Combination therapy for treating HIV

Abstract

This disclosure relates generally to drug combinations for use in the treatment of a Retroviridae viral infection, including an infection caused by the human immunodeficiency virus (HIV).

Description

[0001] COMBINATION THERAPY FOR TREATING HIV

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U. S. Provisional Application No. 63 / 761,648, filed February 21, 2025, the entire contents of which is hereby incorporated by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] This disclosure relates generally to combinations for use in the treatment of a Retroviridae viral infection, including an infection caused by the human immunodeficiency virus (HIV). This disclosure also relates to pharmaceutical compositions comprising said combinations.

[0006] BACKGROUND

[0007] Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human and animal diseases. Among the Lentivirus, HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. Treating HIV-1 infections with highly active antiretroviral therapies (HAART) has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570). However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B„ International Journal of Infectious Diseases 2009, 13:552-559; Smith, R.., et al., Science 2010, 327:697-701). Therefore, there is a pressing need to discover new antiretroviral agents that are active against emerging drag-resistant HIV variants.

[0008] Also of interest in the area of HIV therapies and treatments is providing regimens to patients with improved pharmacokinetic properties, including, for example, increased potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties. While current regimens for treating HIV have progressed enough that patients no longer have to take multiple pills multiple times a day, patients today still are required to take a pill every day for the foreseeable span of their life. Thus, it would be beneficial to have HIV therapies that require patients take medication less than once a day (e.g. once every couple of days, once a week, onceevery other week, once a month, and so forth) or take a smaller effective dose of the medication(s) on a daily, weekly, monthly, or longer basis.

[0009] SUMMARY

[0010] The present application provides, inter alia, a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0011] (a) a compound of Formula la:

[0012]

[0013] la

[0014] or a pharmaceutically acceptable salt thereof; and

[0015] (b) a compound of Formula II:

[0016]

[0017] II

[0018] or a pharmaceutically acceptable salt thereof.The present application further provides a compound of Formula la, or a pharmaceutically acceptable salt thereof, and a compound of Formula II, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0019] The present application further provides a compound of Formula la, or a pharmaceutically acceptable salt thereof, and a compound of Formula II, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0020] DESCRIPTION OF DRAWINGS FIG. 1 shows lenacapavir plasma concentration (nM) in male beagle dogs (n = 3) following an oral dose of lenacapavir at 40 mg fixed dose, with and without encequidar.

[0021] FIG. 2 shows lenacapavir %F improvement in male beagle dogs following an oral dose of lenacapavir at 40 mg fixed dose with encequidar compared to administration without encequidar.

[0022] FIG. 3 shows lenacapavir %F (z.e., bioavailability) improvement in male beagle dogs following an oral dose of (2-(2-(4-(N-(4-chloro-7-(2-((S)-l-(2-((3bS,4a / ?)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-l / 7-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)methylsulfonamido)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetyl)-L-aspartic acid (z'.e., Compound 1) at 350 mg fixed dose with encequidar compared to administration without encequidar.

[0023] FIG. 4 shows plasma pharmacokinetic (PK) profiles of encequidar following intravenous (IV) and oral (PO) administration in non-clinical species (monkey, dog, and rat). Plasma concentration-time profiles are shown for IV administration at 1 mg / kg (blue circles) and PO administration at 10 mg / kg (red squares).

[0024] FIG. 5 shows pharmacokinetic (PK) profiles of orally administered digoxin (5 mg / kg) and paclitaxel (5 mg / kg) in Sprague-Dawley rats, paclitaxel (5 mg / kg) in beagle dogs, and talinolol (1 mg / kg) in cynomolgus monkeys with and without efflux inhibitors. Encequidar (5 mg / kg, red squares) and elacridar (10 mg / kg, green triangles) were co-administered orally to evaluate their effects on substrate plasma concentrations.

[0025] FIG. 6 shows pharmacokinetic (PK) profiles of single-dose intravenous (IV) administration of apixaban (0.33 mg / kg), talinolol (0.33 mg / kg), and lenacapavir (0.33 mg / kg) inbeagle dogs, and paclitaxel (1 mg / kg) in Sprague-Dawley rats. Plasma concentration-time curves are shown with) and without co-administration of the P-gp inhibitors (5 mg / kg PO).

[0026] FIG. 7 shows improvement in bioavailability of lenacapavir in pentagastrin pretreated dogs upon administration of Compound 1, 350 mg fixed PO and solution vehicle.

[0027] DETAILED DESCRIPTION

[0028] The present application provides, inter alia, a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient an HIV capsid inhibitor in combination with a P-glycoprotein inhibitor (PGP) inhibitor. In some embodiments, the HIV is HIV-1.

[0029] In some embodiments, the present disclosure provides a combination of an HIV capsid inhibitor provided herein (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), and a PGP inhibitor (e.g., a compound of Formula II, or a pharmaceutically acceptable salt thereof), or a combination of pharmaceutical compositions each comprising an active agent (z. e., an HIV capsid inhibitor and / or a PGP inhibitor), or a pharmaceutically acceptable salt thereof, provided herein for use in a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, the method comprising administering to the patient the combination of compounds or compositions provided herein.

[0030] In some embodiments, the present disclosure provides a combination of an HIV capsid inhibitor provided herein (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), and a PGP inhibitor (e.g., a compound of Formula II, or a pharmaceutically acceptable salt thereof), or a combination of pharmaceutical compositions each comprising an active agent (z.e., an HIV capsid inhibitor and / or a PGP inhibitor), or a pharmaceutically acceptable salt thereof, provided herein for use in a method of treating a human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient the combination of compounds or compositions provided herein.

[0031] Co-administration includes administration of unit dosages of the compounds provided herein, or pharmaceutically acceptable salts thereof, before or after administration of unit dosages of one or more additional therapeutic agents. For example, one compound provided herein, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be administered within seconds, minutes, or hours of the administration of a second compound provided herein, such as a compound of Formula II, or a pharmaceutically acceptable salt thereof.In some embodiments, a unit dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered first, followed within seconds or minutes by administration of a unit dose of a compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dose of a compound of Formula II, or a pharmaceutically acceptable salt thereof, is administered first, followed within seconds or minutes by administration of a unit dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, a unit dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered first, followed within minutes or hours (e.g., about 1 to about 12 hours) by administration of a unit dose of a compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dose of a compound of Formula II, or a pharmaceutically acceptable salt thereof, is administered first, followed within minutes or hours (e.g., about 1 to about 12 hours) by administration of a unit dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0033] The methods provided herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound as disclosed herein for a given cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.HIV Capsid Inhibitors

[0034] In some embodiments, the HIV capsid inhibitor is a compound of Formula I:

[0035] F F

[0036] y-F

[0037]

[0038] I

[0039] or a pharmaceutically acceptable salt thereof, wherein:

[0040] Z1is II or C(O)X;

[0041]

[0042] X is -NR1R2, Ci-io alkyl, or C2-6 alkenyl,

[0043] wherein the C1-10 alkyl and C2-6 alkenyl are each independently substituted with 1-3 Y groups;

[0044] each Y independently is -B(0H)2, -CN, halogen, Ra, Rb, Rc, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused bicyclic heteroaryl, wherein the phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl are each independently substituted with 1-5 R3groups, or

[0045] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl;

[0046] R1is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc;

[0047] R2is phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl and 5-6 membered monocyclic heteroaryl are each independently optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, Rc, and Cue alkyl,

[0048] wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc; each R3independently is Ra, Rb, Rc, C1-6 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the C1-6 alkyl and 5-6 membered monocyclic heteroaryl are eachindependently optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc;

[0049] each Raindependently is -P(O)(OH)2 or -OP(O)(OH)2;

[0050] each Rbindependently is -C(O)R4, -C(O)NR5R5, -C(O)C(O)OR4,

[0051] -S(O)2R4, -S(O)2NR5R5, or -S(O)2OR4;

[0052] each Rcindependently is -OR4, -OC(O)R4, -OC(O)C(O)OR4, -(O(Ci-4 alkyl))nOR4, - NR5R5, -N+R5R5R5a, -NR5C(O)R4, -NR5C(O)NR5R5,

[0053] -NR5C(O)OR4, -NR5C(O)C(O)OR4, or -NR5S(O)2R4;

[0054] each R4independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rd, and Re; each R5independently is H, Rd, Ci-6 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, naphthalenyl, and 8-10 membered fused bicyclic heteroaryl,

[0055] wherein the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rd, and Re; each R5aindependently is H or C1-3 alkyl;

[0056] each Rdindependently is -C(O)R6, -C(O)OR6, -C(O)NR7R7, -C(O)C(O)OR6, -S(O)2R6, -S(O)2NR7R7, or -S(O)2OR6;

[0057] each Reindependently is -OR6, -OC(O)R6, -OC(O)C(O)OR6, -NR7R7, -NR7C(O)R7, - NR7C(O)NR7R7, -NR7C(O)OR6, -NR7C(O)C(O)OR6, or

[0058] -NR7S(O)2R6;

[0059] each R6independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from CN, halogen, Ra, Rf, and Rg; each R7independently is II, Rf, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rf, and Rg;

[0060] each Rfindependently is -C(O)R8, -C(O)OR8, -C(O)NR8R8, -C(O)C(O)OR8, -S(O)2R8, -S(O)2NR8R8, or -S(O)2OR8;

[0061] each Rgindependently is -OR8, -OC(O)R8, -OC(O)C(O)OR8, -NR8R8, -NR8C(O)R8, -NR8C(O)NR8R8, -NR8C(O)OR8, -NR8C(O)C(O)OR8, or -NR8S(O)2R8;

[0062] each R8independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substitutedwith 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and Ra;

[0063] n is 1, 2, 3, 4, or 5; and

[0064] wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S.

[0065] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0066] Z1is H or C(O)X;

[0067] X is -NRXR2, Ci-io alkyl, or C2-6 alkenyl,

[0068] wherein the CMO alkyl and C2-6 alkenyl are each independently substituted with 1-3 Y groups;

[0069] each Y independently is -CN, halogen, Ra, Rb, Rc, C3-5 monocyclic cycloalkyl, phenyl, or naphthalenyl,

[0070] wherein the phenyl and naphthalenyl are each independently substituted with 1 -5 R3groups, or

[0071] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl;

[0072] R1is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0073] R2is phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl and 5-6 membered monocyclic heteroaryl are each independently optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, Rc, and C1-6 alkyl;

[0074] wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc; each R3independently is Ra, Rb, Rc, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc;

[0075] each Raindependently is -P(O)(OH)2 or -OP(O)(OH)2;

[0076] each Rbindependently is -C(O)R4, -C(O)NR5R5, -C(O)C(O)OR4, -S(O)2R4, - S(O)2NR5R5, or -S(O)2OR4;

[0077] each Rcindependently is -OR4, -OC(O)R4, -OC(O)C(O)OR4, -(0(Cu alkyl))nOR4, - NR5R5, -N+R5R5R5a, -NR5C(O)R4, -NR5C(O)NR5R5, -NR5C(O)OR4, -NR5C(O)C(O)OR4, or -NR5S(O)2R4;

[0078] each R4independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rd, and Re; each R5independently is H, Rd, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, and naphthalenyl;

[0079] each R5aindependently is H or C1-3 alkyl;

[0080] each Rdindependently is -C(O)R6, -C(O)OR6, -C(O)NR7R7, -C(O)C(O)OR6, -S(O)2R6, - S(O)2NR7R7, or -S(O)2OR6:

[0081] each Reindependently is -OR6, -OC(O)R6, -OC(O)C(O)OR6, -NR7R7, -NR7C(O)R7, - NR7C(O)NR7R7, -NR7C(O)OR6, -NR7C(O)C(O)OR6, or -NR7S(O)2R6; each R6independently is II or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and Ra;

[0082] each R7independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0083] n is 1, 2, 3, 4, or 5; and

[0084] wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S.

[0085] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0086] Z1is H or C(O)X;

[0087] X is -NR1R2, Ci-10 alkyl, or C2-4 alkenyl,

[0088] wherein the C1-10 alkyl and C2-4 alkenyl are each independently substituted with 1-3 Y groups;

[0089] each Y independently is -OH, -CN, halogen, Ra, -NR5R5, -N+R5R5R5a, -C(O)NR5R5, - C(O)OR4, -OC(O)R4, -(O(Ci-4alkyl))nOR4, or phenyl,

[0090] wherein the phenyl is substituted with 1-5 R3groups, or

[0091] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl;

[0092] R1is H or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groupsindependently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0093] R2is phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl and 5-6 membered monocyclic hctcroaryl arc each independently optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, Ra, and Ci-6 alkyl,

[0094] wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR5R5, and Ra;

[0095] each R3independently is -OH, Ra, Rb, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, Ra, and Rb;

[0096] each Raindependently is -P(O)(OII)2 or -OP(O)(OII)2;

[0097] each Rbindependently is -C(O)NR5R5;

[0098] each R4independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR7R7, and Ra;

[0099] each R5independently is H, -C(O)OR6, -C(O)C(O)OR6, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR6, =NR5a, -NR7R7, Ra, Rb, and phenyl;

[0100] each R5aindependently is H or C1-3 alkyl;

[0101] each R6independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and Ra;

[0102] each R7independently is H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0103] n is 1, 2, 3, 4, or 5; and

[0104] wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S.

[0105] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0106] Z1is H or C(O)X;X is -NR1R2, Ci-io alkyl, or C2-4 alkenyl,

[0107] wherein the C1-10 alkyl and C2-4 alkenyl are each independently substituted with 1-3 Y groups;

[0108] each Y independently is -OH, -CN, halogen, Ra, -NR5R5, -N+R5R5R5a, -C(O)NR5R5, - C(O)OR4, -OC(O)R4, -(O(Ci-4 alkyl))nOR4, C3-5 monocyclic cycloalkyl, or phenyl,

[0109] wherein the phenyl is substituted with 1-5 R3groups, or two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl;

[0110] R1is H or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0111] R2is phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl and 5-6 membered monocyclic heteroaryl are each independently optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, Ra, and C1-6 alkyl,

[0112] wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR5R5, and Ra;

[0113] each R3independently is -OH, -C(O)OH, Ra, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra;

[0114] each Raindependently is -P(O)(OH)2 or -OP(O)(OH)2;

[0115] each R4independently is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, - NR7R7, and Ra;

[0116] each R5independently is H, -C(O)OR6, -C(O)C(O)OR6, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR6, =NR5a, -NR7R7, Ra, and phenyl;

[0117] each R5aindependently is H or C1-3 alkyl;

[0118] each R6independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and Ra;

[0119] each R7independently is H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substitutedwith 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra;

[0120] n is 1, 2, 3, 4, or 5; and

[0121] wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently have 1-4 ring heteroatoms independently selected from N, O, and S.

[0122] As used herein, a 5-6 membered monocyclic heteroaryl has 1-4 ring heteroatoms independently selected from N, O, and S. As used herein, a 8-10 membered fused bicyclic heteroaryl has 1-4 ring heteroatoms independently selected from N, O, and S.

[0123] In some embodiments, Z1is H. In some embodiments, Z1is C(O)X.

[0124] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci -io alkyl, wherein the Ci-io alkyl is substituted with 1-3 Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-io alkyl, wherein the Ci-io alkyl is substituted with two Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci -io alkyl, wherein the Ci-io alkyl is substituted with one Y group. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-s alkyl, wherein the Ci-s alkyl is substituted with 1-3 Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-s alkyl, wherein the Ci-s alkyl is substituted with 1-2 Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-s alkyl, wherein the Ci-s alkyl is substituted with three Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-s alkyl, wherein the Ci-s alkyl is substituted with two Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-s alkyl, wherein the Ci-s alkyl is substituted with one Y group. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-3 Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-2 Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with three Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z1is C(O)X; and X is C1-6 alkyl, wherein the C1-6 alkyl is substituted with two Y groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X is C1-6 alkyl, wherein the C1-6 alkyl is substituted with one Y group.

[0125] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X substituted with Y is -CH2Y, -CH2CH2Y, -CH2CH2CH2Y, -CH2CH2CH2CH2Y,

[0126] Y

[0127]

[0128] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X substituted with Y is

[0129]

[0130] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1is C(O)X; and X substituted with Y is

[0131] ,r

[0132] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0133] each Y independently is -B(OH)2, -CN, halogen, Ra, Rb, Rc, phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused bicyclic heteroaryl, wherein the phenyl, naphthalenyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered fused bicyclic heteroaryl are each independently substituted with 1-5 R3groups, or

[0134] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl.

[0135] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0136] each Y independently is -CN, halogen, Ra, Rb, Rc, phenyl, or naphthalenyl, wherein the phenyl and naphthalenyl are each independently substituted with 1-5 R3groups,or

[0137] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl.

