Inhibitors of human immunodeficiency virus replication

Abstract

Pharmaceutical compositions comprising a compound of Formula Ia or Formula Ib, or a pharma- ceutically acceptable salt thereof, are described. [Formula 1] JPEG2024535596000039.jpg66146

Description

[Technical field]

[0001] The present invention relates to compounds, pharmaceutical compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the present invention provides pharmaceutical compositions containing inhibitors of HIV and methods of using these compositions in the treatment of HIV infection. [Background technology]

[0002] Acquired immune deficiency syndrome (AIDS) is the result of infection with HIV. HIV remains a major global public health problem. In 2015, an estimated 36.7 million people were living with HIV (including 1.8 million children) - a global HIV prevalence of 0.8%. The majority of this number live in low- and middle-income countries. In the same year, 1.1 million people died from AIDS-related illnesses.

[0003] Current treatment of HIV-infected individuals consists of a combination of approved antiretroviral agents. Currently, close to 48 drugs are approved for HIV infection as single agents, fixed-dose combinations, or one-tablet-per-day regimens. The latter two contain 2-4 approved agents. These agents belong to several different classes that target viral enzymes or the function of viral proteins during the viral replication cycle. Thus, agents are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein). Additionally, pharmacokinetic enhancers (cobicistat or ritonavir) may be used in combination with antiretrovirals (ARVs) that require boosting.

[0004] Several potential therapeutic compounds have been described in the art that appear to act by interfering with the normal function of the HIV viral capsid. No currently approved drugs act by this mechanism, therefore a compound that acts by this mechanism would be a useful addition to the options available for the treatment of HIV infection.

[0005] WO 2020 / 084492 and WO 2020 / 254985 disclose several capsid inhibitor compounds, including the two compounds shown below, which are referred to in this application as compounds of Formula Ia and Formula Ib.

[0006] [ka] Summary of the Invention

[0007] These compounds offer advantages for pharmaceutical use, for example, with respect to one or more of their mechanism of action, binding, inhibitory efficacy, target selectivity, solubility, safety profile, bioavailability and / or reduced dosing frequency. The present disclosure teaches pharmaceutical compositions, methods of administration and methods of treatment utilizing these compounds.

[0008] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof,

[0009] [ka]

[0010] A pharmaceutical composition is provided that includes polyethylene glycol (PEG) and ethanol.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof,

[0012] [ka]

[0013] A pharmaceutical composition is provided that contains water and less than 1% by weight of polyethylene glycol.

[0014] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof,

[0015] [ka]

[0016] A pharmaceutical composition is provided that includes polyethylene glycol (PEG) and ethanol.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof,

[0018] [ka]

[0019] A pharmaceutical composition is provided that contains water and less than 1% by weight of polyethylene glycol.

[0020] In another aspect, the present invention provides a method of treating HIV infection in a patient, comprising the step of administering to said patient a therapeutically effective amount of a pharmaceutical composition of the present invention described below.

[0021] In another aspect, the present invention provides a pharmaceutical composition of the invention as described below for use in therapy.

[0022] In another aspect, the present invention provides a pharmaceutical composition of the invention as described below for use in treating HIV infection in a patient.

[0023] In another aspect, the present invention provides the use of a pharmaceutical composition of the invention as described below in the manufacture of a medicament for the treatment of HIV infection in a patient. [Brief description of the drawings]

[0024] [Figure 1] 1-3 summarize the results of the PK experiments described below and summarized in Tables 1-3. [Diagram 2] 1-3 summarize the results of the PK experiments described below and summarized in Tables 1-3. [Diagram 3] 1-3 summarize the results of the PK experiments described below and summarized in Tables 1-3. [Figure 4] 4-6 summarize the results of the PK experiments described below and summarized in Tables 4-6. [Diagram 5] 4-6 summarize the results of the PK experiments described below and summarized in Tables 4-6. [Figure 6] 4-6 summarize the results of the PK experiments described below and summarized in Tables 4-6. [Figure 7] Figures 7-9 summarize the results of the PK experiments described below and summarized in Tables 7-9. [Figure 8] Figures 7-9 summarize the results of the PK experiments described below and summarized in Tables 7-9. [Figure 9] Figures 7-9 summarize the results of the PK experiments described below and summarized in Tables 7-9. [Figure 10] 10-12 summarize the results of the PK experiments described below and summarized in Tables 10-12. [Figure 11] 10-12 summarize the results of the PK experiments described below and summarized in Tables 10-12. [Figure 12] 10-12 summarize the results of the PK experiments described below and summarized in Tables 10-12. [Figure 13]13-14 summarize the results of the PK experiments described below and summarized in Tables 13-14. [Figure 14] 13-14 summarize the results of the PK experiments described below and summarized in Tables 13-14. [Figure 15] 15-16 summarize the results of the PK experiments described below and summarized in Tables 15-16. [Figure 16] 15-16 summarize the results of the PK experiments described below and summarized in Tables 15-16. [Figure 17] Figures 17-18 summarize the results of the PK experiments described below and summarized in Tables 17-18. [Figure 18] Figures 17-18 summarize the results of the PK experiments described below and summarized in Tables 17-18. [Figure 19] 19-20 summarize the results of the PK experiments described below and summarized in Tables 19-20. [Figure 20] 19-20 summarize the results of the PK experiments described below and summarized in Tables 19-20. [Figure 21] 21-22 summarize the results of the PK experiments described below and summarized in Tables 21-22. [Figure 22] 21-22 summarize the results of the PK experiments described below and summarized in Tables 21-22. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The compound of formula Ia is known by the chemical name N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. Methods for making compounds of formula Ia can be found in WO 2020 / 084492.

[0026] The compound of formula Ib is known by the chemical name N-((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. Methods for making compounds of formula Ib can be found in WO 2020 / 254985.

[0027] Suitably, the compositions of the invention comprise a therapeutically effective amount of a compound of formula Ia or a pharma- ceutically acceptable salt thereof. In one embodiment, the compositions of the invention comprise a therapeutically effective amount of a compound of formula Ia as the free base.

[0028] In one embodiment, the compositions of the invention comprise a therapeutically effective amount of a compound of Formula Ia that is amorphous.

[0029] Suitably, the compositions of the invention comprise a therapeutically effective amount of a compound of formula Ib or a pharma- ceutically acceptable salt thereof.In one embodiment, the compositions of the invention comprise a therapeutically effective amount of a compound of formula Ib as the free base.

[0030] In one embodiment, the compositions of the invention comprise a therapeutically effective amount of a compound of Formula Ib that is amorphous.

