Pharmaceutical compositions for herpes virus

Abstract

The present invention relates to methods and compositions for treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection. In particular, provided are long-acting injectable depot pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament and for the treatment of diseases or disorders caused by, or associated with, herpes virus.

Description

FIELD OF THE INVENTION

[0001] Provided herein are compositions and methods for treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection. In particular, provided herein are long-acting injectable depot pharmaceutical compositions comprising (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1 / 7-indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as ‘Compound T), or a pharmaceutically acceptable salt thereof; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament and for the treatment of diseases or disorders caused by, or associated with, herpes virus. BACKGROUND OF THE INVENTION

[0002] Human herpes viruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing life-long infections in humans. This is accomplished by their ability to exist in the host either as a symptom free latent infection, where the virus lies dormant or, following activation, as a lytic infection with associated symptoms. These viral infections have widespread, worldwide prevalence and it is notable that over 90% of all humans are chronically infected with more than one human herpes virus.

[0003] Human herpes viruses are classified into three subfamilies (a, p and y) based upon their biological characteristics and the family consists of eight members, i.e., Herpes Simplex Virus subtype type 1 and 2 (HSV1, HSV2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and Human Herpes Viruses 6-8 (HHV 6-8).

[0004] HSV1 and 2 infections can cause disease in immune competent individuals. Both subtypes cause cutaneous genital / anal and oro-labial / nasal cavity (cold sore) lesions, although HSV2 is more commonly associated with the former, and HSV1 the latter. It is believed that >80% of genital infections are caused by HSV2. Globally, over 500 million people have genital herpes infections and approximately 50 to 80% of the world’s population have oro-labial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1, can also cause lesions on the fingers (Whitlows) and other areas of the skin.

[0005] The vast majority of HSV infected individuals will not experience any noticeable symptoms. However, some will experience recurrent (and often severe) outbreaks of infection. In the USA, 20 to 40% of the population will get recurrent labial HSV lesions. Significantly, oro-labial cold sores and Whitlow’s provide a very easy route for transmission of the virus to other individuals which can lead to rarer but much more serious HSV-related pathologies. For example, HSV-related ocular keratitis is a major cause of blindness and HSV can also cause encephalitis in neonates, which is a life-threatening condition. Other disorders believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis and possibly Bell's palsy.

[0006] Primary infection with, or reactivation of an existing herpes virus infection, can be a major cause of disease in immunocompromised individuals. Key at-risk populations include patients undergoing solid organ or stem cell transplantation, patients undergoing cancer treatment, individuals with HIV / AIDS, and ICU patients.

[0007] Presently, there is no cure for HSV. Medicines have been developed that can to some degree reduce the occurrence and / or shorten the length of outbreaks, but there is a need for improved therapies.

[0008] Currently, nucleoside analogues, such as acyclovir and its prodrug (e.g., valacyclovir), and penciclovir and its prodrug (famciclovir), are used as agents against herpes viruses such as HSV. In order to exert their effects, these nucleoside analogues must be phosphorylated by viral thymidine kinase (TK) and subsequently converted by cellular kinases to the nucleoside triphosphate, which inhibits the activity of the viral DNA polymerase. If the virus has no functionally active TK, as is the case, for example, with resistant HHV1 mutants or with TK-negative viruses, the nucleoside analogues are unable to exert their effects.

[0009] Nucleoside analogues are clinically administered at very high doses, e.g., doses as high as several hundred milligrams to several grams are typically administered per day. Even at these high doses, which are often administered over long treatment durations, these drugs are unable to completely prevent recurrent outbreaks of symptoms from HSV infection. Nucleoside analogues also do little to address the issue of viral shedding, which can asymptomatically facilitate the transmission of HSV to more individuals. Certain nucleoside analogues, particularly when used at high doses, also give rise to safety concerns. For example, since these agents can incorporate into the genome DNA of a host via the host DNA polymerase, their mutagenicity is of concern, as documented for the nucleoside analogue, ganciclovir (Aoki, Chapter 45 in Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases (Eighth Edition) 2015).

[0010] Given the inadequacy of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments.

[0011] One class of compounds currently being investigated are the helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex consisting of helicase, primase, and cofactor subunits, which have functions that are essential for viral DNA replication. These agents are not nucleoside analogues and do not require phosphorylation by TK to inhibit HSV replication and they are therefore potentially active against TK-deficient HSV, which as described above, is a major mechanism of resistance to nucleoside analogues.

[0012] Two examples of helicase-primase inhibitors are BILS-179 BS (Crute et al., (2002) Nature Medicine 8, p. 386-391) and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p. 201-206).

[0013] BILS-179 BS has been dosed orally to humans but was suspended in early clinical trials due to adverse events (Ruebsamen et al., (2019) Med. Chern. Commun., DOI: 10.1039 / C9MD00233B).

[0014] Another example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative with the chemical name N-Methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide. The compound has been disclosed in WO 2001 / 47904.

[0015] In a human clinical study, the effect of pritelivir on suppression of genital herpes was studied in 156 individuals (Wald et al., (2014) New England Journal of Medicine 370, p. 201-210). Subjects received one of three oral daily doses or one weekly oral dose of pritelivir or placebo for 28 days. The four pritelivir dosing regimens were; a loading dose of 20 mg followed by a daily dose of 5 mg; a loading dose of 100 mg followed by a daily dose of 25 mg; a loading dose of 300 mg followed by a daily dose of 75 mg; and a weekly dose of 400 mg. At high doses, it was found that pritelivir reduced the rate of genital HSV shedding, the primary end point for the study. Pritelivir also reduced the number of days with lesions in otherwise healthy men and women with genital herpes. An oral daily dose of 75 mg had the greatest antiviral effect and this was found to be superior to the less frequently administered weekly dose of 400 mg.

[0016] As highlighted in the study report, although the HSV shedding rate was reduced at the highest daily dose of 75 mg, as compared with placebo, break-through shedding remained. When discussing this finding, it is explained in Wald et al., ((2014) New England Journal of Medicine 370, p. 201-210) that persistent, low-level shedding has also been observed with nucleoside therapy and that the pathogenesis of break-through viral shedding during adequate antiviral therapy with nucleoside analogues is poorly understood; it is not related to lack of adherence to the treatment regimen or viral resistance. The author also raises the question of whether further increases in the daily dose of pritelivir would completely abrogate viral shedding and should be addressed in subsequent clinical studies.

[0017] In accordance with this suggestion, a subsequent clinical study using an even higher daily oral dose was indeed conducted. In a Phase II 28-day clinical study of 91 subjects with recurrent genital HSV-2, daily oral dosing of 100 mg pritelivir (after a loading dose of 400 mg) resulted in HSV shedding in 2.4% of genital swabs analysed, compared with HSV shedding in 5.3% of swabs following daily dosing of 500 mg of valacyclovir. The results of the study are reported in Wald et al., (2016) (J. Am. Med. Assoc. 316(23), p. 2495-2503) and the publication mentions that the 100 mg pritelivir daily dose (after a loading dose of 400 mg) was chosen based on prior trial findings showing high efficacy of the 75 mg daily dose in suppressing viral shedding.

[0018] In a current phase III clinical trial, a 400 mg oral loading dose, followed by 100 mg daily oral dosing of pritelivir for up to 28 days or until all mucocutaneous HSV lesions are healed, whichever is earlier, is being investigated (https: / / www.clinicaltrials.gov / ct2 / show / NCT03073967?term=pritelivir+f&draw=2&rank=2)

[0019] As is apparent from the above, the primary route of administration investigated for all of the small molecule based antiviral therapeutics described above is the oral route of administration. Efforts to improve therapy, e.g. to try and further reduce or prevent HSV shedding and viral reactivation, have largely focussed on using higher oral drug doses (including high loading doses) and more frequent dosing (e.g. multiple daily dosing).

[0020] There is an ongoing need for novel and improved methods for treating HSV infections and the present invention was devised with the foregoing in mind. SUMMARY OF THE INVENTION

[0021] In a first aspect, the present invention provides a long-acting injectable depot pharmaceutical composition comprising a compound (Compound 1) represented by: or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0022] The compound shown above is (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1 / - / -indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as ‘Compound T) and is a potent helicase-primase inhibitor.

[0023] It has been surprisingly found that when Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a long-acting injectable depot pharmaceutical composition in accordance with the present invention, such a composition provides beneficial properties, including certain release characteristics and profiles that allow plasma levels to be achieved for prolonged periods.

[0024] Remarkably, in some embodiments, the long-acting injectable depot compositions of the present invention are able to provide steady and continuous release of Compound 1 for at least 14 days after administration. This offers the possibility for less frequent dosing and / or use of lower doses than other routes of administration. This is an unexpected finding. As described above, the primary route of administration investigated for small molecule based antiviral therapeutics is the oral route and efforts to improve therapy have largely focussed on increasing oral drug doses (including the use of high loading doses) and using more frequent drug dosing regimens (e.g. multiple daily dosing).

[0025] Certain long-acting injectable depot compositions of the present invention are expected to provide steady and continuous release of Compound 1 for prolonged periods with low levels of inter-subject variability in pharmacokinetic plasma concentration levels.

[0026] The present invention satisfies a need for a novel treatment approach for HSV infections which can provide improvements in efficacy and / or safety and / or patient experience or compliance.

[0027] In a second aspect, the present invention provides a method for forming a pharmaceutical composition according to the first aspect. Various techniques may be used for forming the injectable depot compositions of the present invention, however, it has been found that certain processes offer particular advantages. Furthermore, it has also been found that certain chemical and / or physical forms of Compound 1 can be highly suitable for formulation as injectable depot compositions of the present invention.

[0028] In a third aspect, the present invention provides a method for treating or preventing a herpes infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, to the subject, wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect.

[0029] In a fourth aspect of the invention, there is provided a container comprising a pharmaceutical composition according to the first aspect, wherein the container can be a vial, single-use vial, light-protected vial, ampoule, syringe, pre-filled syringe, pre-filled cartridge, or injection pen. BRIEF DESCRIPTION OF THE FIGURES

[0030] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended figures. For the purpose of illustrating the disclosed compositions and methods, there are shown in the figures exemplary embodiments of the compositions and methods; however, the compositions and methods are not limited to the specific embodiments disclosed. In the figures:

[0031] FIG. 1 shows the XRPD diffractogram of Compound 1 free base, Form I.