[0138] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0139] each Y independently is -OH, -CN, halogen, Ra, -NR5R5, -N+R5R5R5a, -C(O)NR5R5, - C(O)OR4, -OC(O)R4, -(O(Ci-4 alkyl))nOR4, or phenyl, wherein the phenyl is substituted with 1-5 R3groups, or

[0140] two Y groups on the same carbon, together with the carbon to which they are attached, form a C3-5 monocyclic cycloalkyl.

[0141] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more Y is phenyl, wherein the phenyl is substituted with 1-5 R3groups.

[0142] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one Y is phenyl, wherein the phenyl is substituted with 1-5 R3groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one Y is phenyl, wherein the phenyl is substituted with 1-3 R3groups. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one Y is phenyl, wherein the phenyl is substituted with three R3groups.

[0143] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is Ra, Rb, Rc, C1-6 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the Ci-6 alkyl and 5-6 membered monocyclic heteroaryl are each independently optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is Ra, Rb, Rc, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is -C(O)NR5R5, -S(O)2R4, -S(O)2NR5R5, -S(O)2OR4, -NR5C(O)R4, -NR5C(O)NR5R5, -NR5S(O)2R4, Ra, or C1-6 alkyl, wherein the Cue alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)NR5R5, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is -OH, -C(O)OH, Ra, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra. In some embodiments of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R3independently is -OH, -C(O)NR5R:’, Ra, or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)NR5R5, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is -OH, Ra, or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is -OH, -C(O)NR5R5, Ra, methyl, -CH2?(O)(OH)2, or -CH2C(O)NR5R5. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is -OH, Ra, methyl, or -CH2P(O)(OH)2.

[0144] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is Ra.

[0145] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)NR5R3, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra.

[0146] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-6 alkyl, wherein the C1-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)NR5R5, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-3 alkyl, wherein the C1-3 alkyl is substituted with 1-3 groups independentlyselected from -OH, -CN, halogen, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is -CH2P(O)(OH)2.

[0147] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is Ci-6 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is C1-3 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R3is methyl.

[0148] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R3is -OP(O)(OH)2 and 1-2 R3is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -C(O)NR5R5, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R3is -OP(O)(OII)2 and 1-2 R3is C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R3is -OP(O)(OH)2, one R3is unsubstituted C1-3 alkyl, and one R3is C1-3 alkyl, wherein the C1-3 alkyl is substituted with 1-3 Ra.

[0149] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one Y is phenyl, wherein the phenyl is substituted with methyl, -OP(O)(OH)2, and -CH2P(O)(OH)2.

[0150] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one Y is phenyl, wherein the phenyl is substituted with methyl, -OP(O)(OH)2, and -CH2C(O)NH(CH(COOH)CH2C(O)OH).

[0151] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each Raindependently is -P(O)(OH)2or -OP(O)(OH)2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more Rais -P(O)(OII)2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more Rais -OP(O)(OH)2.

[0152] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each Rbindependently is -C(O)R4, -C(O)NR5R5, -C(O)C(O)OR4, -S(O)2R4, -S(O)2NR:’R5, or -S(O)2OR4. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more Rbis -C(O)NR’R5.

[0153] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R independently is H, Rd, C1-6 alkyl, or 5-6 membered monocyclic heteroaryl, wherein the C1-6 alkyl is optionally substituted with 1-3 groups independently selectedfrom -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, naphthalenyl, and 8-10 membered fused bicyclic heteroaryl,

[0154] wherein the 5-6 membered monocyclic hctcroaryl is optionally substituted with 1-3 groups independently selected from -CN, halogen, Ra, Rd, and Re.

[0155] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R3independently is H, Rd, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, and naphthalenyl.

[0156] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R" independently is H, -C(O)OR6, -C(O)C(O)OR6, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR6, =NR5a, -NR7R7, Ra, and phenyl.

[0157] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R5independently is H, -C(O)OR6, -C(O)C(O)OR6, or Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with 1-2 groups independently selected from -C(O)OH, -C(O)NH2, =NR5a, -NR7R7, Ra, and phenyl.

[0158] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R5independently is H, -C(O)OR6, -C(O)C(O)OR6, or Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with 1-2 groups independently selected from -C(O)OH, =NR5a, -NR7R7, Ra, and phenyl.

[0159] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R5independently is H, methyl, -CH2CO2H, -CH2P(O)(OH)2, -CH2CH2CO2H, -C(O)OCH3, -C(=NH)NH2, -C(O)C(O)OH,

[0160]

[0161] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R5independently is H, methyl, -CH2CO2H, -CH2CH2CO2H, -C(O)OCH3, -C(=NII)NII2, -C(O)C(O)OII,

[0162]

[0163] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is H.

[0164] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, naphthalenyl, and 8-10 membered fused bicyclic heteroaryl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, and naphthalenyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR6, =NR5a, -NR7R7, Ra, and phenyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with 1-2 groups independently selected from -C(O)OH, =NR5a, -NR7R7, Ra, and phenyl.

[0165] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, naphthalenyl, and 8-10 membered fused bicyclic heteroaryl. In some embodiments of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, one or more R3is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-3 groups independently selected from -CN, halogen, =NR5a, Ra, Rd, Re, phenyl, and naphthalenyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-6 alkyl, wherein the Ci-6 alkyl is substituted with 1-3 groups independently selected from -OH, -CN, halogen, -C(O)OR6, =NR5a, -NR7R7, Ra, and phenyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R5is Ci-4 alkyl, wherein the Ci-4 alkyl is substituted with 1-2 groups independently selected from -C(O)OH, =NR5a, -NR7R7, Ra, and phenyl.

[0166] In some embodiments of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, one R3is

[0167] OH

[0168]

[0169] O

[0170] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one R5is

[0171]

[0172] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each Rdindependently is -C(O)R6, -C(O)OR6, -C(O)NR7R7, -C(O)C(O)OR6, -S(O)2R6, -S(O)2NR7R7, or -S(O)2OR6. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more Rdis -C(O)OR6.

[0173] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R6independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from CN, halogen, Ra, Rf, and Rg. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R6independently is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, CN, halogen, -C(O)OH, and Ra. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R6is H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-2 Ragroups.

[0174] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one or more R6is H.In some embodiments, the compound of Formula l is a compound of Formula la:

[0175]

[0176] or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the compound of Formula I is a compound of Formula lb:

[0178]

[0179] or a pharmaceutically acceptable salt thereof.

[0180] The compound of Formula lb may also be referred to as “Compound 1” or (2-(2-(4-(N-(4-chloro-7-(2-((S)-l-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-l -yn- 1 -yl)pyridin-3-yl)- 1 -(2,2,2-trifhioroethyl)- lH-indazol-3-yl)methylsulfonamido)-2-methyl-4-oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetyl)-L-aspartic acid. Synthesis and characterization of the compounds of Formula la and lb can befound, for example, in U. S. Patent No.: 11,787,825, and U. S. Publication No.: 20240132527, the disclosures of which are incorporated herein by reference in their entireties.

[0181] In some embodiments, the compound of Formula l is a compound of Formula Illa:

[0182]

[0183] or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the compound of Formula I is a compound of Formula Illb:

[0185] F,,F

[0186]

[0187] nib

[0188] or a pharmaceutically acceptable salt thereof.

[0189] The compound of Formula Illb may also be referred to as lenacapavir (or LEN) or N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide. Synthesis and characterization of the compounds of Formula Illa and Formula Illb, and salts thereof, are described, for example, in US 20180051005 and US 20190300505, the contents of each of which are hereby incorporated by reference in their entireties. Various forms and / or uses of the compounds of Formula la andIb are disclosed, for example, in US 20190083478, US 20190084963, US 20200038389A1, and US 20210188815, the contents of each of which are hereby incorporated by reference in their entireties.

[0190] In some embodiments, the compound of Formula I is a compound of Formula Va:

[0191] OH

[0192]

[0193] or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound of Formula I is a compound of Formula Vb:

[0195]

[0196] or a pharmaceutically acceptable salt thereof. Synthesis and characterization of the compound of Formula Va and Vb can be found, for example, in U. S. Patent No.: 11,787,825, and U. S.

[0197] Publication No.: 20240132527, the disclosures of which are incorporated herein by reference in their entireties.The compounds of Formulas la, lb, Va, and Vb convert to lenacapavir (i.e., N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide), an HIV capsid inhibitor that is in development as a long-acting treatment for HIV, in the gastrointestinal tract when administered to a subject (e.g., a human patient).

[0198] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0199] As used in the present disclosure, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0200] A dash

[0201]

[0202] that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring (including a fused, bridged or spirocyclic ring system) indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example, Raain the below structure can be attached to any of the five carbon ring atoms or Raacan replace the hydrogen attached to the nitrogen ring atom:

[0203]

[0204] As another example, Raain the below structure:

[0205]

[0206] Raacan be attached to any of the numbered positions shown below:

[0207]

[0208] A solid line coming out of the center of a ring (including a fused, bridged, or spirocyclic ring system) indicates that the point of attachment for the ring system to the rest of the compound can be at any ring atom of the fused, bridged, or spirocyclic ring system. For example, in the below structure:

[0209]

[0210] the monocyclic heterocyclyl can be attached to the rest of the compound at any of the numbered positions shown below:

[0211]

[0212] As another example, in the below fused bicyclic heterocyclic structure,

[0213]

[0214] the fused bicyclic heterocyclyl can be attached to the rest of the compound at any of the eight numbered positions shown below:

[0215]

[0216] The prefix “Cu.v” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings, wherein x and y are numerical ranges, such as “3 to 12-memberedheterocyclyl”, refers to a ring containing x-y atoms (i.e., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0217] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, or alkylyl group, an “arylene” group or an “arylenyl” group, or arylyl group, respectively.

[0218] “A compound disclosed herein” or “a compound of the present disclosure” or “a compound provided herein” or “a compound described herein” refers to the compounds of Formula I. Also included are the specifically exemplified compounds of Formula I.

[0219] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X”.

[0220] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., Ci-s alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl), or 1 to 2 carbon atoms (i.e., C1-2 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CFE CFE), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CIECf^CIE ) and tert-butyl (i.e. - CIE ); and “propyl” includes n-propyl (i.e. -(CIE CIE) and isopropyl (i.e. -CII(CIl3)2).

[0221] “Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0222] “Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0223] “Alkylene” refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C1-20 alkylene), 1 to 12 carbon atoms (i.e., C1-12 alkylene), 1 to 8 carbon atoms (i.e., Ci-s alkylene), 1 to 6 carbon atoms (i.e., C1-6 alkylene), 1 to 4 carbon atoms (i.e., C1-4 alkylene), 1 to 3 carbon atoms (i.e., C1-3 alkylene), or 1 to 2 carbon atoms (i.e., C1-2 alkylene). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, an alkylene is optionally substituted with an alkyl group. Examples of substituted alkylene groups include -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, and

[0224] -CII2C(CIl2CII3)2.

[0225] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec -butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0226] “Acyl” refers to a group -C(=O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0227] “Amido” refers to both a “C-amido” group which refers to the group -C(=O)NRyRzand an “N-amido” group which refers to the group -NRyC(=O)Rz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0228] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0229] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., Ce-io aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl definedbelow. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.

[0230] “Cyano” or “carbonitrilc” refers to the group -CN.

[0231] “Cyeloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cyeloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cyeloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cyeloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cyeloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cyeloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cyeloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cyeloalkyl). Examples of cyeloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0232] “Bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0233] The term “fused” refers to a ring which is bound to an adjacent ring.

[0234] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1 -di ethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0235] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0236] “Heteroalkylene” refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., Ci -20 heteroalkylene); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-8 heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-6 heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-4 heteroalkylene); 1 to 3 carbonatoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heteroalkylene). For example, -CH2O- is a Ci heteroalkylene and -CH2SCH2- is a C2 heteroalkylene. Examples of heteroalkylene groups include -CH2CH2OCH2-, -CH2SCH2OCH2-, -CH2O-, and -CH2NHCH2-. In some embodiments, a heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH3)N(CH3)CH2-, -CH2OCH(CH3)-, -CH2CH(CH2CH3)S-,

[0237] -CH2NHC(CH3)2-, -C(CH3)2SCH2-, -CH(CH3)N(CH3)CH(CH3)O-, -CH2SC(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2NH-.

[0238] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C1-20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-s heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0239] “Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to a non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, “heterocyclyl” or “heterocyclic ring” or “heterocycle” refer to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to rings that are partially saturated where specified. The term “heterocyclyl” or “heterocyclic ring” or “heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond). A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C2.2o heterocyclyl), 2 to 12 carbon ring atoms (i.e., C2-12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2-10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2-s heterocyclyl), 3 to 12 carbon ring atoms (i.e., C3-i2heterocyclyl), 3 to 8 carbon ring atoms (i.e., C3-s heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl,piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term “bridged- heterocyclyl” refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclyl” includes bicyclic and tricyclic ring systems. Also as used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to ten-membered heterocyclyl. Examples of the spiro- heterocyclyl include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl. As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably. In some embodiments, a heterocyclyl is substituted with an oxo group.

[0240] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0241] “Oxo” refers to the group (=0) or (O).

[0242] “Sulfonyl” refers to the group -S(O)2Rbb, where Rbbis alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0243] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom(s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.

[0244] The terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0245] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl,heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0246] In some embodiments, a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and / or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and / or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the rest of the compound. For example, in the below moiety, the cyclopropyl is substituted with a methyl group:

[0247]

[0248] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( / ?)- or (5)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture’’ is a mixture of stereoisomers at a ratio other than 1:1.

[0249] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non- superimposable mirror images of one another.

[0250] " Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers at a ratio other than 1:1 is a “scalemic” mixture.

[0251] " Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0252] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.

[0253] Some of the compounds provided herein exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0254] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0255] Any formula or structure provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,13N,18F,31P,32P,35S,36Cl and125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as2H,3H,13C and14C are incorporated, are also provided herein. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0256] The present disclosure also includes compounds of Formula I, in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0257] Deuterium labelled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compounds provided herein (e.g., compounds of Formula I).

[0258] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unlessotherwise stated, when a position is designated specifically as " H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure, any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0259] As used herein, the term “consists essentially of” means that, in addition to the listed ingredients, specific further ingredients can be present that do not materially affect the basic and novel properties of the invention.

[0260] Kolliphor® HS-15 (CAS No. 70142-34-6) is a non-ionic solubilizer and emulsifying agent obtained by reacting 15 moles of ethylene oxide with 1 mole of 12-hydroxy stearic acid. Kolliphor® HS-15 consists of polyglycol mono- and di-esters of 12-hydroxystearic acid (= lipophilic part) and of about 30% of free polyethylene glycol (= hydrophilic part). Kolliphor® HS-15 is also known as Macrogol 15 Hydroxy stearate (Ph. Eur.), or Polyoxyl 15 Hydrostearate (USP / NF). Kolliphor® RH 40 is a non-ionic solubilizer and emulsifying agent obtained by reacting 1 mole of hydrogenated castor oil with 40 moles of ethylene oxide. The main constituent of Kolliphor® RH 40 is glycerol polyethylene glycol hydroxy-stearate, which, together with fatty acid glycerol polyglycol esters, forms the hydrophobic part of the product. The hydrophilic part consists of polyethylene glycols and glycerol ethoxylate. Kolliphor® RH 40 is also known as Macroglycerol Hydroxystearate (Ph. Eur.) or Polyoxyl 40 Hydrogenated Castor Oil (USP / NF).

[0261] P-glycoprotein (PGP) Inhibitors

[0262] In some embodiments, the P-glycoprotein (PGP) inhibitor provided herein is selected from verapamil, dexverapamil, cyclosporine, zosuquidar, laniquidar, elacridar, tariquidar, and encequidar.

[0263] In some embodiments, the PGP inhibitor is a compound of Formula II:

[0264]

[0265] II

[0266] or a pharmaceutically acceptable salt thereof. The compound of Formula II may also be referred to as encequidar (or ENC) or N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)-4-oxo-4H-chromene-2-carboxamide. In some embodiments, the PGP inhibitor is a pharmaceutically acceptable salt of encequidar. In some embodiments, the PGP inhibitor is a mesylate salt of encequidar.

[0267] Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. PGP inhibitors may therefore be useful to modulate the PK properties of HIV capsid inhibitors (z.e., compounds of Formula I) disclosed herein. In some embodiments, the use of a PGP inhibitor in combination with a compound of Formula I, or a pharmaceutically acceptable salt thereof, disclosed herein can modulate (e.g. increase) the PK properties of the compound of Formula I, such as AUC, Cmax, and oral bioavailability.