[0031] As used herein, a "therapeutically effective amount" with respect to a compound of the present invention, a salt thereof, or a pharmaceutical composition comprising said compound or a salt thereof, or other pharma- ceutical active agent or composition, refers to an amount of the compound of the present invention, a salt thereof, or a pharmaceutical composition comprising said compound or a salt thereof, sufficient to treat the condition of the patient within the scope of sound medical judgment, but low enough (at a reasonable benefit / risk ratio) to avoid serious side effects. Thus, for example, a therapeutically effective amount of a compound of formula Ia or formula Ib, or a pharma- ceutical composition comprising a compound of formula Ia or a compound of formula Ib, or a salt thereof, when administered to a patient in need thereof, is an amount sufficient to modulate the activity of HIV capsid such that a disease state mediated by said activity is treated, including reduced, alleviated, or prevented. A therapeutically effective amount of a compound, a salt thereof, or a pharmaceutical composition comprising the compound or a salt thereof will vary depending on the particular compound selected (taking into account, for example, the potency, efficacy, and half-life of the compound); the selected route of administration; the condition being treated; the severity of the condition being treated; the age, size, weight, and health of the patient being treated; the medical history of the patient being treated; the duration of treatment; the nature of any concurrent treatments; the desired therapeutic effect; and similar factors, but may nevertheless be routinely determined by one of ordinary skill in the art.

[0032] In one embodiment, the composition of the present invention comprises polyethylene glycol and ethanol. Polyethylene glycol (PEG) has the general chemical formula H-(O-CH 2 -CH 2 ) n It will be understood by one of ordinary skill in the art that the carboxyl group may be written as -OH. In one embodiment, the composition of the present invention is a homogeneous solution.

[0033] In one embodiment, the present invention provides a composition further comprising water. In another embodiment, the present invention provides a composition further comprising lecithin. In yet another embodiment, the present invention provides a composition further comprising propylene glycol. In yet another embodiment, the present invention provides a composition further comprising benzyl alcohol. In yet another embodiment, the present invention provides a composition further comprising benzyl benzoate. In another embodiment, the present invention provides a composition further comprising sucrose acetate isobutyrate (SAIB). In yet another embodiment, the present invention provides a composition further comprising sesame oil.

[0034] In yet another embodiment, the present invention provides a composition further comprising one or more ingredients that are water, lecithin, propylene glycol, benzyl alcohol, benzyl benzoate, SAIB, or sesame oil. In one embodiment, the present invention provides a composition further comprising one or more ingredients that are water, lecithin, propylene glycol, benzyl alcohol, benzyl benzoate, or sesame oil. In one embodiment, the present invention provides a composition further comprising one or more ingredients that are water, lecithin, propylene glycol, benzyl alcohol, or sesame oil. In one embodiment, the present invention provides a composition further comprising one or more ingredients that are propylene glycol, benzyl alcohol, or sesame oil.

[0035] In one embodiment, the lecithin is egg-based, hi another embodiment, the lecithin is soy-based and is about 80% phosphatidylcholine by weight, or is about 100% phosphatidylcholine by weight.

[0036] In one embodiment of the invention, the average molecular weight of the polyethylene glycol is about 200 (PEG 200).

[0037] In another embodiment of the invention, the average molecular weight of the polyethylene glycol is about 300 (PEG 300).

[0038] In another embodiment of the invention, the average molecular weight of the polyethylene glycol is about 400 (PEG 400).

[0039] Suitably, the amount of an ingredient present in a composition is expressed as weight % based on the total weight of the formulation.

[0040] In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition, expressed as a percentage by weight, is about 5-50%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 5-30%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 5-35%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 10-25%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 10-30%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 15-30%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 20-30%. In one embodiment of the invention, the amount of the compound of formula Ia or a pharma- ceutically acceptable salt thereof present in the composition is about 25-35%. In one embodiment of the present invention, the amount of the compound of formula Ia or its pharma- ceutically acceptable salt present in the composition is about 30-40%. In one embodiment of the present invention, the amount of the compound of formula Ia or its pharma- ceutically acceptable salt present in the composition is about 35-45%. In one embodiment of the present invention, the amount of the compound of formula Ia or its pharma- ceutically acceptable salt present in the composition is about 40-50%.

[0041] In one embodiment of the invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition, expressed as a weight percent, is about 5-50%.

[0042] In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 5-30%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 5-35%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 10-25%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 10-30%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 15-30%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 20-30%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 25-35%. In one embodiment of the present invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 30-40%. In one embodiment of the invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 35-45%.In one embodiment of the invention, the amount of the compound of formula Ib or a pharma- ceutically acceptable salt thereof present in the composition is about 40-50%.

[0043] Preferably, the compositions of the present invention are administered subcutaneously.

[0044] In one embodiment, the present invention provides a homogenous solution for subcutaneous administration comprising an amorphous form of the compound of formula Ia. In one embodiment, the present invention provides a homogenous solution for subcutaneous administration comprising an amorphous form of the compound of formula Ib.

[0045] In one embodiment, the present invention provides a heterogeneous suspension for subcutaneous administration. In one embodiment, the present invention provides a heterogeneous suspension for subcutaneous administration comprising an amorphous form of the compound of formula Ia. In one embodiment, the present invention provides a heterogeneous suspension for subcutaneous administration comprising an amorphous form of the compound of formula Ib.

[0046] Preferably, the compositions of the present invention are administered intramuscularly.

[0047] Preferably, the compositions of the present invention are administered intravenously.

[0048] The composition of the present invention comprises a vehicle or carrier, which is an inert medium used as a solvent or diluent in which the active agent Formula Ia or Formula Ib is formulated or administered. Suitable vehicles for the composition of the present invention include, but are not limited to, ethanol (up to about 35% by weight), polyethylene glycol (up to about 85% by weight), modified polyethylene glycol (up to about 85% by weight), propylene glycol (up to about 60% by weight), N-methyl-2-pyrrolidone (NMP) (up to about 5% by weight), dimethylacetamide (DMA) (up to about 50% by weight), dimethylsulfoxide (DMSO) (up to about 5% by weight), water, ethyl lactate, dimethylisosorbide, etc. It will be understood that one or more solvents may comprise a vehicle for a particular pharmaceutical composition.

[0049] The composition of the present invention optionally comprises an oil. Suitable oils for the composition of the present invention include, but are not limited to, sesame oil, soybean oil, castor oil, medium chain triglycerides, safflower oil, and the like. Preferably, in an emulsion, the oil is present in an amount of about 0 to about 50% by weight. Preferably, in an oil-based solution, the oil is present in an amount of up to about 100% by weight. In one embodiment, the present invention provides a homogeneous solution comprising an oil.

