OA18760A

OA18760A - Sodium (2R, 5S, 13AR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13Aoctrahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1B] oxazepin-8-olate.

Info

Publication number: OA18760A
Application number: OA1201600454
Authority: OA
Inventors: Vahid Zia; Ernest A. Carra; Irene Chen
Original assignee: Gilead Sciences, Inc.
Priority date: 2014-06-20
Filing date: 2015-06-19
Publication date: 2019-06-28

Abstract

The present invention relates to sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13aoctahydro-2,5methanopyrido[1’,2':4,5]pyrazino[2,1b][1,3]oxazepin-8-olate Form I.

Description

SODIUM (2R»5S, 13 AR)-7,9-DIOXO-10-((2,4,6-TRIFLUOROBENZYL)CARBAMOYL)-

2,3,4,5,7,9,13,13 A-OCTAHYDRO-2,5-METHANOPYRIDO[ 1 ',2':4,5]PYRAZINO[2,1 -

B][l,3]OXAZEPIN-8-OLATE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application daims priority to and the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application Serial No. 62/015,245, fîled June 20, 2014, the disclosure of which is hereby incorporated by référénce in its entirety.

FIELD

[0002] The present invention relates to sodium (2R,5 S, 13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, the crystalline forms, the pharmaceutical formulations, and the therapeutic uses thereof.

BACKGROUND

[0003] Human immunodefîciency virus infection and related diseases are a major public health problem worldwide. Human immunodefîciency virus type I (HIV-1) encodes three enzymes which are required for virai réplication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and hâve shown effectiveness, particuiarly when employed in combination, toxicity and development of résistant strains hâve limited their usefulness (Palella, et al. /V. Engl. .1 Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).

[0004] A goal of antirétroviral therapy is to achieve viral suppression in the HIV infected patient. Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination thérapies, i.e., several drugs from at least two or more drug classes. In addition, decisions regarding the treatment of HIV infected patients are complicated when the patient requires treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HTV, as well as to treat other conditions the patient may be experiencing, the potential for drug interaction is a criterion for sélection of a drug regimen. As such, there is a need for antirétroviral thérapies having a decreased potential for drug interactions.

[0005] As discussed in co-pending application United States Serial No. 14/133,855, fded December 19, 2013 entitled “POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE”, (2R,5S,13aR)-8-hydroxy-7,9dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[ 1 ’,2':4,5]pyrazino[2,1 -b][ l,3]oxazepine-10-carboxamide demonstrates antiviral activity. As discussed in co-pending application PCT Serial No. US2013/076367, filed December 19, 2013 entitled “POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE”, (2R,5S, 13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ l',2':4,5]pyrazino[2,1 -

b] [ 1,3 ]oxazepi ne-10-carboxamide demonstrates anti-viral activity.

[0006] (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepine-10carboxamide, (Formula I), has the following structure:

(D

[0007] It is desired to hâve physically stable forms of the compound that are suitable for the therapeutic use and the manufacturing process.

BRIEF SUMMARY

[0008] In certain embodiments, the présent invention is directed to sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, having the following structure (Formula II):

[0009] In a still further embodiment, the présent invention is directed to crystalline sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13aoctahydro-2,5-methanopyrido[r,2^,:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate.

[0010] In a still further embodiment, the présent invention is directed to sodium (2R.5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I.

[0011] In a certain embodiment, the présent invention is directed to pharmaceutical formulations comprising sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyridof 1 ',2':4,5]pyrazino[2,1 -b][ l,3]oxazepin-8-olate.

[0012] In another embodiment, the présent invention is directed to methods of treating or prophylactically preventing an HIV infection by administering sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[ 1 ',2’:4,5]pyrazino[2, l-b][ 1,3]oxazepin-8-olate.

[0013] In another embodiment, the présent invention is directed to sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyi)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate for use in methods of treating or prophylactically preventing an HIV infection.

[0014] In another embodiment, the présent invention is directed to the use of sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trif!uorobenzyl )carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[r,2’:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate in the manufacture of a médicament for treating or prophylactically preventing an HIV infection.

DESCRIPTION OF THE FIGURES

[0015] Figure 1: XRPD pattern for sodium (2R,5S,13aR)-7,9-dioxo-l0-((2,4,6

J trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,l3,I3a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I.

[0016] FigureZ: DSCforsodium(2R,5S,l3aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9, 13,13a-octahydro-2,5methanopyrido[ r,2':4,5]pyrazino[2,1 -b] [ 1,3]oxazepin-8-olate Form I.

[0017] Figure 3: TGAforsodium(2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9, 13,13a-octahydro-2,5methanopyridof 1 ',2':4,5]pyrazino[2,1-b][ 1,3]oxazepin-8-olate Form I.

[0018] Figure 4: DVS for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[I',2':4,5]pyrazino[2J-b][l,3]oxazepin-8-olate Form I.

[0019] Figure 5: Dissolution profiles of Formula I Form l, Formula I Form III, and Formula II Form I

[0020] Figure 6: Solubility profiles of Formula I Form III and Formula II Form I in Fasted-State Simulated Gastric Fluid (FaSSGF).

[0021] Figure 7: Solubility profiles of Formula I Form III and Formula II Form I in Fed-State Simulated Intestinal Fluid (FeSSIF) and Fasted-State Simulated Intestinal Fluid (FaSSIF).

[0022] Figure 8: Calculated and Experimental XRPD pattern for sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl )carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[ 1 ',2’:4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate Form 1.

DETAILED DESCRIPTION

[0023] In the following description, certain spécifie details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. The description beiow of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended daims to the spécifie embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limît the daims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

Définitions

[0024] Unless the context requires otherwise, throughout the présent spécification and daims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to”.

[0025] Reference throughout this spécification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the présent invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment’ in various places throughout this spécification are not necessarily ail referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0026] The invention disclosed herein is also meant to encompass ail pharmaceutically acceptable compounds of Formulas (I) and (II) being isotopically-Iabeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ^hC, ⁱ³C, ¹⁴C, ¹³N, ^l5N, ^!5O, ⁱ⁷O, ^l80,³¹ P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ^I23I, and ¹²⁵I, respectively. These radiolabeled compounds could be useful to help détermine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affînity to pharmacologically important site of action. Certain isotopically-Iabeled compounds of Formulas (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium,

i.e. ³H, and carbon-14, i.e. ^I4C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection.

[0027] Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting ffom greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.

[0028] Substitution with positron emitting isotopes, such as ^!1C, ^l8F, ^l5O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formulas (I) and (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0029] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0030] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0031 ] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonie agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animais.

[0032] A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes ail pharmaceutically acceptable carriers, diluents or excipients therefor.

[0033] “Effective amount” or “therapeutically effective amount” refers to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufïicient to effect treatment for disease-states, conditions, or disorders for which the compounds hâve utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue System, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excrétion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the âge, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0034] The term treatment as used herein is intended to mean the administration of a compound or composition according to the présent invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient. The term treatment also encompasses the administration of a compound or composition according to the présent invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the détection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the présent invention to prevent périnatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. In certain embodiments, the term treatment as used herein is intended to mean the administration of a compound or composition according to the présent invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient In certain embodiments, the term “treatment” as used herein is further or alternatively intended to mean the administration of a compound or composition according to the présent invention to maintain a reduced viral load in a patient. The term treatment also encompasses the administration of a compound or composition according to the présent invention postexposure of the individual to the virus but before the appearance of symptoms of the disease; and/or prior to the détection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the présent invention to prevent périnatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. In certain embodiments, the term “treatment” as used herein is further or alternatively intended to mean the administration of a compound or composition according to the présent invention post-exposure of the individual to the virus as a subséquent or additional therapy to a first-line therapy (e.g., for maintenance of low viral load).

