HK40087944A - Crystalline forms of tenofovira lafenamide - Google Patents

Description

Crystalline form of tenofovir alafenamide

This application is a divisional application of Chinese invention patent application filed on January 29, 2018, with application number 201880009292.1 and invention title "Crystal Form of Tenofovir Alaminamide".

Cross-reference to related applications

This application claims priority to U.S. Provisional Application Serial No. 62/452,428, filed January 31, 2017, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

This invention relates to novel crystalline forms of tenofovir alafenamide salts and/or cocrystals, and their pharmaceutical formulations and therapeutic uses.

Background Technology

As discussed in PCT Publication No. WO2002/008241, tenofovir alafenamide has shown antiviral activity.

Tenofovir alafenamide has the following structure:

A stable alternative to nofovir alafenamide with suitable chemical and physical stability is desired.

Summary of the Invention

In some embodiments, the present invention relates to novel crystalline forms of salts and/or eutectics of tenofovir alafenamide.

In some embodiments, the present invention relates to solid tenofovir alafenamide hemipamoate. In some embodiments, the present invention relates to crystalline tenofovir alafenamide hemipamoate form I. In some embodiments, the present invention relates to crystalline tenofovir alafenamide hemipamoate form II.

In some embodiments, the present invention relates to solid tenofovir alafenamide sebacate. In some embodiments, the present invention relates to crystalline tenofovir alafenamide sebacate form I.

In some embodiments, the present invention relates to solid tenofovir alafenamide naphthalene sulfonate (Napsylate). In some embodiments, the present invention relates to crystalline tenofovir alafenamide naphthalene sulfonate form I.

In some embodiments, the present invention relates to solid tenofovir alafenamide orotate. In some embodiments, the present invention relates to crystalline tenofovir alafenamide orotate form I. In some embodiments, the present invention relates to crystalline tenofovir alafenamide orotate form II. In some embodiments, the present invention relates to crystalline tenofovir alafenamide orotate form III.

In some embodiments, the present invention relates to solid tenofovir alafenamide vanillate. In some embodiments, the present invention relates to crystalline tenofovir alafenamide vanillate.

In some embodiments, the present invention relates to solid tenofovir alafenamide bis-xinafoate. In some embodiments, the present invention relates to crystalline tenofovir alafenamide bis-xinafoate.

In some embodiments, the present invention relates to a method of treating HIV infection by administering a therapeutically effective amount of a salt and/or cocrystal of tenofovir alafenamide provided herein.

In some embodiments, the present invention relates to salts and/or cocrystals of tenofovir alafenamide provided herein, used in methods for treating HIV infection.

In some embodiments, the present invention relates to the use of salts and/or cocrystals of tenofovir alafenamide provided herein in the preparation of medicaments for treating HIV infection.

Attached Figure Description

Figure 1 shows the XRPD spectrum of tenofovir alafenamide hemi-dihydroxynaphthyl salt form I.

Figure 2 shows the DSC thermogram of tenofovir alafenamide hemi-dihydroxynaphthyl salt form I.

Figure 3 shows the XRPD spectrum of tenofovir alafenamide hemi-dihydroxynaphthyl salt form II.

Figure 4 shows the DSC thermogram of tenofovir alafenamide semi-dihydroxynaphthyl salt form II.

Figure 5 shows the XRPD spectrum of tenofovir alafenamide sebacate form I.

Figure 6 shows the DSC thermogram of tenofovir alafenamide sebacate form I.

Figure 7 shows the XRPD spectrum of tenofovir alafenamide naphthalene sulfonate form I.

Figure 8 shows the DSC thermogram of tenofovir alafenamide naphthalene sulfonate form I.

Figure 9 shows the XRPD spectrum of tenofovir alafenamide orotate form I.

Figure 10 shows the DSC thermogram of tenofovir alafenamide orotate form I.

Figure 11 shows the XRPD spectrum of tenofovir alafenamide orotate form II.

Figure 12 shows the DSC thermogram of tenofovir alafenamide orotate form II.

Figure 13 shows the XRPD spectrum of tenofovir alafenamide orotate form III.

Figure 14 shows the DSC thermogram of tenofovir alafenamide orotate form III.

Figure 15 shows the XRPD spectrum of tenofovir alafenamide vanillate.

Figure 16 shows the DSC thermogram of tenofovir alafenamide vanillate.

Figure 17 shows the XRPD spectrum of tenofovir alafenamide dibenzonatate.

Figure 18 shows the DSC thermogram of tenofovir alafenamide dibenzonatate.

Detailed Implementation

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details. The following description of several embodiments is given under the understanding that this disclosure is to be considered as examples 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 only 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.

definition

Unless the context otherwise requires, throughout the specification and claims, the word “comprising” and its variations, such as “including” and “containing”, shall be interpreted in an open, inclusive sense, meaning “including but not limited to”.

Throughout this specification, the reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Embodiments of the "compound" as used throughout this specification include the solid, crystalline, salt, and eutectic forms of tenofovir alafenamide disclosed herein.

The phrase "compound" or "compound described herein" refers to salts and/or cocrystals of tenofovir alafenamide. Therefore, "salts and/or cocrystals of tenofovir alafenamide" includes tenofovir alafenamide hemi-dihydroxynaphthyl salt form I, tenofovir alafenamide hemi-dihydroxynaphthyl salt form II, tenofovir alafenamide sebacic acid salt form I, tenofovir alafenamide naphthalene sulfonate form I, tenofovir alafenamide orotate form I, tenofovir alafenamide orotate form II, and tenofovir alafenamide form III.

In addition, “salts and/or cocrystals of tenofovir alafenamide” include tenofovir alafenamide vanillate and tenofovir alafenamide disennarate.

The invention disclosed herein is also intended to include all pharmaceutically acceptable salts and/or cocrystals of tenofovir alafenamide that are isotopically labeled by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds 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. These radiolabeled compounds can be used to help determine or measure the effectiveness of a compound, for example, by characterizing the site or mode of action, or the binding affinity to ^a pharmacologically important site of action. Salts and/or eutectics of certain isotopically labeled tenofovir alafenamide, such as those incorporating radioisotopes, can be used for drug and/or substrate tissue distribution studies. Given their ease of incorporation and readily available detection methods, radioisotopes tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) are particularly suitable for this purpose.

Replacing with a heavier isotope, such as deuterium (i.e., ^2H ), can provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may increase or the dosage requirement may decrease. Therefore, in some cases, a heavier isotope may be preferred.

The use of positron emission tomography (PET) isotopes (e.g., ^11C , ^18F , ^15O , and ^13N ) to replace substrate acceptor occupancy in PET studies is also possible. The preparation of isotopically labeled salts and/or cocrystals of tenofovir alafenamide can generally be performed using conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

"Stable compound" and "stable structure" mean that the compound is robust enough to withstand separation from the reaction mixture to a useful purity and to be formulated into an effective therapeutic agent.

"Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes instances where the event or situation occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups.

"Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye/coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent and/or emulsifier, or one or more of the above, which have been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

"Pharmaceutical composition" refers to formulations of compounds of the present invention (e.g., salts and/or cocrystals of tenofovir alafenamide) and mediators generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). Such mediators include all pharmaceutically acceptable excipients for this purpose.

"Effective amount" or "therapeutic effective amount" means an amount of the compound according to the invention that, when administered to a patient in need, is sufficient to achieve the treatment of a disease state, symptom, or disorder for which the compound is effective. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or patient sought by the researcher or clinician. The amount of the compound according to the invention constituting a therapeutic effective amount will vary depending on factors such as: the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or symptom being treated, the drugs used in combination with or in conjunction with the compound of the invention, and the patient's age, weight, general health, sex, and diet. Such a therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge, the prior art, and this disclosure.

Unless otherwise stated, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of, or preventing the impairment or condition to which this term applies, or one or more symptoms of such impairment or condition. The term "treatment" as used herein refers to the act of treatment, as "treatment" is as immediately stated above. In some embodiments, the term "treatment" is intended to mean administering a compound or composition according to the invention to alleviate or eliminate symptoms of HIV infection and/or reduce viral load in a patient. In some embodiments, the term "treatment" as used herein is intended to mean administering a compound or composition according to the invention to alleviate or eliminate symptoms of HIV infection and/or reduce viral load in a patient. In some embodiments, the term "treatment" as used herein is further or alternatively intended to mean administering a compound or composition according to the invention as a follow-up or additional therapy (e.g., for maintaining a low viral load) after an individual has been exposed to the virus.

"Prevention" (or "preventing") refers to any treatment that prevents the development of clinical symptoms of a disease or condition. The term "prevention" also includes administering a therapeutically effective amount of a compound or composition according to the invention (e.g., pre-exposure prophylaxis) before an individual is exposed to a virus to prevent the development of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood.

The terms "subject" or "patient" refer to an animal, such as a mammal (including a human), that has been or will be a subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and/or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), and/or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "A person in need (or patient)" means a person who may have or is suspected of having a disease or condition that would benefit from certain treatments; for example, treatment with the compounds disclosed herein according to this application.

As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological agent) that effectively inhibits the formation and/or replication of viruses in humans, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and/or replication of viruses in humans.

As used in this article, the term "HIV replication inhibitor" is intended to refer to agents that can reduce or eliminate the ability of HIV to replicate in host cells (whether in vitro, ex vivo, or in vivo).

References to the value or parameter “about” herein include (and describe) embodiments of that value or parameter itself. For example, a description of “about X” includes a description of “X”. Furthermore, the singular forms “a” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, a reference to “the compound” includes a variety of such compounds, and a reference to “the assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

"Pharmaceutically acceptable" or "physiologically acceptable" means a compound, salt, composition, dosage form, or other substance that can be used to prepare a pharmaceutical composition suitable for veterinary or human use.

"Unit dose form" is a physically discrete unit suitable for use as a subject (e.g., human subject and other mammals) at a unit dose, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, along with suitable pharmaceutical excipients.

When referring to, for example, XRPD spectra or DSC thermograms, the term "substantially as shown" means a thermogram or spectrum that is not necessarily the same as those described herein, but falls within the limits of experimental error or deviation when considered by a person skilled in the art.

In some embodiments, with respect to a particular crystalline form of the compound, the terms "substantially pure" or "substantially free" mean that the composition containing that crystalline form contains less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other crystalline forms and/or impurities. In some embodiments, "substantially pure" or "substantially free" means free from substances other than other substances (including other crystalline forms and/or impurities). For example, impurities may include byproducts or reagents from chemical reactions, contaminants, degradation products, other crystalline forms, water, and solvents.

Crystalline forms of tenofovir alafenamide salts and/or eutectic forms

It is desired to develop crystalline forms of tenofovir alafenamide salts and/or cocrystals that can be used in the synthesis of tenofovir alafenamide salts and/or cocrystals. These crystalline forms can serve as intermediates in the synthesis of tenofovir alafenamide salts and/or cocrystals. Under certain conditions, the crystalline forms may possess properties suitable for medical or pharmaceutical applications, such as bioavailability, stability, purity, and/or manufacturability.

Crystalline forms of tenofovir alafenamide salts and/or cocrystals, including substantially pure forms, offer advantages in bioavailability and stability, making them suitable for use as active ingredients in pharmaceutical compositions. Variations in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). Such 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). Crystalline forms offer desired or appropriate hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and/or process control compared to other forms such as non-crystalline or amorphous forms. Therefore, the crystalline forms of salts and/or cocrystals of tenofovir alafenamide can provide advantages such as improvements in the following: the method of preparation of the compound, the stability or storability of the compound in the form of a pharmaceutical product, the stability or storability of the pharmaceutical substance of the compound, and/or the 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 salts and/or eutectics of tenofovir alafenamide described herein, which may exhibit one or more of the aforementioned advantageous characteristics. The methods for preparing the crystalline forms described herein and the characterization of these crystalline forms are described in detail below.

Those skilled in the art will understand that recognized nomenclature systems and symbols can be used to name or identify compound structures. For example, compounds can be named or identified using common names, systematic or non-systematic names. Commonly recognized nomenclature 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 tenofovir alafenamide provided above can also be named or identified as isopropyl (S)-2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propionate under IUPAC and CAS registry number 379270-37-8.

In some embodiments, solid salts and/or eutectics of tenofovir alafenamide are disclosed. In some embodiments, crystalline forms of the salts and/or eutectics of tenofovir alafenamide are disclosed.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt

In some embodiments, solid tenofovir alafenamide hemi-dihydroxynaphthyl salt is provided. In some embodiments, a crystalline form of tenofovir alafenamide hemi-dihydroxynaphthyl salt is provided. In some embodiments, crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I is provided. In some embodiments, crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II is provided.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form I

In some embodiments, crystalline tenofovir alafenamide hemi-dihydroxynaphtholate form I is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Crystalline tenofovir alafenamide hemi-dihydroxynaphtholate form I can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I is applicable to at least one or both of (a)-(b): (a) the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD spectrum substantially as shown in FIG1; (b) the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has a DSC thermogram substantially as shown in FIG2.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has the following characteristics:

Basically, the XRPD map is shown in Figure 1.

