HK40099486A - Choline salt forms of an hiv capsid inhibitor - Google Patents

Description

Choline salt form of HIV capsid inhibitors

This application is a divisional application of Chinese invention patent application filed on August 16, 2018, with application number 201880053111.5 and invention title "Choleline Salt Form of HIV Capsid Inhibitor".

Cross-references to related applications

This application claims the benefit and priority of U.S. Provisional Application Serial No. 62/546,974, filed on August 17, 2017, the entire contents of which are incorporated herein by reference.

Technical Field

This disclosure relates to choline salt forms of HIV capsid inhibitors and pharmaceutical compositions thereof for the treatment or prevention of retroviral infections, including infections caused by HIV.

Background Technology

Positive single-stranded RNA viruses, including those belonging to the subfamily Retrovirinae and genera such as alpha retrovirus, beta retrovirus, gamma retrovirus, delta retrovirus, ε retrovirus, lentiviruses, and spumaviruses, cause numerous human and animal diseases. Among lentiviruses, HIV-1 infection in humans leads to T helper cell depletion and immune dysfunction, resulting in immunodeficiency and vulnerability to opportunistic infections. Highly active antiretroviral therapy (HAART) for HIV-1 infection has been shown to effectively reduce viral load and significantly delay disease progression (Hammer, S.M. et al., JAMA 2008, 300:555-570). However, these treatments can lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, R.J. et al., Science 2010, 327:697-701). Therefore, there is a continued need to discover new antiretroviral agents and develop methods for their preparation and purification, as well as to formulate improved pharmaceutical formulations. The choline salt form of the HIV capsid inhibitor disclosed herein helps to meet these and other needs.

Summary of the Invention

This application provides a choline salt of compound 1:

This application further provides a pharmaceutical composition comprising a choline salt of the compound 1 disclosed herein or its crystalline form, and at least one pharmaceutically acceptable excipient.

This application further provides the crystalline form of the choline salt of compound 1.

This application further provides a method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of choline salt or its crystalline form to a subject in need of such treatment.

This application further provides a choline salt of compound 1 or its crystalline form for therapeutic purposes.

This application further provides a method for using a choline salt of compound 1 or its crystalline form for treating or preventing human immunodeficiency virus (HIV) infection, the method comprising administering a therapeutically effective amount of the choline salt or its crystalline form to a subject in need of such treatment.

This application further provides a method for increasing the amount of isomeric compound A in a starting mixture containing two isomeric compounds:

The amount of isomers relative to isomer B:

A method for determining the amount of isomer B relative to the amount of isomer A, the method comprising:

In the presence of a solvent, the starting mixture is contacted with N,N,N-trimethylethanolammonium hydroxide to form a mixture of N,N,N-trimethylethanolammonium salts of two isomers, wherein the salt mixture has an increased amount of isomer A relative to isomer B, or an increased amount of isomer B relative to isomer A, when compared to the relative amounts of isomers A and B in the starting mixture.

Brief description of the attached diagram

Figure 1 shows the ^1H -NMR characteristics of the N,N,N-trimethylethanolammonium (choline) salt of compound 1, enriched by isomer B (top trace) and enriched by isomer A (bottom trace).

Figure 2 shows the XRPD characteristics of the N,N,N-trimethylethanolammonium (choline) salt of compound 1 derived from isopropanol (top trace: bulk crystal; bottom trace: needle-like structure).

Figure 3 shows the XRPD characteristics of the N,N,N-trimethylethanolammonium (choline) salt of compound 1, material A.

Figure 4 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, in crystalline form I.

Figure 5 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form I.

Figure 6 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form II.

Figure 7 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form II.

Figure 8 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystal form III.

Figure 9 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form III.

Figure 10 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form IV.

Figure 11 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form IV.

Figure 12 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystal form V.

Figure 13 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form V.

Figure 14 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystal form VI.

Figure 15 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form VI.

Figure 16 shows the XRPD characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form VII.

Figure 17 shows the DSC thermogram characteristics of N,N,N-trimethylethanolammonium (choline) salt of compound 1, crystalline form VII.

Figure 18 shows the XRPD characteristics of the ethanol solvate of the N,N,N-trimethylethanolammonium (choline) salt of compound 1.

Figure 19 shows the XRPD characteristics of the tetrahydrofuran solvate of the N,N,N-trimethylethanolammonium (choline) salt of compound 1.

Figure 20 shows the XRPD characteristics of the methyl tert-butyl ether solvate of the N,N,N-trimethylethanolammonium (choline) salt of compound 1.

Detailed description

This invention relates to a novel solid form of the HIV capsid inhibitor N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide (i.e., compound 1, see below). Those skilled in the art will understand that the compound structure can be named or identified using recognized nomenclature systems and symbols. For example, the compound can be named or identified using common names, systematic or non-systematic names. The recognized naming systems and symbols in the field of chemistry include, but are not limited to, the Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Therefore, the compound structure of compound 1 provided above can also be named or identified as: N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-l-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide.

Compound 1 can be a weak acid (pKa 6.7 in sulfonamide) or a weak base (pKa <1 in pyridine) and consists of two transisomers (isomer A and isomer B) that can rotate along one of the C-C bonds, as shown below. In solution, the two transisomers coexist in a ratio of approximately 1:5 to 1:8 (isomer A:isomer B), depending on temperature and pH. The two transisomers can be separated by chromatography, but they reequilibrate in solution (at 37 °C, t _{_1/2} ≈ 1–2 h, and the rotational energy barrier is approximately 24 kcal/mol).

As described herein, isomer A or isomer B can be enriched by crystallization. For the N,N,N-trimethylethanolammonium (choline) salt described herein, any transisomer can be enriched by forming different crystalline forms.

The solid form of the present invention includes the salt form of Compound 1 (both amorphous and crystalline). As used herein, "solid form" generally refers to a solid chemical substance that can be amorphous or crystalline. In some embodiments, the solid form of the present invention is a choline salt of Compound 1, which can be amorphous or crystalline. The crystalline choline salt of Compound 1 can exist in different crystalline forms (i.e., different polymorphic or pseudopolymorphic forms).

As used herein, "crystalline form" refers to certain lattice configurations of a crystalline substance (e.g., a salt). Different crystalline forms of the same substance typically have different lattices (e.g., unit cells) due to different physical properties, which are characteristic of each crystalline form. In some cases, different lattice configurations have different water or solvent contents.

According to the present invention, the crystalline form of the choline salt of compound 1 can be used to synthesize and/or purify compound 1. For example, the crystalline form of the choline salt of compound 1 can be an intermediate in the synthesis of compound 1. Furthermore, different crystalline forms of the choline salt of compound 1 can have different properties regarding bioavailability, stability, purity, and/or manufacturability for medical or pharmaceutical use. Variations in the crystal structure of pharmaceutical substances or active ingredients can affect the dissolution rate (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to continuously prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). These variations can affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms (e.g., solutions or solid oral dosage forms, including tablets and capsules). Compared to other forms (e.g., non-crystalline or amorphous forms), crystalline forms can provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and/or process control. Therefore, the crystalline form of the choline salt of compound 1 can provide advantages such as improved manufacturing process of the compound, stability or storage of the compound in pharmaceutical form, stability or storage of the pharmaceutical substance of the compound and/or bioavailability and/or stability of the compound as an active agent.

Certain solvents and/or methods have been found to produce different crystalline forms of the choline salt of compound 1, which may exhibit one or more of the advantageous characteristics described above. The methods for preparing the crystalline forms described herein and the characterization of these crystalline forms are described in detail below.

In some embodiments, the choline salts or their crystalline forms described herein are purified or substantially separated. “Substantial separation” means that the choline salts or their crystalline forms are at least partially or substantially separated from the environment in which they are formed or detected. Partial separation may include, for example, compositions in which the choline salts or their crystalline forms of the present invention are enriched. Substantial separation may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the choline salts or their crystalline forms of the present invention. In some embodiments, the choline salts or their crystalline forms of the present invention may be prepared having a purity of about 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

Different crystalline forms can be identified using solid-state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), further aid in identifying the forms and in determining stability and solvent/water content.

XRPD spectra of reflections (peaks) are generally considered fingerprints of a specific crystal form. It is well known that the relative intensities of XRPD peaks can vary widely, depending particularly on sample preparation techniques, crystal size distribution, the various filters used, sample setup procedures, and the specific instrument employed. In some cases, new peaks may be observed, or existing peaks may disappear, depending on the instrument type or setup. As used herein, the term "peak" refers to a reflection with a relative height/intensity of at least about 5% of the maximum peak height/intensity. Furthermore, instrument variations and other factors can affect the 2-θ value. Therefore, peak assignments (such as those reported herein) can be altered by adding or subtracting about 0.2° (2-θ), and the terms "substantially" and "about" as used in the context of XRPD herein are intended to include the aforementioned variations.

Similarly, temperature readings associated with DSC can vary by approximately ±3°C, depending on the instrument, specific settings, sample preparation, etc. Therefore, the crystalline form reported herein, or the term "approximately," with a DSC thermogram as shown in any of the figures, should be understood to accommodate this variation.

This invention provides crystalline forms of certain compounds or their salts. In some embodiments, the crystalline form may be substantially anhydrous. In some embodiments, the crystalline form may be hydrated or solvated.

Compound 1N,N,N-trimethylethanolammonium (choline) salt

In some embodiments, compound 1 can be isolated as an N,N,N-trimethylethanolammonium (choline) salt, which can be amorphous or crystalline. In some embodiments, the N,N,N-trimethylethanolammonium (choline) salt of compound 1 is crystalline.

In some embodiments, the N,N,N-trimethylethanolammonium salt of compound 1 is selected from crystalline material A, crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI and crystalline form VII.

In some embodiments, the crystalline material A of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 3.

In some embodiments, the crystalline form I of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 4.

In some embodiments, the crystalline form I of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 5.5°, 7.5°, 7.9°, 14.9°, 15.7°, 16.8°, 17.6°, 19.3°, and 22.4°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form I of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in FIG5.

In some embodiments, the crystalline form I of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram showing a melting initiation at approximately 157°C.

In some embodiments, the crystalline form II of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 6.

In some embodiments, the crystalline form II of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 7.5°, 9.6°, 14.0°, 14.9°, 16.1°, 16.9°, 20.8°, 21.0°, and 26.5°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form II of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in Figure 7.

In some embodiments, the crystalline form II of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram showing a melting initiation at approximately 147°C.

In some embodiments, the crystalline form III of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 8.

In some embodiments, the crystalline form III of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 7.8°, 8.1°, 8.3°, 15.0°, 15.7°, 16.7°, 20.0°, 21.1°, and 21.7°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form III of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in Figure 9.

In some embodiments, the crystalline form III of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram showing a melting initiation at approximately 144°C.

In some embodiments, the crystalline form IV of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 10.

In some embodiments, the crystalline form IV of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 7.5°, 8.0°, 14.8°, 16.1°, 17.0°, 20.3°, 21.1°, 24.6°, and 26.7°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form IV of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram substantially as shown in Figure 11.

In some embodiments, the crystalline form IV of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram with a melting initiation of about 136°C.

In some embodiments, the crystalline form V of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 12.

In some embodiments, the crystalline form V of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 6.9°, 7.9°, 10.7°, 16.7°, 17.6°, 21.1°, 21.8°, 22.8°, and 26.9°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form V of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in Figure 13.

In some embodiments, the crystalline form V of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram with a melting initiation of about 159°C.

In some embodiments, the crystalline form VI of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 14.

In some embodiments, the crystalline form VI of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 6.1°, 8.6°, 9.5°, 15.4°, 20.4°, 21.9°, 22.5°, 24.2°, and 25.2°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form VI of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in FIG15.

In some embodiments, the crystalline form VI of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram showing a melting initiation at approximately 121°C.

In some embodiments, the crystalline form VII of the N,N,N-trimethylethanolammonium salt of compound 1 has an XRPD spectrum substantially as shown in Figure 16.

In some embodiments, the crystalline form VII of the N,N,N-trimethylethanolammonium salt of compound 1 has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from 4.7°, 7.3°, 8.9°, 9.5°, 18.3°, 20.5°, 22.3°, 24.9°, and 28.4°, expressed as 2-θ±0.2°.

In some embodiments, the crystalline form VII of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram that is substantially as shown in Figure 17.

In some embodiments, the crystalline form VII of the N,N,N-trimethylethanolammonium salt of compound 1 is characterized by a DSC thermogram showing a melting initiation at approximately 144°C.

In some embodiments, the N,N,N-trimethylethanolammonium salt of compound 1 is in a solvated form.

In some embodiments, the N,N,N-trimethylethanolammonium salt of compound 1 is in the form of an ethanol solvate.

In some embodiments, the crystalline form of the N,N,N-trimethylethanolammonium salt of compound 1, the ethanol solvate, has an XRPD spectrum substantially as shown in Figure 18.

In some embodiments, the N,N,N-trimethylethanolammonium salt of compound 1 is in the crystalline form of a tetrahydrofuran solvate.

In some embodiments, the crystalline form of the N,N,N-trimethylethanolammonium salt of compound 1, the tetrahydrofuran solvate, has an XRPD spectrum substantially as shown in Figure 19.

In some embodiments, the N,N,N-trimethylethanolammonium salt of compound 1 is in the crystalline form of a methyl tert-butyl ether solvate.

In some embodiments, the crystalline form of the N,N,N-trimethylethanolammonium salt of compound 1, the methyl tert-butyl ether solvate, has an XRPD spectrum substantially as shown in Figure 20.

This application further provides a method for increasing the amount of isomer A in a starting mixture comprising two isomers:

The amount of isomers relative to isomer B:

A method for determining the amount of isomer B relative to the amount of isomer A, the method comprising:

In the presence of a solvent, the starting mixture is contacted with N,N,N-trimethylethanolammonium hydroxide to form a mixture of N,N,N-trimethylethanolammonium salts of two isomers, wherein the salt mixture has an increased amount of isomer A relative to isomer B, or an increased amount of isomer B relative to isomer A, when compared to the relative amounts of isomers A and B in the starting mixture.

