such factors 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 the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combinationwith or coincidentally with the compounds of the disclosure, and the age, bodyweight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0021] "Treatment" or "treating" or "treat" refers to an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing oneormore symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0022] "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compositionsmay, in someembodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0023] "Subject" or "patient" refer to an animal, suchas amammal, including a human, that has beenorwill be the object of treatment, observation or experiment. Themethods described hereinmaybeuseful in human therapy and / or veterinary applications. In some embodiments, the subject or the patient is a mammal. In some embodiments, the subject or the 5 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 patient is human; a domestic animal like a dog or a cat; a farm 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 the patient is a human.

[0024] "Human in need thereof" refers to a human who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the present application to treat a viral infection. III. METHODS OF USE

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

[0026] In some embodiments, the present disclosure provides a method of treating a viral infection in a human in need thereof, themethodcomprisingadministering to thehumana therapeutically effectiveamount of a compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof: wherein the human is not being treated with chloroquine, or an analog or salt thereof, thereby treating the viral infection.

[0027] In some embodiments, the present disclosure provides a method of confirming the administration of the compound of Formula I, Formula Ia, or Formula Ib to a human, 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 ananalogor salt thereof, before theadministering of the compoundof Formula I, Formula Ia, or Formula Ib, 6 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof. In some embodiments, the biological sample is derived from plasma or blood.

[0028] In some embodiments, the present disclosure provides a method of measuring the rate of metabolism of the compound of Formula I, Formula Ia, or Formula Ib in a human, comprising measuring the amount of a compound of Formula II, or asalt thereof, in thehumanatoneormore timepointsafter administrationof compoundofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, thehumanhasnot beenpreviously treatedwith chloroquine, or ananalogor salt thereof, before theadministeringof thecompoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a biological sample obtained from the human. In some embodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a blood sample. In some embodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a plasma sample.

[0029] In some embodiments, the present disclosure provides a method of determining the prophylactic or therapeutic response of a human in the treatment of a viral infection comprisingmeasuring 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 pharmaceutically acceptable salt thereof. In some embodiments, the human has not been previously treatedwith chloroquine, or ananalogor salt thereof, before theadministeringof thecompoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a biological sample obtained from the human. In some embodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a blood sample. In some embodiments, the amount of the compound of Formula II, or a salt thereof, is measured from a plasma sample. A. CHLOROQUINE ADMINISTRATION

[0030] Thepresentmethods provide treatment of a human that does not have an appreciable systemic concentration of chloroquine, orananalogor salt thereof. In someembodiments, thehuman inneed thereof hasnot beenpreviously treated with chloroquine, or an analog or salt thereof, before the administering of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically 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 before the administering of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure allows for a decrease in the systemic concentration of the chloroquine, or an analog or salt thereof, such that the antiviral activity of the compound of the disclosure is not decreased. For example, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure can allow for a decrease in the plasma concentration of the chloroquine, or an analog or salt thereof, as a result of clearance or metabolism.

[0032] In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the 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 of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 14 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 28 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 40 days. In some embodiments, the period of time between the treatment with chloroquine or analog thereof and the administration of the compound of the disclosure is at least 50 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 60 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 90 days. In someembodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 120 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 180 days. In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and the administration of the compound of the disclosure is at least 365 days.

[0033] In some embodiments, the period of time between the treatment with chloroquine, or an analog or salt thereof, and theadministrationof thecompoundof thedisclosure isat least 30mins, at least 1hour, at least 2hours, at least 3hours, 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. 7 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55

[0034] In someembodiments, the humanhas been administered chloroquine, or an analog or salt thereof, in fromabout 1 days to about 365 days prior to receiving a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, or from about 1 day to about 14 days, from about 1 day to about 21 days, from about1day toabout30days, fromabout1day toabout45days, fromabout10days toabout45days, fromabout14days to about 45 days, from about 21 days to about 45 days, from about 28 days to about 45 days, from about 30 days to about 45 days, 10 days to about 60 days, from about 14 days to about 60 days, from about 21 days to about 60 days, from about 28 days to about 60 days, from about 30 days to about 60 days, from about 40 days to about 60 days, from about 10 days to about 90 days, from about 14 days to about 90 days, from about 21 days to about 90 days, from about 28 days to about 90 days, from about 30 days to about 90 days, from about 40 days to about 90 days, from about 10 days to about 365 days, from about 14 days to about 365 days, from about 21 days to about 365 days, from about 28 days to about 365 days, from about 30days to about 365days, or fromabout 60days to about 365days, prior to receivinga first doseof the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the humanhas been administered chloroquine, or an analog or salt thereof, in fromabout 30 days to about 60 days prior to receiving a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the human has been administered chloroquine, or an analog or salt thereof, in from about 21 days to about 45 days prior to receiving a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20hoursof receivinga first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the humanhasnot beenadministered chloroquine, or ananalogor salt thereof, within 1day, 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 a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically 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 a first doseof the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 2 daysof receivingafirst doseof thecompoundofFormula I, Formula Ia, orFormula Ib,or apharmaceutically acceptablesalt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 5 daysof receivingafirst doseof thecompoundofFormula I, Formula Ia, orFormula Ib,or apharmaceutically acceptablesalt thereof. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 7 daysof receivingafirst doseof thecompoundofFormula I, Formula Ia, orFormula Ib,or apharmaceutically acceptablesalt 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 pharmaceutically acceptable salt thereof. In someembodiments, 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 pharmaceutically 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 pharmaceutically acceptable salt thereof.

[0037] In someembodiments, themethod further comprises instructing the humannot to take chloroquine, or an analog or salt thereof, during the treatment of the viral infection.

[0038] In someembodiments, themethod further comprises instructing thehuman towait fromabout 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 pharmaceutically acceptable salt thereof, or from about 1 day to about 4 days, from about 1 day to about 7 days, from about 1 day to about 10 days, from about 1 day to about 14 days, from about 10 days to about 45 days, from about 14 days to about 45 days, from about 21 days to about 45 days, from about 28 days to about 45 days, from about 30 days toabout 45days, 10days toabout 60days, fromabout 14days toabout 60days, fromabout 21days toabout 60days, fromabout 28days to about 60days, fromabout 30days to about 60days, fromabout 40days toabout 60days, fromabout 10days to about 90 days, fromabout 14days to about 90days, fromabout 21 days to about 90days, fromabout 28 days to about 90 days, fromabout 30 days to about 90 days, fromabout 40days to about 90days, fromabout 10 days to about 365 days, from about 14 days to about 365 days, fromabout 21 days to about 365 days, from about 28 days to about 365 days, from about 30 days to about 365 days, or from about 60 days 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 pharmaceutically acceptable salt thereof.

[0039] In someembodiments, themethod further comprises instructing thehuman towait after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof. In someembodiments, themethod further comprises instructing thehuman towait at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 14days, 21days, 28days, 30days, 45days, 60days, 8 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 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 ananalogor salt thereof, before administering the compoundof Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the method further comprises instructing the human to wait from about 30 mins to about one day after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia orFormula Ib, or pharmaceutically acceptable salt thereof. For example towait for at least 30mins, at least 1hour, 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 pharmaceutically acceptable salt thereof.

[0041] In someembodiments, themethod further comprises instructing thehuman towait after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia, or pharmaceutically 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 chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the method further comprises instructing the human to wait from about 30 mins to about one day after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof. For example towait for at least 30mins, 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 pharmaceutically acceptable salt thereof.

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

[0044] In someembodiments, themethod comprises administering to the humana therapeutically effective amount of a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, provided the human has not been administered chloroquine, or an analog or salt thereof, prior to the start of treatment, thereby treating the viral infection. 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,60days, 90days,120days,150days, 180days,210days,240days,270days,300days,330days,or 365daysprior to the start 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 start 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 the start of treatment. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, for at least 30 mins, 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 the start of treatment.

[0045] Various techniques can be used to determine whether or not a human in need thereof has previously taken chloroquine, or ananalogor salt thereof.Non-limiting techniques includeself-reporting, interviewing thehuman, reviewing thehuman’smedical records, ormeasuring the level of chloroquine, or ametabolite, analogor salt thereof, in theplasmaor blood in the human.

[0046] The human in need of treatment for a viral infection may also be evaluated for plasma or blood concentration of thechloroquine, or ananalogor salt thereof, prior toadministrationof thecompoundof thedisclosure, suchasacompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, a human in need of treatment for a viral infection has a plasma or blood concentration measured prior to administration of the compound of the disclosure.

[0047] Concentrations of chloroquine, or an analog or salt thereof, 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, pages 701‑705; Kaewkhao, K. et al. Bioanalysis (2019), vol. 11(5), pages 333‑347; Durcan, L. et al. Journal of Rheumatology (2015), vol. 42(11), pages 2092‑2097; Munster, T. et al. Arthritis Rheumatology (2002), vol. 46(6), pages 1460‑1469.

