Weekly regimen of lenacapavir for the treatment and prevention of HIV

Abstract

This disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising orally administering to the patient a therapeutically effective amount of an HIV capsid inhibitor of formula Ia (e.g., lenakapavir) or a pharmaceutically acceptable salt thereof, according to a specific dosing regimen.

Description

Cross-reference to related applications

[0001] none Technical Field

[0002] This disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising orally administering to the patient a therapeutically effective amount of an HIV capsid inhibitor or a pharmaceutically acceptable salt thereof. Background Technology

[0003] Viral capsid proteins (CAs) are essential for multiple stages of the HIV life cycle. During viral maturation following processing of the Gag polyprotein by the HIV protease, CAs self-assemble into the cone-shaped core of the mature HIV-1 virion. Containing this capsid core are viral RNA, nucleocapsid, reverse transcriptase, and integrase. Failure to generate a suitable core precludes infectivity. Furthermore, CAs contribute to several essential processes during the early stages of HIV replication, including playing a crucial role in regulating appropriate capsid core breakdown (uncoating) kinetics to ensure efficient and productive viral DNA synthesis via coupled reverse transcription, and facilitating the active transport of the pre-integration complex to the nuclear compartment to support viral DNA integration into the transcriptionally active locus. Defects in normal capsid function ultimately inhibit efficient nuclear uptake and integration of viral DNA into the host genome.

[0004] Human immunodeficiency virus (HIV) infection is a life-threatening and serious disease of great public health significance, affecting approximately 38,000,000 people worldwide, with about 26,000,000 receiving antiretroviral (ARV) therapy (UNAIDS. Global HIV & AIDS statistics, 2020 fact sheet). Advances in combination ARV therapies for HIV have led to significant improvements in morbidity and mortality by suppressing viral replication, maintaining immune function, and preventing disease progression to AIDS. Summary of the Invention

[0005] This disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period, and The compound of formula Ia or its pharmaceutically acceptable salt is administered as a monotherapy.

[0006] This disclosure also provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) administering orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; If the patient misses the maintenance dose, the method also includes orally administering about 200 mg to about 700 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses about 1 day to about 7 days after the oral administration during the third time period.

[0007] This disclosure also provides a method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) administering orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; This method includes pre-exposure prophylaxis (PrEP).

[0008] This disclosure also provides a method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) administering orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; If the patient misses the maintenance dose, the method further includes orally administering about 200 mg to about 700 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period; and This method includes pre-exposure prophylaxis (PrEP).

[0009] This disclosure also provides a compound described herein or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0010] This disclosure also provides the use of the compounds described herein or pharmaceutically acceptable salts thereof for the preparation of medicaments for use in any of the methods described herein. Attached Figure Description

[0011] Figure 1 An overview of the structural pharmacokinetic (PK) model of lenakapavir is shown.

[0012] Figure 2 The modeling results of the oral dosing regimen of lenakapavir are shown.

[0013] Figure 3 The modeling results of an oral lenakapavir dosing regimen with a missed dose of lenakapavir are shown.

[0014] Figure 4 The modeling results of an oral lenakapavir dosing regimen with two missed doses are shown. Detailed Implementation

[0015] Lenapamil, a human immunodeficiency virus (HIV-1) capsid inhibitor, is indicated for the treatment of HIV-1 infection (e.g., in heavily treated adults with multidrug-resistant HIV-1 infection who have failed to meet their current antiretroviral regimen due to resistance, intolerance, or safety concerns). The recommended dosage of lenapamil includes a starting dose followed by a maintenance dose. This application provides alternative oral dosing regimens for lenapamil that can be specifically used, for example, in pre-exposure prophylaxis (PrEP) dosing schedules.

[0016] Specifically, this disclosure relates to a method for treating or preventing human immunodeficiency virus (HIV) infection (e.g., HIV-1 and / or HIV-2) in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) The patient is orally administered one or more maintenance doses of a compound of formula Ia, comprising about 200 mg to about 400 mg, or a pharmaceutically acceptable salt thereof, for a second time period, wherein the second time period occurs after the first time period.

[0017] In some embodiments, this disclosure relates to a method of treating or preventing human immunodeficiency virus (HIV) infection (e.g., HIV-1 and / or HIV-2) in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period, and The compound of formula Ia or its pharmaceutically acceptable salt is administered as a monotherapy.

[0018] In some embodiments, this disclosure relates to a method of treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) administering orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; If the patient misses the maintenance dose, the method also includes orally administering about 200 mg to about 700 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses about 1 day to about 7 days after the oral administration during the third time period.

[0019] In some embodiments, this disclosure relates to a method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) The patient is orally administered one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period. In some embodiments of the foregoing embodiments, the method includes pre-exposure prophylaxis (PrEP).

[0020] In some embodiments, this disclosure relates to a method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) administering orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; If the patient misses the maintenance dose, the method further includes orally administering about 200 mg to about 700 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period. In some embodiments of the foregoing implementation, the method includes pre-exposure prophylaxis (PrEP).

[0021] In any of the embodiments provided herein, the compound of formula Ia is a compound of formula Ib: Ib Or their pharmaceutically acceptable salts. Compounds of formula Ib may also be called lenakapavir (or “LEN”) or N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentano[1,2-c]pyrazol-1-yl)acetamide.

[0022] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy (i.e., in the absence of an additional therapeutic agent). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents, such as an anti-HIV agent.

[0023] In some embodiments, the method includes administering a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a compound of formula Ia, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a compound of formula Ib, or a pharmaceutically acceptable salt thereof.

[0024] The synthesis and characterization of compounds of formulas Ia and Ib and their salts are described, for example, in US 20180051005 and US 20190300505, the contents of which are incorporated herein by reference in their entirety. Various forms and / or uses of compounds of formulas Ia and Ib are disclosed, for example, in US 20190083478, US 20190084963, US 20200038389A1 and US 20210188815, the contents of which are incorporated herein by reference in their entirety.

[0025] In some embodiments, the compound of formula Ia or Ib is administered orally as a sodium salt. In some embodiments, the compound of formula Ia is administered orally as a sodium salt. In some embodiments, the compound of formula Ib is administered orally as a sodium salt.

[0026] Where no specific pharmaceutically acceptable salt and / or solvate of a compound of formula Ia or Ib is specifically mentioned, any dose (whether expressed in milligrams or weight percent) should be understood to refer to the amount of free acid (i.e., the compound of formula Ia or Ib). For example, a reference to “50 mg” of formula Ia or Ib or its pharmaceutically acceptable salt refers to an amount of the compound of formula Ia or Ib or its pharmaceutically acceptable salt, which provides the same amount of the compound of formula Ia or Ib as 50 mg of the free acid. In some embodiments, a dose of 50 mg of formula Ia or Ib contains approximately 51.1 mg of the sodium salt of formula Ia.

[0027] In some embodiments, the compounds provided herein (i.e., compounds of formula Ia or Ib) or their pharmaceutically acceptable salts are administered orally in the form of one or more tablets as described herein.

[0028] In some embodiments, the compound of formula Ia or Ib is administered once daily (QD). In some embodiments, the compound of formula Ia or Ib is administered orally once daily (QD).

[0029] In some embodiments, the compound of formula Ia or Ib is administered once weekly (QW). In some embodiments, the compound of formula Ia or Ib is administered orally once weekly (QW).

[0030] In some embodiments, the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered in doses of about 10 mg to about 2000 mg. In some embodiments, the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered in doses of about 10 mg to about 3000 mg. In some embodiments, the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered in doses of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1000 mg. Administered at doses of approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, or approximately 2000 mg.

[0031] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered at a dose of about 600 mg.

[0032] In some implementations, the starting dose provided herein includes oral administration of about 600 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to a patient for a first time period.

[0033] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg.

[0034] In some embodiments, the starting dose provided herein is administered in the form of one or more tablets for a first time period, each of the one or more tablets containing about 300 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof.

[0035] In some implementations, the first time period is approximately one to two days. In some implementations, the first time period is one day. In some implementations, the first time period is two days.

[0036] In some embodiments, the oral administration during the first time period (i.e., the starting dose) is administered in the form of one or two tablets (e.g., one or two tablets on day one; one or two tablets on day two; one or two tablets on day one and one or two tablets on day two; etc.). In some embodiments, the oral administration during the first time period (i.e., the starting dose) is administered in the form of two tablets each. In some embodiments, the oral administration during the starting dose period is administered in the form of one tablet each.

[0037] In some implementations, one or more maintenance doses provided herein each comprise oral administration of about 300 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to a patient for a second time period.

[0038] In some embodiments, one or more maintenance doses provided herein are each administered in a tablet containing about 300 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof for a second time period.

[0039] In some implementations, the second time period begins approximately six to eight days after the first oral administration of the initial dose.

[0040] In some implementations, the second time period begins approximately seven days after the first oral administration of the initial dose.

[0041] In some implementations, the second time period is at least about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks or longer.

[0042] In some implementation schemes, the second time period is at least about 1 year, 2 years, 3 years, 4 years, 5 years, 10 years or longer.

[0043] In some implementations, the second time period is from about 1 week to about 25 years, for example, from about 1 week to about 10 years, from about 1 week to about 5 years, from about 1 week to about 4 years, from about 1 week to about 3 years, from about 1 week to about 2 years, from about 1 week to about 1 year, from about 1 week to about 48 weeks, from about 1 week to about 44 weeks, from about 1 week to about 40 weeks, from about 1 week to about 36 weeks, from about 1 week to about 32 weeks, from about 1 week to about 28 weeks, from about 1 week to about 24 weeks, from about 1 week to about 20 weeks, from about 1 week to about 16 weeks, from about 1 week to about 8 weeks, from about 1 week to about 4 weeks, and so on.

[0044] In some implementations, the second time period includes the continuous administration of one or more maintenance doses throughout the patient's life.

[0045] In some implementations, the third time period begins approximately one to fourteen days after the patient first misses the maintenance dose, for example, within approximately one day, approximately two days, approximately three days, approximately four days, approximately five days, approximately six days, approximately seven days, approximately eight days, approximately nine days, approximately ten days, approximately eleven days, approximately twelve days, approximately thirteen days, or approximately fourteen days.

[0046] In some embodiments, when the patient misses the maintenance dose, the method further includes orally administering about 300 mg to about 600 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses about 1 day to about 7 days after the oral administration during the third time period.

[0047] In some embodiments, when the patient misses the maintenance dose, the method further includes orally administering about 300 mg or about 600 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

[0048] In some embodiments, when the patient misses one or two maintenance doses, the method further includes orally administering about 300 mg or about 600 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

[0049] In some embodiments, when the patient misses a maintenance dose, the method further includes orally administering about 300 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

[0050] In some implementations, when the patient misses two consecutive maintenance doses, the method further includes orally administering about 600 mg of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

[0051] In some implementations, the third time period is approximately one to two days. In some implementations, the third time period is one day. In some implementations, the third time period is two days.

[0052] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg.

[0053] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia, or a pharmaceutically acceptable salt thereof, comprising one or more maintenance doses of approximately 300 mg. The compound of formula Ia or its pharmaceutically acceptable salt is administered as a monotherapy.

[0054] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering about 300 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

[0055] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering about 600 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the second maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

[0056] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; This method includes pre-exposure prophylaxis (PrEP).

[0057] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering approximately 300 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period, approximately one day to fourteen days, after the patient has first missed the maintenance dose, and restarting administration of the one or more maintenance doses approximately one day to seven days after the oral administration during the third time period; and This method includes pre-exposure prophylaxis (PrEP).

[0058] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering approximately 600 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period, approximately one to fourteen days, after the patient has first missed the second maintenance dose, and restarting administration of the one or more maintenance doses approximately one to seven days after the oral administration during the third time period; and This method includes pre-exposure prophylaxis (PrEP).

[0059] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, each comprising one or more maintenance doses of about 300 mg, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, comprising one or more maintenance doses of approximately 300 mg, or a pharmaceutically acceptable salt thereof. Compounds of formula Ib or pharmaceutically acceptable salts thereof are administered as monotherapy.

[0061] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering about 300 mg of a compound of formula Ib or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

[0062] In some embodiments, this disclosure provides a method for treating or preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering about 600 mg of a compound of formula Ib or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the second maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

[0063] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; This method includes pre-exposure prophylaxis (PrEP).

[0064] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering approximately 300 mg of a compound of formula Ib or a pharmaceutically acceptable salt thereof to the patient during a third time period, approximately one day to approximately fourteen days, after the patient has first missed the maintenance dose, and restarting the administration of the one or more maintenance doses approximately one day to approximately seven days after the oral administration during the third time period; and This method includes pre-exposure prophylaxis (PrEP).

[0065] In some embodiments, this disclosure provides a method for preventing HIV in a patient, the method comprising administering a compound of formula Ib to the patient: Ib Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administer orally to the patient a compound of formula Ib or a pharmaceutically acceptable salt thereof, comprising an initial dose of approximately 600 mg, for up to two days; and (ii) Administer orally once weekly to the patient a compound of formula Ib, or a pharmaceutically acceptable salt thereof, each comprising one or more maintenance doses of about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering approximately 600 mg of a compound of formula Ib or a pharmaceutically acceptable salt thereof to the patient during a third time period, approximately one to fourteen days, after the patient has first missed the second maintenance dose, and restarting administration of the one or more maintenance doses approximately one to seven days after the oral administration during the third time period; and This method includes pre-exposure prophylaxis (PrEP).

[0066] In some embodiments, the methods provided herein include preventing human immunodeficiency virus (HIV) infection in a patient. In some embodiments, the patient may be at risk of HIV infection or is at risk of such infection. In some embodiments, the patient has been identified as an individual at risk of sexually transmitted HIV. In some embodiments, the individual has been identified as male (e.g., having sexual intercourse with a male or female) and / or female (e.g., having sexual intercourse with a male or female). In some embodiments, the individual has been identified as: • Engaged in anal sex with at least two different sexual partners and have not consistently used condoms in the past 6 months; and / or • History of sexually transmitted disease (STD) infection (e.g., syphilis, gonorrhea, chlamydia, HBV, or HCV infection) within the past 12 months; and / or • Use of psychoactive drugs (e.g., cocaine, gamma-hydroxybutyric acid (GHB), methylenedioxymethamphetamine (MDMA), methoxyephedrine) during sexual intercourse; and / or • Having sexual intercourse with one or more partners from areas with high HIV prevalence (>1%) (e.g., South America, sub-Saharan Africa, Southeast Asia, Eastern Europe, French Guiana) without consistent condom use; and / or • Having a sexual partner who is an intravenous drug user who shares injection materials; and / or • HIV-infected sexual partners with a detectable plasma viral load (e.g., >50 copies (cp) / mL). and / or • A person who injects drugs, including, for example, but not limited to, a person who injects opioids, stimulants, psychoactive drugs, or a combination of any of the foregoing. Non-limiting examples of opioids include fentanyl and heroin. Non-limiting examples of stimulants include cocaine and amphetamines. Non-limiting examples of psychoactive drugs include benzodiazepines.

[0067] In some implementations, the patient is HIV negative. In some implementations, the HIV is HIV-1. In some implementations, the HIV is HIV-2. In some implementations, the HIV is both HIV-1 and HIV-2.

[0068] As used in this article, "HIV" or "human immunodeficiency virus" refers to HIV-1 and / or HIV-2.

[0069] The term "patient" refers to a person who requires therapeutic or preventative treatment for a viral infection, such as HIV infection.