In some embodiments, the method includes increasing the amount of isomer A relative to the amount of isomer B. In some embodiments, the solvent is selected from acetonitrile, 2-methyltetrahydrofuran, isopropyl acetate, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, and isopropyl ether, or any mixture thereof. In some embodiments, the method of increasing the amount of isomer A relative to the amount of isomer B further includes drying the salt mixture to form a second salt mixture comprising the increased amount of isomer A relative to the amount of isomer B.

In some embodiments, the method includes increasing the amount of isomer B relative to the amount of isomer A. In some embodiments, the solvent is selected from methanol, isopropanol, dichloromethane, isopropyl ether, heptane, and toluene, or any mixture thereof.

In some embodiments, the choline salt or its crystalline form disclosed herein enriches isomer A. In some embodiments, the choline salt or crystalline form disclosed herein enriches isomer B. As used herein, the term "enrichment" refers to the increase in a particular compound, salt, or isomer in a mixture compared to the amount of the compound, salt, or isomer in the mixture prior to enrichment. For example, in a mixture enriched for isomer A, the isomer content of isomer A is increased compared to the relative amounts of isomers A and B in the initial mixture.

The following description was made with the understanding that this disclosure should be considered as an example of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments shown. Headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

When a trade name is used herein, it is intended to independently include one or more active pharmaceutical ingredients of the product under that trade name and the product under that trademark name.

As used herein and in the appended claims, the singular forms “a” and “an” and “the” include the plural objects referred to, unless the context clearly indicates otherwise. Thus, for example, reference to “the compound” includes multiple such compounds, reference to “the assay” includes reference to one or more assays, and so on.

"Pharmaceutical acceptable" refers to compounds, salts, compositions, dosage forms and other materials used to prepare pharmaceutical compositions suitable for veterinary or human use.

"Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

"Pharmaceutically acceptable salt" means a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound (or can be converted into a form having the desired pharmacological activity of the parent compound).

"Subjects" refers to humans, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), etc.

As used herein, “treatment” is a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, a beneficial or desired outcome includes, but is not limited to, relieving symptoms and/or reducing the severity of symptoms and/or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and/or reducing the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and/or c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving disease status, delaying disease progression, improving quality of life, and/or prolonging survival.

As used herein, “delaying” the development of a disease or condition means postponing, hindering, slowing, delaying, stabilizing, and/or prolonging the development of a disease or condition. The delay can vary in length depending on the patient’s medical history and/or the subject being treated. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the individual does not develop the disease or condition. For example, methods of “delaying” the development of AIDS include reducing the probability of disease development and/or mitigating the severity of disease within a given timeframe compared to not using the methods described. Such comparisons can be based on clinical studies using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming the subject’s HIV ⁺ status and assessing the subject’s T-cell count or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpit, or groin, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that are not typically present in individuals with a functioning immune system but are present in patients with AIDS). Development can also refer to disease progression that may initially be undetectable and includes occurrence, relapse, and onset.

As used herein, “prevention” refers to a program to prevent the onset of a disease or condition so as to prevent the development of clinical symptoms of the disease. Therefore, “prevention” involves administering treatment (e.g., administering a therapeutic substance) to a subject before signs of disease are detectable in the subject (e.g., administering a therapeutic substance to the subject in the absence of a detectable pathogen (e.g., a virus) in the subject). A subject may be at risk of developing a disease or condition, such as a subject with one or more known risk factors associated with the development or onset of a disease or condition. Therefore, the term “prevention of HIV infection” refers to administering an anti-HIV therapeutic substance to a subject who does not have a detectable HIV infection. It should be understood that a subject receiving anti-HIV prophylactic treatment may be an individual at risk of HIV infection. Furthermore, it should be understood that prevention may not result in complete immunity from the onset of a disease or condition. In some cases, prevention includes reducing the risk of developing a disease or condition. Reducing the risk may not result in the complete elimination of the risk of developing a disease or condition.

As used herein, an "at-risk" individual is an individual at risk of developing a condition requiring treatment. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not have exhibited a detectable disease prior to the treatments described herein. "At-risk" indicates that an individual possesses one or more so-called risk factors, which are measurable parameters associated with the development of a disease or condition and are known in the art. Individuals possessing one or more of these risk factors are more likely to develop a disease or condition than individuals without these risk factors. For example, individuals at risk for AIDS are those who have HIV.

As used herein, the term "therapeutic effective amount" or "effective amount" refers to an amount that effectively elicits the desired biological or medical response, including an amount of compound sufficient to make treatment of a disease effective when administered to a subject, or an amount that effectively defends against infection or onset of a disease. Effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be in the form of one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic outcome. An effective amount may be considered in the case of administration of one or more therapeutic agents, and if in combination with one or more other agents, administration of an effective amount of a single agent may be considered to potentially or be able to achieve the desired or beneficial outcome. Due to the combined effects of compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compounds may optionally be reduced.

Enantiomers are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a non-1:1 ratio is a semi-racemic mixture.

A “diastereomer” is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry on each chiral carbon can be determined by R or S. Resolved compounds with unknown absolute configurations are designated (+) or (-) based on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D-line wavelength. Some compounds and salts described herein contain one or more asymmetric centers and/or are rotationally restricted around bond axes, thus yielding enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry. This invention aims to include all such possible isomers, including racemic mixtures, partially racemic mixtures, diastereomer mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

Unless otherwise expressly defined, this invention includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly shown (e.g., where a pair of tautomers may exist, presenting one tautomer form is intended to describe two tautomer forms). For example, if a compound containing an amide is mentioned (e.g., by its structure or chemical name), it should be understood that this invention includes the corresponding imine tautomer, and it is described as if the amide alone or the amide and imine acid were explicitly stated. When more than two tautomers may exist, this invention includes all such tautomers even if only one tautomer form is shown by its chemical name and/or structure.

Those skilled in the art will understand that the present invention also includes any salts disclosed herein, which may be enriched in any or all atoms at a level higher than that of naturally occurring isotopes, such as, but not limited to, deuterium ( ^2H or D).

Choline salts of compound 1 in which one to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D are also disclosed, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such salts can increase resistance to metabolism and thus can be used to increase the half-life of compounds when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such salts are synthesized by methods well known in the art, for example by using a starting material in which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosed salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , 18O, ^31P , ^32P , ^35S , ^{18F, 36Cl , 123I} , and ^125I , respectively ^. Substitution with positron emission isotopes (such as ^11C , ^18F , ^15O , and ^13N ) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled salts can generally be prepared by conventional techniques known to those skilled in the art or by replacing previously used unlabeled reagents with appropriate isotopically labeled reagents, using methods similar to those described in the examples listed below.

The compounds described herein may have a chiral center and/or a geometric isomer center (E- and Z-isomers), and it should be understood that all such optical isomers, enantiomers, diastereomers, and geometric isomers are included. When a compound is represented in its chiral form, it should be understood that the embodiments described include, but are not limited to, specific diastereomer- or enantiomer-rich forms. When chirality is not specified but present, it should be understood that the embodiments describe specific diastereomer- or enantiomer-rich forms; or racemic or partially racemic mixtures of these compounds.

In a preferred embodiment, this disclosure relates to the use of the choline salts and crystalline forms of the present invention in the treatment of retroviral infections (including infections caused by HIV), comprising administering a therapeutically effective amount of the choline salts or crystalline forms to a subject in need of such treatment.

In a preferred embodiment, this disclosure relates to the use of the choline salts and crystalline forms of the present invention in the treatment of retroviral infections (including infections caused by HIV), comprising administering a therapeutically effective amount of the choline salts or crystalline forms to a subject in need of such treatment.

The ideal goal is to discover compounds, choline salts, or crystalline forms with low _{EC50 values} . The _EC50 value refers to the concentration of a compound that achieves 50% of its maximum efficacy during testing. Compounds, salts, or crystalline forms with lower _EC50 achieve similar efficacy at lower concentrations compared to compounds with higher _EC50 . Therefore, a lower _EC50 is generally preferred for drug development.

The ideal goal is to discover compounds with good physical and/or chemical stability, their pharmaceutically acceptable salts, or crystalline forms. Increased overall stability of the compound, salt, eutectic, or crystalline form can increase circulation time in vivo. Due to less degradation, stable compounds, salts, or crystalline forms can be administered at lower doses while still maintaining efficacy. Furthermore, due to less degradation, there is less concern about byproducts from the degradation of the compound or salt.

The ideal objective is to discover compounds with improved pharmacokinetic and/or pharmacodynamic properties and long half-lives, as well as their pharmaceutically acceptable salts or crystalline forms. Drugs with moderate or low clearance and long half-lives are advantageous because they can lead to good bioavailability and high exposure in systemic exposure. Reducing the clearance of compounds, salts, cocrystals, or crystalline forms and increasing the half-life of compounds, salts, or crystalline forms can reduce the daily dose required to achieve efficacy, thus providing better efficacy and safety. Therefore, improved pharmacokinetic and/or pharmacodynamic properties and long half-lives can provide better patient compliance.

The ideal goal is to discover compounds with favorable pharmacokinetic properties from extended-release injectable formulations, their pharmaceutically acceptable salts, or crystalline forms. Drugs with low _EC50 and long-acting pharmacokinetics are advantageous because this allows for lower dosing frequency. Lower dosing frequency can provide better patient compliance. Lower dosing frequency is desirable for patients with limited or no access to healthcare.

How to use

In some embodiments, the choline salts or crystalline forms disclosed herein are used to prevent HIV infection in subjects. In some embodiments, the choline salts or crystalline forms disclosed herein are used to prevent HIV infection in subjects at risk of infection. In some embodiments, the choline salts or crystalline forms disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1. The pharmaceutically acceptable salts or crystalline forms disclosed herein are believed to be active against major HIV-1 mutants selected by clinical protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors (INSTIs).

In some embodiments, a method for treating or preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method for treating or preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method for inhibiting HIV viral replication in a subject (e.g., a human), treating AIDS, or delaying the onset of AIDS is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method for inhibiting HIV viral replication in a subject (e.g., a human), treating AIDS, or delaying the onset of AIDS is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form. In some embodiments, the subject is at risk of exposure to HIV, for example, a subject with one or more known risk factors associated with HIV exposure.

In some embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a therapeutically effective amount of a choline salt of compound 1 or its crystalline form. In some embodiments, the subject is at risk of exposure to HIV, for example, a subject with one or more known risk factors associated with HIV exposure.

In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a choline salt of compound 1 or its crystalline form.

In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from: HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof. In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, HIV reverse transcriptase inhibitors, etc. Nucleoside or nucleotide inhibitors of HIV integrase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a Receptor antagonists, DNA methyltransferase inhibitors, HIV-vif gene regulators, Vif dimer antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor regulators, protein 1 regulators containing the COMM domain, HIV ribonuclease H inhibitors, retrocyclin regulators Drugs, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from: HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof. In some embodiments, a method for treating HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, HIV reverse transcriptase inhibitors, etc. Nucleoside or nucleotide inhibitors of transcriptases, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors. Complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimer antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing the COMM domain, HIV ribonuclease H inhibitors, resveratrol modulators, C DK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

In some embodiments, a method of treating HIV infection in a subject (e.g., a human) includes administering to the subject in need a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1 or its cocrystal or crystalline form, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, and HIV nucleoside reverse transcriptase translocation inhibitors.

In some embodiments, a choline salt of compound 1 or its crystalline form is disclosed for medical treatment of HIV infection (e.g., replication of HIV-1 or HIV virus (e.g., HIV-1) or AIDS or delaying the onset of AIDS in a subject (e.g., a human)).

In some embodiments, a choline salt of compound 1 or its crystalline form is disclosed for medical treatment of HIV infection (e.g., replication of HIV-1 or HIV virus (e.g., HIV-1) or AIDS or delaying the onset of AIDS in a subject (e.g., a human)).

In some embodiments, a choline salt of compound 1 or its crystalline form is disclosed for use in the manufacture of a medicament for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in a subject (e.g., a human). One embodiment relates to a choline salt of compound 1 or its crystalline form for use in the preventive or therapeutic treatment of HIV infection or AIDS, or for therapeutic treatment or delaying the onset of AIDS.

In some embodiments, a choline salt of compound 1 or its crystalline form is disclosed for use in the manufacture of a medicament for treating HIV infection or HIV viral replication or AIDS, or for delaying the onset of AIDS in a subject (e.g., a human). One embodiment relates to a choline salt of compound 1 or its crystalline form for use in the preventive or therapeutic treatment of HIV infection or AIDS, or for therapeutic treatment or delaying the onset of AIDS.

In some embodiments, the use of the choline salt of compound 1 or its crystalline form thereof for the manufacture of a medicament for HIV infection in a subject (e.g., a human) is disclosed. In some embodiments, the use of the choline salt of compound 1 or its crystalline form thereof for prophylactic or therapeutic treatment of HIV infection is disclosed.

In some embodiments, the use of the choline salt of compound 1 or its crystalline form thereof for the manufacture of a medicament for HIV infection in a subject (e.g., a human) is disclosed. In some embodiments, the use of the choline salt of compound 1 or its crystalline form thereof for prophylactic or therapeutic treatment of HIV infection is disclosed.

In some embodiments, the administration is given to a subject (e.g., a human) who requires treatment. In some embodiments, the administration is given to a subject (e.g., a human) at risk of developing AIDS.

This document discloses a choline salt of compound 1 or its crystalline form for therapeutic purposes. In one embodiment, the choline salt of compound 1 or its crystalline form is used in a method for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in a subject (e.g., a human).

In some embodiments, the choline salt of compound 1 or its crystalline form is disclosed herein for use in treatment. In some embodiments, the choline salt of compound 1 or its crystalline form is used in methods for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in a subject (e.g., a human).