Basically, the DSC thermogram is shown in Figure 2.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances at maximum intensity, as shown substantially in Figure 1.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 19.0°, 25.7°, 20.1°, 23.8°, and 17.4°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3° and one 2θ reflectance (+/-0.2 degrees 2θ) at 19.0°, 25.7°, 20.1°, 23.8°, and 17.4°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3° and two 2θ reflectances (+/-0.2 degrees 2θ) at 19.0°, 25.7°, 20.1°, 23.8°, and 17.4°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 19.0°, 25.7°, 20.1°, 23.8°, and 17.4°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, and 22.3°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 19.0°, 25.7°, 20.1°, 23.8°, and 17.4°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8° and 17.4°.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 11.2°, 13.1°, 13.8°, 14.8°, 15.8°, 17.4°, 19.0°, 20.1°, 21.0°, 22.3°, 23.8°, 25.7°, and 28.8°.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and one 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and two 2θ reflectances (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has XRPD spectra comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and three 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and four 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and five 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and six 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 14.8°, 22.3°, 19.0°, 25.7°, 20.1°, 23.8°, and 17.4° and seven 2θ reflectance (+/-0.2 degrees 2θ) at 21.0°, 15.8°, 11.2°, 28.8°, 13.1°, 30.6°, 32.9°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 7.4°, 8.4°, 10.6°, 11.2°, 13.1°, 13.8°, 14.8°, 15.8°, 17.4°, 19.0°, 20.1°, 21.0°, 22.3°, 23.8°, 25.7°, 28.8°, 30.6°, and 32.9°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD spectrum comprising any five 2θ reflectances (+/- 0.2 degrees 2θ) selected from the following: 7.4°, 8.4°, 10.6°, 11.2°, 13.1°, 13.8°, 14.8°, 15.8°, 17.4°, 19.0°, 20.1°, 21.0°, 22.3°, 23.8°, 25.7°, 28.8°, 30.6°, and 32.9°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD spectrum comprising any seven 2θ reflectances (+/- 0.2 degrees 2θ) selected from the following: 7.4°, 8.4°, 10.6°, 11.2°, 13.1°, 13.8°, 14.8°, 15.8°, 17.4°, 19.0°, 20.1°, 21.0°, 22.3°, 23.8°, 25.7°, 28.8°, 30.6°, and 32.9°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD spectrum comprising any ten 2θ reflectances (+/- 0.2 degrees 2θ) selected from the following: 7.4°, 8.4°, 10.6°, 11.2°, 13.1°, 13.8°, 14.8°, 15.8°, 17.4°, 19.0°, 20.1°, 21.0°, 22.3°, 23.8°, 25.7°, 28.8°, 30.6°, and 32.9°.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form II

In some embodiments, crystalline tenofovir alafenamide hemi-dihydroxynaphtholate form II is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 3. Crystalline tenofovir alafenamide hemi-dihydroxynaphtholate form II can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 4.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II is applicable to at least one or both of (a)-(b): (a) the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has an XRPD spectrum substantially as shown in FIG3; (b) the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has a DSC thermogram substantially as shown in FIG4.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has the following characteristics:

Basically, the XRPD map is shown in Figure 3.

Basically, the DSC thermogram is shown in Figure 4.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances at maximum intensity, as shown substantially in Figure 3.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, and 23.2°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, and 23.2°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 24.1°, 27.6°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, and 23.2°, and one 2θ reflectance (+/-0.2 degrees 2θ) at 24.1°, 27.6°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, and 23.2°, and two 2θ reflectances (+/-0.2 degrees 2θ) at 24.1°, 27.6°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has XRPD spectra with 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, 23.2°, and 24.1°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has XRPD spectra with 2θ reflectance (+/-0.2 degrees 2θ) at 5.5°, 10.9°, 16.2°, 22.1°, 23.2°, 24.1°, 27.6°, and 29.0°.

In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II has an XRPD pattern comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from 5.5°, 10.9°, 16.2°, 22.1°, 23.2°, 24.1°, 27.6°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I has an XRPD pattern comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from 5.5°, 10.9°, 16.2°, 22.1°, 23.2°, 24.1°, 27.6°, and 29.0°.

Tenofovir alafenamide sebacic acid

In some embodiments, solid tenofovir alafenamide sebacic acid is provided. In some embodiments, crystalline form of tenofovir alafenamide sebacic acid is provided. In some embodiments, crystalline tenofovir alafenamide sebacic acid form I is provided.

Tenofovir alafenamide sebacic acid form I

In some embodiments, crystalline tenofovir alafenamide sebacic acid form I is provided, wherein the crystalline structure displays an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 5. Crystalline tenofovir alafenamide sebacic acid form I can also display a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 6.

In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I is suitable for at least one, at least two, or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide sebacic acid form I has an XRPD spectrum substantially as shown in FIG5; (b) the crystalline tenofovir alafenamide sebacic acid form I has a DSC thermogram substantially as shown in FIG6.

In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has the following characteristics:

Basically, the XRPD map is shown in Figure 5.

Basically, the DSC thermogram is shown in Figure 6.

In some embodiments, the crystalline tenofovir alafenamide sebacate form I has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances at maximum intensity, as shown substantially in Figure 5.

In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8° and one 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8° and two 2θ reflectances (+/-0.2 degrees 2θ) at 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, and 19.8°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8° and 22.1°.

In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and one 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and two 2θ reflectances (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and three 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8° and 22.1° and four 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2° and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and five 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and six 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, and 22.1° and seven 2θ reflectance (+/-0.2 degrees 2θ) at 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 5.3°, 6.6°, 9.4°, 9.6°, 11.7°, 12.6°, 14.8°, 15.7°, 18.7°, 19.3°, 19.8°, 20.9°, 22.1°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD spectrum comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 5.3°, 6.6°, 9.4°, 9.6°, 10.5°, 11.7°, 12.6°, 14.0°, 14.8°, 15.7°, 16.9°, 18.7°, 19.3°, 19.8°, 20.9°, 21.6°, 22.1°, 22.9°, 23.4°, 23.8°, 25.3°, 26.2°, 26.5°, 27.4°, 28.2°, 28.7°, 29.0°, 33.3°, and 37.9°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD spectrum comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 5.3°, 6.6°, 9.4°, 9.6°, 10.5°, 11.7°, 12.6°, 14.0°, 14.8°, 15.7°, 16.9°, 18.7°, 19.3°, 19.8°, 20.9°, 21.6°, 22.1°, 22.9°, 23.4°, 23.8°, 25.3°, 26.2°, 26.5°, 27.4°, 28.2°, 28.7°, 29.0°, 33.3°, and 37.9°. In some embodiments, the crystalline tenofovir alafenamide sebacic acid form I has an XRPD spectrum comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 5.3°, 6.6°, 9.4°, 9.6°, 10.5°, 11.7°, 12.6°, 14.0°, 14.8°, 15.7°, 16.9°, 18.7°, 19.3°, 19.8°, 20.9°, 21.6°, 22.1°, 22.9°, 23.4°, 23.8°, 25.3°, 26.2°, 26.5°, 27.4°, 28.2°, 28.7°, 29.0°, 33.3°, and 37.9°.

Tenofovir alafenamide naphthalene sulfonate

In some embodiments, solid tenofovir alafenamide naphthalene sulfonate is provided. In some embodiments, a crystalline form of tenofovir alafenamide naphthalene sulfonate is provided. In some embodiments, crystalline tenofovir alafenamide naphthalene sulfonate form I is provided.

Tenofovir alafenamide naphthalene sulfonate form I

In some embodiments, crystalline tenofovir alafenamide naphthalene sulfonate form I is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7. Crystalline tenofovir alafenamide naphthalene sulfonate form I can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 8.

In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I is suitable for at least one or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD spectrum substantially as shown in FIG7; (b) the crystalline tenofovir alafenamide naphthalene sulfonate form I has a DSC thermogram substantially as shown in FIG8.

In some embodiments, crystalline tenofovir alafenamide naphthalene sulfonate form I has the following characteristics:

Basically, the XRPD map is shown in Figure 7.

Basically, the DSC thermogram is shown in Figure 8.

In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances at maximum intensity, as shown substantially in Figure 7.

In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°, and one 2θ reflectance (+/-0.2 degrees 2θ) at 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°, and two 2θ reflectances (+/-0.2 degrees 2θ) at 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, and 19.2°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°.

In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and one 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and two 2θ reflectances (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has XRPD spectra comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and three 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and four 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and five 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and six 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 13.6°, 15.3°, 19.2°, 19.4°, 19.8°, 20.6°, 23.8°, and 27.2° and seven 2θ reflectance (+/-0.2 degrees 2θ) at 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.9°, 7.8°, 9.8°, 13.2°, 13.6°, 15.3°, 15.5°, 16.5°, 17.8°, 19.2°, 19.4°, 19.8°, 20.6°, 23.0°, 23.8°, 24.1°, 26.0°, and 27.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD pattern comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.9°, 7.8°, 9.8°, 10.3°, 11.6°, 13.2°, 13.6°, 15.3°, 15.5°, 16.5°, 17.8°, 18.2°, 19.2°, 19.4°, 19.8°, 20.1°, 20.6°, 23.0°, 23.3°, 23.8°, 24.1°, 24.5°, 26.0°, 27.2°, 28.3°, 29.5°, 32.2°, 34.3°, 35.2°, 36.9°, 38.2°, and 39.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD spectrum comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.9°, 7.8°, 9.8°, 10.3°, 11.6°, 13.2°, 13.6°, 15.3°, 15.5°, 16.5°, 17.8°, 18.2°, 19.2°, 19.4°, 19.8°, 20.1°, 20.6°, 23.0°, 23.3°, 23.8°, 24.1°, 24.5°, 26.0°, 27.2°, 28.3°, 29.5°, 32.2°, 34.3°, 35.2°, 36.9°, 38.2°, and 39.2°. In some embodiments, the crystalline tenofovir alafenamide naphthalene sulfonate form I has an XRPD spectrum comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.9°, 7.8°, 9.8°, 10.3°, 11.6°, 13.2°, 13.6°, 15.3°, 15.5°, 16.5°, 17.8°, 18.2°, 19.2°, 19.4°, 19.8°, 20.1°, 20.6°, 23.0°, 23.3°, 23.8°, 24.1°, 24.5°, 26.0°, 27.2°, 28.3°, 29.5°, 32.2°, 34.3°, 35.2°, 36.9°, 38.2°, and 39.2°.

Tenofovir alafenamide orotate

In some embodiments, solid tenofovir alafenamide orotate is provided. In some embodiments, crystalline form of tenofovir alafenamide orotate is provided. In some embodiments, crystalline tenofovir alafenamide orotate form I is provided. In some embodiments, crystalline tenofovir alafenamide orotate form II is provided. In some embodiments, crystalline tenofovir alafenamide orotate form III is provided.

Tenofovir alafenamide orotate form I

In some embodiments, crystalline tenofovir alafenamide orotate form I is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9. Crystalline tenofovir alafenamide orotate form I can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 10.

In some embodiments, the crystalline tenofovir alafenamide orotate form I is suitable for at least one or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide orotate form I has an XRPD spectrum substantially as shown in FIG9; (b) the crystalline tenofovir alafenamide orotate form I has a DSC thermogram substantially as shown in FIG10.

In some embodiments, the crystalline tenofovir alafenamide orotate form I has the following characteristics:

Basically, the XRPD map is shown in Figure 9.

Basically, the DSC thermogram is shown in Figure 10.

In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances at maximum intensity, as shown substantially in Figure 9.

In some embodiments, the crystalline tenofovir alafenamide orotate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8° and one 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8° and two 2θ reflectances (+/-0.2 degrees 2θ) at 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, and 11.8°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7° and 21.5°.

In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, and 21.5° and one or more 2θ reflectances (+/-0.2 degrees 2θ) at 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, and 21.5° and one 2θ reflectance (+/-0.2 degrees 2θ) at 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, and 21.5° and two 2θ reflectances (+/-0.2 degrees 2θ) at 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has XRPD spectra comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, 21.5°, 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has XRPD spectra comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, 21.5°, 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, 21.5°, 27.2°, 28.7°, and 31.5°. In some embodiments, the crystalline tenofovir alafenamide orotate form I has an XRPD pattern comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.0°, 3.5°, 5.9°, 8.9°, 11.8°, 14.8°, 16.0°, 17.7°, 18.7°, 21.5°, 27.2°, 28.7°, and 31.5°.

Tenofovir alafenamide orotate form II

In some embodiments, crystalline tenofovir alafenamide orotate form II is provided, wherein the crystalline structure displays an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 11. Crystalline tenofovir alafenamide orotate form II can display a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 12.

In some embodiments, the crystalline tenofovir alafenamide orotate form II is suitable for at least one or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide orotate form II has an XRPD spectrum substantially as shown in FIG11; (b) the crystalline tenofovir alafenamide orotate form II has a DSC thermogram substantially as shown in FIG12.

In some embodiments, the crystalline tenofovir alafenamide orotate form II has the following characteristics:

Basically, the XRPD map is shown in Figure 11.

Basically, the DSC thermogram is shown in Figure 12.

In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances, as shown substantially in Figure 11.

In some embodiments, the crystalline tenofovir alafenamide orotate form II has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 3.8°, 6.9°, 10.3°, and 13.8°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, and 13.8°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, and 13.8° and one 2θ reflectance (+/-0.2 degrees 2θ) at 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, and 13.8° and two 2θ reflectances (+/-0.2 degrees 2θ) at 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, and 13.8°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, and 13.8°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°.