[0035] “Prévention” or “preventing” means any treatment of a disease or condition that causes the clinicai symptoms of the disease or condition not to develop. The terni prévention also encompasses the administration of a compound or composition according to the présent invention pre-exposure of the individual to the virus (e.g., pre-exposure prophylaxis), to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood.

[0036] The ternis “Subject” or “patient” refer to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal (or the patient). In some embodiments the subject (or the patient) is human, domestic animais (e.g., dogs and cats), farm animais (e.g., cattle, horses, sheep, goats and pigs), and/or laboratory animais (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In one embodiment, the subject (or the patient) is a human. “Human (or patient) in need thereof’ refers to a human who may hâve or is suspect to hâve diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the présent application.

[0037] The term antiviral agent as used herein is intended to mean an agent (compound or biological) that is effective to inhibit the formation and/or réplication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or réplication of a virus in a human being.

[0038] The tenu inhibitor of HIV réplication as used herein is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.

[0039] A “tautomer” refers to a proton shift from one atom of a molécule to another atom of the same molécule. The présent invention includes tautomers of any said compounds.

[0040] Référencé to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. Also, the singular forms a and the include plural référencés unless the context clearly dictâtes otherwise. Thus, e.g., référencé to the compound includes a plurality of such compounds and référencé to the assay includes référencé to one or more assays and équivalents thereof known to those skilled in the art.

[0041 ] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0042] “Unit dosage forms” are physically discrète units suitable as unitary dosages for subjects (e.g., human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

Crystalline Form

Formula II

[0043] It is désirable to develop a crystalline form of sodium (2R.5S, 13 aR)-7,9dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyi)-2,3,4,5,7,9, !3,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate that may be useful in the synthesisof sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ l ’,2':4,5]pyrazino[2, l -b][ l ,3 ]oxazepin-8olate. Aform of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate may be an intermediate to the synthesis of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate. Aform ofsodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoy 1)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[r,2^,:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate may be the final product in the synthesis of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrîdo[ l',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate. A polymorphie form or polymorph or cocrystal may hâve properties such as bioavailabilîty and stability at certain conditions that may be suitable for medical or pharmaceutical uses.

[0044] A crystalline form of sodium (2R.5S, 13aR)-7,9-dioxo-10-((2,4,6 trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,l3a-octahydro-2,5methanopyrido[l^l.2^,:4,5]pyrazino[2J -b][l ,3]oxazepin-8-olate may provide the advantage of bioavailability and stability, suitable for use as an active ingrédient in a pharmaceutical composition. In certain embodiments, a crystalline form sodium (2R,5S,13aR)-7,9-dioxo-10((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4). Variations in the crystal structure of a pharmaceutical drug substance or active ingrédient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently préparé doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingrédient. Such variations may affect the préparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as soîid oral dosage form including tablets and capsules. Compared to other forms such as non-crystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicity, particle size Controls, dissolution rate, solubility, purity, physical and Chemical stability, manufacturability, yield, and/or process control. Thus, crystalline forms of sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13aoctahydro-2,5-methanopyrido[ 1 ’,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate may provide advantages such as: improving the manufacturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingrédient, and/or having suitable bioavailability and/or stability as an active agent.

[0045] The use of certain solvents has been found to produce different polymorphie forms of sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate, including polymorphie Form I, which may exhibit one or more favorable characteristics described above. In certain embodiments, Form I of sodium (2R,5S,l3aR)-7,9-dioxo-10((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4). The processes for the préparation ofthe poiymorphs described herein and characterization ofthese polymorphs are described in greater detail below.

[0046] The compound name provided above is named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature Systems and symbols. By way of example, the compound may be named or identified with common names, systematic or nonsystematic names. The nomenclature Systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordîngly, the compound structure provided above may be named or identified as sodium (2R,5S,!3aR)-7,9-dioxo-lO((2,4,6-tri fluorobenzyl)carbamoyl )-2,3,4,5,7,9,13,13 a-octahydro-2,5methanopyrido[r,2’:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate under IUPAC.

[0047] In particular embodiments, crystalline forms of sodium (2R,5S, !3aR)-7,9dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[ l ',2':4,5]pyrazino[2, l -b][l ,3]oxazepin-8-olate are disclosed.

Formula II, Form I

[0048] In a certain embodiment, novel forms of sodium (2R,5S,l3aR)-7,9-dioxo-lO((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13, l3a-octahydro-2,5methanopyrido[ i',2^,:4,5]pyrazino[2,1-bj[l,3]oxazepin-8-olate, having the following structure (Formula II) are disclosed:

[0049] In a further embodiment, crystalline forms of sodium (2R,5S,l3aR)-7,9-dioxo10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2, l-b][l,3]oxazepin-8-olate are disclosed.

[0050] In a certain embodiment, sodium (2R,5S,l3aR)-7,9-dioxo-l 0-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I is disclosed.

[0051] In one embodiment, provided is polymorphie Form 1 of sodium (2R,5S,13aR)7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5 methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, wherein the poiymorph exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. I and/or FIG. 8. Polymorphie sodium Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG 2. Polymorphie sodium Form I may exhibit a thermographie analysis (TGA) graph substantially as shown in FIG. 3. Polymorphie sodium Form I may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIG 4.

[0052] The term “substantially as shown in” when referring, for example, to an XRPD pattern, a DSC thermogram, or a TGA graph includes a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental eiror or déviations when considered by one of ordinary skill in the art.

[0053] Polymorphie sodium Form I may hâve a unit cell as determined by crystal Xray crystallography of the following dimensions: a = 8.9561 (10) Â; b = 13.9202 (14) Â; c = 31.115 (3) Â; a = 90°; β = 90 °; and γ = 90 °.

[0054] In some embodiments of polymorphie sodium Form I, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or ail of the following (a)-(j) apply: (a) polymorphie Form I has an XRPD pattern substantially as shown in FIG 1 and/or FIG. 8; (b) polymorphie sodium Form I has a DSC thermogram substantially as shown in FIG 2; (c) polymorphie sodium Form I has a TGA graph substantially as shown in FIG. 3; (d) polymorphie sodium Form I has DVS graphs substantially as shown in FIG. 4, (e) polymorphie sodium Form I has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 8.9561 (10) Â; b = 13.9202 (14) Â; c = 31.115 (3) Â; a = 90 β = 90 °; and γ = 90 °; (f) polymorphie sodium Form I has an orthorhombic crystal System; (g) polymorphie sodium Form I has a P212121 space group; (h) polymorphie sodium Form I has a volume of 3879.2(7) Â³; (i) polymorphie Form I has a Z value of 4; and (j) polymorphie Form I has a density of 1 614 Mg/m³.

[0055] In some embodiments, polymorphie sodium Form I has at least one, at least two, at least three, at least four, or ail of the following properties:

a. an XRPD pattern substantially as shown in FIG. 1 and/or FIG.

8,

b. a DSC thermogram substantially as shown in FIG. 2;

c. TGA graphs substantially as shown in FIG 3;

d. DVS graphs substantially as shown in FIG 4; and

e. a unit cell, as determined by crystal X-ray crystallography, of the following dimensions a = 8.9561 (10) Â; b = 13.9202 (14) A; c = 31.115 (3) A; a = 90 β = 90 °; and γ = 90

[0056] In some embodiments, polymorphie sodium Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 20-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG and/or FIG 8.