[0050] The compositions of the present invention optionally include a surfactant. Suitable surfactants include, but are not limited to, phospholipids (up to about 25% by weight), poloxamers (up to about 7% by weight), polysorbates (up to about 7% by weight), sorbitan esters (aka span) (up to about 7% by weight), and the like. In one embodiment, the present invention provides a composition comprising a phospholipid surfactant. In one embodiment, the present invention provides a composition comprising a phospholipid surfactant that is lecithin. In one embodiment, the present invention provides a composition comprising poloxamer 338. In one embodiment, the present invention provides a composition comprising poloxamer 188. In one embodiment, the present invention provides a composition comprising poloxamer 338 or poloxamer 188.

[0051] In one embodiment, the invention provides a heterogeneous suspension comprising a surfactant. In one embodiment, the invention provides a heterogeneous suspension comprising a surfactant. In one embodiment, the invention provides a heterogeneous suspension comprising lecithin. In one embodiment, the invention provides a heterogeneous suspension comprising poloxamer 338. In one embodiment, the invention provides a heterogeneous suspension comprising poloxamer 188. In one embodiment, the invention provides a heterogeneous suspension comprising poloxamer 338 or poloxamer 188.

[0052] When the composition of the present invention is a heterogeneous suspension, it optionally contains an isotonicity / tonicity agent. Suitable isotonicity / tonicity agents include, but are not limited to, mannitol (about 1 to about 5% by weight), trehalose (about 7 to about 10% by weight), sucrose (about 7 to about 10% by weight), glucose (about 3 to about 5% by weight), dextrose (about 3 to about 5% by weight), sodium chloride (about 0.45 to about 0.9% by weight), potassium chloride (about 0.45 to about 0.9% by weight), etc. In one embodiment, the present invention provides a heterogeneous suspension containing mannitol.

[0053] The composition of the present invention optionally comprises a buffering agent. Buffering agents suitable for the composition of the present invention include, but are not limited to, acetate, citrate, tartrate, malic acid and its salts, NaOH and HCl, formate, histidine, phosphate, TRIS, borate, etc. In one embodiment, the present invention provides a composition comprising a buffering agent in an amount of about 1 mM to about 20 mM.

[0054] In one aspect, the present invention provides a composition that is a microsuspension. In one embodiment, the present invention provides a microsuspension composition that includes a viscosity modifier. Viscosity modifiers suitable for the compositions of the present invention include, but are not limited to, sodium carboxymethylcellulose, hyaluronic acid, PVP-K-12, K-19, hydroxyethyl starch, and the like. In one embodiment, the present invention provides a composition that includes a viscosity modifier at a level of 0 to about 1% by weight. In another embodiment, the present invention provides a microsuspension composition that includes a bulking agent. Bulking agents suitable for the compositions of the present invention include, but are not limited to, mannitol (about 3 to about 5% by weight), trehalose (about 7 to about 10% by weight), sucrose (about 7 to about 10% by weight), glucose (about 3 to about 5% by weight), dextrose (about 3 to about 5% by weight), and the like. In one embodiment, the present invention provides a composition that is a lyophilized microsuspension.

[0055] In another aspect, the present invention provides a pharmaceutical composition, wherein the amount of polyethylene glycol present in the pharmaceutical composition is about 10-55%, expressed as % by weight. In one embodiment of the present invention, the amount of polyethylene glycol present in the composition is about 15-50%. In a second embodiment of the present invention, the amount of polyethylene glycol present in the composition is about 20-50%. In one embodiment of the present invention, the amount of polyethylene glycol present in the composition is about 20-40%. In one embodiment of the present invention, the amount of polyethylene glycol present in the composition is about 30-50%. In one embodiment of the present invention, the amount of polyethylene glycol present in the composition is about 40-50%.

[0056] In another aspect, the present invention provides a pharmaceutical composition, wherein the amount of ethanol present in the pharmaceutical composition, expressed as % by weight, is about 1-35%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 5-30%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 5-25%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 10-30%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 10-25%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 15-30%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 15-20%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 15-25%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 20-25%. In one embodiment of the present invention, the amount of ethanol present in the composition is about 25-35%.

[0057] Suitably, the pharmaceutical composition comprises mannitol. In another aspect, the present invention provides a pharmaceutical composition, wherein the amount of mannitol present in the pharmaceutical composition is 1-5%, expressed as a % by weight. In one embodiment of the present invention, the amount of mannitol present in the composition is about 2-4%.

[0058] Suitably, the pharmaceutical composition comprises lecithin. In another aspect, the present invention provides a pharmaceutical composition, wherein the amount of lecithin present in the pharmaceutical composition is about 1-25%, expressed as % by weight. In one embodiment of the present invention, the amount of lecithin in the composition is about 5-25%. In one embodiment of the present invention, the amount of lecithin in the composition is about 10-20%. In one embodiment of the present invention, the amount of lecithin in the composition is about 1-5%. In another embodiment of the present invention, the amount of lecithin present in the composition is about 1%, 2%, 3%, 4%, or 5%.

[0059] In one embodiment of the present invention, the lecithin is egg-based.In another embodiment of the present invention, the lecithin is soybean-based.In one embodiment, when soybean-based, the lecithin is about 80% by weight phosphatidylcholine.In one embodiment, when soybean-based, the lecithin is 100% by weight phosphatidylcholine.

[0060] In another aspect, the present invention provides a composition that is a homogeneous solution.

[0061] In yet another aspect, the present invention provides a composition that is a heterogeneous suspension.

[0062] In one aspect, the present invention provides a pharmaceutical composition, wherein the amount of water present in the pharmaceutical composition is about 1%, 2%, 3%, 4%, or 5%, as measured by Karl Fischer titration. In one embodiment of the present invention, the amount of water present in the composition is less than about 3%. In one embodiment of the present invention, the amount of water present in the composition is less than about 2.5%. In one embodiment of the present invention, the amount of water present in the composition is less than about 2%. In one embodiment of the present invention, the amount of water present in the composition is less than about 1.5%. In one embodiment of the present invention, the amount of water present in the composition is less than about 1%.

[0063] It is understood that all the above embodiments are applicable to the composition of the present invention comprising formula Ia or a pharma- ceutically acceptable salt thereof. It is understood that all the above embodiments are applicable to the composition of the present invention comprising formula Ib or a pharma- ceutically acceptable salt thereof. It is understood that the above embodiments are applicable to the composition of the present invention comprising the compound of formula Ia as a free base. It is understood that the above embodiments are applicable to the composition of the present invention comprising the compound of formula Ia as a free base. It is understood that the above embodiments are applicable to the composition of the present invention comprising the compound of formula Ia as an amorphous compound, as a pharma- ceutically acceptable salt or free base thereof. It is understood that the above embodiments are applicable to the composition of the present invention comprising the compound of formula Ib as an amorphous compound, as a pharma- ceutically acceptable salt or free base thereof.