In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°, and one or more 2θ reflectances (+/-0.2 degrees 2θ) at 18.4° and 21.6°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°, and one 2θ reflectance (+/-0.2 degrees 2θ) at 18.4° and 21.6°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has XRPD spectra comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.4°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 18.4°, 19.0°, 21.6°, 22.8°, and 29.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form II has XRPD spectra comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.4°, 3.8°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 18.4°, 19.0°, 21.6°, 22.8°, and 29.0°. In some embodiments, crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.4°, 3.8°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 18.4°, 19.0°, 21.6°, 22.8°, and 29.0°. In some embodiments, crystalline tenofovir alafenamide orotate form II has an XRPD pattern comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.4°, 3.8°, 6.9°, 10.3°, 13.8°, 15.4°, 17.3°, 18.4°, 19.0°, 21.6°, 22.8°, and 29.0°. Tenofovir alafenamide orotate form III

In some embodiments, crystalline tenofovir alafenamide orotate form III is provided, wherein the crystalline structure displays an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 13. Crystalline tenofovir alafenamide orotate form III can display a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 14.

In some embodiments, the crystalline tenofovir alafenamide orotate form III is suitable for at least one or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide orotate form III has an XRPD spectrum substantially as shown in Figure 13; (b) the crystalline tenofovir alafenamide orotate form III has a DSC thermogram substantially as shown in Figure 14.

In some embodiments, the crystalline tenofovir alafenamide orotate form III has the following characteristics:

Basically, the XRPD map is shown in Figure 13.

Basically, the DSC thermogram is shown in Figure 14.

In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances, as shown substantially in Figure 13.

In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0°, and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0° and one 2θ reflectance (+/-0.2 degrees 2θ) at 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0° and two 2θ reflectances (+/-0.2 degrees 2θ) at 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 9.4°, 12.4°, 15.7°, and 19.0°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 24.5°, 26.6°, and 28.9°.

In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 24.5°, 26.6°, and 28.9° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 6.9°, 22.8°, and 27.6°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 24.5°, 26.6°, and 28.9° and one 2θ reflectance (+/-0.2 degrees 2θ) at 6.9°, 22.8°, and 27.6°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 24.5°, 26.6°, and 28.9°, and two 2θ reflectances (+/-0.2 degrees 2θ) at 6.9°, 22.8°, and 27.6°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra comprising 2θ reflectance (+/-0.2 degrees 2θ) at 3.8°, 6.9°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 22.8°, 24.5°, 26.6°, 27.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has XRPD spectra comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.8°, 6.9°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 22.8°, 24.5°, 26.6°, 27.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 3.8°, 6.9°, 8.3°, 9.4°, 12.4°, 15.7°, 16.4°, 19.0°, 22.8°, 24.5°, 26.6°, 27.6°, and 28.9°. In some embodiments, the crystalline tenofovir alafenamide orotate form III has an XRPD pattern comprising any ten 2θ reflectances (+/-0.2 degrees 2θ):

Tenofovir alafenamide vanillate

In some embodiments, a solid tenofovir alafenamide vanillate is provided. In some embodiments, a crystalline form of tenofovir alafenamide vanillate is provided.

Tenofovir alafenamide vanillate

In some embodiments, crystalline tenofovir alafenamide vanillate is provided, wherein the crystalline structure displays an XRPD pattern substantially as shown in Figure 15. Crystalline tenofovir alafenamide vanillate can display a DSC thermogram substantially as shown in Figure 16.

In some embodiments, the crystalline tenofovir alafenamide vanillate is suitable for at least one, at least two, or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide vanillate has an XRPD spectrum substantially as shown in Figure 15; (b) the crystalline tenofovir alafenamide vanillate has a DSC thermogram substantially as shown in Figure 16.

In some embodiments, crystalline tenofovir alafenamide vanillate has the following properties:

Basically, the XRPD map is shown in Figure 15.

Essentially, it is the DSC thermogram shown in Figure 16.

In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven, or at least eight 2θ reflectances, as shown substantially in Figure 15.

In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8°. In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 14.2°, 15.2°, 19.0°, and 19.8°. In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8° and one 2θ reflectance (+/-0.2 degrees 2θ) at 14.2°, 15.2°, 19.0°, and 19.8°. In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8° and two 2θ reflectances (+/-0.2 degrees 2θ) at 14.2°, 15.2°, 19.0°, and 19.8°. In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8° and three 2θ reflectance (+/-0.2 degrees 2θ) at 14.2°, 15.2°, 19.0°, and 19.8°. In some embodiments, crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, and 22.8° and four 2θ reflectance (+/-0.2 degrees 2θ) at 14.2°, 15.2°, 19.0°, and 19.8°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern containing 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, 19.8° and 22.8°.

In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and one 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and two 2θ reflectances (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and three 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and four 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and five 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and six 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 14.2°, 15.2°, 19.0°, and 22.8° and seven 2θ reflectance (+/-0.2 degrees 2θ) at 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 6.6°, 9.3°, 10.8°, 12.3°, 14.2°, 15.2°, 18.4°, 19.0°, 19.8°, 22.1°, 22.8°, 25.0°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD spectrum comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 6.6°, 9.3°, 10.8°, 12.3°, 14.2°, 15.2°, 15.9°, 18.4°, 19.0°, 19.8°, 21.6°, 22.1°, 22.8°, 25.0°, 27.7°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD spectrum comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 6.6°, 9.3°, 10.8°, 12.3°, 14.2°, 15.2°, 15.9°, 18.4°, 19.0°, 19.8°, 21.6°, 22.1°, 22.8°, 25.0°, 27.7°, and 32.4°. In some embodiments, the crystalline tenofovir alafenamide vanillate has an XRPD spectrum comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 6.6°, 9.3°, 10.8°, 12.3°, 14.2°, 15.2°, 15.9°, 18.4°, 19.0°, 19.8°, 21.6°, 22.1°, 22.8°, 25.0°, 27.7°, and 32.4°.

Tenofovir alafenamide disennarate

In some embodiments, a solid tenofovir alafenamide dibenzonaphthyl salt is provided. In some embodiments, a crystalline form of tenofovir alafenamide dibenzonaphthyl salt is provided.

Tenofovir alafenamide disennarate

In some embodiments, crystalline tenofovir alafenamide dibenzonaphthol is provided, wherein the crystalline structure displays an XRPD pattern substantially as shown in Figure 17. Crystalline tenofovir alafenamide dibenzonaphthol can also display a DSC thermogram substantially as shown in Figure 18.

In some embodiments, the crystalline tenofovir alafenamide dibenzonaphthyl salt is suitable for at least one, at least two, or all of the following (a)-(b): (a) the crystalline tenofovir alafenamide dibenzonaphthyl salt has an XRPD spectrum substantially as shown in Figure 17; (b) the crystalline tenofovir alafenamide dibenzonaphthyl salt has a DSC thermogram substantially as shown in Figure 18.

In some embodiments, crystalline tenofovir alafenamide dibenzonatate has the following characteristics:

Basically, the XRPD map is shown in Figure 17.

Essentially, it is a DSC thermogram as shown in Figure 18.

In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern showing at most two, at least three, at least four, at least five, at least six, at least seven or at least eight 2θ reflectances, as shown substantially in Figure 17.

In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 11.2°, 18.8°, 21.7°, and 25.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4° and one 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 11.2°, 18.8°, 21.7°, and 25.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4° and two 2θ reflectances (+/-0.2 degrees 2θ) at 7.7°, 11.2°, 18.8°, 21.7°, and 25.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4°, and three 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 11.2°, 18.8°, 21.7°, and 25.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 14.4°, and 15.4°, and four 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 11.2°, 18.8°, 21.7°, and 25.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has XRPD spectra containing 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7° and 25.5°.

In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and one or more 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and one 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 18.8°, 21.7°, 21.9°, 25.5°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 44.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and two 2θ reflectances (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and three 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and four 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and five 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and six 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7°, and 25.5° and seven 2θ reflectance (+/-0.2 degrees 2θ) at 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising 2θ reflectance (+/-0.2 degrees 2θ) at 4.5°, 7.7°, 8.9°, 11.2°, 13.4°, 14.4°, 14.7°, 15.4°, 15.7°, 17.0°, 18.3°, 18.8°, 21.7°, 21.9°, 25.5°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD spectrum comprising any five 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 4.5°, 7.7°, 8.9°, 11.2°, 13.4°, 14.4°, 14.7°, 15.4°, 15.7°, 17.0°, 18.3°, 18.8°, 21.7°, 21.9°, 25.5°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD spectrum comprising any seven 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 4.5°, 7.7°, 8.9°, 11.2°, 13.4°, 14.4°, 14.7°, 15.4°, 15.7°, 17.0°, 18.3°, 18.8°, 21.7°, 21.9°, 25.5°, 25.9°, 32.9°, 33.8°, and 36.5°. In some embodiments, the crystalline tenofovir alafenamide dibenzonatate has an XRPD pattern comprising any ten 2θ reflectances (+/-0.2 degrees 2θ) selected from the following: 4.5°, 7.7°, 8.9°, 11.2°, 13.4°, 14.4°, 14.7°, 15.4°, 15.7°, 17.0°, 18.3°, 18.8°, 21.7°, 21.9°, 25.5°, 25.9°, 32.9°, 33.8°, and 36.5°.

Pharmaceutical Composition

For administration purposes, in some embodiments, the compounds described herein are administered as raw material chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a salt and/or cocrystal of tenofovir alafenamide provided herein, and a pharmaceutically acceptable excipient. The salt and/or cocrystal of tenofovir alafenamide is present in the composition in an amount effective in treating a particular disease or condition of interest. The active salt and/or cocrystal of tenofovir alafenamide can be determined by those skilled in the art, for example, as described herein. Those skilled in the art can readily determine suitable therapeutically effective concentrations and dosages. In some embodiments, the salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount from about 5 mg to about 1,000 mg. In some embodiments, the salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount from about 5 mg to about 100 mg. In some embodiments, the salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount from about 20 mg to about 75 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 25 mg to about 50 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 25 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 50 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 75 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 100 mg. In some embodiments, a salt and/or cocrystal of tenofovir alafenamide is present in the pharmaceutical composition in an amount of about 25 mg, 28 mg, 30 mg, 33 mg, 35 mg, 38 mg, 40 mg, 43 mg, 45 mg, 48 mg, or about 50 mg.

In some embodiments, the pharmaceutical composition of the present invention administered may be a long-acting formulation. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for at least 10 days. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for at least 15 days. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for at least 30 days. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for at least 60 days. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for at least 90 days. In some embodiments, the pharmaceutical composition of the present invention administered to a subject is active for up to 6 months.

The compounds of the present invention, administered in pure form or in a suitable pharmaceutical composition, can be administered via any acceptable method of pharmaceutical application to provide similar efficacy. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients and can be formulated into solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), sublingual, oral, rectal, vaginal, intranasal, and pulmonary administration. In one embodiment, the pharmaceutical composition is a subcutaneous injection. In one embodiment, the pharmaceutical composition is in unit dose form, wherein the unit dose form is a subcutaneous injection. In one embodiment, the pharmaceutical composition is a tablet. The pharmaceutical compositions of the present invention are formulated to ensure bioavailability of the active ingredient contained therein when administered to a patient. The compositions administered to a subject or patient are in the form of one or more dose units, wherein, for example, tablets may be single dose units, and containers of the compounds of the present invention in aerosol form may contain multiple dose units. Practical methods for preparing such dose forms are known or obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered will contain a therapeutically effective amount of the compound of the present invention for treating a disease or condition of interest according to the teachings of the present invention.

In some embodiments, the pharmaceutical compositions of the present invention can be administered by intramuscular injection. In particular, references to "activity" include maintaining a minimum concentration (Cmin) above an effective level against HIV.

The pharmaceutical compositions of the present invention can be prepared using methods well known in the pharmaceutical industry. For example, a pharmaceutical composition intended for injection can be prepared by mixing the compounds of the present invention with sterile distilled water to form a solution. Surfactants or other solubilizing excipients may be added to promote the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention to promote the dissolution or homogeneous suspension of the compounds in an aqueous delivery system.

In other embodiments, the preparation of a solid pharmaceutical composition for oral administration can be achieved by mixing a therapeutically effective amount of the compound of the invention with at least one suitable pharmaceutically acceptable excipient to form a solid preformation composition, which can then be readily subdivided into equally effective unit-dose forms, such as tablets, pills, and capsules. Thus, in some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a salt and/or cocrystal of tenofovir alafenamide and a pharmaceutically acceptable excipient.

The compounds of the present invention are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health condition, sex, and diet; the method and timing of administration; the rate of excretion; the combination of drugs; the severity of the specific disease or condition; and the subject receiving treatment. In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents, once daily, twice daily, three times daily, or four times daily, as long as the patient is infected, latently infected, or is taking preventative measures against infection (e.g., for many years, months, weeks, or days). In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents every seven days. In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents every 14 days. In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents every 21 days. In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents every 28 days. In some embodiments, the compounds of the present invention may be administered once monthly, alone or in combination with other antiviral agents.