[0057] In certain embodiments, polymorphie sodium Form I has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 20) at 5.5, 16.1, and 23.3. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20reflections (+/- 0.2 degrees 20) at 5.5, 16.1, and 23,3 and one or more of the degree 20reflections (+/- 0.2 degrees 20) at 22.1, 28.5, and 22.5. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 20) at

5.5, 16.1, and 23.3 and one of the degree 29-reflections (+/- 0.2 degrees 20) at 22.1, 28.5, and

22.5, In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 20) at 5.5, 16.1, and 23.3 and two of the degree 20reflections (+/- 0.2 degrees 20) at 22.1, 28.5, and 22.5. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 20) at

5.5, 16.1, and 23.3 and three ofthe degree 20-reflections (+/- 0.2 degrees 20) at 22.1, 28.5, and 22.5. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 20) at 5.5, 16.1, 23.3, 22.1, 28.5, and 22.5. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising degree 20reflections (+/- 0.2 degrees 20) at 5.5, 16.1, 23.3, 22.1, 28.5, 22.5, 19.5, and 26.6. In one embodiment, polymorphie sodium Form I has an XRPD pattern comprising any three degree 20-reflections (+/- 0.2 degrees 20) selected from the group consisting of 5.5, 16.1, 23.3, 22.1,

28.5, 22.5, 19.5, 26.6, and 17.9.

Pharmaceutical Compositions

[0058] For the purposes of administration, in certain embodiments, the compounds described herein are administered as a raw Chemical or are formulated as pharmaceutical compositions. Pharmaceutical compositions ofthe présent invention comprise a compound of Formula (Π), including forms and co-crystals thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The compound of Formula (II) is présent in the composition in an amount which is effective to treat a particular disease or condition of interest. The activity of compounds of Formula (II) can be determined by one skilled in the art, for example, as described in co-pending application Serial No. 14/133,855, filed December 19, 2013 entitled “POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE”. The activity of compounds of Formula (II) can also be determined by one skilled on the art, for example, as described in co-pending PCT Serial No. US2013/076367, filed December 19, 2013 entitled, “POLYCYCLICCARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE.” Appropriate concentrations and dosages can be readily determined by one skilled in the art. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount from about 25 mg to about 500 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount of about 100 mg to about 300 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition ïn an amount of about 5 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount of about 25 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount of about 50 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is présent in the pharmaceutical composition in an amount of about 5 mg, 25 mg, 50 mg, 75, mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg.

Formula I!

[0059] Provided are also compositions comprising at least one polymorph (e.g., any one or more of Formula II polymorphie Forms I) as described herein. In a particular embodiment, a composition comprising Formula Π polymorphie Form I, described herein is provided. In other embodiments, the compositions described herein may comprise substantially pure polymorphie forms, or may be substantially free of other polymorphe and/or impurities.

[0060] In some embodiments, the composition comprises a polymorphie form of sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyi)-2,3,4,5,7,9,13,l3aoctahydro-2,5-methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate. In certain embodiments are provided compositions comprising a polymorphie form as described herein, wherein the sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ l',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate within the composition is substantially pure (Àe., substantially pure Form I). In particular embodiments of compositions comprising a polymorphie form of sodium (2R,5 S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[l^,,2':4.5]pyrazino[2,l-b][l,3]oxazepin-8-olate, 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 sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b] [ 1,3]oxazepin-8olate présent in the composition is Formula II, Form I, disclosed herein. In certain embodiments, the composition includes 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 Form I of sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate.

[0061] In other embodiments of compositions comprising a polymorphie 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 sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate présent in the composition are other polymorphs of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2’:4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate and/or impurities.

[0062] In yet other embodiments of compositions comprising the polymorphie forms disclosed herein, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about l% of the total mass relative to the mass of the polymorphie forms présent. Impurities may, for example, include by-products from synthesizing sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ’,2':4,5]pyrazino[2, l-b][ I,3]oxazepin-8olate, contaminants, dégradation products, other polymorphie forms, amorphous form, water, and solvents. In certain embodiments, impurities include by-products from the process of synthesizing sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8oiate. In certain embodiments, impurities include contaminants from the process of synthesizing sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ l',2’:4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate. In certain embodiments, impurities include dégradation products of sodium (2R,5 S, 13aR)-7,9-dioxo-10-((2,4,6-trif1uorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate. In certain embodiments, impurities include other polymorphie forms of sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,I3a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising a polymorphie form disclosed herein, impurities are selected from the group consisting of byproducts from synthesizing sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyI)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, contaminants, dégradation products, other polymorphie forms, water, solvents and combinations thereof.

[0063] In yet other embodiments, the composition comprising Formula II, Form I disclosed herein has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline sodium (2R,5S,13aR)-7,9-dioxo-I0-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[ 1 ',2’:4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate.

[0064] In some embodiments, the terni “substantially pure” or “substantially free” with respect to a particular polymorphie form of a compound means that the composition comprising the polymorphie form contains less than 95%, less than 90%, less than 80%, 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 polymorphie forms and/or impurîties. In certain embodiments, “substantially pure” or “substantially free of ’ refers to a substance free of other substances, including other polymorphie forms and/or impurîties. Impurîties may, for example, include by-products or left over reagents from Chemical reactions, contaminants, dégradation products, other polymorphie forms, water, and solvents.

Administration

[0065] Administration of the compounds disclosed herein in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions described herein can be prepared by combining a compound disclosed herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into préparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aérosols. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into préparations in solid, semi-solid, liquid or gaseous forms, such as solid dispersions and solid solutions. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parentéral, sublingual, buccal, rectal, vaginal, and intranasal. In one embodiment, the pharmaceutical compositions is prepared for oral administration. In a spécifie embodiment, the pharmaceutical compositions is a tablet. Pharmaceutical compositions of the invention are formulated so as to ailow the active ingrédients contained therein to be bioavaiiable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice qfPharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention for treatment of a disease or condition of interest in accordance with the teachings of this disclosure.

[0066] The pharmaceutical compositions disclosed herein may be prepared by methodoiogy well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with stérile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension.

Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.

[0067] For example, a solid pharmaceutical composition intended for oral administration can be prepared by mixing a compound ofthe invention with at least one suitable pharmaceutical excipient to form a solid preformulation composition, which then may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Accordîngly, in one embodiment, a pharmaceutical composition is provided, which includes a compound of Formula (II) and a pharmaceutical excipient.

[0068] The compounds disclosed herein are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity ofthe spécifie compound employed; the metabolic stability and length of action of the compound; the âge, body weight, general health, sex, and diet of the patient; the mode and time ofadministration; the rate ofexcrétion; the drug combination; the severity ofthe particular disorder or condition; and the subject undergoing therapy. In some embodiments, the compounds of the invention can be administered alone or in combination with other antiviral agents once or twice daily for as long as the patient is infected, latently infected, or to prevent infection (e.g. for multiple years, months, weeks, or days).

Combination Therapy

[0069] In one embodiment, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with 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 an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0070] In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0071] In certain embodiments, the présent invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.

[0072] One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating or preventing an HIV infection in a human having or at risk of having the infection. One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating an HIV infection in a human having or at risk of having the infection. One embodiment provides a compound disclosed herein for use in a method for treating or preventing an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. One embodiment provides a compound disclosed herein for use in a method for treating an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In certain embodiments, the présent invention provides a compound disclosed herein in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection, for use in a method for treating an HIV infection. In certain embodiments, the présent invention provides a compound disclosed herein for use in a method for treatîng an HIV infection, wherein the compound is administered in combination with one or more additional therapeutic agents which are suîtabîe for treating an HTV infection.