[0070] As used herein, the term "prevention" refers to the administration of a compound, a pharmaceutically acceptable salt thereof, or a composition containing the compound or a pharmaceutically acceptable salt thereof, before or after exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood. The term also refers to the prevention of the onset of disease symptoms and / or the prevention of the virus from reaching detectable levels in the blood. This term includes pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. The term also refers to the prevention of perinatal HIV transmission from mother to infant by administering a compound, a pharmaceutically acceptable salt thereof, or a composition containing the compound or a pharmaceutically acceptable salt thereof to the mother before delivery and to the infant during the first few days of life. The term also refers to the prevention of HIV transmission via blood transfusion.

[0071] As used in this article, the term "C" tau "" refers to the drug concentration observed at the end of the dosing interval.

[0072] As used herein, the term "exposure period" refers to the time during which a patient is exposed to HIV, ranging from a single event to multiple events over a long period. For example, the exposure period for a patient who has had sexual intercourse with an HIV-positive partner once is limited to the time and duration of that single sexual encounter with that partner. As another example, the exposure period for a patient who has had sexual intercourse with an HIV-positive partner multiple times over a long period (e.g., days, weeks, months, or years) is the range from the first to the last sexual encounter with that partner.

[0073] In some embodiments, the methods disclosed herein may include event-driven administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to a patient. As used herein, the terms “event-driven” or “event-driven administration” mean administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the following circumstances: (1) prior to an event that would expose the patient to HIV (or otherwise increase the patient’s risk of HIV infection) (e.g., 2 hours, 1 day, 2 days, 5 days, 7 days, 10 days, 14 days, 28 days (i.e., one month) or more prior to the event); and / or (2) during an event that would expose the patient to HIV (or otherwise increase the patient’s risk of HIV infection) (or more than one relapse event); and / or (3) after an event that would expose the patient to HIV (or otherwise increase the patient’s risk of HIV infection) (or after the final event in a series of relapse events). In some embodiments, event-driven administration is performed before the patient’s exposure to HIV. In some embodiments, event-driven administration is performed during the patient’s exposure to HIV. In some implementations, event-driven administration is performed after a patient has been exposed to HIV.

[0074] In some implementations, event-driven administration is performed before and during a patient's exposure to HIV.

[0075] In some implementations, event-driven application is performed both before and after a patient's exposure to HIV.

[0076] In some implementations, event-driven application is performed both during and after a patient's exposure to HIV.

[0077] In some embodiments, the methods disclosed herein involve administration before and / or after an event that would expose a patient to HIV or otherwise increase the patient's risk of HIV infection, such as as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). Examples of events that could increase the patient's risk of HIV infection include, but are not limited to, not using a condom during anal sex with an HIV-positive partner or a partner with an unknown HIV status; having anal sex with more than three sexual partners; exchanging money, gifts, shelter, or drugs for anal sex; having sexual intercourse with a male partner and being diagnosed with a sexually transmitted infection; and having sexual intercourse with a known HIV-positive sexual partner without consistent condom use. In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).

[0078] In some implementations, the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered to the patient prior to exposure to HIV.

[0079] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered to a patient during exposure to HIV.

[0080] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered to a patient after exposure to HIV.

[0081] In some implementations, compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, are administered to patients before and during their exposure to HIV.

[0082] In some implementations, compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, are administered to patients before and after exposure to HIV.

[0083] In some implementations, compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, are administered during and after a patient’s exposure to HIV.

[0084] In some implementations, compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, are administered to patients before, during, and after their exposure to HIV.

[0085] In some embodiments, the dose of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof administered during each time period (i.e., before, during, and after exposure) may be different, i.e., independently selected from any dose disclosed herein.

[0086] In some implementations, for example, when administered as PrEP, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered 1 hour to 240 hours (i.e., within 10 days), 1 hour to 216 hours, 1 hour to 192 hours, 1 hour to 168 hours, 1 hour to 144 hours, 1 hour to 120 hours, 1 hour to 96 hours, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 24 hours, or 1 hour to 12 hours before an event that would increase the patient's risk of HIV infection (e.g., before sexual intercourse or other HIV exposure events). In some embodiments, the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day before an event that increases the patient's risk of HIV infection (e.g., before sexual intercourse or other HIV exposure). In some embodiments, the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered 72, 60, 48, 24, 12, 9, 6, 4, 3, 2, or 1 hour before an event that increases the patient's risk of HIV infection (e.g., before sexual intercourse or other HIV exposure). In some embodiments, when the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered before an event that increases the patient's risk of HIV infection, it is administered daily before that event (e.g., sexual intercourse). In some embodiments, when a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered before an event that would increase the patient's risk of HIV infection, it is administered one to three times prior to that event. In some embodiments, when a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered before an event that would increase the patient's risk of HIV infection, it is administered once (i.e., once) prior to that event.

[0087] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately 14 days to approximately one day prior to the patient's exposure to HIV. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once daily, approximately 14 days prior to the patient's exposure to HIV.

[0088] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately 10 days to approximately 5 days prior to the patient's exposure to HIV. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once approximately 10 days to approximately 5 days prior to the patient's exposure to HIV.

[0089] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately 8 to 6 days prior to the patient's exposure to HIV. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once approximately 8 to 6 days prior to the patient's exposure to HIV.

[0090] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately 7 days prior to the patient's exposure to HIV. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once approximately 7 days prior to the patient's exposure to HIV.

[0091] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately 72 hours to approximately 1 hour prior to the patient's exposure to HIV. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once approximately 72 hours to approximately 1 hour prior to the patient's exposure to HIV.

[0092] In some implementations of the methods provided herein, pre-exposure prophylaxis (PrEP) includes continuous PrEP.

[0093] In some embodiments in which a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered prior to the patient’s exposure to HIV, the methods disclosed herein further include administering one or more additional doses of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof during and / or after the patient’s exposure to HIV.

[0094] In some embodiments, for example, when administered as part of a PrEP regimen or as part of a PEP regimen, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered during the period of the patient's exposure to HIV. In some embodiments in which a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered prior to HIV exposure, the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered approximately every 7 days, approximately every 14 days, approximately every 21 days, approximately every 28 days, approximately every 35 days, approximately every 42 days, or approximately every 6 months, or approximately every 12 months during the period of HIV exposure (e.g., during the period of sexual activity with a known HIV-positive sexual partner). In some embodiments, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered approximately every 7 days, approximately every 14 days, approximately every 21 days, approximately every 28 days, approximately every 35 days, approximately every 42 days, approximately every 6 months, or approximately every 12 months during the period of the patient's exposure to HIV.

[0095] In some embodiments, the dose of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof administered before HIV exposure differs from the dose administered during and / or after HIV exposure. For example, in some embodiments, the dose of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is increased, for example, as a double dose, a triple dose, etc., compared to an earlier dose (e.g., a dose administered before HIV exposure). In some embodiments, the increased dose of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is a double dose. In some embodiments, the dose of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is reduced, for example, by half, compared to an earlier dose (e.g., a dose administered before HIV exposure).

[0096] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered in a single dose approximately 1 hour to approximately 10 days prior to the patient's exposure to HIV.

[0097] Other examples of PrEP and / or PEP can be found in, for example, the following literature: a clinical trial overview entitled “On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men” (Clinical Trial No. NCT01473472); a clinical trial overview entitled “Prevention of HIV in Île-de-France” (Clinical Trial No. NCT03113123); and Molina et al., N. Engl. J. Med. The full text of each of these documents (2015, 353:2237-2246) is incorporated into this paper by reference.

[0098] In some implementations, for example, when administered as part of a PrEP regimen or as part of a PEP regimen, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 to 72 hours, 1 to 48 hours, 1 to 36 hours, 1 to 24 hours, or 1 to 12 hours after an event that increases the patient’s risk of HIV infection (e.g., after sexual intercourse or other HIV exposure).

[0099] In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered for 7, 14, 21, 28, 30, or 45 days after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered for 30 days after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered less than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered for 1, 2, 3, 4, or 5 days after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered daily after an event that increases the patient's risk of HIV infection, it is administered once to three times after that event. In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once after an event that increases the patient's risk of HIV infection, it is administered once after that event.

[0100] In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, may be administered approximately once weekly, approximately once monthly, approximately every two months, approximately every three months, approximately every four months, approximately every five months, approximately every six months, or approximately every twelve months after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, may be administered approximately once weekly after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, may be administered approximately once monthly after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 2 months after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 3 months after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 4 months after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 5 months after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 6 months after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events). In some embodiments, for example, when administered as a PEP, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered approximately every 12 months after an event that would increase the patient's risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events).

[0101] In some implementations, for example, when administered as a PEP, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof may be administered for one month, two months, three months, four months, five months, six months, or twelve months after an event that would increase the patient’s risk of HIV infection (e.g., after sexual intercourse or other HIV exposure events).

[0102] In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after an event that increases the risk of HIV infection in a patient, it is administered one to fifty times after that event. In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after an event that increases the risk of HIV infection in a patient, it is administered one to forty times after that event. In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after an event that increases the risk of HIV infection in a patient, it is administered one to thirty times after that event. In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after an event that increases the risk of HIV infection in a patient, it is administered one to twenty times after that event. In some embodiments, when a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after an event that increases the risk of HIV infection in a patient, it is administered one to fifteen times after that event. In some embodiments, when a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered after an event that would increase the patient's risk of HIV infection, it is administered one to ten times after that event. In some embodiments, when a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered after an event that would increase the patient's risk of HIV infection, it is administered one to five times after that event.

[0103] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered during a patient’s exposure to HIV (e.g., during a period of sexual activity with a known HIV-positive sexual partner).

[0104] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered after a patient has been exposed to HIV (e.g., finally exposed), such that the exposure occurs after a period of sexual intercourse with a known HIV-positive sexual partner. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered from about 1 hour to about 14 days after a patient has been exposed to HIV (e.g., finally exposed). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once from about 1 hour to about 14 days after a patient has been exposed to HIV (e.g., finally exposed). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered from about 1 hour to about 7 days after a patient has been exposed to HIV (e.g., finally exposed). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once from about 1 hour to about 7 days after a patient has been exposed to HIV (e.g., finally exposed). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered from about 1 hour to about 72 hours after a patient's exposure to HIV (e.g., final exposure). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once from about 1 hour to about 72 hours after a patient's exposure to HIV (e.g., final exposure). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered from about 1 hour to about 24 hours after a patient's exposure to HIV (e.g., final exposure). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once from about 1 hour to about 24 hours after a patient's exposure to HIV (e.g., final exposure). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered from about 24 hours to about 72 hours after a patient's exposure to HIV (e.g., final exposure). In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once from about 24 hours to about 72 hours after a patient's exposure to HIV (e.g., final exposure).

[0105] In some implementations, for example, when administered as PrEP, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered before (e.g., before sexual activity) and after an event that would increase the patient’s risk of HIV infection. For example, in some embodiments, when administered as PrEP, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered 1 hour to 240 hours (i.e., within 10 days), 1 hour to 216 hours, 1 hour to 192 hours, 1 hour to 168 hours, 1 hour to 144 hours, 1 hour to 120 hours, 1 hour to 96 hours, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 24 hours, or 1 hour to 12 hours before an event that would increase the patient’s risk of HIV infection (e.g., before sexual activity), and 1 hour to 240 hours (i.e., within 10 days) after such an event, 1 hour to 216 hours, 1 hour to 192 hours, 1 hour to 168 hours, 1 hour to 144 hours, 1 hour to 120 hours, 1 hour to 96 hours, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, or 1 hour to 12 hours after such an event. For example, in some embodiments, one or more (e.g., one, two, or three) doses of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, are administered one to ten days (e.g., seven days) before an event that increases the patient's risk of HIV infection (e.g., before sexual intercourse) and once during a period of one to ten days after that event. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or five times a week, or once or more (e.g., once, twice, or three times), starting one to 48 hours after an event that increases the patient's risk of HIV infection (e.g., after sexual intercourse).

[0106] This article also provides a method for reducing the risk of HIV infection in patients, which involves administering to patients a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, to a patient in combination with safer sexual practices. In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, to a patient at risk of HIV infection. Examples of patients at high risk of HIV infection include, but are not limited to, patients at risk of sexually transmitted HIV.

[0108] In some embodiments, the risk of HIV infection is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95% (compared to patients who have not been administered a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof according to any of the methods provided herein). In some embodiments, the risk of HIV infection is reduced by about 80%, 85%, or 90%. In some embodiments, the risk of HIV infection is reduced by at least about 75%. In some embodiments, the risk of HIV infection is reduced by at least about 80%. In some embodiments, the risk of HIV infection is reduced by at least about 85%. In some embodiments, the risk of HIV infection is reduced by at least about 90%.

[0109] In some implementations, the patient is a patient who has undergone intensive treatment. In some implementations, the methods provided herein include treating human immunodeficiency virus (HIV) infection in patients who have undergone intensive treatment.

[0110] In some embodiments, this disclosure relates to the use of compounds of formula Ia or Ib or pharmaceutically acceptable salts thereof in the treatment of infections caused by HIV, including administering a therapeutically effective amount to a patient in need, wherein the patient is a patient with multidrug-resistant HIV infection who has undergone intensive treatment.

[0111] As used herein, “patients who have undergone intensive treatment” refers to HIV-infected patients who have limited treatment options due to multidrug-resistant HIV infection. For example, in some implementations, “patients who have undergone intensive treatment” refers to HIV patients who have developed resistance to at least one class of antiretroviral drugs selected from the group consisting of NRTI, NNRTI, PI, and INSTI.

[0112] In some implementations, "multidrug-resistant HIV infection" refers to resistance to at least one class of antiretroviral drugs selected from the group consisting of NRTI, NNRTI, PI, and INSTI. In some implementations, "multidrug-resistant HIV infection" refers to resistance to at least one class of antiretroviral drugs selected from the group consisting of NRTI, NNRTI, PI, and INSTI. In some implementations, "multidrug-resistant HIV infection" refers to resistance to at least one class of antiretroviral drugs selected from the group consisting of NRTI, NNRTI, PI, and INSTI. In some implementations, "multidrug-resistant HIV infection" refers to resistance to at least one class of antiretroviral drugs selected from the group consisting of NRTI, NNRTI, PI, and INSTI.

[0113] As used in this article, the term "NRTI" refers to nucleoside reverse transcriptase inhibitors or nucleotide reverse transcriptase inhibitors.

[0114] As used in this article, the term "NNRTI" refers to a non-nucleoside reverse transcriptase inhibitor or a non-nucleotide reverse transcriptase inhibitor.

[0115] As used in this article, the term "PI" refers to a protease inhibitor.

[0116] As used in this article, the term "INSTI" refers to an integrase strand transfer inhibitor.

[0117] As used in this article, when referring to HIV therapy or HIV treatment regimens, the terms "failed" or "not passed" mean a future outcome in HIV patients that excludes the use of the same agent or class of treatment. This could be due to insufficient initial viral response caused by pre-existing viral resistance, viral rebound due to emergency viral resistance, or patient inability to continue treatment due to intolerance or safety issues.

[0118] In the disclosed methods, the patient who has undergone intensive treatment is infected with multidrug-resistant HIV. In some embodiments, the patient who has undergone intensive treatment has multidrug-resistant HIV infection and is on an unapproved HIV treatment regimen. In some embodiments, the patient who has undergone intensive treatment has a viral load greater than approximately 1,000 copies of HIV RNA / mL.

[0119] In some embodiments, HIV infection is HIV-1 infection. In some embodiments, HIV-1 infection is characterized by resistance to antiretroviral drugs, such as resistance to one, two, three, four, or more classes of antiretroviral drugs (e.g., PI, NRTI, NNRTI, INSTI, etc.) via HIV-1 mutants. In some embodiments, HIV-1 infection is characterized by resistance to one or more classes of antiretroviral drugs via HIV-1 mutants. In some embodiments, HIV-1 infection is characterized by resistance to two or more classes of antiretroviral drugs via HIV-1 mutants. In some embodiments, HIV-1 infection is characterized by resistance to three or more antiretroviral drugs via HIV-1 mutants.