This document also discloses a choline salt of compound 1 or its crystalline form, used in methods for treating or preventing HIV infection in subjects with this need. In some embodiments, a choline salt of compound 1 or its crystalline form is provided in methods for treating HIV infection in subjects with this need. In some embodiments, the subject with this need is a human infected with HIV. In some embodiments, the subject with this need is a human infected with HIV but who has not yet developed AIDS. In some embodiments, the subject with this need is a subject at risk of developing AIDS. In some embodiments, the subject with this need is a human infected with HIV and who has developed AIDS.

In some embodiments, this document discloses a choline salt of compound 1 or its crystalline form, used in methods for treating or preventing HIV infection in a subject with this need. In some embodiments, a choline salt of compound 1 or its crystalline form is provided in methods for treating HIV infection in a subject with this need. In some embodiments, the subject with this need is a human infected with HIV. In some embodiments, the subject with this need is a human infected with HIV but who has not yet developed AIDS. In some embodiments, the subject with this need is a subject at risk of developing AIDS. In some embodiments, the individual subject with this need is a human infected with HIV and who has developed AIDS.

In one embodiment, a choline salt of compound 1 or its crystalline form is provided in a method of treating or preventing HIV infection in a subject in need of such treatment, in combination with one or more (e.g., one, two, three or four; or one or two; or one to three; or one to four) other therapeutic agents as described herein. In one embodiment, the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimer antagonists, and HIV-1 viral infection factor inhibitors. HIV-1 inhibitors, including TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, resveratrol modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other medicines for treating HIV, and combinations thereof.

In some embodiments, a choline salt of compound 1 or its crystalline form is provided in a method of treating or preventing HIV infection in a subject as described herein, in combination with one or more (e.g., one, two, three or four; or one or two; or one to three; or one to four) other therapeutic agents as described herein. In one embodiment, the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimer antagonists, and HIV-1 viral infection factor inhibitors. HIV-1 inhibitors, including TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, resveratrol modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other medicines for treating HIV, and combinations thereof.

In one embodiment, a choline salt of compound 1 or its crystalline form is provided in combination with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate (wherein the second additional therapeutic agent is emtricitabine) for the treatment or prevention of HIV infection in a subject with such need. In a particular embodiment, a choline salt of compound 1 or its crystalline form is provided in combination with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate (wherein the second additional therapeutic agent is emtricitabine) for the treatment or prevention of HIV infection in a subject with such need.

In some embodiments, a choline salt of compound 1 or its crystalline form is provided in a method of treating or preventing HIV infection in a subject with a need, in combination with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate, and a second additional therapeutic agent ( wherein the second additional therapeutic agent is emtricitabine). In one particular embodiment, a choline salt of compound 1 or its crystalline form is provided in a method of treating or preventing HIV infection in a subject with a need, in combination with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate, and a second additional therapeutic agent ( wherein the second additional therapeutic agent is emtricitabine).

In some embodiments, a pharmaceutically acceptable salt of compound 1 or its eutectic or crystalline form is provided, in combination with at least one additional therapeutic agent selected from:

(1) Nucleoside reverse transcriptase translocation inhibitors (“NRTTIs”) such as 4’-ethynyl-2-fluoro-2’-deoxyadenosine triphosphate (also known as MK-8591 and EFdA);

(2) Nucleoside or nucleotide reverse transcriptase inhibitors (“NRTIs”) such as tenofovir alafenamide fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, GS-9131 and GS-9148.

(3) Non-nucleoside or non-nucleotide reverse transcriptase inhibitors (“NNRTIs”) such as efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine;

(4) Protease inhibitors (“PIs”) such as ampranavir, atazanavir, becanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-31091; and

(5) Integrase strand transfer inhibitors (“INSTI”) such as Bictegravir, cabottegravir, raltegravir and dolutegravir.

In one particular embodiment, a choline salt of compound 1 or a crystalline form thereof is provided for preventing HIV infection from taking hold and/or preventing the establishment of permanent infection and/or preventing the onset of symptoms of disease and/or preventing the virus in the blood from reaching detectable levels, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) are provided. For example, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a choline salt of compound 1 or a crystalline form thereof. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a combination of a choline salt of compound 1 or a crystalline form thereof with one or more other therapeutic agents. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a pharmaceutical composition comprising a therapeutically effective amount of a choline salt of compound 1 or a crystalline form thereof and a choline excipient.

In some embodiments, a choline salt of compound 1 or a crystalline form thereof is provided for preventing HIV infection from taking hold and/or preventing the establishment of permanent infection and/or preventing the onset of symptoms of disease and/or preventing the virus in the blood from reaching detectable levels, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) are provided. For example, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a choline salt of compound 1 or a crystalline form thereof. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a combination of a choline salt of compound 1 or a crystalline form thereof with one or more other therapeutic agents. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a pharmaceutical composition comprising a therapeutically effective amount of a choline salt of compound 1 or a crystalline form thereof and a choline excipient.

In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a choline salt of Compound 1 or its crystalline form, in combination with safer sexual practices. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering it to an individual at risk of contracting HIV. Examples of individuals at high risk of contracting HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering a choline salt of Compound 1 or its crystalline form in combination with safer sexual practices. In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and/or HIV-2) include administering the medication to an individual at risk of contracting HIV. Examples of individuals at high risk of contracting HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

In some implementations, the risk of contracting HIV is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some implementations, the risk of contracting HIV is reduced by at least 75%. In some implementations, the risk of contracting HIV is reduced by about 80%, 85%, or 90%.

In another embodiment, the use of the choline salt of compound 1 or its crystalline form therein in the manufacture of a medicament for treating said infection in humans who are infected with HIV or at risk of infection is disclosed.

In some embodiments, the use of the choline salt of compound 1 or its crystalline form thereof is disclosed in the manufacture of a medicament for treating said infection in humans who are infected with HIV or at risk of infection.

This article also discloses the choline salt of compound 1 or its crystalline form, which is used for therapeutic treatment or to delay the onset of AIDS.

In some embodiments, this document discloses a choline salt of compound 1 or its crystalline form for use in therapeutic treatment or to delay the onset of AIDS.

This article also discloses the choline salt of compound 1 or its crystalline form for use in the preventive or therapeutic treatment of HIV infection.

In some embodiments, this document discloses a choline salt of compound 1 or its crystalline form for use in the preventive or therapeutic treatment of HIV infection.

In some embodiments, the choline salt of compound 1 or its crystalline form may be used as a research tool.

Application route

The choline salt of Compound 1 or its crystalline form (also referred to herein as the active ingredient) can be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. In some embodiments, the disclosed compound can be administered parenterally. In some embodiments, the disclosed compound can be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the disclosed compound, salt, and crystalline form are orally bioavailable and can be administered orally.

In some embodiments, the choline salt of compound 1 or its crystalline form may be administered using a syringe suitable for administering the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the choline salt of compound 1 or its crystalline form.

In some embodiments, a pharmaceutically acceptable salt of compound 1 or its eutectic or crystalline form may be administered by injection using an injection device. In some embodiments, the injection device is or includes a syringe that can be used manually or as part of an injection device containing a syringe (e.g., but not limited to, having a needle-type safety shield). Various injection devices may be used, such as, but not limited to, handheld or wearable autoinjectors, handheld or wearable manual injectors, on-body injectors, syrettes, jet injectors, or pen injectors, each of which may be reusable or disposable.

In some embodiments, an auto-injector containing a syringe can be used to administer the choline salt or crystalline form of Compound 1. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the choline salt or crystalline form of Compound 1.

Dosing regimen

The choline salt of compound 1 or its crystalline form may be administered to the subject for the required duration of time or duration according to an effective dosing regimen, such as at least about one day, at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about six months, or at least about twelve months or longer. In one variation, the salt or crystalline form may be administered daily or intermittently. In one variation, the salt or crystalline form may be administered monthly. In one variation, the salt or crystalline form may be administered every two months. In one variation, the salt or crystalline form may be administered every three months. In one variation, the salt or crystalline form may be administered every four months. In one variation, the salt or crystalline form may be administered every five months. In one variation, the salt or crystalline form may be administered every six months.

In some embodiments, the choline salt of compound 1 or its crystalline form may be administered to a subject for at least about 1 month, at least about 4 months, or at least about 6 months. In some embodiments, the choline salt of compound 1 or its crystalline form may be administered subcutaneously to a subject for at least about 1 month. In some embodiments, the choline salt of compound 1 or its crystalline form may be administered subcutaneously or intramuscularly to a subject for at least about 4 months or at least about 6 months.

The dosage or frequency of administration of the choline salt or its crystalline form of compound 1 may be adjusted as the treatment progresses based on the physician's judgment.

In some implementations, the dosage or frequency of administration of the choline salt or its crystalline form of compound 1 may be adjusted as the treatment progresses, based on the judgment of the administering physician.

The choline salt of compound 1 or its crystalline form may be administered to a subject (e.g., a human) in an effective amount. In some embodiments, the choline salt of compound 1 or its crystalline form is administered once daily.

In some embodiments, the choline salt of compound 1 or its crystalline form thereof may be administered to a subject (e.g., a human) in a therapeutically effective amount. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered once daily. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered monthly. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered every three months. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered every four months. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered every six months.

The choline salt of compound 1 disclosed herein, or its crystalline form, can be administered in effective doses. For example, the dose can be from 1 mg to 1000 mg of the compound. In some embodiments, the dose is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of the compound. In some embodiments, the dose is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

In some embodiments, the choline salt of compound 1 or its crystalline form is administered at a once-daily dose. In some embodiments, the choline salt of compound 1 or its crystalline form is administered at a once-daily dose of about 1 mg.

In some embodiments, the choline salt of compound 1 or its crystalline form is administered monthly. In some embodiments, the choline salt of compound 1 or its crystalline form is administered monthly at a dose of about 100 mg.

In some embodiments, the choline salt of compound 1 or its crystalline form is administered every 6 months. In some embodiments, the choline salt of compound 1 or its crystalline form is administered every 6 months at a dose of about 600 mg.

Combination therapy

In some embodiments, a method is provided for treating or preventing said infection in a human who is infected with HIV or at risk of infection, comprising administering to said human a therapeutically effective amount of a choline salt of the disclosed compound 1 herein, or a crystalline form thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) other therapeutic agents. In one embodiment, a method is provided for treating said infection in a human who is infected with HIV or at risk of infection, comprising administering to said human a therapeutically effective amount of a choline salt of the disclosed compound 1 herein, or a crystalline form thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) other therapeutic agents.

In some embodiments, a method for treating or preventing said infection in a human who is infected with HIV or at risk of infection is provided, comprising administering to the human a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) other therapeutic agents. In one embodiment, a method for treating said infection in a human who is infected with HIV or at risk of infection is provided, comprising administering to the human a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof, combined with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) other therapeutic agents.

In one embodiment, a pharmaceutical composition is provided comprising a choline salt of compound 1 or its crystalline form thereof, and one or more (e.g., one, two, three or four; or one or two; or one to three; or one to four) other therapeutic agents, as well as a choline excipient.

In some embodiments, a pharmaceutical composition comprising a choline salt of compound 1 or its crystalline form thereof, and one or more (e.g., one, two, three or four; or one or two; or one to three; or one to four) other therapeutic agents, and a choline excipient, is provided.

In some embodiments, this disclosure provides a method of treating HIV infection, comprising administering to a subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof in combination with a therapeutically effective amount of one or more other therapeutic agents suitable for treating HIV infection.

In some embodiments, this disclosure provides a method of treating HIV infection, comprising administering to a subject in need a therapeutically effective amount of a choline salt of compound 1 or its crystalline form thereof in combination with a therapeutically effective amount of one or more other therapeutic agents suitable for treating HIV infection.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one other therapeutic agent. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with two other therapeutic agents. In other embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with three other therapeutic agents. In still other embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class and/or may be therapeutic agents selected from different classes.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one other therapeutic agent. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with two other therapeutic agents. In other embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with three other therapeutic agents. In yet another embodiment, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class and/or may be therapeutic agents selected from different classes.

Administration of HIV combination therapy

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is administered together with one or more other therapeutic agents. Co-administration of the choline salt of compound 1 disclosed herein, or its crystalline form, with one or more other therapeutic agents generally means simultaneous or sequential administration of the choline salt of compound 1, or its crystalline form, and one or more other therapeutic agents, such that therapeutically effective amounts of the choline salt of compound 1, or its crystalline form, and one or more other therapeutic agents are present in the subject's body. When administered sequentially, the combination may be administered two or more times.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is administered together with one or more other therapeutic agents. Co-administration of the choline salt of compound 1 disclosed herein, or its crystalline form, with one or more other therapeutic agents generally means simultaneous or sequential administration of the choline salt of compound 1, or its crystalline form, and one or more other therapeutic agents, such that therapeutically effective amounts of the choline salt of compound 1, or its crystalline form, and one or more other therapeutic agents are present in the subject's body. When administered sequentially, the combination may be administered two or more times.

Co-administration includes administering a unit dose of a choline salt or crystalline form of Compound 1 before or after administering a unit dose of one or more other therapeutic agents. For example, the choline salt or crystalline form of Compound 1 may be administered within seconds, minutes, or hours after administering one or more other therapeutic agents. In some embodiments, a unit dose of a choline salt or crystalline form of Compound 1 is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a choline salt or crystalline form of Compound 1 within seconds or minutes. In other embodiments, a unit dose of a choline salt or crystalline form of Compound 1 is administered first, followed by a unit dose of one or more other therapeutic agents several hours (e.g., 1-12 hours). In still other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a choline salt or crystalline form of Compound 1 several hours (e.g., 1-12 hours).

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one or more other therapeutic agents to form a unit dosage form for simultaneous administration to a subject. In some embodiments, this unit dosage form can be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, local (including oral and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In some embodiments, the disclosed compound is administered parenterally. In some embodiments, the unit dosage form can be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the unit dosage form is orally bioavailable and can be administered orally. In some embodiments, the unit dosage form can be a solid dosage form for oral administration.