Compositions comprising salts and/or cocrystals of tenofovir alafenamide as described herein are also provided. In one embodiment, a composition comprising one salt and/or cocrystal of tenofovir alafenamide as described herein is provided. In one embodiment, a composition comprising two salts and/or cocrystals of tenofovir alafenamide as described herein is provided. In one embodiment, a composition comprising three salts and/or cocrystals of tenofovir alafenamide as described herein is provided. In one embodiment, a composition comprising four salts and/or cocrystals of tenofovir alafenamide as described herein is provided. In other embodiments, the compositions described herein may comprise a substantially pure crystalline form or may be substantially free of other crystalline forms and/or impurities.

In some embodiments, the composition comprises a salt and/or a crystalline cocrystal of tenofovir alafenamide. In some embodiments, compositions comprising the crystalline forms described herein are provided, wherein the salt and/or cocrystal of tenofovir alafenamide in the composition are substantially pure (i.e., substantially pure tenofovir alafenamide hemi-dihydroxynaphthyl salt form I, tenofovir alafenamide hemi-dihydroxynaphthyl salt form II, tenofovir alafenamide sebacic acid salt form I, tenofovir alafenamide naphthalene sulfonate form I, tenofovir alafenamide orotate form I, tenofovir alafenamide orotate form II, and tenofovir alafenamide form III as described herein). In certain embodiments of the composition comprising a salt and/or eutectic form of tenofovir alafenamide, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of a salt and/or eutectic form of tenofovir alafenamide present in the composition is one of the crystalline forms disclosed herein. In some embodiments, the composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of a salt and/or eutectic form of tenofovir alafenamide.

In some embodiments, compositions comprising the crystalline form as described herein are provided, wherein the salt and/or cocrystal of tenofovir alafenamide in the composition is substantially pure tenofovir alafenamide vanillate and/or tenofovir alafenamide dibenzonaphthylate as described herein. In specific embodiments of compositions comprising the crystalline form of the salt and/or cocrystal of tenofovir alafenamide, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the salt and/or cocrystal of tenofovir alafenamide present in the composition is tenofovir alafenamide vanillate or tenofovir alafenamide dibenzonaphthylate as disclosed herein. In some embodiments, the composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of tenofovir alafenamide vanillate or tenofovir alafenamide disennarate as disclosed herein.

In other embodiments of the composition comprising the crystalline form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the salts and/or cocrystals of tenofovir alafenamide present in the composition are other amorphous or crystalline forms and/or impurities of the salts and/or cocrystals of tenofovir alafenamide.

In other embodiments of compositions comprising the crystalline forms disclosed herein, impurities constitute less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the total mass relative to the mass of the crystalline forms present. For example, impurities may include byproducts of the synthesis of tenofovir alafenamide salts and/or cocrystals, contaminants, degradation products, other crystalline forms, amorphous forms, water, and solvents. In some embodiments, impurities include byproducts from the process of synthesizing tenofovir alafenamide salts and/or cocrystals. In some embodiments, impurities include contaminants from the process of synthesizing tenofovir alafenamide salts and/or cocrystals. In some embodiments, impurities include degradation products of tenofovir alafenamide salts and/or cocrystals. In some embodiments, impurities include other crystalline forms of tenofovir alafenamide salts and/or cocrystals. In some embodiments, impurities include other crystalline forms of tenofovir alafenamide salts and/or cocrystals and/or amorphous forms of tenofovir alafenamide salts and/or cocrystals. In some embodiments, the impurities include water or solvents. In some embodiments of compositions comprising the crystalline forms disclosed herein, the impurities are selected from byproducts of the synthesis of tenofovir alafenamide salts and/or eutectics, contaminants, degradation products, other crystalline forms, amorphous forms, water, solvents, and combinations thereof.

Combination therapy

In some embodiments, a method for treating or preventing HIV infection in humans who are infected with HIV or at risk of HIV infection is provided, comprising administering to the human a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating HIV infection in humans who are infected with HIV or at risk of HIV infection is provided, comprising administering to the human a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and pharmaceutically acceptable carriers, diluents, or excipients.

In some embodiments, this disclosure provides a method of treating HIV infection, comprising administering to a patient in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other therapeutic agents suitable for treating HIV infection.

In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In a further embodiment, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

Administration of HIV combination therapy

In some embodiments, the compounds disclosed herein are administered together with one or more other therapeutic agents. Co-administration of the compounds disclosed herein with one or more other therapeutic agents generally means administering the compounds disclosed herein and one or more other therapeutic agents simultaneously or sequentially, such that therapeutically effective amounts of the compounds disclosed herein and one or more other therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more doses.

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

In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents in a single dose for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

In some embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more other compounds for treating HIV. In some embodiments, the tablet may contain additional active ingredients for treating 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 implementations, such tablets are suitable for once-daily administration.

HIV combination therapy

In the above embodiments, the additional therapeutic agent may be an anti-HIV drug. This includes HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene-editing products (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells). CAR-T and engineered T-cell receptor (TCR-T) cells, 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 inhibitors. Due to modulators, Vif dimerization 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 capture 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 agent is 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, bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

HIV combination therapy

Examples of combination therapies include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (erticagvir, 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); durenavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; Efaviramide, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertigvir; (zidovudine and lamivudine; AZT+3TC); (abacavir sulfate and lamivudine; ABC+3TC); (lopinavir and ritonavir); (durutexvir, abacavir, and lamivudine); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Derlinavir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Cabotegravir and rilpivirine; Cabotegravir and rilpivirine hydrochloride; Dulutegravir sulfate and lamivudine; Lamivudine, nevirapine, and zidovudine; Rytegvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine... Vortisone and tenofovir disoproxil fumarate; duluthvir + 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; tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidesin; and APH-0812.

Other HIV medications

Examples of other drugs used to treat HIV include acetaminophen, arapovir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, and APH-08. 12. 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 protease inhibitors

Examples of HIV protease inhibitors include ampranavir, atazanavir, brecanavir, derenavir, fusanavir, fusanavir 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-310911.

HIV reverse transcriptase inhibitors

Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapiverine, delavudine, delavudine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500.

Examples of HIV reverse transcriptase nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azivudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and (didazoxin, ddl), abacavir, abacavir sulfate, alovudine, aprecitabine, censa Vudine, Didanoxin, Avtabin, Fesinavir, Fisalvudinetidoxil, CMX-157, Dapiril, Doravirin, Etravirine, OCR-5753, Tenofovir Disoproxil Orotic Acid, Fozivudinetidoxil, Lamivudine, Phosphazid, Stavudine, Zacitabine, Zidovudine, GS-9131, GS-9148, and KP-1461.

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, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, retegvir, dulutegravir, JTK-351, bictegravir, AVX-15567, and ca. Botegravir (long-acting injectable), 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 cabotegravir.

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 cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include apravirone, vicvirone, maravirone, cinevirone, PRO-140, adaptavir (RAP-101), nifevirone (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 epovitide, enfvirtide, BMS-986197, enfvirtide biobetter, enfvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

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

Examples of CXCR4 inhibitors include plexafor, 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 bortezomib (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, ubiquitin inhibitors such as lagozola analogs, and GSK-343.

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

Examples of PKC activators include indolinamide, prostratin, phorbol B, and DAG-lactone.

Capsid inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitors or compounds that disrupt the capsid, 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 such as 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; interferon α-n3; and pegylated interferon α. Interferon-γ; Hydroxyurea; Mycophenolate mofetil (MPA) and its ester derivative Mycophenolate mofetil (MMF); Ribavirin; Rintatolimod; Polyethylene imine (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 edaralis, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifoxine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, and CL. R-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-111 7. 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.

α-4/β-7 antagonists

Examples of integrin α-4/β-7 antagonists include PTG-100, TRK-170, abrumarumab, etrolizumab, carotegrast methyl ester, and vedolizumab.

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

Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include Fab derivatives, bnAB (a broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, HIV-targeting antibody-recruiting 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, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant monoclonal antibodies (PGT-121), ibalizumab, Immuglo, and MB-66.

Examples of antibodies that target HIV in this manner include bavitimab, 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: WO2004/096286 (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). The following companies have been involved in the patent applications: US2013/0165489 (University of Pennsylvania), US2014/0221378 (Japan Tobacco Company), US2014/0221380 (Japan Tobacco Company), WO2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), and WO2013/091096 (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, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, and Ad35-GRIN. , NAcGM3/VSSP ISA-51, Poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-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, rAAV1-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, AVAX, MYM-V201, MVA-CMDR, DNA-Ad5gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.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-p24B/C fusion vaccines, GTU-based DNA vaccines, HIVgag/pol/nef/env DNA vaccines, anti-T AT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, 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, rgp160 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, rAd5gag-pol env A/B/C vaccine.

HIV combination therapy

In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are 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); (erticavir, cobistat, tenofovir disoproxil fumarate and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, Emtricitabine and Rilpivirine); (Tenofovir Alamonamide, Emtricitabine, Cobistat and Eticagvir); Adefovir; Adefovir Dipivoxil; Cobistat; Emtricitabine; Tenofovir; Tenofovir Disoproxil Fumarate; Tenofovir Alamonamide; Tenofovir Alamonamide Hemifumarate; (Durutexvir, Abacavir and Lamivudine); Durutvir, Abacavir Sulfate and Lamivudine; Raltegravir; Rritegvir and Lamivudine; Maraviro; Enfuvir; (Lopinavir and Ritonavir); (Zidovudine and Lamivudine; AZT+3) TC); (Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derlinavir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Darunavir; Lamivudine; Prolastin; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefenavir; Nefenavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldehyde-interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine Mesylate; Radha-108 (receptol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirex, Lamivudine and Tenofovir Disoproxil Fumarate; Phosphazid; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir Sulfate.

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. The specific categories are not intended to limit the function of the compounds listed in those categories.

In one embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a compound that inhibits HIV protease. In yet another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are 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 compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from tenofovir, tenofovir desoprothiolane, tenofovir desoprothiolane fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

The compounds disclosed herein (e.g., salts and/or cocrystals of tenofovir alafenamide) may be combined with one or more other therapeutic agents at any dose of the compounds disclosed herein (e.g., 1 mg to 500 mg of salts and/or cocrystals of tenofovir alafenamide).

In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are 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 compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. Compounds disclosed herein (e.g., compounds of formula (I)) may be combined with the pharmaceutical agents provided herein at any dose of said compound (e.g., 1 mg to 500 mg of the compound), as each dose combination is specifically and separately listed.

In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are 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 compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate, and 200 mg of emtricitabine. Compounds disclosed herein (e.g., compounds of formula (I)) may be combined with the pharmaceutical agents provided herein at any dose of said compound (e.g., from 1 mg to 500 mg of the compound), as each dose combination is specifically and individually listed.

In one embodiment, a kit is provided comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

Fertility control (contraception) combination therapy

Treatment agents used for fertility control (contraception) include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levomefolate, levonorgestrel, linegestrel, medroxyprogesterone acetate, mestriol, mifepristone, misoprostol, normegestrol acetate, norethindrone, isethindrone, norethindrone oxime, olmexifen, segestersone acetate, ulipristal acetate, and any combination thereof.

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

Gene therapy and cell therapy

Gene therapy and cell therapy, including genetic modification of silent genes; genetic methods that directly kill infected cells; immune cell infusions designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or to activate the patient’s own immune system to kill infected cells, or to detect and kill infected cells; and genetic methods that alter cell activity to further change the endogenous immune response to infection.

Examples of dendritic cell therapy include AGS-004.

Gene-edited products

The genome editing systems selected are: CRISPR/Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system and large-scale nuclease system.

Examples of HIV targeting the CRISPR/Cas9 system include EBT101.

CAR-T cell therapy

An immune effector cell population engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen contains an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof.

Examples of HIV CAR-T include VC-CAR-T.

TCR-T cell therapy

TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

HBV combination

In some embodiments, a method for treating or preventing HBV infection in a person who is infected or at risk of infection is provided, comprising administering to the person a combination of a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating HBV infection in a person who is infected or at risk of infection is provided, comprising administering to the person a combination of a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

In some embodiments, this disclosure provides a method for treating HBV infection, comprising administering to a patient in need a combination of a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents suitable for treating HBV infection.

In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In a further embodiment, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

Administration of HBV combination therapy

In some embodiments, when the compounds disclosed herein are combined with one or more other therapeutic agents as described above, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more doses.

The co-administration of the compounds disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and one or more other therapeutic agents such that a therapeutically effective amount of each agent is present in the patient.

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

In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents in a single dose for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

In some embodiments, the compounds disclosed herein are formulated into tablets, which may optionally contain one or more other compounds that can be used to treat HBV. In some embodiments, the tablets may contain another active ingredient for treating HBV.