[0120] In some implementations, HIV-1 mutants are resistant to protease inhibitors (PI), nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTI), or integrase strand transfer inhibitors (INSTI).

[0121] In some implementations, HIV-1 infection is characterized by HIV-1 mutants, including but not limited to: (a) HIV-1 mutants resistant to PI (e.g., I50V, I84V / L90M, G48V / V82A / L90M, G48V / V82S, etc.); (b) HIV-1 mutants resistant to NRTI (e.g., K65R, M184V, 6TAM, etc.). (c) HIV-1 mutants resistant to NNRTI (e.g., K103N, Y181C, Y188L, L100I / K103N, K103N / Y181C, etc.); and / or (d) HIV-1 mutants resistant to INSTI (Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R, R263K / M50I, etc.).

[0122] In some implementations, the HIV-1 mutant is resistant to protease inhibitors selected from I50V, I84V / L90M, G48V / V82A / L90M, and G48V / V82S.

[0123] In some implementations, HIV-1 mutants are resistant to nucleoside or nucleotide reverse transcriptase inhibitors selected from K65R, M184V, and 6TAM.

[0124] In some implementations, HIV-1 mutants are resistant to nonnucleoside or nonnucleotide reverse transcriptase inhibitors selected from K103N, Y181C, Y188L, L100I / K103N, and K103N / Y181C.

[0125] In some implementations, HIV-1 mutants are resistant to integrase strand transfer inhibitors selected from Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R, and R263K / M50I.

[0126] In some embodiments, the patient is infected with HIV-1 resistant to at least one antiretroviral drug. In some embodiments, the patient is infected with multidrug-resistant HIV-1. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one, two, three, four, or more antiretroviral drugs. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some embodiments, the different classes of antiretroviral drugs are selected from NRTIs, NNRTIs, and PIs. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NRTI and at least one NNRTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NRTI and at least one PI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NRTI and at least one INSTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NNRTI and at least one PI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NNRTI and at least one INSTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NRTI, at least one NNRTI, and at least one PI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 resistant to at least one NRTI, at least one NNRTI, and at least one INSTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one NRTI, at least one PI, and at least one INSTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one NNRTI, at least one PI, and at least one INSTI. In some embodiments, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one NRTI, at least one NNRTI, at least one PI, and at least one INSTI.

[0127] In some implementations, the patient is infected with multidrug-resistant HIV-1, which is resistant to at least one antiretroviral drug that is an NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC). ® ), Lamivudine (3TC; Epivir) ® Zidovudine (AZT); Retrovir ® ), and doxorinosine (ddI; Videox-EC) ® ), and dideoxyinosine (Videx) ® Tenofovir, tenofovir alafenamide (Vemlidy) ® Tenofovir disoproxil fumarate (Viread) ® Stavudine (d4T; Zerit) ® ), zacitabine (ddeoxycytidine, ddC; Hivid) ® ) and Ziagen ® ).

[0128] In some implementations, the patient is infected with multidrug-resistant HIV-1, which is resistant to at least one antiretroviral drug that is an NNRTI (neuro-internal respiratory tract inhibitor). Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva). ® Intellectual ® Rilpivirine (Edurant) ® ), Viramune ® ) and dlavudine (Rescriptor ® ).

[0129] In some implementations, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one antiretroviral drug that acts as a PI (pipeline). Examples of PIs include, but are not limited to, agenerase inhibitors. ® Azanavir (Reyataz) ® Prezista ® ), fosanavir (Telzir) ® Lexiva ® Indinavir (Crixivan) ® ), Lopinavir (Kaletra) ® ), nelfinavir (Viracept) ® ritonavir (Norvir) ® ), saquinavir (Invirase) ® ) and telanavir (Aptivus ® ).

[0130] In some implementations, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one antiretroviral drug that is an INSTI. Examples of INSTIs include, but are not limited to, retegvir (Isentress ® ), Etiraperivir (Vitekta) ® ), Tivicay ® ), Cabotewe and Bicagwe.

[0131] In some implementations, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one antiretroviral drug that acts as a gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, epovitamide, emfuvirtide, BMS-986197, emfuvirtide biomodification, emfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide.

[0132] In some implementations, the patient is infected with multidrug-resistant HIV-1 that is resistant to at least one antiretroviral drug that acts as a CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirone, vevicvirone, maravirone, cinevirovirone, PRO-140, adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0133] In some embodiments of the disclosed method, the patient has previously been treated with at least one antiretroviral drug prior to treatment with a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 3 months, such as at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 3 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 6 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 9 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 12 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 18 months. In some embodiments, the patient has previously been treated with at least one antiretroviral drug for at least 24 months. In some implementations, the patient has previously been treated with at least one antiretroviral drug for at least 30 months. In some implementations, the patient has previously been treated with at least one antiretroviral drug for at least 36 months.

[0134] In some embodiments of the disclosed method, the patient had not passed a previous HIV treatment regimen prior to treatment with a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments of the disclosed method, the patient had not passed an HIV treatment regimen at the start of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the previous HIV treatment regimen included administration of at least one antiretroviral drug. In some embodiments, the HIV-infected patient had relapsed after an initial response to a previous HIV treatment regimen (e.g., antiretroviral therapy). In some embodiments, prior to treatment with a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the patient had a viral load greater than about 50 copies of HIV RNA / mL after approximately 48 weeks of therapy (e.g., antiretroviral therapy).

[0135] In some embodiments, the prior treatment regimen includes administering at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the prior treatment regimen includes administering at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some embodiments, the different classes of antiretroviral drugs are selected from NRTIs, NNRTIs, and PIs. In some embodiments, the prior treatment regimen includes administering at least one NRTI and at least one NNRTI. In some embodiments, the prior treatment regimen includes administering at least one NRTI and at least one PI. In some embodiments, the prior treatment regimen includes administering at least one NRTI and at least one INSTI. In some embodiments, the prior treatment regimen includes administering at least one NNRTI and at least one PI. In some embodiments, the prior treatment regimen includes administering at least one NNRTI and at least one INSTI. In some embodiments, the prior treatment regimen includes administration of at least one PI and at least one INSTI. In some embodiments, the prior treatment regimen includes administration of at least one NRTI, at least one NNRTI, and at least one PI. In some embodiments, the prior treatment regimen includes administration of at least one NRTI, at least one NNRTI, and at least one INSTI. In some embodiments, the prior treatment regimen includes administration of at least one NRTI, at least one PI, and at least one INSTI. In some embodiments, the prior treatment regimen includes administration of at least one NNRTI, at least one PI, and at least one INSTI.

[0136] In some implementations, the prior treatment regimen included the administration of at least one antiretroviral drug that acts as a gp41 fusion inhibitor.

[0137] In some implementations, the prior treatment regimen included the administration of at least one antiretroviral drug that acts as a CCR5 co-receptor antagonist.

[0138] In some implementations, prior treatment regimens include the administration of at least one antiretroviral drug as an NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC). ® ), Lamivudine (3TC; Epivir) ® Zidovudine (AZT); Retrovir ®), and doxorinosine (ddI; Videox-EC) ® ), and dideoxyinosine (Videx) ® Tenofovir, tenofovir alafenamide (Vemlidy) ® Tenofovir disoproxil fumarate (Viread) ® Stavudine (d4T; Zerit) ® ), zacitabine (ddeoxycytidine, ddC; Hivid) ® ) and Ziagen ® ).

[0139] In some implementations, prior treatment regimens include the administration of at least one antiretroviral drug that is an NNRTI. Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva). ® Intellectual ® Rilpivirine (Edurant) ® ), Viramune ® ) and dlavudine (Rescriptor ® ).

[0140] In some implementations, the prior treatment regimen includes the administration of at least one antiretroviral drug as a PI. Examples of PIs include, but are not limited to, agenerase. ® Azanavir (Reyataz) ® Prezista ® ), fosanavir (Telzir) ® Lexiva ® Indinavir (Crixivan) ® ), Lopinavir (Kaletra) ® ), nelfinavir (Viracept) ® ritonavir (Norvir) ® ), saquinavir (Invirase) ® ) and telanavir (Aptivus ® ).

[0141] In some implementations, prior treatment regimens include the administration of at least one antiretroviral drug as an INSTI. Examples of INSTIs include, but are not limited to, retegvir (Isentress ® ), Etiraperivir (Vitekta) ® ), Tivicay ® ), Cabotewe and Bicagwe.

[0142] In some implementations, the prior treatment regimen includes administration of at least one antiretroviral drug that is a gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, epovitamide, emfuvirtide, BMS-986197, emfuvirtide biomodifiers, emfuvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide.

[0143] In some implementations, the prior treatment regimen included administration of at least one antiretroviral drug as a CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirone, vevicvirone, maravirone, cineviro, PRO-140, adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0144] In some embodiments of the disclosed method, HIV-infected patients who have undergone intensive treatment have a viral load of about 200 copies of HIV-1 RNA / mL (c / mL) to about 1,000,000 c / mL at the start of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, such as about 200 c / mL to about 500,000 c / mL, about 200 c / mL to about 250,000 c / mL, about 200 c / mL to about 100,000 c / mL, about 200 c / mL to about 50,000 c / mL, about 200 c / mL to about 25,000 c / mL, about 200 c / mL to about 10,000 c / mL, about 200 c / mL to about 5,000 c / mL, about 200 c / mL to about 3,000 c / mL, about 200 c / mL to about 2,000 c / mL, about 200 c / mL to about 2,000 c / mL, about 200 c / mL to about 5,000 c / mL, about 200 c / mL to about 3 ...5,000 c / mL, about 200 c / mL to about 5,000 c / mL, about 200 c / mL to about 5,000 c / mL, about 200 c / mL to about 5,000 c / mL mL to about 1,000 c / mL, about 200 c / mL to about 750 c / mL, about 200 c / mL to about 500 c / mL, about 500 c / mL to about 1,000,000 c / mL, about 500 c / mL to about 500,000 c / mL, about 500 c / mL to about 250,000 c / mL, about 500 c / mL to about 100,000 c / mL, about 500 c / mL to about 50,000 c / mL, about 500 c / mL to about 25,000 c / mL, about 500 c / mL to about 10,000 c / mL, about 500 c / mL to about 5,000 c / mL, about 500 c / mL Approximately 3,000 c / mL, approximately 500 c / mL to approximately 2,000 c / mL, approximately 500 c / mL to approximately 1,000 c / mL, approximately 500 c / mL to approximately 750 c / mL, approximately 750 c / mL to approximately 1,000,000 c / mL, approximately 750 c / mL to approximately 500,000 c / mL, approximately 750 c / mL to approximately 250,000 c / mL, approximately 750 c / mL to approximately 100,000 c / mL, approximately 750 c / mL to approximately 50,000 c / mL, approximately 750 c / mL to approximately 25,000 c / mL, approximately 750 c / mL to approximately 10,000 c / mL, approximately 750 c / mL From about 5,000 c / mL, from about 750 c / mL to about 3,000 c / mL, from about 750 c / mL to about 2,000 c / mL, from about 750 c / mL to about 1,000 c / mL, from about 1,000 c / mL to about 1,000,000 c / mL, from about 1,000 c / mL to about 500,000 c / mL, from about 1,000 c / mL to about 250,000 c / mL, from about 1,000 c / mL to about 100,000 c / mL, from about 1,000 c / mL to about 50,000 c / mL, from about 1,000 c / mL to about 25,000 c / mL, from about 1,000 c / mL to about 10,000 c / mL, about 1,000 c / mL to about 5,000 c / mL, about 1,000 c / mL to about 3,000 c / mL, about 1,000 c / mL to about 2,000 c / mL, about 2,000 c / mL to about 1,000,000 c / mL, about 2,000 c / mL to about 500,000 c / mL, about 2,000 c / mL to about 250,000 c / mL, about 2,000 c / mL to about 100,000 c / mL, about 2,000 c / mL to about 50,000 c / mL, about 2,000 c / mL to about 25,000 c / mL, about 2,000 c / mL to about 10,000 c / mL, about 2,000 c / mL approximately 5,000 c / mL, approximately 2,000 c / mL to approximately 3,000 c / mL, approximately 3,000 c / mL to approximately 1,000,000 c / mL, approximately 3,000 c / mL to approximately 500,000 c / mL, approximately 3,000 c / mL to approximately 250,000 c / mL, approximately 3,000 c / mL to approximately 100,000 c / mL, approximately 3,000 c / mL to approximately 50,000 c / mL, approximately 3,000 c / mL to approximately 25,000 c / mL, approximately 3,000 c / mL to approximately 10,000 c / mL, approximately 3,000 c / mL to approximately 5,000 c / mL, approximately 5,000 c / mL to approximately 1,000,000 c / mL Approximately 5,000 c / mL to approximately 500,000 c / mL, approximately 5,000 c / mL to approximately 250,000 c / mL, approximately 5,000 c / mL to approximately 100,000 c / mL, approximately 5,000 c / mL to approximately 50,000 c / mL, approximately 5,000 c / mL to approximately 25,000 c / mL, approximately 5,000 c / mL to approximately 10,000 c / mL, approximately 10,000 c / mL to approximately 1,000,000 c / mL, approximately 10,000 c / mL to approximately 500,000 c / mL, approximately 10,000 c / mL to approximately 250,000 c / mL, approximately 10,000 c / mL to approximately 100,000 c / mL, approximately 10,000 c / mL 00 c / mL to about 50,000 c / mL, about 10,000 c / mL to about 25,000 c / mL, about 25,000 c / mL to about 1,000,000 c / mL, about 25,000 c / mL to about 500,000 c / mL, about 25,000 c / mL to about 250,000 c / mL, about 25,000 c / mL to about 100,000 c / mL, about 25,000 c / mL to about 50,000 c / mL, about 50,000 c / mL to about 1,000,000 c / mL, about 50,000 c / mL to about 500,000 c / mL, about 50,000 c / mL to about 250,000 c / mL, about 50,Viral loads ranging from approximately 1,000 c / mL to approximately 100,000 c / mL, approximately 100,000 c / mL to approximately 1,000,000 c / mL, approximately 100,000 c / mL to approximately 500,000 c / mL, approximately 100,000 c / mL to approximately 250,000 c / mL, approximately 250,000 c / mL to approximately 1,000,000 c / mL, approximately 250,000 c / mL to approximately 500,000 c / mL, or approximately 500,000 c / mL to approximately 1,000,000 c / mL.

[0145] In some implementations, the patient has a viral load of more than about 200 copies of HIV-1 RNA / mL (c / mL) at the start of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, such as a viral load of more than about 500 c / mL, about 750 c / mL, about 1,000 c / mL, about 2,000 c / mL, about 3,000 c / mL, about 5,000 c / mL, about 10,000 c / mL, about 25,000 c / mL, about 50,000 c / mL, about 100,000 c / mL, about 250,000 c / mL, about 500,000 c / mL, or more than about 1,000,000 c / mL at the start of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load greater than about 200 c / mL when starting administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load greater than about 500 c / mL when starting administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load greater than about 750 c / mL when starting administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load greater than about 1,000 c / mL when starting administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load greater than about 2,000 c / mL when starting administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments of the disclosed method, administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, results in a reduction in viral load in the patient. In some embodiments, the viral load is reduced by approximately 0.5 log after a certain period of time following administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, compared to the viral load at the start of administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. 10 To approximately 2.5 log 10For example, the viral load after a certain amount of time following administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof decreased by approximately 0.5 log compared to the viral load at the start of administration of the compound or a pharmaceutically acceptable salt thereof. 10 Approximately 1 log 10 Approximately 1.5 log 10 Approximately 2 logs 10 or approximately 2.5 log 10 In some implementations, the viral load after approximately 24 weeks of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is reduced by approximately 0.5 log compared to the viral load at the start of administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. 10 In some implementations, the viral load after approximately 24 weeks of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is reduced by approximately 1 log compared to the viral load at the start of administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. 10 In some implementations, the viral load after approximately 24 weeks of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is reduced by approximately 1.5 log compared to the viral load at the start of administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. 10 In some implementations, the viral load after approximately 2 log10 weeks of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof was reduced compared to the viral load at the start of administration of the compound or a pharmaceutically acceptable salt thereof. 10 In some implementations, the viral load after approximately 24 weeks of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is reduced by approximately 2.5 log compared to the viral load at the start of administration of the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof. 10 .