[0064] In another embodiment, the present invention provides a pharmaceutical composition comprising about 20% by weight of the compound of formula Ia or the compound of formula Ib, about 45% by weight of PEG200, about 20% by weight of ethanol, and about 15% by weight of lecithin. In another embodiment, the present invention provides a pharmaceutical composition comprising about 30% by weight of the compound of formula Ia or the compound of formula Ib, about 45% by weight of PEG200, and about 25% by weight of ethanol. In another embodiment, the present invention provides a composition comprising about 30% by weight of the compound of formula Ia or the compound of formula Ib, about 50% by weight of PEG200, and about 20% by weight of ethanol. In another embodiment, the present invention provides a composition comprising about 20% by weight of the compound of formula Ia or the compound of formula Ib, about 55% by weight of PEG200, and about 20% by weight of ethanol. In yet another embodiment, the present invention provides a composition comprising about 19% by weight of the compound of formula Ia, about 61% by weight of PEG200, and about 20% by weight of ethanol.

[0065] heterogeneous suspension In one embodiment, the composition of the invention comprises water and contains less than 1% by weight of polyethylene glycol, hi another embodiment, the composition of the invention is a heterogeneous suspension.

[0066] In one aspect, the present invention provides a composition, wherein the suspended solid comprises a compound of formula Ia or a pharma- ceutically acceptable salt thereof. In another aspect, the present invention provides a composition, wherein the suspended solid comprises a compound of formula Ib or a pharma- ceutically acceptable salt thereof. In one aspect, the present invention provides a composition, wherein the suspended solid comprises a compound of formula Ia as a free base. In one aspect, the present invention provides a composition, wherein the suspended solid comprises a compound of formula Ib as a free base. It is understood that the above embodiment applies to the composition of the present invention, wherein the suspended solid comprises a compound of formula Ia as an amorphous compound, as a pharma- ceutically acceptable salt thereof or as a free base. It is understood that the above embodiment applies to the composition of the present invention, wherein the suspended solid comprises a compound of formula Ib as an amorphous compound, as a pharma- ceutically acceptable salt thereof or as a free base thereof.

[0067] In one embodiment of the present invention, the composition of the suspended solid is about 20% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 25% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 30% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 35% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 40% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 45% by weight of the compound of formula Ia. In another embodiment of the present invention, the composition of the suspended solid is about 50% by weight of the compound of formula Ia. It is understood that these embodiments apply to the composition of the present invention, in which the suspended solid comprises the compound of formula Ia as a pharma- ceutically acceptable salt or free base, or as an amorphous compound, as its pharma- ceutically acceptable salt or free base.

[0068] In one embodiment of the present invention, the composition of the suspended solid is about 20% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 25% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 30% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 35% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 40% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 45% by weight of the compound of formula Ib. In another embodiment of the present invention, the composition of the suspended solid is about 50% by weight of the compound of formula Ib. It is understood that these embodiments apply to the composition of the present invention, in which the suspended solid comprises the compound of formula Ib as a pharma- ceutically acceptable salt or free base, or as an amorphous compound, as its pharma- ceutically acceptable salt or free base.

[0069] In one aspect, the invention provides compositions further comprising one or more of the following additives: sodium acetate, acetic acid, mannitol, sodium chloride, poloxamer 338, or poloxamer 188. In one embodiment, the invention provides pharmaceutical compositions comprising poloxamer 338 or poloxamer 188. In one embodiment, the invention provides pharmaceutical compositions comprising poloxamer 338 and poloxamer 188. In one embodiment, the invention provides pharmaceutical compositions comprising mannitol or sodium chloride. In one embodiment, the invention provides pharmaceutical compositions comprising mannitol and sodium chloride. In one embodiment, the invention provides pharmaceutical compositions comprising sodium acetate or acetic acid. In one embodiment, the invention provides pharmaceutical compositions comprising sodium acetate and acetic acid.

[0070] Suitably, the mass of the compound of formula Ia or the compound of formula Ib is expressed relative to the total volume of the formulation. In one embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 50-500 mg / mL. In another embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 150-300 mg / mL. In yet another embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 200-300 mg / mL. In yet another embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 250-350 mg / mL. In yet another embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 300-400 mg / mL. In another embodiment, the composition comprises the compound of formula Ia or the compound of formula Ib in a concentration of about 350-450 mg / mL. In another embodiment, the composition comprises a compound of formula Ia or a compound of formula Ib at a concentration of about 400-500 mg / mL. In one aspect, the composition comprises a compound of formula Ia or a compound of formula Ib at a concentration of about 200 mg / mL, about 225 mg / mL, about 250 mg / mL, about 275 mg / mL, about 300 mg / mL, about 325 mg / mL, about 350 mg / mL, about 375 mg / mL, about 400 mg / mL, about 450 mg / mL or about 500 mg / mL. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a compound of formula Ib at a concentration of about.

[0071] In one embodiment, the invention provides a composition comprising about 300 mg / mL of the compound of formula Ia or the compound of formula Ib, about 5.4% by weight of P338, about 3.5% by weight of mannitol, and the balance of the formulation is water or aqueous acetate buffer.

[0072] In one embodiment, the composition of the invention further comprises one or more of glycerol, polyvinylpyrrolidone K19, polyvinylpyrrolidone K12, Span, urea, NMP, ethyl lactate, polysorbate 80, or polysorbate 20.

[0073] In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of formula Ia or a pharma- ceutically acceptable salt thereof.

[0074] In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of formula Ib or a pharma- ceutically acceptable salt thereof.

[0075] In one embodiment, the pharmaceutical composition of the present invention comprises about 20%-30% by weight of the compound of formula Ia or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 20%-30% by weight of the compound of formula Ia as the free base. In another embodiment, the pharmaceutical composition of the present invention comprises about 20%-30% by weight of the compound of formula Ib or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 20%-30% by weight of the compound of formula Ib as the free base.

[0076] In one embodiment, the pharmaceutical composition of the present invention comprises about 20% by weight of the compound of formula Ia or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 20% by weight of the compound of formula Ia as the free base. In another embodiment, the pharmaceutical composition of the present invention comprises about 20% by weight of the compound of formula Ib or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 20% by weight of the compound of formula Ib as the free base.

[0077] In one embodiment, the pharmaceutical composition of the present invention comprises about 30% by weight of the compound of formula Ia or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 30% by weight of the compound of formula Ia as the free base. In another embodiment, the pharmaceutical composition of the present invention comprises about 30% by weight of the compound of formula Ib or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the present invention comprises about 30% by weight of the compound of formula Ib as the free base.