[0073] One embodiment provides the use of a compound disclosed herein thereof, in combination with one or more (e.g., one, two, three, one ortwo, or one to three) additional therapeutic agents in the manufacture of a médicament for treating or preventing an HIV infection in a human having or at risk of having the infection. One embodiment provides the use of a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a médicament for treating an HIV infection in a human having or at risk of having the infection. One embodiment provides the use of a compound disclosed herein in the manufacture of a médicament for treating or preventing an HTV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. One embodiment provides the use of a compound disclosed herein thereof, in the manufacture of a médicament for treating an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In certain embodiments, the présent invention provides the use of a compound disclosed herein thereof, in combination with one or more additional therapeutic agents which are suitable for treating an HTV infection, in treating an HIV infection. In certain embodiments, the présent invention provides the use of a compound disclosed herein thereof for treating an HIV infection, wherein the compound is administered in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection.

[0074] A compound as disclosed herein (e.g., any compound of Formula (II)) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula II (e.g., from 50 mg to 1000 mg of compound).

[0075] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.

[0076] In one embodiment, combination pharmaceutical agents comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided

[0077] In one embodiment, kits comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.

[0078] In the above embodiments, the additional therapeutic agent may be an antiHIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytîc site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4l inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV capsid (“capsid inhibitors”, e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0079] In other embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADHoxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, protéasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors), compounds that target the HIV capsid (“capsid inhibitors”; e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based thérapies (e.g., Pd-1 modulators, Pd-Ll modulators, toll like receptors modulators,, IL-15 agonists, ), HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab dérivatives) including those targeting HIV gpl20 or gp41, combination drugs for HIV, HIV pi7 matrix protein inhibitors, IL-13 antagonists, Peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfide isomerase inhibitors, Complément C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity 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 Ribonucléase H inhibitors, Retrocyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complément Factor H modulators, Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors, Cyclin dépendent kinase inhibitors Proprotein convertase PC9 stimulators, ATP dépendent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, HIV gene therapy, PI3K inhibitors, compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), W02014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources), and other drugs for treating HIV, and combinations thereof.

[0080] In certain embodiments, the additional therapeutic is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytîc site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0081] In certain embodiments a compound of Formula (II) is formulated as a tablet, which may optionally contain one or more other compounds usefiil for treating HIV In certain embodiments, the tablet can contain another active ingrédient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or aliosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof. In certain embodiments, the tablet can contain one or more active ingrédients for treating HIV, such as HIV nucleoside or nucléotide inhibitors of reverse transcriptase. In certain embodiments, such tablets are suitable for once daily dosing.

[0082] In further embodiments, the additional therapeutic agent is selected from one or more of:

(1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE2147 (AGI 776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DGI 7, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirine, BILR 355 BS, VRX 840773, lersivirine (UK453061), RDEA806, KM023 and MK-1439;

(3) HIV nucleoside or nucléotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxîl, apricitibine (AVX754), KP-1461, GS-9131 (Gilead Sciences), fosalvudine tidoxil (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate (Gilead Sciences), GS7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) and CMX-157 (Chimerix);

(4) HTV integrase inhibitors selected from the group consisting of curcumin, dérivatives of curcumin, chicoric acid, dérivatives of chicoric acid, 3,5dicaffeoylquinic acid, dérivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, dérivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, dérivatives of caffeic acid phenethyl ester, tyrphostin, dérivatives of tyrphostin, quercetin, dérivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir, dolutegravir sodium, and GSK-744;

(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCIN1) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WG 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by référencés in its entirety herein;

(7) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(8) the CXCR4 inhibitor AMD-070;

(9) the entry inhibitor SP01 A;

(10) the gpl20 inhibitor BMS-488043;

(11) the G6PD and NADH-oxidase inhibitor immunitin;

(12) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15O5O, PF-232798 (Pfizer), and CCR5mAb004;

(13) CD4 attachaient inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068), (14) pharmacokinetic enhancers selected from the group consisting of cobicistat and SPI-452; and (15) other drugs for treating HIV selected from the group consisting of BAS-100, SPI452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX0I0 (ipilimumab), PBS 119, ALG 889, and PA1050040 (PA-040), and combinations thereof.

[0083] In certain embodiments, the additional therapeutic agent is selected from one or more of:

(1) Combination drugs selected from the group consisting of ATRIPLA® (efavirenz+tenofovir disoproxil fumarate +emtricitabine), COMPLERA® or EVIPLERA® (rilpivirine+tenofovir disoproxil fumarate +emtricitabine), STRIBILD® (elvitegravir+cobicistat+tenofovir disoproxil fumarate +emtricitabine), dolutegravir + abacavir sulfate +lamivudine, TRIUMEQ® (dolutegravir + abacavir + lamivudine), lamivudine + nevirapine + zidovudine, dolutegravir+rilpivirine, dolutegravir+rilpivirine hydrochloride, atazanavir sulfate + cobicistat, atazanavir + cobicistat, darunavir + cobicistat, efavirenz + lamivudine + tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate + emtricitabine + cobicistat + elvitegravir, tenofovir alafenamide hemifumarate + emtricitabine, tenofovir alafenamide + emtricitabine, tenofovir alafenamide hemifumarate + emtricitabine + rilpivirine, tenofovir alafenamide + emtricitabine + rilpivirine , Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate+ emtricitabine + cobicistat, APH-0812, raltegravir + lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir), atazanavir sulfate + ritonavir, COMBIVIR® (zidovudine+lamivudine, AZT+3TC), EPZICOM® (Kivexa®, abacavir sulfate Hamivudine, ABC+3TC), TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovir disoproxil fumarate +emtricitabine, TDF+FTC), doravirine + lamivudine + tenofovir disoproxil fumarate, doravirine + lamivudine + tenofovir disoproxil, tenofovir + lamivudine and lamivudine + tenofovir disoproxil fumarate;

(2) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;

(3) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, rilpivirine, efavirenz, K.M-023, VM-1500, lentinan and AIC-

292;

(4) HTV nucleoside or nucléotide inhibitors of reverse transcriptase selected from the group consisting of VIDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil, and festinavir;

(5) HIV integrase inhibitors selected from the group consisting of curcumin, dérivatives of curcumin, chicoric acid, dérivatives of chicoric acid, 3,5dicaffeoylquinic acid, dérivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, dérivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, dérivatives of caffeic acid phenethyl ester, tyrphostin, dérivatives of tyrphostin, quercetin, dérivatives of quercetin, raltegravir, elvitegravir, dolutegravir and cabotegravir, (6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) selected from the group consisting of CX-05168, CX-05045 and CX-14442;

(7) HIV gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide and albuvirtide;

(8) HIV entry inhibitors selected from the group consisting of cenicriviroc;

(9) HIV gpl20 inhibitors selected from the group consisting of Radha-108 (Receptol) and BMS-663068;

(10) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir (RAP-101), nifeviroc (TD-0232), TD0680, and vMTP (Haimipu);

(11) CD4 attachaient inhibitors selected from the group consisting of ibalizumab;

(12) CXCR4 inhibitors selected from the group consisting of plerixafor, ALT-1188, vMTP and Haimipu;

(13) Pharmacokinetic enhancers selected from the group consisting of cobicistat and ritonavir;

(14) Immune-based thérapies selected from the group consisting of dermaVir, interleukîn-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester dérivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl 1, tlrl2 and tlrl3), rintatolimod and IR-103;