[0147] In some embodiments of the disclosed method, after a certain period of time following administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the viral load in the patient is about 200 c / mL or less, such as about 175 c / mL or less, about 150 c / mL or less, about 125 c / mL or less, about 100 c / mL or less, about 75 c / mL or less, or about 50 c / mL or less. In some embodiments, after about 24 weeks of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the viral load in the patient is about 200 c / mL or less. In some embodiments, after about 24 weeks of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the viral load in the patient is about 200 c / mL or less. In some embodiments, after about 24 weeks of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the viral load in the patient is about 100 c / mL or less. In some implementations, after approximately 24 weeks of administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, the viral load in the patient is approximately 50 c / mL or less.

[0148] In some embodiments of the disclosed method, patients who have undergone intensive treatment are simultaneously treated with at least one additional antiretroviral agent. In some embodiments, the antiretroviral agent is selected from NRTI, NNRTI, PI, INSTI, gp41 fusion inhibitors, and CCR5 co-receptor antagonists.

[0149] In some implementations, the patient is treated simultaneously with at least one NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC). ® ), Lamivudine (3TC; Epivir) ® Zidovudine (AZT); Retrovir ® ), and doxorinosine (ddI; Videox-EC) ® ), and dideoxyinosine (Videx) ® Tenofovir, tenofovir alafenamide (Vemlidy) ® Tenofovir disoproxil fumarate (Viread) ® Stavudine (d4T; Zerit) ® ), zacitabine (ddeoxycytidine, ddC; Hivid) ® ) and Ziagen ® ).

[0150] In some implementations, the patient is treated simultaneously with at least one NNRTI. Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva). ® Intellectual® Rilpivirine (Edurant) ® ), Viramune ® ) and dlavudine (Rescriptor ® ).

[0151] In some implementations, the patient is treated simultaneously with at least one PI. Examples of PIs include, but are not limited to, agenerase. ® Azanavir (Reyataz) ® Prezista ® ), fosanavir (Telzir) ® Lexiva ® Indinavir (Crixivan) ® ), Lopinavir (Kaletra) ® ), nelfinavir (Viracept) ® ritonavir (Norvir) ® ), saquinavir (Invirase) ® ) and telanavir (Aptivus ® ).

[0152] In some implementations, the patient is treated simultaneously with at least one INSTI. Examples of INSTIs include, but are not limited to, retegvir (Isentress ® ), Etiraperivir (Vitekta) ® ), Tivicay ® ), Cabotewe and Bicagwe.

[0153] In some implementations, patients are treated simultaneously with at least one gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, epovitamide, emfuvirtide, BMS-986197, emfuvirtide biomodifiers, emfuvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide.

[0154] In some implementations, patients are treated concurrently with at least one CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirone, vevicvirone, maravirone, cinevirovirone, PRO-140, adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0155] This disclosure also provides a method for treating HIV-1 infection in a multidrug-resistant HIV-1 patient who has undergone intensive treatment, the method comprising administering to a patient who has previously been treated with an HIV treatment regimen comprising administration of at least one antiretroviral drug and has failed to complete that treatment regimen a therapeutically effective amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the HIV treatment regimen comprises administration of at least one antiretroviral drug, such as those described herein. In some embodiments of the method, administration of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof results in a reduction in the HIV viral load in the patient.

[0156] A method for treating HIV-1 infection in a patient with multidrug-resistant HIV-1 who has undergone intensive treatment is also disclosed. The method comprises administering a therapeutically effective amount of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, to a patient who has previously been treated with an HIV treatment regimen comprising administration of at least one antiretroviral drug and has failed to complete that regimen. The multidrug-resistant HIV-1 is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from NRTI, NNRTI, PI, and INSTI. In some embodiments, the patient has a viral load greater than about 200 c / mL at the start of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and administration of the compound results in a reduction of the HIV viral load in the patient.

[0157] In some embodiments, a method for treating HIV-1 infection in a patient with multidrug-resistant HIV-1 who has undergone intensive treatment is disclosed. The method comprises administering a therapeutically effective amount of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, to a patient who has previously been treated with an HIV treatment regimen comprising administration of at least one antiretroviral drug and has failed to complete that regimen. The multidrug-resistant HIV-1 is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from NRTI, NNRTI, PI, and INSTI. In some embodiments, the patient has a viral load greater than about 200 c / mL at the start of administration of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and administration of the compound results in a reduction of the HIV viral load in the patient.

[0158] Salts and Compositions The method of this invention includes administering a salt of a compound of formula Ia or Ib, such as a pharmaceutically acceptable salt. A salt generally refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. A pharmaceutically acceptable salt is one that, within reasonable medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid. A list of suitable salts is available in […]. Remington's Pharmaceutical Sciences 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science The full text of each of these documents is incorporated herein by reference in , 66, 2 (1977). In some implementations, the salt is a sodium salt.

[0159] Compounds of formula Ia or Ib or salts thereof may be present in a composition (such as a pharmaceutical composition or formulation) wherein the composition comprises at least one compound other than compounds of formula Ia or Ib or salts thereof.

[0160] In some embodiments, the composition comprises a compound of formula Ia or Ib or a salt thereof and one or more additional compounds (e.g., one or more additional therapeutic compounds) or salts thereof. In some embodiments, the composition comprises a compound of formula Ia or Ib or a salt thereof; bicagvir or a salt thereof; and one or more additional compounds (e.g., one or more additional therapeutic compounds, such as tenofovir alafenamide or a pharmaceutically acceptable salt thereof) or salts thereof.

[0161] The composition may include a compound of formula Ia or Ib or a salt thereof and a mixture of one or more solvents, substrates, carriers, etc. In some embodiments, the composition contains more than about 25% by weight (e.g., more than about 25% by weight, more than about 50% by weight, more than about 75% by weight, more than about 80% by weight, more than about 90% by weight, or more than about 95% by weight) of a compound of formula Ia or Ib or a salt thereof.

[0162] This disclosure further includes pharmaceutical compositions comprising compounds of formula Ia or Ib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" means any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for acceptable use in humans or domestic animals.

[0163] The administration of compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, can be performed via any approved pharmaceutical administration modality used for similar utilities. The pharmaceutical compositions of this disclosure can be prepared by combining compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, with a suitable pharmaceutically acceptable carrier, and in specific embodiments, are formulated as preparations in solid, semi-solid, liquid, or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Exemplary routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal administration. In some embodiments, the pharmaceutical compositions of this disclosure are tablets. The pharmaceutical compositions of this disclosure are formulated to allow the active ingredient contained therein to be bioavailable when the composition is administered to a patient. The composition to be administered to a patient is in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit, and a container for a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in aerosol form may contain multiple dose units. The actual methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the composition to be administered will contain a therapeutically effective amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof for the purpose of preventing HIV infection or reducing the risk of HIV infection, as described herein.

[0164] In some implementations, the compound of formula Ia or Ib or its pharmaceutically acceptable salt is administered orally.

[0165] In some embodiments, the active ingredient (e.g., a compound of formula Ia or Ib) is present as a free acid. In some embodiments, the active ingredient (e.g., a compound of formula Ia or Ib) is present as a sodium salt. In some embodiments, the active ingredient is a compound of formula Ia. In some embodiments, the active ingredient is a compound of formula Ib.

[0166] In some implementations, the compound of formula Ia or Ib or its pharmaceutically acceptable salt is administered orally.

[0167] In some embodiments, an oral formulation of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and at least one excipient is provided. The excipient may include ethanol, medium-chain triglycerides, vitamin E d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), glyceryl monocaprylate, glycerol, and / or pharmaceutically acceptable oils. Examples of suitable medium-chain triglycerides include, but are not limited to, MIGLYOL 810, MIGLYOL 821, and MIGLYOL 840. Examples of suitable pharmaceutically acceptable oils include, but are not limited to, sesame oil, castor oil, safflower oil, vegetable oils, and soybean oil. The oral formulation may include any combination of one or more suitable excipients. The excipients together may be present in greater than about 65%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95% of the total oral formulation by weight.

[0168] In some embodiments, an oral formulation of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and at least one excipient is prepared in a hard capsule or soft capsule. In some embodiments, the hard capsule or soft capsule comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and one or more excipients selected from the group consisting of: ethanol, propylene glycol, glycerin, d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), polyoxyethylene 35 castor oil (e.g., Kolliphor). ® EL), glyceryl monocaprylate (e.g., Capmul) ® MCM), PEG 400 caprylic / capric glyceride (e.g., Labrasol) ® ), PEG 400, diethylene glycol monoethyl ether (e.g., Transcutol) ® ), propylene glycol monooctanoate type II (e.g., Capryol) ® 90), glyceryl monooleate type 40 (e.g., Peceol) ™ ), medium-chain triglycerides (e.g., Miglyol) ® 812N), monolinoleic glycerides (e.g., Maisine) ® ) and polysorbate 80. In some embodiments, the hard capsule or soft capsule comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and one or more excipients selected from the group consisting of: ethanol, medium-chain triglycerides (e.g., Miglyol) ®812N), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), glyceryl monocaprylate (e.g., Capmul) ® MCM), PEG 400 caprylic / capric glyceride (e.g., Labrasol) ® ) and PEG400.

[0169] In some embodiments, the hard or soft capsule further includes a capsule shell. In some embodiments, the capsule shell contains one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients of the capsule shell are selected from the group consisting of gelatin shell, plasticizer, opacifier, and colorant. Plasticizers, opacifiers, and colorants are well known in the art. In some embodiments, the capsule shell contains one or more pharmaceutically acceptable excipients selected from the group consisting of gelatin, glycerin, titanium dioxide, and iron oxide. In some embodiments, the iron oxide includes iron oxide (yellow).

[0170] In some embodiments, an oral formulation of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is provided. In some embodiments, the oral formulation comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and glyceryl monocaprylate. In some embodiments, the oral formulation comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, about 5% to about 20% ethanol, about 10% to about 30% vitamin E TPGS, and about 50% to about 85% MIGLYOL 812. In some embodiments, the oral formulation comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, about 8% to about 15% ethanol, about 15% to about 25% vitamin E TPGS, and about 60% to about 77% MIGLYOL 812. In some embodiments, the oral formulation comprises a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, about 10% ethanol, about 20% vitamin E TPGS, and about 70% MIGLYOL 812. In some embodiments, the oral formulation is prepared in a hard gelatin capsule. In some embodiments, the oral formulation is prepared in a soft gelatin capsule.

[0171]

[0172] In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is from about 30 w / w to about 85 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is from about 40 w / w to about 80 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is from about 50 w / w to about 80 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is from about 60 w / w to about 70 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is about 65.9 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsule containing the compound of formula Ia or Ib and glyceryl monocaprylate is about 65.94 w / w.

[0173] In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing a compound of formula Ia or Ib and glyceryl monocaprylate is from about 1 w / w% to about 40 w / w. In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing a compound of formula Ia or Ib and glyceryl monocaprylate is from about 1 w / w% to about 35 w / w. In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing a compound of formula Ia or Ib and glyceryl monocaprylate is from about 2 w / w% to about 30 w / w. In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing a compound of formula Ia or Ib and glyceryl monocaprylate is from about 3 w / w% to about 28 w / w. In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing compound Ia or Ib and glyceryl monocaprylate is about 3.4 w / w. In some embodiments, the amount of compound Ia or Ib in the hard or soft gelatin capsule containing compound Ia or Ib and glyceryl monocaprylate is about 3.42 w / w.

[0174] In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further include a capsule shell. In some embodiments, the capsule shell comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients of the capsule shell are selected from the group consisting of gelatin shell, plasticizer, opacifier, and colorant. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further include one or more pharmaceutically acceptable excipients selected from the group consisting of gelatin, glycerol, titanium dioxide, and iron oxide. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further include gelatin. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further include glycerol. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further comprise titanium dioxide. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further comprise iron oxide. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin and glycerol. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin, glycerol, and titanium dioxide. In some embodiments, the hard or soft gelatin capsules comprising a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin, glycerol, titanium dioxide, and iron oxide. In some embodiments, the iron oxide in the hard or soft gelatin capsules comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide includes iron oxide (yellow).

[0175] In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 10 w / w to about 40 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 10 w / w to about 30 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 15 w / w to about 25 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 18 w / w to about 22 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 19.6 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 19.60 w / w.

[0176] In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 3 w / w% to about 25 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 5 w / w% to about 20 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 5 w / w% to about 15 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 8 w / w% to about 12 w / w. In some embodiments, the amount of glycerol in the hard or soft gelatin capsule containing the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 10.8 w / w. In some embodiments, the amount of glycerol in the hard or soft gelatin capsule containing the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 10.80 w / w.

[0177] In some embodiments, the amount of titanium dioxide in the hard or soft gelatin capsules containing the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 2 w / w%. In some embodiments, the amount of titanium dioxide in the hard or soft gelatin capsules containing the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.05 w / w% to about 1.5 w / w. In some embodiments, the amount of titanium dioxide in the hard or soft gelatin capsules containing the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.1 w / w% to about 1.0 w / w. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.1 w / w% to about 0.5 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.2 w / w. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.22 w / w.

[0178] In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules comprising the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 1 w / w%. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules comprising the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.5 w / w%. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules comprising the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.15 w / w. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules comprising the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.1 w / w%. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules comprising the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.02 w / w.

[0179] In some embodiments, the hard gelatin capsules or soft capsules comprise about 30 w / w% to about 85 w / w% of glyceryl monocaprylate and about 1 w / w% to about 40 w / w% of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 40 w / w% to about 80 w / w% of glyceryl monocaprylate and about 1 w / w% to about 35 w / w% of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 50 w / w% to about 80 w / w% of glyceryl monocaprylate and about 2 w / w% to about 30 w / w% of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 60 w / w% to about 70 w / w% of glyceryl monocaprylate and about 3 w / w% to about 28 w / w% of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 65.9 w / w of glyceryl monocaprylate and about 3.4 w / w of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 65.94 w / w of glyceryl monocaprylate and about 3.42 w / w of a compound of formula Ia or Ib.