The choline salt or crystalline form of the compound 1 disclosed herein, in combination with one or more other therapeutic agents, may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, local (including oral and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In some embodiments, the choline salt or crystalline form of the compound 1 disclosed herein may be administered parenterally. In some embodiments, the choline salt or crystalline form of the compound 1 disclosed herein may be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the choline salt or crystalline form of the compound 1 disclosed herein is orally bioavailable and may be administered orally.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is formulated into tablets, said tablets optionally containing one or more other compounds that can be used to treat HIV. In some embodiments, said tablets may contain one or more other compounds that can be used to treat HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In some embodiments, a pharmaceutically acceptable salt of compound 1 disclosed herein, or its cocrystal or crystalline form, is formulated into a tablet, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablet may contain one or more other compounds that can be used to treat HIV, such as HIV nucleoside reverse transcriptase translocation inhibitors, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In some implementations, such tablets are suitable for once-daily administration.

HIV combination therapy

In some embodiments, a pharmaceutically acceptable salt of compound 1 disclosed herein or its eutectic or crystalline form is administered with at least one additional therapeutic agent.

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

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

In some embodiments, additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV nucleoside reverse transcriptase translocation inhibitors, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof. In some embodiments, additional therapeutic agents are selected from immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (e.g., CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies such as chimeric antigen receptor T-cells, CAR-T (e.g., (axicabtagene ciloleucel)), and engineered T-cell receptors, TCR-T.

HIV combination therapy

Examples of combination therapies include: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); durenavir, tenofovir alafenamide hemifumarate, and emtricitabine... Tabin and Cobistat; Efavirane, Lamivudine, and Tenofovir Disoproxil Fumarate; Lamivudine and Tenofovir Disoproxil Fumarate; Tenofovir and Lamivudine; Tenofovir Alamonamide and Emtricitabine; Tenofovir Alamonamide Hemifumarate and Emtricitabine; Tenofovir Alamonamide Hemifumarate, Emtricitabine, and Rilpivirine; Tenofovir Alamonamide Hemifumarate, Emtricitabine, Cobistat, and Eticagvir; (Zidovudine and Lamivudine; AZT+3TC); (Abacavir Sulfate and Lamivudine; ABC+3TC); (Lopinavir and (ritonavir); (drutavir, abacavir, and lamivudine); (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobistat; atazanavir sulfate and cobistat; atazanavir sulfate and ritonavir; drutavir and cobistat; durutavir and rilpivirine; durutavir and rilpivirine hydrochloride; cabotagvir and rilpivirine; cabotagvir and rilpivirine hydrochloride; durutavir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; retagvir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine Verin, lamivudine, and tenofovir disoproxil fumarate; durutigvir + 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 + ribavirin hydrochloride; lopinavir, ritonavir, zidovudine, and lamivudine; Vacc-4x and romidepsin; and APH-0812.

Other HIV medications

Examples of other drugs used to treat HIV include acemannan, alisporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1 virus, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, and BlockAide. ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV nucleoside reverse transcriptase translocation inhibitors.

Examples of HIV nucleoside reverse transcriptase translocation inhibitors (“NRTTIs”) include 4’-ethynyl-2-fluoro-2’-deoxyadenosine triphosphate (also known as MK-8591 and EFdA).

HIV protease inhibitors

Examples of HIV protease inhibitors include ampranavir, atazanavir, brecanavir, derenavir, forosanavir, forosanavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-31091.

HIV reverse transcriptase inhibitors

Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapivirine, delavudine, delavudine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500. Other examples of non-nucleoside reverse transcriptase inhibitors are disclosed in U.S. Patent Publication No. US2016/0250215.

Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apritabine, and sissav. Censavudine, dazovir, elvucitabine, fesinavir, fosalvudine tidoxil, CMX-157, dapoxil, doravirin, ectavirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.

In some embodiments, examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanovine, ddl), abacavir, abacavir sulfate, and aloxetine. Fudin, aritabine, cilsavdine, didanoxin, avtabin, fesinavir, fozavudine tetate, CMX-157, dapirine, doravirine, ectavirine, OCR-5753, tenofovir disoproxil orotate, fozavudine tetate, lamivudine, zisaviin, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, KP-1461 and 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA).

HIV integrase inhibitors

Examples of HIV integrase inhibitors include erticagvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, retegvir, dulutegvir, and JTK. -351, Bittegvir, AVX-15567, Diketoquinoline-4-1 derivatives, Integrase-LEDGF inhibitors, Ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, Stilbene disulfonic acid, T-169, and Cabotegvir.

Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include ceniviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include apraviroc, vicriviroc, maraviroc, seniverol, PRO-MO, adaviroc (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

HIV maturation inhibitors

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Latency reversal agent

Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (saturated aniline hydroxamic acid, or saturated aniline, aniline, and hydroxamic acid), IL-15, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as lagazole analogs, and GSK-343).

Examples of HDAC inhibitors include romidesin, vorinostat, and panobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG lactone.

Capsid inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid interference compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, and the AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immunotherapy

Examples of immunotherapy-based therapies include Toll-like receptor modulators (e.g., TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13); programmed cell death protein 1 (Pd-1) modulators; programmed cell death-ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; quinine (hydroxychloroquine); interleukins (aldeleukin, IL-2); interferon α; interferon α-2b; infectin α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (m Mycophenolate mofetil (MPA) and its ester derivatives mycophenolate mofetil (MMF); ribavirin; rintatolimod; polymeric polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107; interleukin-15/Fc fusion protein; normferon; pegylated interferon α-2a; pegylated interferon α-2b; recombinant interleukin-15; RPI-MN; GS-9620; and IR-103.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, and sonolixi. The following are listed: sib), taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-nef single-domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, antibodies targeting gp140, gp41-based HIV therapeutic antibodies, recombinant human mAbs (PGT-121), ibalizumab, Immuglo, and MB-66.

Examples of antibodies that target HIV in this way include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014, and VRC07.

Pharmacokinetic enhancers

Examples of pharmacokinetic enhancers include cobistat and ritonavir.

Other treatments

Other examples of therapeutic agents include compounds disclosed in the following: WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO2014/100323 (Gilead Sciences). Gilead Sciences, Inc., US2013/0165489 (University of Pennsylvania), US2014/0221378 (Japan Tobacco Company), US2014/0221380 (Japan Tobacco Company), WO 2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), and WO 2013/091096 (Boehringer Ingelheim).

HIV vaccine

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multibranched DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM. 3/VSSP ISA-51, Multi-ICLC Adjuvant Vaccine, Tat Immune, GTU-Multi-HIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVINHIV-1gag Vaccine, SeV-Gag Vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101 CombiHIVvac, AD VAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirus particle vaccines), CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccines, HIV gag/pol/nef/env DNA vaccines, anti-TAT H IV vaccines, conjugated peptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-key/MHC class II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidesin, variant gp120 peptide vaccine, rAd5 gag-pol env A/B/C vaccine.

HIV combination therapy

In one particular embodiment, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one, two, three, four, or more other therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (etigavir, cobistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide) (Aminophene, emtricitabine and rilpivirine); (tenofovir alafenamide, emtricitabine, cobistat and erticagvir); adefovir; adefovir dipivoxil; cobistat; emtricitabine; tenofovir; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (durutegvir, abacavir and lamivudine); durutegvir, abacavir sulfate and lamivudine; retegvir; retegvir and lamivudine; maraviro; enfuvir peptide; (lopinavir and ritonavir); (zidovudine and lamivudine); AZT+3TC); (Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derrenavirvir and cobistat; Atazanavir; Atazanavir sulfate; Duluthigvir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derrenavirvir; Lamivudine; Prasatine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nafenavir; Nafenavir Mesylates; interferon; didanoxin; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; adeleukin; zalcitabine; telanavir; ampravir; delavudine; delavudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; azidophosphine; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with one, two, three, four, or more other therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (etigavir, cobistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine). (Tenofovir alafenamide, emtricitabine, cobistat, and erticagvir); Adefovir; Adefovir dipivoxil; Cobistat; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; (Durutegvir, abacavir, and lamivudine); Durutegvir, abacavir sulfate, and lamivudine; Rettegvir; Rettegvir and lamivudine; Maraviro; Enfuvir peptide; (Lopinavir and ritonavir); (Zidovudine and lamivudine; AZT+3TC); (Abacavir sulfate and lamivudine); ABC+3TC); (Abacavir sulfate, Zidovudine, and Lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and Cobistat; Atazanavir and Cobistat; Derrenavir and Cobistat; Atazanavir; Atazanavir sulfate; Duluthigvir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derrenavir; Lamivudine; Prasatine; Fosanavir; Fosanavir calcium Efavironel; Etravirine; Nafenavir; Nafenavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate Tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; interleukin; zalcitabine; telanavir; ampravir; delavudine; delavudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; zishophosphide; lamivudine, nevirapine and zidovudine; abacavir; abacavir sulfate; 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA); and bispyridoxine, or pharmaceutically acceptable salts thereof.

Those skilled in the art will understand that the other therapeutic agents listed above may be included in more than one of the categories listed above. A specific category is not intended to limit the function of the compounds listed in those categories.

In one specific embodiment, the choline salt or crystalline form of Compound 1 disclosed herein is combined with one or two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In one specific embodiment, the choline salt or crystalline form of Compound 1 disclosed herein is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV transcriptase. In another specific embodiment, the choline salt or crystalline form of Compound 1 disclosed herein is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In yet another embodiment, the choline salt or crystalline form of Compound 1 disclosed herein is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the choline salt or crystalline form of Compound 1 disclosed herein is combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the choline salt or crystalline form of Compound 1 disclosed herein is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In some embodiments, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with one or two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In one particular embodiment, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another particular embodiment, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In yet another embodiment, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the choline salt of Compound 1 disclosed herein, or its crystalline form, is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In one particular embodiment, the choline salt of compound 1 disclosed herein or its crystalline form is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bispyribacvir (or a pharmaceutically acceptable salt thereof), or 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

In one particular embodiment, the choline salt of compound 1 disclosed herein, or its eutectic or crystalline form, is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

In some embodiments, the choline salt of compound 1 disclosed herein or its crystalline form is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bispyribacvir (or a pharmaceutically acceptable salt thereof) or 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

In some embodiments, the choline salt of compound 1 disclosed herein or its crystalline form is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

In one specific embodiment, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, wherein the second additional therapeutic agent is emtricitabine. In one specific embodiment, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, wherein the second additional therapeutic agent is emtricitabine. In one specific embodiment, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir alafenamide hemifumarate, wherein the second additional therapeutic agent is emtricitabine. In some embodiments, the choline salt of compound 1 or its crystalline form thereof is administered simultaneously with the first and second additional therapeutic agents disclosed above. Optionally, the choline salt of compound 1 or its crystalline form thereof is combined with the first and second additional therapeutic agents disclosed above in a unit dosage form for simultaneous administration to a subject. In other embodiments, the choline salt of compound 1 or its crystalline form thereof and the first and second additional therapeutic agents disclosed above are administered sequentially.

In some embodiments, the choline salt of compound 1 disclosed herein or its crystalline form is combined with bismuth subtilis or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutically acceptable salt of compound 1 disclosed herein, or its eutectic or crystalline form, is combined with 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

The choline salt of compound 1 disclosed herein or its crystalline form may be combined with one or more other therapeutic agents at any dose (e.g., 1 mg to 1000 mg salt or crystalline form).

In some embodiments, the choline salt of compound 1 disclosed herein or its crystalline form may be combined with one or more other therapeutic agents at any dose (e.g., 1 mg to 1000 mg salt or crystalline form).

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. The choline salt of compound 1 disclosed herein, or its crystalline form, may be combined with the pharmaceutical preparations provided herein at any dose (e.g., 1 mg to 1000 mg of salt or crystalline form) as specifically and individually listed for each dose combination.

In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In some embodiments, the choline salt of compound 1 disclosed herein, or its crystalline form, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. The choline salt of compound 1 disclosed herein, or its crystalline form, may be combined with the pharmaceutical preparations provided herein at any dose (e.g., 1 mg to 1000 mg of salt or crystalline form), as each dose combination is specifically and individually listed.

In some embodiments, the choline salt of compound 1 disclosed herein or its crystalline form thereof is combined with 20-80 mg of bispyribacvir or its choline salt thereof. The choline salt of compound 1 disclosed herein or its crystalline form thereof may be combined with the pharmaceutical preparations provided herein at any dose (e.g., 1 mg to 1000 mg of salt or crystalline form) as specifically and individually listed for each dose combination.

In one embodiment, a kit is provided comprising a choline salt or crystalline form thereof of compound 1 disclosed herein, in combination with one or more (e.g., one, two, three, one or two, or one to three) other therapeutic agents.

In some embodiments, a kit is provided comprising a choline salt or crystalline form thereof of compound 1 disclosed herein, in combination with one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents.

Pharmaceutical Composition

The pharmaceutical compositions disclosed herein comprise a choline salt of compound 1 disclosed herein or its crystalline form, and one or more pharmaceutically acceptable excipients and optional other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration.

In some embodiments, the pharmaceutical compositions disclosed herein comprise a choline salt of compound 1 disclosed herein or its crystalline form, along with one or more pharmaceutically acceptable excipients and optional other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration.