(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV (vCP 1521)/AIDS VAX B/E (gpl20) (RV144), monomeric gpl20 HIV-1 subtype C vaccine (Novartis), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409,Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), AGS-004, gp]40[delta]V2.TVl+ MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX , HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIVPT123, rAAVl-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYMV201, MVA-CMDR, ETV-01, CDX-1401, rcAd26.MOSl HIV-Env and DNA-Ad5 gag/pol/nef/nev (HVTN505);

(16) HIV antibodies, bispeciftc antibodies and “antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab dérivatives) including BMS-936559, TMB-360 and those targeting HIV gpl20 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117 , PGT145, PGT121, MDX010 (ipilimumab),

VRC01, A32, 7B2, 10E8, VRC-07-523 and VRC07;

(17) latency reversing agents selected from the group consisting of Histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; Protéasome inhibitors such as Velcade; protein kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactones, lonomycin, GSK-343, PMA SAHA BRD4 inhibitors, IL-15, JQ1, disulffam, and amphotericin B;

(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide;

(19) HIV maturation inhibitors selected from the group consisting ofBMS-955176 and GSK-2838232;

(20) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR1401, (21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences),

WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and (22) other drugs for treating HIV selected from the group consisting of BanLec, MK8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND

02, metenkefalin, PGN-007, Acemannan, Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY-635, naltrexone, AAV-eCD4-Ig gene therapy and PA-1050040 (PA040);

and combinations thereof.

[0084] In certain embodiments, a compound disclosed herein is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents. The two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents. In a spécifie embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another spécifie embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein is combined with two HIV nucleoside or nucléotide inhibitors of reverse transcriptase

[0085] In certain embodiments, a compound disclosed herein, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. In a spécifie embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another spécifie embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein is combined with two HIV nucleoside or nucléotide inhibitors of reverse transcriptase.

[0086] In certain embodiments, a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.

[0087] In a particular embodiment, a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0088] In a particular embodiment, a compound disclosed herein is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0089] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine.

[0090] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additionai therapeutic agent is emtricitibine.

[009l] In a particular embodiment, a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents selected from Triumeq® (dolutegravir+abacavir +lamivudine), dolutegravir + abacavir sulfate + lamivudine, raltegravir, raltegravir + lamivudine, Truvada® (tenofovir disoproxil fumarate +emtricitabine, TDF+FTC), maraviroc, enfiivirtide , Epzicom® (Livexa®, abacavir sulfate -Hamivudine, ABC+3TC), Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild ® (elvitegravir+cobicistat+tenofovir disoproxil fumarate +emtricitabine), rilpivirine, rilpivirine hydrochloride, Compléta® (Eviplera®, rilpivirine+tenofovir disoproxil fumarate +emtricitabine), Cobicistat, atazanavir sulfate + cobicistat, atazanavir + cobicistat, darunavir + cobicistat, Atripla® (efavirenz+tenofovir disoproxil fumarate +emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir , emtricitabine , atazanavir_sulfate + ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zaîcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hiviral, lamivudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate , phosphazid, lamivudine + nevirapine + zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, darunavir + cobicistat, atazanavir sulfate + cobicistat, atazanavir + cobicistat, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0092] In a particular embodiment, a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemiftimarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

[0093] In a particular embodiment, a compound disclosed herein is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0094] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0095] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0096] In certain embodiments, a compound disclosed herein is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 5-10, 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 10 mg tenofovir alafenamide fümarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (II)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

[0097] In certain embodiments, a compound disclosed herein is combined with 200400 mg tenofovir disproxil, tenofovir disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil, tenofovir disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (Π)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

[0098] In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0099] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0100] In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both présent in the body of the patient.

[0101] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.

XRPD Data

[0102] In certain embodiments, the crystalline forms are characterized by the interlattice plane intervals determined by an X-ray powder diffraction pattern (XRPD). The diffractogram of XRPD is typically represented by a diagram plotting the intensity of the peaks versus the location ofthe peaks, i.e., diffraction angle 26 (two-theta) in degrees. The intensities are often given in parenthesis with the following abbreviations: very strong = vst; strong = st; medium = m; weak w, and very weak == vw. The characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to conveniently distinguish this crystalline structure from others.

[0103] Those skilied in the art recognize that the measurements of the XRPD peak locations and/or intensity for a given crystalline form of the same compound will vary within a margin of error. The values of degree 26 allow appropriate error margins. Typically, the error margins are represented by “±”. For example, the degree 26 of about “8.7±0.3 dénotés a range from about 8.7+0.3, i.e., about 9.0, to about 8.7-0.3, i.e., about 8.4. Depending on the sample préparation techniques, the calibration techniques applied to the instruments, human operational variation, and etc, those skilled in the art recognize that the appropriate error of margins for a XRPD can be ±0.5, ±0.4; ±0.3; ±0.2, ±0.1; ±0.05; or less. In certain embodiments of the invention, the XRPD margin of error is ±0.2.

[0104] Additional details of the methods and equipment used for the XRPD analysis are described in the Examples section.

[0105] The XRPD peaks for the crystalline forms of sodium (2R,5S,13aR)-7,9-dioxo10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8-olate (Formula II) of the présent invention can be found below in Table 1

[ΟΙ06] Table 1: XRPD peaks for crystalline forms of Formula II Form I

Formula II Form I
Peak Position [°20]	Relative Intensity [%]
5.5	100.0
16.1	87.3
17.9	22.4
19.5	38.0
22.1	61.8
22.5	42.2
23.3	60.4
26.6	27.3
28.5	42.9

Préparation of the Polymorphs

[0107] One method of synthesizing (2R,5S, 13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -

b][ 1,3]oxazepinc-10-carboxamide (e.g. a compound of Formula (I)) has been previously described in PCT Publication No. W02014/100323. This référencé is hereby incorporated herein by référencé in its entirety, and specifically with respect to the synthesis of (2R,5S, 13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxamide. One method of synthesizing sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ‘,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate (e.g. a compound of Formula (II)) is described herein.

[0108] For example, in one aspect, provided is a method of producing a composition comprising one or more polymorphs of sodium (2R,5 S, 13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, wherein the method comprises combining a compound of Formula (II) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (II). In another aspect, provided is another method of producing a composition comprising one or more polymorphs of sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6 trifluorobenzyl)carbamoyl)-2,3,4,5,7,9, 13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, wherein the method comprises combining sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2':4,5]pyrazino[2,1 -b][ 1,3]oxazepin-8olate with a suitable solvent or a mixture of suitable solvents.

[0109] The choice of a particular solvent or combination of solvents affects the formation favoring one polymorphie form of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate over another. Solvents suitable for polymorph formation may include, for example, methanol, éthanol, water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, and any mixtures thereof.

[0110] In another aspect, provided is also one or more polymorphs of sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate produced according to any of the methods described herein.

[OUI] It should be understood that the methods for preparing the polymorphs described herein (including any polymorphie Form I) may yield quantity and quality différences compared to the methods for preparing sodium (2R,5S,13aR)-7,9-dioxo-10((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate produced on laboratory scale.

Formula II, Form I

[0112] In one embodiment, provided is a method of producing a composition comprising polymorphie Form I of sodium (2R,5S,I3aR)-7,9-dioxo-l 0-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, wherein the method comprises combining (2R,5S, 13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifiuorobenzyl)-2,3,4,5,7,9,13,13aoctahydro-2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b][ 1,3]oxazepine- 10-carboxamide with a sodium base (e.g. sodium hydroxide) in a solvent to produce a composition comprising polymorphie Form I of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate, wherein the solvent is selected from the group consisting of ethanoi, dimethylformamide, and any mixture thereof In an embodiment, the solvent is a mixture of éthanol and dimethylformamide.