[0180] In some embodiments, the hard gelatin capsules or soft capsules comprise about 30 w / w% to about 85 w / w% of glyceryl monocaprylate, about 1 w / w% to about 40 w / w% of a compound of formula Ia or Ib, about 10 w / w% to about 40 w / w% of gelatin, about 3 w / w% to about 25 w / w% of glycerol, about 0.01 w / w% to about 2 w / w% of titanium dioxide, and about 0.01 w / w% to about 1 w / w% of iron oxide. In some embodiments, the hard gelatin capsules or soft capsules comprise about 40 w / w% to about 80 w / w% of glyceryl monocaprylate, about 1 w / w% to about 35 w / w% of a compound of formula Ia or Ib, about 10 w / w% to about 30 w / w% of gelatin, about 5 w / w% to about 20 w / w% of glycerol, about 0.05 w / w% to about 1.5 w / w% of titanium dioxide, and about 0.01 w / w% to about 0.5 w / w% of iron oxide. In some embodiments, the hard gelatin capsules or soft capsules comprise about 50 w / w% to about 80 w / w% of glyceryl monocaprylate, about 2 w / w% to about 30 w / w% of a compound of formula Ia or Ib, about 15 w / w% to about 25 w / w% of gelatin, about 5 w / w% to about 15 w / w% of glycerol, about 0.1 w / w% to about 1.0 w / w% of titanium dioxide, and about 0.01 w / w% to about 0.15 w / w% of iron oxide. In some embodiments, the hard gelatin capsules or soft capsules comprise about 60 w / w% to about 70 w / w% of glyceryl monocaprylate, about 3 w / w% to about 28 w / w% of a compound of formula Ia or Ib, about 18 w / w% to about 22 w / w% of gelatin, about 8 w / w% to about 12 w / w% of glycerol, about 0.1 w / w% to about 0.5 w / w% of titanium dioxide, and about 0.01 w / w% to about 0.1 w / w% of iron oxide. In some embodiments, the hard gelatin capsules or soft capsules comprise about 65.9 w / w% of glyceryl monocaprylate, about 3.4 w / w% of a compound of formula Ia or Ib, about 19.6 w / w% of gelatin, about 10.8 w / w% of glycerol, about 0.2 w / w% of titanium dioxide, and about 0.02 w / w% of iron oxide. In some embodiments, the hard gelatin capsules or soft capsules contain about 65.94 w / w of glyceryl monocaprylate, about 3.42 w / w of a compound of formula Ia or Ib, about 19.60 w / w of gelatin, about 10.80 w / w of glycerol, about 0.22 w / w of titanium dioxide and about 0.02 w / w of iron oxide.

[0181] In some embodiments, the iron oxide in hard or soft gelatin capsules comprising a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide includes iron oxide (yellow). In some embodiments, the hard or soft gelatin capsules comprise about 65.9 w / w% glyceryl monocaprylate, about 3.4 w / w% of a compound of formula Ia or Ib, about 19.6 w / w% gelatin, about 10.8 w / w% glycerol, about 0.2 w / w% titanium dioxide, and about 0.02 w / w% iron oxide (yellow). In some embodiments, the hard gelatin capsules or soft capsules contain about 65.94 w / w of glyceryl monocaprylate, about 3.42 w / w of a compound of formula Ia or Ib, about 19.60 w / w of gelatin, about 10.80 w / w of glycerol, about 0.22 w / w of titanium dioxide and about 0.02 w / w of iron oxide (yellow).

[0182] In some embodiments, the hard gelatin capsules or soft gelatin capsules comprise a sodium salt of a compound of formula Ia or Ib and a glyceryl monocaprylate. In some embodiments, the concentration of the compound of formula Ia or Ib in the hard gelatin capsules or soft gelatin capsules comprising a sodium salt of a compound of formula Ia or Ib and a glyceryl monocaprylate is from about 10 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula Ia or Ib in the hard gelatin capsules or soft gelatin capsules comprising a sodium salt of a compound of formula Ia or Ib and a glyceryl monocaprylate is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 10 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 20 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 30 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 40 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 50 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 75 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 100 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 125 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 150 mg / ml.In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 175 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 200 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 225 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 250 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 275 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 300 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 325 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 350 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 375 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 400 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 425 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 450 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 475 mg / ml. In some embodiments, the concentration of compound Ia or Ib in a hard or soft gelatin capsule containing a sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 500 mg / ml.

[0183] In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 30 w / w to about 99 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 50 w / w to about 99 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 60 w / w to about 99 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 75 w / w to about 98 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 80.09 w / w to about 94.85 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is from about 80.1 w / w to about 94.9 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is about 80.09 w / w. In some embodiments, the amount of glyceryl monocaprylate in hard or soft gelatin capsules containing the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate is about 80.1 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsules containing the sodium salt of the compound of formula Ia or Ib and glyceryl monocaprylate is about 94.85 w / w. In some embodiments, the amount of glyceryl monocaprylate in the hard or soft gelatin capsules containing the sodium salt of the compound of formula Ia or Ib and glyceryl monocaprylate is about 94.9 w / w.

[0184] In some embodiments, the amount of sodium salt of compound Ia or Ib in hard or soft gelatin capsules containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is from about 1 w / w% to about 40 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in hard or soft gelatin capsules containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is from about 1 w / w% to about 35 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in hard or soft gelatin capsules containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is from about 2 w / w% to about 30 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in hard or soft gelatin capsules containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is from about 3 w / w% to about 28 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in a hard or soft gelatin capsule containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 5.15 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in a hard or soft gelatin capsule containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 5.2 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in a hard or soft gelatin capsule containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 19.9 w / w. In some embodiments, the amount of sodium salt of compound Ia or Ib in a hard or soft gelatin capsule containing sodium salt of compound Ia or Ib and glyceryl monocaprylate is about 19.91 w / w.

[0185] In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise a capsule shell. In some embodiments, the capsule shell comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients of the capsule shell are selected from the group consisting of gelatin shell, plasticizer, opacifier, and colorant. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise one or more pharmaceutically acceptable excipients selected from the group consisting of gelatin, glycerol, titanium dioxide, and iron oxide. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise glycerol. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise titanium dioxide. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise iron oxide. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin and glycerol. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin, glycerol, and titanium dioxide. In some embodiments, hard or soft gelatin capsules comprising the sodium salt of a compound of formula Ia or Ib and glyceryl monocaprylate further comprise gelatin, glycerol, titanium dioxide, and iron oxide. In some embodiments, the iron oxide in hard or soft gelatin capsules comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide includes iron oxide (yellow).

[0186] In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 10 w / w to about 40 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 10 w / w to about 30 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 15 w / w to about 25 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 18 w / w to about 22 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 19.6 w / w. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 19.60 w / w.

[0187] In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 3 w / w% to about 25 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 5 w / w% to about 20 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 5 w / w% to about 15 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 8 w / w to about 12 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 10.8 w / w. In some embodiments, the amount of glycerol in a hard or soft gelatin capsule comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 10.80 w / w.

[0188] In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 2 w / w%. In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.05 w / w% to about 1.5 w / w. In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.1 w / w% to about 1.0 w / w. In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.1 w / w% to about 0.5 w / w%. In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.2 w / w. In some embodiments, the amount of titanium dioxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.22 w / w.

[0189] In some embodiments, the amount of iron oxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 1 w / w%. In some embodiments, the amount of iron oxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.5 w / w%. In some embodiments, the amount of iron oxide in hard or soft gelatin capsules containing a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.15 w / w. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules containing the sodium salt of the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.01 w / w% to about 0.1 w / w%. In some embodiments, the amount of iron oxide in the hard or soft gelatin capsules containing the sodium salt of the compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide is about 0.02 w / w.

[0190] In some embodiments, the hard gelatin capsules or soft capsules disclosed herein comprise about 30 w / w% to about 99 w / w% of glyceryl monocaprylate and about 1 w / w% to about 40 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 50 w / w% to about 99 w / w% of glyceryl monocaprylate and about 1 w / w% to about 35 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 60 w / w% to about 99 w / w% of glyceryl monocaprylate and about 2 w / w% to about 30 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 75 w / w% to about 98 w / w% of glyceryl monocaprylate and about 3 w / w% to about 28 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 80.09 w / w% to about 94.85 w / w% of glyceryl monocaprylate and about 5.15 w / w% to about 19.91 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 80.1 w / w% to about 94.9 w / w% of glyceryl monocaprylate and about 5.2 w / w% to about 19.9 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 94.85 w / w% of glyceryl monocaprylate and about 5.15 w / w% of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 94.9 w / w% of glyceryl monocaprylate and about 5.2 w / w% of a sodium salt of a compound of formula Ia or Ib.

[0191] In some embodiments, the hard gelatin capsules or soft capsules comprise about 80.09 w / w of glyceryl monocaprylate and about 19.91 w / w of a sodium salt of a compound of formula Ia or Ib. In some embodiments, the hard gelatin capsules or soft capsules comprise about 80.1 w / w of glyceryl monocaprylate and about 19.9 w / w of a sodium salt of a compound of formula Ia or Ib.

[0192] In some embodiments, the iron oxide in hard or soft gelatin capsules comprising a sodium salt of a compound of formula Ia or Ib, glyceryl monocaprylate, gelatin, glycerol, titanium dioxide, and iron oxide includes iron oxide (yellow).

[0193] In some embodiments, the oral formulation of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is a tablet. In some embodiments, the tablet is prepared from a spray-dried dispersion of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 5 mg to about 500 mg. In some embodiments, the amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 25 mg to about 500 mg. In some embodiments, the amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 25 mg to about 400 mg. In some embodiments, the amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 25 mg to about 300 mg. In some embodiments, the amount of a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 50 mg to about 500 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 75 mg to about 500 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 50 mg to about 400 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 50 mg to about 300 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 75 mg to about 400 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is from about 75 mg to about 300 mg.In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 1 20mg, approximately 125mg, approximately 130mg, approximately 135mg, approximately 140mg, approximately 145mg, approximately 150mg, approximately 155mg, approximately 160mg, approximately 165mg, approximately 170mg, approximately 175mg, approximately 180mg, approximately 185mg, approximately 190mg, approximately 195mg, approximately 200mg, 205mg, approximately 210mg, approximately 215mg, approximately 220mg, approximately 225mg, approximately 230mg, approximately 235mg, approximately 240mg, approximately 245mg Approximately 250mg, approximately 255mg, approximately 260mg, approximately 265mg, approximately 270mg, approximately 275mg, approximately 280mg, approximately 285mg, approximately 290mg, approximately 295mg, approximately 300mg, approximately 305mg, approximately 310mg, approximately 315mg, approximately 320mg, approximately 325mg, approximately 330mg, approximately 335mg, approximately 340mg, approximately 345mg, approximately 350mg, approximately 355mg, approximately 360mg, approximately 365mg, approximately 370mg, approximately 37 5 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, or about 500 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 5 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 10 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 20 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 25 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 30 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 40 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 50 mg.In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 75 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 100 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 125 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 150 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 175 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 200 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 225 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 250 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 275 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 300 mg.

[0194] In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 325 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 350 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 375 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 400 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 425 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 450 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 475 mg. In some embodiments, the amount of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in the tablet is about 500 mg.

[0195] In some embodiments, the tablets herein comprise a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of formula Ia, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of formula Ia and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a sodium salt of a compound of formula Ia and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of formula Ib, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of formula Ib and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a sodium salt of a compound of formula Ib and one or more pharmaceutically acceptable excipients.

[0196] The pharmaceutically acceptable excipients for tablets disclosed herein should be compatible with other components of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of tablet formulation and may include, for example, [examples of suitable excipients]. Handbook of Pharmaceutical Excipients (Rowe, Sheskey & Quinn, eds.), 6th edition, 2009. As used herein, the term "excipient" is intended to refer in particular to alkalizing agents, solubilizers, gliding agents, fillers, binders, lubricants, diluents, preservatives, surfactants, dispersants, etc. The term also includes pharmaceutical agents such as sweeteners, flavoring agents, colorants, and preservatives. These components are typically present in tablets as mixtures.

[0197] Examples of solubilizers include, but are not limited to, surfactants (including ionic and nonionic surfactants) such as sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and polyethylene glycol. Examples of lubricants, flow aids, and flow promoters include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitate, glyceryl behenate, sodium stearate fumarate, colloidal silica, and talc.

[0198] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium carboxymethyl starch, and sodium cross-linked carboxymethyl cellulose. Examples of fillers (also known as leavening agents or diluents) include, but are not limited to, starch, maltodextrin, polyols (such as lactose), and cellulose. Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, and starch.

[0199] In some embodiments, the tablets disclosed herein comprise a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from the group consisting of: a matrix forming agent, a surfactant, a filler, a disintegrant, and a lubricant. In some embodiments, the tablet comprises about 1 w / w% to about 10 w / w% of a matrix forming agent. In some embodiments, the matrix forming agent comprises copovidone. In some embodiments, the tablet comprises about 0.01 w / w% to about 10 w / w% of a surfactant. In some embodiments, the surfactant comprises poloxamer 407. In some embodiments, the tablet comprises about 25 w / w% to 85 w / w% of one or more fillers. In some embodiments, one or more fillers comprise microcrystalline cellulose and / or mannitol. In some embodiments, the tablet comprises about 1 w / w% to about 30 w / w% of a disintegrant. In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the tablet comprises about 0.01 w / w% to about 10 w / w% of a lubricant. In some implementations, the lubricant includes magnesium stearate.

[0200] The tablets disclosed herein may be uncoated or coated (in which case they include an external film coating). While uncoated tablets may be used, it is more common to provide coated tablets, in which case conventional non-enteric coatings may be used. Film coatings are known in the art and can be composed of hydrophilic polymeric materials, but not limited to polysaccharide materials, such as hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinyl alcohol-co-ethylene glycol), and other water-soluble polymers. Although the water-soluble material contained in the film coating of a tablet may include a single polymeric material, it may also be formed using a mixture of more than one polymer. The coating may be white or colored. Suitable coatings include, but are not limited to, polymeric film coatings, such as those containing polyvinyl alcohol, for example, "Opadry". ® II (which comprises partially hydrolyzed PVA, titanium dioxide, polyethylene glycol 3350, and talc, with optional coloring such as iron oxide or indigo carmine or iron oxide yellow or FD&C yellow #6). The amount of coating will typically be between 1 and 8% of the weight of the uncoated tablet.

[0201] In some embodiments, the tablets disclosed herein comprise a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients are selected from the group consisting of: copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone. In some embodiments, one or more pharmaceutically acceptable excipients include poloxamer 407. In some embodiments, one or more pharmaceutically acceptable excipients include microcrystalline cellulose. In some embodiments, one or more pharmaceutically acceptable excipients include mannitol. In some embodiments, one or more pharmaceutically acceptable excipients include croscarmellose sodium. In some embodiments, one or more pharmaceutically acceptable excipients include magnesium stearate. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone and poloxamer 407. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone, poloxamer 407, and microcrystalline cellulose. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone, poloxamer 407, microcrystalline cellulose, and mannitol. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone, poloxamer 407, microcrystalline cellulose, mannitol, and croscarmellose sodium. In some embodiments, one or more pharmaceutically acceptable excipients include copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate.

[0202] In some embodiments, the tablets disclosed herein comprise a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablets comprise a compound of formula Ia or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablets comprise a compound of formula Ib or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablets comprise a compound of formula Ia, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a sodium salt of the compound of formula Ia, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a sodium salt of the compound of formula Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a sodium salt of the compound of formula Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate.

[0203] In some embodiments, the tablets disclosed herein comprise a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 5 mg to about 500 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 25 mg to about 500 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 25 mg to about 400 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 25 mg to about 300 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 50 mg to about 300 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 5 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 10 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 25 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 30 mg.In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 40 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 50 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 75 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 100 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 125 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 150 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 175 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 200 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 225 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 250 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 275 mg.In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 300 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 325 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 350 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 375 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 400 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 425 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 450 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 475 mg. In some embodiments, the amount of compound Ia or Ib in a tablet comprising a sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 500 mg.

[0204] In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 5 w / w% to about 45 w / w. In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 10 w / w% to about 40 w / w. In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 15 w / w% to about 35 w / w. In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 15 w / w to about 25 w / w. In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20.46 w / w. In some embodiments, the amount of the sodium salt of compound Ia or Ib in a tablet comprising the sodium salt of compound Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20.5 w / w.

[0205] In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 1 w / w% to about 10 w / w. In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 2 w / w% to about 10 w / w. In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 3 w / w% to about 8 w / w. In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 3 w / w to about 6 w / w. In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 4.88 w / w. In some embodiments, the amount of copovidone in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 4.9 w / w.