[0032] FIG. 2 shows a DSC thermogram of Compound 1 free base, Form I.

[0033] FIG. 3 shows a TGA thermogram of Compound 1 free base, Form I

[0034] FIG. 4 shows DVS analysis of Compound 1 free base, Form I

[0035] FIG. 5 shows the XRPD diffractogram of freshly prepared Formulation 1 of Example 6 at To days.

[0036] FIG. 6 shows the XRPD diffractogram of Formulation 2 of Example 6 at Tw days.

[0037] FIG. 7 shows an overlay of the XRPD diffractograms of (1) freshly prepared Formulation 1 at To days, and (2) the XRPD diffractogram of Formulation 2 at Tw days.

[0038] FIG. 8 shows the mean plasma concentration-time profile of Compound 1 after intravenous dosing of the solution formulation disclosed in Example 7 at 1 mg / kg in sprague-dawley rats (n=3).

[0039] FIG. 9 shows the mean plasma concentration-time profile of Compound 1 after subcutaneous dosing of the suspension formulation disclosed in Example 5 at 200 mg / kg in sprague-dawley rats (n=3).

[0040] FIG. 10 shows individual plasma concentration-time profiles of Compound 1 after subcutaneous dosing of the suspension formulation disclosed in Example 5 at 200 mg / kg in sprague-dawley rats.

[0041] FIG. 11 shows the mean plasma concentration-time profile of Compound 1 after subcutaneous dosing of the suspension formulation disclosed in Example 5 at 200 mg / kg (closed diamonds) and the mean plasma concentration-time profile of Compound 1 after subcutaneous dosing of the suspension formulation disclosed in Example 4 at 100 mg / kg (closed circles) over a 168 hour time period in sprague-dawley rats (n=3). DETAILED DESCRIPTION OF THE INVENTION

[0042] The disclosed compositions, uses thereof and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions and methods are not limited to the specific compositions and methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions and methods. Definitions

[0043] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0044] Reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

[0045] It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0046] As used herein, the singular forms “a,” “an,” and “the” include the plural unless the context clearly dictates otherwise.

[0047] As used herein, Cmax refers to the geometric mean maximum concentration of the active agent. This may be measured in vivo following administration of a composition of the invention to a subject and measuring the plasma levels of the drug at various timepoints after dosing.

[0048] As used herein, AUC refers to the area under the curve and is the definite integral of the concentration of the active agent in blood plasma as a function of time.

[0049] As used herein, “patient” or “subject” refers to a mammal, including a domestic animal, animal kept as livestock and a zoo animal. Conveniently, the “patient” or “subject” is a human being.

[0050] It is to be appreciated that references to “treating” or “treatment” may include prevention as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes one or more of the following: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject (conveniently a human) that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. As used herein, “treating” and like terms may specifically include reducing the severity and / or frequency of HSV induced symptoms, eliminating HSV induced symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of HSV induced symptoms and / or their underlying cause, delaying, preventing and / or slowing the progression of HSV induced conditions, and improving or remediating damage caused, directly or indirectly, by HSV infections. The term "preventing," as used herein with respect to an HSV infection or HSV-related disorder, refers to reducing the likelihood of HSV infection.

[0051] In one embodiment, “treating” or “treatment” of a state, disorder or condition means (1) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (2) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. Conveniently, “treating” and like terms mean reducing the severity and / or frequency of HSV induced symptoms, eliminating HSV induced symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of HSV induced symptoms and / or their underlying cause, delaying, preventing and / or slowing the progression of HSV induced conditions, and / or improving or remediating damage caused, directly or indirectly, by HSV infections.

[0052] A “therapeutically effective amount” or “therapeutically effective dose” means the amount of a compound or a pharmaceutically acceptable salt thereof that, when administered to a patient or subject for treating a disease, is sufficient to effect such treatment for the disease. As used herein, the phrase “therapeutically effective dose” or “therapeutically effective amount” may specifically refer to the amount of Compound 1, or a pharmaceutically acceptable salt thereof, dosed to a patient or subject using a long-acting injectable pharmaceutical composition, as described herein, which is effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and / or regression of conditions caused by, or associated with, HSV or prevention of the development of conditions caused by, or associated with, HSV, as determined by any means suitable in the art.

[0053] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. Further, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0054] The term “about” when used in reference to numerical ranges, cut-offs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term “about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1 % or less, variations of ± 0.5% or less, or variations of ± 0.1 % or less from the specified value.

[0055] At various places in the present specification, values are disclosed in groups or in ranges. It is specifically intended that the description include all individual subcombination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0056] As used herein, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited process steps.

[0057] The use of any and all examples, or exemplary language herein, for example, “such as,” “including,” or “for example,” is intended merely to illustrate better the present teachings and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present teachings. Compound 1

[0058] The compound referred to herein as ‘Compound T is (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1 / 7-indene-2-carbonyl)indoline-6-sulfonamide and is a potent helicase-primase inhibitor. The compound is disclosed as Example 35 in WO2023 / 225162A1 (PCT Application No. PCT / US2023 / 022679).

[0059] Compound 1 is a potent helicase-primase inhibitor and has an in-vitro mean EC50 value of approximately 1 nM against both HSV-1 and HSV-2. The in-vitro EC50 value against HSV-1 and / or HSV-2 can be determined in accordance with methods known to the skilled person, such as those disclosed in Field et al. (2013, Antiviral Res. 100, p. 297299). The in-vitro EC50 value can also be determined in accordance with the assays described in the Examples section of the present application.

[0060] Compound 1 shows no or low levels of carbonic anhydrase inhibition, such as inhibition of carbonic anhydrase I and / or carbonic anhydrase II. Carbonic anhydrase inhibition can be measured using a carbonic anhydrase I assay as described in Katritzky et al. (J. Med. Chern. 1987, 30:2058) and a carbonic anhydrase I assay as described in lyeret al. (J. Biomol. Screen 2006, 11:782).

[0061] In some embodiments, a pharmaceutically acceptable salt of the Compound of 1 is used. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of Compound 1 and, which typically is not biologically or otherwise undesirable.

[0062] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic group such as an amine with a suitable acid affording a physiologically acceptable anion.

[0063] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalicacid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, aspartic acid, glutamic acid, glucuronic acid, glycolic acid, and other acids known to persons skilled in the art.

[0064] It is to be understood that Compound 1 may exhibit polymorphism, and that the invention encompasses all such forms (including anhydrous / non-solvated forms, solvates and hydrates).

[0065] The solid may be present in any suitable form, such as amorphous form, anhydrate, hydrate or solvate crystalline form(s).

[0066] In an embodiment Compound 1 is present in the composition as a crystalline solid. The crystalline solid may be present in any suitable form, such as anhydrate, hydrate or solvate forms. It is also to be understood that Compound 1 may be pure, essentially pure, or have a purity level greater than 75%, such as greater than 85%, greater than 90%, greater than 95%, greater than 97%, greater than 98%, or greater than 99% with respect to other crystalline forms (for example as measured by X-Ray powder diffraction).

[0067] In a convenient embodiment the Compound 1 present in the compositions of the invention is Compound 1 free base form and the free base form is present in the composition as a crystalline solid. It has been found that certain crystalline solid forms of Compound 1 are suited to the long-acting injectable depot compositions of the present invention. Conveniently, the Compound 1 crystalline free base form is Form I, as described in the Examples. Pharmaceutical Compositions of the Invention

[0068] In a first aspect, the present invention provides a long-acting injectable depot pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

[0069] As used herein, “long-acting injectable depot pharmaceutical composition”, refers to a pharmaceutical composition, which is a formulation adapted for administration to a subject (conveniently a human) via the subcutaneous or intramuscular route, wherein upon administration, a depot is formed from which the active ingredient of the composition (Compound 1) is released over a prolonged period of time.

[0070] In an embodiment, prolonged release refers to continuous active ingredient release over a period of at least 5 days, such as at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 56 days, at least 72 days, at least 96 days, at least 120 days, at least 180 days, at least 240 days, at least 300 days, or at least 365 days. The prolonged release of the active ingredient means that the active ingredient plasma levels may be kept at a therapeutically effective plasma concentration for at least 5 days, such as at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 56 days, at least 72 days, at least 96 days, at least 120 days, at least 180 days, at least 240 days, at least 300 days, or at least 365 days after administration of the composition, which a person skilled in the art will understand corresponds to “long-acting”.

[0071] It is to be understood that the rate of release of Compound 1 may vary during the prolonged release period, for example a short "initial burst" of active agent may be observed shortly after administration followed by a period of lower release. However, prolonged release means that plasma levels of Compound 1 can be kept at therapeutically effective plasma concentrations throughout most if not all of the duration of the prolonged release period.

[0072] In one embodiment, the pharmaceutical composition provides a short "initial burst" of active agent shortly after administration followed by a period of lower release. Advantageously, certain compositions of the invention are able to provide a rapid initial release to achieve a high plasma levels of Compound 1, followed by continuous release to maintain plasma levels at therapeutically effective concentrations over a prolonged period of time.

[0073] In an embodiment, the pharmaceutical composition releases less than 20% (conveniently less than 10%), by weight of the total amount of the active agent contained within the pharmaceutical composition within a period of 24 hours (conveniently 48 hours) after administration.

[0074] In an embodiment, the pharmaceutical composition is for administration twice a month, once a month, once every two months, once every three months, once every six months, or once every year. In an embodiment, the pharmaceutical composition is for administration once a month, once every two months, or once every three months. In an embodiment, the pharmaceutical composition is for administration once every three months, once every six months, or once every year.