[0048] In some embodiments, the human has a plasma or blood concentration of the chloroquine, or an analog or salt thereof, of from about 0.1 ng / mL to about 5000 ng / mL at the time a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered to the human, or from about 0.1 ng / mL to about 4000ng / mL, fromabout 0.1 ng / mL to about 3000ng / mL, fromabout 0.1 ng / mL to about 2000ng / mL, fromabout 0.1 ng / mL to about 1000 ng / mL, from about 0.1 ng / mL to about 500 ng / mL, fromabout 0.1 ng / mL to about 400 ng / mL, fromabout 0.1 ng / mL toabout300ng / mL, fromabout0.1ng / mL toabout200ng / mL, fromabout0.1ng / mL toabout100ng / mL, fromabout 0.1ng / mL toabout 80ng / mL, fromabout 0.1ng / mL toabout 60ng / mL, fromabout 0.1ng / mL toabout 50ng / mL, fromabout 0.1 ng / mL to about 40 ng / mL, from about 0.1 ng / mL to about 30 ng / mL, from about 0.1 ng / mL to about 20 ng / mL, or from about 0.1 ng / mL to about 10 ng / mL, from about 5 ng / mL to about 4000 ng / mL, from about 5 ng / mL to about 3000 ng / mL, 9 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 from about 5 ng / mL to about 2000 ng / mL, from about 5 ng / mL to about 1000 ng / mL, from about 5 ng / mL to about 500 ng / mL, from about 5 ng / mL to about 400 ng / mL, from about 5 ng / mL to about 300 ng / mL, from about 5 ng / mL to about 200 ng / mL, from about 5 ng / mL to about 100 ng / mL, from about 5 ng / mL to about 80 ng / mL, from about 5 ng / mL to about 60 ng / mL, from about 5 ng / mL to about 50 ng / mL, from about 5 ng / mL to about 40 ng / mL, from about 5 ng / mL to about 30 ng / mL, from about 5 ng / mL to about 20 ng / mL, or from about 5 ng / mL to about 10 ng / mL, at the time a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered to the human. In some embodiments, the human has a plasma or blood concentration of the chloroquine, or an analog or salt thereof, of from about 0.1 ng / mL to about 50 ng / mL, at the time a first dose of the compound of the disclosure is administered to the human.

[0049] In some embodiments, the human has a plasma or blood concentration of the chloroquine, or an analog or salt thereof, of less than 5000 ng / mL at the time a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered to the human, or less than 4000 ng / mL, 3000 ng / mL, 2000 ng / mL, 1000ng / 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 the compound of the disclosure is administered to the human.

[0050] In some embodiments, the human has a plasma or blood concentration of the chloroquine, or an analog 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 pharmaceutically acceptable salt thereof, is administered to the human.

[0051] "Chloroquine, or an analog or salt thereof" refers to chloroquine (also known as CQ, N’‑(7-chloroquinolin‑4- yl)‑N,N-diethyl-pentane‑1,4-diamine and CAS Number 54‑05‑7), hydroxychloroquine (also known as HCQ, 2‑[{4‑[(7- chloroquinolin‑4-yl)amino]pentyl}(ethyl)amino]ethanol and CAS Number 118‑42‑3), and metabolites thereof in the plasma after administration to a human. Members include chloroquine, desethylchloroquine (also known as DCQ, 4- N‑(7-chloroquinolin‑4-yl)‑1-N-ethylpentane‑1,4-diamine andCASNumber 1476‑52‑4), hydroxychloroquine, desethylhy- droxychloroquine (also known as DHCQ, cletoquine, 2‑[4‑[(7-chloroquinolin‑4-yl)amino]pentylamino]ethanol, and CAS Number 4298‑15‑1), and bidesethylhydroxychloroquine (also known as BDCQ), or a pharmaceutically acceptable salt thereof. Illustrative examples include chloroquine, or a pharmaceutically acceptable salt thereof. An example is chlor- oquine phosphate, commercially available as Aralen®. Chloroquine has the chemical structure: An alternative example includes hydroxychloroquine, or a pharmaceutically acceptable salt thereof. An example is hydroxychloroquine sulfate, commercially available as Plaquenil®. Hydroxychloroquine has the chemical structure:

[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 hydroxychlor- oquine, or a pharmaceutically acceptable salt thereof. For example, the chloroquine, or an analog or salt thereof, can be hydroxychloroquine sulfate. 10 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 B. COMPOUNDS

[0053] The present disclosure includes use of antiviral compounds that when administered to a human in need thereof produce the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0054] The present disclosure also includes use of compounds of Formula I, Formula Ia and Formula Ib, or a pharmaceutically acceptable salt thereof.

[0055] The compound of Formula I was described inWO2012 / 012776. The IUPACname for 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 pharmaceutically acceptable salt thereof, has the structure:

[0056] Thecompoundof Formula Iawasdescribed inWO2016 / 069826. The IUPACname for the compoundof Formula Ia is (S)‑2-ethylbutyl 2‑(((S)‑(((2R,3S,4R,5R)‑5‑(4-aminopyn-olo[2,1-f][1,2,4]triazin‑7-y1)‑5-cyano‑3,4-dihydroxytetrahy- drofuran‑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 pharmaceu- tically acceptable salt thereof, has the structure:

[0057] Thecompoundof Formula Ibwasdescribed inWO2016 / 069826. The IUPACname for the compoundof Formula Ib is (S)‑2-ethylbutyl 2‑(((R)‑(((2R,3S,4R,5R)‑5‑(4-aminopyrrolo[2,1-f][1,2,4]triazin‑7-y1)‑5-cyano‑3,4-dihydroxytetrahy- drofuran‑2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate. The compound of Formula Ib, or a pharmaceutically acceptable salt thereof, has the structure: 11 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55

[0058] In some embodiments, administering a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, to a human in need thereof produces a compound of Formula II or a pharmaceutically acceptable salt thereof:

[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 someembodiments, 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 IVas described in U.S. Patent Application Publication No. 20180346504, or a combination thereof. In some embodiments, the compound of Formula Ia is crystalline.

[0061] The compounds of Formula I, Formula Ia and Formula Ib, or a pharmaceutically acceptable salt thereof, can be combined with one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipient comprises an aqueous vehicle. In some embodiments, the pharmaceutical compositions provided herein comprise the compound of Formula I, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical compositions provided herein comprise the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical composi- tions provided herein comprise the compound of Formula Ib, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. The aqueous vehicle comprises water and optionally one or more components selected from a co- solvent, a surfactant, a suspending agent, a tonicity agent, a buffer, a cyclodextrin, and an anti-microbial agent or preservative. Exemplary formulations may be found in U.S. Patent Application Publication No. 2019 / 0083525.

[0062] In some embodiments, the method of treating the viral infection in the human in need thereof comprises administering to the human the compound of Formula I, or a pharmaceutically acceptable salt thereof: In some embodiments, the method comprises administering the compound of Formula I.

[0063] In some embodiments, the method of treating the viral infection in the human in need thereof, comprises administering to the human a compound of Formula Ia, or a pharmaceutically acceptable salt thereof: 12 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 In some embodiments, the method comprises administering the compound of Formula Ia.

[0064] In some embodiments, the method of treating the viral infection in the human in need thereof comprises administering to the human a compound of Formula Ib, or a pharmaceutically acceptable salt thereof: In some embodiments, the method comprises administering the compound of Formula Ib.

[0065] The compound of the disclosure can be administered by any route appropriate to 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), implants, and the like. It will be appreciated that the preferred routemay vary, for example, with the condition of the human.

[0066] In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered by inhalation or intravenously. In someembodiments, the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered by inhalation.

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

[0068] In some embodiments, the humanweighs at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptablesalt thereof, isadministered in thefirst doseof150‑250mgonday1,andadministered in a second dose of 50‑150 mg on each of the following 4 days. In some embodiments, the second dose of 50‑150 mg is administered for an additional 1 to 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 pharmaceutically acceptable salt thereof, is administered in the first dose of 150‑250 mg on day 1, and administered in a second dose of 50‑150 mg on each of the following 4, 5, 6, 7, 8, or 9 days. In some embodiments, the human weighs at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 150‑250 mg on day 1, and administered in a seconddoseof 50‑150mgoneachof the following 9days. In someembodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the compoundofFormula I, Formula Ia, orFormula Ib, or apharmaceutically acceptable salt thereof, is administeredover from about 30 to about 120 minutes.

[0069] In some embodiments, the humanweighs at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200 mg on day 1, and administered intravenously in a seconddoseof 100mgoneachof the following4days. In someembodiments, the second dose of 100mg is administered for an additional 1 to 5 days. In some embodiments, the humanweighs at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered 13 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 intravenously in the first dose of 200mg on day 1, and administered intravenously in a second dose of 100mg on each of the following 4, 5, 6, 7, 8, or 9 days. In someembodiments, the humanweighs at least 40 kg, and the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200 mg on day 1, and administered intravenously in 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 pharmaceutically acceptable salt thereof, is administered intravenously once daily. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously over from about 30 to about 120 minutes.

[0070] In some embodiments, the humanweighs at least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 150‑250 mg on day 1, and administered in a second dose of 50‑150 mg on each of the following 4 days. In some embodiments, the second dose of 50‑150 mg is administered for an additional 1 to 5 days. In some embodiments, the human weighs at least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 150‑250 mg on day 1, and administered in a seconddoseof 50‑150mgoneachof the following4, 5, 6, 7, 8, or 9days. In someembodiments, thehumanweighsat least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 150‑250 mg on day 1, and administered 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 pharmaceutically acceptable salt thereof, is administered once daily. In someembodiments, the compoundof Formula Ia, or apharmaceutically acceptable salt thereof, is administeredover from about 30 to about 120 minutes.

[0071] In some embodiments, the humanweighs at least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200mg on day 1, and administered intravenously in a second dose of 100 mg on each of the following 4 days. In some embodiments, the second dose of 100 mg is administered for an additional 1 to 5 days. In some embodiments, the human weighs at least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200mg on day 1, and administered intravenously in a second dose of 100 mg on each of the following 4, 5, 6, 7, 8, or 9 days. In some embodiments, the human weighs at least 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, isadministered intravenously in thefirst doseof200mgonday1,andadministered intravenously inaseconddose of 100 mg on each of the following 9 days. In some embodiments, the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously oncedaily. In someembodiments, the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously over from about 30 to about 120 minutes.