[0113] Provided is also polymorphie Form I of sodium (2R,5S,l3aR)-7,9-dioxo-10((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,l3,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate prepared by combining (2R.5S, 13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-

2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxamide with a sodium base (e.g. sodium hydroxide) in a solvent, wherein the solvent is selected from the group consisting of éthanol, dimethylformamide, and any mixture thereof. In an embodiment, the solvent is a mixture of éthanol and dimethylformamide.

Uses in Manufacturing of Drug Product

Formula II

[0114] Provided are also a use of the polymorphs described herein in the manufacture of a drug product. The one or more of the polymorphie forms described herein (e.g., polymorphie Form I) may be used as an intermediate in the manufacturing process to produce the drug product.

[0115] In certain embodiments, Form I of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2‘:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate are used in the manufacture of an active pharmaceutical ingrédient.

Articles of Manufacture and Kits

[0116] Compositions comprising one or more of sodium (2R,5S,13aR)-7,9-dioxo-10((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate and formulated in one or more pharmaceutical 1 y acceptable carriers, excipients or other ingrédients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5 methanopyrido[l',2':4,5]pyrazino[2, l-b][I,3]oxazepin-8-olate, and a label containing instructions for use of the compoundfs/

[0117] In some embodiments, the article of manufacture is a container comprising a dosage form of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2,1 -b] [ 1,3]oxazepin-8olate, and one or more pharmaceutically acceptable carriers, excipients or other ingrédients. In one embodiment of the articles of manufacture described herein, the dosage form is a tablet.

[0118] Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use in the kit may be for treating HIV. In certain embodiments, the instructions for use in the kit may be for treating HIV.

[0119] In certain embodiments, the polymorphie and solvaté forms described herein may potentialiy exhibit improved properties. For example, in certain embodiments, the polymorphie and solvaté forms described herein may potentialiy exhibit improved stability. Such improved stability could hâve a potentialiy bénéficiai impact on the manufacture of the Compound of Formula I, such as for example offering the ability to store process intermediate for extended periods of time. Improved stability could also potentialiy benefit a composition or pharmaceutical composition of the Compound of Formula II. In certain embodiments, the polymorphie and solvaté forms described herein may also potentialiy resuit in improved yield of the Compound of Formula II, or potentialiy resuit in an improvement of the quality of the Compound of Formula II. In certain embodiments, the polymorphie and solvaté forms described herein may also exhibit improved pharmacokinetic properties and/or potentialiy improved bioavailability.

Methods

Syuthesis

Sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ', 2 ':4,5]pyrazino[2,1-b][1,3]oxazepin-8oiate (Formula II)

[0120] (2R,5S, 13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2':4,5]pyrazino[2,1-b][1,3]oxazepine-10carboxamide (20 g) and éthanol (80 mL) were added to a reaction vessel and warmed to about 75 °C. Aqueous sodium hydroxide (22 mL 2 M solution) was added over approximately 30 minutes, after which the slurry was cooled to approximately 20 °C over approximately one hour. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2’:4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I was collected by filtration, washed with EtOH (50 mL) and dried under vacuum.

[0121] *H NMR (400 MHz, DMSO-d6) δ 10.63 (t, J= 5.8 Hz, 1 H), 7.88 (s, 1 H), 7.29 -7.07(m, 2H), 5.20 (dd, J = 8.6, 3.6 Hz, 1 H), 5.09 (t, J = 4.1 Hz, lH),4.52(m, 3H), 4.35 (dd, J= 12.8, 3.6 Hz, 1H), 3.87 (dd,./= 12.7, 8.7 Hz, 1H),2.O3- 1.80 (m, 3H), 1.76-1.64 (m, 2H), 1.50-1.40 (m, 1H).

Characterization

[0122] Sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trif!uorobenzyl)carbamoyI)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8olate Form I was characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning calorimetry (DSC), thermographie analysis (TGA), and dynamic vapor sorption (DVS) using the procedures described below.

[0123] X-Ray Powder Diffraction. XRPD analysis was conducted on a diffractometer (PANanalytical XPERT-PRO, PANanalytical B.V., Almelo, Netherlands) using copper radiation (Cu Κα, λ = 1.5418 Â). Samples were prepared for analysis by depositing the powdered sample in the center of an aluminum holder equipped with a zero background plate. The generator was operated at a voltage of 45 kV and amperage of 40 mA. Slits used were Soller 0.02 rad., antiscatter 1.0°, and divergence. The sample rotation speed was 2 sec. Scans were performed from 2 to 40° 2Θ during 5-15 min with a step size of 0.0167° 20. Data analysis was performed by X’Pert Highscore version 2.2c (PANalytical B.V., Almelo, Netherlands) and X’Pert data viewer version 1.2d (PANalytical B.V., Almelo, Netherlands).

[0124] The XRPD pattern for sodium (2R,5S,13aR)-7,9-dioxo-l 0-((2,4,6trifluorobenzy 1 )carbamoyl )-2,3,4,5,7,9,13,13 a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I is represented in Figure

1. The calculated XRPD pattern for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I represented in Figure 1 was calculated by using Mercury 3.1 Development (Build RC5). Single crystal data for sodium (2R.5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13aoctahydro-2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-o1ate Form I was input into Mercury 3.1 Development (Build RC5) to calculate the XRPD pattern for sodium (2R,5S, 13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-oIate Form I. Bulk material, such as stoichiometry arity between the température was obtained on a Rigaku Miniflex II XRD using power settings of 40kV, 15mA, scan speed of 2.0000 degrees per minute, a Miniflex 300/600 goniometer and an ASC-6 attachment, a scan range of 3.000 to 40.000 degrees, an incident slit of 1.250 degress, a length limiting sût of 10.0 mm, and SC-70 detector, a receiving slit #1 of 1.250 degrees, continuous scan mode, and a receiving slit #2 of 0.3mm. The sample was prepared by smoothing about 20 mg of solids on a Silicon disk mounted in a métal holder. Acquisition température was ~21 °C.

[0125] The XRPD pattern for sodium (2R,5S,I3aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I is further represented in Figure 8. The calculated XRPD pattern for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I represented in Figure 8 was calculated by using Mercury 3.1 Development (Build RC5), Single crystal data for sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13aoctahydro-2,5-methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-oiate Form I was input into Mercury 3.1 Development (Build RC5) to calculate the XRPD pattern for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[r,2’.4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form 1 Bulk material, such as stoichiometry arity between the température was obtained on a Rigaku Miniflex II XRD using power settings of 40kV, 15mA, scan speed of 2.0000 degrees per minute, a Miniflex 300/600 goniometer and an ASC-6 attachment, a scan range of 3.000 to 40.000 degrees, an incident slit of 1.250 degress, a length limiting slit of 10.0 mm, and SC-70 detector, a receiving slit #1 of 1.250 degrees, continuous scan mode, and a receiving slit #2 of

0.3mm. The sample was prepared by smoothing about 20 mg of solids on a Silicon disk mounted în a métal holder. Acquisition température was ~2l °C.

[0126] Figure 8 compares the calculated XRPD pattern of sodium (2R,5S,13aR)-7,9dioxo-I0-((2,4,6-trifluorobenzyl)carbamoyi)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I to the experimental XRPD pattern of sodium (2R,5S,13aR)-7,9-dioxo-l 0-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ l',2’:4,5]pyrazino[2,1 -b] [ 1,3]oxazepin-8olate Form I. The comparison shows the degree to which the calculated XRPD and experimental XRPD agree. Strong agreement indicates the solved crystal structure is also the crystal structure of the material analyzed directly by XRPD. This détermination can support orthogonal data about the composition of the bulk material, such as stoichiometry.