[0075] Advantageously, the applicants have found that the prolonged release provided by certain compositions of the invention, and the resultant continuous plasma levels at therapeutically effective concentration over a prolonged period allow the possibility of using lower than expected doses of Compound 1. In an embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 14 days (conveniently at least 28 days, at least 56 days, at least 96 days, at least 120 days, at least 180 days, at least 240 days, or at least 300 days), is about 100 to 1200 mg (conveniently 300 to 900 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

[0076] In an embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 14 days (conveniently at least 28 days, at least 56 days, at least 96 days, at least 120 days, at least 180 days, at least 240 days, or at least 300 days), is about 5 to 1000 mg (conveniently 10 to 600 mg, 10 to 400 mg, 25 to 400 mg, 50 to 400 mg, or 50 to 300 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

[0077] In an embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 1 month, is about 100 to 900 mg (conveniently 100 to 600 mg) of Compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 1 month, is about 25 to 500 mg (conveniently 25 to 300 mg or 50 to 300 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

[0078] In an embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 3 months, is about 300 to 900 mg (conveniently 300 to 600 mg) of Compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 3 months, is about 100 to 500 mg (conveniently 100 to 400 mg or 100 to 300 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

[0079] In an embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 6 months, is about 300 to 1200 mg (conveniently 300 to 900 mg) of Compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the dose administered in a single administration of a long-acting injectable depot pharmaceutical composition, which is capable of providing prolonged release over a period of at least 6 months, is about 200 to 800 mg (conveniently 200 to 600 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

[0080] In an embodiment, the dose is administered in a single administration of a long-acting injectable depot pharmaceutical composition in an injection volume of about 0.1 to about 10 mL. Conveniently the dose is administered in an injection volume of about 0.1 to about 5 mL, about 0.1 to about 3 mL, about 0.1 to about 1.5 mL, or about 0.1 to about 0.75 mL. More conveniently, the dose is administered in an injection volume of about 0.1 to about 0.5 mL.

[0081] In a convenient embodiment, the pharmaceutical composition is designed for subcutaneous or intramuscular injection. In a further aspect of the present invention, the pharmaceutical composition is for subcutaneous administration. In a yet further aspect of the present invention, the pharmaceutical composition is for intramuscular administration. Conveniently, the dose of Compound 1 is administered subcutaneously in an injection volume of about 0.1 to about 10 mL, about 0.1 to about 5 mL, 0.1 to about 3 mL, or about 0.1 to about 1.5 mL. Conveniently, the dose of Compound 1 is administered intramuscularly in an injection volume of about 0.1 to about 10 mL, about 0.1 to about 5 mL, or about 0.1 to about 3 mL.

[0082] In an embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound 1. In a convenient embodiment, the pharmaceutical composition comprises Compound 1 in its free base form.

[0083] In a convenient embodiment, the pharmaceutical composition comprises the free base form of Compound 1, wherein the free base form is present as a crystalline solid.

[0084] It has been found that certain crystalline solid forms of the helicase-primase inhibitor, Compound 1, are surprisingly well suited to the long-acting injectable depot compositions of the present invention. In an embodiment the crystalline solid comprises Form I. Form I is characterized by an XRPD pattern substantially as shown in FIG. 1, The XRPD 20 peak values are shown in Table 4. In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (± 0.2° 20). In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (± 0.2° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8° 20 (± 0.2° 20), In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (± 0.1° 20). In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (±0.1° 20) and further comprising at least one, two or three specific peaks selected from the peaks at 12.5, 18.5 and 22.8° 20 (± 0.1° 20), In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (± 0.2° 20) and further comprising at least two, five, ten, fifteen or twenty specific peaks selected from the peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.5, 19.8, 20.3, 22.8, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.2° 20). In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (±0.1° 20) and further comprising at least two, five, ten, fifteen or twenty specific peaks selected from the peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.5, 19.8, 20.3, 22.8, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.1° 20). In an embodiment, Form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 230 °C. In an embodiment, Form I is characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2 ° 20 (± 0.1° 20) and a DSC thermogram having an endotherm onset of about 225°C to about 230 °C.

[0085] The benefits of the present invention are not limited to a particular type of long-acting injectable depot pharmaceutical composition having a particular mechanism of drug release. The pharmaceutical composition adapted for subcutaneous and / or intramuscular administration can be an aqueous based depot, an aqueous based suspension depot, a solution in organic solvent based formulation, a suspension in organic solvent based depot, a gel based depot, an in-situ gelling depot formulation, an oil-based depot, an emulsion based depot, a monolithic polymer based depot, a microparticle polymer based depot or a solid implant depot.

[0086] In an embodiment, the pharmaceutical composition of the present invention comprises a rate-controlling agent to help provide prolonged release of Compound 1. In an embodiment, the rate-controlling agent comprises at least one biodegradable polymer. Suitable biodegradable polymers are polymers capable of breaking down under physiological conditions such that the polymer and its degradation products do not invoke any unacceptable toxicity or immune response. Such polymers may be natural or synthetic in origin. Examples of natural biodegradable polymers include polysaccharides such as chitosan, alginate and dextran, or polyesters such as polyhydroxyalkanoates. Examples of synthetic biodegradable polymers include polymers of lactic acid and glycolic acid and copolymers thereof. In an embodiment, the biodegradable polymer is poly(lactic-co-glycolic acid) or polylactic acid, wherein each polymer is end-capped with either acid or ester groups. Conveniently, the biodegradable polymer is poly(lactic-co-glycolic acid). Poly(lactic-co-glycolic acid) is referred to herein also as PLGA. Conveniently, the biodegradable polymer is PLGA end-capped with acid groups. In an embodiment, the biodegradable polymer is PLGA, wherein the PLGA has a lactic acid weight content of about 5 to 95% with the balance being glycolic acid.

[0087] In a convenient embodiment, the pharmaceutical composition of the present invention is an aqueous based suspension, an oil-based suspension, a solution in organic solvent-based formulation, or an in-situ gelling depot formulation.

[0088] In a preferred embodiment, the pharmaceutical composition of the present invention is an oil-based depot, conveniently an oil-based suspension depot. Surprisingly, it has been found that certain oil-based suspension depot compositions provide active ingredient plasma levels at therapeutically effective plasma concentrations for prolonged periods without the need for a polymer-based rate-controlling agent. This can be particularly advantageous as it allows high drug loading, smaller administration volumes and lower excipient levels. In an embodiment, the pharmaceutical composition of the present invention does not comprise a rate-controlling agent or contains less than 20% or less than 15,10, 5, 3, 2 or 1% by weight of the total composition of a rate-controlling agent. In one embodiment, conveniently, the pharmaceutical composition of the present invention does not comprise a rate-controlling agent, such as a biodegradable polymer.

[0089] In a particular embodiment, the pharmaceutical composition is an oil-based suspension depot and the free base form of Compound 1 is suspended as a crystalline solid. Conveniently, the suspended crystalline solid is substantially present as Form I, such as the suspended crystalline solid is greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, or greater than 99.5% by weight of Compound 1 Form I.

[0090] Conveniently, the oil-based depot pharmaceutical composition comprises one or more pharmaceutically acceptable oils. In one embodiment, the one or more pharmaceutically acceptable oils are selected from castor oil, PEG-60 hydrogenated castor oil, polyoxyl 35 castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides, and long chain triglycerides.

[0091] The term “medium chain triglycerides” refers to triglycerides with two or three fatty acids having a saturated or unsaturated aliphatic tail of 6-12 carbons atoms. Examples of fatty acids having an aliphatic tail of 6-12 carbon atoms include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid and lauric acid. In an embodiment, the medium chain triglyceride is Miglyol®, preferably Miglyol® 812 N.

[0092] The term “long chain triglycerides” refers to triglycerides with two or three fatty acids having a saturated or unsaturated aliphatic tail of 13-21 carbon atoms. Examples of fatty acids having an saturated or unsaturated aliphatic tail of 13-21 carbon atoms include tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, a-linolenic acid, stearidonic acid, eicosapentaenoic acid, linoleic acid, linolelaidic acid, y-linolenic acid, dihomo-y-linolenic acid, arachidonic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid and mead acid.

[0093] Suitably, the oil-based depot pharmaceutical composition comprises a single oil. In one embodiment, the oil-based pharmaceutical composition is an oil-based suspension depot pharmaceutical composition and comprises medium chain triglycerides, such as Miglyol® 812 N. Suitably, the total amount of oil present is at a level of between about 50% and about 99% by weight of the final composition, preferably about 70-99% by weight of the final composition.

[0094] It has also been found that release can be influenced by the particle size of Compound 1 in an oil-based suspension depot composition. Suitable methods to determine the particle size distribution of a sample will be apparent to a person of skill in the art and include techniques such as laser diffraction. The term Dx (or Dvx) refers to the particle size up to and including which x% of the total volume of material in the sample is contained. For example, a D50 (or Dvso) of 10 p.m, means that 50% of the sample has a particle size of 10 p.m or smaller.

[0095] In an embodiment, the pharmaceutical composition is an oil-based nanosuspension depot composition. Conveniently, the particle size volume distribution of the suspended particles of Compound 1 in the oil-based nanosuspension depot composition are such that less than 10% of the particles have a size greater than 500 nm, when measured by laser diffraction analysis.

[0096] In an embodiment, the pharmaceutical composition of the present invention is a solution in organic solvent-based formulation. The organic solvent may be any suitable organic solvent that solubilises Compound 1 and is biocompatible. The suitable biocompatible organic solvent, after the formulation has been injected in-vivo, diffuses from the formulation leading to solidification of the formulation. Conveniently, the biocompatible solvent is non-toxic, water miscible, and does not cause severe tissue irritation or necrosis at the site of injection / implantation. Examples of such solvents may include benzyl alcohol, benzyl benzoate, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, oleic acid, and I-dodecylazacycloheptan-2-one. In an embodiment, the organic solvent is selected from N- methyl pyrrolidone (NMP), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, benzyl benzoate and mixtures thereof. The solution in organic solvent based formulation may optionally further comprise an aqueous media (such as aqueous buffer or saline) and / or a surfactant (such as a polyethylene glycol fatty ester, e.g. PEG-15 hydroxystearate).