[0072] In someembodiments, thehumanweighs from3.5kg to less than40kg, and thecompoundofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 2.5‑10mg / kg on day 1, andadministered ina seconddoseof 1‑5mg / kgoneachof the following4days. In someembodiments, theseconddoseof 1‑5mg / kg is administered for anadditional 1 to 5days. In someembodiments thehumanweighs from3.5 kg to less than40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 2.5‑10 mg / kg on day 1, and administered in a second dose of 1‑5 mg / kg on each of the following 4, 5, 6, 7, 8, or 9 days. In some embodiments the human weighs from 3.5 kg to less than 40 kg, and the compoundofFormula I, Formula Ia, orFormula Ib, or apharmaceutically acceptable salt thereof, is administered in thefirst dose of 2.5‑10 mg / kg on day 1, and administered in a second dose of 1‑5 mg / kg on each of the following 9 days. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered over from about 30 to about 120 minutes.

[0073] In someembodiments, thehumanweighs from3.5kg to less than40kg, and thecompoundofFormula I, Formula Ia, orFormula Ib, or apharmaceutically acceptable salt thereof, is administered intravenously in thefirst doseof 5mg / kgon day 1, and administered intravenously in a second dose of 2.5 mg / kg on each of the following 4 days. In some embodiments, the second dose of 2.5 mg / kg is administered for an additional 1 to 5 days. In some embodiments the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 5 mg / kg on day 1, and administered intravenously in a second dose of 2.5 mg / kg on each of the following 4, 5, 6, 7, 8, or 9 days. In some embodiments the humanweighs from3.5 kg to less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 5 mg / kg on day 1, and administered intravenously in 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 pharmaceutically acceptable salt thereof, is administered intravenously once daily. In some embodiments, the compound of Formula I, Formula Ia, or Formula Ib, or a pharma- ceutically acceptable salt thereof, is administered intravenously over from about 30 to about 120 minutes.

[0074] In some embodiments, the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 2.5‑10mg / kg on day 1, and administered in a second dose of 1‑5 mg / kg on each of the following 4 days. In some embodiments, the second dose of 1‑5 mg / kg is administered for an additional 1 to 5 days. In someembodiments the humanweighs from3.5 kg to less than 40 kg, and the 14 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 compoundof Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first doseof 2.5‑10mg / kgon day1,andadministered inaseconddoseof1‑5mg / kgoneachof the following4,5, 6, 7, 8, or 9days. In someembodiments the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered in the first dose of 2.5‑10mg / kg on day 1, and administered in a second doseof 1‑5mg / kg on each of the following 9days. In someembodiments, the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered over from about 30 to about 120 minutes.

[0075] In some embodiments, the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 5 mg / kg on day 1, and administered intravenously in a second dose of 2.5 mg / kg on each of the following 4 days. In some embodiments, the second dose of 2.5mg / kg is administered for an additional 1 to 5 days. In some embodiments, the humanweighs from3.5 kg to less than 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously in thefirst doseof 5mg / kgonday1,andadministered intravenously inaseconddoseof2.5mg / kgoneachof the following 4, 5, 6, 7, 8, or 9 days. In some embodiments, the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 5 mg / kg on day 1, and administered intravenously in 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 pharmaceutically acceptable salt thereof, is administered intravenously once daily. In some embodiments, the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, is administered intravenously over from about 30 to about 120 minutes. C. VIRAL INFECTIONS

[0076] Any suitable viral infection can be treated by the method of the present disclosure. In 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 anArenaviridae virus. In some embodiments, themethod of treating anArenaviridae virus infection comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, the method comprises treating anArenaviridae virus infection selected from the group consisting of Allpahuayo virus (ALLV), Amapari virus (AMAV), 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, Lassa virus (LASV), Latino virus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus, Machupo virus (MACV), Mobala virus (MOBV), Morogoro virus, Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinhal virus, Pirital virus (PIRV), Sabia virus (SABV), Skinner Tank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and White- water Arroyo virus (WWAV) by administering a compound of the disclosure provided herein. In some embodiments, the Arenaviridae virus is Lassa or Junin. In some embodiments, the method comprises treating a Lassa virus infection by administering a compound of the disclosure provided herein. In some embodiments, the method comprises treating a Junin virus infection by administering a compound of the disclosure provided herein.

[0078] In some embodiments, the viral infection is caused by aCoronaviridae virus. In some embodiments, themethod of treating aCoronaviridae virus infection comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, theCoronavir- idae virus infection is selected from the group consisting of a Severe Acute Respiratory Syndrome (SARS) infection, SARS-CoV‑2 (also known as 2019-nCov and COVID‑19) infection, Middle Eastern Respiratory Syndrome (MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, or WW1) infections, or a zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infection. In some embodiments, the Coronaviridae virus is SARS, SARS-CoV‑2, or MERS. In some embodiments, theCoronaviridae virus is SARS. In some embodiments, theCoronavir- idae virus is SARS-CoV‑2. In some embodiments, the Coronaviridae virus is MERS. In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology 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 having at least 80% sequence homology 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 having at least 90% sequence homology a viral polymerase selected from SARS-CoV polymerase, SARS-CoV‑2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least 95%sequence homology a viral polymerase selected from SARS-CoV polymerase, SARS-CoV‑2 polymerase, andMERS polymerase. In some embodi- ments, the viral infection is caused by a virus having at least 97% sequence homology 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 having at least 99% sequence homology a viral polymerase selected from SARS-CoV polymerase, SARS-CoV‑2 polymerase, and MERS polymerase. 15 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55

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

[0080] In some embodiments, the viral infection is caused by a Flaviviridae virus. In some embodiments, themethod of treating a Flaviviridae virus infection comprises administering a compound of the disclosure, such as a compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, the Flaviviridae virus isselected from thegroupconsistingof: dengue, yellow fever,WestNile, andZika. In someembodiments, themethod of treating a dengue virus infection comprises administering a compound of the disclosure provided herein. In some embodiments, the Flaviviridae virus is yellow fever. In some embodiments, the method of treating a yellow fever virus infection comprises administering a compound of the disclosure provided herein. In some embodiments, the method of treating a West Nile virus infection comprises administering a compound of the disclosure provided herein. In some embodiments, the method of treating a Zika virus infection comprises administering a compound of the disclosure provided herein. In some embodiments, the method of treating a hepatitis C virus infection comprises administering a compound of the disclosure provided herein.

[0081] In someembodiments, the viral infection is causedbyaPneumoviridae virus. In someembodiments, themethod of treating aPneumoviridae virus infection comprises administering a compoundof the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, the Pneumo- viridae virus is respiratory syncytial virus or humanmetapneumovirus. In some embodiments, thePneumoviridae virus is respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is human metapneumovirus.

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

[0083] In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in methods of treating an Arenaviridae virus infection. In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use inmethodsof treatinganArenaviridaevirus infection selected from thegroupofAllpahuayo virus (ALLV), Amapari virus (AMAV), 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, Lassa virus (LASV), Latino virus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus,Machupo virus (MACV), Mobala virus (MOBV),Morogoro virus,Mopeia virus (MOPV),Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinhal virus, Pirital 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 disclosure provided herein. In some embodiments, the Arenaviridae virus is Lassa or Junin. In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in methods of treating a Lassa virus infection. In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in methods of treating a Junin virus infection.

[0084] In some embodiments, the present disclosure provides a compound of the disclosure provided herein for use in methods of treating a Coronaviridae virus infection. In some embodiments, the Coronaviridae virus infection is selected from the group consisting of a Severe AcuteRespiratory Syndrome (SARS) infection, SARS-CoV‑2 (also known as 2019- nCovandCOVID‑19) infection,MiddleEasternRespiratorySyndrome (MERS) infection, other humancoronavirus (229E, NL63, 0C43, HKU1, orWW1) infections, or a zoonotic coronavirus (PEDVor HKUCoV isolates such as HKU3, HKU5, or HKU9) infection. In someembodiments, theCoronaviridaevirus isSARS,SARS-CoV‑2, orMERS. In someembodiments, the Coronaviridae virus is SARS. In some embodiments, the present disclosure provides a compound of the disclosure provided herein for use in methods 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 disclosure provided herein for use in methods of treating a SARS-nCoV‑2 infection. In some embodi- ments, the Coronaviridae virus is MERS. In some embodiments, the present disclosure provides a compound of the disclosure provided herein for use in methods of treating a Middle East Respiratory Syndrome (MERS) infection.

[0085] In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use inmethodsof treatingaFiloviridaevirus infection. In someembodiments, the Filoviridae virus is Ebola or Marburg. In some embodiments, the Filoviridae virus is an Ebola virus. In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically 16 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 acceptable salt thereof, for use in methods of treating an Ebola virus infection. In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in methods of treating an Ebola virus infection selected from the group consisting of: Zaire (i.e. Ebola virus, EBOV), Sudan, Tai Forest, Bundibugyo, and Reston. In some embodiments, the Filoviridae virus is a Marburg virus. In some embodi- ments, thepresent disclosureprovidesacompoundof thedisclosureprovidedherein, or pharmaceutically acceptable salt thereof, for use in methods of treating a Marburg virus infection.

[0086] In some embodiments, the present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in methods of treating a Flaviviridae virus infection. In some embodi- ments, the Flaviviridae virus is selected from the group consisting of: dengue, yellow fever, West Nile, and Zika. In some embodiments, the Flaviviridae virus is dengue virus. In some embodiments, the Flaviviridae virus is yellow fever. In some embodiments, the Flaviviridae virus isWest 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 present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in a method of treating a Pneumoviridae virus infection. In some embodiments, thePneumoviridae virus is respiratory syncytial virus or humanmetapneumovirus. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is human metapneumovirus.