[0268] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to 4,000 mg of the PGP inhibitor, for example, about 2,000 to 4,000 mg, about 1 to 2,000 mg, about 1 to 1,000 mg, about 1 to 500 mg, about 10 to 500 mg, about 20 to 500 mg, about 1 to 300 mg, about 10 to 300 mg, about 20 to 300 mg, about 1 to 200 mg, about 10 to 200 mg, about 20 to 200 mg, about 1 to 100 mg, about 10 to 100 mg, about 20 to 100 mg, about 50 to 300 mg, about 75 to 200 mg, or about 15 to 150 mg of the PGP inhibitor.

[0269] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to about 50 mg of the PGP inhibitor.

[0270] In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 50 mg of the PGP inhibitor.

[0271] In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 30 mg of the PGP inhibitor.

[0272] In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 20 mg of the PGP inhibitor.

[0273] In some embodiments, the methods provided herein comprise administering to the subject about 14 mg to about 16 mg of the PGP inhibitor.

[0274] In some embodiments, the methods provided herein comprise administering to the subject about 15 mg of the PGP inhibitor.

[0275] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to 4,000 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof, for example, about 2,000 to 4,000 mg, about 1 to 2,000 mg, about 1 to1,000 mg, about 1 to 500 mg, about 10 to 500 mg, about 20 to 500 mg, about 1 to 300 mg, about 10 to 300 mg, about 20 to 300 mg, about 1 to 200 mg, about 10 to 200 mg, about 20 to 200 mg, about 1 to 100 mg, about 10 to 100 mg, about 20 to 100 mg, about 50 to 300 mg, about 75 to 200 mg, or about 15 to 150 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to about 50 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 50 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 30 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 25 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 25 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 20 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 20 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 19 mg to about 21 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 20 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 14 mg to about 16 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to about 50 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 50 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to thesubject about 10 mg to about 30 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 25 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 25 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 20 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 20 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 19 mg to about 21 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 20 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 14 mg to about 16 mg of a pharmaceutically acceptable salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg of a pharmaceutically acceptable salt of the compound of Formula II.

[0278] In some embodiments, the methods provided herein comprise administering to the subject about 1 mg to about 50 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 50 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 30 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 25 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 25 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg to about 20 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 10 mg to about 20 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 19 mg to about 21 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 20 mg of a mesylate salt of the compound ofFormula II. In some embodiments, the methods provided herein comprise administering to the subject about 14 mg to about 16 mg of a mesylate salt of the compound of Formula II. In some embodiments, the methods provided herein comprise administering to the subject about 15 mg of a mesylate salt of the compound of Formula II.

[0279] Combinations of HIV Capsid Inhibitor and PGP Inhibitor

[0280] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0281] (a) a compound of Formula I:

[0282] Z1

[0283] N

[0284] 'sr

[0285] o '°

[0286]

[0287] I

[0288] or a pharmaceutically acceptable salt thereof; and

[0289] (b) a compound of Formula II:

[0290]

[0291] II

[0292] or a pharmaceutically acceptable salt thereof, wherein Z1is defined according to the definitions provided herein for compounds of Formula I.The compounds provided herein (e.g., a compound of Formula I and a compound of Formula II), or a salt thereof, can be present in one or more compositions (such as one or more pharmaceutical compositions or formulations) where each composition includes at least one compound other than the active agent (i.e., the compound of Formula I or compound of Formula II), or a salt thereof.

[0293] Compositions provided herein can include mixtures containing the active agent, or salt thereof, and one or more solvents, substrates, carriers, etc. In some embodiments, the composition comprises a compound provided herein, or salt thereof, in an amount greater than about 25% by weight, for example, greater than about 25% by weight, greater than about 50% by weight, greater than about 75% by weight, greater than about 80% by weight, greater than about 90% by weight, or greater than about 95% by weight.

[0294] The present disclosure further includes pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula I or compound of Formula II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable earner” is meant to refer to any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0295] Administration of the compounds provided herein, or a pharmaceutically acceptable salt thereof, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the disclosure can be prepared by combining the active agent, or a pharmaceutically acceptable salt thereof, with an appropriate pharmaceutically acceptable carrier and, in specific embodiments, are formulated into preparations in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Exemplary routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. In some embodiments, pharmaceutical compositions of the disclosure are tablets.

[0296] Pharmaceutical compositions of the disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of the active agent, or a pharmaceutically acceptable salt thereof, for treating an HIV infection, as described herein.

[0297] The pharmaceutical compositions disclosed herein can be also prepared by other methodologies known in the pharmaceutical art.

[0298] The terms “effective amount” or “therapeutically effective amount” refer to an amount of the compounds provided herein, or pharmaceutically acceptable salts thereof, which when administered to a patient in need thereof, are sufficient (e.g., sufficient in combination) to effect treating an HIV infection, as described herein. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of the compounds which constitute therapeutically effective amounts will vary depending on such factors 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 the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds provided herein, and the age, body weight, general health, sex and diet of the patient. Such therapeutically effective amounts can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0299] In certain embodiments, the active ingredient in a composition provided herein (for example, a compound of Formula IIIa or IIIb) is present as a free acid. In certain embodiments, the active ingredient (for example, a compound of Formula IIIa or IIIb) is present as a sodium salt.

[0300] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula la, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula la.

[0301] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula lb.

[0302] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula II.In some embodiments, the active ingredient in a composition provided herein is a compound of Formula IIIa, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula IIIa. In some embodiments, the active ingredient in a composition provided herein is a sodium salt of the compound of Formula IIIa.

[0303] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula IIIb, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula IIIb. In some embodiments, the active ingredient in a composition provided herein is a sodium salt of the compound of Formula IIIb.

[0304] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula Va, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula Va.

[0305] In some embodiments, the active ingredient in a composition provided herein is a compound of Formula Vb, or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient in a composition provided herein is a compound of Formula Vb.

[0306] In some embodiments, the methods provided herein comprise administration of:

[0307] (a) a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

[0308] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0309] In some embodiments, the methods provided herein comprise administration of:

[0310] (a) a pharmaceutical composition comprising a compound of Formula la, and one or more pharmaceutically acceptable excipients; and

[0311] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0312] In some embodiments, the methods provided herein comprise administration of:

[0313] (a) a pharmaceutical composition comprising a compound of Formula la, and one or more pharmaceutically acceptable excipients; and(b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0314] In some embodiments, the methods provided herein comprise administration of:

[0315] (a) a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

[0316] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0317] In some embodiments, the methods provided herein comprise administration of:

[0318] (a) a pharmaceutical composition comprising a compound of Formula lb, and one or more pharmaceutically acceptable excipients; and

[0319] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0320] In some embodiments, the methods provided herein comprise administration of:

[0321] (a) a pharmaceutical composition comprising a compound of Formula lb, and one or more pharmaceutically acceptable excipients; and

[0322] (b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0323] In some embodiments, the methods provided herein comprise administration of:

[0324] (a) a pharmaceutical composition comprising a compound of Formula Illa, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

[0325] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0326] In some embodiments, the methods provided herein comprise administration of:

[0327] (a) a pharmaceutical composition comprising a compound of Formula Illa, and one or more pharmaceutically acceptable excipients; and

[0328] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.In some embodiments, the methods provided herein comprise administration of:

[0329] (a) a pharmaceutical composition comprising a compound of Formula Illa, and one or more pharmaceutically acceptable excipients; and

[0330] (b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0331] In some embodiments, the methods provided herein comprise administration of:

[0332] (a) a pharmaceutical composition comprising a sodium salt of the compound of Formula Illa, and one or more pharmaceutically acceptable excipients; and

[0333] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0334] In some embodiments, the methods provided herein comprise administration of:

[0335] (a) a pharmaceutical composition comprising a sodium salt of the compound of Formula Illa, and one or more pharmaceutically acceptable excipients; and

[0336] (b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0337] In some embodiments, the methods provided herein comprise administration of:

[0338] (a) a pharmaceutical composition comprising a compound of Formula Illb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

[0339] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0340] In some embodiments, the methods provided herein comprise administration of:

[0341] (a) a pharmaceutical composition comprising a compound of Formula Illb, and one or more pharmaceutically acceptable excipients; and

[0342] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0343] In some embodiments, the methods provided herein comprise administration of:

[0344] (a) a pharmaceutical composition comprising a compound of Formula Illb, and one or more pharmaceutically acceptable excipients; and(b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0345] In some embodiments, the methods provided herein comprise administration of:

[0346] (a) a pharmaceutical composition comprising a sodium salt of the compound of Formula Illb, and one or more pharmaceutically acceptable excipients; and

[0347] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0348] In some embodiments, the methods provided herein comprise administration of:

[0349] (a) a pharmaceutical composition comprising a sodium salt of the compound of Formula Illb, and one or more pharmaceutically acceptable excipients; and

[0350] (b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0351] In some embodiments, the methods provided herein comprise administration of:

[0352] (a) a pharmaceutical composition comprising a compound of Formula Va, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

[0353] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0354] In some embodiments, the methods provided herein comprise administration of:

[0355] (a) a pharmaceutical composition comprising a compound of Formula Va, and one or more pharmaceutically acceptable excipients; and

[0356] (b) a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0357] In some embodiments, the methods provided herein comprise administration of:

[0358] (a) a pharmaceutical composition comprising a compound of Formula Va, and one or more pharmaceutically acceptable excipients; and

[0359] (b) a pharmaceutical composition comprising a compound of Formula II, and one or more pharmaceutically acceptable excipients.

[0360] The pharmaceutically acceptable excipients of the tablets disclosed herein should be compatible with the other ingredients of the formulation and physiologically innocuous to therecipient thereof. Examples of suitable excipients are well known to the person skilled in the art of tablet formulation and may be found e.g. in Handbook of Pharmaceutical Excipients (eds. Rowe, Shcskcy & Quinn), 6th edition 2009. As used herein the term “excipients” is intended to refer to inter alia basifying agents, solubilisers, glidants, fillers, binders, lubricant, diluents, preservatives, surface active agents, dispersing agents and the like. The term also includes agents such as sweetening agents, flavoring agents, coloring agents and preserving agents. Such components will generally be present in admixture within the tablet.

[0361] Examples of solubilisers include, but are not limited to, surfactants (including both ionic and non-ionic surfactants) such as sodium lauryl sulphate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and macrogols. Examples of lubricants, glidants and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide, and talc.

[0362] Examples of disintegrants include, but are not limited to, starches, celluloses, crosslinked PVP, sodium starch glycolate, croscarmellose sodium, and the like. Examples of fillers (also known as bulking agents or diluents) include, but are not limited to, starches, maltodextrins, polyols (such as lactose), and celluloses. Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, starches, and the like.

[0363] The tablets disclosed herein may be uncoated or coated (in which case they include an outer film coat). Although uncoated tablets may be used, it is more usual to provide a coated tablet, in which case a conventional non-enteric coating may be used. Film coatings are known in the art and can be composed of hydrophilic polymer materials, but are not limited to, polysaccharide materials, such as hydroxypropylmethyl cellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water soluble polymers. Though the water-soluble material included in the film coating of the tablets may include a single polymer 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 comprising polyvinyl alcohol e.g. ‘Opadry® II’ (which includes part-hydrolysed PVA, titanium dioxide, macrogol 3350 and talc, with optional colouring such as iron oxide or indigo carmine or iron oxide yellow or FD& C yellow #6). The amount of coating will generally be between about 1-8% of the uncoated tablet’s weight.In some embodiments of the methods provided herein, each tablet provided herein further comprises an outer film coat. In some embodiments of the methods provided herein, each tablet comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, provided herein further comprises an outer film coat. In some embodiments of the methods provided herein, each tablet comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, provided herein further comprises an outer film coat.

[0364] In some embodiments of the methods provided herein, the outer film coat provides from about 1% to about 10% weight gain based on the uncoated tablet.

[0365] The compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound, or a pharmaceutically acceptable salt thereof, may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of the compounds provided herein, or pharmaceutically acceptable salts thereof, include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 pg to about 30 mg per day, or from about 30 pg to about 300 pg per day.

[0366] Therapeutically effective amounts of the compounds provided herein amounts may include, for example, from about 0.1 mg per dose to about 2000 mg per dose, such as from about 0.1 mg per dose to about 2000 mg per dose, from about 1 mg per dose to about 2000 mg per dose, from about 5 mg per dose to about 2000 mg per dose, from about 10 mg per dose to about 2000 mg per dose, from about 50 mg per dose to about 2000 mg per dose, from about 100 mg per dose to about 2000 mg per dose, from about 200 mg per dose to about 2000 mg per dose, from about 300 mg per dose to about 2000 mg per dose, from about 400 mg per dose to about 2000 mg per dose, from about 500 mg per dose to about 2000 mg per dose, from about 600 mg per dose to about 2000 mg per dose, from about 700 mg per dose to about 2000 mg per dose, from about 800 mg per dose to about 2000 mg per dose, from about 900 mg per dose to about 2000 mg per dose, from about 1000 mg per dose to about 2000 mg per dose, from about 1100 mg per dose to about 2000 mg per dose, from about 1200 mg per dose to about 2000 mg per dose, from about 1300 mg per dose to about 2000 mg per dose, from about 1400 mg per dose toabout 2000 mg per dose, from about 1500 mg per dose to about 2000 mg per dose, from about 1600 mg per dose to about 2000 mg per dose, from about 1700 mg per dose to about 2000 mg per dose, from about 1800 mg per dose to about 2000 mg per dose, or from about 1900 mg per dose to about 2000 mg per dose.

[0367] In some embodiments, a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 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, about 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or about 2000 mg.

[0368] In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 5 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 250 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 350 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 400 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 450 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 550 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 600 mg. In some embodiments, a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt thereof, is about 650 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 700 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 750 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 800 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 850 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 900 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 950 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1000 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1050 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1100 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1150 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1200 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1250 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1300 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1350 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1400 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1450 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1500 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1550 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1600 mg. In some embodiments, a therapeutically effectiveamount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1650 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1700 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1750 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1800 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1850 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1900 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 1950 mg. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, is about 2000 mg.

[0369] A single dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, a single dose can be administered once or twice every four to eight weeks. In some embodiments, a single dose can be administered once or twice every four to seven weeks. In some embodiments, a single dose can be administered once or twice every four to six weeks. In some embodiments, a single dose can be administered once or twice every four to five weeks.

[0370] The frequency of dosage of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, will be determined by the needs of the individual patient and can be, for example, once per day, once per week, once per month, once per every two months, once per every three months, or once per every six months. Administration of the compound, or a pharmaceutically acceptable salt thereof, continues for as long as necessary to treat the Retroviridae infection, including an HIV infection, or any other indication described herein. For example, a compound, or a pharmaceutically acceptable salt thereof, can be administered to a human suffering from a Retroviridae infection, including an HIV infection, for the duration of the human’s life.

[0371] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, followed by a period of several or more days during which a patient does not receive a daily dose of the compound or a pharmaceutically acceptable salt thereof. For example, a patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, every other day, or three times per week. Again by way of example, a patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, or a pharmaceutically acceptable salt thereof, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound, or a pharmaceutically acceptable salt thereof. Alternating periods of administration of the compound, or a pharmaceutically acceptable salt thereof, followed by nonadministration of the compound, or a pharmaceutically acceptable salt thereof, can be repeated as clinically required to treat the patient.

[0372] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds, or pharmaceutically acceptable salts thereof, may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, 28 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, or 45 days, for one cycle of treatment. Treatment cycles are well known for Retroviridae infections, including an HIV infection. In some embodiments, treatment cycles are frequently alternated with resting periods of about 1 to 45 days, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 days), between cycles. In some embodiments, the compound is administered on the same day, each month (e.g., on the first day of each month, the second day of each month, and the like). In some embodiments, the treatment cycles provided herein may be continuous.

[0373] In some embodiments, the compounds provided herein are administered on a split dosing schedule (e.g., a compound of Formula la or lb and the PGP inhibitor are administered in the morning and a compound of Formula la or lb and / or the PGP inhibitor is administered in the evening).

[0374] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and in the evening.In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and a compound provided herein (e.g., a compound of Formula la or lb) is administered to the patient in the evening.

[0375] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and the PGP inhibitor provided herein (e.g., encequidar) is administered to the patient in the evening.

[0376] In some embodiments, the morning and the evening doses may be between about 8 hours apart and about 16 hours apart, e.g., between about 10 hours apart and about 14 hours apart, about 12 hours apart, and the like. In some embodiments, the morning and evening doses are 12 hours apart.

[0377] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0378] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and a compound provided herein (e.g., a compound of Formula la or lb) is administered to the patient in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0379] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor provided herein (e.g., encequidar) are administered to the patient in the morning and the PGP inhibitor provided herein (e.g., encequidar) is administered to the patient in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, onceevery 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0380] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor (e.g., encequidar) are administered to the patient in the morning and in the evening, once per month.

[0381] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor (e.g., encequidar) are administered in the morning and a compound provided herein (e.g., a compound of Formula la or lb) is administered to the patient in the evening, once per month.