[0097] In an embodiment, the pharmaceutical composition of the present invention is an in-situ gelling depot formulation. The term "in situ gelling depot formulation" as used herein refers to a formulation comprising Compound 1, a biodegradable polymer (such as the biodegradable polymers described as rate-controlling agents above) and a biocompatible solvent, which is delivered to a patient as an injectable liquid but solidifies into a solid depot formulation as the liquid solvent diffuses away in vivo. The suitable biocompatible solvent refers to any solvent in which the components of the formulation can be dissolved and which after the formulation has been injected in-vivo diffuses from the formulation leading to solidification of the formulation. Conveniently, the solvent for the biodegradable polymer be non-toxic, water miscible, and otherwise biocompatible. The solvents must also be biocompatible so that they do not cause severe tissue irritation or necrosis at the site of implantation. Furthermore, the solvent should be water miscible so that it will diffuse quickly into the body fluids and allow water to permeate into the polymer solution and cause it to coagulate or solidify. Examples of such solvents include benzyl alcohol, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, oleic acid, and l-dodecylazacycloheptan-2-one.

[0098] One or more pharmaceutically acceptable excipients is included in the composition according to the present invention. The long-acting injectable depot pharmaceutical compositions of the invention comprise at least one excipient selected from the group consisting of a solvent, co-solvent, wetting or suspending agent, an isotonic agent, a pH adjusting agent, a stabiliser, an emulsifier and a viscosity modifier.

[0099] Suitable wetting or suspending agents, included in the formulations of the present invention, include cellulose derivatives, polyvinylpyrrolidone, polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters and poloxamers.

[00100] Isotonic agents that can be included in the long-acting injectable depot pharmaceutical compositions of the present invention are, for example, sodium chloride, dextrose, mannitol, sorbitol, lactose, and / or sodium sulfate.

[00101] The pH adjusting agent contained in long-acting injectable depot pharmaceutical compositions of the present invention may be hydrochloric acid or sodium hydroxide, but is not limited thereto.

[00102] The depot preparation of the present invention may further contain a preservative and the preservative may be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, parabens, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, thiomerosal, meta-cresol or chlorobutanol, or the like.

[00103] In some embodiments, the long-acting injectable depot pharmaceutical compositions of the invention comprise at least one viscosity modifier. In some cases, the viscosity modifier is selected from the group consisting of sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, crosslinked carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, acacia, gelatin, and polyvinyl pyrrolidone.

[00104] The long-acting injectable depot pharmaceutical compositions of the present invention may be stored by freeze-drying, e.g. in a suitable vial, and can be resuspended, for injection immediately before injection. Compositions can be stored in a pre-filled syringe.

[00105] Advantageously, the compositions of the invention may demonstrate good stability on storage. Therefore, in an embodiment, the composition is stable for at least four weeks, such as for at least eight weeks, or at least twelve weeks. In this context, ‘stable’ may refer to the physical and / or chemical stability of the active agent (Compound 1) within the long-acting injectable depot pharmaceutical composition. ‘Stable’ may also refer to the release profile or pharmacokinetics of the composition being maintained over the storage period referred to. ‘Stable’ may also refer to the appearance of the composition; for example, for an aqueous based suspension depot composition it may refer to the homogeneity of the suspension being maintained over the storage period referred to.

[00106] Physical stability relates to maintenance of the active agent in the same physical form. When the long-acting injectable depot pharmaceutical composition is a suspension and the active agent is suspended as a crystalline solid, then the physical form (as determined by XRPD) of the suspended solid does not change during the storage period referred to.

[00107] In an embodiment, the long-acting injectable depot pharmaceutical composition is a suspension comprising Compound 1, or a pharmaceutically acceptable salt thereof, suspended as a crystalline solid, wherein the composition is physically stable for at least one week, two weeks, three weeks, four weeks, six weeks or eight weeks. In an embodiment, the composition is a suspension comprising Compound 1 free base suspended as a crystalline solid (conveniently, Form I), wherein the composition is physically stable for at least one week, two weeks, three weeks, four weeks, six weeks or eight weeks as determined by XRPD of the suspended solid. In an embodiment, the composition is an oil-based suspension comprising Compound 1 free base suspended as Form I crystalline solid, wherein the composition is physically stable for at least one week, two weeks, three weeks, four weeks, six weeks or eight weeks as determined by XRPD of the suspended solid.

[00108] Chemical stability relates to low levels of impurities being formed over the storage period referred to. Typically, these are impurities related to the active agent and may be measured by suitable techniques such as HPLC or LC-MS.

[00109] Release of the active agent from the compositions of the invention can be determined by methods known in the art. For example, release rates may be determined using in-vitro dissolution tests, which mimic an aqueous physiological-type environment. The term "aqueous physiological-type environment" as used herein refers to the body of a warm blooded animal, particularly human. In particular embodiments, the compositions of the invention are designed for sub-cutaneous or intra-muscular administration and the term "aqueous physiological-type environment" for such compositions refers to the subcutaneous or intra-muscular environments of such a body. These conditions may be simulated in vitro by placing a composition in an aqueous dissolution medium, optionally buffered to a physiological pH, at a temperature of from 35 to 40°C. The amount of active released over a given time period may be determined by sampling the dissolution medium and measuring the concentration of the active using a suitable analytical method, for example HPLC.

[00110] Release of the active from the compositions of the invention can also be determined by in-vivo methods known in the art. For example, release in vivo can be tested by measuring plasma concentrations at predetermined time periods and thereby obtaining a plasma concentration versus time profile for the compound of interest.

[00111] Other tests may also be used to determine the amount of release of the active agent in vivo. Animals (e.g., mice, rats, dogs etc.) may be used as models to investigate release characteristics. For example, for a subcutaneous or intramuscular composition, animals can receive the composition under investigation and after specified periods of time, the animals can be sacrificed and the subcutaneous or intramuscular composition can be extracted / retrieved and analysed. By determining the content of the active agent remaining in the composition at specified periods of time, the amount and extent of release can be calculated.

[00112] Advantageously, compositions of the invention are able to maintain a therapeutically effective plasma concentration of the drug throughout a prolonged period. Pharmacokinetics

[00113] The present invention provides long-acting injectable depot pharmaceutical compositions that provide certain advantages over prior art compositions in terms of providing steady and continuous plasma Compound 1 levels for prolonged periods, such that viral shedding and viral reactivation may be reduced or even eliminated.

[00114] In an embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean plasma concentration of Compound 1 of at least 25 ng / mL after administration throughout at least 80% (such as at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or substantially all) of at least a 10 day period.

[00115] In an embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention comprises Compound 1, or a pharmaceutically acceptable salt thereof, which produces a plasma concentration of the Compound 1 in the subject after administration of at least 25 ng / mL (such as at least 50 ng / mL, or at least 100 ng / mL) for at least 80% (such as at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or substantially all) of the dosing interval. Conveniently, the dosing interval is at least 10 days (such as at least 14 days, at least 21 days, at least 28 days, at least 56 days, at least 72 days, at least 96 days, at least 120 days, at least 180 days, at least 240 days, at least 300 days, or at least 365 days). In an embodiment, the dosing interval is at least 14 days or at least 28 days. Conveniently, the dosing interval is at least 56 days, at least at least 96 days, at least 120 days, at least 180 days, at least 240 days, at least 300 days, or at least 365 days.

[00116] Compound 1 is subject to plasma protein binding. Dependent on the extent of the plasma protein binding, the free fraction (unbound active agent) may be low relative to the protein bound fraction. In an embodiment, the plasma concentrations referred to above refer to the total (unbound and protein bound) plasma concentrations. Therefore, in an embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean total plasma concentration of Compound 1 of at least 25 ng / mL throughout at least a 10 day period. In an embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean total (unbound and protein bound) plasma concentration of Compound 1 of at least 200 ng / mL (such as at least 300 ng / mL, or at least 500 ng / mL) throughout at least a 10 day period. In a further embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean total (unbound and protein bound) plasma concentration of Compound 1 of at least 50 ng / mL (such as at least 100 ng / mL, at least 200 ng / mL, at least 300 ng / mL, at least 500 ng / mL, at least 600 ng / mL, at least 1000 ng / mL, or at least 2000 ng / mL) throughout at least a 10 day period.

[00117] In a further embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean total (unbound and protein bound) plasma concentration of Compound 1 of at least 300 ng / mL, at least 500 ng / mL, or at least 600 ng / mL, throughout at least a 10 day period. In a further embodiment, the long-acting injectable depot pharmaceutical composition according to the present invention, after administration to a subject in need of treatment thereof, maintains in the subject a geometric mean total (unbound and protein bound) plasma concentration of Compound 1 of about 50 ng / mL to about 4000 ng / mL throughout at least a 10 day period. Particular Compositions of the Invention

[00118] In one embodiment, the present invention provides a long-acting injectable depot pharmaceutical composition comprising Compound 1 and one or more pharmaceutically acceptable excipients, wherein the long-acting injectable depot pharmaceutical composition continuously releases Compound 1 at a rate resulting in therapeutic plasma concentrations of the Compound 1 for a period of at least 1 month after subcutaneous or intramuscular administration. Conveniently, the long-acting injectable depot pharmaceutical composition comprises about 1 wt. % to about 80 wt. % of Compound 1. Conveniently, the long-acting injectable depot pharmaceutical composition comprises about 10 wt. % to about 40 wt. % of Compound 1. Conveniently, the long-acting injectable depot pharmaceutical composition comprises 300 to 900 mg of Compound 1 (conveniently, 25 to 400 mg of Compound 1) and the long-acting injectable depot pharmaceutical composition is administered in an injection volume of about 0.1 to about 3 mL. Conveniently, the long-acting injectable depot pharmaceutical composition is an oilbased suspension.

[00119] In one embodiment, the present invention provides a long-acting injectable depot pharmaceutical composition comprising: a) Compound 1 free base form (conveniently Form I); and b) one or more pharmaceutically acceptable excipients; wherein the long-acting injectable depot pharmaceutical composition continuously releases Compound 1 at a rate resulting in therapeutic plasma concentrations of the helicase-primase inhibitor for a period of at least 1 month after a single subcutaneous or intramuscular administration.