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

HBV combination therapy

In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, other therapeutic agents may be selected from HBV combination drugs, other drugs used to treat HBV, 3-dioxygenase (IDO) inhibitors, antisense oligonucleotides targeting viral mRNA, apolipoprotein A1 modulators, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, cyclophilic protein inhibitors, cytokines, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesol X receptor agonists, gene modifiers or edits, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerases, etc. HBV synthase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV vaccines, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus e antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV- 1. Reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunoglobulin agonists, immunoglobulin G modulators, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon α1 ligands, interferon α2 ligands, interferon α5 ligand modulators, interferon α ligands, interferon α ligand modulators, interferon α receptor ligands, interferon β ligands, interferon ligands, interferon receptor modulators, interleukin-2 ligands IPi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin β receptor activators, microRNA (miRNA) gene therapy agents, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurine cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors PEG-interferon λ, peptidyl prolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitor, recombinant scavenger receptor A (SRA) protein, recombinant thymosin α-1, retinoic acid-induced gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitor, RNA DNA polymerase inhibitor, short interfering RNA (siRNA), short synthetic hairpin RNA (sshRNA), SLC10A1 gene inhibitor, SMAC mimic, Src tyrosine kinase inhibitor, interferon gene stimulator (STING) agonist, NOD1 stimulator, T cell surface glycoprotein CD28 inhibitor, T cell surface glycoprotein CD8 regulator, thymosin agonist, thymosin α1 ligand, Tim-3 inhibitor, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 gene stimulator, toll-like receptor (TLR) regulator, viral ribonucleotide reductase inhibitor, zinc finger nuclease or synthetic nuclease (TALEN) and combinations thereof.

In some embodiments, the compounds disclosed herein are formulated into tablets, which may optionally contain one or more other compounds for treating HBV. In some embodiments, the tablets may contain another active ingredient for treating HBV, such as a 3-dioxygenase (IDO) inhibitor, an apolipoprotein A1 modulator, an arginase inhibitor, a B- and T-lymphocyte attenuator inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, a CCR2 chemokine antagonist, a CD137 inhibitor, a CD160 inhibitor, a CD305 inhibitor, a CD4 agonist and modulator, a compound targeting HBcAg, a compound targeting hepatitis B core antigen (HBcAg), a core protein allosteric modulator, a covalently closed circular DNA (cccDNA) inhibitor, a cyclophilic protein inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor, a DNA polymerase inhibitor, a nuclease modulator, an epigenetic modifier, a farnesol X receptor agonist, or HBs. HBV inhibitors, including HBsAg secretion or assembly inhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus e antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, IPI4 inhibitors, and lysine decarboxylase inhibitors. Formulations, histone demethylation inhibitors, KDM1 inhibitors, KDM5 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin β receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurine cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors Formulations, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl-proline isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-induced gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimics, Src tyrosine kinase inhibitors, interferon gene stimulating factor (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, Toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more other therapeutic agents selected from: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilic protein inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators. Ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

HBV combination therapy

Examples of combination therapies used to treat HBV include (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

Other HBV medications

Examples of other medications used to treat HBV include alpha-hydroxytophenone, amadoxovir, beta-hydroxycytosine nucleoside, CCC-0975, ibrutinib, ezetimibe, cyclosporine A, gentiopicroside (gentiopicroside), JNJ-56136379, nitrozonide, birinapant, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, and allofer. on, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK- II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPBB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai ( Ganxikang), MIV-210, OB-AI-004, PF-06, jujube glycoside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, and US20150210682 (Roche), US 2016/0122344 (Roche), WO2015173164, WO2016023877, US201 Compounds disclosed in WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche).

HBV vaccine

HBV vaccines include both preventative and therapeutic vaccines. Examples of HBV preventative vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, and Tetrabhay. Hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX recombinant hepatitis B vaccine (intramuscular injection, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorphic yeast, intramuscular injection, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Eufovac, Eutravac, anrix-DTaP-IPV-Hep B HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac Bmcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine and DTaP-rHB-Hib vaccine.

Examples of therapeutic HBV vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilon PA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, and CVI-HBV- 002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944 (INO-1800), therapeutic vaccines based on recombinant VLP (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, and Lm HBV.

HBV DNA polymerase inhibitor

Examples of HBV DNA polymerase inhibitors include adefovir, entriacitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecoxyethyl ester, CMX-157, bexifovir, entecavir, entecavir maleate, telbivudine, pramovir, clavudine, ribavirin, lamivudine, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidazole hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolic acid (MPA) and its ester derivative mycophenolic acid molybdate (MMF), WF-10, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, and IR-103.

Toll-like receptor (TLR) modulators

TLR modifiers include modifiers for TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3 modifiers include lintatoril, poly-ICLC, Apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, remiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharmaceuticals), US20080306050 (Array Biopharmaceuticals), and US2 The compounds disclosed in US20110092485 (Vindex Pharmaceuticals), US20110118235 (Vindex Pharmaceuticals), US20120082658 (Vindex Pharmaceuticals), US20120219615 (Vindex Pharmaceuticals), US20140066432 (Vindex Pharmaceuticals), US20140088085 (Vindex Pharmaceuticals), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics).

Examples of TLR9 modifiers include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, zoolimod (MGN-1703), linimod, and CYT-003-QbG10.

Interferon α receptor ligand

Examples of interferon α receptor ligands include interferon PEGylated interferon, interferon α-1b, interferon α1b Veldona, Infradure, interferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant supercomplex interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, peg interferon Bioferon, Novaferon, In... Mutag (Inferon), Interferon Shaferon, Interferon α-2b (Axxo), Alfaferone, Interferon α-2b (BioGeneric Pharma), Interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, Interferon α-2b (IFN, Labora) torios Bioprofarma), interferon α2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon α2b (Zydus-Cadila), interferon α2a, Optipeg A, Realfa 2B, Reliferon, interferon α-2b (Amega), interferon α-2b (Virchow), ropeg interferon α-2b, rHSA-IFNα-2a (recombinant human serum albumin interferon α2a fusion protein), rHSA-IFNα2b, recombinant human Interferon α-(1b, 2a, 2b), peg interferon α-2b (Amega), peg interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products), Andafen, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, and Interapo (Interapa).

Hyaluronidase inhibitor

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B surface antigen (HBsAg) inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006, and REP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belapatacept, PSI-001, PRS-010, Probody mAb, tremelimumab, and JHL-1155.

Cyclic protein inhibitors

Examples of cyclic protein inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

HBV virus enters inhibitor

Examples of HBV virus inhibitors include Myrcludex B.

Antisense oligonucleotides targeting viral mRNA

Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, and GSK-3389404.

Short interfering RNA (siRNA) and ddRNAi

Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

Examples of DNA-guided RNA interference (ddRNAi) include BB-HB-331.

Nucleotide endonuclease regulators

Examples of endonuclease regulators include PGN-514.

Ribonucleotide reductase inhibitors

Examples of ribonucleotide reductase inhibitors include Trimidox.

HBV E antigen inhibitors

Examples of HBV E antigen inhibitors include baicalein.

Covalently closed circular DNA (cccDNA) inhibitors

Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

Farnesol X receptor agonists

An example of a farnesoid X receptor agonist is EYP-001.

HBV antibody

Examples of HBV antibodies targeting hepatitis B surface antigen include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B virus infection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include Zutectra, Shang Sheng GanDi, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, anigantibe, Niuliva, CT-P24, Hepatitis B Immunoglobulin (IV, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies include, for example, HBC-34.

CCR2 chemokine antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

thymosin agonists

Examples of thymosin agonists include thymosin alpha 1 and recombinant thymosin alpha 1 (GeneScience).

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simmoleukin.

Nucleoprotein regulators

Nucleoprotein modulators can be HBV nucleoprotein or capsid protein inhibitors. Examples of nucleoprotein modulators include AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, mofexidine mesylate, JNJ-379, and DVR-23. Capsid assembly inhibitors are, for example, AB-423.

Examples of capsid inhibitors include the compounds disclosed in the following: US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO201418 4365 (Yang Sen), WO2014184350 (Yang Sen), WO2014161888 (Yang Sen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Yang Sen), WO2013144129 (Roche).

Retinol can induce gene 1 stimulants

Examples of retinoic acid-induced gene 1 stimulants include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

NOD2 stimulants

Examples of NOD2 stimulants include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, perifoxine, RG-7666, and GS. K-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, mequitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2,3-dioxygenase (IDO) pathway inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indomod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in US20100015178 (Inset), US2016137652 (Flexus Biosciences), WO2014073738 (Flexus Biosciences), and WO2015188085 (Flexus Biosciences).

PD-1 inhibitors

Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400.

PD-L1 inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

Recombinant thymosin α-1

Examples of recombinant thymosin α-1 include NL-004 and PEGylated thymosin α-1. Bruton's tyrosine kinase (BTK) inhibitors.

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, and RG-78. 45, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and compounds disclosed in US20140330015 (Ono Pharmaceutical Co., Ltd.), US20130079327 (Ono Pharmaceutical Co., Ltd.), and US20130217880 (Ono Pharmaceutical Co., Ltd.).

KDM inhibitors

Examples of KDM5 inhibitors include the compounds disclosed in the following: WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), and WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics) as well as GSK-2879552, RG-6016, and ORY-2001.

HBV replication inhibitors

Examples of hepatitis B virus replication inhibitors include isothiazide, IQP-HBV, RM-5038, and Xingantie.

Arginase inhibitors

Examples of arginase inhibitors include CB-1158, C-201, and resminostat.

HBV combination therapy

In one specific embodiment, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents selected from the following: adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, entecavir, telbivudine, or lamivudine. In another specific embodiment, the disclosed compound or a pharmaceutically acceptable salt thereof is combined with the first additional therapeutic agent selected from the following: adefovir... In one embodiment, a pharmaceutical composition is provided comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof, one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents in combination, and pharmaceutically acceptable carriers, diluents, or excipients. HBV DNA polymerase inhibitor combination therapy

In one embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HBV DNA polymerase inhibitor. In another embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from: immunomodulators, TLR modulators, interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclic protein inhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, and ribonucleotide reductase inhibitors. Agents, including hepatitis B virus e antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies, including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators (HBV nucleo or capsid protein regulators), retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, arginase inhibitors, STING agonists, and P... I3K inhibitors, lymphotoxin β receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, CD137 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, recombinant thymosin α-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD2 7. Regulators, CD70 regulators, OX40 regulators, epigenetic modifiers, NKG2D regulators, Tim-4 regulators, B7-H4 regulators, B7-H3 regulators, NKG2A regulators, GITR regulators, CD160 regulators, HEVEM regulators, CD161 regulators, Axl regulators, Mer regulators, Tyro regulators, gene modifiers or edits such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), IAP inhibitors, SMAC mimics, KDM5 inhibitors, IDO inhibitors, and hepatitis B virus replication inhibitors.

In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with HBV DNA polymerase inhibitors, one or two additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies, including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigen and "antibody-like" therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators, and one or two additional therapeutic agents selected from HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV nucleo or capsid protein modulators).

In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the following: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies, including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigen and “antibody-like” therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators.

In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with HBV DNA polymerase inhibitors and at least a second additional therapeutic agent selected from: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV nucleo or capsid protein inhibitors).

HBV combination therapy

In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from: adefovir/tenofovir/desopoxetine fumarate, tenofovir, tenofovir/desopoxetine, tenofovir/desopoxetine fumarate, tenofovir/desopoxetine hemifumarate, entecavir, telbivudine, or lamivudine; and the at least second additional therapeutic agent is selected from: immunomodulators, TLR modulators, interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclic protein inhibitors, etc. Formulations, HBV vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonuclease inhibitors, hepatitis B virus E antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies, including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., Fab derivatives and TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV nucleo or capsid protein modulators), retinoids Acid-induced gene 1 stimulants, RIG-I-like receptor stimulants, NOD2 stimulants, NOD1 stimulants, IDO inhibitors, recombinant thymosin α-1, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β-receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, IPI4 inhibitors, CD137 inhibitors, cytotoxic cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, BTK inhibitors, TI GIT regulators, CD47 regulators, SIRPα regulators, ICOS regulators, CD27 regulators, CD70 regulators, OX40 regulators, NKG2D regulators, Tim-4 regulators, B7-H4 regulators, B7-H3 regulators, NKG2A regulators, GITR regulators, CD160 regulators, HEVEM regulators, CD161 regulators, Axl regulators, Mer regulators, Tyro regulators, gene modifiers or edits such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), IAP inhibitors, SMAC mimics, KDM5 inhibitors, and hepatitis B virus replication inhibitors.

In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from: adefovir/tenofovir/desopoxetine fumarate, tenofovir alafenamide, tenofovir, tenofovir/desopoxetine, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir, telbivudine, or lamivudine, and wherein the at least second additional therapeutic agent is selected from: pegylated interferon, interferon α1b, interferon pegylated interferon, interferon ribavirin, interferon β-1a Bioferon. Ingaron, Inmutag (Inferon), Algeron, Interferon-A, Oligotide, Zutectra, Shaferon, Interferon α-2b (AXXO), Alfaferone, Interferon α-2b (BioGeneric Pharma), Feron, Interferon-α2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion Pegaferon, PDferon-B, interferon α-2b (IFN, Laboratorios Bioprofarma), α-interferon α-2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon α-2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon α-2b (Amega), interferon α-2b (Virchow), polyethylene glycol interferon α-2b (Amega), Reaferon-EC Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, Interleukin-2 (IL-2, Immunex), Recombinant Human Interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon, and celmoleukin.