[0206] In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.01 w / w% to about 10 w / w. In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.05 w / w% to about 8 w / w. In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.5 w / w% to about 4 w / w. In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.5 w / w% to about 3.0 w / w%. In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.3 w / w. In some embodiments, the amount of poloxamer 407 in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.33 w / w.

[0207] In some embodiments, the amount of microcrystalline cellulose in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 5 w / w% to about 45 w / w. In some embodiments, the amount of microcrystalline cellulose in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 10 w / w% to about 40 w / w. In some embodiments, the amount of microcrystalline cellulose in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 15 w / w% to about 35 w / w. In some embodiments, the amount of microcrystalline cellulose in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 18 w / w to about 30 w / w. In some embodiments, the amount of microcrystalline cellulose in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 21.28 w / w. In some embodiments, the amount of microcrystalline cellulose in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 21.3 w / w.

[0208] In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 15 w / w% to about 70 w / w. In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 20 w / w% to about 60 w / w. In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 30 w / w% to about 55 w / w. In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 40 w / w to about 50 w / w. In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 42.55 w / w. In some embodiments, the amount of mannitol in the tablet comprising the sodium salt of the compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 42.6 w / w.

[0209] In some embodiments, the amount of sodium croscarmellose in the tablet comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 1 w / w% to about 30 w / w. In some embodiments, the amount of sodium croscarmellose in the tablet comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 1 w / w% to about 20 w / w. In some embodiments, the amount of sodium croscarmellose in the tablet comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 4 w / w% to about 16 w / w. In some embodiments, the amount of crosylcarboxymethyl cellulose sodium in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, crosylcarboxymethyl cellulose sodium, and magnesium stearate is from about 6 w / w to about 10 w / w. In some embodiments, the amount of crosylcarboxymethyl cellulose sodium in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, crosylcarboxymethyl cellulose sodium, and magnesium stearate is about 8.0 w / w. In some embodiments, the amount of crosylcarboxymethyl cellulose sodium in tablets containing the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, crosylcarboxymethyl cellulose sodium, and magnesium stearate is about 8.00 w / w.

[0210] In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.01 w / w% to about 10 w / w. In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.05 w / w% to about 8 w / w. In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 0.5 w / w% to about 4 w / w. In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is from about 1.0 w / w to about 3.0 w / w. In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.5 w / w. In some embodiments, the amount of magnesium stearate in tablets comprising the sodium salt of a compound of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.50 w / w.

[0211] In some embodiments, the tablets disclosed herein comprise about 5 w / w% to about 45 w / w% of a sodium salt of a compound of formula Ia or Ib, about 1 w / w% to about 10 w / w% of copovidone, about 0.01 w / w% to about 10 w / w% of poloxamer 407, about 5 w / w% to about 45 w / w% of microcrystalline cellulose, about 15 w / w% to about 70 w / w% of mannitol, about 1 w / w% to about 30 w / w% of croscarmellose sodium, and about 0.01 w / w% to about 10 w / w% of magnesium stearate, as well as one or more pharmaceutically acceptable excipients. In some embodiments, the tablets disclosed herein comprise about 5 w / w% to about 45 w / w% of a sodium salt of a compound of formula Ia or Ib, about 1 w / w% to about 10 w / w% of copovidone, about 0.01 w / w% to about 10 w / w% of poloxamer 407, about 5 w / w% to about 45 w / w% of microcrystalline cellulose, about 15 w / w% to about 70 w / w% of mannitol, about 1 w / w% to about 30 w / w% of croscarmellose sodium, and about 0.01 w / w% to about 10 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 10 w / w% to about 40 w / w% of the sodium salt of a compound of formula Ia or Ib, about 2 w / w% to about 10 w / w% of copovidone, about 0.05 w / w% to about 8 w / w% of poloxamer 407, about 10 w / w% to about 40 w / w% of microcrystalline cellulose, about 20 w / w% to about 60 w / w% of mannitol, about 1 w / w% to about 20 w / w% of croscarmellose sodium, and about 0.05 w / w% to about 8 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 15 w / w% to about 35 w / w% of the sodium salt of a compound of formula Ia or Ib, about 3 w / w% to about 8 w / w% of copovidone, about 0.5 w / w% to about 4 w / w% of poloxamer 407, about 15 w / w% to about 35 w / w% of microcrystalline cellulose, about 30 w / w% to about 55 w / w% of mannitol, about 4 w / w% to about 16 w / w% of croscarmellose sodium, and about 0.5 w / w% to about 4 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 15 w / w% to about 25 w / w% of the sodium salt of a compound of formula Ia or Ib, about 3 w / w% to about 6 w / w% of copovidone, about 0.5 w / w% to about 3.0 w / w% of poloxamer 407, about 18 w / w% to about 30 w / w% of microcrystalline cellulose, about 40 w / w% to about 50 w / w% of mannitol, about 6 w / w% to about 10 w / w% of croscarmellose sodium, and about 1.0 w / w% to about 3.0 w / w% of magnesium stearate.

[0212] In some embodiments, the tablet comprises about 20.5 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, and about 1.5 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 20.46 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, and about 1.50 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 20.5 w / w% of the sodium salt of the compound of formula Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, and about 1.5 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 20.46 w / w% of the sodium salt of the compound of formula Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, and about 1.50 w / w% of magnesium stearate.

[0213] In some embodiments, the tablets disclosed herein further include an outer film coating. In some embodiments, tablets comprising sodium salts of compounds of formula Ia or Ib, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate include an outer film coating. In some embodiments, the outer film coating provides a weight increase of about 1% to about 8% based on the uncoated tablet. In some embodiments, the outer film coating provides a weight increase of about 2% to about 6% based on the uncoated tablet. In some embodiments, the outer film coating provides a weight increase of about 2% to about 4% based on the uncoated tablet. In some embodiments, the outer film coating provides a weight increase of about 4% to about 6% based on the uncoated tablet. In some embodiments, the outer film coating provides a weight increase of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, or about 8% based on the uncoated tablet. In some embodiments, the outer film coating provides a weight increase of about 1% based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 2% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 3% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 4% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 5% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 6% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 7% weight gain based on the uncoated tablet. In some embodiments, the outer film coating provides approximately 8% weight gain based on the uncoated tablet. In some embodiments, the outer film coating includes Opadry. ® II. In some embodiments, the outer film coating includes Opadry. ® II White. In some embodiments, the outer film coating includes Opadry. ® II White 85F18422.

[0214] In some implementations, the outer film coating includes Opadry. ® II Green. In some embodiments, the outer film coating includes Opadry. ® II Green 85F110187. In some embodiments, the outer film coating includes Opaldy. ® II Green 85F110186.

[0215] In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 3% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® II. White85F18422 weight increase, wherein the weight increase is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 3.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II White 85F18422 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of the compound of formula Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 3% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II White 85F18422 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of the compound of formula Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 3.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II White 85F18422 is based on uncoated tablets.

[0216] In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 4% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ®The weight increase of II Green85F110187 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 4.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110187 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of the compound of formula Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 4% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110187 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of the compound of formula Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 4.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110187 is based on uncoated tablets.

[0217] In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 4% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ®The weight increase of II Green85F110186 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of a compound of formula Ia or Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 4.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110186 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.5 w / w% of the sodium salt of the compound of formula Ib, about 4.9 w / w% of copovidone, about 1.3 w / w% of poloxamer 407, about 21.3 w / w% of microcrystalline cellulose, about 42.6 w / w% of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 4% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110186 is based on uncoated tablets. In some embodiments, the tablets comprise about 20.46 w / w% of the sodium salt of the compound of formula Ib, about 4.88 w / w% of copovidone, about 1.33 w / w% of poloxamer 407, about 21.28 w / w% of microcrystalline cellulose, about 42.55 w / w% of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 4.0% of [unclear - possibly a specific ingredient or ingredient] from Opadry. ® The weight increase of II Green 85F110186 is based on uncoated tablets.

[0218] The pharmaceutical compositions disclosed herein can also be prepared by other methods known in the pharmaceutical field. For example, in some embodiments, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof with sterile distilled water to form a solution. In some embodiments, a surfactant is added to promote the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof to promote the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0219] The term "effective amount" or "therapeutic effective amount" refers to an amount of a compound of formula Ia or Ib, or another anti-HIV agent, or a pharmaceutically acceptable salt thereof, sufficient, when administered to a patient in need, to achieve, as described herein, prevention of HIV infection or reduction of the risk of HIV infection. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or in the patient sought by the researcher or clinician. The amount of a compound of formula Ia or Ib, or other anti-HIV agent constituting a therapeutically effective amount, will vary depending on factors such as: the compound, salt, or composition used for administration; the time of administration; the route of administration; the rate of excretion of the compound; the duration of treatment; the type and severity of the disease state or disorder being treated; the drugs used in combination with or concurrently with a compound of formula Ia or Ib; and the patient's age, weight, general health condition, sex, and diet. Such a therapeutically effective amount can be routinely determined by those skilled in the art after taking into account their own knowledge, prior art, and the contents of this disclosure.

[0220] In some embodiments of the methods provided herein, each oral administration is performed as a tablet containing a sodium salt of a compound of formula Ia or Ib.

[0221] In some embodiments of the methods provided herein, each tablet is prepared by spray drying dispersion technology.

[0222] In some embodiments of the methods provided herein, each tablet comprises about 5 w / w% to about 45 w / w% of a sodium salt of a compound of formula Ia or Ib, about 1 w / w% to about 10 w / w% of copovidone, about 0.01 w / w% to about 10 w / w% of poloxamer 407, about 5 w / w% to about 45 w / w% of microcrystalline cellulose, about 15 w / w% to about 70 w / w% of mannitol, about 1 w / w% to about 30 w / w% of croscarmellose sodium, and about 0.01 w / w% to about 10 w / w% of magnesium stearate, as well as one or more pharmaceutically acceptable excipients.

[0223] In some embodiments of the methods provided herein, each tablet comprises about 15 w / w% to about 25 w / w% of a sodium salt of a compound of formula Ia or Ib, about 3 w / w% to about 6 w / w% of copovidone, about 0.5 w / w% to about 3.0 w / w% of poloxamer 407, about 18 w / w% to about 30 w / w% of microcrystalline cellulose, about 40 w / w% to about 50 w / w% of mannitol, about 6 w / w% to about 10 w / w% of croscarmellose sodium, and about 1.0 w / w% to about 3.0 w / w% of magnesium stearate.

[0224] In some embodiments of the methods provided herein, each tablet contains about 300 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments of the methods provided herein, each tablet contains about 306.8 mg of a sodium salt of a compound of formula Ia or Ib.

[0226] In some embodiments of the methods provided herein, each tablet further includes an outer film coating.

[0227] In some embodiments of the methods provided herein, the outer film coating provides a weight gain of about 1% to about 8% based on the uncoated tablet. In some embodiments of the methods provided herein, the outer film coating provides a weight gain of about 2% to about 5% based on the uncoated tablet.

[0228] In some embodiments of the methods provided herein, the outer film coating provides approximately 2% weight gain based on the uncoated tablet. In some embodiments of the methods provided herein, the outer film coating provides approximately 3% weight gain based on the uncoated tablet. In some embodiments of the methods provided herein, the outer film coating provides approximately 4% weight gain based on the uncoated tablet. In some embodiments of the methods provided herein, the outer film coating provides approximately 5% weight gain based on the uncoated tablet.

[0229] Combination therapy Patients treated with a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, typically demonstrate a benefit from treatment with other therapeutic agents, including those for treating retroviral infections, including HIV infection. In some embodiments, the other therapeutic agent is an agent for treating HIV infection. Therefore, one aspect of this disclosure is a method of treating HIV infection comprising administering to a patient in need a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in combination with one or more compounds that can be used to treat HIV infection.

[0230] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0231] In some embodiments, when a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential manner.

[0232] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered simultaneously with an additional therapeutic agent.

[0233] In some embodiments, a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered sequentially. When administered sequentially, the combination may be administered in two or more doses.

[0234] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient.

[0235] In some implementations, a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

[0236] Co-administration includes administering a unit dose of the compound provided herein or a pharmaceutically acceptable salt thereof before or after administering a unit dose of one or more additional therapeutic agents. The compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof within seconds or minutes. In some embodiments, a unit dose of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof is administered first, followed by a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1 hour to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof after a period of several hours (e.g., 1 hour to 12 hours).

[0237] HIV Combination therapy In the above-described embodiments, one or more additional therapeutic agents may be anti-HIV agents. In some cases, adjunctive therapy agents can be HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF-α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocycline modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic cell ICAM-3-extracting non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0238] In some implementations, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0239] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0240] In some embodiments, one or more adjunctive therapeutic agents are selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, agonists of HIV bNAb, TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for the treatment of HIV, as well as combinations thereof.

[0241] In some implementations, one or more additional therapeutic agents may be selected from durutexvir, cabotevir, direravir, bicagvir, issavirline, rilpivirline, and lenapapvir, as well as combinations thereof.

[0242] HIV combination drugs Examples of combination drugs include, but are not limited to, ATRIPLA ® (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); COMPLERA ® (EVIPLERA) ® Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (Ertiravir, Cobistat, Tenofovir Disoproxil Fumarate, and Emtricitabine); TRUVADA® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY ® (Tenofovir alafenamide and emtricitabine); ODEFSEEY ® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (Tenofovir alafenamide, emtricitabine, cobistat, and ertiravir); diravir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertiravir; tenofovir analogues; COMBIVIR ® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM ® (LIVEXA) ® Abacavir sulfate and lamivudine; ABC+3TC); KALETRA ® (ALUVIA) ® (Lopinavir and ritonavir); TRIUMEQ ® (Durutvir, Abacavir, and Lamivudine); BIKTARVY ® (Bicagvir + Emtricitabine + Tenofovir Alamote), DOVATO ® (Dolutegravir + Lamivudine), TRIZIVIR ®(Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dulutegravir + lamivudine, Lamivudine + abacavir + zidovudine, Lamivudine + abacavir, Lamivudine + tiramisu fumarate Nofovir dipivoxil, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir dipivoxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotevir + rilpivirine, 3-BNC117 + ibevitra, elpida (essavirin, VM-1500) and VM-1500A, as well as dual-targeting HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0243] other HIV drug Examples of other medications used to treat HIV include, but are not limited to, aspergillin C, acemannan, aliporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, and 1.5-Dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryozoin-1, bryozoin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, antisense oligonucleotides modified with fluoro-β-D-arabinose (FANA), FX-101, Griffithsin, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, Hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, NOV-205, OB-002H, ODE-Bn-TFV, PA-1050040 (PA-040), PC- 707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogue, TBL-1004HI, VG-1177, XL-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro, and ABBV-1882.

[0244] HIV protease inhibitors Examples of HIV protease inhibitors include, but are not limited to, ampravir, atazanavir, becanavir, drenellavir, forosanavir, forosanavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, ASC-09+ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent Nos. 10,294,234 and U.S. Patent Application Publications Nos. US2020030327 and US2019210978.

[0245] HIV Gag protein inhibitors Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0246] HIV Ribonuclease H Inhibitors Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0247] HIV Nef Inhibitors Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0248] HIV Reverse transcriptase inhibitors Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, dapirine, delavudine, delavudine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, isavirine (extended-release oral, for HIV infection), isavirine (long-acting injectable nanosuspension, for HIV infection), and isavirine (VM-1500). Additional non-limiting examples of non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include compounds disclosed in U.S. Patent No. 10,548,898.