[00120] In one embodiment, the present invention provides a long-acting injectable depot pharmaceutical composition comprising: a) Compound 1 free base form (conveniently Form I); and b) one or more pharmaceutically acceptable excipients; wherein the long-acting injectable depot pharmaceutical composition comprises 300 to 900 mg of Compound 1 (conveniently, 25 to 400 mg of Compound 1) and the long-acting injectable depot pharmaceutical composition is administered in an injection volume of about 0.1 to about 3 mL. Conveniently, the long-acting injectable depot pharmaceutical composition continuously releases Compound 1 at a rate resulting in therapeutic plasma concentrations of Compound 1 for a period of at least 1 month (preferably at least 3 months) after a single subcutaneous or intramuscular injection. Conveniently, the long-acting injectable depot pharmaceutical composition is an oil-based suspension. Suitably, the oil-based suspension comprises a single oil. Conveniently, the oil-based suspension comprises medium chain triglycerides, such as Miglyol® 812 N. Suitably, the total amount of oil present is at a level of between about 50% and about 99% by weight of the final composition, preferably about 70-99% by weight of the final composition. Preparation of the Compositions

[00121] In a second aspect, the present invention provides a method for forming a pharmaceutical composition according to the first aspect.

[00122] In an embodiment, the pharmaceutical composition of the present invention is an oil-based suspension depot. In an embodiment, a process for the preparation of the oilbased suspension depot comprises the steps of: a) incorporating Compound 1, or a pharmaceutically acceptable salt thereof, in a oilbased vehicle, such as Miglyol® 812 N, wherein the oil-based vehicle optionally comprises a suspending agent; and b) mixing Compound 1, or a pharmaceutically acceptable salt thereof (e.g. by stirring and / or vortexing and / or sonication) to provide a homogenous suspension suitable for subcutaneous or intramuscular administration. Therapeutic Methods, Uses and Applications

[00123] The present invention provides a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is administered via the injectable route of administration. Conveniently, Compound 1 or a pharmaceutically acceptable salt thereof, is administered by subcutaneous or intramuscular injection.

[00124] The present invention provides a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention. Conveniently, the pharmaceutical composition is administered by subcutaneous or intramuscular injection.

[00125] The present invention also provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

[00126] The present invention also provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a herpes virus (conveniently a HSV) infection in a subject in need thereof.

[00127] The present invention also provides the use of a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a herpes virus (conveniently a HSV) infection in a subject in need thereof.

[00128] In a particular embodiment, the present invention provides a method for inhibiting HSV replication in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00129] In one embodiment, the present invention also provides a method for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00130] In one embodiment, the present invention provides a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00131] In one embodiment, the present invention provides a method for suppressing recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00132] In an embodiment, the present invention provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in suppressing the recurrence of HSV symptoms or outbreaks in a subject in need thereof.

[00133] In an embodiment, the present invention provides the use of a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the suppression of the recurrence of HSV symptoms or outbreaks in a subject in need thereof.

[00134] In one embodiment, the present invention provides a method for treating or preventing a disease or disorder caused, exacerbated, or accelerated by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention. In a particular embodiment, the disease or disorder caused, exacerbated, or accelerated by, or associated with, HSV infection, is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s), Herpes genitalis, HSV-related keratitis, HSV-related encephalitis, pneumonia, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis, and Bell's palsy.

[00135] In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (oro-labial cold sores or Whitlow’s) or genital herpes. In one embodiment, the disease or disorder is recurrent herpes labialis or recurrent genital herpes. Individuals with a history of multiple recurrences of herpes labialis or recurrent genital herpes, e.g. HSV which recurs six times or more annually, may be regarded as having recurrent HSV.

[00136] In one embodiment, the herpes virus being treated is HSV2. In a further embodiment, the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes.

[00137] In one embodiment, the herpes virus being treated is HSV1. In yet a further embodiment, both herpes virus HSV1 and HSV2 are being treated.

[00138] In one embodiment, the herpes virus being treated is resistant to nucleoside antiviral therapy. In one embodiment, the nucleosidic antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[00139] In one embodiment, the herpes virus infection being treated is resistant to nucleosidic antiviral therapy, e.g., acyclovir-resistant mucocutaneous HSV infection. In a further embodiment, the HSV infection being treated is a mucocutaneous HSV infection resistant to therapy with antiviral therapy with nucleoside analogues, such as acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir.

[00140] In a particular embodiment, the subject in need of the methods disclosed herein, is immunocompromised. The subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation, chronic glucocorticoid use or a genetic immunodeficiency.

[00141] In a particular embodiment, the subject in need of the methods disclosed herein, is a neonate or an infant.

[00142] In a particular embodiment, the subject is a herpes-positive patient.

[00143] In a particular embodiment, the subject in need of the methods disclosed herein, has acyclovir-resistant mucocutaneous HSV infection. This subject may have been diagnosed with this condition on the basis of clinical failure, e.g., no improvement after oral or iv doses for at least 7 days with approved doses of acyclovir.

[00144] In a particular embodiment, the subject in need of the methods disclosed herein, has a primary genital HSV-related herpes infection. In one embodiment, the subject in need of the methods disclosed herein, has severe or progressive genital HSV-related herpes infection.

[00145] In a particular embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce recurrence of HSV infections (i.e., provide a suppressive therapy) causing diseases or disorders, such as herpes labialis or genital herpes. In one embodiment, the reduction in the number of recurrences of lesions over a period of one year can be reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the rate of lesions over one year can be reduced by 90% or more.

[00146] In a particular embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce the duration of recurrent episodes of HSV infection, e.g., by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days.

[00147] In a particular embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from HSV infections in diseases or disorders, such as herpes labialis or genital herpes. The time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.

[00148] In one embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce pain or pain intensity (for example, at a lesion site) caused as a consequence of HSV infections in diseases or disorders, such as herpes labialis or genital herpes.

[00149] In a particular embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce viral shedding or reduce the rate of viral shedding in individuals with frequently recurring HSV, e.g., genital HSV2. For example, a within-subject genital HSV mucocutaneous shedding rate can be measured by taking swabs of skin and mucosa and for HSV detection, e.g. by analysing samples for HSV DNA with a real-time, quantitative, fluorescent polymerase-chain-reaction (PCR) assay. The frequency of HSV2 detection (the viral shedding rate) can be defined as the number of days with a genital swab that was positive for HSV divided by the total number of days on which genital swabs were obtained. Reduction in the HSV shedding rate among subjects receiving the compositions of the invention relative to the shedding rate among subjects receiving placebo or other treatments can be compared. The quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes can also be monitored.

[00150] In a particular embodiment, the present invention provides a method for reducing (or substantially supressing or eliminating) break-through HSV shedding in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00151] In an embodiment, the present invention provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in reducing (or substantially supressing or eliminating) break-through HSV shedding in a subject in need thereof.

[00152] In an embodiment, the present invention provides the use of a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the reduction (or substantial suppression or elimination) of break-through HSV shedding in a subject in need thereof.

[00153] In a particular embodiment, the present invention provides a method for preventing transmission of an infectious disease caused by HSV, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00154] In a particular embodiment, the present invention provides a method for reducing side effects observed when Compound 1, or a pharmaceutically acceptable salt thereof, is administered via an oral route of administration to a subject with an infectious disease caused by HSV, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00155] Pharmaceutical compositions according to the present invention are injectable depot compositions and are therefore to be dosed by intramuscular or subcutaneous administration. In a convenient embodiment, the pharmaceutical compositions according to the present invention are administered by subcutaneous administration. In a convenient embodiment, the pharmaceutical compositions according to the present invention are administered by intramuscular administration.

[00156] For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the nature and severity of the infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 pg / kg body weight. In some cases, the administration dose of the compound may be less than 400 pg / kg body weight. In other cases, the administration dose may be less than 200 pg / kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 pg / kg body weight. In an embodiment, the therapeutically effective amount of the Compound 1 or a pharmaceutically acceptable salt thereof, is about 5 mg to about 900 mg, such as about 100 mg to about 600 mg. In a further embodiment, the therapeutically effective amount of the Compound 1 or a pharmaceutically acceptable salt thereof, is about 5 mg to about 600 mg, such as about 25 mg to about 400 mg, or such as about 50 mg to about 300 mg.

[00157] Advantageously, the applicants have found that the prolonged release provided by the compositions of the invention and the resultant steady plasma levels kept at a therapeutically effective plasma concentration over a prolonged period after administration allow the possibility of using lower than expected doses.

[00158] The dose may be conveniently administered twice a month or less, once a month or less, once every two, three, four, five or six months or less. Conveniently, the dose may be conveniently administered once a month, once every two months or once every three months.

[00159] In a convenient embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection. In a convenient embodiment, the unit dosage form of the pharmaceutical composition comprises about 5 mg to about 900 mg (such as about 100 mg to about 900 mg) of the Compound 1, or a pharmaceutically acceptable salt thereof. In a most convenient embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection comprising about 100 mg to about 600 mg of the Compound 1, or a pharmaceutically acceptable salt thereof. In a further convenient embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection comprising about 25 mg to about 400 mg of the Compound 1, or a pharmaceutically acceptable salt thereof.

[00160] In a convenient embodiment, the unit dosage form of the pharmaceutical composition comprises about 100 mg to about 1200 mg (such as about 100 mg to about 900 mg) of Compound 1, or a pharmaceutically acceptable salt thereof. In a most convenient embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection comprising about 100 mg to about 900 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a yet more convenient embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection comprising about 200 mg to about 900 mg, such as about 200 mg to about 600 mg, about 300 mg to about 900 mg, or about 300 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a further embodiment, the unit dosage form of the pharmaceutical composition is a subcutaneous injection comprising about 25 mg to about 400 mg, such as about 25 mg to about 300 mg, or about 25 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[00161] In one embodiment, the present invention provides a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention (for example, certain long-acting injectable depot pharmaceutical compositions comprising an oil-based suspension), wherein no loading dose, such as an oral administration loading dose, is required prior to administration of long-acting injectable depot pharmaceutical composition according to the first aspect of the invention. Combinations

[00162] Pharmaceutical compositions of the present invention may be administered alone as a sole therapy or can be administered in addition with one or more other substances and or treatments. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.