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

[0089] In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an Arenaviridae virus infection. In someembodiments, the present disclosure provides theuseof a compoundof the disclosure provided herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an Arenaviridae virus infection selected from thegroupof:Allpahuayovirus (ALLV),Amapari virus (AMAV),BearCanyonvirus (BCNV),Catarina virus, Chapare virus, Cupixi virus (CPXV), Dandenong virus, Flexal virus (FLEV), Guanarito virus (GTOV), Ippy virus (IPPYV), Junin virus (JUNV), Kodoko virus, Lassa virus (LASV), Latino virus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus, Machupo virus (MACV), Mobala virus (MOBV), Morogoro virus, Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus (PICV), Pinhal virus, Pirital 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 or Junin. In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in themanufacture of amedicament for treating a Lassa virus infection. In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in themanufacture of amedicament for treating a Junin virus infection.

[0090] In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Coronaviridae virus infection. In someembodiments, theCoronaviridae virus infection is selected from the group consisting of a Severe Acute Respiratory Syndrome (SARS) infection, SARS-CoV‑2 (also known as 2019-nCov and COVID‑19) infection, Middle Eastern Respiratory Syndrome (MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, or WW1) infections, or a zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infection. In some embodiments, theCoronaviridae virus is SARS, SARS-CoV‑2, or MERS. In some embodiments, theCoronaviridae virus is SARS. In someembodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a SARS infection. In some embodiments, theCoronaviridae virus is SARS-CoV‑2. In someembodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically 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 present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceu- tically acceptable salt thereof, in the manufacture of a medicament for treating a MERS infection.

[0091] In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in themanufacture of amedicament for treating aFiloviridae virus infection. In someembodiments, theFiloviridaevirus isEbolaorMarburg. In someembodiments, theFiloviridaevirus is anEbolavirus. In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in themanufactureof amedicament for treatinganEbolavirus infection. In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceu- tically acceptable salt thereof, in the manufacture of a medicament for treating an Ebola virus infection selected from the 17 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 group consisting of: Zaire (i.e. Ebola virus, EBOV), Sudan, Taï Forest, Bundibugyo, and Reston. In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a Marburg virus infection.

[0092] In some embodiments, the present disclosure provides the use of a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, in themanufacture of amedicament for treating a Flaviviridae virus infection. In someembodiments, theFlaviviridae virus is selected from the group consisting of: dengue, yellow fever,West Nile, and Zika. In some embodiments, the Flaviviridae virus is dengue virus. In some embodiments, the Flaviviridae virus is yellow fever. In some embodiments, the Flaviviridae virus isWest 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 present disclosure provides a compound of the disclosure provided herein, or pharmaceutically acceptable salt thereof, for use in a manufacture of a medicament for treating a Pneumoviridae virus infection. In some embodiments, the Pneumoviridae virus is respiratory syncytial virus or human metapneumovirus. In some embodiments, the Pneumoviridae virus is a respiratory syncytial virus. In some embodiments, the Pneumoviridae virus is human metapneumovirus.

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

[0095] In some embodiments, the present disclosure provides a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: themethod comprising administering to the human an antiviral compound, wherein the human has not been administered chloroquine, or an analog or salt thereof, the antiviral compound is converted to the compound of Formula II upon administration to the human, and the plasma or blood concentration of the compound of Formula II is 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 to the human an antiviral compound. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 10 days of administering to the human an antiviral compound.

[0096] In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 mins, 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 administering to the human an antiviral compound. 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, 14days, 21days, 28days, 30days,45days, 60days,75days, 90days,120days, 150days, 180days,210days,240 days, 270 days, 300 days, 330 days, or 365 days, of administering to the human an antiviral compound. In some embodiments, the human has a plasmaor blood concentration of the chloroquine, or an analog or salt thereof, of less than 50 ng / mL, such as less than 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 the antiviral compound is administered to the human. In some embodiments, the human hasaplasmaorblood concentration of the chloroquine, or ananalogor salt thereof, of less than50ng / mL, at the timeafirst 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 pharmaceutically acceptable salt thereof. In some embodiments, the plasma or blood concentration of the compound of Formula II in the human is higher than a second concentration of a compound of Formula II in a reference human treated 18 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 with chloroquine, or an analog or salt thereof, and the antiviral compound. In some embodiments, the plasma or blood concentration of the compound of Formula II in the human is from about 1.1 times to about 10 times higher, such as from about1.2 times toabout5 times, fromabout1.3 times toabout5 times, fromabout1.2 times toabout4 times, fromabout1.3 times to about 4 times, fromabout 1.2 times to about 3 times, fromabout 1.3 times to about 3 times, fromabout 1.2 times to about 2 times, or fromabout 1.3 times 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 plasma or blood concentration of the compound of Formula II in the human is at least 1.1 times higher, such as 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 concentrationof thecompound ina referencehuman treatedwith chloroquine, or ananalogor salt thereof, and theantiviral compound.

[0098] In some embodiments, the present disclosure provides a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof, comprises: (a) administering to the human a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof; (b)measuring theplasmaorbloodconcentrationof thecompoundofFormula II in thehuman;and (c)adjustingany remainingdosesof the compoundof Formula I, Formula Ia, or Formula Ib, to optimize theplasmaor blood concentration of thecompoundofFormula II in thehuman. Insomeembodiments, themethodcomprisesadministering to thehumanadaily dose. In some embodiments, the method comprises administering to the human 10 daily doses.

[0099] In some embodiments, the plasma or blood concentration of the compound of Formula II in the human is from about 1.1 times to about 10 times higher, such as from about 1.2 times to about 5 times, from about 1.3 times to about 5 times, from about 1.2 times to about 4 times, from about 1.3 times to about 4 times, from about 1.2 times to about 3 times, fromabout 1.3 times toabout 3 times, fromabout 1.2 times toabout 2 times, or fromabout 1.3 times toabout 2 times, higher than a second concentration of the compound in a reference human treatedwith chloroquine, or an analog or salt thereof, and a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the plasma or blood concentration of the compound of Formula II in the human is at least 1.1 times higher, such as 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 timeshigher thana 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 pharmaceutically acceptable salt thereof.

[0100] In someembodiments, thepresentdisclosureprovidesamethodofdeterminingadeliverydoseofacompoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, for treating 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, to determine the delivery 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 pharmaceutically acceptable salt thereof, as the delivery dose.

[0101] In some embodiments, the method of determining a delivery dose comprises determining whether the human has been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection. In some embodiments, the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 10 days prior to the treatment of the viral infection. In some embodiments, determining whether the human has beenadministered chloroquine, or ananalog thereof, comprises self-reporting, interviewing the human, reviewing the human’smedical records, or measuring the level of chloroquine, or an analog or salt thereof, in the plasma or blood in 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, 10days, 14days, 21days, 28days, 30days, 45days, 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 administering to the human an antiviral compound.

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

[0103] In someembodiments, when the humanhas been administered chloroquine, or an analog or salt thereof, prior to treating the viral infection, themethod comprises increasing the original doseof the compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof, by fromabout 1.1 times to about 10 times higher, to determine the delivery dose, or fromabout 1.2 times to about 5 times, fromabout 1.3 times to about 5 times, fromabout 1.2 times to about 4 times, fromabout 1.3 times to about 4 times, fromabout 1.2 times to about 3 times, fromabout 1.3 times to about 3 times, 19 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 from about 1.2 times to about 2 times, or from about 1.3 times to about 2 times, higher to determine the delivery dose. In someembodiments, when the humanhas been administered chloroquine, or an analog or salt thereof, prior to treating the viral infection, themethod comprises increasing theoriginal doseof the compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof, by at least 1.1 times higher to determine the delivery dose, or 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, or10 timeshigher, todetermine thedelivery dose. In some embodiments, the human has not been administered chloroquine, or an analog or salt thereof, within 30 minutes, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20hoursof receivinga first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the humanhasnot beenadministered chloroquine, or ananalogor salt thereof, within 1day, 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 administering to the human an antiviral compound.

[0104] In someembodiments, thepresent disclosureprovidesamethodof formingacompoundofFormula II in ahuman in need thereof, 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, 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. 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 a first dose of the compound of Formula Ia. In someembodiments, the humanhas 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, 10days, 14days, 21 days, 28days, 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 administering 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 1 day before administering the compound of Formula Ia.

[0105] In someembodiments, the present disclosure provides amethodof reducing the risk of decreasedefficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, comprises: (a) determining if 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 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, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20hoursof receivinga first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the humanhasnot beenadministered chloroquine, or ananalogor salt thereof, within 1day, 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 administering the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof. In someembodiments, if the human is determined to have taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, thehumanwaitsat least1daybeforeadministering thecompoundofFormula Ia, or pharmaceutically acceptable salt thereof.

[0106] For themethodsof the present disclosure requiring instructing thehumannot to take chloroquine, or ananalogor salt thereof, while being treated with the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, any number of actions alone or in combination can be taken in the event that the human is administered chloroquine, or an analog or salt thereof, after receiving the instructions and after receiving the compound of Formula Ia, or a pharmaceu- tically acceptable salt thereof. In some embodiments, the human stops taking chloroquine, or an analog or salt thereof. In someembodiments, thehumanwaits after the last doseof chloroquine, or ananalogor salt thereof, for at least 30minutes, 1 hour, 2hours, 3hours, 4 hours, 5 hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20hours before receivingafirst dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the human waits after the last dose of 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, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days before receiving a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, after instructing the humannot to take chloroquine, or an analog or salt thereof, the human waits at least 1daybeforeadministering the compoundofFormula Ia, or pharmaceutically acceptable salt thereof. In some embodiments, the human takes an additional 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 20 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 doses, or 10dosesof the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, as compared to a reference human who has not been administered chloroquine, or an analog or salt thereof. In some embodiments, the human takes a higher dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, as compared toa referencehumanwhohasnot beenadministered chloroquine, or an analog or salt thereof, or at least 1.1 times, 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 dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, as compared to a reference human who has not been administered chloroquine, or an analog or salt thereof.