In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from: adefovir/tenofovir/desopoxetine fumarate, tenofovir, tenofovir/desopoxetine, tenofovir/desopoxetine fumarate, tenofovir/desopoxetine hemifumarate, entecavir/telbivudine, or lamivudine, and wherein the at least second additional therapeutic agent is selected from: immunomodulators, TLR modulators, etc. Hepatitis B inhibitors, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies, including HBV antibodies and bispecific antibodies targeting the hepatitis B virus surface antigen and "antibody-like" therapeutic proteins (such as Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, IDO inhibitors, and NOD2 stimulators.

In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, the first additional therapeutic agent being selected from: adefovir/tenofovir/desotropide fumarate, tenofovir, tenofovir/desotropide, tenofovir/demandoxetine fumarate, tenofovir/demandoxetine hemifumarate, entecavir/tebivudine, or lamivudine, and the at least second additional therapeutic agent being selected from: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV nucleo or capsid protein modulators).

In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with: a first additional therapeutic agent selected from adefovir tenofovir dessotropide fumarate, tenofovir alafenamide, tenofovir, tenofovir dessotropide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir telbivudine, or lamivudine; or one, two, or three additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies, including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies and "antibody-like" antibodies. "Therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulants, RIG-I-like receptor stimulants, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulants; and one or two additional therapeutic agents selected from HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV nucleo or capsid protein modulators)."

In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with: a first additional therapeutic agent selected from adefovir/tenofovir/desotropide fumarate, tenofovir alafenamide, tenofovir, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir, telbivudine, or lamivudine; or one or two additional therapeutic agents selected from immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies, including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies and "antibody-like" antibodies. Therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulants, RIG-I-like receptor stimulants, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulants; and one or two additional therapeutic agents selected from HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV nucleo or capsid protein modulators).

In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with: a first additional therapeutic agent selected from adefovir tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, entecavir telbivudine, or lamivudine; and one, two, three, or four additional therapeutic agents selected from immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, and HBV antibodies, including those targeting hepatitis B. HBV antibodies and bispecific antibodies against the surface antigen of the HBV virus and "antibody-like" therapeutic proteins (e.g., Fab derivatives or TCR-like antibodies), cyclic protein inhibitors, retinoic acid-inducible gene 1 stimulants, RIG-I-like receptor stimulants, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, NOD2 stimulants, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV nucleo or capsid protein modulators).

In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a compound, such as those disclosed below: U.S. Publication No. 2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), U.S. Publication No. 2014/0045849 (Yanssen), U.S. Publication No. 2014/0073642 (Yanssen), WO2014/056953 (Yanssen), W O2014/076221 (Yang Sen), WO2014/128189 (Yang Sen), U.S. Publication No. 2014/0350031 (Yang Sen), WO2014/023813 (Yang Sen), U.S. Publication No. 2008/0234251 (Array Biopharmaceuticals), U.S. Publication No. 2008/0306050 (Array Biopharmaceuticals), U.S. Publication No. 2010/0029585 (Ventirx Pharma), U.S. Publication No. 2011/0092485 (Ventirx Pharma), US2011/0118235 (Ventirx Pharma). a) U.S. Publication No. 2012/0082658 (Ventirx Pharma), U.S. Publication No. 2012/0219615 (Ventirx Pharma), U.S. Publication No. 2014/0066432 (Ventirx Pharma), U.S. Publication No. 2014/0088085 (Ventirx Pharma), U.S. Publication No. 2014/0275167 (Novira Therapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2014/0030221 (Gilead Sciences), U.S. Publication No. 2013/0344030 (Gilead Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Publication No. 2014/0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013/0267 517 (Roche), WO2014131847 (Yang Sen), WO2014033176 (Yang Sen), WO2014033170 (Yang Sen), WO2014033167 (Yang Sen), WO2015/059212 (Yang Sen), WO2015118057 (Yang Sen), WO2015011281 (Yang Sen), WO2014184365 (Yang Sen), WO2014184350 (Yang Sen), WO2014161888 (Yang Sen), WO2013096744 (Novira), US20150225355 (Novira), US201401783 37 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), US20100015178 (Inset), US2016137652 (Flexus Biosciences), WO2014073738 ( Flexus Biosciences, Inc., WO2015188085 (Flexus Biosciences, Inc.), U.S. Publication No. 2014/0330015 (Ono Pharmaceutical Co., Ltd.), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical Co., Ltd.), U.S. Publication No. 2013/0217880 (Ono Pharmaceutical Co., Ltd.), WO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092 (Genentech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epit... Herapeutics, US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (OryzonGenomics), and other drugs used to treat HBV, as well as combinations thereof.

In some embodiments, compounds such as those disclosed herein (e.g., any salt and/or cocrystal of tenofovir alafenamide) may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of the compounds disclosed herein (e.g., 10 mg to 1000 mg of any salt and/or cocrystal of tenofovir alafenamide).

In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are 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. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. Compounds disclosed herein (e.g., salts and/or cocrystals of tenofovir alafenamide) may be combined with the pharmaceutical agents provided herein at any compound dose (e.g., 50 mg to 500 mg of the compound), as various dose combinations are specifically and individually listed.

In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Compounds disclosed herein (e.g., salts and/or cocrystals of tenofovir alafenamide) may be combined with the pharmaceutical agents provided herein at any compound dose (e.g., 50 mg to 500 mg of the compound), as various dose combinations are specifically and separately listed.

In one embodiment, a kit is provided comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof, combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

XRPD data

In some embodiments, the crystalline form is characterized by the intergranular plane spacing determined by X-ray powder diffraction (XRPD). XRPD diffraction patterns are typically represented by plotting the peak intensities versus their positions, i.e., diffraction angles 2θ(2-θ) in degrees. Characteristic peaks of a given XRPD can be selected based on their positions and relative intensities to conveniently distinguish the crystal structure from other crystal structures.

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

Those skilled in the art will recognize that measurements of XRPD peak positions and/or intensities for a given crystalline form of the same compound will vary within an error range. Values in 2θ degrees allow for an appropriate error range. Typically, the error range is expressed in "±". For example, a 2θ degree of approximately "8.7 ± 0.3" represents a range from approximately 8.7 ± 0.3 (i.e., approximately 9.0) to approximately 8.7 ± 0.3 (i.e., approximately 8.4). Depending on sample preparation techniques, calibration techniques applied to the instrument, variations in human operation, etc., those skilled in the art will recognize that an appropriate error range for XRPD can be ±0.5; ±0.4; ±0.3; ±0.2; ±0.1; ±0.05; or smaller. In some embodiments of the invention, the XRPD error range is ±0.05. In some embodiments of the invention, the XRPD error range is ±0.1. In some embodiments of the invention, the XRPD error range is ±0.2. In some embodiments of the invention, the XRPD error range is ±0.5.

Further details of the methods and apparatus used for XRPD analysis are described in the Examples section.

The XRPD peaks of crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I are shown in Table 1A below.

Table 1A: XRPD peaks of crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form I

The XRPD peaks of crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II are shown in Table 1B below.

Table 1B: XRPD peaks of crystalline tenofovir alafenamide hemi-dihydroxynaphthyl salt form II

The XRPD peaks of crystalline tenofovir alafenamide sebacate form I are shown in Table 1C below.

Table 1C: XRPD peaks of crystalline tenofovir alafenamide sebacate form I

The XRPD peaks of crystalline tenofovir alafenamide naphthalene sulfonate form I are shown in Table 1D below.

Table 1D: XRPD peaks of crystalline tenofovir alafenamide naphthalene sulfonate form I

The XRPD peaks of crystalline tenofovir alafenamide orotate form I are shown in Table 1E below.

Table 1E: XRPD peaks of crystalline tenofovir alafenamide orotate form I

The XRPD peaks of crystalline tenofovir alafenamide orotate form II are shown in Table 1F below.

Table 1F: XRPD peaks of crystalline tenofovir alafenamide orotate form II

The XRPD peaks of crystalline tenofovir alafenamide orotate form III are shown in Table 1G below.

Table 1G: XRPD peaks of crystalline tenofovir alafenamide orotate form III

The XRPD peaks of crystalline tenofovir alafenamide vanillate are shown in Table 1H below.

Table 1H: XRPD peaks of crystalline tenofovir alafenamide vanillate

The XRPD peaks of crystalline tenofovir alafenamide dibenzonaphthol are shown in Table 1I below.

Table 1I: XRPD peaks of crystalline tenofovir alafenamide dibenzonatate

Preparation of crystalline form

A method for synthesizing tenofovir alafenamide was previously described in PCT Publication No. WO2002/008241, filed July 20, 2001. That reference is incorporated herein by reference in its entirety (particularly concerning the synthesis of tenofovir alafenamide).

For example, in one aspect, a method is provided for producing a composition comprising one or more crystalline forms of a salt and/or eutectic of tenofovir alafenamide, wherein the method comprises combining the salt and/or eutectic of tenofovir alafenamide with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more crystalline forms of a salt and/or eutectic of tenofovir alafenamide. In another aspect, another method is provided for producing a composition comprising one or more crystalline forms of a salt and/or eutectic of tenofovir alafenamide, wherein the method comprises combining the salt and/or eutectic of tenofovir alafenamide with a suitable solvent or a mixture of suitable solvents.

The choice of a particular solvent or combination of solvents, or the method of combining solvents, influences the formation of a crystalline form of tenofovir alafenamide that is more favorable than another crystalline form. Solvents suitable for crystal formation may include, for example: tetrahydrofuran, acetone, ethanol, acetonitrile, isopropanol, methyl ethyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, methyl tert-butyl ether, toluene, water, and any mixtures thereof.

The presence of impurities may affect the formation of tenofovir alafenamide in a manner that favors one crystalline form over another. In some embodiments, this form is prepared by a method comprising tenofovir alafenamide containing impurities. In another embodiment, this form is prepared by a method comprising substantially pure tenofovir alafenamide.

In another aspect, one or more crystalline forms of tenofovir alafenamide produced according to any of the methods described herein are also provided. In another aspect, one or more crystalline forms of salts and/or eutectics of tenofovir alafenamide produced according to any of the methods described herein are also provided.

It should be understood that the method described herein for preparing the crystalline form can produce differences in quantity and quality compared to methods for preparing tenofovir alafenamide on a laboratory scale. Tenofovir alafenamide hemi-dihydroxynaphthyl salt

In some embodiments, a method for preparing tenofovir alafenamide hemi-dihydroxynaphthyl acid is provided, wherein the method includes combining tenofovir alafenamide with dihydroxynaphthyl acid. In some embodiments, a method for preparing tenofovir alafenamide hemi-dihydroxynaphthyl acid is provided, wherein the method includes combining tenofovir alafenamide with dihydroxynaphthyl acid and tetrahydrofuran. In some embodiments, a method for preparing tenofovir alafenamide hemi-dihydroxynaphthyl acid is provided, wherein the method includes combining tenofovir alafenamide with dihydroxynaphthyl acid and tetrahydrofuran at about 50 to 60°C. In some embodiments, a method for preparing tenofovir alafenamide hemi-dihydroxynaphthyl acid is provided, wherein the method includes combining tenofovir alafenamide with dihydroxynaphthyl acid and tetrahydrofuran in an open vial under natural evaporation at about 50 to 60°C.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form I

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide hemi-dihydroxynaphthylate form I, wherein the method comprises combining tenofovir alafenamide hemi-dihydroxynaphthylate with a solvent. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide hemi-dihydroxynaphthylate form I comprises combining tenofovir alafenamide hemi-dihydroxynaphthylate with a solvent selected from: water, ethanol, acetonitrile, acetone, isopropanol, methyl ethyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and toluene, and any mixtures thereof.

A crystalline form of tenofovir alafenamide hemi-dihydroxynaphthylate, form I, is provided, produced by combining tenofovir alafenamide hemi-dihydroxynaphthylate with a solvent. The solvent is selected from water, ethanol, acetonitrile, acetone, isopropanol, methyl ethyl ketone, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and toluene, and any mixtures thereof.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form II

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide hemi-dihydroxynaphthylate form II, wherein the method comprises combining tenofovir alafenamide hemi-dihydroxynaphthylate with a solvent. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide hemi-dihydroxynaphthylate form II comprises combining tenofovir alafenamide hemi-dihydroxynaphthylate with dichloromethane.

A crystalline form of tenofovir alafenamide hemi-dihydroxynaphthyl acid salt II is provided, produced by combining tenofovir alafenamide hemi-dihydroxynaphthyl acid salt with a solvent. A crystalline form of tenofovir alafenamide hemi-dihydroxynaphthyl acid salt II is also provided, produced by combining tenofovir alafenamide hemi-dihydroxynaphthyl acid salt with dichloromethane.

Tenofovir alafenamide sebacic acid

In some embodiments, a method for preparing tenofovir alafenamide sebacic acid is provided, wherein the method includes combining tenofovir alafenamide with sebacic acid. In some embodiments, a method for preparing tenofovir alafenamide sebacic acid is provided, wherein the method includes combining tenofovir alafenamide with sebacic acid and acetone in a naturally evaporating open vial.

Tenofovir alafenamide sebacic acid form I

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide sebacic acid form I, wherein the method comprises combining tenofovir alafenamide sebacic acid with a solvent. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide sebacic acid form I comprises combining tenofovir alafenamide sebacic acid with a solvent selected from tetrahydrofuran and heptane, and any mixture thereof.