Pharmaceutical compositions containing choline salts or crystalline forms of compound 1 disclosed herein can be prepared using conventional carriers (e.g., inactive ingredients or excipient materials), which can be selected according to convention. Tablets may contain excipients, including flow aids, fillers, binders, etc. Aqueous compositions can be prepared aseptically and are generally isotonic when intended for delivery by means other than oral administration. All compositions may optionally contain excipients, such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 5th Edition, American Pharmacists Association, 1986. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

While the active ingredient can be administered alone, it is preferred to present the active ingredient in the form of a pharmaceutical composition. Veterinary and human compositions comprise at least a choline salt of compound 1 disclosed herein, or a crystalline form thereof, and one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a choline salt of compound 1, or a crystalline form thereof, a pharmaceutically acceptable excipient, and a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents as defined above. In one embodiment, the pharmaceutical composition comprises a choline salt of compound 1, or a crystalline form thereof, a pharmaceutically acceptable excipient, and one other therapeutic ingredient. The carrier is "acceptable" in the sense of compatibility with the other components of the composition and physiological harmlessness to the recipient.

The compositions include those suitable for a variety of routes of administration. The compositions can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical industry. Such methods involve the step of combining the active ingredient with one or more inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.). The preparation of the composition can be achieved by uniformly and tightly binding the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then shaping the product if necessary. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

The compositions described herein that are suitable for oral administration may exist as discrete units (unit dosage forms), including but not limited to capsules, flat capsules or tablets, each containing a predetermined amount of the active ingredient.

For example, when intended for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents to provide a palatable formulation, including sweeteners, flavoring agents, coloring agents, and preservatives. Tablets containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate alone, or both, can be used in combination with waxes.

In some embodiments, oral dosage forms (e.g., tablets) are disclosed herein, which can be prepared by hot melt extrusion or spray dry dispersion (SDD) technology.

In some embodiments, this document discloses hard capsules filled with powder, beads, or granules containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing hard or soft capsules. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

In some embodiments, this document discloses hard or soft capsules filled with a liquid or semi-solid mixture containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing hard or soft capsules. These excipients may be, for example, solubilizing oils such as maize oil, sesame oil, or corn oil; medium-chain triglycerides and related esters such as derived palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as caprylic/caprylic triglyceride or propylene glycol monocaprylate; viscosity modifiers such as cetyl alcohol, stearyl alcohol, or glyceryl stearate; and solubilizers and surfactants such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate.

The pharmaceutical compositions of the present invention can be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. The suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oils are generally used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can also be used to prepare injectable formulations.

In some embodiments, the sterile injectable formulations disclosed herein may also be sterile injectable solutions or suspensions prepared from lyophilized powders reconstituted in a non-toxic, parenteral-acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oils are typically used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can also be used to prepare the injectable formulation.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will contain one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in *Handbook of Pharmaceutical Excipients* (edited by Rowe, Sheskey, and Quinn), 6th edition, 2009.

Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, parenteral administration (e.g., SC or IM formulations) is disclosed herein comprising a choline salt of compound 1 disclosed herein or its crystalline form and poloxamer, particularly poloxamer 338. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in the parenteral administration disclosed herein is less than about 5%, for example less than about 3%, about 2%, about 1%, or about 0.5%.

In some embodiments, the parenteral preparations disclosed herein (e.g., SC or IM preparations) are aqueous suspensions. In some embodiments, the parenteral preparations disclosed herein (e.g., SC or IM preparations) are aqueous suspensions comprising a choline salt or crystalline form of compound 1 disclosed herein and saline solution. In some embodiments, the parenteral preparations disclosed herein (e.g., SC or IM preparations) are aqueous suspensions comprising a choline salt or crystalline form of compound 1 disclosed herein, saline solution, and poloxamer (e.g., poloxamer 338, 188, or 207).

In some embodiments, the disclosed composition is a solid dosage form, including solid injectable dosage forms, such as solid reservoir forms.

The amount of active ingredient that can be combined with an inactive ingredient to form a dosage form can vary depending on the intended treatment of the subject and the specific method of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active substance, formulated together with an appropriate and convenient amount of a carrier material (e.g., an inactive ingredient or excipient material). In some embodiments, the carrier material varies from about 5% to about 95% (by weight) of the total composition.

It should be understood that, in addition to the ingredients specifically mentioned above, the compositions of these embodiments may contain other agents conventional in the art and relevant to the type of composition discussed, such as flavoring agents, those suitable for oral administration.

In some embodiments, compositions comprising the active ingredients disclosed herein in a variation do not contain agents that affect the metabolic rate of said active ingredient. Therefore, it should be understood that compositions comprising the choline salt of compound 1 or its crystalline form in some embodiments do not contain agents that affect (e.g., slow down, inhibit, or delay) the metabolism of the choline salt of compound 1 or its crystalline form, or any other active ingredient applied alone, sequentially, or simultaneously with the salt or crystalline form. It should also be understood that any methods, kits, articles, etc., detailed herein in some embodiments do not contain agents that affect (e.g., slow down, inhibit, or delay) the metabolism of the choline salt of compound 1 or its crystalline form, or any other active ingredient applied alone, sequentially, or simultaneously with the choline salt of compound 1 or its crystalline form.

reagent kits and products

This disclosure relates to a kit comprising a choline salt or its crystalline form of compound 1 disclosed herein. In one embodiment, the kit may comprise one or more additional therapeutic agents as described above. The kit may further comprise instructions for use, for example, for inhibiting HIV reverse transcriptase, for example, for treating HIV infection or AIDS, or as a research tool. Although electronic storage media (e.g., disks or optical discs) containing instructions for use are also acceptable, instructions for use are generally written instructions.

This disclosure also relates to pharmaceutical kits comprising one or more containers containing a choline salt of Compound 1 disclosed herein or its crystalline form. Optionally associated with the containers may be a notification in the form prescribed by a government authority regulating the manufacture, use, or sale of the drug, reflecting authorization by the authority to manufacture, use, or sell for human administration. Each component (if there are more than one component) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. The kit may be a unit dosage form, a bulk package (e.g., a multi-dose package), or a subunit dose. The kit may also include multiple unit doses of the compound and instructions for use, and the packaged amount is sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and dispensing facility).

In some embodiments, the invention also relates to a pharmaceutical kit comprising one or more containers containing a choline salt of Compound 1 disclosed herein or its crystalline form. Optionally associated with the containers may be a notification in the form prescribed by a government authority regulating the manufacture, use, or sale of the drug, reflecting authorization by the authority to manufacture, use, or sell it for human administration. Each component (if there are more than one component) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. The kit may be a unit dosage form, a bulk package (e.g., a multi-dose package), or a subunit dose. The kit may also include multiple unit doses of the compound and instructions for use, and the packaged amount is sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and dispensing facility).

Also disclosed are articles comprising a unit dose of a choline salt of the disclosed compound 1 or its crystalline form, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packaging, etc. The articles may be further sterilized and/or sealed.

Example

General methods

X-ray powder diffraction (XRPD)

Under the following experimental settings, XRPD patterns were acquired on a PANanalytical XPERT-PRO diffractometer: 45 kV, 40 mA, scanning range 2 to 40°, step size 0.0084 or 0.0167°, measurement time: 5 min.

Differential scanning calorimetry (DSC)

DSC thermograms were acquired on a TA Instruments Q2000 system equipped with a 50-position autosampler. Energy and temperature calibration were performed using certified indium. Typically, 1–5 mg of each sample was heated from 25 °C to 300 °C at a rate of 10 °C/min in a perforated aluminum pot. The sample was purged with dry nitrogen at a rate of 50 mL/min throughout the measurement. The onset of endothermic melting was recorded as the melting point.

Proton nuclear magnetic resonance ( ^1H NMR)

^1H NMR spectra were acquired on a Varian 400-MR 400MHz instrument with a 7620AS sample converter. Default proton parameters were as follows: spectral width: 14 to -2 ppm (6397.4 Hz); relaxation delay: 1 sec; pulse: 45°; acquisition time: 2.049 sec; scan or repetition count: 8; temperature: 25 °C. Samples were prepared in dimethyl sulfoxide-d6 unless otherwise specified. Offline analysis was performed using MestReNova software.

Intermediate 1.(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate

Step 1. (S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

3,6-Dibromopyridinecarboxaldehyde (76.0 g, 0.287 mol) and (S)-2-methylpropane-2-sulfinamide (36.51 g, 0.301 mol) were combined in NMP (N-methyl-2-pyrrolidone) (200 mL). Solid _Cs₂CO₃ (41.94 g, 0.316 mol) was added to the reaction mixture in _a single addition. The reaction mixture was stirred for approximately 2 hours and then cooled to approximately 5 °C. Water (1.3 L) was added to the reaction mixture. The resulting suspension was stirred for approximately 1 hour, and the solid was separated by filtration, washed with water (5 x 100 mL), and dried to provide the title compound. MS (m/z) 368.9 [M+H] ^⁺ .

Step 2. (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

(S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (65.5 g, 177.95 mmol) was added to a reaction vessel, followed by DMF (dimethylformamide) (260 mL). The mixture was stirred for about 5 minutes until homogeneous, and the solution was cooled to about 8°C. After about 90 minutes, (3,5-difluorobenzyl)zinc bromide (0.5 M in tetrahydrofuran (THF), 516.04 mL) was added dropwise to the reaction mixture. The mixture was stirred for another about 2.5 hours. After about 10 minutes, an aqueous solution of 5% AcOH (acetic acid) (640 mL) was added to the reaction mixture, followed by a one-time addition of CPME (cyclopentyl methyl ether) (320 mL). The mixture was stirred for about 5 minutes, heated to room temperature, and the layers were separated. The organic layer was washed with 5% AcOH (320 mL), then treated with 0.5 M NaOH (330 mL) and washed with brine. Collect the organic layer, dry _it with _Na₂SO₄ , and filter it. Add MeOH (methanol) (33 mL) to the crude mixture. Add 3 M HCl/CPME (128 mL) dropwise to the stirred mixture over about 15 minutes. After stirring for about 1 hour, remove the precipitate by filtration. Dilute the filtrate with hexane (300 mL) and extract the product with water (450 mL). Alkalize the aqueous layer with 8 M NaOH and extract it with CPME (375 mL). Wash the organic layer with brine, dry it with _{Na₂SO₄ ,} and filter it to provide the title compound in solution, which can be used directly in the next step. MS (m/z) 497.0 [M+H] ^⁺ .

Step 3. (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl-1-amine

The resulting (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide solution was diluted to a volume of 700 mL with CPME, and acetonitrile (350 mL) was added to it. At room temperature, concentrated HCl (37%, 16.4 mL) was added dropwise to the stirred mixture over approximately 10 minutes. The slurry was stirred vigorously for approximately 4 hours. The solid was filtered and washed with 2:1 CPME (cyclopropyl methyl ether):ACN to provide the title compound. MS (m/z) 393.3 [M+H] ⁺ .

Step 4. (S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate

In a reaction vessel, 190 mL of 2-MeTHF (2-methyltetrahydrofuran), 190 mL of water, and (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl-1-amine (46.9 g, 0.11 mol) were added, followed by fractional addition of _NaHCO₃ (30.34 g, 0.36 mol). The reaction mixture was cooled to approximately 5 °C, and 27.47 g, 0.13 mol of ditert-butyl dicarbonate was added. The reaction mixture was stirred at approximately 0 °C for approximately 2 hours and then at ambient temperature for approximately 2 hours. The reaction mixture was diluted with water and extracted with MTBE (methyl tert-butyl ether). The organic layer was washed with brine, dried, and concentrated. The crude compound was purified by silica gel column chromatography to provide the title compound. MS (m/z) 492.8 [M+H] ^⁺ . ^¹H NMR (400 MHz, methanol-d⁴) δ 7.85 (d, ¹H), 7.42 (d, ¹H), 6.90–6.72 (m, ³H), 5.33 (dd, ¹H), 3.10 (dd, ¹H), 2.92 (dd, ¹H), 1.36 (s, ⁹H). Intermediate: 2,4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentabor-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine

Step 1.7-Bromo-4-chloro-1H-indazole-3-amine

Hydrazine monohydrate (5.77 mL) was added to EtOH (ethanol) (60 mL) containing 13.9 g (59.3 mmol) of 3-bromo-6-chloro-2-fluorobenzyl nitrile (EtOH). The reaction mixture was heated to approximately 80 °C for about 3 hours. After cooling to ambient temperature, EtOH (20 mL) was added to allow stirring. The solid was separated by filtration, washed with cold EtOH, and dried to provide the title compound. MS (m/z) 247.9 [M+H] ⁺ .

Step 2.7-Bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine

7-Bromo-4-chloro-1H-indazole-3-amine ( _397.2 g, 1.6 mol) and _Cs₂CO₃ (1052 g, 3.2 mol) were charged into a reactor and diluted with DMF (dimethylformamide) (4000 mL). 2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) was slowly added via a feeding funnel. After the addition was complete, the reaction mixture was allowed to be stirred for about 1 hour, during which time _H₂O (16 L) was slowly added. After the addition was complete, the mixture was allowed to be stirred at about 15 °C for about 12 hours. The slurry was filtered and the collected solids were suspended in DMF (800 mL). _H₂O (4800 mL) was added, and the resulting solids were collected by filtration and dried to provide the title compound. MS (m/z) 330.1 [M+H] ^⁺ .

Step 3. 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentabor-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine

In a reaction vessel, 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (15.00 g, 45.66 mmol), bis(pinacol)diboron (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 mL), and DMF (dimethylformamide) (30 mL) were added. Bis(triphenylphosphine)palladium(II) dichloride (0.64 g, 0.91 mmol) was added, and the reaction solution was degassed by bubbling argon for approximately 2 minutes. The reaction mixture was heated to approximately 105 °C for approximately 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a Celite pad and the silica gel was washed with EtOAc. The filtrate was washed with 5% LiCl solution and brine. The organic layer was separated, dried, and concentrated under reduced pressure. The residue was treated with IPAc/heptane (1/10) at approximately 60 °C, then cooled to ambient temperature and stirred for approximately 15 hours. The solid was collected by filtration and dried to give the title compound. MS (m/z) 376.7 [M+H] ⁺¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (d, 1H), 7.06 (d, 1H), 5.55 (s, 2H), 5.45 (q, 2H), 1.32 (s, 12H).