[0107] In some embodiments, the present disclosure provides a method of preventing a contraindication in a human suffering froma viral infection, themethod comprising: (a) determining if the humanhas 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 a contraindication in the human. In some embodiments, if the human is determined to have 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 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0108] In some embodiments, preventing a contraindication in the human is in comparison to a second humanwho has taken chloroquine, or an analog or salt thereof, prior to the administration of the compound of Formula Ia, or pharma- ceutically acceptable salt thereof, or who has not been instructed not to take chloroquine, or an analog or salt thereof. In someembodiments, the secondhumanwhohas taken chloroquine, or an analogor salt thereof, prior to the administration of the compound of Formula Ia, or pharmaceutically acceptable salt thereof, is more likely than the human to have a contraindication after administration of the compound of Formula Ia or pharmaceutically acceptable salt thereof. In some embodiments, the second humanwhohas not been instructed not to take chloroquine, or an analog or salt thereof, prior to the administration of the compound of Formula Ia, or pharmaceutically acceptable salt thereof, is more likely than the human to have a contraindication after administration of the compound of Formula Ia or pharmaceutically acceptable salt thereof. In some embodiments, the second human is at least 1.1 times, such as 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 than the human to have a contraindication after administration of the compound of Formula Ia or pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the present 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 if 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 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 as compared to a second human that 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 someembodiments, the plasmaor blood concentration of the compound of Formula II in the human after administration is from about 50% to about 100% of a second plasma or blood concentration of the compound of Formula II in a second human that hasnot takenchloroquine, or ananalogor salt thereof, prior toadministrationof thecompoundofFormula Ia, or a pharmaceutically acceptable salt thereof, or from about 60% to about 100%, fromabout 70% to about 100%, fromabout 80% to about 100%, or from about 90% to about 100%, of a second plasma or blood concentration of the compound of Formula II in a second human that has not taken chloroquine, or an analog or salt thereof, prior to administration of the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof. In someembodiments, if the human is determined to have 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 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the present disclosure provides a method of reducing the risk of a reduced plasma concentration of a compound of Formula II, in a human suffering from a viral infection, the method comprising: (a) determining if the human has taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or apharmaceutically acceptable salt thereof, (b) instructing thehumannot to takechloroquine, or ananalogor salt thereof, while being treated with the compound aof 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 21 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the risk of a reduced plasma concentration of the compound of Formula II. In some embodiments, if the human is determined to have 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 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0111] In some embodiments, reducing the risk of a reduced plasma concentration of a compound of Formula II 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 pharmaceutically acceptable salt thereof, as compared to a second human that hasnot takenchloroquine, or ananalogor salt thereof, prior toadministrationof thecompoundofFormula Ia, or a pharmaceutically acceptable salt thereof. In someembodiments, the plasma concentration of the compound of Formula II in the human after administration is from about 50% to about 100% of a second concentration of the compound of Formula II in a second human that has not taken chloroquine, or an analog or salt thereof, prior to administration of the compoundof Formula Ia, or apharmaceutically acceptable salt thereof, or fromabout 60% toabout 100%, fromabout 70% to about 100%, from about 80% to about 100%, or from about 90% to about 100%, of a second concentration of the compound of Formula II in a second human that 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.

[0112] For themethodsof the present disclosure requiringdetermining if the humanhas takenchloroquine, or ananalog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, the determining can be performed by any suitable means. For example, non-limiting techniques include self-reporting, interviewing thehuman, reviewing thehuman’smedical records, ormeasuring the level of chloroquine, or ananalogor salt thereof, in the plasma or blood in the human. In some embodiments, the determining includes measuring the level of chloroquine, or a metabolite, analog or salt thereof, in the plasma or blood in the human. IV. KITS

[0113] In some embodiments, the present disclosure provides the use of 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 instance, in some embodiments, the kit comprises instructing the human not to take chloroquine, or an analog or salt thereof, during the treatment of the viral infection.

[0114] In some embodiments, the kit comprises instructing the human to wait after taking chloroquine, or an analog or salt thereof, at least 30minutes, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20 hours before administering the compound of Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof. In someembodiments, the kit comprises instructing thehuman towait after taking chloroquine, or ananalogor salt thereof, such as 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, 30days, 45days, 60days, 75days, 90days, 120days, 150days, 180days, 210days, 240days, 270days, 300days, 330days, or 365daysafter taking chloroquine, or ananalogor salt thereof, before administering the compoundof Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, the kit 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 pharmaceutically acceptable salt thereof. In someembodiments, 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 I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructing the human towait at least 14 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof. In someembodiments, the kit comprises instructing the human towait at least 21 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula I, Formula Ia or Formula Ib, or pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the kit comprises instructing the human to wait after taking chloroquine, or an analog or salt thereof, at least 30minutes, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 8hours, 10hours, 12hours, 16hours, or 20 hours before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructing the human to wait after taking chloroquine, or an analog or salt thereof, such asat least 1day, 2days, 3days, 4 days, 5days, 6 days, 7days, 8days, 9days, 10days, 14days, 21days, 28days, 30days, 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 pharmaceutically acceptable salt thereof. In someembodiments, thekit comprises instructing thehuman towait at least 10 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises instructing 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 pharmaceutically acceptable salt thereof. In someembodiments, thekit comprises instructing thehuman towait at least 21 22 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 days after taking chloroquine, or an analog or salt thereof, before administering the compound of Formula Ia, or pharmaceutically 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 bulb 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 someexamples thenebulizer is a vibratingmeshnebulizer (e.g. eFlow® rapid). In some embodiments, the nebulizer is a 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). V. EXAMPLES Example 1. Chloroquine Effect on Compound of Formula Ia in Cells

[0117] Antiviral potency of the compound of Formula Ia against respiratory syncytial virus (RSV) was determined in HEp2 cells in the following manner. HEp2 cells (3 x 103 / well) were suspended in DMEM medium + GlutaMAX (supplemented with 10% FBS and 1% Penicillin / Streptomycin) and seeded into 96 well plates. After a 4-hour incubation at 370C+5%CO2, three-fold serial dilutions of the compound (finalRDVconcentration of 9.28nM to2000nM)wereadded to each well using an HP D300e digital dispenser. To determine the effect of chloroquine (CQ) on Formula Ia antiviral activity, the Formula Ia dilution series was additionally spiked with DMSO or 4X increasing concentrations of CQ (final concentrations: 10 nM, 40 nM, 160 nM, 640 nM, and 2560 nM). The cells were then infected with RSVA2 virus diluted in DMEMmedium+GlutaMAXat anMOI=4and incubated for 4 days at 37°Cand5%CO2. The final volume in eachwell was 200µL. Uninfected and untreated wells were included as controls for 100% cell viability. Following the incubation, 100µL of culture supernatant was removed from each well and replaced with 100 µL of CellTiter-Glo reagent (Promega). The plates were then rocked for 2 minutes followed by a 10-minute incubation at 250C. Cell viability was then assessed by measuring luminescence signal using and Envision plate reader. Values were normalized to the uninfected and infected DMSOcontrols (as 100%and 0% infection, respectively) and datawas fit using non-linear regression analysis with theXL fit software.EC50 valuesweredeterminedas thepoint thenon-linear regressioncurveof 50% infection. Thecompileddata was generated using three biological replicates each containing technical duplicates for each CQ concentration.

[0118] The effect of the combination of the compound of Formula Ia and concentrations of chloroquine (CQ) on RSV replication in HEp2 cells were measured. Results show that CQ antagonizes the anti-RSV activity of the compound of Formula Ia in a dose-dependent manner as demonstrated by higher Formula Ia EC50 values with increasing concentra- tions of CQ (Table 1). Table 1. Effect of Chloroquine on Anti-RSV Activity of Formula Ia in HEp2 Cells Chloroquine (nM) Formula Ia RSV EC50 (nM) Formula Ia RSV EC50 fold change P value 0 49.5 ± 13.1 1 - 10 58.4 ± 12.8 1.19 ± 0.10 0.075 40 72.1 ± 24.8 1.45 ± 0.19 0.052 160 99.6 ± 30.3 2.02 ± 0.17 0.0088 640 138.3 ± 33.8 2.86 ± 0.50 0.023 2560 209.0 ± 18.2 4.43 ± 1.13 0.034 Example 2: Metabolism Data

[0119] A549-hACE2andNHBEcellswere seeded in 6-well plates at 4 x 105 and2.5 x 105 cells / well, respectively. HEp‑2 cells were seeded in 12-well plates at 2.5 x 105 cells / well. Twenty-four hours later, cell culture medium was replaced with medium containing 1µMFormula Ia alone, or in combination with 1 or 10µMof either CQorHCQ, and incubated at 37°C. At 2, 8, 24 and48h post drug addition, cells werewashed 3 timeswith ice-cold tris-buffered saline, scraped into 0.5mL ice- cold 70% methanol and stored at ‑80°C. Extracts were centrifuged at 15,000 g for 15 minutes and supernatants were transferred to clean tubes for evaporation in a miVac Duo concentrator (Genevac). Dried samples were reconstituted in mobile phaseA containing 3mMammonium formate (pH5)with 10mMdimethylhexylamine (DMHA) inwater for analysis by LC-MS / MS, using a multi-stage linear gradient from 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) HSTcolumn (Phenomenex) connected to an 23 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 LC‑20ADXR (Shimadzu) ternary pump system and an HTS PAL autosampler (LEAP Technologies). Detection was performed on a Qtrap (6500+ AB Sciex) mass spectrometer operating in positive ion and multiple reaction monitoring modes. Analyteswere quantified using a 7-point standard curve ranging from0.624 to 160 pmol permillion cells prepared in extracts from untreated cells. For normalization by cell number, multiple untreated culture wells were counted at each timepoint.