[0078] It is understood that the above embodiment applies to the composition of the invention comprising a compound of formula Ia as an amorphous compound, as a pharma- ceutically acceptable salt or free base.It is understood that the above embodiment applies to the composition of the invention comprising a compound of formula Ib as an amorphous compound, as a pharma- ceutically acceptable salt or free base.

[0079] Suitably, in one embodiment, the particle diameter of the compound of formula Ia or the compound of formula Ib is measured by laser diffraction technique. This type of analysis is used in the general practice of particle size evaluation. An example of an instrument that can perform this analysis is the Malvern Mastersizer MS3000 instrument. Particle size is reported as percentile of distribution. Percentile (e.g. X50) refers to the volume percent of the total volume of test material that has a spherical equivalent diameter less than the reported value. The term "average particle diameter" refers to X50, which is synonymous with D50 or 50th percentile distribution.

[0080] In one embodiment, the average particle diameter of the compound of formula Ia or the compound of formula Ib is ≦about 0.2 μm. In another embodiment, the average particle diameter of the compound of formula Ia or the compound of formula Ib ranges from about 0.2 μm to about 0.5 μm. In another embodiment, the average particle diameter of the compound of formula Ia or the compound of formula Ib ranges from about 0.5 μm to about 3 μm. In another embodiment, the average particle diameter of the compound of formula Ia or the compound of formula Ib ranges from about 3 μm to about 5 μm. In another embodiment, the average particle diameter of the compound of formula Ia or the compound of formula Ib ranges from about 5 μm to about 10 μm.

[0081] In one embodiment of the invention, for compounds of formula Ia, D10 is <0.9 μM, D50 is <2 μM, and D90 is <4 μM. In one embodiment of the invention, for compounds of formula Ib, D10 is <0.9 μM, D50 is <2 μM, and D90 is <4 μM.

[0082] In one embodiment, rather than the specific stereoisomers depicted above in Formula Ia and Formula Ib, the compositions of the present invention include any isomer of the compound of Formula Ia or the compound of Formula Ib, which are included within the scope of the present invention.

[0083] In one embodiment, the stereoisomers depicted in formulas Ia and Ib are ≧95% of all stereoisomers of the same chemical formula.

[0084] The salt of the present invention is a pharma- ceutically acceptable salt. Such salt may be an acid addition salt or a base addition salt. For a review of suitable pharma- ceutically acceptable salts, see, for example, Berge et al., J. Pharm, Sci., 66, 1-19, 1977.

[0085] Representative pharma- ceutically acceptable acid addition salts include 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, hydrogen sulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estholate), edetate (ethylenediaminetetraacetate), estholate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate ( esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,The salts include, but are not limited to, 5-disulfonate (napadisilate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

[0086] Representative pharma- ceutically acceptable base addition salts include aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), and the like. amine, cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

[0087] In one embodiment, the salt of the compound of formula Ia is a sodium salt. In another embodiment, the salt of the compound of formula Ib is a sodium salt. In another embodiment, the salt of the compound of formula Ia is a potassium salt. In another embodiment, the salt of the compound of formula Ib is a potassium salt.

[0088] In another aspect, the present invention discloses a method for preventing HIV infection and reducing the risk of infection in a patient, comprising administering a pharmaceutical composition of the present invention. Pre-exposure prophylaxis (or PrEP) is when a person at risk of HIV infection takes HIV antiretroviral drugs to lower the chance of HIV infection. PrEP has been shown to be effective in reducing the risk of infection. As used herein, "HIV" or "human immunodeficiency virus" refers to HIV-1 and / or HIV-2.

[0089] As used herein, a "patient" refers to a human.

[0090] The compounds, salts and compositions of the present invention are believed to have the HIV capsid as their biological target, and thus their mechanism of action is to alter in one or more ways the function of the HIV capsid.

[0091] The compounds of formula Ia and formula Ib and their salts may be used alone or in combination with other therapeutic agents or their prodrugs.Accordingly, the combination therapy according to the present invention comprises the administration of at least one compound of the present invention or its pharmaceutically acceptable salt, and at least one other agent that may be useful in the treatment of HIV infection.The compound of the present invention or its pharmaceutically acceptable salt, and the other agent may be formulated and administered together in a single pharmaceutical composition, or may be formulated and administered separately.When formulated and administered separately, administration may be performed simultaneously or sequentially in any order.

[0092] Suitable other agents include abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, indinavir. , islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598. In one embodiment, the present invention relates to a compound of formula Ia or a pharma- ceutically acceptable salt thereof in combination with abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, and another therapeutic agent selected from the group consisting of indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.In another embodiment, the present invention provides a combination of a compound of formula Ib or a pharma- ceutically acceptable salt thereof with abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, and another therapeutic agent selected from the group consisting of indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0093] In one embodiment, the present invention provides a combination of a compound of formula Ia and abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, indinavir, istravir, and another therapeutic agent selected from the group consisting of ravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598. In another embodiment, the present invention provides a combination of a compound of formula Ib and abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, indinavir, and another therapeutic agent selected from the group consisting of islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0094] In one embodiment, the present invention provides a compound of formula Ia that is amorphous, and one or more of the following compounds: abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, indinavir, and another therapeutic agent selected from the group consisting of rivaroxaban, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598. In another embodiment, the present invention provides a compound of formula Ib that is amorphous and one or more of the following compounds: abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937 / VH3739937, indinavir, baclo ... and another therapeutic agent selected from the group consisting of cefovir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0095] In one embodiment, the other agent is selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598.

[0096] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598.

[0097] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598.

[0098] In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia, which is amorphous, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib that is amorphous and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, pleziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, and S-365598.

[0099] In one embodiment, the other agent is selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598.

[0100] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598.

[0101] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598.

[0102] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, and S-365598.

[0103] In another embodiment, the other agent is selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0104] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0105] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0106] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0107] In another embodiment, the other agent is selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0108] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0109] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0110] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib, which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0111] In another embodiment, the other agent is dolutegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is dolutegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is dolutegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia and the other therapeutic agent is dolutegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib and the other therapeutic agent is dolutegravir. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia that is amorphous and the other therapeutic agent is dolutegravir. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib that is amorphous and the other therapeutic agent is dolutegravir.

[0112] In another embodiment, the other agent is cabotegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is cabotegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is cabotegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia and the other therapeutic agent is cabotegravir. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib and the other therapeutic agent is cabotegravir. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ia that is amorphous and the other therapeutic agent is cabotegravir. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula Ib that is amorphous and the other therapeutic agent is cabotegravir.

[0113] In yet another embodiment, the other agent is S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib or a pharma- ceutically acceptable salt thereof, and the other therapeutic agent is S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia and the other therapeutic agent is S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib and the other therapeutic agent is S-365598. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia that is amorphous and the other therapeutic agent is S-365598. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ib that is amorphous and the other therapeutic agent is S-365598.