Intermediate 3,2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-l-yl)acetic acid

Step 1. Lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hex-2-ylene)acetyl-1-olate

A reactor was charged with bicyclo[3.1.0]hexane-3-one (95.6 g, 0.99 mol), ethyl 2,2,2-trifluoroacetate (113.2 mL, 0.95 mol), and THF (50 mL). The reaction mixture was cooled to approximately 0 °C. LiHMDS (lithium bis(trimethylsilyl)amide) (1 L 1.0 M THF solution, 1 mol) was added via a feeding funnel at a rate maintaining the internal temperature below approximately 1 °C. After the addition was complete, hexane (235 mL) was added via a feeding funnel at a steady flow and the mixture was stirred for approximately 15 min. The resulting solid was collected by filtration, washed with hexane (3 x 400 mL), and dried to provide the title compound.

Step 2. Ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropen[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)

Lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hex-2-ylene)acetate (177.2 g, 0.89 mol) and EtOH (ethanol) (779 mL) were charged into a reactor. The temperature was brought to approximately 0 °C and maintained at approximately 0 °C. HCl/dioxane (4.0 N, 443 mL) was added via a feeding funnel, followed by solid hydrazine ethyl acetate HCl salt (138.4 g, 0.90 mol). The reaction temperature was adjusted to approximately 35 °C. After approximately 1 hour, the reaction volume was reduced by -40% by distillation under reduced pressure. Water (1.3 L) was added with vigorous stirring and the temperature was adjusted to approximately 15 °C. The resulting solid was collected by filtration, washed with water (3 x 500 mL) and hexane (3 x 400 mL), and dried to give the title compound. MS (m/z) 275.1 [M+H] ⁺ .

Step 3. Ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)

A reactor was charged with ethyl acetate 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (291.2 g, 1.06 mol), acetonitrile (1.65 L), and water (825 mL). N-hydroxyphthalimide (17.4 g, 0.103 mol) and _NaClO₂ (41.0 g, 0.45 mol, -20% of the total amount added) were then added. The reaction mixture was heated to approximately 50 °C, and the remaining _NaClO₂ (163.0 g, 1.80 mol) was added in five portions over approximately 2 hours. After the initial material was consumed, the temperature was adjusted to approximately 20 °C, and an aqueous solution of sodium bisulfite (40% w/w, 350 mL) was added via a feeding funnel. Ethyl acetate (1.75 L) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (ethyl acetate) (500 mL). The organic layers were combined and washed with a saturated aqueous solution of _NaHCO3 (500 mL) and a 1:1 water/salt solution (500 mL). The organic layer was concentrated under reduced pressure and co-evaporated with IPAc (isopropyl acetate) (300 mL). The crude solid was crystallized from the IPAc/heptane mixture. The resulting solid was collected by filtration, washed with heptane, and dried to provide the title compound. MS (m/z) 289.0 [M+H] ⁺ .

Step 4. 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropen[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid

To a solution of ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (80.40 g, 278.95 mmol) in 167 mL of 2-MeTHF, 2 M aqueous sodium hydroxide solution (167 mL) was added. After stirring at room temperature for about 25 minutes, the reaction mixture was diluted with 2-MeTHF and slowly acidified by dropwise addition of concentrated HCl. The organic layer was separated and the aqueous layer was extracted with another portion of 2-MeTHF. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The resulting oil was added to ethyl acetate. Hexane was added under vigorous stirring until a solid was observed to form. The solid was separated by filtration and dried to provide the title compound. MS (m/z) 259.00 [MH] ^- .

Step 5. 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropenzo[3,4]cyclopentadieno[1,2-c]pyrazol-5,2’-[1,3]dithiacyclopentane]-1(3bH)-yl)acetic acid

To a solution of 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid (3.0 g, 11.5 mmol) in DCM (dichloromethane) (25 mL), 1,2-ethanedithiol (1.07 mL, 12.68 mmol) was added, followed by boron trifluoride-acetic acid complex (4.0 mL, 28.8 mmol). The reaction mixture was stirred overnight at room temperature. Water (60 mL) and 2-MeTHF (60 mL) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude substance was dissolved in ethyl acetate (2 mL) and diluted with hexane (12 mL) under vigorous stirring to provide a solid. The solid was separated by filtration and dried to provide the title compound. MS (m/z) 337.12 [M+H] ⁺ .

Step 6. 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropen[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid

At approximately 0°C, pyridine hydrofluoride (5.0 mL) was added to a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 mL). The suspension was stirred at approximately 0°C for approximately 10 minutes. A solution of 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropenzo[3,4]cyclopentadieno[1,2-c]pyrazol-5,2'-[1,3]dithiacyclopentane]-1(3bH)-yl)acetic acid (5.00 g, 14.9 mmol) was added dropwise to the suspension. After the addition was complete, the reaction mixture was stirred at approximately 0°C for approximately 15 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) with vigorous stirring. The organic layer was removed and the aqueous layer was acidified to pH-1 with concentrated HCl. The aqueous phase was extracted with three portions of MTBE (methyl tert-butyl ether). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to MTBE (16 mL) and filtered to remove any resulting solid. The solution was then extracted with 2N NaOH (16 mL). The aqueous layer was diluted with water (16 mL) under vigorous stirring and stirred at room temperature for about 15 minutes. The resulting solid was removed by filtration. The aqueous layer was acidified to pH 1 by slow dropwise addition of concentrated HCl under vigorous stirring to obtain a solid precipitate. The solid was separated by filtration to provide the title compound. MS (m/z) 281.12 [M+H] ⁺ .

Step 7. 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid

2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid was isolated by chiral supercritical fluid chromatography (SFC) under the following conditions to its constituent enantiomers (2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid (intermediate 3) and 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid): Instrument: Thar 350 Preparative SFC; Column: ChiralPak IC-10u, 300×50mm I.D; Mobile phase: 35% isopropanol (0.1% _NH3 - _H2O ) and _CO2 ; Flow rate: 200mL/min; Column temperature: 38℃; UV detection: 220nm; Sample preparation: Dissolve the compound in isopropanol to -45mg/mL; Injection: 6.5mL per injection. Analytical SFC [Mobile phase: A is _CO2 and B isopropanol (0.05% DEA); Gradient: B 20%; A; Flow rate: 2.35mL/min; Column: Chiralpak IC-3, 150x4.6mm, 3μm; Wavelength: 254nm]. The desired isomer, 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropeno[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid, was eluted at t = 3.39 min; ^¹H NMR (400 MHz, chloroform-d) δ 4.93 (s, 2H), 2.52–2.43 (m, 2H), 1.44–1.38 (m, 1H), 1.15 (m, 1H).

Intermediate 4: 3-Methyl-3-(methanesulfonyl)but-l-yne

3-Chloro-3-methylbut-1-yne (15.00 g, 146.3 mmol, 16.4 mL) was added dropwise to a stirred suspension of sodium methanesulfinate (18.47 g, 175.5 mmol) and copper chloride (I) (1.45 g, 14.6 mmol) in DMF (dimethylformamide) (50 mL). The resulting reaction mixture was heated to approximately 40 °C and stirred for approximately 16 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with water and brine. The organic layer was collected, dried over sodium sulfate, and then filtered. The solution was concentrated under vacuum and purified by silica gel chromatography to provide the title compound. Mp: 114.8–115.5 °C. ^¹H NMR (400 MHz, chloroform-d) δ 3.04 (s, 3H), 2.58 (s, 1H), 1.67 (s, 6H).

Example 1. N-((S)-l-(3-(4-chloro-3-(methanesulfonamido)-l-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-l-yl)acetamide (Compound 1)

Step 1. (S)-(1-(3-bromo-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate

A reactor was charged with (S)-(l-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate tert-butyl ester (intermediate 1, 50.00 g, 101.8 mmol), 3-methyl-3-methanesulfonyl-but-l-yne (17.86 g, 122.2 mmol), DMF (dimethylformamide) (90 mL), and _Et3N (triethylamine) (42.5 mL, 305.4 mmol). The reaction mixture was heated to approximately 50 °C. Bis(triphenylphosphine)palladium(II) dichloride (2.14 g, 3.1 mmol) and copper iodide (I) (0.58 g, 3.1 mmol) were added. After approximately 30 minutes, the reaction mixture was diluted with MeCN (acetonitrile) (200 mL), followed by dropwise addition of a 7% _NH4Cl aqueous solution (200 mL). A slurry was formed and adjusted to ambient temperature. After approximately 3 hours, the solids were collected by filtration. The filter cake was washed twice with MeCN/water (1:1, 75 mL) and then with MTBE (methyl tert-butyl ether) (75 mL). The solid was dried to provide the title compound. MS (m/z) 556 [M+H] ⁺ . ^1H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 8.2 Hz, 1H), 7.29–7.15 (m, 1H), 6.70–6.55 (m, 2H), 5.79 (d, J = 9.0 Hz, 1H), 5.57–5.45 (m, 1H), 3.21–3.05 (m, 4H), 2.99–2.88 (m, 1H), 1.80 (s, 6H), 1.40* (s, 7H), 1.30* (s, 2H). * indicates the presence of a transisomer in a ratio of 4.6:1.

Step 2. (S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate

(S)-(1-(3-bromo-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate (1000.0 mg, 1.79 mmol), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentabor-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (808.5 mg, 2.15 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (65.6 mg, 0.09 mmol), and cesium carbonate (876.7 mg, 2.69 mmol) were placed in a round-bottom flask and placed under argon atmosphere. Add dioxane (10 mL) and water (2 mL), and degas the suspension by bubbling argon for about one minute. After degassing, equip the reaction flask with a reflux condenser and heat to about 80 °C overnight. Cool the reaction mixture to room temperature and remove the aqueous layer. Concentrate the organic layer under vacuum, and purify the resulting residue by silica gel column chromatography to provide the title compound. MS (m/z) 726.1 [M+H] ⁺ . ¹ H NMR (400MHz, chloroform-d) δ 7.69–7.55 (m), 7.55–7.42 (m), 7.16–7.06 (m), 7.07–6.96 (m), 6.89 (d), 6.60 (tt), 6.44 (dd), 6.20 (d), 6.16 (d), 6.08 (s), 5.69–5.53 (m), 5.29 (s), 5.26 (d), 4.95–4.85 ( m),4.64(q),4.59–4.46(m),4.36–4.19(m),3.94–3.76(m),3.64–3.54(m),3.18(s),3.17(s), 3.01–2.84(m),2.78–2.68(m),1.86–1.82(m),1.38(s),1.34(s),1.26(s),1.23(s),1.15(s).

Step 3. (S)-(1-(3-(4-chloro-3-(N-(methanesulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate

At ambient temperature, (S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)tert-butyl carbamate (37.89 g, 52.18 mmol) was dissolved in dichloromethane (380 mL) with stirring. Triethylamine (21.82 mL, 156.54 mmol) was added, followed by the slow addition of methanesulfonyl chloride (8.08 mL, 104.36 mmol). When the reaction was complete, water (200 mL) was added and the mixture was stirred for about 0.5 hours. The organic layer was separated and the aqueous layer was extracted once with dichloromethane. The combined organic layers were washed with water and brine, dried over _MgSO4 , filtered, and concentrated to a small volume. Hexane was added. Pour off the liquid suspension. Dry the remaining solid under reduced pressure to give the title compound. MS (m/z): 882.69 [M+H] ⁺ . ¹ H NMR (400MHz, methanol-d ₄ )δ7.87(d),7.83(d),7.76(s),7.74(s),7.69(s),7.67(s),7.65(s),7.52– 7.47(m),7.46(s),7.37(d),7.33(d),7.11–7.03(m),4.79–4.55(m),4.51( t),4.36(dt),4.20–4.05(m),3.64(s),3.62(s),3.60(s),3.59(s),3.23(s) ),3.04(d),3.01(d),2.95–2.83(m),1.81(s),1.34(s),1.29(s),0.98(s).

Step 4. (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)-N-(methanesulfonyl)methanesulfonamide

Trifluoroacetic acid (80 mL) was added to (S)-(1-(3-(4-chloro-3-(N-(methanesulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate tert-butyl (39 g, 44 mmol) dissolved in dichloromethane (120 mL). The reaction mixture was stirred at ambient temperature for about 50 minutes. The reaction mixture was diluted with dichloromethane and slowly poured into an ice-cold saturated aqueous solution of _NaHCO3 . The organic layer was separated, washed with water and brine, dried over _MgSO4 , filtered, and concentrated to dryness to give the title compound. MS (m/z): 782.84 [M+H] ⁺ . ^1H NMR (400MHz, chloroform-d) δ 7.61(d), 7.54–7.44(m), 7.40(d), 7.33(d), 7.20(d), 6.66–6.57(m), 6.44(d), 6.33(d), 6.17(d), 4.64(s), 3.68(s), 3.64(s), 3.61(s), 3.55(s), 3.19(s), 3.05(dd), 2.85–2.72(m), 1.86(s), 1.62(s).

Step 5. N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropen[3,4]cyclopentadien[1,2-c]pyrazol-1-yl)acetamide

(S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)-N-(methanesulfonyl)methanesulfonamide (1757 mg, 2.25 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4, 4a,5-Tetrahydro-1H-cyclopropen[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid (intermediate 3,666 mg, 2.36 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (854 mg, 2.25 mmol) were placed in a round-bottom flask and dissolved in DMF (dimethylformamide) (10.0 mL). N,N-diisopropylethylamine (0.80 mL, 4.49 mmol) was added to the solution dropwise at a rapid rate. After the addition was complete, the reaction mixture was stirred at room temperature for about 15 minutes to provide the unseparated intermediate N-((S)-1-(3-(4-chloro-3-(N-(methanesulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide (MS(m/z) 1046.65 [M+H] ⁺ ). 2N aqueous sodium hydroxide solution (5.0 mL) was added to the solution. The mixture was stirred at room temperature for about 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected and washed with two portions of 5% lithium chloride solution, followed by washing with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title compound as an amorphous solid. MS (m/z) 968.24 [M+H] ⁺ . ¹ H NMR (400MHz, methanol-d ₄ )δ7.87–7.57(m),7.33–7.09(m),6.80–6.70(m),6.54(d),6.47(d),6.37–6.19(m),5.02-4.94(m),4.90–4.70(m),4.70–4.51( m),3.94(dq),3.32-3.28(m),3.23(d),3.07(dd,J＝13.1,7.6Hz),2.93(dd),2.68–2.35(m),1.81(s),1.41(q),1.12–1.00(m). ¹⁹ F NMR (377 MHz, methanol- _d4 ) δ–63.65,–71.78(t),–72.35(t),–82.75(dd),–105.70(ddd),–111.73 to–113.10(m).