[0120] Themetabolism of the compound of Formula Ia to the active triphosphate species (Formula Ia-TP) species was evaluated inA549-hACE2,NHBE,andHEp‑2cell cultures following incubationwith thecompoundofFormula Iaaloneand when combinedwithCQorHCQ.The concentrations ofCQandHCQused in these in vitro assays correspond to systemic and lung exposures that result from doses recommended under the former EUA guidance for COVID‑19. The average systemic exposures range from 610‑760 nM for CQ and approximately 1.7 µM for HCQ, which can achieve lung concentrations in excess of 20 µM for either drug {Salman 2017, Zhao 2014}. In A549-hACE2 cells, co-incubation of the compound of Formula Ia and 1 µM CQ or HCQ did not significantly reduce Formula Ia-TP levels compared to the Formula Ia-TP in the absence of CQor HCQ; however, incubation at 10µMof either CQor HCQdid significantly lower the production of Formula Ia-TP (Table 2; Figure 1). While Formula Ia-TP levels trended lower in NHBE cultures treated with either concentration of CQ or 1 µM HCQ, these differences were not statistically significant. Conversely, treatment of NHBE cultures with 10 µM HCQ significantly reduced Formula Ia-TP levels (Table 3; Figure 2). In HEp‑2 cervical carcinoma cells, treatment with CQ or HCQ at either 1 or 10 µM showed a dose-dependent reduction in formation of intracellular Formula Ia-TP (Table 4; Figure 3). Significant CQ or HCQ antagonism of Formula Ia-TP formation in Hep‑2 cellswas observed at 8 h post treatment and persisted for 48 h. The observed reductions in Formula Ia-TP in the presence of CQ or HCQ indicates a potential antagonistic effect on the compound of Formula Ia metabolism to its active tripho- sphate. Table 2. Effect of CQ or HCQ on RDV-TP Formation in A549-hACE2 Cells Treatment time (h) Mean RDV-TP (pmol / million cells)a 1 µM Formula Ia 1 µM Formula Ia + 1 µM CQ 1 µM Formula Ia + 10µMCQ 1 µM Formula Ia + 1µMHCQ 1 µM Formula Ia + 10 µM HCQ 2 3.6 ± 0.2 2.4 ± 0.1 0.7 ± 0.1 2.8 ± 0.3 1.0 ± 0.1 8 11.4± 0.8 10.0 ± 0.3 2.5 ± 0.1 10.3 ± 1.2 2.2 ± 0.3 24 6.8 ± 1.3 5.8 ± 1.2 1.7 ± 0.4 7.0 ± 2.0 2.2 ± 0.6 48 3.0 ± 0.5 2.9 ± 0.6 1.8 ± 0.4 2.8 ± 0.3 1.8 ± 0.4 Average Formula Ia-TP con- centration (pmol / million cells)b 6.5 ± 0.8 5.6 ± 0.8 1.8 ± 0.3 6.2 ± 1.3 2.0 +0.4 P valuec NA 0.8497 0.0030 0.9960 0.0041 a Values are mean ± SEM of duplicate samples collected at each timepoint from two separate experiments. b Average Formula Ia-TP concentration was determined using GraphPad Prism 8.1.2 from the total area under the curve fromFormula Ia ‑TPconcentrations detected by LC-MSat 0, 2, 8, 24, and 48 h; and divided by the total timeof the assay (48 h). c P value is 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. Effect of CQ or HCQ on RDV-TP Formation in NHBE Cultures Treatment time (h) Mean RDV-TP (pmol / million cells)a 1 µM Formula Ia 1 µM Formula Ia + 1 µM CQ 1 µM Formula Ia + 10µMCQ 1 µM Formula Ia + 1µMHCQ 1 µM Formula Ia + 10 µM HCQ 2 4.4 ± 0.5 2.2 ± 0.2 1.8 ± 0.5 2.2 ± 0.2 1.1 ± 0.5 8 19.4± 3.8 12.1 ± 2.8 12.3 ± 4.6 11.1 ± 1.8 9.9 ± 1.4 24 16.7± 1.0 12.9 ± 1.2 9.7 ± 0.6 10.8 ± 1.2 9.2 ± 1.2 48 14.2± 0.6 14.7 ± 0.5 13.0 ± 1.0 13.6 ± 0.5 10.5 ± 0.6 24 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Treatment time (h) Mean RDV-TP (pmol / million cells)a 1 µM Formula Ia 1 µM Formula Ia + 1 µM CQ 1 µM Formula Ia + 10µMCQ 1 µM Formula Ia + 1µMHCQ 1 µM Formula Ia + 10 µM HCQ Average Formula Ia-TP con- centration (pmol / million cells)b 15.3± 1.5 12.0 ± 1.2 10.2 ± 1.8 10.6 ± 1.0 8.8 ± 0.9 P valuec NA 0.2724 0.0507 0.0753 0.0112 a Values are mean ± SEM of duplicate samples collected at each timepoint from two separate experiments. b Average Formula Ia -concentration was determined using GraphPad Prism 8.1.2 from the total area under the curve fromFormula Ia ‑TPconcentrationsdetectedbyLC-MSat 0, 2, 8, 24, and48h; anddividedby the total timeof the assay (48 h). c P value is 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. Effect of CQ or HCQ on RDV-TP Formation in HEp‑2 cells Treatment time (h) Mean RDV-TP (pmol / million cells)a 1 µM Formula Ia 1 µM Formula Ia + 1 µM CQ 1 µM Formula Ia + 10µMCQ 1 µM Formula Ia + 1µMHCQ 1 µM Formula Ia + 10 µM HCQ 2 BLQ BLQ BLQ BLQ BLQ 8 22.8± 1.4 7.7 ± 0.3 3.0 ± 0.5 5.8 ± 1.2 0.4 ± 0.3 24 40.8± 5.6 15.9 ± 2.0 6.2 ± 1.0 15.0 ± 3.2 3.9 ± 0.8 48 45.9± 5.6 20.7 ± 3.2 10.2 ± 2.0 20.0 ± 2.5 7.8 ± 0.6 Average Formula Ia-TP con- centration (pmol / million cells)b 33.7± 4.4 13.6 ± 2.0 5.8 ± 1.2 12.6 ± 2.3 3.7 ± 0.6 P valuec NA 0.0002 <0.0001 <0.0001 <0.0001 a Values are mean ± SEM of duplicate samples collected at each timepoint from two separate experiments. b Average Formula Ia ‑TP concentration was determined using GraphPad Prism 8.1.2 from the total area under the curve fromFormula Ia ‑TPconcentrations detected by LC-MSat 0, 2, 8, 24, and 48 h; and divided by the total timeof the assay (48 h). c P value is 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. SARS-CoV‑2 Antiviral Data

[0121] The anti-SARS-CoV‑2 activities of the compound of Formula Ia and either CQ or HCQwere evaluated in A549- hACE2 transformed airway epithelial cells. The compound of Formula Ia, CQ, and HCQ individually exhibit potent in vitro antiviral activities against SARS-CoV‑2, with EC50 values of approximately 59.5 nM, 451 nM, and 365 nM, respectively (Table 5). The compound of Formula Ia EC50 values were not observably different when combined with CQ or HCQ at concentrations up to 2.5 µM (Table 5); however, the overall Nluc signal in the assay decreased in the presence of CQ or HCQ in a dose-dependent manner (Figure 4). As shown in Figure 4A, the Nluc signal at 0 µM Formula Ia (DMSO) + CQ corresponds to the Nluc signal at the specific CQ concentration in that treatment condition. The baseline Nluc signal of each Formula Ia titration curve is lowered to levels corresponding to the CQ concentration in that treatment condition. Similar effects are observed in the HCQ-treatment conditions Figure 4B). At 10 µM of either CQ or HCQ alone, the Nluc signalwas fully suppressed, indicatingacomplete inhibitionofSARS-CoV‑2 replicationbyeitherCQorHCQalone.Due to the potent antiviral activity of CQ and HCQ at the 10 µM concentration, a standard EC50 value comparison is unable to reveal the potential decrease in Formula Ia activity against SARS-CoV‑2 when combined with CQ or HCQ. Cytotoxicity was not observed at Formula Ia and HCQ combination concentrations analyzed (data not shown). 25 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 Table 5. SARS-CoV‑2 Nluc EC50 values of RDV + CQ or HCQ in A549-hACE2 cells Treatment EC50 (nM)b Formula Ia + DMSO 59.5 CQ + DMSO 451 HCQ + DMSO 365 Formula Ia + 10 nm CQ 52.0 Formula Ia + 40 nm CQ 52.4 Formula Ia + 160 nm CQ 52.2 Formula Ia + 640 nm CQ 46.0 Formula Ia + 2500 nm CQ 39.8 Formula Ia + 10000 nm CQ NDc Formula Ia + 10 nm HCQ 63.6 Formula Ia + 40 nm HCQ 50.7 Formula Ia + 160 nm HCQ 60.0 Formula Ia + 640 nm HCQ 56.2 Formula Ia + 2500 nm HCQ 63.0 Formula Ia + 10000 nm HCQ NDc a n=1 b EC50 values were defined in GraphPad Prism 8.1.2 as the concentration at which there was a 50% decrease in the Nluc counts per second (CPS) relative to DMSO vehicle alone (0% virus inhibition) and uninfected control culture (100% virus inhibition). c ND denotes where EC50 values could not be calculated due to complete inhibition of Nluc signal by CQ or HCQ.

[0122] Although the foregoing disclosure has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the sameextent as if each referencewas individually incorporatedby reference.Wherea conflict exists between the instant application and a reference provided herein, the instant application shall dominate. The invention will now be described with reference to the following clauses.