[0249] Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azavudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil fumarate, and VIDEX. ® and VIDEX EC ® (Dysinosteroids, DDL), Abacavir, Abacavir sulfate, Alovudine, Aritabine, Cesarvudine, Dysinosteroids, Avtabin, Fertinavir, Fosalvudine tidoxil, CMX-157, Dapirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil fumarate, Fosalvudine tidoxil, Lamivudine, Azide, Stavudine, Zacitabine, Zidovudine, Rovafovir etarafenamide (GS-9131), GS-9148, MK-8504, MK-8583, VM-2500, and KP-1461.

[0250] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0251] HIV Integrase inhibitors Examples of HIV integrase inhibitors include, but are not limited to, erteiravir, erteiravir (extended-release microcapsules), curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, retegvir, PEGylated retegvir, dulutegravir, and JTK-351. Bicagvir, AVX-15567, Cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017. Additional non-limiting examples of HIV integrase inhibitors include compounds disclosed in U.S. Patent No. 11,084,832.

[0252] Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0253] HIV Viral infectious agent inhibitors Examples of inhibitors of HIV infectious agents include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0254] HIV Entry inhibitor Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cineviro, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0255] Examples of CCR5 inhibitors include, but are not limited to, apravirone, vevicvirone, maravirone, maravirone (long-acting injectable nanoemulsion), suniverone, lerolimumab (PRO-140), adatavir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, celavirone, and vMIP (Haimipu).

[0256] Examples of gp41 inhibitors include, but are not limited to, Abovetine, Enfuvirtide, Griffon (a gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biomodification, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifvirtide.

[0257] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogues. Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbial agents, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir (aminobutyric acid), IQP-0831, VVX-004, and BMS-663068.

[0258] Examples of gp160 inhibitors include, but are not limited to, tetrandrine.

[0259] Examples of CXCR4 inhibitors include, but are not limited to, praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0260] HIV Maturation inhibitors Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0261] Latency reversal agent Examples of latency reversal agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, such as GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabelon), ionomycin, and IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW- 242) SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (aminosuccinate or succinyl, aniline and isohydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as lagazole analogs, APH-0812 and GSK-343). Examples of PKC activators include, but are not limited to, indolelactam, prostratin, phorbol B and DAG-lactone.

[0262] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0263] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0264] Histone deacetylase ( HDAC Inhibitors In some embodiments, the agent as described herein is combined with histone deacetylases such as histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, romidesin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0265] Capsid inhibitors Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK WO2019 / 087016).

[0266] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0267] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2014221356 and US2016016973.

[0268] Cytochrome P450 3 Inhibitors Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0269] RNA Polymerase regulators Examples of RNA polymerase regulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264.

[0270] Immune checkpoint modulators In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blockage or inhibition of inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Stimulation or activation of immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., in Xu et al., J Exp Clin Cancer Research (2018) 37:110). In various implementations, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in the following literature: Davis et al., Semin Immunol (2017) 31:64–75; and Chiossone et al., Nat Rev Immunol .(2018) 18(11):671-688).

[0271] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); transmembrane and immunoglobulin domain-containing receptors 2 (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitors 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); inducible T cell costimulatory factors (ICOS, CD278); inducible T cell costimulatory ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137) TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269); TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC MHC class I peptide-associated sequence A (MICA); MHC class I peptide-associated sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); containing T-cell immunoglobulin and mucin domains 4 (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactohemagglutinin 9 (LGALS9).Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); Early retinoic acid transcript 1E (RAET1E; ULBP4); Early retinoic acid transcript 1G (RAET1G; ULBP5); Early retinoic acid transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Cytokine immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); Cytokine lectin-like receptor C1 (KLRC1, NKG) 2A, CD159A); cytotoxic cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); cytotoxic cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); cytotoxic cell lectin-like receptor C3 (KLRC3, NKG2E); cytotoxic cell lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); cytotoxic cells Cellular immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1).

[0272] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T-cell suppressor immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-containing immunomodulatory receptors. Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In various implementation schemes, the reagents described herein are combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors.Exemplary T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulators (ICOS, CD278); inducible T-cell costimulator ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al. J Exp Clin Cancer Research .(2018) 37:110.

[0273] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al. Semin Immunol (2017) 31:64–75; Fang et al., Semin Immunol (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol.(2018) 18(11):671-688.

[0274] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0275] Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to, ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28) and PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

[0276] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, and BI-754091. AGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181 (Bug's maize), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP- 3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), and PD-L1 / PD-L1 / PD-L1. -L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (C TLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0277] In various implementation schemes, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058 and AGEN-1307.

[0278] TNF Receptor superfamily ( TNFRSF Member agonists or activators In various implementations, the agent as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 35). 5) TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, ... TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), ...CD268, NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11 D: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).

[0279] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0280] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0281] In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

[0282] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373, and ADG-106.

[0283] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to: MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0284] Bispecific and trispecific natural killer ( NK Cell adaptors In various embodiments, the agent as described herein is combined with a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against (e.g., with Fc) of: NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell adaptors that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in Felices et al. Methods Mol Biol (2016) 1441:333–346; Fang et al., Semin Immunol (2017) 31:37-54. Examples of trispecific NK cell adaptors (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0285] Indoleamine - Pyrrole -2,3- dioxygenase ( IDO1 Inhibitors In various implementations, the agent as described herein is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0286] Toll α-receptors ( TLR agonists In various implementations, the agent as described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesamote), vesamote analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, teiramod, and BDB-001.TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), and US20080234251 (Array). Compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rapamod, polyICLC, and RIBOXXON. ® Apoxxim, RIBOXXIM ®IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0287] CDK Inhibitors or antagonists In some embodiments, the agents described herein are combined with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370.

[0288] STING agonists RIG-I and NOD2 regulator In some embodiments, the agents described herein are combined with interferon gene stimulators (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-I modulators (such as RGT-100) or NOD2 modulators (such as SB-9200 and IR-103).

[0289] LAG-3 and TIM-3 Inhibitors In some implementations, the agents described herein are combined with anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0290] In some embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0291] Interleukin agonists In some embodiments, the agent as described herein is combined with the following substances: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12); examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); BC-IL (Cel-Sci), PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, A Examples of IL-15 agonists include LKS-4230, CUI-101, and Neo-2 / 15; examples of IL-15 agonists include ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0292] Examples of additional immunotherapies that can be combined with the agents disclosed herein include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, gepon, nomfullon, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0293] Phosphatidylinositol 3- kinase ( PI3K Inhibitors Examples of PI3K inhibitors include, but are not limited to, adexixib, avocadolixib, bupalixib, orotic acid CAI, copanlixib, duvelixib, gladalixib, neratinib, panolixib, perifoxine, idalixib, piracexib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolixib, tacelilixib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-7423. , EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-76 66. RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0294] α-4 / β-7 Antagonist Examples of integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, aliruzumab, ectolizumab, methylcarograss, and vedolzumab.

[0295] HPK1 Inhibitors Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0296] HIV Targeted antibodies Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, DARTs. ® DUOBODIES ® BITES ® XmAbs ® TandAbs ® Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and HIV-targeting antibodies. Antibodies targeting gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, recombinant human mAb (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibodies targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0297] Various bNAb can be used. Examples include, but are not limited to, those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including... Antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include those described in the following literature: Klein et al., Nature , 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA , 110(41): 16538-43 (2013); Scheid et al., Science , 333: 1633-1637 (2011); Scheid et al., Nature , 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res ., 42 (Database Special): Dl 133-9 (2014); Mascola et al., Immunol Rev. , 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176 and 8ANC131 (all of which bind to the CD4 binding site).

[0298] Further broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO The references 2017 / 133639 and WO 2017 / 133640 are incorporated herein by reference in their entirety for all purposes. Additional examples include, but are not limited to, those mentioned in the following literature: Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (Database Special):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all of which are combined with gp41 MPER).

[0299] Examples of supplemental antibodies include, but are not limited to, bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (epavirin), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PG T-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, D RVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0300] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB-Bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0301] Examples of in vivo delivered bNAb include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered B cells encoding 3BNC117 (Hartweger et al.). J. Exp.Med .,2019, 1301).

[0302] Pharmacokinetic enhancers Examples of pharmacokinetic enhancers include, but are not limited to, cobistat and ritonavir.

[0303] Additional treatment Examples of supplemental therapeutic agents include, but are not limited to, WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO Compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (PharmaResources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0304] HIV vaccine Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pichinde), and arenavirus-based vaccines. Vaccines, including trimer-based HIV-1 vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines; rhabdovirus-based vaccines, such as VSV and Malabar virus; recombinant human CMV (rhCMV)-based vaccines; and A virus-based vaccines, such as Similac forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology , 2017, :DOI 10.1128 / CVI.00298-16); mRNA-based therapeutic vaccines formulated by LNP; self-replicating RNA / self-amplifying RNA vaccines formulated by LNP.

[0305] Examples of vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvanted vaccine, BG505SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA trivalent vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConMSOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomeric gp120 HIV-1 C subtype vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-branched recombinant adenovirus-5 (rAd5), rAd5 gag-pol envA / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 GAG vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, based on N123-VRC-34.01 HIV vaccines with inducible epitopes, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 The following vaccines are available: gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, and anti-TAT. HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x+romidesin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+ VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccines, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccines, gp120 (A, B, C, A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag primiparous-boost plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, arenavirus-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TFchTrimer, CD40 HIVRI Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0306] Combination therapy with birth control pills In some embodiments, the agents described herein are combined with contraceptive or birth control regimens. Therapeutic agents for birth control (contraceptives) that can be combined with the agents disclosed herein include, but are not limited to, cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenetetrahydrofolate, norethindrone, isethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0307] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: ATRIPLA ® (Efavirenz, Tenofovir disoproxil fumarate, and Emtricitabine); COMPLERA ® (EVIPLERA) ® Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (Ertiravir, Cobistat, Tenofovir Disoproxil Fumarate, and Emtricitabine); TRUVADA ® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY ® (Tenofovir alafenamide and emtricitabine); ODEFSEEY® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (Tenofovir alafenamide, emtricitabine, cobistatin, and erteiravir); BIKTARVY ® (Bicagvir + Emtricitabine + Tenofovir Alamonamide), Adefovir; Adefovir Dipropionate; Cobistat; Emtricitabine; Tenofovir; Tenofovir Alamonamide and Etileravir; Tenofovir Alamonamide + Etileravir (rectal preparation, HIV infection); Tenofovir Disoproxil Fumarate; Tenofovir Disoproxil Fumarate; Tenofovir Alamonamide; Tenofovir Alamonamide Hemifumarate; TRIUMEQ ® (Durutexvir, abacavir, and lamivudine); Durutvir, abacavir sulfate, and lamivudine; Rettagvir; PEGylated Rettagvir; Rettagvir and lamivudine; Lamivudine + lopinavir + ritonavir + abacavir; Maraviro; Tenofovir + emtricitabine + maraviro, enfuvir peptide; ALUVIA ® (KALETRA) ® (Lopinavir and ritonavir); COMBIVIR ® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM ® (LIVEXA) ® Abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR ® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Duriravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertiravir; Ritonavir; Atazanavir sulfate and Ritonavir; Duriravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Doxorinosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efavirex, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0308] In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In further embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0309] In another embodiment, the pharmaceutical agent or pharmaceutical composition thereof disclosed herein is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from dulutegravir, cabotevir, durenavir, bicagvir, issavirline, rilpivirline and lenapapvir, and the second adjunctive therapeutic agent being selected from emtricitabine and lamivudine.

[0310] In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with a first adjunctive therapeutic agent (contraceptive), the first adjunctive therapeutic agent being selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, norgestrel, norethindrone, isethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0311] Gene therapy and cell therapy In some implementations, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy.

[0312] Gene-edited products In some embodiments, the agents described herein are combined with a gene editor (e.g., an HIV-targeted gene editor). In various embodiments, the genome editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and broad-spectrum nuclease complexes. Exemplary HIV-targeted CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0313] CAR-T Cell therapy In some embodiments, the agents described herein may be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, a N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4 CAR-T cell therapy (CD4 CAR+C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0314] TCR T Cell therapy In some embodiments, the agents described herein are combined with a population of TCR-T cells. The TCR-T cells are engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

[0315] B Cell therapy In some embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells genetically modified to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al.). Sci.Immunol. 4, eaax0644 (2019) May 17, 2019.

[0316] Compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof, may be combined with one, two, three, or four additional therapeutic agents at any dose of compounds of formula Ia or Ib, or pharmaceutically acceptable salts thereof.

[0317] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two or one to three) additional therapeutic agents.

[0318] In one embodiment, one or more additional therapeutic agents in the kit are anti-HIV agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene-editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptors, TCR-T, autologous T-cell therapy), compounds targeting the HIV capsid, latency reversal agents, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing COMM domains, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic cell ICAM-3 non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0319] In some implementations, one or more additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0320] In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In yet another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In still another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and a nucleoside inhibitor of HIV reverse transcriptase.

[0321] HIV Long-acting therapy Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotevir, rilpivirine, any integrase LA, VM-1500 LAI, maraviro (LAI), tenofovir implants, doravirine, retegvir, and long-acting durutvir.

[0322] In some implementations, the methods provided herein further include administering one, two, three, or four additional therapeutic agents to the patient.

[0323] In some embodiments of the methods provided herein, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectious agent inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing the COMM domain, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3 non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0324] In some embodiments of the methods provided herein, the additional therapeutic agent is selected from the group consisting of: HIV protease inhibitory compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for the treatment of HIV or any combination thereof.

[0325] In some embodiments of the methods provided herein, the additional therapeutic agent is selected from the group consisting of: bicagvir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide fumarate.

[0326] In some embodiments of the methods provided herein, the additional therapeutic agent is selected from the group consisting of: bicagvir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.

[0327] Example This disclosure will be described in more detail by way of specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit this disclosure in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results.

[0328] Example 1. Pharmacokinetic Modeling and Simulation of Oral Dosing Regimen for Lenapavir The pharmacokinetics (PK) of LEN (50 mg–1800 mg) after a single dose has been characterized; within the evaluated dose range, the increase in oral LEN exposure was less than dose-proportional, with maximum plasma concentrations occurring between 4 and 8 hours post-dose, and a half-life of 10 to 13 days. In phase 2 / 3 clinical studies, a mean trough concentration of 15.5 ng / mL (which is an inhibition quotient of 4 (IQ4; i.e., 4 times the 95% effective concentration of in vitro protein corrected from MT-4 cells)) was associated with high virological inhibition rates.

[0329] The aim of this analysis was to identify LEN dosing regimens that could be used, for example, in combination with other antiretroviral agents, by simulating various weekly dosing regimens that would rapidly achieve and maintain LEN concentrations above the inhibition quotient 4 (IQ4).

[0330] PK data were collected from several clinical studies of healthy participants and HIV-1 patients receiving intravenous (IV) / oral / SC LEN, and a two-compartment population pharmacokinetic (PopPK) model of LEN with first-order absorption and linear elimination was constructed to simulate various weekly dosing regimens (loading dose + maintenance dose) that can rapidly achieve and maintain effective LEN concentrations throughout the dosing interval. Various scenarios of missed oral dosing, ranging from 1 to 3 weeks, were simulated to assess the tolerance window; these simulations were performed using a PopPK model that incorporates variability and covariate effects. An overview of the model is provided in [link to model description]. Figure 1 The pharmacokinetic parameters of lenakapavir are shown in Table 1, where CL = clearance rate; F... po =Oral bioavailability; F sc =SC bioavailability; GI = gastrointestinal tract; HTE = those who have undergone intensive treatment; IIV = inter-individual variability; K a =Absorption rate constant; K dir =Direct absorption rate constant; K tr =Transport absorption rate constant; PK =Pharmacokinetics; Q =Intercompartmental CL; V c = Central chamber volume; V p = Peripheral chamber volume.