[0382] In some embodiments, a compound provided herein (e.g., a compound of Formula la or lb) and the PGP inhibitor (e.g., encequidar) are administered in the morning and the PGP inhibitor (e.g., encequidar) is administered to the patient in the evening, once per month.

[0383] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and in the evening.

[0384] In some embodiments, a pharmaceutical composition provided herein (e.g.. a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) is administered to the patient in the evening.

[0385] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) is administered to the patient in the evening.

[0386] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, onceevery 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0387] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) is administered to the patient in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0388] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) is administered to the patient in the evening, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days.

[0389] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and in the evening, once per month.

[0390] In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) is administered to the patient in the evening, once per month.In some embodiments, a pharmaceutical composition provided herein (e.g., a tablet comprising a compound of Formula la or lb) and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) are administered to the patient in the morning and a pharmaceutical composition comprising the PGP inhibitor provided herein (e.g., a solution or suspension comprising a compound of Formula II) is administered to the patient in the evening, once per month.

[0391] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 100 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 200 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 300 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 350 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 400 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 450 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 500 once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 550 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 600 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 650 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 700 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 750 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 800 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 850 mgonce or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 900 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 950 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1000 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1050 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1100 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1150 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1200 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1250 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1300 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1350 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1400 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1450 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1500 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1550 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1600 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1650 mg once or twice monthly. In some embodiments, a compound provided herein, or apharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1700 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1750 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1800 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1850 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1900 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 1950 mg once or twice monthly. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered orally in a single dose of about 2000 mg once or twice monthly.

[0392] In some embodiments, the single dose described herein is administered once every month. In some embodiments, the single dose described herein is administered once or twice every month.

[0393] In some embodiments, the single dose described herein is administered once every month. In some embodiments, the single dose described herein is administered once or twice every month.

[0394] In some embodiments, a single dose can be administered once or twice every four weeks. In some embodiments, a single dose can be administered once or twice every five weeks. In some embodiments, a single dose can be administered once or twice every six weeks. In some embodiments, a single dose can be administered once or twice every seven weeks. In some embodiments, a single dose can be administered once or twice every eight weeks.

[0395] In some embodiments, a single dose can be administered once or twice every 30 days. In some embodiments, a single dose can be administered once or twice every 31 days. In some embodiments, a single dose can be administered once or twice every 32 days. In some embodiments, a single dose can be administered once or twice every 33 days. In some embodiments, a single dose can be administered once or twice every 34 days. In some embodiments, a single dose can be administered once or twice every 35 days. In some embodiments, a single dose can be administered once or twice every 36 days. In some embodiments, a single dose can be administered once or twice every 37 days. In someembodiments, a single dose can be administered once or twice every 38 days. In some embodiments, a single dose can be administered once or twice every 39 days. In some embodiments, a single dose can be administered once or twice every 40 days. In some embodiments, a single dose can be administered once or twice every 41 days. In some embodiments, a single dose can be administered once or twice every 42 days. In some embodiments, a single dose can be administered once or twice every 43 days. In some embodiments, a single dose can be administered once or twice every 44 days. In some embodiments, a single dose can be administered once or twice every 45 days.

[0396] Pharmaceutical Compositions of Compounds of Formula la and Formula Ib (Compound 1) In some embodiments, the pharmaceutical composition (i.e. formulation) comprising the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, is suitable for oral administration. In some embodiments, the formulation comprising the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, is a tablet. In some embodiments, the formulation comprising the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, is a tablet suitable for oral administration.

[0397] In some embodiments, the active ingredient is a compound of Formula la (i.e., a free acid form of the compound of Formula la). In some embodiments, the active ingredient is a compound of Formula lb (i.e., a free acid form of the compound of Formula lb).

[0398] In some embodiments, the active ingredient is an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the active ingredient is an amorphous form of the free acid form of the compound of Formula lb.

[0399] In some embodiments, the tablet disclosed herein comprise a compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of a diluent, a disintegrant, and a lubricant.

[0400] In some embodiments, the tablet provided herein comprises about 30 w / w% to about 80 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, for example, about 30 w / w%, about 35 w / w%, about 40 w / w%, about 45 w / w%, about 50 w / w%, about 55 w / w%, about 60 w / w%, about 65 w / w%, about 70 w / w%, about 75 w / w%, or about 80 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, the tablet provided herein comprises about 30 w / w% to about 80 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 30 w / w% to about 80 w / w% of a free acid form of thecompound of Formula la. In some embodiments, the tablet provided herein comprises about 30 to about 80!\ ’f7< of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 30 w / w% to about 80 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 30 w / w% to about 80 w / w% of an amorphous form of the compound of Formula lb.

[0402] In some embodiments, the tablet provided herein comprises about 35 \\'l\\: / ( to about 75 \ l\,f7 of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 35 w / w% to about 75 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 35 w / w% to about 75 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 35 w / w% to about 75 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 35 w / w% to about 75 w / w% of an amorphous form of the compound of Formula lb.

[0403] In some embodiments, the tablet provided herein comprises about 40

[0404]

[0405] to about 70 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 40 w / w% to about 70 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 40 w / w% to about 70 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 40 w / w% to about 70 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 40 w / w% to about 70 w / w% of an amorphous form of the compound of Formula lb.

[0406] In some embodiments, the tablet provided herein comprises about 50

[0407]

[0408] to about 70 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 50 w / w% to about 70 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 50 w / w% to about 70 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 50 w / w% to about 70 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 50 w / w% to about 70 w / w% of an amorphous form of the compound of Formula lb.In some embodiments, the tablet provided herein comprises about 55 w / w% to about 65 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 55

[0409]

[0410] to about 65 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 55 to about 65 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 55 w / w% to about 65 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 55 w / w% to about 65 w / w% of an amorphous form of the compound of Formula lb.

[0411] In some embodiments, the tablet provided herein comprises about 58 w / w% to about 62 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 58

[0412]

[0413] to about 62 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 58 to about 62 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 58 w / w% to about 62 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 58 w / w% to about 62 w / w% of an amorphous form of the compound of Formula lb.

[0414] In some embodiments, the tablet provided herein comprises about 59 w / w% to about 61 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 59 w / w% to about 61 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 59 w / w% to about 61

[0415]

[0416] of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 59 w / w% to about 61 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 59 w / w% to about 61 w / w% of an amorphous form of the compound of Formula lb.

[0417] In some embodiments, the tablet provided herein comprises about 60 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 60 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 60 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 60 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tabletprovided herein comprises about 60 w / w% of an amorphous form of the compound of Formula lb.

[0418] In some embodiments, the tablet provided herein comprises about 40 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 40 w / w% of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 40 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 40 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 40 w / w% of an amorphous form of the compound of Formula lb.

[0419] In some embodiments, the tablet provided herein comprises about 70 w / w% of a free acid form of the compound of Formula la or lb. In some embodiments, the tablet provided herein comprises about 70

[0420]

[0421] of a free acid form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 70 w / w% of a free acid form of the compound of Formula lb. In some embodiments, the tablet provided herein comprises about 70 w / w% of an amorphous form of the compound of Formula la. In some embodiments, the tablet provided herein comprises about 70 w / w% of an amorphous form of the compound of Formula lb.

[0422] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected frommannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate, or any combination thereof.

[0423] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof.

[0424] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof.In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidonc, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, and one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, crospovidone, and magnesium stearate, or any combination thereof.

[0425] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, mannitol, microcrystalline cellulose, crospovidone, poloxamer 407, and magnesium stearate.

[0426] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, mannitol, microcrystalline cellulose, crospovidone, and magnesiumstearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate.

[0427] In some embodiments, the tablet comprises the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la or lb, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula la, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises the free acid form of the compound of Formula lb, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula la, microcrystalline cellulose, crospovidone, and magnesium stearate. In some embodiments, the tablet comprises an amorphous form of the free acid form of the compound of Formula lb, microcrystalline cellulose, crospovidone, and magnesium stearate.

[0428] In some embodiments, the tablet consists essentially of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, crospovidone, magnesium stearate, and microcrystalline cellulose. In some embodiments, the tablet consists essentially of the free acid form of the compound of Formula la or lb, crospovidone, magnesium stearate, and microcrystalline cellulose. In some embodiments, the tablet consists essentially of the free acid form of the compound of Formula la, crospovidone, magnesium stearate, and microcrystalline cellulose. In some embodiments, the tablet consists essentially of the free acid form of the compound of Formula lb, crospovidone, magnesium stearate, and microcrystalline cellulose. In some embodiments, the tablet consists essentially of an amorphous form of the free acid form of the compound of Formula la, crospovidone, magnesium stearate, and microcrystalline cellulose. In some embodiments, the tablet consists essentially of an amorphous form of the free acid form of the compound of Formula lb, crospovidone, magnesium stearate, and microcrystalline cellulose.

[0429] In some embodiments, the tablet comprises about 10 \:lr / to about 30 w / w% of mannitol, for example, about 10 w / w%, about 11 w / w%, about 12 w / w%, about 13 w / w%, about 14 about 15 w / w%, about 16 w / w%, about 17 w / w%, about

[0430]

[0431] 18 about 19 w / w%, about 20 w / w%, about 21 w / w%, about 22 w / w%, about 23 w / w%, about 24 w / w%, about 25w / w%, about 26 w / w%, about 27 w / w%, about 28 w / w%, about 29 w / w%, about 30 w / w% mannitol.

[0432] In some embodiments, the tablet comprises about 12 w / w% to about 30 w / w% of mannitol. In some embodiments, the tablet comprises about 10 w / w% to about 20 w / w% of mannitol. In some embodiments, the tablet comprises about 10 w / w% to about 17 w / w% of mannitol. In some embodiments, the tablet comprises about 12 v7v7(to about 17 ilvT / c of mannitol. In some embodiments, the tablet comprises about 11 / \\:f< mannitol. In some embodiments, the tablet comprises about 11.75 XN! XN% mannitol. In some embodiments, the tablet comprises about 12 w / w% mannitol. In some embodiments, the tablet comprises about 12.75 w / w% mannitol. In some embodiments, the tablet comprises about 14 w / w% mannitol. In some embodiments, the tablet comprises about 14.25 / \\’f / mannitol. In some embodiments, the tablet comprises about 16 w / w% mannitol. In some embodiments, the tablet comprises about 16.75 w / w% mannitol. In some embodiments, the tablet comprises about 20 w / w% to about 30 of mannitol. In some embodiments, the tablet comprises about 25 w / w% to about 30 / w'7 of mannitol. In some embodiments, the tablet comprises about 25 / \ ’ / < to about 28 w / w% of mannitol. In some embodiments, the tablet comprises about 26 v7 77r of mannitol. In some embodiments, the tablet comprises about 26.75 w / w% of mannitol. In some embodiments, the tablet comprises about 27 w / w% of mannitol.

[0433] In some embodiments, the tablet comprises about 0.1 w / ' to about 5 w / w% poloxamer 407, for example, about 0.1 w / w%, about 0.5 w / w%, about 1 w / w%, about 2 w / w%, about 3 w / w%, about 4 w / w%, or about 5 / IXN% poloxamer 407. In some embodiments, the tablet comprises about 1 w / w% to about 5 w / w% poloxamer 407. In some embodiments, the tablet comprises about 2 w / w% to about 4 w / w% poloxamer 407. In some embodiments, the tablet comprises about 3!\\:7 poloxamer 407.

[0434] In some embodiments, the tablet comprises about 10 w / w% to about 35

[0435]

[0436] of microcrystalline cellulose, for example, about 10 w / w%, about 11 w / w%, about 12 w / w%, about 13 w / w%, about 14 w / w%, about 15 v / hN%, about 16 w / w%, about 17 w / w%, about 18 w / w%, about 19 w / w%, about 20

[0437]

[0438] . about 21 w / w%, about 22 w / w%, about 23 w / w%, about 24 XN! XN%, about 25

[0439]

[0440] about 26

[0441]

[0442] about 27 w / w%, about 28 XN! XN%, about 29 N! XN%, about 30 XNIXN%, about 31 w / w%, about 32 w / w%, about 33

[0443]

[0444] about 34 w / w%, or about 35 XN! XN% microcrystalline cellulose.

[0445] In some embodiments, the tablet comprises about 10 XN! W% to about 20 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 10 w / w% to about17 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 11 \ l\:fZ of microcrystalline cellulose. In some embodiments, the tablet comprises about 11.75 w / wfi of microcrystalline cellulose. In some embodiments, the tablet comprises about 12 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 12.75 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 14 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 14.25 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 16 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 16.25

[0446]

[0447] of microcrystalline cellulose.

[0448] In some embodiments, the tablet comprises about 20 w / w% to about 35 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 25 w / w% to about 35 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 25 w / w% to about 30 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 26 w / w% to about 29 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 27

[0449]

[0450] to about 29 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 26.75 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 27 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 27.5 w / w% of microcrystalline cellulose. In some embodiments, the tablet comprises about 28 / v Z of microcrystalline cellulose. In some embodiments, the tablet comprises about 28.5 w / fl of microcrystalline cellulose.

[0451] In some embodiments, the tablet comprises about

[0452]

[0453] 1 to about 15 w / w% of crospovidone, for example, about 1 w / w%, about 2 w / w%, about 3 w / w%, about 4 w / w%, about 5 w / w%, about 6 wl\:f / r, about 7 w / w%, about 8 •w N%, about 9 N! W%, about 10 w / w%, about 11 w / w%, about 12 w / w%, about 13 w / w%, about 14 I Z. or about 15 w / w% crospovidone.

[0454] In some embodiments, the tablet comprises about 5 w / w% to about 15 w / w% of crospovidone. In some embodiments, the tablet comprises about 3 w / w% to about 11 w / w% of crospovidone. In some embodiments, the tablet comprises about 4 w / w% to about 10 w / w% of crospovidone. In some embodiments, the tablet comprises about 8 w / w% to about

[0455]

[0456] 12 of crospovidone. In some embodiments, the tablet comprises about 9 w / w% to about 11 w / w% of crospovidone. In some embodiments, the tablet comprises about 4

[0457]

[0458] of crospovidone. In some embodiments, the tablet comprises about 5 w / w% of crospovidone. In some embodiments, the tablet comprises about 10 w / w% of crospovidone.In some embodiments, the tablet comprises about 1 w / w% to about 5 w / w% of magnesium stearate, for example, about 1. about 2 \ l\: / r, about 3

[0459]

[0460] , about 4

[0461]

[0462] or about 5 w / w% magnesium stearate. In some embodiments, the tablet comprises about 1 to about 3 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 1 w / w% to about 2.5 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 1.5 lv(to about 2 w / w% of magnesium stearate. In some embodiments, the tablet comprises about 1.5 \\'l\\: / ( of magnesium stearate. In some embodiments, the tablet comprises about 2

[0463]

[0464] of magnesium stearate.

[0465] In some embodiments, the tablet comprises:

[0466] about 30 il' % to about 80 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0467] about 0 w / w% to about 30 lw' / r of mannitol;

[0468] about 10 vi / c to about 35 w / w% of microcrystalline cellulose;

[0469] about 1

[0470]

[0471] to about 15 w / w% of crospovidone;

[0472] about 0 \\’l\:fr to about 5 w / w% poloxamer 407; and

[0473] about 1 w / w% to about 5 w / w% magnesium stearate.

[0474] In some embodiments, the tablet comprises:

[0475] about 30 w / w% to about 80 w / w% of the free acid form of the compound of Formula la or lb;

[0476] about 0 w / w% to about 30 w / w% of mannitol;

[0477] about 10 w / w7< to about 35 w / w% of microcrystalline cellulose;

[0478] about 1 w / w% to about 15 w / w% of crospovidone;

[0479] about 0 w / w% to about 5 w / w% poloxamer 407; and

[0480] about 1 \\’l\:fr to about 5 w / w% magnesium stearate.

[0481] In some embodiments, the tablet comprises:

[0482] about 35 vihx% to about 45 w / w% of the free acid form of the compound of Formula la or lb;

[0483] about 25 WI'< N% to about 30 w / w% of mannitol;

[0484] about 25 W!^N% to about 30 \\:l\\'f< of microcrystalline cellulose;

[0485] about 3

[0486]

[0487] to about 6 w / w% of crospovidone; and

[0488] about 1 w / w% to about 3 w / w% magnesium stearate.

[0489] In some embodiments, the tablet comprises:

[0490] about 40 w / w% of the free acid form of the compound of Formula la or lb;about 27 w / w% of mannitol;

[0491] about 27.5 w / w% of microcrystalline cellulose;

[0492] about 4 w / w% of crospovidonc; and

[0493] about 1.5 \N w% of magnesium stearate.

[0494] In some embodiments, the tablet comprises:

[0495] about 40 w / w% of the free acid form of the compound of Formula la or lb; about 26.75 w / w% of mannitol;

[0496] about 26.75 w / w% of microcrystalline cellulose;

[0497] about 5 w / w% of crospovidone; and

[0498] about 1.5 W:! W(of magnesium stearate.