[0123] Clause 1. Amethod of treating a viral infection in a human in need thereof, themethod 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: 26 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 wherein the human is not being treated with chloroquine, or an analog or salt thereof, thereby treating the viral infection.

[0124] Clause 2. The method of clause 1, wherein the human has not been administered chloroquine, or an analog or salt thereof, within 1 day of receiving a first dose of the compound of Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof.

[0125] Clause 3. The method of clause 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 pharmaceutically acceptable salt thereof.

[0126] Clause 4. The method of clause 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 pharmaceutically acceptable salt thereof.

[0127] Clause5. Themethodof anyoneof clauses 1 to 4,wherein thehumanhasnot beenadministered chloroquine, or ananalogorsalt thereof,within365daysof receiving thefirst doseof thecompoundofFormula I, Formula Ia, orFormula Ib, or pharmaceutically acceptable salt thereof.

[0128] Clause 6. The method of any one of clauses 1 to 5, further comprising instructing the human not to take chloroquine, or an analog or salt thereof, during the treatment of the viral infection.

[0129] Clause 7. The method of any one of clauses 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 pharmaceutically acceptable salt thereof.

[0130] Clause 8. The method of any one of clauses 1 to 7, wherein the human is not administered chloroquine, or an analog or salt thereof, during the treatment of the viral infection.

[0131] Clause9. Themethodof anyoneof clauses 1 to 8,wherein thehumanhas aplasmaor blood concentration of the chloroquine, or an analog 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 pharmaceutically acceptable salt thereof, is administered to the human.

[0132] Clause 10. The method of any one of clauses 1 to 9, wherein the chloroquine, or an analog or salt thereof, is chloroquine, desethylchloroquine, hydroxychloroquine, desethylhydroxychloroquine, or bidesethylhydroxychloroquine, or a pharmaceutically acceptable salt thereof.

[0133] Clause 11. The method of clause 10, wherein the chloroquine, or an analog or salt thereof, is chloroquine, or a pharmaceutically acceptable salt thereof.

[0134] Clause 12. The method of clause 11, wherein the chloroquine, or an analog or salt thereof, is chloroquine phosphate.

[0135] Clause13.Themethodof clause10,wherein thechloroquine, or ananalogor salt thereof, ishydroxychloroquine, or a pharmaceutically acceptable salt thereof.

[0136] Clause14. Themethodof clause 13,wherein the chloroquine, or ananalogor salt thereof, is hydroxychloroquine 27 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 sulfate.

[0137] Clause 15. Themethod of any one of clauses 1 to 14, comprising administering to the human the therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof: Formula I.

[0138] Clause 16. Themethod of any one of clauses 1 to 15, comprising administering to the human the therapeutically effective amount of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof:

[0139] Clause 17. Themethod of any one of clauses 1 to 16, comprising administering to the human the therapeutically effective amount of the compound of Formula Ia:

[0140] Clause18. Themethodof any oneof clauses 1 to 17,wherein the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered by inhalation or intravenously.

[0141] Clause 19. The method of clause 18, wherein the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0142] Clause 20. The method of clause 18, wherein the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered by inhalation.

[0143] Clause21.Themethodofanyoneof clauses1 to19,wherein thehumanweighsat least 40kg,and thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200mg on day 1, and administered intravenously in a second dose of 100mg on each of the following 4 days.

[0144] Clause 22. Themethod of clause 21, wherein the second dose of 100mg is administered for an additional 1 to 5 days.

[0145] Clause 23. The method of clause 21 or 22, wherein the human weighs at least 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in the first dose of 200mg on day 1, and administered intravenously in a second dose of 100mg on each of the following 9 days.

[0146] Clause 24. Themethod of any one of clauses 1 to 19, wherein the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered intravenously in thefirst doseof 5mg / kgonday1,andadministered intravenously inaseconddoseof2.5mg / kgoneachof the following 4 days.

[0147] Clause25.Themethodof clause24,wherein theseconddoseof 2.5mg / kg is administered for anadditional 1 to5 days.

[0148] Clause 26. The method of clause 24 or 25, wherein the human weighs from 3.5 kg to less than 40 kg, and the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, is administered 28 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 intravenously in thefirst doseof 5mg / kgonday1,andadministered intravenously inaseconddoseof2.5mg / kgoneachof the following 9 days.

[0149] Clause27. Themethodof anyoneof clauses1 to26,wherein the viral infection is causedbyavirus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Pneumoviridae, and Paramyxoviridae.

[0150] Clause 28. The method of clause 27, wherein the viral infection is caused by an Arenaviridae virus.

[0151] Clause 29. The method of clause 28, wherein the Arenaviridae virus is Lassa or Junin.

[0152] Clause 30. The method of clause 27, wherein the viral infection is caused by a Coronaviridae virus.

[0153] Clause 31. Themethod of clause 30, wherein theCoronaviridae virus is SARS virus, SARS-CoV‑2 virus, MERS virus, 229E virus, NL63 virus, OC43 virus, or HKU1 virus.

[0154] Clause 32. The method of clause 30, wherein the Coronaviridae virus is SARS, SARS-CoV‑2, or MERS.

[0155] Clause 33. The method of clause 32, wherein the Coronaviridae virus is SARS-CoV‑2.

[0156] Clause34. Themethodof anyoneof clauses30‑32,wherein the viral infection is causedbyavirus havingat least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, SARS- CoV‑2 polymerase, and MERS polymerase.

[0157] Clause 35. Themethod of any one of clauses 30‑32, 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.

[0158] Clause 36. The method of any one of clauses 30‑32, 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.

[0159] Clause 37. The method of any one of clauses 30‑32 and 34‑36, 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.

[0160] Clause 38. The method of clause 27, wherein the viral infection is caused by a Filoviridae virus.

[0161] Clause 39. The method of clause 38, wherein the Filoviridae virus is Ebola or Marburg.

[0162] Clause 40. The method of clause 27, wherein the viral infection is caused by a Flaviviridae virus.

[0163] Clause 41. The method of clause 40, wherein the Flaviviridae virus is dengue, yellow fever, West Nile, or Zika.

[0164] Clause 42. The method of clause 41, wherein the Flaviviridae virus is yellow fever.

[0165] Clause 43. The method of clause 27, wherein the viral infection is caused by a Pneumoviridae virus.

[0166] Clause 44. The method of clause 43, wherein the Pneumoviridae virus is respiratory syncytial virus or human metapneumovirus.

[0167] Clause 45. The method of clause 44, wherein the Pneumoviridae virus is respiratory syncytial virus.

[0168] Clause 46. The method of clause 27, wherein the viral infection is caused by a Paramyxoviridae virus.

[0169] Clause 47. The method of clause 46, wherein the Paramyxoviridae virus is Nipah or parainfluenza virus.

[0170] Clause 48. A method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: the method comprising administering to the human an antiviral compound, wherein the humanhas not beenadministered chloroquine, or ananalog or salt thereof, the antiviral compound is converted to the compound of Formula II upon administration to the human, and the plasma or blood concentration of the compound of Formula II is optimized in the absence of chloroquine, or an analog or salt thereof.

[0171] Clause 49. The method of clause 48, wherein the human has not been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection.

[0172] Clause 50. The method of clause 48, wherein the human has not been administered chloroquine, or an analog 29 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 thereof, within 10 days prior to the treatment of the viral infection.

[0173] Clause51. Themethod of clause 48,wherein thehumanhasa plasmaor blood concentration of the 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.

[0174] Clause 52. The method of clause 48 or 51, wherein the plasma or blood concentration of the compound of Formula II in the human is higher than a second concentration of a compound of Formula II in a reference human treated with chloroquine, or an analog or salt thereof.

[0175] Clause53. Themethod of any oneof clauses 48 to 52,wherein the antiviral compound is a compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0176] Clause 54. A method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically 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 pharmaceutically acceptable salt thereof: 30 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 (b) measuring the plasma or blood concentration of the compound of Formula II in the human; and (c) adjusting any remaining doses 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.

[0177] Clause 55. The method of clause 54, comprising administering to the human a daily dose.

[0178] Clause 56. The method of clause 54, comprising administering to the human 10 daily doses.

[0179] Clause 57. Amethod of determining a delivery dose of a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, for treating a viral infection in a human in need thereof, 31 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the method comprising: (a) providing an original dose of the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically 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 pharmaceutically acceptable salt thereof, to determine the delivery dose, or (c2) if the humanhasnot beenadministered chloroquine, or ananalogor salt thereof, selecting theoriginal doseof the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, as thedelivery dose.

[0180] Clause 58. The method of clause 57, wherein the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection.

[0181] Clause 59. The method of clause 57, wherein the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 10 days prior to the treatment of the viral infection.

[0182] Clause 60. Amethod of forming a compound of Formula II in a human in need thereof, 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, wherein the compound of Formula Ia ismetabolized to the compound of Formula II in the absence of chloroquine, or an analog or salt thereof, wherein the compound of Formula II has the structure: and wherein the compound of Formula Ia has the structure:

[0183] Clause 61. The method of clause 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 pharmaceutically acceptable salt thereof, the human waits at least 1 day before administering the compound of Formula Ia.

[0184] Clause 62. A method of reducing the risk of decreased efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, 32 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the method comprising: (a) determining if 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 thehumannot to takechloroquine, or ananalogor salt thereof,whilebeing treatedwith thecompoundof 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 efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

[0185] Clause 63. Themethod of clause 62,wherein if the human is determined to have taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, the humanwaits at least 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0186] Clause 64. A method of preventing a contraindication in a human suffering from a viral infection, the method comprising: (a) determining if 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 thehumannot to takechloroquine, or ananalogor salt thereof,whilebeing treatedwith thecompoundof 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 a contraindication in the human.