Example 2. N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium (choline) salt

100 mg of compound 1 and 25 mg of choline hydroxide solution (50% aqueous solution, 1 equivalent) were stirred in about 1 mL of isopropanol (IPA). The mixture was dried to obtain an amorphous solid. About 1 mL of IPA was added to the solid, which remained an amorphous solid after stirring for about 2 hours. 10 μL of water was added, and the solid was mostly dissolved. The solution was kept at about 21 °C, and crystallization was carried out over several days. The crystals obtained after filtration and drying at about 50 °C under vacuum were named N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1. ^1H -NMR showed that N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 was enriched in isomer B, as shown in Figure 1 (top trace).

The crystals from the above experiments were initially bulk crystals. After two months under undisturbed conditions in a sealed tube, the crystals transformed into needle-like shapes. XRPD analysis showed a different pattern for the needle-like crystals compared to the original bulk crystals, as shown in Figure 2.

1H-NMR spectroscopy confirmed that the needle-like crystals were still choline salts, but enriched in isomer A (Figure 1, bottom trace). UPLC (ultra-high performance liquid chromatography) analysis showed that it contained approximately 64.8% isomer A and approximately 35.1% isomer B. After drying, the material lost its crystallinity, as shown in Figure 3, and was named material A, N,N,N-trimethylethanolammonium (choline) salt of compound 1. Further experiments were conducted by stirring the N,N,N-trimethylethanolammonium (choline) salt crystal form I or material A of compound 1 in other solvents at approximately 22°C. Salts formed from MeOH, DCM, or toluene enriched in isomer B, while salts formed from MeCN, 2-MeTHF, i-PrOAc, EtOH, THF, or MTBE enriched in isomer A.

Form I

The N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 is enriched with isomer B, and it was prepared as described above. The XRPD spectrum of the N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 is shown in Figure 4. A list of 2-θ peaks is provided in Table 1 below.

Table 1

The DSC thermogram of N,N,N-trimethylethanolammonium (choline) salt I of compound 1 is shown in Figure 5, and it shows a melting initiation of about 157 °C.

Form II

The N,N,N-trimethylethanolammonium (choline) salt crystalline form II of compound 1 is enriched with isomer B, and it is obtained by slurrying the N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 in MeOH/IPE (1:1 volume mixture) at about 22 °C for one week, filtering, and drying the solid at about 22 to about 50 °C under vacuum.

The XRPD spectrum of N,N,N-trimethylethanolammonium (choline) salt crystalline form II of compound 1 is shown in Figure 6. A list of 2-θ peaks is provided in Table 2 below.

Table 2

The DSC thermogram of N,N,N-trimethylethanolammonium (choline) salt II of compound 1 is shown in Figure 7, and it shows a melting initiation of about 147 °C.

Form III

The N,N,N-trimethylethanolammonium (choline) salt crystalline form III of compound 1 was enriched with isomer B, and it was obtained by slurrying the N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 in a DCM/heptane mixture (1:1 volume mixture) at about 22 °C for about 24 h, filtering, and drying the solid at about 50 °C and under vacuum.

The XRPD spectrum of N,N,N-trimethylethanolammonium (choline) salt crystalline form III of compound 1 is shown in Figure 8. A list of 2-θ peaks is provided in Table 3 below.

Table 3

The DSC thermogram of N,N,N-trimethylethanolammonium (choline) salt III of compound 1 is shown in Figure 9, and it shows a melting initiation of about 144 °C.

Form IV

The N,N,N-trimethylethanolammonium (choline) salt crystalline form IV of compound 1 was enriched for isomer B, and was obtained by slurrying the N,N,N-trimethylethanolammonium (choline) salt crystalline form I of compound 1 in toluene at about 22 °C for about 2 weeks, filtering, and drying the solid at about 50 °C under vacuum. The XRPD spectrum of the N,N,N-trimethylethanolammonium (choline) salt crystalline form IV of compound 1 is shown in Figure 10. A list of 2-θ peaks is provided in Table 4 below.

Table 4

The DSC thermogram of N,N,N-trimethylethanolammonium (choline) salt IV of compound 1 is shown in Figure 11, and shows a melting initiation of about 136 °C.

Form V

The N,N,N-trimethylethanolammonium (choline) salt crystalline form V of compound 1 is enriched isomer A, and its preparation is by slurrying the N,N,N-trimethylethanolammonium (choline) salt material A of compound 1 in MeCN/IPE (1:1 volume mixture) at about 22 °C, filtering, and drying the solid at about 50 °C and under vacuum.

The XRPD spectrum of the N,N,N-trimethylethanolammonium (choline) salt crystalline form V of compound 1 is shown in Figure 12. A list of 2-θ peaks is provided in Table 5 below.

Table 5

The DSC thermogram of the N,N,N-trimethylethanolammonium (choline) salt crystal form V of compound 1 is shown in Figure 13, and it shows a melting initiation of about 159 °C.

Form VI

The N,N,N-trimethylethanolammonium (choline) salt crystalline form VI of compound 1 is enriched isomer A, and its preparation is by slurrying the N,N,N-trimethylethanolammonium (choline) salt material A of compound 1 in 2-MeTHF at about 22°C for about 24 h, filtering, and drying the solid at about 50°C and under vacuum.

The XRPD spectrum of the N,N,N-trimethylethanolammonium (choline) salt crystalline form VI of compound 1 is shown in Figure 14. A list of 2-θ peaks is provided in Table 6 below.

Table 6

The DSC thermogram of the N,N,N-trimethylethanolammonium (choline) salt crystalline form VI of compound 1 is shown in Figure 15, and it shows a melting initiation of about 121 °C.

Form VII

The N,N,N-trimethylethanolammonium (choline) salt crystalline form VII of compound 1 is enriched isomer A, and its preparation is by slurrying the N,N,N-trimethylethanolammonium (choline) salt material A of compound 1 in i-PrOAc at about 22°C for about 24 h, filtering, and drying the solid at about 50°C and under vacuum.

The XRPD spectrum of the N,N,N-trimethylethanolammonium (choline) salt crystalline form VII of compound 1 is shown in Figure 16. A list of 2-θ peaks is provided in Table 7 below.

Table 7

The DSC thermogram of N,N,N-trimethylethanolammonium (choline) salt VII of compound 1 is shown in Figure 17, and it shows a melting initiation of about 144 °C.

Example 3. N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium (choline) salt, ethanol solvate

The ethanol solvate form of compound 1, N,N,N-trimethylethanolammonium (choline) salt, enriched isomer A, which was prepared by slurrying the N,N,N-trimethylethanolammonium (choline) salt crystal form I or material A of compound 1 in an EtOH/heptane mixture (1:1 volume mixture) at about 22 °C for about 24 h. The XRPD pattern of the ethanol solvate form is shown in Figure 18. After drying, the material lost its crystallinity.

Example 4. N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienzo[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium (choline) salt, tetrahydrofuran (THF) solvate

The tetrahydrofuran (THF) solvate form of the N,N,N-trimethylethanolammonium (choline) salt of compound 1 was enriched in isomer A, which was prepared by slurrying the N,N,N-trimethylethanolammonium (choline) salt crystal form I or material A of compound 1 in a THF/heptane mixture (1:1 volume mixture) at about 22 °C for about 24 h. The XRPD pattern of the tetrahydrofuran solvate form is shown in Figure 19. After drying, the material lost its crystallinity.

Example 5. N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropenzo[3,4]cyclopentadienozo[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium (choline) salt, methyl tert-butyl ether (MTBE) solvate

The isomer A of the N,N,N-trimethylethanolammonium (choline) salt of compound 1 was enriched in methyl tert-butyl ether (MTBE) solvate form, and was prepared by slurrying the N,N,N-trimethylethanolammonium (choline) salt material A of compound 1 in MTBE at about 22°C for about two weeks. The XRPD pattern of the MTBE solvate is shown in Figure 20. After drying, the material lost its crystallinity.

Representative synthesis of the compounds described herein can also be found in U.S. Patent Application Serial No. 15/680,041, filed August 17, 2017, which was published on February 22, 2018 as U.S. Patent Application No. 2018-0051005A1, the entire contents of which are incorporated herein by reference.

Biological Examples

Example A

Test A: Antiviral assay in MT4 cells

For the antiviral assay, four copies of the compound, each a three-fold serially diluted 0.4 μL of the 189X test concentration in DMSO, were added to 40 μL of cell growth medium (RPMI 1640, 10% FBS, 1% penicillin-streptomycin, 1% L-glutamine, 1% HEPES) in each well of a 384-well plate (10 concentrations).

At 37°C, 1 mL aliquots of MT4 cells were pre-infected for 3 hours with 25 μL of cell growth medium (simulated infection) or a fresh 1:250 dilution of HIV-IIIb concentrated ABI stock solution (0.004 m.o.i.). Infected and uninfected cells were diluted in cell growth medium, and 35 μL (2000 cells) was added to each well of the assay plate.

The assay plate was then kept in a humidified, 5% _CO2 incubator at 37°C. After 5 days of incubation, 25 μL of 2X concentrated CellTiter-Glo™ reagent (catalog number G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was performed by incubating at room temperature for 10 minutes, followed by reading the chemiluminescence using an Envision plate reader (PerkinElmer). The _EC50 value was calculated based on the concentration of the compound that caused a 50% reduction in the luminescence signal, with the luminescence signal representing a measure of HIV-1 replication.

As described in Examples B-D, Compound 1 offers advantages over structurally similar compounds (hereinafter referred to as Compounds A and B) disclosed in U.S. Patent Publications 2014/0296266A1 and 2014/0303164A1:

Example B

Test B: Cytotoxicity Assay

The compound's cytotoxicity and corresponding CC ₅₀ values were determined using the same protocol as described in the antiviral assay (Test A), except that uninfected cells were used.

The compounds disclosed herein demonstrate antiviral activity compared to compounds A and B, as described in Table A (Test A).

Table A

compound <![CDATA[EC₅₀(nM)]]> <![CDATA[CC₅₀(nM)]]> Compound 1 0.185 30068 Compound A 1.715 21839 Compound B 2.991 14491

Example C

Test C. Pharmacokinetics after intravenous administration to Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys

Learning Analysis

Test items and preparations

Compound 1 was prepared for intravenous administration at a concentration of 0.5 mg/mL in 5% ethanol, 20% PG, 45% PEG 300, and 30% pH 2 (0.01N HCl) water. Compounds A and B were prepared for intravenous infusion at a concentration of 0.5 mg/mL in a sterile solution of 5% ethanol, 45% PEG 400, and 50% water (pH 2.0). All IV formulations were in solution form.

Animals used

Each rat IV dosing group consisted of 3 male SD rats. At the time of administration, the animals typically weighed between 0.317 and 0.355 kg. Animals were fasted overnight before administration and for up to 4 hours after administration. Each canine IV dosing group consisted of 3 male juvenile beagles. At the time of administration, the animals weighed between -10 and 12 kg. Animals were fasted overnight before administration and for up to 2 hours after administration.

Each cynomolgus monkey IV administration group consisted of 3 male juvenile cynomolgus monkeys weighing between -3.2 and 4 kg. Animals were fasted overnight prior to administration and for up to 2 hours after administration.

Dosage

For the IV infusion group, the test compound was administered via intravenous infusion over 30 minutes. The infusion rate was adjusted according to the animal's body weight to deliver a dose of 1 mg/kg at 2 mL/kg.

Sample collection

Serial venous blood samples were collected from each animal at designated time points following drug administration (approximately 0.4 mL per rat and 1.0 mL per dog). Blood samples were collected into Vacutainer ^™ tubes (Becton-Disckinson Corp., New Jersey, USA) containing EDTA as an anticoagulant and immediately placed on wet ice pending centrifugation to obtain plasma. Centrifugation was initiated within 1 hour of collection. All samples were then placed in 96-well tubes and kept on dry ice for storage at approximately -70°C.

Determination of the concentration of compound 1 in plasma

The concentration of the test compound in plasma was measured using the LC/MS/MS method.

calculate

Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. A summary of the pharmacokinetic parameters is shown in Tables B and C below.

Table B

Table C

Example D

Test D. Metabolic stability in cultured human liver hepatocytes

Radiolabeled test compounds are prepared according to methods known in the art, wherein tritium is introduced into the structure in place of one or more hydrogen atoms.

The radiolabeled compound was incubated in confluent, cryopreserved hepatocytes at a substrate concentration of 0.25 μM and a radioactive concentration of 10 μCi/mL. The final hepatocyte concentration was 1 million cells/mL. The hepatocyte/compound reaction mixture was dissolved in InVitroGRO ^™ KHB buffer (catalog number Z99074, Bioreclamation IVT, Inc., Baltimore, MD) at pH 7.4. Incubation was performed in duplicate, including a cell-free control and a positive control. Incubation was performed with gentle shaking in a humid atmosphere at 37°C under 95% air/5% _CO2 (v/v). After 0, 1, 3, and 6 hours, aliquots (100 mL) were removed and added to 200 mL of quenching solution containing 0.1% (v/v) TFA/5% water/95% acetonitrile (v/v). The samples were placed on a shaker for 10 minutes and then centrifuged at 3000g for 30 minutes. The supernatant sample was analyzed using a Dionex HPLC/PerkinElmer Flow Scintillation Analyzer, as described below.