[00163] Also contemplated herein are methods that include administering a second, third or fourth active agent. For example, in addition to being infected with HSV, a subject or patient can further have HSV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HSV. Contemplated herein are also disclosed pharmaceutical compositions in combination with at least one other agent that has previously been shown to treat these HSV-infection-related conditions. Such conjoint treatment may be achieved independently (by way of simultaneous, sequential or separate administration of the individual components of the treatment) and / or via pharmaceutical compositions of the present invention that include a second active agent.

[00164] Therefore, provided herein is a method for treating or preventing HSV infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition according to the first aspect of the invention, and coadministering to the subject a therapeutically effective amount of an additional therapeutic agent.

[00165] In an embodiment, the additional therapeutic agent is selected from one or more of the following agents: Complement receptor 2 antagonists; Duffy antigen chemokine receptor modulators; Envelope glycoprotein GP350 modulators; Glucocorticoid receptor agonists; Helicase inhibitors; helicase-primase inhibitors; HIV gp160 protein inhibitors; HIV gp41 protein inhibitors; HIV-1 reverse transcriptase inhibitors; HLA class I antigen A-2 alpha modulators; HI_A class I antigen A-24 alpha modulators; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein H modulators; Human cytomegalovirus glycoprotein inhibitors; Human cytomegalovirus glycoprotein L modulators; Immunoglobulin G agonists; Interferon alpha 2 ligands; Interferon gamma receptor antagonists; Latent membrane protein 1 modulators; Latent membrane protein 2 modulators; Latent membrane protein 2 stimulators; Progesterone receptor agonists; Secreted protein BARF1 modulators; Serine threonine protein kinase UL97 modulators; T-cell surface glycoprotein CD8 stimulators; Thymidine kinase inhibitors; Trans acting transcription protein ICP4 modulators; Transferase inhibitors; Unspecified gene inhibitors; Adenosylhomocysteinase inhibitors; Basigin inhibitors; Basigin modulators; CCR5 chemokine modulators; CD4 agonists; CD4 modulators; CD89 agonists; CMV 65kDa lower matrix phosphoprotein modulators; CRISPR associated endonuclease Cas9 modulators; Cyclin dependent kinase inhibitors; Cyclin dependent kinase inhibitors; Cyclin-dependent kinase-9 inhibitors; DNA polymerase inhibitors; DNA primase inhibitors; Endonuclease modulators; Epstein-Barr nuclear antigen 1 inhibitors; Epstein-Barr nuclear antigen 1 modulators; Epstein- Barr nuclear antigen 1 stimulators; Fatty acid synthase inhibitors; Herpesvirus envelope glycoprotein B stimulators; Herpesvirus envelope glycoprotein D inhibitors; Herpesvirus envelope glycoprotein D modulators; HIV gp120 protein inhibitors; HLA class I antigen A-11 alpha modulators; Hsp 90 inhibitors; Human cytomegalovirus glycoprotein B inhibitors; Human cytomegalovirus glycoprotein B modulators; Human cytomegalovirus glycoprotein inhibitors; Hyaluronidase inhibitors; Immunoglobulin agonists; Interferon alpha 1 ligands; Interferon alpha 2 ligands; Interferon alpha ligand inhibitors; Interferon alpha ligand modulators; Interferon beta ligands; Large terminase protein inhibitors; LAT gene inhibitors; NAD-dependent deacetylase sirtuin modulators; Nicotinic acetylcholine receptor antagonists; NKG2D ligand modulators; Nucleotidyltransferase inhibitors; Protein Jumonji inhibitors; Ribonuclease stimulators; Serine threonine protein kinase LIL97 inhibitors; Syntaxin-5 inhibitors; TAT protein modulators; T-cell surface glycoprotein CD8 stimulators; TLR-4 agonists; and viral ribonucleotide reductase inhibitors. In some embodiments, the one of more therapeutic agents are selected from famciclovir, acyclovir, and valacyclovir.

[00166] In an embodiment, the additional therapeutic agent is selected from one or more of the following agents: i. nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir and ganciclovir; ii. pyrophosphate polymerase inhibitors, such as foscarnet; iii. saturated aliphatic alcohols, such as docosanol; iv. agents such as idoxuridine, trifluridine and vidarabine; v. a corticosteroid; and vi. other helicase-primase inhibitors, such as amenamevir.

[00167] In some cases, a disclosed pharmaceutical composition according to the first aspect of the invention may be administered as part of a combination therapy in conjunction with one or more antivirals, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciciovir or the respective prodrugs valaciclovir or famciclovir.

[00168] In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of Compound 1 first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy. Kits

[00169] In a fourth aspect of the invention, there is provided a container comprising a pharmaceutical composition according to the first aspect, wherein the container can be a vial, single-use vial, light-protected vial, ampoule, syringe, pre-filled syringe, pre-filled cartridge, or injection pen.

[00170] In one embodiment, the pharmaceutical compositions and methods described herein provide kits for the treatment of disorders, such as the one described herein. These kits comprise a pharmaceutical composition described herein in a container or other suitable packaging and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

[00171] The pharmaceutical compositions of the invention may be utilized for diagnostics and as research tools.

[00172] Besides being useful for human treatment, pharmaceutical compositions of the invention, may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Conveniently, such animals include horses, dogs and cats.

[00173] The invention is illustrated below by the following non-limiting examples. EXAMPLES

[00174] The following abbreviations are used within this specification: DCM:       Dichloromethane DMSO:       Dimethyl sulfoxide DSC:         Differential Scanning Calorimetry DVS:        Dynamic Vapor Sorption eq:           Equivalents EtOAc:       Ethyl acetate hr:            Hours HPLC:       High Performance Liquid Chromatography MeOH:      Methanol NaBHsCN:   Sodium cyanoborohydride NaH:        Sodium hydride min:          Minutes m / z          Mass to charge ratio Na2SO4:      Sodium sulfate NMR:        Nuclear magnetic resonance spectroscopy PVP:         Polyvinylpyrrolidone RH:          Relative Humidity RT:         Room Temperature (~22°C) SFC         Supercritical Fluid Chromatography TFA:          Trifluoroacetic acid TGA:        Thermogravimetric analysis THF:         Tetrahydrofuran LIPLC:       Ultra Performance Liquid Chromatography Vol:         Volume XRPD:       X-Ray Powder Diffraction Materials and Methods X-Ray Powder Diffraction (XRPD) analysis

[00175] Unless stated otherwise, XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ker radiation produced using a long, fine-focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg-Brentano geometry. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate. Antiscatter slits (SS) were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. Differential Scanning Calorimetry

[00176] Differential Scanning Calorimetry (DSC) data were collected using a TA Instruments 2920 and Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into a T zero aluminium DSC pan, covered with a lid and crimped. The weight was then accurately recorded. A weighed aluminium pan configured as the sample pan was placed on the reference side of the cell. The sample was heated from -30°C to 250°C at 10°C / minute. Thermogravimetric Analysis

[00177] Thermogravimetric Analysis (TGA) data were collected using a TA Instruments Discovery thermogravimetric analyser. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in an aluminium pan and inserted into the TG furnace. The furnace was heated under a nitrogen purge. The sample was heated from ambient to 350°C at 10°C / minute. Moisture sorption / desorption

[00178] Moisture sorption / desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCI and PVP were used as calibration standards. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Weight percentages reported in the data section are relative to the total sample mass introduced prior to equilibration at 5% RH as measured on the instrument. EXAMPLE 1: Synthesis of ( / ?)-5-fluoro-2-methvl-1-(( / ?)-5-(pyridin-2-vl)-2,3-dihvdro-1H-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1)

[00179] Compound 1 was prepared according to the procedures described in Example 35 of PCT Application No. PCT / US2023 / 022679. Preparation of Intermediate 2: 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid Intermediate 2 Preparation of Intermediate 2.1: To a stirred suspension of 60% NaH (22.72 g, 2 equiv) in THF (1000 mL) at 0 °C was added diethyl carbonate (86 mL, 1.5 equiv). To this was added 5-bromo-indan-1-one (100 g, 473.1 mmol) portion wise at this temperature. The reaction mixture continued to stir at this temperature until gas evolution subsided. The reaction mixture was slowly heated to 50 °C and maintained stirring for 2h. Progress of the reaction was monitored by TLC, and after consumption of starting material, the reaction mixture was allowed to cool to RT. The reaction was diluted with EtOAc (10V). To this was added 3N aq HCI dropwise. Both layers were separated. Aqueous layer was extracted with EtOAc (2 x 5V). The combined organic layer was washed with brine solution (5V), dried (Na2SO4) and evaporated to obtain the crude, which was purified by column chromatography on silica gel to afford Intermediate 2.1. LCMS: 283.0 [M+H],

[00180] Preparation of Intermediate 2.2: To a solution of Intermediate 2.1 (56 g, 197.9 mmol) in TFA (280 mL) at 0°C was added triethyl silane (224 mL) dropwise and the reaction mixture was stirred at rt for 24 h. Progress of the reaction was monitored by TLC. After consumption of starting materials, the reaction mixture was evaporated to dryness under reduced pressure to obtain the crude. The crude was purified by column chromatography on silica gel to obtain Intermediate 2.2. LC / MS: 269.0 [M+H],

[00181] Preparation of Intermediate 2.3: A stirred solution of Intermediate 2.2 (40 g, 148.7 mmol) and 2-tributylstannylpyridine (57.5 g, 1.05 equiv) in 1,4 dioxane (400 mL) was degassed for 10 min using argon, at which time Pd(PPh3)4 (8.6 g, 5 mol%) was added and again degassed for another 10 min. The reaction mixture was heated to 90 °C for 16h. The reaction mixture was filtered through Celite pad and the Celite pad was washed with ethyl acetate twice. The combined filtrate was evaporated to dryness to obtain crude. The crude was purified by column chromatography on silica gel to afford Intermediate 2.3. LC / MS: 268.1 [M+H],