[0127] XRPD peaks are found in Table 1 above.

[0128] Differential scanning calorimetry: Thermal properties of sodium (2R, 5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I were evaluated using a Differentiai Scanning Calorimetry (DSC) instrument (TA Q1000, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of solid sample was placed in a standard aluminum pan vented with a pinhole for each experiment and heated at a rate of 10 °C/min under a 50 mL/min nitrogen purge. Data analysis was conducted using Universal Analysis 2000 Version 4.7 A (TA Instruments, New Castle, DE, USA). Heat of fusion analysis was conducted by sigmoidal intégration of the endothermie melting peak.

[0129] The DSC for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form f is represented in Figure

2.

[0130] Thermogravimetric analysis: Thermogravimetric analysis (TGA) of sodium (2R,5 S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyI)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-

2.5- methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I was performed on a TGA instrument (TA Q500, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of solid sample was placed in an open aluminum pan for each experiment and heated at a rate of 10 °C/min under a 60 mL/min nitrogen purge using. Data analysis was conducted using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE, USA).

[0131] The TGA for sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I is represented in Figure

3.

[0132] Dynamic vapor sorption. The hygroscopicity of sodium (2R,5S, 13aR)-7,9dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I was evaluated at about 25 °C using a dynamic vapor sorption (DVS) instrument (TGA Q5000 TA Instruments, New Castle, DE). Water adsorption and desorption were studied as a fonction of relative humidity (RH) over the range of 0 to 90% at room température. The humidity in the chamber was increased from the initial level 50% RH to 60% RH and held until the solid and atmosphère reached équilibration. The equilibrium test was continued until passed or expired after 10 hours. At this point, RH was raised 10% higher and the process was repeated until 90% RH was reached and equilibrated. During this period, the water sorption was monitored. For desorption, the relative humidity was decreased in a similar manner to measure a foll sorption/desorption cycle. The cycle was optionally repeated. Ail experiments were operated in dm/dt mode (mass variation over time) to détermine the équilibration endpoint. Approximately 3 mg of solid sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate was used. Data analysis was conducted using Universal Analysis 2000 Version 4.7A(TA Instruments, New Castle, DE, USA).

[0133] The DVS for sodium (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I is represented in Figure

4.

[0134] The indexing data for Formula II Form I is summarized in Table 2 below.

Table 2: Indexing Data for Formula II Form I

Formand Identification	Solvent	Unit Cell Dimensions
Distance (A)	Angle (°)
a	b	c	a	β	γ
Formula II Form 1	methano 1	9.105	13,986	31.384	90	90	90

[0135] The single crystal X-ray diffraction studies were carried out on a Broker APEX II Ultra diffractometer equipped with Mo K« radiation (λ = 0.71073 Â). Crystals of the subject compound were eut into a 0.22 x 0,18 x 0.04 mm section and mounted on a Cryoloop with Paratone-N oil. Data were collected in a nitrogen gas stream at 100 (2) K. A total of 15725 reflections were collected covering the indices, -9<=A<=10, -13<=A<=16, 37<=/<=36. 7163 reflections were found to be symmetry independent, with a 7?mt of 0.0682. Indexing and unit-cell refinement indicated an orthorhombic lattice. The space group, which was uniquely defined by the systematic absences in the data, was found to be P2i2i2i. The data were integrated using the Broker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced a complété phasing model compatible with the proposed structure.

[0136] Ail nonhydrogen atoms were refined anisotropically by full-matrix leastsquares (SHELXL-2014). Ail hydrogen atoms were placed using a riding model Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. Crystallographic data are summarized in Table 2A. The absolute stereochemistry was set to conform to previously studied samples of the same compound.

[0137] The single crystal X-ray crystallography data for Formula II Form I is summarized in Table 2A below.

Table 2A: Single Crystal Data for Formula II, Form I

C42 H34 F6 N6 Na2 010	Acquisition Temp.	Space Group	Z	Unit Cell Dimensions
100(2) K	P212121	4	Distance (Â)	Angle (°)
Form and Identification	Solvent	Solvent in lattice	Density ( Mg/m³)	a	b	c	a	β	y
Formula Π Form I	Ethanol/DMF	none	1.614	8.9561 (10)	13.9202 (14)	31.115 (3)	90	90	90

Dissolution Profile

[0138] The intrinsic dissolution profile of sodium (2R,5S,13aR)-7,9-dioxo-l0-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[T,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate (Formula II) Form I ofthe présent invention and the intrinsic dissolution profiles of Form I and Form III of Formula I, the free acid, (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ r,2‘:4,5]pyrazino[2,1 -b] [ l,3]oxazepine-10carboxamide (disclosed in the co-pending United States Provisional Application 62/015,238 filed on June 20, 2014 titled CRYSTALLINE FORMS OF (2R,5S,13AR)-8-HYDROXY-7,9DIOXO-N-(2,4,6-TRIFLUOROBENZYL)-2,3,4,5,7,9,13,13 A-OCTAHYDRO-2,5METHANOPYRIDO[ 1 ’,2':4,5]P YRAZINO[2,1 -B][ 1,3]OXAZEPINE-10CARBOXAMIDE), were measured by characterizing API dissolution from a constant surface area. Approximately 150 mg of the drug substance was compressed at 1500 psi for approximately 3 seconds using a hydraulic press (Carver Press, Fred Carver, NJ, USA). The compressed drug substance formed a fiat disk (surface area -0.49 cm²), which was mounted onto a dissolution apparatus (VanKel Industries Inc., Edison, NJ, VK7000, W1120A-0288). The rotating disk (100 rpm) was then lowered into the dissolution medium (500 mL of 0.01N HCl) which was equilibrated to 37±1°C. Samples were pulled at pre-determined time points and drug concentrations were measured using an appropriate UPLC-UV method. The intrinsic dissolution rate constant (K) was calculated using the following équation:

[0139] Where C is the concentration of the active at time t, A is the surface area of the tablet (-0.49 cm²) and V is the volume of the media (500 mL). Note that the term active as used herein refers to the parent molécule, whose structure is shared by both Formula I and Formula II.

[0140] The dissolution profiles can be found in Figure 5.

Solubility

[0141] The solubility of the sodium forrn of the present invention and the ffee acid, (2R,5S, 13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,l3a-octahydro-

2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxamide Form III in biorelevant media was determined at room température as a fonction of time. Solubility was determined in the following biorelevant media: 0.1 mM Fasted-State Simulated Gastric Fluid (FaSSGF) pH 1.6 (0.08 mM taurocholate, 0.02 mM lecithin, 34.2 mM NaCl); 18.75 mM Fed-State Simulated Intestinal Fluid (FeSSIF) pH 5 (15 mM taurocholate, 3.75 mM lecithin, 0.12 M NaCl); and 3.75mM Fasted-State Simulated Intestinal Fluid (FaSSIF) pH 5 (3 mM taurocholate, 0.75 mM lecithin, 0.10 M NaCl). Approximately 20 mg of the drug substance was mixed on a magnetic stir-piate in 50 mL of biorelevant media. Samples (—1 mL) were pulled every 5-10 min for 2 hours. The samples were immediately filtered/centrifoged for 10 min in a Spin-X tube equipped with a 0.45 pm nylon filter. The resulting filtrate was analyzed using an appropriate UPLC-UV method.

[0142] The solubility profiles in FaSSGF can be found in Figure 6. The solubility profiles in FeSSIF and FaSSIF can be found in Figure Ί.