[0114] GSK3640254 is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile, Antimicrob Agents Chemother. 2022;66(1):e0187621. doi:10.1128 / AAC.01876-21; GSK3739937, also known as VH3739937, is an HIV maturation inhibitor and a compound in clinical trial NCT04493684; N6LS, also known as VRC-HIVMAB091-00-AB, is a human monoclonal antibody and a compound in clinical trial NCT03538626; S-365598 is a third generation HIV integrase strand transfer inhibitor (INSTI) discovered by Shionogi Corporation; and S-648414 is a compound in clinical trial NCT04147715. EXAMPLES

[0115] Formulation A (heterogeneous suspension) is seen in Table A.

[0116] [Table 1]

[0117] Preparation of Formulation A: Sodium acetate (438.36 mg) and glacial acetic acid (104 μL) were dissolved in water (500 mL) to obtain a 10 mM acetate buffer solution. The acetate buffer solution (440.41 g) was combined with poloxamer 338 (34.88 g) and mannitol (24.43 g) and the resulting solution was filtered through a 0.2 μm filter. The pH of the solution was measured to be pH 5.04. The solution (278.25 g) was combined with the compound of formula Ia (110.25 g). The stirred suspension was maintained at 1-25°C, the stirrer tip speed was set at 5.5 m / sec, and circulated at 45-145 mL / min through a wet bead mill (Netzsch Minicer) containing 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired average particle diameter of approximately 0.3 μm was achieved. The formulation had a concentration of approximately 300 mg / mL of the suspended amorphous form of the compound of Formula Ia, 5.4 w / vol % P338 and 3.5 w / vol % mannitol, with the remainder of the composition consisting of the aqueous acetate buffer described above.

[0118] Formulation B (heterogeneous suspension) is seen in Table B.

[0119] [Table 2]

[0120] Preparation of Formulation B: Sodium acetate (435.72 mg) and glacial acetic acid (104 μL) were dissolved in water (500 mL) to obtain a 10 mM acetate buffer solution. Acetate buffer (440.85 g) was combined with poloxamer 338 (34.89 g) and mannitol (24.46 g) and the resulting solution was filtered through a 0.2 μm filter. The pH of the vehicle was measured to be pH 5.02. The solution (278.25 g) was combined with compound of formula Ib (110.25 g). The stirred suspension was maintained at 1-25°C, the stirrer tip speed was set at 5.8 m / sec, and circulated at 45-145 mL / min through a wet bead mill (Netzsch Minicer) containing 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired average particle diameter of approximately 0.2 μm was achieved. The formulation had a concentration of approximately 300 mg / mL of the suspended amorphous form of the compound of formula Ib, 5.4 w / vol % P338 and 3.5 w / vol % mannitol, with the remainder of the composition consisting of the aqueous acetate buffer described above.

[0121] Preparation of Formulation C: PEG200 (135 g) was charged to a glass bottle equipped with a lid, and the solution was heated to 45°C with stirring. Compound of formula Ia (60 g) was slowly added to the solution while maintaining stirring and heating. After addition, heating and stirring were maintained until a homogenous solution was obtained. The solution was cooled to room temperature with stirring. A solution of lecithin (45 g, egg-based "Lipoid E80" containing 80 wt% phosphatidylcholine) in ethanol (60 g, anhydrous) was added to the bottle. The mixture was stirred for 15-30 minutes to obtain a clear homogenous solution. The composition of the solution was 20 w / w% compound of formula Ia, 45 w / w% PEG200, 20 w / w% ethanol, and 15 w / w% lecithin.

[0122] Preparation of Formulation D: PEG 200 (67.5 g) was added to a capped glass bottle and the solution was heated to 45° C. with stirring. Compound of formula Ib (45 g) was slowly added to the solution while maintaining heating and stirring. After addition, heating and stirring were maintained until a homogenous solution was obtained. The solution was cooled to room temperature with stirring. Ethanol (37.5 g, anhydrous) was added to the solution and the mixture was stirred for 15-30 minutes to obtain a clear homogenous solution. The composition of the solution was 30 w / w% compound of formula Ib, 45 w / w% PEG 200, and 25 w / w% ethanol.

[0123] Preparation of Formulation E: PEG 200 (150 g) was charged to a glass bottle equipped with a lid, and the solution was heated to 45°C with stirring. Compound of formula Ia (90 g) was slowly added to the solution while maintaining heating and stirring. After addition, heating and stirring were maintained until a homogenous solution was obtained. The solution was cooled to room temperature with stirring. Ethanol (60 g, anhydrous) was added to the solution, and the mixture was stirred for 15-30 minutes to obtain a clear homogenous solution. The composition of the solution was 30 w / w% compound of formula Ia, 50 w / w% PEG 200, and 20 w / w% ethanol. Density = 1.11 g / mL; viscosity = 49.9 mPa-s.

[0124] Preparation of Formulation F: A glass bottle equipped with a lid was charged with PEG200 (3.99 mL), ethanol (0.52 mL) and water (0.67 mL), and the mixture was then vortexed. The compound of formula Ib (931 mg) was slowly added to the solution, and the mixture was then vortexed. The mixture was sonicated to obtain a clear homogenous solution. The composition of the solution was PEG200 (69%), ethanol (6.3%), water (10.3%), and compound of formula Ib (14.3%).

[0125] Preparation of Formulation G: A glass bottle equipped with a lid was charged with PEG200 (2.54 mL), ethanol (0.52 mL), propylene glycol (0.73 mL), and water (0.52 mL), and the mixture was then vortexed. The compound of formula Ib (772 g) was slowly added to the solution, and the mixture was then vortexed. The mixture was sonicated to obtain a clear homogenous solution. The composition of the solution was PEG200 (53.7%), ethanol (7.7%), propylene glycol (14.2%), water (9.8%), and compound of formula Ib (14.5%).

[0126] Preparation of Formulation H: A glass bottle equipped with a lid was charged with PEG200 (1.75 mL), ethanol (0.35 mL), and sesame oil (1.40 mL), and the mixture was then vortexed. The compound of formula Ib (628 g) was slowly added to the solution, and the mixture was then vortexed. The solution was sonicated to obtain a clear homogenous solution. The composition of the solution was PEG200 (47.3%), ethanol (6.6%), sesame oil (31%), and compound of formula Ib (15.1%).