[0499] In some embodiments, the tablet comprises:

[0500] about 50

[0501]

[0502] to about 80 v7 7< of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0503] about 10 w / w% to about 20 w / w% of mannitol;

[0504] about 10 wl' % to about 20 w / w% of microcrystalline cellulose; about 5 w / w% to about 15 77r of crospovidone; and

[0505] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0506] In some embodiments, the tablet comprises:

[0507] about 55 lv7rto about 75 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0508] about 10 w / w7< to about 20 v7v7< of mannitol;

[0509] about 10 vihx% to about 20 w / w% of microcrystalline cellulose; about 5 w / w% to about 15 w / w% of crospovidone; and

[0510] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0511] In some embodiments, the tablet comprises:

[0512] about 55 vihx% to about 75 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0513] about 10 lv77< to about 20 w / w% of mannitol;

[0514] about 10 W!^N% to about 20 w / w% of microcrystalline cellulose; about 5 il / % to about 15 w / w% of crospovidone;

[0515] about 2 w / w% to about 4 w / w% poloxamer 407; and

[0516] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0517] In some embodiments, the tablet comprises:about 50 w / w% to about 80 w / w% of the free acid form of the compound of Formula la or lb;

[0518] about 1

[0519]

[0520] 0 to about

[0521]

[0522] 20 of mannitol;

[0523] about 10 w / w% to about 20 w / w% of microcrystalline cellulose;

[0524] about 5 w / w% to about 15 w / w% of crospovidone; and

[0525] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0526] In some embodiments, the tablet comprises:

[0527] about 55 w / w' / < to about 75 w / w% of the free acid form of the compound of Formula la or lb;

[0528] about 10 lv / ( to about 20 w / w% of mannitol;

[0529] about 10 / \f< to about 20 w / w% of microcrystalline cellulose;

[0530] about 5 w / w% to about 15 lw' / r of crospovidone; and

[0531] about 1

[0532]

[0533] to about 3 w / w% of magnesium stearate.

[0534] In some embodiments, the tablet comprises:

[0535] about 55 w < N% to about 75 ' l / % of the free acid form of the compound of Formula la or lb;

[0536] about 10 w / w% to about 20 w / w% of mannitol;

[0537] about 10 w / w% to about 20 w / w% of microcrystalline cellulose;

[0538] about 5 w / w% to about 15 w / w% of crospovidone;

[0539] about 2

[0540]

[0541] to about 4 \\:l 7'r poloxamer 407; and

[0542] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0543] In some embodiments, the tablet comprises:

[0544] about 60 w / w% of the free acid form of the compound of Formula la or lb; about 16.75 w / w% of mannitol;

[0545] about 16.75 w / w% of microcrystalline cellulose;

[0546] about 5 w / w% of crospovidone; and

[0547] about 1.5 'w / 'N^c of magnesium stearate.

[0548] In some embodiments, the tablet comprises:

[0549] about 70 W!^N% of the free acid form of the compound of Formula la or lb; about 11.75 w / w% of mannitol;

[0550] about 11.75 w / w% of microcrystalline cellulose;

[0551] about 5 w / w% of crospovidone; and

[0552] about 1.5 \ l\:fr of magnesium stearate.In some embodiments, the tablet comprises:

[0553] about 60 w / w% of the free acid form of the compound of Formula la or lb; about 14.25 w / w% of mannitol;

[0554] about 14.25 w / w% of microcrystalline cellulose;

[0555] about 10 w / w% of crospovidone; and

[0556] about 1.5 w / w% of magnesium stearate.

[0557] In some embodiments, the tablet comprises:

[0558] about 60

[0559]

[0560] of the free acid form of the compound of Formula la or lb; about 12.75 w / w% of mannitol;

[0561] about 12.75 w / w% of microcrystalline cellulose;

[0562] about 10 / \f< of crospovidone;

[0563] about 3 w / w% poloxamer 407; and

[0564] about 1.5 w / w% of magnesium stearate.

[0565] In some embodiments, the tablet comprises or consists essentially of:

[0566] about 50 w / w'l to about 70 ' l / % of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0567] about 25 w / w% to about 35 w / w% of microcrystalline cellulose;

[0568] about 5 w / w% to about 15

[0569]

[0570] of crospovidone; and

[0571] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0572] In some embodiments, the tablet comprises or consists essentially of:

[0573] about 55 w / w7< to about 65 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0574] about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0575] about 8 \\’l\:fr to about 12!\ / < of crospovidone; and

[0576] about 1 w / w% to about 3

[0577]

[0578] of magnesium stearate.

[0579] In some embodiments, the tablet comprises:

[0580] about 60 lvi% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0581] about 28.5 w / w% of microcrystalline cellulose;

[0582] about 10 w / w% of crospovidone; and

[0583] about 1.5

[0584]

[0585] of magnesium stearate.

[0586] In some embodiments, the tablet comprises:about 60 w / w% of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof;

[0587] about 28

[0588]

[0589] of microcrystalline cellulose;

[0590] about 10 w / w% of crospovidone; and

[0591] about 2 w / w% of magnesium stearate.

[0592] In some embodiments, the tablet comprises or consists essentially of:

[0593] about 50 lwf< to about 70 v7v77 of the free acid form of the compound of Formula la or lb;

[0594] about 25 vilvi% to about 35 w / w% of microcrystalline cellulose;

[0595] about 5 V V A to about 15 w / w% of crospovidone; and

[0596] about 1 / w'7 to about 5 w / w% of magnesium stearate.

[0597] In some embodiments, the tablet comprises or consists essentially of:

[0598] about 55 vil % to about 65 w / w% of the free acid form of the compound of Formula la or lb;

[0599] about 25 wl' % to about 30 ^NIW% of microcrystalline cellulose;

[0600] about 8 w / w% to about 12 77r of crospovidone; and

[0601] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0602] In some embodiments, the tablet comprises:

[0603] about 60!v / r of the free acid form of the compound of Formula la or lb; about 28.5!\ < of microcrystalline cellulose;

[0604] about 10 w / w% of crospovidone; and

[0605] about 1.5 w / w% of magnesium stearate.

[0606] In some embodiments, the tablet comprises:

[0607] about 60

[0608]

[0609] of the free acid form of the compound of Formula la or lb; about 28

[0610]

[0611] of microcrystalline cellulose;

[0612] about 10 w / w% of crospovidone; and

[0613] about 2

[0614]

[0615] of magnesium stearate.

[0616] In some embodiments, the tablet comprises or consists essentially of:

[0617] about 50 WI^N% to about 70 w / w% of an amorphous form of the free acid form of the compound of Formula la or lb;

[0618] about 25 w / w% to about 35 w / w% of microcrystalline cellulose;

[0619] about 5 w / w% to about 15 w / w% of crospovidone; and

[0620] about 1 w / w% to about 5 w / w% of magnesium stearate.In some embodiments, the tablet comprises or consists essentially of:

[0621] about 55 w / w% to about 65 ^NIW% of an amorphous form of the free acid form of the compound of Formula la or lb;

[0622] about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0623] about 8 w / w% to about 12 w / w% of crospovidone; and

[0624] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0625] In some embodiments, the tablet comprises:

[0626] about 60

[0627]

[0628] of an amorphous form of the free acid form of the compound of Formula la or lb;

[0629] about 28.5 lv7(of microcrystalline cellulose;

[0630] about 10 l\f7< of crospovidone; and

[0631] about 1.5

[0632]

[0633] of magnesium stearate.

[0634] In some embodiments, the tablet comprises:

[0635] about 60 w / w% of an amorphous form of the free acid form of the compound of Formula la or lb;

[0636] about 28 w / w% of microcrystalline cellulose;

[0637] about 10 w / w% of crospovidone; and

[0638] about 2 w / w% of magnesium stearate.

[0639] In some embodiments, the tablet comprises or consists essentially of:

[0640] about 50!\ < to about 70 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof:

[0641] about 25 vil % to about 35 w / w% of microcrystalline cellulose;

[0642] about 5 w / w% to about 15 w / w% of crospovidone; and

[0643] about 1 / w'7 to about 5 w / w% of magnesium stearate.

[0644] In some embodiments, the tablet comprises or consists essentially of:

[0645] about 55 vihx% to about 65 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof;

[0646] about 25 v7v77< to about 30 \:!v7f of microcrystalline cellulose;

[0647] about 8 w / w% to about 12 7 7 / r of crospovidone; and

[0648] about 1 w / w7 to about 3 w / w% of magnesium stearate.

[0649] In some embodiments, the tablet comprises:

[0650] about 60 / v7r of the compound of Formula la, or a pharmaceutically acceptable salt thereof;about 28.5 w / w% of microcrystalline cellulose;

[0651] about 10 w / w% of crospovidone; and

[0652] about 1.5

[0653]

[0654] of magnesium stearate.

[0655] In some embodiments, the tablet comprises:

[0656] about 60 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof;

[0657] about 28 w / w% of microcrystalline cellulose;

[0658] about 10 w / w' / < of crospovidone; and

[0659] about 2 w / w% of magnesium stearate.

[0660] In some embodiments, the tablet comprises or consists essentially of:

[0661] about 50

[0662]

[0663] to about 70 w / w% of the free acid form of the compound of Formula la; about 25 w / w% to about 35 w / w% of microcrystalline cellulose;

[0664] about 5

[0665]

[0666] to about 15 w / w% of crospovidone; and

[0667] about 1 \ / ^r(7< to about 5 w / w% of magnesium stearate.

[0668] In some embodiments, the tablet comprises or consists essentially of:

[0669] about 55 w / w% to about 65 w / w% of the free acid form of the compound of Formula la; about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0670] about 8 w / w% to about 12 \r / \^7< of crospovidone; and

[0671] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0672] In some embodiments, the tablet comprises:

[0673] about 60

[0674]

[0675] of the free acid form of the compound of Formula la;

[0676] about 28.5 w / w% of microcrystalline cellulose;

[0677] about 10 w / w% of crospovidone; and

[0678] about 1.5 w / w% of magnesium stearate.

[0679] In some embodiments, the tablet comprises:

[0680] about 60 w / w% of the free acid form of the compound of Formula la;

[0681] about 28 w / w% of microcrystalline cellulose;

[0682] about 10 w / w% of crospovidone; and

[0683] about 2 w / w% of magnesium stearate.

[0684] In some embodiments, the tablet comprises or consists essentially of:

[0685] about 50 w / w% to about 70 w / w% of an amorphous form of the free acid form of the compound of Formula la;

[0686] about 25 w / w% to about 35 of microcrystalline cellulose;about 5 w / w% to about 15 w / w% of crospovidone; and

[0687] about 1 \\’l\:f / r to about 5 w / w% of magnesium stearate.

[0688] In some embodiments, the tablet comprises or consists essentially of:

[0689] about 55 w / w% to about 65 w / w% of an amorphous form of the free acid form of the compound of Formula la;

[0690] about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0691] about 8 w / w% to about 12 w / w% of crospovidone; and

[0692] about 1 w’lw' / t to about 3 w / w% of magnesium stearate.

[0693] In some embodiments, the tablet comprises:

[0694] about 60 w / w' / < of an amorphous form of the free acid form of the compound of Formula la;

[0695] about 28.5

[0696]

[0697] of microcrystalline cellulose;

[0698] about 10 w / w% of crospovidone; and

[0699] about 1.5 w / w% of magnesium stearate.

[0700] In some embodiments, the tablet comprises:

[0701] about 60 w / w% of an amorphous form of the free acid form of the compound of Formula la;

[0702] about 28 w / w% of microcrystalline cellulose;

[0703] about 10 w / w% of crospovidone; and

[0704] about 2 w / w% of magnesium stearate.

[0705] In some embodiments, the tablet comprises or consists essentially of:

[0706] about 50 w / w% to about 70 w / w% of the compound of Formula lb, or a pharmaceutically acceptable salt thereof;

[0707] about 25 w / w% to about 35 w / w% of microcrystalline cellulose;

[0708] about 5 w / w% to about 15 w / w% of crospovidone; and

[0709] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0710] In some embodiments, the tablet comprises or consists essentially of:

[0711] about 55 WI'< N% to about 65 w / w% of the compound of Formula lb, or a pharmaceutically acceptable salt thereof;

[0712] about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0713] about 8 w / w% to about 12 w / w% of crospovidone; and

[0714] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0715] In some embodiments, the tablet comprises:about 60 w / w% of the compound of Formula lb, or a pharmaceutically acceptable salt thereof;

[0716] about 28.5

[0717]

[0718] of microcrystalline cellulose;

[0719] about 10 w / w% of crospovidone; and

[0720] about 1.5 w / w% of magnesium stearate.

[0721] In some embodiments, the tablet comprises:

[0722] about 60 lwf7< of the compound of Formula lb, or a pharmaceutically acceptable salt thereof;

[0723] about 28

[0724]

[0725] of microcrystalline cellulose;

[0726] about 10 w / w% of crospovidone; and

[0727] about 2 w / w% of magnesium stearate.

[0728] In some embodiments, the tablet comprises or consists essentially of:

[0729] about 50 w / w% to about 70 w / w% of the free acid form of the compound of Formula lb; about 25 w / w% to about 35 w / w% of microcrystalline cellulose;

[0730] about 5 w / w% to about 15 w / w% of crospovidone; and

[0731] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0732] In some embodiments, the tablet comprises or consists essentially of:

[0733] about 55 w / w% to about 65 w / w% of the free acid form of the compound of Formula lb; about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0734] about 8 w / w% to about 12 w / w% of crospovidone; and

[0735] about 1 w / w% to about 3 w / w% of magnesium stearate.

[0736] In some embodiments, the tablet comprises:

[0737] about 60 w / w% of the free acid form of the compound of Formula lb;

[0738] about 28.5 l\f7< of microcrystalline cellulose;

[0739] about 1

[0740]

[0741] 0 of crospovidone; and

[0742] about 1.5 w / w% of magnesium stearate.

[0743] In some embodiments, the tablet comprises:

[0744] about 60 lv77< of the free acid form of the compound of Formula lb;

[0745] about 28

[0746]

[0747] of microcrystalline cellulose;

[0748] about 10 w / w% of crospovidone; and

[0749] about 2 w / w% of magnesium stearate.

[0750] In some embodiments, the tablet comprises or consists essentially of:about 50 w / w% to about 70 w / w% of an amorphous form of the free acid form of the compound of Formula lb;

[0751] about 25

[0752]

[0753] to about 35

[0754]

[0755] of microcrystalline cellulose;

[0756] about 5 w / w% to about 15 w / w% of crospovidone; and

[0757] about 1 w / w% to about 5 w / w% of magnesium stearate.

[0758] In some embodiments, the tablet comprises or consists essentially of:

[0759] about 55 w / w% to about 65 w / w% of an amorphous form of the free acid form of the compound of Formula lb;

[0760] about 25 w / w% to about 30 w / w% of microcrystalline cellulose;

[0761] about 8 w / w% to about 12 w / w% of crospovidone; and

[0762] about 1 \\'l\:f7 to about 3 w / w% of magnesium stearate.

[0763] In some embodiments, the tablet comprises:

[0764] about 60 w / w% of an amorphous form of the free acid form of the compound of Formula lb;

[0765] about 28.5 w / w% of microcrystalline cellulose;

[0766] about 10 w / w% of crospovidone; and

[0767] about 1.5 w / w% of magnesium stearate.

[0768] In some embodiments, the tablet comprises:

[0769] about 60 w / w% of an amorphous form of the free acid form of the compound of Formula lb;

[0770] about 28 w / w7< of microcrystalline cellulose;

[0771] about 10 w / w% of crospovidone; and

[0772] about 2 w / w% of magnesium stearate.

[0773] In some embodiments, the tablets disclosed herein consist essentially of the components described herein. In some embodiments, the tablets disclosed herein consist of the components described herein.

[0774] In some embodiments, the tablet comprises about 1 mg to about 2000 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof, for example, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof.

[0775] In some embodiments, the tablet comprises about 225 mg to about 375 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 250 mg to about 375 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 275 mg to about 375 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 300 mg to about 350 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof.

[0776] In some embodiments, the tablet comprises about 300 mg to about 310 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 305 mg to about 307 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 306 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 306 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 306 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 306 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 306 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 306 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 300 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 300 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 300 mg of thefree acid form of the compound of Formula la. In some embodiments, the tablet comprises about 300 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 300 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 300 mg of an amorphous form of the free acid form of the compound of Formula lb.

[0777] In some embodiments, the tablet comprises about 100 mg to about 500 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 200 mg to about 450 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 250 mg to about 450 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 300 mg to about 400 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 325 mg to about 375 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 340 mg to about 360 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 345 mg to about 355 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 349 mg to about 351 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises about 350 mg of the compound of Formula la or lb, or a pharmaceutically acceptable salt thereof.