Bioavailability

[0143] The bioavailability of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate (Formula Π) Form I was compared to the bioavailability of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[l ',2':4,5]pyrazino[2,1 b][l,3]oxazepine-10-carboxamide (Formula I) Form ΠΙ.

[0144] Each dosing group consisted of 6 male, non-naïve purebred beagle dogs. At dosing, the animais weighed between 10 to 13 kg. The animais were fasted ovemight prior to dose administration and up to 4 hr after dosing. Each subject was pre-treated with pentagastrin (6 pg/kg) and dosed 30 minutes later with a single 25 mg strength tablet of Formula II Form I or Formula I Form III. Each subject was given 10 mL of water to aid in swallowing.

[0145] Serial venous blood samples (approximately 1 mL each) were taken from each animal at 0, 0.250, 0.483, 0.583, 0.750, 1.00, 1.50, 2.00, 4.00, 8.00, 12.0, and 24.0 hours after dosing. The blood samples were collected into Vacutainer™ tubes containing EDTA-K2 as the anti-coagulant and were immediately placed on wet ice pending centrifugation for plasma An LC/MS/MS method was used to measure the concentration of the test compound in plasma. An aliquot of 100 pL of each plasma sample was added to a clean 96 well plate, and 400 pL of cold acetonitrile/intemal standard solution (ACN)/(ISTD) was added. After protein précipitation, an aliquot of 110 pL of the supematant was transferred to a clean 96well plate and diluted with 300 pL of water. An aliquot of 25 pL of the above solution was injected into a TSQ Quantum Ultra LC/MS/MS system utilizing a Hypersil Gold Cis HPLC column (50 X 3.0 mm, 5 pm; Thermo-Hypersil Part # 25105-053030). An Agilent 1200 sériés binary pump (P/N G1312ABin Pump) was used for elution and séparation, and an HTS Pal autosampler (LEAP Technologies, Carrboro, NC) was used for sample injection. A TSQ Quantum Ultra triple quadrupole mass spectrometer was utilized in sélective reaction monitoring mode (Thermo Finnigan, San José, CA). Liquid chromatography was performed using two mobile phases: mobile phase A contained 1% acetonitrile in 2.5 mM ammonium formate aqueous solution with pH of 3.0, and mobile phase B contained 90% acetonitrile in 10 mM ammonium formate with pH of 4.6. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The resulting data are shown in Table 3: F (%) refers to oral bioavailability, AUC refers to area under the curve and is a measure of total plasma exposure of the indicated compound; Cmax refers to the peak plasma concentration of the compound after administration.

Table 3: Bioavailability of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[T,2^,:4,5]pyrazino[2, l-b][l,3]oxazepin-8-olate Form I and (2R,5S,13aR)-8hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[ 1 ',2’:4,5]pyrazino[2,1 -b][ 1,3]oxazepine-l 0-carboxamide Form III.

Form	Formulation	%F	AUCi... (uM i hr)	Gmax (uM)
Formula I Form ΠΙ	1 Dry Granulation	10 ±6	27 ± 13	6 ± 2
Formula II Form I	2 Dry Granulation	28±7	71 ±16	13 ± 1

¹ Tabler. 30% active. 56% microcrystalline cellulose, 13% croscarmellose sodium. 1% magnésium stéarate ² Tabler 30% active, 56% microcrystalline cellulose, 13% croscarmellose sodium, 1% magnésium stéarate

Siability

[0146] The stability of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate Form I was tested. As seen in Table 4, below, the compound is stable after four weeks of storage under accelerated conditions. In Table 5, AN refers to area normalization and is the relative peak area of the active with respect to other impurities and components contained in the sample. LS refers to labile strength and is the amount of active présent relative to the theoretical amount.

Table 4: Stability of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5methanopyrido[l^,,2':4₍5]pyrazino[2,l-b][l,3]oxazep’ⁿ-8-olate Form I

Storage Conditions	Storage Time (weeks)	%AN	% LS
Starting matcrial	0	94.4 ±0.1	99.8 ±0.1
40°C (closcd)	1	95.2 ±0.3	108.0 ± 0.2
2	94.4 ±0.1	102.4 ±0.1
4	94,4 ±0.0	97.0 ± 0.0
40°C/75% RH (opcn)	1	94.9 ±0.1	103.3 ±6.9
2	94.4 ± 0.0	108.5 ±0.4
4	94.4 ±0.0	102.9 ±0.1
25°C/60% RH (open)	I	95.0 ± 0.2	104.8 ±0.1
2	94.4 ± 0.1	101.6 ±0.1
4	94.4 ±0.0	103.0 ±0.8

[0147] Each ofthe référencés including ail patents, patent applications and publications cited in the present application is incorporated herein by référencé in its entirety, as if each of them is individualiy incorporated. Further, it would be apprecîated that, in the above teachîng of invention, the skilled in the art couid make certain changes or modifications to the invention, and these équivalents would still be within the scope of the invention defined by the appended daims ofthe application. Each of the référencés including ail patents, patent applications and publications cited in the present application is incorporated herein by référencé in its entirety, as if each ofthem is individualiy incorporated. Further, it would be apprecîated that, in the above teaching of invention, the skilled in the art couid make certain changes or modifications to the invention, and these équivalents would still be within the scope of the invention defined by the appended daims of the application.

Claims

What is Claimed:

1. A compound of Formula II:
2. The compound of claim 1, characterized by being crystalline.
3. The compound of claim 2, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 5.5°, 16.1°, and 23.3° 2-Θ ± 0.2° 2-Θ.
4. The compound of claim 3, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 22.1°, and 28.5° 2-Θ ± 0.2° 2-Θ.
5. The compound of claim 4, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 22.5 and 19.5° 2-Θ ± 0.2° 2-Θ.
6. The compound of claim 5, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 26.6° and 17.9° 2-Θ ± 0.2° 2-Θ.
7. The compound of claim 2, characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 1
8. The compound of claim 2, characterized by differential scanning calorimetry (DSC) pattern substantielly as set forth in Figure 2.
9. The compound of claim 2, characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in Figure 4.
10. The compound of any one of daims 1 to 9, characterized in being partially or fully hydrated.
11. The compound of any one of daims 1 to 9, characterized in being anhydrous or essentially anhydrous.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of daims 1 to 11, and a pharmaceutically acceptable carrier or excipient.
13. The pharmaceutical composition of daim 12, further comprising one to three additional therapeutic agents.
14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agents are each anti-HIV drugs.
15. The pharmaceutical composition of daim 13 or claim 14, wherein the additional therapeutic agents are each independently selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, and other drugs for treating HIV.
16. The pharmaceutical composition of any one of daims 12 to 14, wherein at least two of the additional therapeutic agents are each HIV nucleosîde inhibitors of reverse transcriptase.
17. The pharmaceutical composition of claim 12, further comprising tenofovir disoproxil fumarate and emtricitabine.
18. The pharmaceutical composition of claim 12, further comprising tenofovir alafenamide and emtricitabine.
19. The pharmaceutical composition of claim 12, further comprising tenofovir alafenamide hemifumarate and emtricitabine.
20. The pharmaceutical composition of any one of daims 12 to 18, wherein the pharmaceutical composition is in a unit dosage form.
21 The pharmaceutical composition of daim 20, wherein the unit dosage form is a tablet.
22 Use of a compound of any one of daims 1 to 11 for treating or prophylactically preventing an HTV infection.
23. Use of a compound of any one of daims I to 11 for the manufacture of a médicament for treating or prophylactically preventing an HIV infection.
24. A compound of any one of daims 1 to 11 for use in a method for treating or prophylactically preventing an HIV infection.
25. A method for treating or prophylactically preventing an HIV infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of any one of daims I to 11