Crystalline tenofovir alafenamide sebacic acid form I is provided, produced by combining tenofovir alafenamide sebacic acid with a solvent. Crystalline tenofovir alafenamide sebacic acid form I is provided, produced by combining tenofovir alafenamide sebacic acid with a solvent selected from tetrahydrofuran and heptane, and any mixture thereof.

Tenofovir alafenamide naphthalene sulfonate

In some embodiments, a method for preparing tenofovir alafenamide naphthalene sulfonate is provided, wherein the method includes combining tenofovir alafenamide with 2-naphthalene sulfonic acid. In some embodiments, a method for preparing tenofovir alafenamide naphthalene sulfonate is provided, wherein the method includes combining tenofovir alafenamide with 2-naphthalene sulfonic acid and acetone.

Tenofovir alafenamide naphthalene sulfonate form I

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide naphthalene sulfonate form I, wherein the method comprises combining tenofovir alafenamide with 2-naphthalene sulfonic acid and acetone in a naturally evaporating open vial.

A crystalline form of tenofovir alafenamide naphthalene sulfonate, form I, is provided, produced by combining tenofovir alafenamide with 2-naphthalene sulfonic acid and acetone in an open vial during natural evaporation.

Tenofovir alafenamide orotate

In some embodiments, a method for preparing tenofovir alafenamide orotic salt is provided, wherein the method includes combining tenofovir alafenamide with orotic acid. In some embodiments, a method for preparing tenofovir alafenamide orotic salt is provided, wherein the method includes combining tenofovir alafenamide with orotic acid and acetone.

Tenofovir alafenamide orotate form I

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide orotate form I, wherein the method comprises combining tenofovir alafenamide with orotate and acetone.

A crystalline form of tenofovir alafenamide naphthalene sulfonate, form I, is provided, produced by combining tenofovir alafenamide with orotic acid and acetone.

Tenofovir alafenamide orotate form II

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide orotate form II, wherein the method includes combining tenofovir alafenamide orotate form I with a solvent. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide orotate form II includes combining tenofovir alafenamide orotate form I with a solvent selected from isopropanol, tetrahydrofuran, ethyl acetate, toluene, or combinations thereof. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide orotate form II includes combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is isopropanol. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide orotate form II includes combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is tetrahydrofuran. In some embodiments, a method of producing a composition comprising crystalline tenofovir alafenamide orotate form II includes combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is ethyl acetate. In some embodiments, a method of producing a composition comprising crystalline tenofovir alafenamide orotate form II includes combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is toluene.

Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent. Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent selected from isopropanol, tetrahydrofuran, ethyl acetate, toluene, or combinations thereof. Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is isopropanol. Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is tetrahydrofuran. Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is ethyl acetate. Crystalline tenofovir alafenamide orotate form II is provided, produced by combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is toluene.

Tenofovir alafenamide orotate form II

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide orotate form III, wherein the method includes combining tenofovir alafenamide orotate form I with a solvent. In some embodiments, the method for producing a composition comprising crystalline tenofovir alafenamide orotate form III includes combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is water.

Crystalline tenofovir alafenamide orotate form III is provided, produced by combining tenofovir alafenamide orotate form I with a solvent. Crystalline tenofovir alafenamide orotate form III is provided, produced by combining tenofovir alafenamide orotate form I with a solvent, wherein the solvent is water.

Tenofovir alafenamide vanillate

In some embodiments, a method for preparing tenofovir alafenamide vanillic acid is provided, wherein the method includes combining tenofovir alafenamide with vanillic acid. In some embodiments, a method for preparing tenofovir alafenamide vanillic acid is provided, wherein the method includes combining tenofovir alafenamide with vanillic acid and acetone. In some embodiments, a method for preparing tenofovir alafenamide vanillic acid is provided, wherein the method includes combining tenofovir alafenamide with vanillic acid and acetone at a temperature of about 50°C.

Tenofovir alafenamide vanillate

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide vanillate, wherein the method includes combining tenofovir alafenamide with vanillic acid and a solvent. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide vanillate, wherein the method includes combining tenofovir alafenamide with vanillic acid and acetone.

This article provides a crystalline tenofovir alafenamide vanillate produced by combining tenofovir alafenamide with vanillic acid and acetone.

Tenofovir alafenamide dibenzonatate

In some embodiments, a method for preparing tenofovir alafenamide dibenzonaphthylcarboxylate is provided, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphthylcarboxylic acid and a solvent. In some embodiments, a method for preparing tenofovir alafenamide dibenzonaphthylcarboxylate is provided, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphthylcarboxylic acid in tetrahydrofuran. In some embodiments, a method for preparing tenofovir alafenamide dibenzonaphthylcarboxylate is provided, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphthylcarboxylic acid in tetrahydrofuran, wherein the tetrahydrofuran is evaporated and replaced with a second solvent. In some embodiments, a method for preparing tenofovir alafenamide dibenzonaphthylcarboxylate is provided, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphthylcarboxylic acid in tetrahydrofuran, wherein the tetrahydrofuran is evaporated and replaced with dichloromethane. In some embodiments, a method for preparing tenofovir alafenamide dibenzonaphthyl salt is provided, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphthoic acid in tetrahydrofuran (THF), wherein the tetrahydrofuran is evaporated and replaced with dichloromethane, and wherein the dichloromethane is evaporated.

Tenofovir alafenamide dibenzonatate

In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylcarboxylate, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and a solvent or mixture of solvents. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylcarboxylate, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and THF. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylcarboxylate, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and THF, evaporating the THF, adding dichloromethane, and evaporating the dichloromethane. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylcarboxylate, wherein the method includes a first step of combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and THF, a second step of evaporating the THF, a third step of adding dichloromethane, and a fourth step of evaporating the dichloromethane. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylcarboxylate, wherein the method includes generating tenofovir alafenamide dibenzonaphthylcarboxylate seed crystals by combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid in THF, wherein the tenofovir alafenamide dibenzonaphthylcarboxylate seed crystals are then used to crystallize a solution of 1-hydroxy-2-naphtholic acid in a solvent selected from: methanol, ethanol, acetone, isopropanol, methyl isobutyl ketone (MIBK), ethyl acetate, isopropyl acetate, toluene, or mixtures thereof. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylate, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and acetone. In some embodiments, a method is provided for producing a composition comprising crystalline tenofovir alafenamide dibenzonaphthylate, wherein the method comprises combining tenofovir alafenamide with 1-hydroxy-2-naphtholic acid and acetone, and then evaporating the acetone.

Uses in manufacturing pharmaceutical products

The use of the crystalline forms described herein in the manufacture of pharmaceutical products is also provided. One or more crystalline forms described herein (e.g., the compounds described herein) can be used in manufacturing processes to produce pharmaceutical products. One or more crystalline forms described herein (e.g., the compounds described herein) can be used as intermediates in manufacturing processes to produce pharmaceutical products.

In some embodiments, crystalline salts and/or cocrystals of tenofovir alafenamide are used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide hemi-dihydroxynaphthyl salt form I is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide hemi-dihydroxynaphthyl salt form II is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide sebate form I is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide naphthalenesulfonate form I is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide orotate form I is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide orotate form II is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide orotate form III is used to manufacture the active pharmaceutical ingredient.

In some embodiments, tenofovir alafenamide vanillate is used to manufacture the active pharmaceutical ingredient. In some embodiments, tenofovir alafenamide dibenzonatate is used to manufacture the active pharmaceutical ingredient.

Products and reagent kits

Compositions comprising one or more crystalline forms described herein (e.g., compounds described herein) and formulated in one or more pharmaceutically acceptable excipients or other ingredients can be prepared, placed in suitable containers, and labeled for the treatment of specified conditions. Therefore, an article, such as a container comprising a dosage form of one or more crystalline forms described herein and a label containing instructions for use of the compound, is also contemplated.

In some embodiments, the article is a container comprising one or more crystalline forms described herein, and one or more pharmaceutically acceptable excipients or other ingredients in a dosage form. In some embodiments of the article described herein, the dosage form is a solution.

Kits have also been considered. For example, a kit may contain a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treating a medical condition. In another embodiment, the kit may contain multiple individual dosage forms, each containing a therapeutically effective amount of the compound as described herein, and instructions for administering them to a person in need. Each individual dosage form may contain a combination of a therapeutically effective amount of the compound as described herein with at least one pharmaceutically effective excipient. Individual dosage forms may be, for example, solutions, tablets, pills, capsules, sachets, sublingual medications, lyophilized powders, spray-dried powders, or liquid compositions for oral, parenteral, or topical application. Instructions for use in the kit may be for treating HIV infection. Instructions may be for any viral infection and method described herein. Instructions may be for preventing or treating existing viral infections.

In some embodiments, the crystalline or salt forms described herein may potentially exhibit improved properties. For example, in some embodiments, the crystalline or salt forms described herein may potentially exhibit improved stability. Such improved stability may have a potentially beneficial effect on the preparation of the compounds described herein, such as the ability to provide process intermediates for long-term storage. Improved stability may also be beneficial to compositions of the compounds described herein or pharmaceutical compositions. In some embodiments, the crystalline or salt forms described herein may also potentially lead to increased yields of the compounds described herein, or may result in improved quality of the compounds described herein. In some embodiments, the crystalline, salt, and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.

method

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form I

At approximately 50 to 60 °C, tenofovir alafenamide (approximately 1 g) was mixed with dihydroxynaphthyl acid (approximately 0.4 g) and tetrahydrofuran (approximately 10 mL). The solution was placed in a glass vial with an open cap and allowed to evaporate. The sample was further dried in an oven. The solid was mixed with acetonitrile. Tenofovir alafenamide hemihydroxynaphthyl acid form I was isolated and characterized as described below. It was also found that acetonitrile could be substituted with ethanol, acetone, isopropyl acetate, methyl ethyl ketone, tetrahydrofuran, or toluene to form tenofovir alafenamide hemihydroxynaphthyl acid form I.

In another method for producing tenofovir alafenamide hemi-dihydroxynaphthyl acid form I, tenofovir alafenamide (about 10 g), dihydroxynaphthyl acid (about 4 g), and tetrahydrofuran (about 150 mL) are combined at about 70 °C. The solution is filtered and evaporated. The solid is dissolved in acetone (about 100 mL) at about 40 °C and cooled to about room temperature. Tenofovir alafenamide hemi-dihydroxynaphthyl acid form I seed crystals are added. Tenofovir alafenamide hemi-dihydroxynaphthyl acid form I is isolated and characterized as described below.

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form II

Tenofovir alafenamide hemi-dihydroxynaphthyl salt form I (approximately 100 mg) was mixed with dichloromethane (approximately 1 mL). Tenofovir alafenamide hemi-dihydroxynaphthyl salt form II was isolated and characterized as described below.

Tenofovir alafenamide sebacic acid form I

Tenofovir alafenamide (approximately 1 g) was mixed with sebacic acid (approximately 0.4 g) and acetone (approximately 10 mL). The solution was placed in a glass vial with an open cap and allowed to evaporate. Tenofovir alafenamide sebacic acid form I was isolated and characterized as described below.

Tenofovir alafenamide naphthalene sulfonate form I

Tenofovir alafenamide (approximately 1 g) was mixed with 2-naphthalenesulfonic acid (approximately 0.4 g) and acetone (approximately 10 mL). The solution was placed in a glass vial with an open cap and allowed to evaporate. Tenofovir alafenamide naphthalenesulfonate form I was isolated and characterized as described below.

Tenofovir alafenamide orotate form I

Tenofovir alafenamide (approximately 1 g) was mixed with orotic acid (approximately 0.3 g) and acetone (approximately 10 mL). The solution was placed in a glass vial with an open cap and allowed to evaporate. Tenofovir alafenamide orotic acid form I was isolated and characterized as described below.

Tenofovir alafenamide orotate form II

Tenofovir alafenamide orotate form I was mixed with isopropyl acetate at approximately room temperature for at least 12 hours. Tenofovir alafenamide orotate form II was isolated and characterized as described below. It was also found that tetrahydrofuran, ethyl acetate, or toluene could be used instead of isopropyl acetate to form tenofovir alafenamide orotate form II.

Tenofovir alafenamide orotate form III

Tenofovir alafenamide orotate form I was mixed with water at approximately room temperature for at least 12 hours. Tenofovir alafenamide orotate form III was then isolated and characterized as described below.

Tenofovir alafenamide vanillate

1 g of tenofovir alafenamide free base was dissolved in 10 mL of acetone at 50 °C, filtered, and mixed with 0.35 g (1 equivalent) of vanillic acid to obtain a solution. The solution was stirred overnight at about 21 °C to form a slurry. The slurry was separated by filtration and dried under vacuum at 50 °C.

Tenofovir alafenamide dibenzonatate

4 g of tenofovir alafenamide free base was mixed with 1.5 equivalents of 1-hydroxy-2-naphthoic acid in 10 mL of THF to form a solution, which was dried into a foam at approximately 50 °C in a rotary evaporator. At approximately 21 °C, 200 mg to 500 mg of the resulting solid was stirred in 1 mL of DCM. The sample was evaporated with the cap open, resulting in a thick slurry. The slurry was further evaporated at 57 °C, and crystallized over a period of 16 hours. This crystalline material was used to induce crystallization of solutions of tenofovir alafenamide and 1.5 equivalents of 1-hydroxy-2-naphthoic acid in solvents such as methanol, ethanol, acetone, isopropanol, MIBK, ethyl acetate, isopropyl acetate, and toluene, all of which crystallized in the same form.