Liquid chromatography-radiochromatography

Quantification was performed by comparing the radiolabeled metabolite peaks with the parent peaks measured on a Radiomatic 625TR FlowScintillation Analyzer connected to a Dionex/Chromeleon chromatography system. The column was a Phenomenex Synergi fusion RP (150 × 4.6 mm, 4 mm) maintained at 32°C. Mobile phase A consisted of 0.1% (v/v) TFA in 99% water/1% acetonitrile (v/v). Mobile phase B consisted of 0.1% (v/v) TFA in 5% water/95% acetonitrile (v/v). A 100 mL sample injection volume was used, and the flow rate was 1 mL/min. The gradient was as follows: mobile phase B linearly increased from 2% to 75% over 47 minutes, held at 75% for 3 minutes, returned to 2%, and held at 2% for 10 minutes.

Metabolic stability is determined by measuring the change in the relative abundance of metabolites and the parent compound over time and calculating the disappearance rate of the parent compound. Predicted human liver clearance values are calculated using stability data according to methods known in the art. The predicted human liver clearance values are shown in Table D below.

Table D

The following can be deduced from the above comparative data:

Compound 1 was significantly more potent than compounds A and B in HIV antiviral assays (approximately 9-fold and 16-fold more potent, respectively). Compound 1 had a longer in vivo terminal half-life in rats compared to compounds A and B (approximately 14-fold and 9-fold longer, respectively). Compound 1 also exhibited lower in vivo clearance in rats compared to compounds A and B (approximately 10-fold and 8.6-fold lower, respectively). Compound 1 had a longer in vivo terminal half-life in dogs compared to compounds A and B (approximately 5-fold and 4-fold longer, respectively). Compound 1 also had lower in vivo clearance in dogs compared to compounds A and B (approximately 3-fold and 4-fold lower, respectively). Compound 1 was more stable in human hepatocytes compared to compounds A and B, with lower predicted hepatic clearance (approximately 9-fold and 4-fold more stable, respectively).

The data above indicate that, compared with compounds A and B, compound 1 has improved antiviral efficacy and improved pharmacokinetic properties (demonstrated by a longer half-life in rats and dogs and a lower predicted human clearance).

The specific pharmacological reactions observed may vary depending on the specific active compound selected or the presence of a drug carrier, as well as the type of formulation and route of administration used, and such expected variations or differences in the results should be taken into account in accordance with the practice of this disclosure.

The embodiments disclosed herein describe the synthesis of the disclosed compounds, salts, and crystalline forms, as well as intermediates for the preparation of the compounds. It should be understood that the various steps described herein can be combined. It should also be understood that different batches of the compounds can be combined and then carried out in the next synthetic step.

All references (including publications, patents, and patent documents) are incorporated herein by reference as if they were separately incorporated by reference. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of this disclosure.

Claims (65)

1. A pharmaceutically acceptable salt, which is N-((S)-1-(3-(4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropen[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium salt. 2. A crystalline form of the salt according to claim 1. 3. The crystalline form of claim 2, selected from crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI and crystalline form VII. 4. The crystalline form of claim 3, wherein the crystalline form I has at least three XRPD peaks selected from 5.5°, 7.5°, 7.9°, 14.9°, 15.7°, 16.8°, 17.6°, 19.3° and 22.4°, expressed as 2-θ±0.2°. 5. The crystalline form of claim 3, wherein the crystalline form is crystalline form I, wherein the crystalline form I has at least three XRPD peaks selected from 5.5°, 7.5°, 7.9°, 14.9°, 15.7°, 16.8°, 17.6°, 19.3° and 22.4°, expressed as 2-θ±0.2°. 6. The crystalline form according to any one of claims 3 to 5, wherein the crystalline form I is characterized by an XRPD pattern substantially as shown in FIG4. 7. The crystalline form according to any one of claims 3 to 6, wherein the crystalline form I is characterized by having a DSC thermogram with a melting initiation of about 157°C. 8. The crystalline form according to any one of claims 3 to 7, wherein the crystalline form I is characterized by a DSC thermogram substantially as shown in FIG5. 9. The crystalline form of claim 3, wherein the crystalline form II has at least three XRPD peaks selected from 7.5°, 9.6°, 14.0°, 14.9°, 16.1°, 16.9°, 20.8°, 21.0° and 26.5°, expressed as 2-θ±0.2°. 10. The crystalline form of claim 3, wherein the crystalline form is crystalline form II, wherein the crystalline form II has at least three XRPD peaks selected from 7.5°, 9.6°, 14.0°, 14.9°, 16.1°, 16.9°, 20.8°, 21.0° and 26.5°, expressed as 2-θ±0.2°. 11. The crystalline form of any one of claims 3, 9 and 10, wherein the crystalline form II is characterized by an XRPD pattern substantially as shown in FIG6. 12. The crystalline form according to any one of claims 3 and 9-11, wherein the crystalline form II is characterized by having a DSC thermogram with a melting initiation of about 147°C. 13. The crystalline form of any one of claims 3 and 9-12, wherein the crystalline form II is characterized by a DSC thermogram substantially as shown in FIG7. 14. The crystalline form of claim 3, wherein the crystalline form III has at least three XRPD peaks selected from 7.8°, 8.1°, 8.3°, 15.0°, 15.7°, 16.7°, 20.0°, 21.1° and 21.7°, expressed as 2-θ±0.2°. 15. The crystalline form of claim 3, wherein the crystalline form is crystalline form III, wherein the crystalline form III has at least three XRPD peaks selected from 7.8°, 8.1°, 8.3°, 15.0°, 15.7°, 16.7°, 20.0°, 21.1° and 21.7°, expressed as 2-θ±0.2°. 16. The crystalline form of any one of claims 3, 14 and 15, wherein the crystalline form III is characterized by an XRPD pattern substantially as shown in FIG8. 17. The crystalline form of any one of claims 3 and 14-16, wherein the crystalline form III is characterized by a DSC thermogram having a melting initiation of about 144°C. 18. The crystalline form of any one of claims 3 and 14-17, wherein the crystalline form III is characterized by a DSC thermogram substantially as shown in FIG9. 19. The crystalline form of claim 3, wherein the crystalline form IV has at least three XRPD peaks selected from 7.5°, 8.0°, 14.8°, 16.1°, 17.0°, 20.3°, 21.1°, 24.6° and 26.7°, expressed as 2-θ±0.2°. 20. The crystalline form of claim 3, wherein the crystalline form is crystalline form IV, wherein the crystalline form IV has at least three XRPD peaks selected from 7.5°, 8.0°, 14.8°, 16.1°, 17.0°, 20.3°, 21.1°, 24.6° and 26.7°, expressed as 2-θ±0.2°. 21. The crystalline form of any one of claims 3, 19 and 20, wherein the crystalline form IV is characterized by an XRPD pattern substantially as shown in FIG10. 22. The crystalline form of any one of claims 3 and 19-21, wherein the crystalline form IV is characterized by a DSC thermogram having a melting initiation of about 136°C. 23. The crystalline form of any one of claims 3 and 19-22, wherein the crystalline form IV is characterized by a DSC thermogram substantially as shown in FIG11. 24. The crystalline form of claim 3, wherein the crystalline form V has at least three XRPD peaks selected from 6.9°, 7.9°, 10.7°, 16.7°, 17.6°, 21.1°, 21.8°, 22.8° and 26.9°, expressed as 2-θ±0.2°. 25. The crystalline form of claim 3, wherein the crystalline form is crystalline form V, wherein the crystalline form V has at least three XRPD peaks selected from 6.9°, 7.9°, 10.7°, 16.7°, 17.6°, 21.1°, 21.8°, 22.8° and 26.9°, expressed as 2-θ±0.2°. 26. The crystalline form of any one of claims 3, 24 and 25, wherein the crystalline form V is characterized by an XRPD pattern substantially as shown in FIG12. 27. The crystalline form of any one of claims 3 and 24-26, wherein the crystalline form V is characterized by having a DSC thermogram with a melting initiation of about 159°C. 28. The crystalline form of any one of claims 3 and 24-27, wherein the crystalline form V is characterized by a DSC thermogram substantially as shown in FIG13. 29. The crystalline form of claim 3, wherein the crystalline form VI has at least three XRPD peaks selected from 6.1°, 8.6°, 9.5°, 15.4°, 20.4°, 21.9°, 22.5°, 24.2° and 25.2°, expressed as 2-θ±0.2°. 30. The crystalline form of claim 3, wherein the crystalline form is crystalline form VI, wherein the crystalline form VI has at least three XRPD peaks selected from 6.1°, 8.6°, 9.5°, 15.4°, 20.4°, 21.9°, 22.5°, 24.2° and 25.2°, expressed as 2-θ±0.2°. 31. The crystalline form of any one of claims 3, 29 and 30, wherein the crystalline form VI is characterized by an XRPD pattern substantially as shown in FIG14. 32. The crystalline form of any one of claims 3 and 29-31, wherein the crystalline form VI is characterized by having a DSC thermogram with a melting initiation of about 121°C. 33. The crystalline form of any one of claims 3 and 29-32, wherein the crystalline form VI is characterized by a DSC thermogram substantially as shown in FIG15. 34. The crystalline form of claim 3, wherein the crystalline form VII has at least three XRPD peaks selected from 4.7°, 7.3°, 8.9°, 9.5°, 18.3°, 20.5°, 22.3°, 24.9° and 28.4°, expressed as 2-θ±0.2°. 35. The crystalline form of claim 3, wherein the crystalline form is crystalline form VII, wherein the crystalline form VII has at least three XRPD peaks selected from 4.7°, 7.3°, 8.9°, 9.5°, 18.3°, 20.5°, 22.3°, 24.9° and 28.4°, expressed as 2-θ±0.2°. 36. The crystalline form of any one of claims 3, 34 and 35, wherein the crystalline form VII is characterized by an XRPD pattern substantially as shown in FIG16. 37. The crystalline form of any one of claims 3 and 34-36, wherein the crystalline form VII is characterized by having a DSC thermogram with a melting initiation of about 144°C. 38. The crystalline form of any one of claims 3 and 34-37, wherein the crystalline form VII is characterized by a DSC thermogram substantially as shown in FIG17. 39. A formulation comprising the pharmaceutically acceptable salt of claim 1, or the crystalline form of any one of claims 2 to 38, wherein isomer A is enriched. 40. A formulation comprising a pharmaceutically acceptable salt as described in claim 1, or a crystalline form as described in any one of claims 2 to 38, wherein isomer B is enriched. 41. A formulation comprising a pharmaceutically acceptable salt as described in claim 1, or a crystalline form as described in any one of claims 2 to 38, wherein isomer A: With isomer B: The molar ratio is approximately 1:5 to approximately 1:8. 42. A pharmaceutical composition comprising a pharmaceutically acceptable salt of claim 1, or a crystalline form of any one of claims 2 to 38, and at least one pharmaceutically acceptable excipient. 43. A method of treating or preventing human immunodeficiency virus (HIV) infection, comprising administering to a subject in need a therapeutically effective amount of the pharmaceutically acceptable salt of claim 1, or the crystalline form of any one of claims 2 to 38. 44. The method of claim 43, wherein the method comprises administering the salt or crystalline form in combination with one, two, three or four other therapeutic agents. 45. The method of claim 44, wherein the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimer antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. 46. The method of claim 44 or 45, wherein the additional therapeutic agent is selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV nuclear reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other medicines for treating HIV, or any combination thereof. 47. The method of any one of claims 44 to 46, wherein the additional therapeutic agent is selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, pirategavir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate. 48. The method of any one of claims 44 to 46, wherein the additional therapeutic agent is selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bispyribine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. 49. The pharmaceutically acceptable salt of claim 1, or the crystalline form of any one of claims 2 to 38, for therapeutic purposes. 50. A method of using the pharmaceutically acceptable salt of claim 1, or the crystalline form of any one of claims 2 to 38, for the treatment or prevention of human immunodeficiency virus (HIV) infection, the method comprising administering a therapeutically effective amount of the pharmaceutically acceptable salt or crystalline form to a subject in need of such treatment. 51. The pharmaceutically acceptable salt or crystalline form used in claim 50, wherein the method comprises administering one, two, three, or four additional therapeutic agents. 52. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the additional therapeutic agent is administered simultaneously with the salt or crystalline form. 53. The pharmaceutically acceptable salt or crystalline form used in claim 52, wherein the salt or crystalline form is combined with the additional therapeutic agent to form a unit dosage form for simultaneous administration. 54. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is applied and the additional therapeutic agent is applied sequentially. 55. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimer antagonists, H HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, resveratrol modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. 56. The pharmaceutically acceptable salt or crystal used in claim 51, wherein the additional therapeutic agent is selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other medicines for the treatment of HIV, or any combination thereof. 57. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bispyribine or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate. 58. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bispyribine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate. 59. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bispyribine or a pharmaceutically acceptable salt thereof, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate or tenofovir disoproxil fumarate. 60. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine. 61. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. 62. The pharmaceutically acceptable salt or crystalline form used in claim 51, wherein the salt or crystalline form is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. 63. A method for increasing the amount of isomer A in a starting mixture comprising two isomers: The amount of isomers relative to isomer B: Or a method for increasing the amount of isomer B relative to the amount of isomer A, said method comprising: In the presence of a solvent, the starting mixture is contacted with N,N,N-trimethylethanolammonium hydroxide to form a mixture of N,N,N-trimethylethanolammonium salts of two isomers, wherein the salt mixture has an increased amount of isomer A relative to isomer B, or an increased amount of isomer B relative to isomer A, when compared with the relative amounts of isomers A and B in the starting mixture. 64. The method of claim 63, wherein the method comprises increasing the amount of isomer A relative to the amount of isomer B. 65. The method of claim 63, wherein the method comprises increasing the amount of isomer B relative to the amount of isomer A.