[00182] Preparation of Intermediate 2: To a stirred solution of Intermediate 2.3 (35 g, 131.1 mmol) in methanol (350 mL) at 0°C was added 2N aq NaOH solution (140 mL, 2.2 equiv) and the reaction mixture was stirred at rt for 4h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 100 mL. The residue was diluted with water (10V) and the aqueous layer washed with ethyl acetate (2 x 2 V). The aqueous phase was neutralized with 2N aq HCI solution and extracted with 10% Methanol / DCM (3 x 5V). The organic layer was dried over sodium sulfate and concentrated to afford the crude. Then the crude was taken with 10% isopropanol / toluene (10V) solution and treated with activated carbon. The solvent was then removed under reduced pressure. The residue was taken in 30% toluene / hexane, stirred for 30 min and filtered, and then dried under vacuum. This process was repeated two additional times to afford Intermediate 2. LC / MS: 238.1 [M-H], Preparation of Intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid. Intermediate 19 was obtained as the first eluent of SFC purification of Intermediate 2 using a Chiralpak AD-H column with 20% methanol as co-solvent. LC / MS: 238.1 [M-H], Preparation of Intermediate 21:

[00183] Preparation of Intermediate 21.1: 5-fluoro-2-methylindoline (40 g, 268 mmol, 1 eq) was taken up in acetic acid (200 mL, 5V). NaBHsCN (50 g, 815 mmol, 3 eq) was added portion-wise while maintaining the temperature below 10° C. The resulting solution was warmed to RT and stirred for 3 h, at which time the reaction was diluted with ice-cold water (500 mL). The reaction was then extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over Na2SO4 and concentrated in vacuo. The crude Intermediate 21.1 was isolated as a thick yellow oil and used in the next step without further purification. LC / MS: 151.2 [M+H],

[00184] Preparation of Intermediate 21.2: To a stirred solution of Intermediate 21.1 (35 g, 86.6 mmol) in DCM (300 mL) was added triethylamine (35 mL, 1 vol) followed by acetyl chloride (35mL, 1 vol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The residue was quenched with cold water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (100200 silica gel, eluted 8% EtOAc-Hexane) to afford Intermediate 21.2. LC / MS: 193.2 [M+H],

[00185] Preparation of Intermediate 21.3: To a stirred solution of Intermediate 21.2 (35 g, 0.011 mol) in chlorosulfonic acid (250 mL, 10 V) at 0 °C under nitrogen and the reaction mixture was stirred at 50 °C for 3h. Upon completion of the reaction, the mixture was diluted with ice-cold water. The precipitate was filtered, taken up in dichloromethane (50 mL), and added to a solution of concentrated ammonium hydroxide (20 mL). After vigorous stirring for 15 minutes at RT, the solvent was removed under pressure and the resulting solid was filtered and rinsed with water to afford Intermediate 21.3. LC / MS: 272.3 [M+H],

[00186] Preparation of Intermediates fR>21 and fS>21: A racemic mixture of Intermediate 21.3 (30 g, 110 mmol, 1 equiv) in 500 mL of 2N sodium hydroxide was heated at 100°C for 3 hours. The reaction was cooled to RT and the pH was adjusted to 7 with acetic acid. The precipitate was filtered, washed with water, and dried under vacuum. The resulting de-acetylated racemic mixture was then subjected to chiral SFC purification using a ChiralPak IG 240 x 4.6 mm column with a mobile phase consisting of 70:20:10 hexane: methanol: MTBE. Intermediate fRJ-21 was collected as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H], Intermediate fSj-21 was collected as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H], Preparation of Compound 1: Intermediate (R)-21b Compound 1

[00187] Intermediate (iRJ-21 was taken up in THF (10 V) and dimethylformamide dimethyl acetal (1.2 equiv) was added at once. The solution was stirred at RT for 30 minutes and the solvent was then removed under reduced pressure to afford the crude residue Intermediate fR]-21a (LC / MS: 286.1 [M+H]) which was used directly in the next step without further purification.

[00188] Intermediate (7?)-21a was taken up in acetonitrile (10 V). Intermediate 19 (1 equiv) was added, followed by TCFH (2 equiv). The suspension was placed in a RT water bath and / V-methylimidazole (5 equiv) was added dropwise. The solution stirred at RT for 1 hour, at which time LC / MS analysis indicated complete conversion to Intermediate (R)-21b (LC / MS: 507.2 [M+H]). Hydrazine hydrate (50 equiv) was then added at once and allowed to stir at RT for 30 minutes, after which time water was added (5 V). The resulting precipitate was filtered and dried under reduced pressure to afford Compound 1.1H NMR (400 MHz, DMSO-d6) 6 8.69 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 6.6 Hz, 1H), 8.10 - 7.84 (m, 4H), 7.58 (s, 2H), 7.51 - 7.24 (m, 3H), 4.90 (t, J = 7.5 Hz, 1H), 3.77 (p, J = 8.2 Hz, 1H), 3.46 (ddt, J = 34.0, 17.5, 8.7 Hz, 3H), 3.20 (ddd, J = 59.1, 16.3, 8.3 Hz, 2H), 2.80 (d, J = 16.9 Hz, 1H), 1.30 (d, J = 6.2 Hz, 3H). LC / MS: 452.1 [M+H], EXAMPLE 2: Biological assay data for ( / ?)-5-fluoro-2-methvl-1-(( / ?)-5-(pyridin-2-vl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1) HSV-2 Cellomics Assay

[00189] Compound 1 was tested for its ability to inhibit HSV-2 replication by monitoring the expression of the HSV protein gD using a high-throughput immunofluorescence-based assay. 10-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 0.2 or 2 mM in 100% DMSO. 250 nl of compounds were spotted in quadruplicates onto black collagen-coated 384-well microplates with clear bottom (Greiner cat# 781956) using a Labcyte ECHO acoustic dispenser. The final starting concentration in the assay was either 1 or 10 pM. DMSO (no compound) and pritelivir were included on each microplate as negative and positive controls, respectively.

[00190] ARPE-19 cells (ATCC cat# CRL-2302) were maintained DMEM / F-12 Glutamax medium (Thermo Fisher Scientific cat# 10565018) supplemented with 10% FBS (Corning cat# 35-011-CV) and 1% Penicillin-Streptomycin (cat# 30-002-CI). Prior to confluence, cells were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium (DMEM / F-12 Glutamax, 2% FBS, 1% PenicillinStreptomycin) and counted. Cell density was adjusted to 150,000 cells / ml and infected with HSV-2 virus (MS strain, ATCC cat# VR-540) at a MOI of 0.06 in a 50 ml conical tube for 1 hour under constant rocking. Cells were then spun for 5 minutes at 1000 rpm and the media replaced with assay medium containing either 2% FBS or 10% human serum (EMD Millipore cat# S1-100ML). 50 pl of the infection suspension were added into microplate wells that were pre-spotted with compounds (7,500 cells per well). Plates were incubated for 16 hours at 37°C.

[00191] Cell culture medium was aspirated using a Biomek Fx and 50 pl of a paraformaldehyde solution (Electron Microscopy Sciences cat# 15712-S) diluted to 4% in DPBS (Corning cat# 21-031-CM) were added per well. After a 30-minute incubation at room temperature, plates were washed 4 times with 100 pl / well of PBS using a Biotek plate washer. A 1:500 solution of primary antibody (anti-HSV gD , Virusys cat# P1103) was prepared in permeabilization buffer (Invitrogen cat# 00-8333-56) and 50 pl were added into wells. After a 1-hour incubation at room temperature, 50 pl of a 1:1000 solution of secondary antibody (Alexa Fluor 488 goat anti-mouse, Thermo Fisher Scientific cat# A11001) and DAPI (Thermo Fisher Scientific cat# 62248) in permeabilization buffer were added into wells and plates were incubated in the dark at room temperature for 1 hour. Plates were washed 4 times again and 50 pl of DPBS were added to all wells prior to sealing the plates with a black adhesive seal. Fluorescence was measured on a Cellomics plate reader.

[00192] Data analysis was carried out using the Thermo Scientific HCS Studio software. Briefly, cells were identified using the DAPI nuclear stain and thresholds were set to filter cells out based on shape and size. A second threshold based on green fluorescence intensity (detection of HSV-2 gD) was set to identify HSV-2 infected cells. Data was reported as the average fluorescence intensity of HSV-2 infected cells. EC50 values were defined as the compound concentration that caused a 50% decrease in the average fluorescence intensity and was calculated using a sigmoidal dose-response model to generate curve fits. EC50 for pritelivir in this assay was 150 nM. Data for Compound 1 is reported in Table 1. Table 1: Biological assay data for Compound 1 Compound EC5o-HSV2-FBS (nM) EC50-HSV2-10% Human Serum (nM) CC5o-MT4 (nM) Compound 1 7.0 57.5 24000 MT-4 CCso Assay

[00193] Compounds were tested in 384-well plates: 18 compounds in duplex. Compounds were diluted in 7 points, 3-fold with DMSO by Bravo. Assay plate, which contains 20 uL medium with compounds, was seeded 2000 MT-4 cells in 20 uL / well by Multi-drop to start the assay. The plate was incubated at 37°C for 5 days. On 6th day, the CellTiter Gio 40 uL was added in each well. Luminescence was read by Victor II. CC50 values are defined as the compound concentration that causes a 50% decrease in luminescence signal, and were calculated using a sigmoidal dose-response model to generate curve fits. Data for Compound 1 is reported in Table 1 above. HSV qPCR Assay

[00194] HSV replication in the presence or absence of compounds was measured by qPCR according to the following procedure: DMSO stock compound solutions (1-10 mM) were serially diluted (2.5-fold) in DMSO in clear round bottom 96-well plates. Compounds were then diluted 1:20 in assay medium (DMEM / F12 Glutamax + 2% Fetal bovine serum + 1% Penicillin Streptomycin) and 10 pL of these dilutions were added to 96-well tissue culture plates for final starting concentrations between 0.5 and 5 pM.