[0778] In some embodiments, the tablet comprises about 100 mg to about 500 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 200 mg to about 450 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 250 mg to about 450 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 300 mg to about 400 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 325 mg to about 375 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 340 mg to about 360 mg of the free acid form of the compound of Formula laor lb. In some embodiments, the tablet comprises about 345 mg to about 355 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 349 mg to about 351 mg of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 350 mg of the compound of the free acid form of the compound of Formula la or lb.

[0779] In some embodiments, the tablet comprises about 100 mg to about 500 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 200 mg to about 450 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 250 mg to about 450 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 300 mg to about 400 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 325 mg to about 375 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 340 mg to about 360 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 345 mg to about 355 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 349 mg to about 351 mg of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 350 mg of the compound of the free acid form of the compound of Formula la.

[0780] In some embodiments, the tablet comprises about 100 mg to about 500 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 200 mg to about 450 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 250 mg to about 450 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 300 mg to about 400 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 325 mg to about 375 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 340 mg to about 360 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 345 mg to about 355 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 349 mg to about 351 mg of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 350 mg of the compound of the free acid form of the compound of Formula lb.In some embodiments, the tablet comprises about 100 mg to about 500 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 200 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 250 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 300 mg to about 400 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 325 mg to about 375 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 340 mg to about 360 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 345 mg to about 355 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 349 mg to about 351 mg of an amorphous form of the free acid form of the compound of Formula la or lb. In some embodiments, the tablet comprises about 350 mg of the compound of an amorphous form of the free acid form of the compound of Formula la or lb.

[0781] In some embodiments, the tablet comprises about 100 mg to about 500 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 200 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 250 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 300 mg to about 400 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 325 mg to about 375 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 340 mg to about 360 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 345 mg to about 355 mg of an amorphous form of the free acid form of the compound of Formula la. In some embodiments, the tablet comprises about 349 mg to about 351 mg of an amorphous form of the free acid form of the compound of Formula la. Insome embodiments, the tablet comprises about 350 mg of the compound of an amorphous form of the free acid form of the compound of Formula la.

[0782] In some embodiments, the tablet comprises about 100 mg to about 500 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 200 mg to about 475 mg of the free acid form of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 200 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 250 mg to about 450 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 300 mg to about 400 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 325 mg to about 375 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 340 mg to about 360 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 345 mg to about 355 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 349 mg to about 351 mg of an amorphous form of the free acid form of the compound of Formula lb. In some embodiments, the tablet comprises about 350 mg of the compound of an amorphous form of the free acid form of the compound of Formula lb.

[0783] The tablets disclosed herein may be uncoated or coated (in which case they include an outer film coat). Although uncoated tablets may be used, it is more usual to provide a coated tablet, in which case a conventional non-enteric coating may be used. Film coatings are known in the art and can be composed of hydrophilic polymer materials, but are not limited to, polysaccharide materials, such as hydroxypropylmethyl cellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water soluble polymers. Though the water-soluble material included in the film coating of the tablets may include a single polymer 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 comprising polyvinyl alcohol e.g. ‘Opadry® II’ (which includes part-hydrolysed PVA, titanium dioxide, macrogol 3350 and talc, with optional colouring such as iron oxide or indigo carmine or iron oxide yellow or FD& C yellow #6). The amount of coating will generally be between about 1-8% of the uncoated tablet’s weight. In some embodiments, the amount of coating will generally bebetween about 2-6% of the uncoated tablet’s weight. In some embodiments, the amount of coating will generally be between about 3-4% of the uncoated tablet’s weight.

[0784] In some embodiments, the amount of coating is 1% of the uncoatcd tablet’s weight. In some embodiments, the amount of coating is 2% of the uncoated tablet’s weight. In some embodiments, the amount of coating is 3% of the uncoated tablet’s weight. In some embodiments, the amount of coating is 4% of the uncoated tablet’s weight. In some embodiments, the amount of coating is 5% of the uncoated tablet’s weight. In some embodiments, the amount of coating is 6% of the uncoated tablet's weight. In some embodiments, the amount of coating is 7% of the uncoated tablet’s weight. In some embodiments, the amount of coating is 8% of the uncoated tablet’s weight.

[0785] In some embodiments, the coating is Opadry II Purple 85F140073. Opadry II Purple 85F140073 contains 40.00% w / w polyvinyl alcohol (USP / Ph. Eur.), 24.20% w / w titanium dioxide (USP / Ph. Eur.), 20.20% w / w macrogol / polyethylene glycol (USP / Ph. Eur.), 14.80% w / w talc (USP / Ph. Eur.), 0.58% w / w iron oxide red (NF), and 0.22% w / w ferrosoferric oxide / black iron oxide (NF).

[0786] In some embodiments, the coating is Opadry II Gray 85F97517. Opadry II Gray 85F97517 contains 40.00% w / w polyvinyl alcohol (USP / Ph. Eur.), 24.74% w / w titanium dioxide, (USP / Ph. Eur.), 20.20% w / w macrogol / polyethylene glycol (NF / Ph. Eur.), 14.80% (w / w) talc (USP / Ph. Eur.), and 0.26% w / w ferrosoferric oxide / black iron oxide (NF). In some embodiments, the coating is Opadry TF Gray 273F175005. Opadry TF Gray 273F175005 contains 37.000% w / w polyvinyl alcohol (USP / FCC / PhEur / JPE / ChP / GB), 34.850% w / w calcium carbonate (USP / FCC / PhEur / JP / JECFA / JSFA / GB), 14.500% w / w microcrystalline cellulose (NF / PhEur / JP / ChP), 7.000% w / w macrogol 6000 JP / PEG (USP / FCC / PhEur / JECFA / JP), 5.000% w / w magnesium aluminometasilicate (Type IA NF / Type A PhEur / JP), 1.000% carnauba wax (NF / FCC / PhEur / JP / ChP / GB), 0.500% xanthan gum (NF / FCC / PhEur / JPE / ChP / JECFA), 0.150% w / w ferrosoferric oxide (NF) / black iron oxide (JPE / JECFA / ChP).

[0787] In some embodiments, the methods described herein may comprise administering about 800 mg to about 1200 mg of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, in the form of any of the pharmaceutical compositions recited in this section.Pharmaceutical Compositions of Compounds of Formula II (encequidar)

[0788] In some embodiments, the pharmaceutical composition (z.e. formulation) comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is suitable for oral administration. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a suspension or solution.

[0789] In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a solution. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is an injectable solution. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a solution suitable for oral administration. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is an injectable solution suitable for oral administration.

[0790] In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a suspension. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is an injectable suspension. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a suspension suitable for oral administration. In some embodiments, the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is an injectable suspension suitable for oral administration.

[0791] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 10 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, for example, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0792] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 3 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0793] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1.5 mg / mL to about 2.5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1.9 mg / mL to about 2.1 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0795] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 2 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0796] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises carboxymethyl cellulose.

[0797] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 0.1 w / w% to about 2 w / w% carboxymethyl cellulose, for example, about 0.1 w / w%, about 0.2 w / w%, about 0.3 w / w%, about 0.4 w / w%, about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 vf / r. about 1 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, or about 2 \ l\’c / carboxymethyl cellulose.

[0798] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 0.1 w / w% to about 1 w / w% carboxy methyl cellulose.

[0799] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 0.4 w / w% to about 0.6 w / w% carboxymethyl cellulose.

[0800] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 0.5 w / w% carboxymethyl cellulose.

[0801] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 98

[0802]

[0803] to about 99.9 w / w% water, for example, about 98 w / w%, about 98.1 w / w%, about 98.2 w / w%, about 98.3 w / w%, about 98.4 w / w%, about 98.5 w / w%, about 98.6 w / w%, about 98.7 ilvi%, about 98.8 'wl'f / %, about98.9 w / w%, about 99 w / w%, about 99.2 w / w%, about 99.3 w / w%, about 99.4 •w w%, about 99.5 'w w%, about 99.6 w / w%, about 99.7 w / w%, about 99.8 w / w%, or about 99.9 w / w% water.

[0804] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 99

[0805]

[0806] to about 99.9 w / w% water.

[0807] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 99.5 w / w% water.

[0808] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises carboxymethyl cellulose and water.

[0809] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 10 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 0.1 w / w% to about 2 \ l\:fr carboxymethyl cellulose, and about 98 w / w' / i to about 99.9 w / w% water.

[0810] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 0.1 w / w% to about 1 w / w% carboxymethyl cellulose, and about 99 w / w% to about 99.9 w / w% water.

[0811] In some embodiments, the suspension comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 2 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 0.5 w / w% carboxymethyl cellulose, and about 99.5 w / w% water.

[0812] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises Kolliphor HS-15, N-methylpyrrolidone, PEG 300, water, or any combination thereof.

[0813] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises Kolliphor IIS- 15.

[0814] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 5 'W / 'N^O to about 15 w / w% Kolliphor HS-15, for example, about 6 \\’l\: / r. about 7 w / w%, about 8 w / w%, about 9 w / w%, about 10 w / w%, about 11 / lN%, about 12 w / w%, about 13 w / w%, about 14 w / w%, or about 15 w / w% Kolliphor HS-15.

[0815] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 8 w / w% to about 12 il' % Kolliphor HS-15.In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 9 w / w% to about 11 w / w% Kolliphor HS-15.

[0816] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 10 w / w% Kolliphor HS-15.

[0817] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises N-methylpyrrolidone.

[0818] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 w / w% to about 10 l i% N-methylpyrrolidone, for example, about 1 w / w%, about 2 w / w%, about 3 w / w%, about 4 w / w%, about 5 w / w%, about 6 •wl'N^o, about 7 w / w%, about 8 w / w%, about 9 w / w%, about 10 w / w% N-methylpyrrolidone.

[0819] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 3 w / w% to about 7 w / w% N-methylpy rrolidone.

[0820] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 4 il'w% to about 6 w / w% N-methylpyrrolidone.

[0821] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 5 w / w% N-methylpyrrolidone.

[0822] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises polyethylene glycol 300 (i.e., PEG 300).

[0823] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 20 l\ / < to about 40 w / w% PEG 300, for example, about 20 w / w%, about 21 w / w%, about 22 w / w%, about 23 w / w%, about 24 about 25 w / w%, about 26 w / w%, about 27 w / w%, about 28 lw%, about 29 w / w%, about 30 w / w%, about 31 w / w%, about 32 w / w%, about 33 vMo, about 34 w / w%, about 35

[0824]

[0825] about 36 about 37 w / w%, about 38 w / w%, about 39

[0826]

[0827] . or about 40 w / w% PEG 300.

[0828] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 25

[0829]

[0830] to about 35 w / w% PEG 300.In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 29 w / w% to about 31

[0831]

[0832] PEG 300.

[0833] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 30 w / w% PEG 300.

[0834] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises water.

[0835] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 45

[0836]

[0837] to about 65 w / w% water, for example, about 45 w / w%, about 46 w / w%, about 47 w / w%, about 48 w / w%, about 49 \ l\:f7. about 50 w / w%, about 51 w / w%, about 52 w / w%, about 53 w / w%, about 54 w / w%, about 55 Nl^N%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 / l i%, or about 60 w / w% water.

[0838] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 50!\ ’ / < to about 60 •wl'w^c water.

[0839] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 54 w / w% to about 56 w / w% water.

[0840] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 55 w / w% water.

[0841] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.

[0842] In some embodiments, the solution consists essentially of the compound of Formula II, or a pharmaceutically acceptable salt thereof, Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.

[0843] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 10 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 5 w / w% to about 15 w / w% Kolliphor HS-15, about 1 / lv^c to about 10 w / w% N-methylpyrrolidone, about 20 w / w% to about 40 w / w% PEG 300, and about 45 w / w% to about 65 w / w% waler.

[0844] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, consists essentially of about 1 mg / mL to about 10 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 5w / w% to about 15 w / w% Kolliphor HS-15, about 1 w / w% to about 10 w / w% N-methylpyrrolidone, about 20

[0845]

[0846] to about 40 w / w% PEG 300, and about 45 w / w% to about 65 w / w% water.

[0847] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3

[0848]

[0849] to about 7

[0850]

[0851] N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

[0852] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, consists essentially of about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 8 XN / XN% to about 12 \\7v.'' / < Kolliphor IIS-15, about 3 XN / XN% to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

[0853] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 1.5 mg / mL to about 2.5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 9

[0854]

[0855] to about 11 w / w% Kolliphor HS-15, about 4 w / w% to about 6 w / w% N-methylpyrrolidone, about 29 XNIXN% to about 31 XNIXN% PEG 300, and about 54 XN! XN% to about 56 w / w% water.

[0856] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, consists essentially of about 1.5 mg / mL to about 2.5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 9 XNI' % to about 11 XNIXN% Kolliphor HS-15, about 4 XNIXN% to about 6 XNIXN% N-methylpyrrolidone, about 29 \ l\:f / r to about 31 XNIXN% PEG 300, and about 54 WIXN% to about 56 XNIXN% water.

[0857] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 2.0 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 10 l\f / Kolliphor HS-15, about 5 XN! XN% N-methylpyrrolidone, about 30 XNIV / % PEG 300, and about 55 XNIV / % water.

[0858] In some embodiments, the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, consists essentially of about 2.0 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 10 XNIXN%Kolliphor HS-15, about 5 w / w% N-methylpyrrolidone, about 30 w / w% PEG 300, and about 55 SNISN% water.

[0859] In some embodiments, the methods described herein may comprise administering about 10 mg to about 25 mg of the compound of Formula II, or a pharmaceutically acceptable salt thereof, in the form of any of the pharmaceutical compositions recited in this section.

[0860] Pharmaceutical Compositions of Compounds of Formula Illa and Formula Illb

[0861] In some embodiments, the pharmaceutical composition (z.e. formulation) comprising the compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, is suitable for oral administration.

[0862] In some embodiments, the oral formulation of a compound of Formula Illa or Illb, 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 Illa or Illb, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 5 mg to about 500 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 25 mg to about 500 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 25 mg to about 400 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 25 mg to about 300 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 50 mg to about 500 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 75 mg to about 500 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 50 mg to about 400 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 50 mg to about 300 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 75 mg to about 400 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 75 mg to about 300 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, 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 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 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 a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 5 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 10 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 20 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 25 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 30 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 40 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 50 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 75 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 100 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 125 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 150 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or apharmaceutically acceptable salt thereof, in the tablet is about 175 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 200 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 225 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 250 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 275 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 300 mg.

[0863] In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 325 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 350 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 375 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 400 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 425 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 450 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 475 mg. In some embodiments, the amount of a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, in the tablet is about 500 mg.

[0864] In some embodiments, the tablet herein comprises a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of Formula la or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of Formula la and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a sodium salt of the compound of Formula la and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of Formula lb or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises a compound of Formula lb and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet comprises asodium salt of the compound of Formula lb and one or more pharmaceutically acceptable excipients.

[0865] In some embodiments, the tablets disclosed herein comprise a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of a matrix former, 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 former. In some embodiments, the matrix former comprises copovidone. In some embodiments, the tablet comprises about 0.01 w / w% to about 10 v / of a surfactant. In some embodiments, the surfactant comprises poloxamer 407. In some embodiments, the tablet comprises about 25-85 w / w% of one or more fillers. In some embodiments, the one or more fillers comprises 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 embodiments, the lubricant comprises magnesium stearate.

[0866] In some embodiments, the tablet disclosed herein comprises a compound of Formula Illa or Illb or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from the group consisting of copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone. In some embodiments, the one or more pharmaceutically acceptable excipient comprises poloxamer 407. In some embodiments, the one or more pharmaceutically acceptable excipient comprises microcrystalline cellulose. In some embodiments, the one or more pharmaceutically acceptable excipient comprises mannitol. In some embodiments, the one or more pharmaceutically acceptable excipient comprises croscarmellose sodium. In some embodiments, the one or more pharmaceutically acceptable excipient comprises magnesium stearate. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone and poloxamer 407. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone, poloxamer 407, and microcrystalline cellulose. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone, poloxamer 407, microcrystalline cellulose, and mannitol. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone, poloxamer 407, microcrystallinecellulose, mannitol, and croscarmellose sodium. In some embodiments, the one or more pharmaceutically acceptable excipient comprises copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate.

[0867] In some embodiments, the tablet disclosed herein comprises a compound of Formula Illa or Illb or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a compound of Formula lb, or a pharmaceutically acceptable salt thereof, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a compound of Formula la, 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 la, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a compound of Formula lb, 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 lb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate.