[0127] Preparation of Formulation I: Water (455.94 g) was combined with poloxamer 338 (31.26 g) and mannitol (25.07 g) and the resulting solution was filtered through a 0.2 μm filter to provide "vehicle". To the vehicle (247.63 g) was added the compound of formula Ib (64.09 g). The stirred suspension, maintained at 1-25° C., was followed by vehicle (50.40 g) circulated at 50-145 mL / min through a wet bead mill (Netzsch Minicer) with agitator tip speed set at 5.8 m / sec and 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired average particle diameter of approximately 0.78 μm was achieved. The concentration of the formulation was about 168.95 mg / mL of the compound of formula Ib, about 6.49 wt / vol% P338, and about 5.2 wt / vol% mannitol, with the remainder of the composition being water.

[0128] Preparation of formulation J: Water (455.13 g) was combined with poloxamer 338 (31.29 g) and mannitol (25.01 g) and the resulting solution was filtered through a 0.2 μm filter to provide "vehicle". To the vehicle (238.34 g) was added the compound of formula Ia (64.51 g). The stirred suspension, maintained at 1-25° C., was followed by vehicle (50.40 g) circulated at 73-145 mL / min through a wet bead mill (Netzsch Minicer) with agitator tip speed set at 5.8 m / sec and 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired average particle diameter of approximately 0.40 μm was achieved. The formulation had a concentration of about 177 mg / mL of the compound of formula Ia, about 6.3 wt / vol% P338, and about 5.03 wt / vol% mannitol, with the remainder of the composition being water.

[0129] Preparation of Formulation K: A mixing vessel was charged with 1299.8 grams of PEG200 and 427.2 grams of ethanol. The solution was stirred at ambient temperature for 15 minutes while 40.85 grams of the compound of formula Ia was slowly added. The solution was stirred for about 2 hours until the compound was completely dissolved and a clear homogenous solution was obtained. The resulting solution had a viscosity of 25 cP and a density of 1.089 g / mL.

[0130] General procedure for the analysis of blood samples: General Procedure A: The blood samples were 2The plasma was collected in EDTA tubes, placed on water ice immediately after collection, and centrifuged as soon as possible to obtain plasma. Plasma samples were stored at -70°C or below until analysis by LC-MS / MS. All in vitro samples were injected on a MDS Sciex 5000 triple quadrupole LC-MS / MS system. The analytical column used was a Waters Acquity 1.7 μm CSH Fluror Phenyl (2.1 mm × 50 mm) maintained at 50°C. Mobile phase A consisted of 0.1 (v / v)% formic acid in MilliQ purified water. Mobile phase B consisted of 0.1 (v / v)% formic acid in acetonitrile. The flow rate was 0.80 mL / min. The gradient was as follows: Mobile phase B was held at 20% for 0.2 min, then increased linearly from 20% to 75% over 0.4 min, then further increased linearly from 75% to 95% over 0.55 min, then held at 95% for 0.35 min, and held at 20% for 0.49 min.

[0131] General Procedure B: The blood samples were 2 The plasma was collected in EDTA tubes, placed on water ice immediately after collection, and centrifuged as soon as possible to obtain plasma. Plasma samples were stored at -70°C or below until analysis by LC-MS / MS. All in vitro samples were injected on a MDS Sciex 6500+ triple quadrupole LC-MS / MS system. The analytical column used was a Waters Acquity 1.7 μm BEH (C18, 2.1 mm × 50 mm, 1.7 μm) maintained at 35°C. Mobile phase A consisted of 0.1 (v / v)% formic acid in MilliQ purified water. Mobile phase B consisted of 0.1 (v / v)% formic acid in acetonitrile. The flow rate was 0.80 mL / min. The gradient was as follows: mobile phase B was held at 2% for 0.2 min, then increased linearly from 2% to 75% over 0.4 min, then further increased linearly from 75 to 95% over 0.55 min, then held at 95% for 0.35 min, and held at 2% for 0.49 min.

[0132] Procedure for determining pharmacokinetic parameters of Formulation A in in vivo experiments Wistar Han rats were administered "Formulation A" as a subcutaneous injection at 1 mL / kg, as a subcutaneous injection at 3.33 mL / kg, or as an intramuscular injection at 0.5 mL / kg. Blood samples were collected at the times indicated in Tables 1-3 and analyzed according to General Procedure A. The results of the PK experiments are described in Tables 1-3 and Figures 1-3.

[0133] [Table 3]

[0134] [Table 4]

[0135] [Table 5]

[0136] Procedure for determining pharmacokinetic parameters of Formulation B in in vivo experiments Wistar Han rats were administered "Formulation B" at 1.04 mL / kg subcutaneously, 3.46 mL / kg subcutaneously, or 0.52 mL / kg intramuscularly. Blood samples were collected at the times indicated in Tables 4-6 and analyzed according to General Procedure B. The results of the PK experiments are shown in Tables 4-6 and Figures 4-6.

[0137] [Table 6]

[0138] [Table 7]

[0139] [Table 8]

[0140] Procedure for determining the pharmacokinetic parameters of Formulation C in in vivo experiments Wistar Han rats were administered "Formulation C" as a subcutaneous injection at 1.5 mL / kg, a subcutaneous injection at 5 mL / kg, or an intramuscular injection at 0.5 mL / kg. Blood samples were collected at the times indicated in Tables 7-9 and analyzed according to General Procedure A. The results of the PK experiments are shown in Tables 7-9 and Figures 7-9.

[0141] [Table 9]

[0142] [Table 10]

[0143] [Table 11]

[0144] Procedure for determining the pharmacokinetic parameters of Formulation D in in vivo experiments Wistar Han rats were administered "Formulation D" at 0.91 mL / kg subcutaneously, 3.03 mL / kg subcutaneously, or 0.45 mL / kg intramuscularly. Blood samples were collected at the times indicated in Tables 10-12 and analyzed according to General Procedure B. The results of the PK studies are shown in Tables 10-12 and Figures 10-12.

[0145] [Table 12]

[0146] [Table 13]

[0147] [Table 14]

[0148] Procedure for determining the pharmacokinetic parameters of Formulation F in in vivo experiments Wistar Han rats were administered "Formulation F" as a subcutaneous injection at 0.33 mL / kg or as an intramuscular injection at 0.33 mL / kg. Blood samples were collected at the times indicated in Tables 13-14 and analyzed according to General Procedure B. The results of the PK studies are shown in Tables 13-14 and Figures 13-14.

[0149] [Table 15]

[0150] [Table 16]

[0151] Procedure for determining pharmacokinetic parameters of Formulation G in in vivo experiments Wistar Han rats were administered "Formulation G" as a subcutaneous injection at 0.33 mL / kg or as an intramuscular injection at 0.33 mL / kg. Blood samples were collected at the times indicated in Tables 15-16 and analyzed according to General Procedure B. The results of the PK studies are shown in Tables 15-16 and Figures 15-16.