Alternatively, dissolve 4 g of tenofovir alafenamide free base in 40 mL of acetone at 50 °C, filter, and add 3.16 g of 1-hydroxy-naphthoic acid (2 equivalents) to form a solution. Dry the solution in a rotary evaporator at 50 °C to form a foam, and then dissolve it in 40 mL of IPAc (isopropyl acetate). Introduce the solution with crystals of tenofovir alafenamide dibenzonaphthoate, sonicate, and a thick slurry will quickly form. Dilute the slurry with 16 mL of IPAc, filter, and dry in a vacuum oven at 50 °C for 3 days.

The crystalline form of the present invention was characterized using various analytical techniques, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), using the methods described below.

X-ray powder diffraction (XRPD): Under the following experimental settings, XRPD patterns were collected on a PANanalyticalXPERT-PRO diffractometer at 45 kV, 40 mA, scanning range 2 to 40°, step size 0.0084 or 0.0167°, and measurement time 5 minutes.

The XRPD spectrum of tenofovir alafenamide hemi-dihydroxynaphthyl salt form I is shown in Figure 1.

The XRPD spectrum of tenofovir alafenamide hemi-dihydroxynaphthyl salt form II is shown in Figure 3.

The XRPD spectrum of tenofovir alafenamide sebacate form I is shown in Figure 5.

The XRPD spectrum of tenofovir alafenamide naphthalene sulfonate form I is shown in Figure 7.

The XRPD spectrum of tenofovir alafenamide orotate form I is shown in Figure 9.

The XRPD spectrum of tenofovir alafenamide orotate form II is shown in Figure 11.

The XRPD spectrum of tenofovir alafenamide orotate form III is shown in Figure 13.

The XRPD spectrum of tenofovir alafenamide vanillate is shown in Figure 15.

The XRPD spectrum of tenofovir alafenamide dibenzonatate is shown in Figure 17.

Differential Scanning Calorimetry (DSC): DSC thermograms were collected on a TA Instruments Q2000 system equipped with a 50-position autosampler. Energy and temperature calibration was performed using certified indium. Typically, 1–5 mg of each sample was heated from 25 °C to 300 °C at 10 °C/min in a pinhole aluminum disk. Throughout the measurement, the sample was purged with dry nitrogen at 50 mL/min. The onset of endothermic melting was reported as the melting point.

The DSC of tenofovir alafenamide hemi-dihydroxynaphthyl salt form I is shown in Figure 2.

The DSC of tenofovir alafenamide hemi-dihydroxynaphthyl salt form II is shown in Figure 4.

The DSC of tenofovir alafenamide sebacate form I is shown in Figure 6.

The DSC of tenofovir alafenamide naphthalene sulfonate form I is shown in Figure 8.

The DSC of tenofovir alafenamide orotate form I is shown in Figure 10.

The DSC of tenofovir alafenamide orotate form II is shown in Figure 12.

The DSC of tenofovir alafenamide orotate form III is shown in Figure 14.

The DSC of tenofovir alafenamide vanillate is shown in Figure 16.

The DSC of tenofovir alafenamide dibenzonatate is shown in Figure 18.

Solubility screening

In a vial containing a pre-weighed solid, deionized water was added in small increments at approximately 22°C. The solid/liquid mixture was stirred using a vortex mixer and kept at room temperature. The addition of deionized water was continued and mixing was repeated until the solid was completely dissolved. The solubility of various salts was measured using the method described above, and the values are shown in Table 2 below.

Table 2

Salt form solubility TAF hemi-dihydroxynaphthyl acid salt 0.15 mg/mL TAF sebacate 0.7 mg/mL TAF naphthalenesulfonate 7mg/mL TAF orotate 1.7 mg/mL TAF vanillic acid salt 1.6 mg/mL TAF dibenzoate 0.2 mg/mL TAF hemifumarate (control) 20mg/mL

The lower solubility of the salt form (compared to hemifumarate) provides an extended release duration corresponding to long-acting formulations.

Each reference, including all patents, patent applications, and publications cited in this application, is incorporated herein by reference in its entirety as if each of them were individually incorporated. Furthermore, it will be understood that, given the foregoing teachings of this invention, those skilled in the art may make certain changes or modifications to the invention, and such equivalents shall still be within the scope of the invention as defined by the appended claims.

Claims (76)

1. Tenofovir alafenamide hemi-dihydroxynaphthyl salt; Tenofovir alafenamide sebacic acid; Tenofovir alafenamide naphthalenesulfonate; or Tenofovir alafenamide orotate. 2. The tenofovir alafenamide hemi-dihydroxynaphthyl salt as described in claim 1. 3. The crystalline form of claim 2, wherein the crystalline form is tenofovir alafenamide hemi-dihydroxynaphthyl salt form I. 4. The crystalline form according to claim 3, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 7.4°, 8.4°, 10.6°, 14.8° and 22.3°2-θ ± 0.2°2-θ. 5. The crystalline form of claim 4, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 17.4°, 19.0°, 20.1°, 23.8°, and 25.7°2-θ ± 0.2°2-θ. 6. The crystalline form of claim 5, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 11.2°, 13.1°, 13.8°, 15.8°, 21.0°, and 28.8°2-θ ± 0.2°2-θ. 7. The crystalline form according to any one of claims 3-5, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 1. 8. The crystalline form according to any one of claims 3-6, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 2. 9. The crystalline form of claim 2, wherein the crystalline form is tenofovir alafenamide hemi-dihydroxynaphthyl salt form II. 10. The crystalline form according to claim 9, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 5.5°, 10.9°, 16.2°, 22.1°, and 23.2°2-θ ± 0.2°2-θ. 11. The crystalline form of claim 9, wherein the X-ray powder diffraction (XRPD) pattern has an additional peak at approximately 24.1°2-θ ± 0.2°2-θ. 12. The crystalline form according to any one of claims 9-11, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 3. 13. The crystalline form according to any one of claims 9-12, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 4. 14. The tenofovir alafenamide sebacic acid salt as claimed in claim 1. 15. The crystalline form of claim 14, wherein the crystalline form is tenofovir alafenamide sebacate form I. 16. The crystalline form of claim 15, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 5.3°, 6.6°, 9.4°, 9.6° and 19.8°2-θ ± 0.2°2-θ. 17. The crystalline form of claim 16, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 14.8°, 15.7°, 18.7°, 19.3°, and 22.1°2-θ ± 0.2°2-θ. 18. The crystalline form of claim 17, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 11.7°, 12.6°, 20.9°, 23.4°, 23.8°, 26.2°, 28.2°, and 29.0°2-θ ± 0.2°2-θ. 19. The crystalline form according to any one of claims 15-18, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 5. 20. The crystalline form according to any one of claims 15-19, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 6. 21. The tenofovir alafenamide naphthalene sulfonate according to claim 1. 22. The crystalline form of claim 21, wherein the crystalline form is tenofovir alafenamide naphthalene sulfonate form I. 23. The crystalline form of claim 22, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 3.9°, 7.8°, 13.6°, 15.3° and 19.2°2-θ ± 0.2°2-θ. 24. The crystalline form of claim 23, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 19.4°, 19.8°, 20.6°, 23.8°, and 27.2°2-θ ± 0.2°2-θ. 25. The crystalline form of claim 24, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 9.8°, 13.2°, 15.5°, 16.5°, 17.8°, 23.0°, 24.1°, and 26.0°2-θ ± 0.2°2-θ. 26. The crystalline form according to any one of claims 22-25, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 7. 27. The crystalline form according to any one of claims 23-26, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 8. 28. The tenofovir alafenamide orotate as claimed in claim 1. 29. The crystalline form of claim 28, wherein the crystalline form is tenofovir alafenamide orotate form I. 30. The crystalline form of claim 29, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 3.0°, 5.9°, 8.9°, and 11.8°2-θ ± 0.2°2-θ. 31. The crystalline form of claim 30, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 14.8°, 16.0°, 17.7°, 18.7°, and 21.5°2-θ ± 0.2°2-θ. 32. The crystalline form according to any one of claims 29-31, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 9. 33. The crystalline form according to any one of claims 29-32, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 10. 34. The crystalline form of claim 28, wherein the crystalline form is tenofovir alafenamide orotate form II. 35. The crystalline form of claim 34, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 3.4°, 6.9°, 10.3°, and 13.8°2-θ ± 0.2°2-θ. 36. The crystalline form of claim 35, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 15.4°, 17.3°, 19.0°, 22.8°, and 29.0°2-θ ± 0.2°2-θ. 37. The crystalline form of claim 36, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 18.4° and 21.6°2-θ ± 0.2°2-θ. 38. The crystalline form according to any one of claims 34-37, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 11. 39. The crystalline form according to any one of claims 34-38, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 12. 40. The crystalline form of claim 28, wherein the crystalline form is tenofovir alafenamide orotate form III. 41. The crystalline form of claim 40, characterized in that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 3.8°, 9.4°, 12.4°, 15.7° and 19.0°2-θ ± 0.2°2-θ. 42. The crystalline form of claim 41, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 8.3°, 16.4°, 24.5°, 26.6°, and 28.9°2-θ ± 0.2°2-θ. 43. The crystalline form of claim 42, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at approximately 6.9°, 22.8°, and 27.6°2-θ ± 0.2°2-θ. 44. The crystalline form according to any one of claims 40-43, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 13. 45. The crystalline form according to any one of claims 40-43, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 14. 46. A pharmaceutical composition comprising a therapeutically effective amount of the form of any one of claims 1-45 and a pharmaceutically acceptable excipient. 47. The pharmaceutical composition of claim 46, further comprising one to three additional therapeutic agents. 48. The pharmaceutical composition of claim 47, wherein the additional therapeutic agent each has anti-HIV activity. 49. The pharmaceutical composition of any one of claims 46-48, wherein the pharmaceutical composition is in unit dose form. 50. The pharmaceutical composition of claim 49, wherein the unit dose form is a subcutaneous injection. 51. A pharmaceutical composition prepared by combining a therapeutically effective amount of the form of any one of claims 1-45 with a pharmaceutically acceptable excipient. 52. Use in any of the forms of claims 1-45 for the treatment of HIV infection. 53. A method for treating viral infection in humans, the method comprising administering a therapeutically effective amount, in any one of claims 1-47, to a person in need. 54. The method of claim 53 for treating a viral infection in a human being, wherein the viral infection is caused by HIV. 55. The form of any one of claims 1-45, used in a method for treating an infection caused by HIV. 56. Tenofovir alafenamide vanillate; or Tenofovir alafenamide dibenzonatate. 57. The crystalline form of claim 56, wherein the crystalline form is tenofovir alafenamide vanillate. 58. The crystalline form of claim 57, characterized in that the X-ray powder diffraction pattern has peaks at approximately 6.6°, 9.3°, 14.2°, 15.2°, 19.0° and 22.8°2-θ±0.2°2-θ. 59. The crystalline form of claim 57, characterized in that the X-ray powder diffraction pattern has peaks at approximately 10.8°, 12.3°, 18.4°, 19.8°, 22.1°, 25.0° and 32.4°2-θ±0.2°2-θ. 60. The crystalline form according to any one of claims 56-59, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 15. 61. The crystalline form according to any one of claims 56-60, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 16. 62. The crystalline form of claim 56, wherein the crystalline form is tenofovir alafenamide dibenzonatate. 63. The crystalline form according to claim 62, characterized in that the X-ray powder diffraction pattern has peaks at approximately 4.5°, 8.9°, 11.2°, 14.4°, 15.4°, 18.8°, 21.7° and 25.5°2-θ±0.2°2-θ. 64. The crystalline form according to claim 62, characterized in that the X-ray powder diffraction pattern has peaks at approximately 7.7°, 14.7°, 21.9°, 25.9°, 32.9°, 33.8° and 36.5°2-θ±0.2°2-θ. 65. The crystalline form according to any one of claims 62-64, characterized in that the X-ray powder diffraction (XRPD) pattern is substantially as shown in Figure 17. 66. The crystalline form according to any one of claims 62-65, characterized in that the differential scanning calorimetry (DSC) spectrum is substantially as shown in Figure 18. 67. A pharmaceutical composition comprising a therapeutically effective amount of the form of any one of claims 56-66 and a pharmaceutically acceptable excipient. 68. The pharmaceutical composition of claim 67, further comprising one to three additional therapeutic agents. 69. The pharmaceutical composition of claim 68, wherein the additional therapeutic agent each has anti-HIV activity. 70. The pharmaceutical composition of any one of claims 56-66, wherein the pharmaceutical composition is in unit dose form. 71. The pharmaceutical composition of claim 70, wherein the unit dose form is a subcutaneous injection. 72. A pharmaceutical composition prepared by combining a therapeutically effective amount of any one of claims 56-66 with a pharmaceutically acceptable excipient. 73. Use in any of the forms of claims 56-66 for the treatment of HIV infection. 74. A method for treating viral infection in humans, the method comprising administering a therapeutically effective amount, in any one of claims 56-66, to a person in need. 75. The method of claim 74 for treating a viral infection in a human being, wherein the viral infection is caused by HIV. 76. The form of any one of claims 56-66, used in a method for treating an infection caused by HIV.