[0868] In some embodiments, the tablet disclosed herein comprises a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 5 mg to about 500 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 25 mg to about 500 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 25 mg to about 400 mg. In some embodiments, the amount of the compound ofFormula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 25 mg to about 300 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 50 mg to about 300 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 5 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 10 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 25 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 30 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 40 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 50 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 75 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about100 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmcllosc sodium, and magnesium stearate is about 125 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 150 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 175 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 200 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 225 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 250 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 275 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 300 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 325 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 350 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about375 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmcllosc sodium, and magnesium stearate is about 400 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 425 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 450 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 475 mg. In some embodiments, the amount of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 500 mg.

[0869] In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 5 w / w% to about 45 w / w%. In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 10 w / w% to about 40 w / w%. In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 15 w / w% to about 35

[0870]

[0871] In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 15 w / w% to about 25 w / w%. In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesiumstearate is about 20.46 w / w%. In some embodiments, the amount of the sodium salt of the compound of Formula Illa or Illb in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20.5 w / w%.

[0872] In some embodiments, the amount of copovidone in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1 w / w% to about 10 w / w%. In some embodiments, the amount of copovidone in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 2 w / w% to about 10 w / w%. In some embodiments, the amount of copovidone in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 3 w / w% to about 8 w / w%. In some embodiments, the amount of copovidone in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 3

[0873]

[0874] to about 6 w / w%. In some embodiments, the amount of copovidone in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, 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 the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 4.9 w / w%.

[0875] In some embodiments, the amount of poloxamer 407 in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.01 w / w% to about 10 w / w%. In some embodiments, the amount of poloxamer 407 in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.05 w / w% to about 8

[0876]

[0877] In some embodiments, the amount of poloxamer 407 in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.5 NlN% to about 4 v \\: / r. In some embodiments, the amount of poloxamer 407 in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407,microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.5 w / w% to about 3.0 w / w%. In some embodiments, the amount of poloxamer 407 in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, 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 the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.33 w / w%.

[0878] In some embodiments, the amount of microcrystalline cellulose in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 5 w / w% to about 45 w / w%. In some embodiments, the amount of microcrystalline cellulose in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 10 w / w% to about 40

[0879]

[0880] In some embodiments, the amount of microcrystalline cellulose in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 15 w / w% to about 35 w / w%. In some embodiments, the amount of microcrystalline cellulose in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 18 w / w% to about 30 w / w%. In some embodiments, the amount of microcrystalline cellulose in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, 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 the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 21.3 w / w%.

[0881] In some embodiments, the amount of mannitol in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 15 w / w% to about 70 w / w%. In some embodiments, the amount of mannitol in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 20 w / w% to about 60 w / w%.In some embodiments, the amount of mannitol in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 30 w / w% to about 55 w / w%. In some embodiments, the amount of mannitol in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, 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 a sodium salt of the compound of Formula Illa or Illb, 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 a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 42.6 w / w%.

[0882] In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1 w / w% to about 30 w / w%. In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1 w / w% to about 20 w / w%. In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 4 w / w% to about 16 w / w%. In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 6 w / w% to about 10 w / w%. In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 8.0 w / w%. In some embodiments, the amount of croscarmellose sodium in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 8.00 w / w%.

[0883] In some embodiments, the amount of magnesium stearate in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407,microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.01 w / w% to about 10 w / w%. In some embodiments, the amount of magnesium stearate in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.05 w / w% to about 8 w / w%. In some embodiments, the amount of magnesium stearate in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 0.5 w / w% to about 4

[0884]

[0885] In some embodiments, the amount of magnesium stearate in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.0 w / w% to about 3.0 w / w%. In some embodiments, the amount of magnesium stearate in the tablet comprising a sodium salt of the compound of Formula Illa or Illb, 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 the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate is about 1.50 w / w%.

[0886] In some embodiments, the tablet disclosed herein comprises about 5 w / w% to about 45 w / w% of a sodium salt of the compound of Formula Illa or Illb, 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 \\'l\\:7( to about 45 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, about 0.01 w / w% to about 10 w / w% of magnesium stearate, and one or more pharmaceutically acceptable excipients. In some embodiments, the tablet disclosed herein comprises about 5

[0887]

[0888] to about 45 w / w% of a sodium salt of the compound of Formula Illa or Illb, 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 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 a sodium salt of the compound of Formula Illa or Illb, about 2 w / w% to about 10 of copovidone, about 0.05 w / w% to about 8

[0889]

[0890] 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 8w / w% of magnesium stearate. In some embodiments, the tablet comprises about 15 w / w% to about 35 w / w% of a sodium salt of the compound of Formula Illa or Illb, 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

[0891]

[0892] of a sodium salt of the compound of Formula Illa or Illb, about 3 w / w% to about 6

[0893]

[0894] of copovidone, about 0.5

[0895]

[0896] to about 3.0 w / w% of poloxamer 407, about 18 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.

[0897] In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of the compound of Formula Illa or Illb, 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' / i of magnesium stearate. In some embodiments, the tablet comprises about 20.46 w / w' / < of a sodium salt of the compound of Formula Illa or Illb, 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 a sodium salt of the compound of Formula Illb, 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

[0898]

[0899] 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 a sodium salt of the compound of Formula Illb, 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

[0900]

[0901] of magnesium stearate.

[0902] In some embodiments, the tablet disclosed herein further comprises an outer film coat. In some embodiments, the tablet comprising a sodium salt of the compound of Formula Illa or Illb, copovidone, poloxamer 407, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate further comprises an outer film coat. In some embodiments, the outer film coat provides from about 1% to about 8% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides from about 2% to about 6% weight gain based on theuncoated tablet. In some embodiments, the outer film coat provides from about 2% to about 4% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides from about 4% to about 6% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, or about 8% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 1% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 2% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 3% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 4% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 5% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 6% weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 7 % weight gain based on the uncoated tablet. In some embodiments, the outer film coat provides about 8% weight gain based on the uncoated tablet. In some embodiments, the outer film coat comprises Opadry® II. In some embodiments, the outer film coat comprises Opadry® II White. In some embodiments, the outer film coat comprises Opadry® II White 85F18422.

[0903] In some embodiments, the outer film coat comprises Opadry® II Green. In some embodiments, the outer film coat comprises Opadry® II Green 85F110187. In some embodiments, the outer film coat comprises Opadry® II Green 85F110186.

[0904] In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.9 w / w% copovidone, about 1.3 w / w% 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% weight gain from Opadry® II White 85F18422, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.88 w / w% copovidone, about 1.33 w / w% 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% weight gain from Opadry® II White 85F18422, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula lb, about 4.9 w / w% copovidone, about 1.3 w / w% poloxamer 407, about 21.3

[0905]

[0906] of microcrystalline cellulose, about 42.6

[0907]

[0908] of mannitol, about 8.0 w / w% of croscarmellose sodium, about 1.5 w / w% of magnesium stearate, and about 3% weight gain from Opadry® IIWhite 85F18422, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46 w / w% of a sodium salt of a compound of Formula lb, about 4.88 w / w% copovidone, about 1.33 w / w% poloxamer 407, about 21.28

[0909]

[0910] 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% weight gain from Opadry® II White 85F18422, wherein the weight gain is based on the uncoated tablet.

[0911] In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.9 w / w% copovidone, about 1.3

[0912]

[0913] 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% weight gain from Opadry® II Green 85F110187, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.88 w / w% copovidone, about 1.33 w / w% 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% weight gain from Opadry® II Green 85F110187, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula Illb, about 4.9 w / w% copovidone, about 1.3 w / w% 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% weight gain from Opadry® II Green 85F110187, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46

[0914]

[0915] of a sodium salt of a compound of Formula Illb, about 4.88 w / w% copovidone, about 1.33 w / w% 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% weight gain from Opadry® II Green 85F110187, wherein the weight gain is based on the uncoated tablet.

[0916] In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.9 w / w% copovidone, about 1.3 w / w% 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% weight gain from Opadry® II Green 85F110186, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46 w / w% of a sodium salt of a compound of Formula Illa or Illb, about 4.88 w / w% copovidone, about 1.33 w / w% poloxamer407, 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% weight gain from Opadry® II Green 85F110186, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.5 w / w% of a sodium salt of a compound of Formula Illb, about 4.9 w / w% copovidone, about 1.3 w / w% 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% weight gain from Opadry® II Green 85F110186, wherein the weight gain is based on the uncoated tablet. In some embodiments, the tablet comprises about 20.46 w / w% of a sodium salt of a compound of Formula Illb, about 4.88

[0917]

[0918] copovidone, about 1.33 w / w% poloxamer 407, about 21.28 \ I\:Z of microcrystalline cellulose, about 42.55 \\:l ‘ / r of mannitol, about 8.00 w / w% of croscarmellose sodium, about 1.50 w / w% of magnesium stearate, and about 4.0% weight gain from Opadry® II Green 85F110186, wherein the weight gain is based on the uncoated tablet.

[0919] In some embodiments of the methods provided herein, each oral administration is administered as a tablet comprising the sodium salt of the compound of Formula Illa or Illb.

[0920] In some embodiments of the methods provided herein, each tablet comprising a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, is prepared from a spray-dried dispersion technology.

[0921] In some embodiments of the methods provided herein, each tablet comprises about 5 w / w% to about 45

[0922]

[0923] of the sodium salt of the compound of Formula Illa or Illb, about 1 w / w% to about

[0924]

[0925] 10 of copovidone, about 0.01 w / w% to about 10 w / w% of poloxamer 407, about 5 w / w% to about 45

[0926]

[0927] 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

[0928]

[0929] 10 of magnesium stearate, and one or more pharmaceutically acceptable excipients.

[0930] In some embodiments of the methods provided herein, each tablet comprises about 15 w / w% to about 25 w / w% of the sodium salt of the compound of Formula Illa or Illb, 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 to about 3.0 w / w% magnesium stearate.

[0931] In some embodiments of the methods provided herein, each tablet comprising a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, comprisesabout 300 mg of the compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof.

[0932] In some embodiments of the methods provided herein, each tablet comprising a compound of Formula Illa or Illb, or a pharmaceutically acceptable salt thereof, comprises about 306.8 mg of the sodium salt of the compound of Formula Illa or Illb.

[0933] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0934] (a) a compound of Formula la:

[0935]

[0936] la

[0937] or a pharmaceutically acceptable salt thereof; and

[0938] (b) a compound of Formula II:

[0939]

[0940] II

[0941] or a pharmaceutically acceptable salt thereof.In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0942] (a) a pharmaceutical composition comprising a compound of Formula la:

[0943]

[0944] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, as disclosed herein; and

[0945] (b) a pharmaceutical composition comprising a compound of Formula II:

[0946]

[0947] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, as disclosed herein.

[0948] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising a compound of Formula la:

[0949]

[0950] or a pharmaceutically acceptable salt thereof, crospovidone, magnesium stearate, and microcrystalline cellulose; and

[0951] (b) a solution comprising a compound of Formula II:

[0952]

[0953] or a pharmaceutically acceptable salt thereof, Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.

[0954] The tablet may consist essentially of the compound of Formula la, or a pharmaceutically acceptable salt thereof, crospovidone, magnesium stearate, and microcrystalline cellulose. The solution may consist essentially of the compound of Formula II, or a pharmaceutically acceptable salt thereof, Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0955] (a) a tablet comprising about 30 w / w% to about 80 w / w% of a compound of Formula la:

[0956]

[0957] la

[0958] or a pharmaceutically acceptable salt thereof, about 0 w / w% to about 30 w / w% of mannitol, about 10 w / w% to about 35 w / w% of microcrystalline cellulose, about 1 w / w% to about 15 of crospovidone, about 0 w / w% to about 5 w / w% poloxamer 407; and about 1 w / w% to about 5 w / w% magnesium stearate; and

[0959] (b) a solution comprising about 1 mg / mL to about 5 mg / mL of a compound of Formula II:

[0960] II

[0961]

[0962] or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3

[0963]

[0964] to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water. The tablet may consist essentially of about 30 w / w% to about 80 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof, about 0 w / w% to about 30

[0965]

[0966] of mannitol, about 10 w / w% to about 35 w / w% of microcrystalline cellulose, about 1 w / w% to about 15

[0967]

[0968] of crospovidone, about 0 w / w% to about 5 w / w% poloxamer 407; and about 1

[0969]

[0970] to about 5 w / w% magnesium stearate. The solution may consist essentially of about 1 mg / mL to about 5 mg / mL of a compound of Formula II, or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3 w / w% to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

[0971] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:

[0972] (a) a tablet comprising about 55 w / w% to about 65 w / w% of a compound of Formula la:

[0973]

[0974] la

[0975] or a pharmaceutically acceptable salt thereof, about 5

[0976]

[0977] to about 15 w / w7< crospovidone, about 1 w / w% to about 3 w / w% magnesium stearate, and about 25 w / w% to about 30 w / w% microcrystalline cellulose; and(b) a solution comprising about 1 mg / mL to about 5 mg / mL of a compound of Formula II:

[0978]

[0979] II

[0980] or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3 w / w% to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35

[0981]

[0982] PEG 300, and about 50 w / w% to about 60 w / w% water. The tablet may consist essentially of about 55 to about 65 w / w% of a compound of Formula la, or a pharmaceutically acceptable salt thereof, about 5 w / w% to about 15 w / w% crospovidone, about 1 w / w% to about 3 w / w% magnesium stearate, and about 25 w / w% to about 30 w / w% microcrystalline cellulose. The solution may consist essentially of about 1 mg / mL to about 5 mg / mL of a compound of Formula II, or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3

[0983]

[0984] to about 7

[0985]

[0986] N-methylpyrrolidone, about 25

[0987]

[0988] to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

[0989] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising about 60 w / w% of a compound of Formula la:

[0990]

[0991] la

[0992] or a pharmaceutically acceptable salt thereof, about 10 w / w% crospovidone, about 1.5 w / w% magnesium stearate, and about 28.5 w / w% microcrystalline cellulose; and

[0993] (b) a solution comprising about 2 mg / mL of a compound of Formula II:

[0994]

[0995] II

[0996] or a pharmaceutically acceptable salt thereof, about 10 w / w% Kolliphor HS-15, about 5 w / w% N-methylpyrrolidone, about 30 w / w% PEG 300, and about 55 w / w% water.

[0997] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising about 60 w / w% of a compound of Formula la:

[0998]

[0999] la

[1000] or a pharmaceutically acceptable salt thereof, about 10 w / w% crospovidone, about 2 w / w% magnesium stearate, and about 28 w / w% microcrystalline cellulose; and

[1001] (b) a solution comprising about 2 mg / mL of a compound of Formula II:

[1002]

[1003] II

[1004] or a pharmaceutically acceptable salt thereof, about 10 w / w% Kolliphor HS-15, about 5 w / w% N-methylpyrrolidone, about 30 w / w% PEG 300, and about 55 w / w% water.

[1005] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of a compound of Formula la:

[1006]

[1007] la

[1008] or a pharmaceutically acceptable salt thereof; and

[1009] (b) about 10 mg to about 25 mg of a compound of Formula II:

[1010]

[1011] II

[1012] or a pharmaceutically acceptable salt thereof.

[1013] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of the free acid form of the compound of Formula la:

[1014]

[1015] la;

[1016] and

[1017] (b) about 10 mg to about 25 mg of a pharmaceutically acceptable salt of the compound of Formula II:

[1018]

[1019] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II is a mesylate salt.

[1020] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of an amorphous form of the free acid form of the compound of Formula la:

[1021]

[1022] la;

[1023] and

[1024] (b) about 10 mg to about 25 mg of a mesylate salt of the compound of Formula II:

[1025]

[1026] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of a compound of Formula lb:

[1027]

[1028] lb

[1029] or a pharmaceutically acceptable salt thereof; and

[1030] (b) about 10 mg to about 25 mg of a compound of Formula II:

[1031]

[1032] II

[1033] or a pharmaceutically acceptable salt thereof.

[1034] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of the free acid form of the compound of Formula lb:

[1035]

[1036] lb;

[1037] and

[1038] (b) about 10 mg to about 25 mg of a pharmaceutically acceptable salt of the compound of Formula II:

[1039]

[1040] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II is a mesylate salt.

[1041] In some embodiments, the present disclosure provides a method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of an amorphous form of the free acid form of the compound of Formula lb:

[1042]

[1043] lb;

[1044] and

[1045] (b) about 10 mg to about 25 mg of a mesylate salt of the compound of Formula II:

[1046]

[1047] The description provided herein is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[1048] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[1049] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[1050] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[1051] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (i.e., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associatedwith the disease or condition (i.e., stabilizing the disease or condition, halting or delaying the worsening or progression of the disease or condition, and / or halting or delaying the spread (i.e., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (i.e., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[1052] “Patient” or “subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the patient is a human.

[1053] The term “therapeutically effective amount” or “effective amount” of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to improve a symptom of a Retroviridae viral infection, including but not limited to HIV infection. The therapeutically effective amount may vary depending on the subject, and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art. In some embodiments, the compounds provided herein, or a pharmaceutically acceptable salts thereof, are administered orally.