[0331] Including weight relative to CL and V c V p The effects of F and Q were investigated using fixed allometric growth indices of 0.75 and 1 for CL and volume of distribution, respectively; a dose-dependent effect on F was found. po Furthermore, it was found that age, sex, and dosage affected CL.

[0332] Table 1.

[0333] Simulations were conducted to assess lenapavir exposure in the dosing scenarios presented below.

[0334] Scene 1 Day 1 and Day 2: 600 mg orally once daily (QD) Day 8: 300 mg orally once a week (QW) (7 days from the first dose). Scene 2 Day 1 and Day 2: 600mg orally once daily. Day 8: 300mg orally once every 7 days (from the first dose). Simulations showed that an oral loading dose of 600 mg on days 1 and 2, followed by an oral 300 mg QW dose, maintained a mean trough concentration above 90% CI above IQ4 (15.5 ng / mL) throughout the dosing interval; this regimen rapidly achieved IQ4 within 4 hours (see [link to original text]). Figure 2 ).

[0335] like Figure 3 As shown, simulations indicate that LEN 300mg QW allows for a 7-day tolerance window. If one oral LEN dose is missed, it should be taken as soon as possible, and the normal dosing regimen can then be restarted (i.e., one dose on the scheduled day) to maintain an average LEN concentration above IQ4. If two oral LEN doses are missed, simulations suggest that taking two doses as soon as possible and then restarting the normal regimen on the scheduled day will result in concentrations above IQ4 and within safety limits (see [link to simulation]). Figure 4 If the dose is to be taken on the scheduled dosing day, only two doses should be taken; never take three doses on the same day.

[0336] These data suggest that the expected oral LEN QW regimen (600 mg on days 1 and 2, followed by 300 mg QW) can be rapidly achieved within the dosing interval and subsequently maintain LEN concentrations above IQ4, and that oral LEN 300 mg QW dosing allows HIV patients a 7-day margin of error after the last missed dose.

[0337] Example 2. Spray-dried dispersion (SDD) tablets Tablets prepared from the spray-dried dispersion of the sodium salt of compound Ia are prepared with the composition shown in Table 2 below (containing the composition of Opadry). ® II White 85F18422 is made with an outer film coating, wherein the outer film coating provides a 3% weight increase based on the uncoated tablet.

[0338] Table 2. Composition of 300mg fixed-dose SDD tablets

[0339] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Every reference cited in this application, including all patents, patent applications, and publications, is incorporated herein by reference in its entirety.

Claims

1. A method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Orally administer to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period, and The compound of formula Ia or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

2. A method for treating or preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Orally administer to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; When the patient misses the maintenance dose, the method further includes orally administering about 200 mg to about 700 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting the administration of the one or more maintenance doses about 1 day to about 7 days after the oral administration during the third time period.

3. A method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Orally administer to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; The method described includes pre-exposure prophylaxis (PrEP).

4. A method for preventing human immunodeficiency virus (HIV) infection in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) administering orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 500 mg to about 700 mg, for a first time period; and (ii) Orally administer to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 200 mg to about 400 mg, for a second time period, wherein the second time period occurs after the first time period; When the patient misses a maintenance dose, the method further includes orally administering about 200 mg to about 700 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period; and The method described includes pre-exposure prophylaxis (PrEP).

5. The method according to any one of claims 1 to 4, wherein the initial dose comprises orally administering about 600 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for the first time period.

6. The method of claim 5, wherein the initial dose is administered in one or more tablets over the first time period, each of the one or more tablets containing about 300 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the first time period is about one day to about two days.

8. The method according to any one of claims 1 to 6, wherein the first time period is two days.

9. The method according to any one of claims 1 to 8, wherein each of the one or more maintenance doses comprises orally administering about 300 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for the second time period.

10. The method of claim 9, wherein the one or more maintenance doses are each administered as a tablet comprising about 300 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof for the second time period.

11. The method according to any one of claims 1 to 10, wherein the second time period begins about six to about eight days after the first oral administration of the starting dose.

12. The method according to any one of claims 1 to 10, wherein the second time period begins approximately seven days after the first oral administration of the starting dose.

13. The method according to any one of claims 1 to 12, wherein the second time period comprises continuously administering the one or more maintenance doses throughout the patient's life.

14. The method according to any one of claims 2 and 4 to 13, wherein the third time period begins about one day to about fourteen days after the patient first misses the maintenance dose.

15. The method according to any one of claims 2 and 4 to 14, wherein when the patient misses the maintenance dose, the method further comprises orally administering to the patient about 300 mg to about 600 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof for a third time period, and restarting administration of the one or more maintenance doses about 1 day to about 7 days after the oral administration during the third time period.

16. The method according to any one of claims 2 and 4 to 14, wherein when the patient misses the maintenance dose, the method further comprises orally administering to the patient about 300 mg or about 600 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

17. The method according to any one of claims 2 to 14, wherein when the patient misses one or two maintenance doses, the method further comprises orally administering to the patient about 300 mg or about 600 mg of a compound of formula Ia or a pharmaceutically acceptable salt thereof for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

18. The method according to any one of claims 2 and 4 to 14, wherein when the patient misses a maintenance dose, the method further comprises orally administering about 300 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

19. The method according to any one of claims 2 to 14, wherein when the patient misses two consecutive maintenance doses, the method further comprises orally administering about 600 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient for a third time period, and restarting administration of the one or more maintenance doses for about 1 day to about 7 days after the oral administration during the third time period.

20. The method according to any one of claims 2 and 4 to 19, wherein the third time period is about one day to about two days.

21. The method according to any one of claims 2 and 4 to 19, wherein the third time period is one day.

22. A method of treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once weekly, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg. The compound of formula Ia or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

23. A method of treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once a week, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering about 300 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

24. A method of treating or preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once a week, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering about 600 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the second maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period.

25. A method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once a week, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg; The method described includes pre-exposure prophylaxis (PrEP).

26. A method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once a week, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg; When the patient misses the maintenance dose, the method further includes orally administering about 300 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the maintenance dose, the third time period being about one day to about fourteen days, and restarting the administration of the one or more maintenance doses about one day to about seven days after the oral administration during the third time period; and The method described includes pre-exposure prophylaxis (PrEP).

27. A method for preventing HIV in a patient, the method comprising administering a compound of formula Ia to the patient: Ia Or a pharmaceutically acceptable salt thereof, the method comprising: (i) Administer orally to the patient a compound of formula Ia or a pharmaceutically acceptable salt thereof, comprising an initial dose of about 600 mg, for up to two days; as well as (ii) Once a week, administer orally to the patient one or more maintenance doses of a compound of formula Ia or a pharmaceutically acceptable salt thereof, each comprising about 300 mg; When the patient misses two consecutive maintenance doses, the method further includes orally administering approximately 600 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient during a third time period after the patient first misses the second maintenance dose, the third time period being approximately one day to approximately fourteen days, and restarting administration of the one or more maintenance doses approximately one day to approximately seven days after the oral administration during the third time period; and The method described includes pre-exposure prophylaxis (PrEP).

28. The method according to any one of claims 1 to 27, wherein the compound of formula Ia is applied as a sodium salt.

29. The method according to any one of claims 1 to 28, wherein each oral administration is administered as a tablet comprising a sodium salt of a compound of formula Ia.

30. The method of claim 29, wherein each tablet is prepared by spray drying dispersion technology.

31. The method of claim 29 or 30, wherein each tablet comprises about 5 w / w% to about 45 w / w% of the sodium salt of the compound of formula Ia, about 1 w / w% to about 10 w / w% of copovidone, about 0.01 w / w% to about 10 w / w% of poloxamer 407, about 5 w / w% to about 45 w / w% of microcrystalline cellulose, about 15 w / w% to about 70 w / w% of mannitol, about 1 w / w% to about 30 w / w% of croscarmellose sodium, and about 0.01 w / w% to about 10 w / w% of magnesium stearate, and one or more pharmaceutically acceptable excipients.

32. The method of claim 29 or 30, wherein each tablet comprises about 15 w / w% to about 25 w / w% of the sodium salt of the compound of formula Ia, about 3 w / w% to about 6 w / w% of copovidone, about 0.5 w / w% to about 3.0 w / w% of poloxamer 407, about 18 w / w% to about 30 w / w% of microcrystalline cellulose, about 40 w / w% to about 50 w / w% of mannitol, about 6 w / w% to about 10 w / w% of croscarmellose sodium, and about 1.0 w / w% to about 3.0 w / w% of magnesium stearate.

33. The method according to any one of claims 29 to 32, wherein each tablet contains about 300 mg of the compound of formula Ia or a pharmaceutically acceptable salt thereof.

34. The method according to any one of claims 29 to 32, wherein each tablet contains about 306.8 mg of the sodium salt of the compound of formula Ia.

35. The method according to any one of claims 29 to 34, wherein each tablet further comprises an outer film coating.

36. The method of claim 35, wherein, based on the uncoated tablet, the outer film coating provides a weight gain of about 1% to about 8%.

37. The method of claim 35, wherein the outer film coating provides approximately 4% weight gain based on the uncoated tablet.

38. The method according to any one of claims 2 to 21 and 23 to 37, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

39. The method according to any one of claims 1 to 38, wherein the method comprises administering a compound of formula Ia or a pharmaceutically acceptable salt thereof to the patient in an event-driven manner.

40. The method according to any one of claims 1 to 39, wherein the method includes post-exposure prophylaxis (PEP).

41. The method according to any one of claims 1, 2, 5 to 24 and 28 to 40, wherein the method comprises pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).

42. The method according to any one of claims 1 to 41, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered to the patient prior to exposure to the HIV.

43. The method according to any one of claims 1 to 42, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered once daily for about 14 days to about once daily before the patient is exposed to the HIV.

44. The method according to any one of claims 1 to 42, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered once approximately 10 days to approximately 5 days before the patient is exposed to the HIV.

45. The method according to any one of claims 1 to 42, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered once approximately 7 days before the patient is exposed to the HIV.

46. ​​The method according to any one of claims 1 to 42, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered once approximately 72 hours to approximately 1 hour before the patient is exposed to the HIV.

47. The method according to any one of claims 2 and 4 to 47, wherein the pre-exposure prophylaxis (PrEP) comprises continuous PrEP.

48. The method according to any one of claims 1 to 47, the method comprising administering a compound of formula Ia or a pharmaceutically acceptable salt thereof during the period during which the patient is exposed to the HIV.

49. The method according to any one of claims 1 to 48, the method comprising administering a compound of formula Ia or a pharmaceutically acceptable salt thereof after the patient has been finally exposed to the HIV.

50. The method according to any one of claims 1 to 49, wherein the patient is a patient who has undergone intensive treatment.

51. The method of claim 50, wherein the HIV infection is characterized by HIV-1 infection with resistance to one or more antiretroviral drugs.

52. The method of claim 50, wherein the HIV infection is characterized by HIV-1 infection with resistance to two or more antiretroviral drugs in an HIV-1 mutant.

53. The method of claim 50, wherein the HIV infection is characterized by HIV-1 infection with resistance to three or more antiretroviral drugs in an HIV-1 mutant.

54. The method according to any one of claims 50 to 53, wherein the HIV-1 mutant is resistant to protease inhibitors (PI), nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTI), or integrase strand transfer inhibitors (INSTI).

55. The method of claim 54, wherein the HIV-1 mutant is resistant to a protease inhibitor selected from I50V, I84V / L90M, G48V / V82A / L90M and G48V / V82S.

56. The method of claim 54, wherein the HIV-1 mutant is resistant to nucleoside or nucleotide reverse transcriptase inhibitors selected from K65R, M184V and 6TAM.

57. The method of claim 54, wherein the HIV-1 mutant is resistant to non-nucleoside or non-nucleotide reverse transcriptase inhibitors selected from K103N, Y181C, Y188L, L100I / K103N, and K103N / Y181C.

58. The method of claim 54, wherein the HIV-1 mutant is resistant to an integrase strand transfer inhibitor selected from Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R and R263K / M50I.

59. The method according to any one of claims 50 to 58, wherein the patient is infected with HIV-1 that is resistant to at least one antiretroviral drug.

60. The method according to any one of claims 50 to 59, wherein the patient is infected with multidrug-resistant HIV-1, the multidrug-resistant HIV-1 being resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

61. The method according to any one of claims 50 to 59, wherein the patient is infected with multidrug-resistant HIV-1, the multidrug-resistant HIV-1 being resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and integrase strand transfer inhibitors (INSTI).

62. The method according to claim 60 or 61, wherein the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI).

63. The method according to any one of claims 54 to 62, wherein the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), doxorinosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (deoxycytidine, ddC), and abacavir.

64. The method according to any one of claims 54 to 63, wherein the NNRTI is selected from efavirenz, ectavirin, rilpivirine, nevirapine, and delavudine.

65. The method according to any one of claims 54 to 64, wherein the PI is selected from ampravir, atazanavir, drenavirvir, fosanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and telanavir.

66. The method according to any one of claims 54 to 65, wherein the INSTI is selected from Retegwer, Ertiravir, Durutvir, Cabotevir, and Bicagwer.

67. The method according to any one of claims 50 to 66, wherein the patient has previously been treated with at least one antiretroviral drug for at least 3 months.

68. The method according to any one of claims 50 to 66, wherein the patient has previously been treated with at least one antiretroviral drug for at least 6 months.

69. The method according to any one of claims 50 to 66, wherein the patient has previously been treated with at least one antiretroviral drug for at least 9 months.

70. The method according to any one of claims 50 to 66, wherein the patient has previously been treated with at least one antiretroviral drug for at least 12 months.

71. The method according to any one of claims 50 to 70, wherein the patient has not undergone a prior HIV treatment regimen that includes administration of at least one antiretroviral drug.

72. The method according to any one of claims 67 to 71, wherein the prior treatment regimen comprises administering at least one antiretroviral drug from each of two different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

73. The method according to any one of claims 67 to 71, wherein the prior treatment regimen comprises administering at least one antiretroviral drug from each of three different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

74. The method according to claim 72 or 73, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs).

75. The method according to any one of claims 1 to 74, wherein the patient has not undergone an HIV treatment regimen comprising the administration of at least one antiretroviral drug when initiating administration of a compound of formula Ia or a pharmaceutically acceptable salt thereof.

76. The method according to any one of claims 1 to 75, wherein administration of the compound of formula Ia or a pharmaceutically acceptable salt thereof results in a reduction of viral load in the patient.

77. The method according to any one of claims 1 to 37 and 39 to 76, wherein the method further comprises administering one, two, three or four additional therapeutic agents to the patient.

78. The method of claim 77, wherein the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectious agent inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing the COMM domain, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3 non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

79. The method according to claim 77 or 78, wherein the additional therapeutic agent is selected from the group consisting of: HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for the treatment of HIV or any combination thereof.

80. The method according to any one of claims 77 to 79, wherein the additional therapeutic agent is selected from the group consisting of: bicagvir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide fumarate.

81. The method according to any one of claims 77 to 80, wherein the additional therapeutic agent is selected from the group consisting of: bicagvir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.

82. The method according to any one of claims 77 to 81, wherein the additional therapeutic agent is administered simultaneously with a compound of formula Ia or a pharmaceutically acceptable salt thereof.

83. The method according to any one of claims 77 to 82, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is combined with the additional therapeutic agent in a single dosage form for simultaneous administration.

84. The method according to any one of claims 77 to 81, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is administered sequentially with the additional therapeutic agent.

85. The method according to any one of claims 1 to 84, wherein the compound of formula Ia or a pharmaceutically acceptable salt thereof is a compound of formula Ib: Ib Or their pharmaceutically acceptable salts.

86. The method of claim 85, wherein the compound of formula Ib is administered as the sodium salt.

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