[0187] Clause 65. Themethod of clause 64,wherein if the human is determined to have taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, the humanwaits at least 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0188] Clause 66. Amethod ofmaintaining efficacy of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, 33 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the method comprising: (a) determining if 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 thehumannot to takechloroquine, or ananalogor salt thereof,whilebeing treatedwith thecompoundof 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.

[0189] Clause 67. Themethod of clause 61,wherein if the human is determined to have taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, the humanwaits at least 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

[0190] Clause 68. A method of reducing the risk of a reduced plasma concentration of a compound of Formula II, in a human suffering from a viral infection, the method comprising: (a) determining if 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 thehumannot to takechloroquine, or ananalogor salt thereof,whilebeing treatedwith thecompoundof 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, 34 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 thereby reducing the risk of a reduced plasma concentration of the compound of Formula II.

[0191] Clause 69. Themethod of clause 68,wherein if the human is determined to have taken chloroquine, or an analog or salt thereof, prior to administration of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof , the humanwaits at least 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof. Claims 1. Anantiviral compound for use in amethod of optimizing a plasmaor blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: the method comprising administering to the human the antiviral compound, wherein the human has not been administered chloroquine, or an analog or salt thereof, the antiviral compound is converted to the compound of Formula II upon administration to the human, and theplasmaor blood concentration of the compoundof Formula II is optimized in theabsenceof chloroquine, or an analog or salt thereof. 2. Theantiviral compound for useaccording to claim1,wherein thehumanhasnot beenadministered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection, preferably within 10 days prior to the treatment of the viral infection. 3. The antiviral compound for use according to claim 1, wherein the human has a plasma or blood concentration of the 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. 4. The antiviral compound for use according to claim 1 or 3, wherein the plasma or blood concentration of the compound of Formula II in the human is higher than a second concentration of a compound of Formula II in a reference human treated with chloroquine, or an analog or salt thereof. 5. Theantiviral compound for useof anyoneof claims1 to4,wherein theantiviral compound is a compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof 35 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 6. AcompoundofFormula I, Formula Ia, orFormula Ib, or apharmaceutically acceptable salt thereof, for use in amethod of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: the method comprising: (a) administering to the human the compound of Formula I, Formula Ia, or Formula Ib, or the pharmaceutically acceptable salt thereof: 36 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 (b) measuring the plasma or blood concentration of the compound of Formula II in the human; and (c) adjustingany remainingdosesof thecompoundofFormula I, Formula Ia, orFormula Ib, tooptimize theplasma or blood concentration of the compound of Formula II in the human. 7. AcompoundofFormula I, Formula Ia, orFormula Ib, or apharmaceutically acceptable salt thereof, for use in amethod of determining a delivery dose of the compound of Formula I, Formula Ia, or Formula Ib, or the pharmaceutically acceptable salt thereof, for treating a viral infection in a human in need thereof, 37 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the method comprising: (a) providing an original dose of the compound of Formula I, Formula Ia, or Formula Ib, or the pharmaceutically 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 compoundof Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, to determine the delivery dose, or (c2) if thehumanhasnot beenadministeredchloroquine, orananalogor salt thereof, selecting theoriginal doseof the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, as the delivery dose. 8. The compound or pharmaceutically acceptable salt for use according to claim 7, wherein the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection, or within 10 days prior to the treatment of the viral infection. 9. A compound of Formula Ia for use in a method of forming a compound of Formula II in a human in need thereof, comprising administering to the human a therapeutically effective amount of the compound of Formula Ia, and instructing the human not to take 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, wherein the compound of Formula II has the structure: and wherein the compound of Formula Ia has the structure: 38 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 10. The compound for use according to claim 9, wherein if 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 humanwaits at least 1 day before administering the compound of Formula Ia. 11. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the risk of decreasedefficacyof the compoundof Formula Ia, or apharmaceutically acceptable salt thereof, in ahumansuffering from a viral infection, the method comprising: (a) determining if 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 efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof. 12. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof for use in a method of preventing a contraindication in a human suffering from a viral infection, the method comprising: (a) determining if 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, 39 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 (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 a contraindication in the human. 13. Acompoundof Formula Ia, or a pharmaceutically acceptable salt thereof for use in amethod ofmaintaining efficacy of the compound of Formula Ia, or the pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining if 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 maintaining efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof. 14. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, for use in amethod of reducing the risk of a reduced plasma concentration of a compound of Formula II, in a human suffering from a viral infection, 40 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 the method comprising: (a) determining if 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 a reduced plasma concentration of the compound of Formula II. 15. The compound or pharmaceutically acceptable salt according to any one of claims 10, 11, 12, or 14, wherein if the human isdetermined tohave takenchloroquine, or ananalogor salt thereof, prior toadministrationof thecompoundof Formula Ia, or a pharmaceutically acceptable salt thereof , the human waits at least 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof. 41 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 42 EP 4 748 374 A1 43 EP 4 748 374 A1 44 EP 4 748 374 A1 45 EP 4 748 374 A1 46 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 47 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 48 EP 4 748 374 A1 5 10 15 20 25 30 35 40 45 50 55 49 EP 4 748 374 A1 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 63032321

[0001] • EP 21733348

[0001] • WO 2017184668 A

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[0061] Non-patent literature cited in the description • WARREN, T et al. Nature, 2016, vol. 531, 381-385

[0003] • LO MK et al.Sci. Reports, 2017, vol. 7, 43395

[0003] • SHEAHAN TP et al. Sci. Transl. Med., 2017, vol. 9, eaal3653

[0003] • AGOSTINI ML et al.MBio, 2018, vol. 9 (2), e00221- 18

[0003] • Cell Research, 2020, vol. 30, 269-271

[0003] • WALKER, O et al. British Journal Clinical Pharma- cology, 1983, vol. 16, 701-705

[0047] • KAEWKHAO, K. et al. Bioanalysis, 2019, vol. 11 (5), 333-347

[0047] • DURCAN, L. et al. Journal of Rheumatology, 2015, vol. 42 (11), 2092-2097

[0047] • MUNSTER, T. et al. Arthritis Rheumatology, 2002, vol. 46 (6), 1460-1469

[0047] • CHEMICAL ABSTRACTS, 54‑05‑7

[0051] • CHEMICAL ABSTRACTS, 118‑42‑3

[0051] • CHEMICAL ABSTRACTS, 1476‑52‑4

[0051] • CHEMICAL ABSTRACTS, 4298‑15‑1

[0051] • CHEMICAL ABSTRACTS, 1809249‑37‑3

[0056] 瑞德西韋治療方法 摘要 本文提供治療或預防受試者病毒感染的方法，包括給予受試者式 I、式 Ia 或式 Ib 的化 合物或其藥學上可接受的鹽，其中受試者未接受氯奎或其類似物或鹽的治療。 摘 要

Claims

1. An antiviral compound for use in a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: the method comprising administering to the human the antiviral compound, wherein the human has not been administered chloroquine, or an analog or salt thereof, the antiviral compound is converted to the compound of Formula II upon administration to the human, and the plasma or blood concentration of the compound of Formula II is optimized in the absence of chloroquine, or an analog or salt thereof.

2. The antiviral compound for use according to claim 1, wherein the human has not been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection, preferably within 10 days prior to the treatment of the viral infection.

3. The antiviral compound for use according to claim 1, wherein the human has a plasma or blood concentration of the 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.

4. The antiviral compound for use according to claim 1 or 3, wherein the plasma or blood concentration of the compound of Formula II in the human is higher than a second concentration of a compound of Formula II in a reference human treated with chloroquine, or an analog or salt thereof.

5. The antiviral compound for use of any one of claims 1 to 4, wherein the antiviral compound is a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof 6. A compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, for use in a method of optimizing a plasma or blood concentration of a compound of Formula II, or a pharmaceutically acceptable salt thereof, in a human in need thereof: the method comprising: (a) administering to the human the compound of Formula I, Formula Ia, or Formula Ib, or the pharmaceutically acceptable salt thereof: (b) measuring the plasma or blood concentration of the compound of Formula II in the human; and (c) adjusting any remaining doses 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.

7. A compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, for use in a method of determining a delivery dose of the compound of Formula I, Formula Ia, or Formula Ib, or the pharmaceutically acceptable salt thereof, for treating 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 the pharmaceutically 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 pharmaceutically acceptable salt thereof, to determine the delivery 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 pharmaceutically acceptable salt thereof, as the delivery dose.

8. The compound or pharmaceutically acceptable salt for use according to claim 7, wherein the method comprises determining whether the human has been administered chloroquine, or an analog thereof, within 1 day prior to the treatment of the viral infection, or within 10 days prior to the treatment of the viral infection.

9. A compound of Formula Ia for use in a method of forming a compound of Formula II in a human in need thereof, comprising administering to the human a therapeutically effective amount of the compound of Formula Ia, and instructing the human not to take 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, wherein the compound of Formula II has the structure: and wherein the compound of Formula Ia has the structure:

10. The compound for use according to claim 9, wherein if 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 1 day before administering the compound of Formula Ia.

11. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the risk of decreased efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining if 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 efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

12. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof for use in a method of preventing a contraindication in a human suffering from a viral infection, the method comprising: (a) determining if 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 a contraindication in the human.

13. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof for use in a method of maintaining efficacy of the compound of Formula Ia, or the pharmaceutically acceptable salt thereof, in a human suffering from a viral infection, the method comprising: (a) determining if 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 maintaining efficacy of the compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

14. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the risk of a reduced plasma concentration of a compound of Formula II, in a human suffering from a viral infection, the method comprising: (a) determining if 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 a reduced plasma concentration of the compound of Formula II.

15. The compound or pharmaceutically acceptable salt according to any one of claims 10, 11, 12, or 14, wherein if the human is determined to have 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 1 day before administering the compound of Formula Ia, or pharmaceutically acceptable salt thereof.

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