[1054] The methods provided herein comprise administration of compounds provided herein (e.g., administration of a compound of Formula I and a compound of Formula II), and salts thereof, such as pharmaceutically acceptable salts. A salt generally refers to a derivative of a disclosed compound wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. A pharmaceutically acceptable salt is one that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, 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 or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional nontoxic salts of the parent compound formed, for example, from non-toxic inorganic or organicacids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. In some embodiments, the salt of the compound of Formula Illa or Illb is a sodium salt.

[1055] Synthesis

[1056] As will be appreciated by those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[1057] Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and / or alumina chromatography.

[1058] During any of the processes for preparation of the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4thed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[1059] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art willrecognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Isolation of final compounds can be performed by various methods known to those skilled in the art but is optimally reverse phase HPLC followed by lyophilization from various organic solvents. Repeated lyophilization can optionally be performed to reduce the amount of residual acidic modifiers resulting from the purification process. In some embodiments, the final compounds provided herein were isolated as mono- or bis- trifluoracetic acid salts.

[1060] The methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or diastereomerically pure.

[1061] Additional Combination Therapies

[1062] Patients being treated by administration of the compounds provided herein, or pharmaceutically acceptable salts thereof, often exhibit diseases or conditions that benefit from treatment with additional therapeutic agents, including agents that are therapeutic for Retroviridae infections, including an HIV infection. In some embodiments, the additional therapeutic agent is an agent that is therapeutic for an HIV infection. Thus, one aspect of the disclosure is a method of treating an HIV infection comprising administering the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, in combination with one or more compounds useful for the treatment of an HIV infection to a subject, particularly a human subject, in need thereof.

[1063] In some embodiments, the methods provided herein further comprise administering to the patient one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof (i.e., administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a compound of Formula II, or a pharmaceutically acceptable salt thereof, and one more additional therapeutic agents).In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with one, two, three, four or more additional therapeutic agents.

[1064] In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with one additional therapeutic agent. In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with two additional therapeutic agents. In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with three additional therapeutic agents. In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[1065] In some embodiments, when the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are administered in combination with one or more additional therapeutic agents as described herein, each compound or composition is administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[1066] In some embodiments, the compounds, or a pharmaceutically acceptable salts thereof, or compositions of the present disclosure, are co-administered with one or more additional therapeutic agents.

[1067] Co-administration includes administration of unit dosages of the compounds, salts, and compositions provided herein, before or after administration of unit dosages of one or more additional therapeutic agents. The compounds, salts, and compositions provided herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound, salt, or composition provided herein, is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in some embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of compound, salt, or composition provided herein, within seconds or minutes. In some embodiments, a unit dose of a compound, salt, orcomposition provided herein is administered first, followed, after a period of hours (i.e., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (i.e., 1-12 hours), by administration of a unit dose of compound, salt, or composition provided herein.

[1068] HIV Combination Therapy

[1069] In some embodiments, the additional therapeutic agent or agents may be an anti-HIV agent. In some instances, the additional therapeutic agent can be HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of 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, inhibitors of Tat-TAR-P-TEFb, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T-cell receptors, TCR-T, autologous T-cell therapies, engineered B cells, NK cells), latency reversing agents, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, Fatty acid synthase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF alpha 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, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, Cytochrome P4503 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxy cytidine kinase inhibitors, cyclin dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidaseinhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P- Glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, Prolyl endopeptidase inhibitors, Phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[1070] In some embodiments, the additional therapeutic agent or agents are selected from combination drags for HIV, other drags 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 reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.

[1071] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drags for HIV, other drags 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 reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, and combinations thereof.

[1072] In some embodiments, the additional therapeutic agent or agents are chosen from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, T cell and NK cell recruiting bispecific antibodies, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drags for treating HIV, and combinations thereof.

[1073] In some embodiments, the additional therapeutic agent or agents any are chosen from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[1074] HIV Combination Drugs

[1075] 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® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarateand emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine);

[1076] ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; 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, cobicistat, and elvitegravir; tenofovir analog; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine;

[1077] ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKT AR VY® (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO® (dolutegravir + lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + albuvirtide, elpida (elsulfavirine, VM-1500), and VM-1500A, and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[1078] Other HIV Drugs

[1079] Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB-728-T, 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, bryostatin- 1, bryostatin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid(FAN A) -modified antisense oligonucleotides, FX-101, griffithsin, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, IL- 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 analogs, TBL-1004HI, VG-1177, xl-081, AVLCO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (A VC), 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.

[1080] HIV Protease Inhibitors

[1081] Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, 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, e.g., in U. S. Patent No. 10,294,234, and U. S. Patent Application Publication Nos. US2020030327 and US2019210978.

[1082] HIV Gag Protein Inhibitors

[1083] Examples of HIV Gag protein inhibitors include, but are not limited to, HRF- 10071.

[1084] HIV Ribonuclease H Inhibitors

[1085] Examples of HIV ribonuclease II inhibitors include, but are not limited to, NSC-727447.

[1086] HIV Nef Inhibitors

[1087] Examples of HIV Nef inhibitors include, but are not limited to, FP- 1.

[1088] HIV Reverse Transcriptase Inhibitors

[1089] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, Ml-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained release oral, HIV infection), elsulfavirine (long acting injectable nanosuspension, HIV infection), and elsulfavirine (VM-1500). Additional non- limiting examples of non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include the compounds disclosed in U. S. Patent No. 10,548,898.

[1090] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8583, VM-2500, and KP-1461.

[1091] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[1092] HIV Integrase Inhibitors

[1093] Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended-release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, PEGylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, 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 the compounds disclosed in U. S. Patent No. 11,084,832.Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[1094] HIV Viral Infectivity Factor Inhibitors

[1095] Examples of HIV viral infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives, and Irino-L.

[1096] HIV Entry Inhibitors

[1097] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, gpl60 inhibitors, and CXCR4 inhibitors.

[1098] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc and vMIP (Haimipu).

[1099] Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, griffithsin (gp41 / gpl20 / gpl60 inhibitor), BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 ftision inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, C13hmAb, lipuvirtide, PIE- 12 trimer and sifuvirtide.

[1100] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs

[1101] Examples of gpl20 inhibitors include, but are not limited to, anti-HIV microbicide, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[1102] Examples of gpl60 inhibitors include, but are not limited to, fangchinoline.

[1103] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT- 1188, N15 peptide, and vMIP (Haimipu).

[1104] HIV Maturation Inhibitors

[1105] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254 and GSK-2838232.Latency

[1106]

[1107] Examples of latency reversing agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HD AC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitor of apoptosis proteins, such as APG-1387, LBW- 242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio- 1143), PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic 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 largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactones.

[1108] Additional examples of TLR7 agonists include, but are not limited to, those described in U. S. Patent Application Publication No. US2010143301.

[1109] Additional examples of TLR8 agonists include, but are not limited to, those described in U. S. Patent Application Publication No. US2017071944.

[1110] Histone Deacetylase (HD AC) Inhibitors

[1111] In some embodiments, the compounds, salts, and compositions disclosed herein are combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HD AC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HD AC inhibitors include without limitation, 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), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[1112] Capsid Inhibitors

[1113] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacapavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, HIV-1 capsidinhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK WO2019 / 087016).

[1114] Additional examples of capsid inhibitors include, but not limited to, those described in U. S. Patent Application Publication Nos. US2018051005 and US2016108030.

[1115] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U. S. Patent Application Publication Nos. US2014221356 and US2016016973.

[1116] P4503 inhibitors

[1117] Examples of Cytochrome P4503 inhibitors include, but are not limited to, those described in U. S. Patent No. 7,939,553.

[1118] RNA polymerase modulators

[1119] Examples of RNA polymerase modulators include, but are not limited to, those described in U. S. Patent Nos. 10,065,958 and 8,008,264.

[1120] Immune Checkpoint Modulators

[1121] In some embodiments, the compounds, salts, and compositions disclosed 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 one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics. In various embodiments, the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[1122] Examples of immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1(NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRA1LR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, GDI 12); CD226 (DNAM-1);

[1123] Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); 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); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); lymphocyte activating 3 (CD223): killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin like receptor Cl (KLRC1, NKG2A, CDL59A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and Hematopoietic Progenitor Kinase 1 (HPK1,

[1124] MAP4K1).In some embodiments, the compounds, salts, and compositions disclosed herein are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation 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 immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3);

[1125] TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the agents, as described herein, are combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (IGOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); 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, CD 155). See, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[1126] In some embodiments, the compounds, salts, and compositions disclosed herein are combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like rece...

Claims

WHAT IS CLAIMED IS:

1. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a compound of Formula la:laor a pharmaceutically acceptable salt thereof; and(b) a compound of Formula II:or a pharmaceutically acceptable salt thereof.

2. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a pharmaceutical composition comprising a compound of Formula la:laor a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and(b) a pharmaceutical composition comprising a compound of Formula II:or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. The method of claim 2, wherein the pharmaceutical composition comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, is a tablet.

4. The method of claim 3, wherein the tablet comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, crospovidone, magnesium stearate, and microcrystalline cellulose.

5. The method of claim 3 or 4, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 55 w / w% to about 65 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

6. The method of claim 3 or 4, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 60 v \: / ( of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 3 to 6, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 5 w / w% to about 15 crospovidone.

8. The method of any one of claims 3 to 6, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 10 w / w% crospovidone.

9. The method of any one of claims 3 to 8, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 1 w / w% to about 3 w / w% magnesium stearate.

10. The method of any one of claims 3 to 8, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 1.5 w / w% magnesium stearate.

11. The method of any one of claims 3 to 10, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 25 w / w% to about 30 w / w% microcrystalline cellulose.

12. The method of any one of claims 3 to 10, wherein the tablet comprising the compound of Formula la, or a pharmaceutically acceptable salt thereof, comprises about 28.5 w / w% microcrystalline cellulose.

13. The method of claim 3 or 4, wherein the tablet comprises about 55 w / w% to about 65 w / w% of the compound of Formula la, or a pharmaceutically acceptable salt thereof, about 5 w / w% to about 15 w / w% crospovidone, about 1 w / w% to about 3 w / w% magnesium stearate, and about 25 w / w% to about 30 w / w% microcrystalline cellulose.

14. The method of claim 3 or 4, wherein the tablet comprises about 60of the compound of Formula la, or a pharmaceutically acceptable salt thereof, about 10 \\'l\:f7 crospovidone, about 1.5magnesium stearate, and about 28.5 w / w% microcrystalline cellulose.

15. The method of any one of claims 2 to 14, wherein the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a suspension or solution.

16. The method of any one of claims 2 to 15, wherein the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a suspension suitable for oral administration.

17. The method of claim 15 or 16, wherein the suspension comprises the compound of Formula II, or a pharmaceutically acceptable salt thereof, carboxymethyl cellulose, and water.

18. The method of any one of claims 15 to 17, wherein the suspension comprises about 0.1to about 1 carboxymethyl cellulose.

19. The method of any one of claims 15 to 17, wherein the suspension comprises about 0.5 w / w% carboxymethyl cellulose.

20. The method of any one of claims 15 to 19, wherein the suspension comprises about 99 to about 99.9 w!\\:f7< water.

21. The method of any one of claims 15 to 19, wherein the suspension comprises about 99.5 w / w% water.

22. The method of any one of claims 2 to 14, wherein the pharmaceutical composition comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, is a solution.

23. The method of any one of claims 15 or 22, wherein the solution comprises the compound of Formula II, or a pharmaceutically acceptable salt thereof, Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.

24. The method of any one of claims 15, 22, and 23, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 8 w / w% to about 12 w / w% Kolliphor HS-15.

25. The method of any one of claims 15, 22, and 23, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 10 w / w% Kolliphor HS-15.

26. The method of any one of claims 15, 22, and 23 to 25. wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 3to about 7 N-methylpyrrolidone.

27. The method of any one of claims 15, 22, and 23 to 25, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 5 w / w% N-methylpyrrolidone.

28. The method of any one of claims 15, 22, and 23 to 27, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 25 w / w% to about 35 w / w% PEG 300.

29. The method of any one of claims 15, 22, and 23 to 27, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 30 w / w% PEG 300.

30. The method of any one of claims 15, 22, and 23 to 29, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 50 w / w% to about 60 w / w% water.

31. The method of any one of claims 15, 22, and 23 to 29, wherein the solution comprising the compound of Formula II, or a pharmaceutically acceptable salt thereof, comprises about 55 w / w% water.

32. The method of any one of claims 15 to 31, wherein the solution or suspension comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 15 to 31, wherein the solution or suspension comprises about 2 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 15 to 31, wherein the solution or suspension comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 0.1 w / w% to about 1 w / w% carboxymethyl cellulose, and about 99 w / w% to about 99.9 w / w% water.

35. The method of any one of claims 15 to 17, wherein the suspension comprises about 2 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 0.5 w / w% carboxymethyl cellulose, and 99.5 w / w% water.

36. The method of any one of claims 15, 22, and 23, wherein the solution comprises about 1 mg / mL to about 5 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3 w / w% to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

37. The method of any one of claims 15, 22, and 23, wherein the solution comprises about 2 mg / mL of the compound of Formula II, or a pharmaceutically acceptable salt thereof, about 10 w / w% Kolliphor HS-15, about 5 w / w% N-methylpyrrolidone, about 30PEG 300, and about 55 w / w% water.

38. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising a compound of Formula la:or a pharmaceutically acceptable salt thereof, crospovidone, magnesium stearate, and microcrystalline cellulose; and(b) a solution comprising a compound of Formula II:IIor a pharmaceutically acceptable salt thereof, Kolliphor HS-15, N-methylpyrrolidone, PEG 300, and water.

39. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising about 55 w / w% to about 65 w / w% of a compound of Formula la:laor a pharmaceutically acceptable salt thereof, about 5 w / w% to about 15 w / w% crospovidone, about 1 w / w% to about 3 w / w% magnesium stearate, and about 25 w / w% to about 30 w / w% microcrystalline cellulose; and(b) a solution comprising about 1 mg / mL to about 5 mg / mL of a compound of Formula II:IIor a pharmaceutically acceptable salt thereof, about 8 w / w% to about 12 w / w% Kolliphor HS-15, about 3to about 7 w / w% N-methylpyrrolidone, about 25 w / w% to about 35 w / w% PEG 300, and about 50 w / w% to about 60 w / w% water.

40. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) a tablet comprising about 60 w / w% of a compound of Formula la:laor a pharmaceutically acceptable salt thereof, about 10 w / w% crospovidone, about 1.5 w / w% magnesium stearate, and about 28.5 w / w% microcrystalline cellulose; and(b) a solution comprising about 2 mg / mL of a compound of Formula II:or a pharmaceutically acceptable salt thereof, about 10 w / w% Kolliphor HS-15, about 5 w / w% N-methylpyrrolidone, about 30 w / w% PEG 300, and about 55 w / w% water.

41. The method of any one of claims 3 to 40, wherein the tablet comprises about 800 mg to about 1200 mg of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 3 to 40, wherein the tablet comprises about 900 mg to about 1100 mg of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 3 to 40, wherein the tablet comprises about 1000 mg of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 3 to 40, wherein the tablet comprises about 300 mg to about 400 mg of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

45. The method of any one of claims 3 to 40, wherein the tablet comprises about 350 mg of the compound of Formula la, or a pharmaceutically acceptable salt thereof.

46. The method of any one of claims 1 to 45, wherein the method comprises orally administering the compound of Formula la, or a pharmaceutically acceptable salt thereof, to the patient once every month.

47. The method of any one of claims 3 to 46, wherein the method comprises orally administering the compound of Formula la, or a pharmaceutically acceptable salt thereof, to the patient once every month.

48. The method of any one of claims 1 to 47, which is a method of treating HIV.

49. The method of any one of claims 1 to 48, wherein the HIV is HIV-1.

50. The method of any one of claims 1 to 49, wherein the patient is a human.

51. The method of any one of claims 1 to 50, wherein the compound of Formula la is administered as a free acid form.

52. The method of any one of claims 1 to 50, wherein the compound of Formula la is administered as an amorphous free acid form.

53. The method of any one of claims 1 to 50, wherein the compound of Formula la is a compound of Formula lb:Ibor a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the compound of Formula la is administered as a free acid form.

55. The method of claim 53 or 54, wherein the compound of Formula lb is administered as an amorphous free acid form.

56. The method of any one of claims 1 to 55, wherein the compound of Formula II is administered as a pharmaceutically acceptable salt.

57. The method of any one of claims 1 to 56, wherein the compound of Formula II is administered as a mesylate salt.

58. A method of treating a human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient:(a) about 800 mg to about 1200 mg of a compound of Formula lb:or a pharmaceutically acceptable salt thereof; and(b) about 10 mg to about 25 mg of a compound of Formula II:or a pharmaceutically acceptable salt thereof.

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