[0152] [Table 17]

[0153] [Table 18]

[0154] Procedure for determining the pharmacokinetic parameters of Formulation H in in vivo experiments Wistar Han rats were administered "Formulation H" as a single subcutaneous injection at 0.33 mL / kg or as a single intramuscular injection at 0.33 mL / kg. Blood samples were collected at the times indicated in Tables 17-18 and analyzed according to General Procedure B. The results of the PK studies are presented in Tables 17-18 and Figures 17-18.

[0155] [Table 19]

[0156] [Table 20]

[0157] Procedure for determining pharmacokinetic parameters of Formulation I in in vivo experiments Wistar Han rats were administered "Formulation I" as a subcutaneous injection at 0.25 mL / kg or as an intramuscular injection at 0.25 mL / kg. Blood samples were collected at the times indicated in Tables 19-20 and analyzed according to General Procedure A. The results of the PK studies are presented in Tables 19-20 and Figures 19-20.

[0158] [Table 21]

[0159] [Table 22]

[0160] Procedure for determining pharmacokinetic parameters of formulation J in in vivo experiments Wistar Han rats were administered "Formulation J" as a subcutaneous injection at 0.28 mL / kg or as an intramuscular injection at 0.28 mL / kg. Blood samples were collected at the times indicated in Tables 21-22 and analyzed according to General Procedure A. The results of the PK studies are shown in Tables 21-22 and Figures 21-22.

[0161] [Table 23]

[0162] [Table 24]

[0163] The data generated above and depicted in the figures show that the pharmaceutical compositions of the present invention extend the release profile of the compounds of Formula Ia and Formula Ib, suggesting their use in sustained administration of the compounds.

Claims

1. A pharmaceutical composition comprising a compound of Formula Ia or Formula Ib or a pharmaceutically acceptable salt thereof, 【Chemical 1】 【Chemistry 2】 The pharmaceutical composition further comprises polyethylene glycol and ethanol.

2. A pharmaceutical composition comprising a compound of formula Ia or formula Ib, 【Chemistry 3】 【Chemistry 4】 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises polyethylene glycol and ethanol.

3. 10. The pharmaceutical composition of claim 1, further comprising at least one selected from the group consisting of water, lecithin, propylene glycol, benzyl alcohol, and sesame oil.

4. 10. The pharmaceutical composition of claim 1, further comprising propylene glycol, benzyl alcohol, or sesame oil.

5. The pharmaceutical composition of claim 1, wherein the average molecular weight of the polyethylene glycol is 400 (PEG 400).

6. The pharmaceutical composition of claim 1, wherein the amount of ethanol is 5 to 25% by weight, or the amount of ethanol is 20% by weight, or the composition is a homogeneous solution.

7. The pharmaceutical composition of claim 1, comprising 20% ​​by weight of a compound of formula Ib or a pharmaceutically acceptable salt thereof, 45% by weight of PEG 200, 20% by weight of ethanol, and 15% by weight of lecithin.

8. A pharmaceutical composition according to any one of claims 1 to 7, comprising the compound of formula Ib.

9. A pharmaceutical composition comprising a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, 【Chemistry 5】 【Chemistry 6】 The pharmaceutical composition further comprises water and contains less than 1% by weight of polyethylene glycol.

10. 10. The pharmaceutical composition of claim 9, further comprising one or more of sodium acetate, acetic acid, mannitol, sodium chloride, poloxamer 338, or poloxamer 188.

11. 10. The pharmaceutical composition of claim 9, comprising poloxamer 338 or poloxamer 188, and further comprising sodium acetate and acetic acid, and further comprising mannitol or sodium chloride.

12. 10. The pharmaceutical composition of claim 9, wherein the compound of formula Ib has a mean particle diameter of 0.2 μm to 0.5 μm, or the compound of formula Ib has a mean particle diameter of ≦0.2 μm.

13. The pharmaceutical composition of claim 9, comprising 300 mg / mL of the compound of formula Ib or a pharmaceutically acceptable salt thereof, 5.4% by weight of P338, 3.5% by weight of mannitol, and the remainder of the composition being water or aqueous acetate buffer, and is a heterogeneous suspension.

14. A pharmaceutical composition according to any one of claims 9 to 13, comprising the compound of formula Ib.

15. 15. The pharmaceutical composition of claim 14, wherein the compound of formula Ib has a mean particle diameter of 0.2 μm to 0.5 μm, or the compound of formula Ib has a mean particle diameter of ≦0.2 μm.

16. The pharmaceutical composition of claim 14, comprising 300 mg / mL of the compound of formula Ib, 5.4% by weight of P338, 3.5% by weight of mannitol, and the remainder of the composition being water or aqueous acetate buffer, and is a heterogeneous suspension.

17. 10. The pharmaceutical composition of claim 1 for use in a method for treating HIV infection in a human, comprising: The method comprises administering a therapeutically effective amount of the pharmaceutical composition.

18. 18. The pharmaceutical composition of claim 17, wherein the administration is by intramuscular or subcutaneous injection.

19. The pharmaceutical composition of claim 17, wherein the method further comprises administering at least one other agent used to treat HIV infection in humans.

20. The pharmaceutical composition of claim 19, wherein the at least one other active agent is selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, GSK4023991 / VH4023991, and S-365598.

21. The pharmaceutical composition of claim 19, wherein the at least one other active agent is selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, GSK4023991 / VH4023991, S-365598, bictegravir, and islatravir.

22. 10. The pharmaceutical composition of claim 1 for use in therapy.

23. 10. The pharmaceutical composition of claim 1 for use in treating HIV infection in humans.

24. 10. The pharmaceutical composition of claim 1 for use in the manufacture of a medicament for the treatment of HIV infection in humans.

25. The pharmaceutical composition of claim 9 for use in a method for treating HIV infection in a human, the method comprising administering a therapeutically effective amount of the pharmaceutical composition.

26. The pharmaceutical composition of claim 25, wherein the administration is by intramuscular or subcutaneous injection.

27. The pharmaceutical composition of claim 25, wherein the method further comprises administering at least one other agent used to treat HIV infection in humans.

28. The pharmaceutical composition of claim 27, wherein the at least one other active agent is selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, GSK4023991 / VH4023991, and S-365598.

29. The pharmaceutical composition of claim 27, wherein the at least one other active agent is selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937 / VH3739937, GSK4000422 / VH4000422, GSK4023991 / VH4023991, S-365598, bictegravir, and islatravir.

30. A pharmaceutical composition according to claim 9 for use in therapy.

31. The pharmaceutical composition of claim 9 for use in a method for treating HIV infection in humans.

32. The pharmaceutical composition of claim 9 for use in the manufacture of a medicament for treating HIV infection in humans.

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