[00195] ARPE-19 cells (ATCC cat # CRL-2302) that were maintained in growth medium (DMEM / F12 Glutamax + 10% FBS + 1% Penicillin streptomycin) were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium, counted, and cell density was adjusted to 2.8E+05 cells / ml with assay medium. Cells were then infected with HSV-1 (KOS strain, ATCC cat# VR-1493) or HSV-2 virus (MS strain, ATCC cat# VR-540) at a MOI 0.05 in a 50-ml conical tube for 1 hour under constant rocking. 90 pL of the infection suspension (25,000 cells) were added to assay plates in which compounds were already added. After an overnight incubation at 37°C, cell culture medium was removed, and cell lysis was performed using the prepGEM Universal kit (MicroGEM cat# PUN1000). Specifically, 100 pL of prepGEM master mix (94.75 pL Water, 5 pL buffer, 0.25 pL enzyme stock) were added to each well and plates were incubated at room temperature for 15 minutes, with the 5 last minutes on a plate shaker. The cell lysates were then transferred to a 96-well PCR compatible microplate (Applied Biosystems, Cat #N8010560). Plates were sealed with a heat resistant plastic sealer and heated on a thermal cycler using the following conditions: 75°C for 10 min, 95°C for 5 minutes. Finally, plates were cooled down to room temperature with light shaking before proceeding to the qPCR setup.

[00196] qPCR reactions were carried out in a total reaction volume of 20 pL, using the QuantiNova multiplex PCR kit (Qiagen Cat #208456). 15 pL of reagent mix (5pL of 4X QuantiNova Master Mix, 0.1 pL of QN Rox reference dye, 1 pL of 20X HSV primer / probe mix and 8.9 pL PCR grade water) and 5 pL of cell lysate were added to wells of a 96-well fast optical microplate (Applied Biosystems cat# 4246906). Plates were sealed with a clear sealer, spun down, and qPCR reactions were performed in an Applied Biosystems Quantstudio 7 Flex instrument using the following conditions: 95°C for 2 minutes, then 40 cycles alternating between 95°C for 5 seconds and 60°C for 30 seconds.

[00197] Analysis was performed using dCT method where dCT = CT (test)- CT (DMSO). Fold change was calculated using the 2A-dCT equation. This fold change was then converted to percentage relative to DMSO control (no drug). EC50 values were determined by non-linear regression analysis using GraphPad Prism software.

[00198] EC50 for both pritelivir and amenamevir in this assay were 14 nM. EC50 for acyclovir was 1250 nM. Data for Compound 1 is reported in Table 2. Table 2: Biological assay data for Compound 1 Compound EC50-HSV2-qPCR (nM) IC50-hCAII (nM) IC50-hCAI (nM) Compound 1 1.1 2900 35300 Carbonic anhydrase (esterase) biochemical assay

[00199] Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit the human carbonic anhydrase (hCA)-mediated hydrolysis of 4-nitrophenyl acetate (4NPA) (Verpoorte et al, JBC, 1967). 10-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 10 mM in 100% DMSO. 200 nl of compounds were then spotted in quadruplicates onto clear 384-well microplates (Perkin Elmer cat# 6007640) using a Labcyte ECHO acoustic dispenser. Final starting concentration in the assay was 50 pM. DMSO (no compound) and acetazolamide were included on each microplate as negative and positive controls, respectively.

[00200] A 1.5 pM solution of hCAI (R&D systems cat# 2180-CA) or a 1 pM solution of hCAII (Genscript cat# U3256FL150-4 / P5GA002) was prepared in assay buffer (25 mM Tris (pH 7.5), 100 mM NaCI, 1% DMSO) and 20 pl were added to compounds using a Biotek Micro Flo. Following a preincubation at room temperature for 15 minutes, 20 pl of a 4 mM solution of 4NPA substrate (Sigma cat# N8130) in assay buffer were added to start the reaction. Microplates were incubated at room temperature for 60 min after which absorbance at 405 nM was read on an Envision plate-reader. IC50 values were defined as the compound concentration that caused a 50% decrease in absorbance signal and were calculated using a sigmoidal dose-response model to generate curve fits. IC50 of acetazolamide was 0.04 uM in the hCAII assay and 1.1 uM in the hCAI assay. Data for Compound 1 is reported in Table 2 above. Plasma Stability Assay

[00201] The test compound was incubated at 2 pM in either rat or human plasma (BiolVT, Westbury, NY) up to 4 hours at 37°C. At specified time points, an aliquot from the incubation was quenched by addition of 9 volumes of 100% acetonitrile containing internal standard. Following the last collection, samples were centrifuged at 4500 rpm for 10 min and supernatants were transferred to a new plate containing an equal volume of water for analysis by liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS / MS). The percentage of test compound remaining (analyte to internal standard peak area ratio) in plasma after incubation was plotted versus incubation time and plasma half-life (t1 / 2) was calculated from the linear fit of the natural logarithm of the curve. Stability Assay in Cryopreserved Hepatocytes

[00202] Test compound was incubated at 1 pM with either rat or human cryopreserved hepatocytes (BiolVT, Westbury, NY) up to 6 hours at 37°C in a 24-well plate format (1x106 cells / mL per well). At specified time points, samples were transferred to a 96-well plate and quenched with 2 volumes of a solution containing 90% acetonitrile 10% methanol 0.1% formic acid and internal standard. Sample plate was centrifuged at 3200 rpm for 15 min and supernatants transferred to a new plate containing half volume of water. The resulting solution was analyzed by LC-MS / MS. Data (analyte to internal standard peak area ratio) was plotted on a semi-log scale and fitted using an exponential fit. Assuming first order kinetics, the half-life (t1 / 2) and rate of metabolism were determined. Predicted hepatic clearance was calculated from the half-life using the well-stirred model. Data for Compound 1 is reported in Table 3 below. Table 3: Hepatocyte stability assay data for Compound 1 Compound Predicted human hepatic clearance (L / hr / kg) Compound 1 0.055 EXAMPLE 3: Preparation of Compound 1 Free Base Form I

[00203] (R,E)- / V'-((5-fluoro-2-methylindolin-6-yl)sulfonyl)- / V, / V-dimethylformimidamide (20.3 g, 71.1 mmol) and (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (17.0 g, 71.0 mmol) were dissolved in dichloromethane (170 mL). The mixture was cooled to 10 °C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in dichloromethane (50wt%, 85.3 mL, 142 mmol) was added slowly to the mixture. The mixture was warmed to 20 °C and stirred for 1 h, and then triethylamine (80.0 mL, 574 mmol) was added slowly to the mixture. The mixture was left stirring at 20 °C. After complete consumption of (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid, the mixture was cooled to 10 °C and water (85 mL) was slowly added to the mixture. The stirring was stopped, and the resulting layers were separated. The organic layer was concentrated by distillation at reduced pressure to a minimum volume, then acetonitrile (170 mL) was charged; this was repeated one additional time. To the resulting mixture was slowly added aqueous ammonium hydroxide (23wt%, 351mL, 4.26 mol). Following complete consumption of intermediate (E)- / V'-((( / ?)-5-fluoro-2-methyl-1-(( / ?)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indolin-6-yl)sulfonyl)- / V, / \ / -dimethylformimidamide, a slurry was formed. The slurry was filtered, and the solids were washed twice with water (2 x 170 mL). The solids were dried to constant weight (29.1 g, 91% yield). XRPD analysis of the solids showed that it was crystalline (designated as Compound 1 Form I).

[00204] A representative XRPD pattern of Compound 1 Form I is shown in FIG. 1. Peak positions present in the XRPD diffractogram acquired for Form I are listed in Table 4. Table 4 Peak list of Compound 1 Form I No. Pos. [°2Th.] Rei. I nt. [%] 1 12.3 10 2 12.5 19 3 13.3 2 4 14.4 2 5 16.6 7 6 17.3 11 7 18.0 100 8 18.5 43 9 19.8 7 10 20.3 3 11 21.2 22 12 22.8 6 13 23.2 12 No. Pos. [°2Th.] Rei. I nt. [%] 14 24.0 12 15 24.6 4 16 25.0 3 17 25.3 3 18 26.5 19 19 27.6 5 20 28.1 4 21 28.7 6 22 29.5 3 23 30.9 4 24 31.5 2 25 32.2 4 26 36.4 4 27 37.1 3

[00205] The DSC thermogram (FIG. 2) indicates a melting onset at about 230 °C.

[00206] The TGA thermogram shows a weight loss of about 0.4% from 40 to 200 °C, indicating an unsolvated form (FIG. 3). 5

[00207] The DVS analysis is shown in FIG. 4 and indicates that the form is non- hygroscopic with about 0.1% water uptake from 0 to 90% RH at 25 °C.

[00208] Single crystals of Compound 1 Form I were prepared by dissolving about 40 mg of Compound 1 in 1 mL of acetone at about 50 °C and then held for 3 days. A slurry formed and the sample was subjected to SCXRD analysis at about 100 K. The result was 10 consistent with Compound 1 Form I with the parameters in Table 5. Table 5: Crystal Lattice Parameters of Compound 1 Form I Temperature 100.00 K Crystal system Monoclinic Space group C 1 2 1 Unit cell dimensions a = 19.6326(18) A b = 7.6161(7) A c= 14.8409(14) A a= 90° p = 104.029(8)° y = 90° Z 4 Calculated density (g / cm-3) 1.393 Goodness-of-fit on F2 1.055

[00209] The crystalline Compound 1 free base Form I obtained according to this procedure was used in Examples 4, 5 and 6. EXAMPLE 4: Preparation of 20 mq / mL Compound 1 oil suspension

[00210] An oil-based suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N at a concentration of 20 mg / mL was prepared as follows: 1) 160.21 mg of Compound 1 free base Form I, prepared as described in Example 3, was weighed in a 10 mL sterile amber vial. 2) 8.01 mL of Miglyol® 812 N was added slowly and mixed using a vortex mixer for 90 seconds at 3000 RPM. 3) The contents of the vial was sonicated for 5 mins. 4) The contents were mixed again for 2 min at 3000 RPM using a vortex mixer. After mixing, the suspension appeared milky. Small particulates were observed in the suspension. 5) The contents of the vial were sonicated for an additional 30 min to provide a homogenous suspension. 6) Syringeability of the suspension was tested using a BD 22G x 1.5inch PrecisionGlide Needle (Aiguille). The suspension was withdrawn with ease. 7) A 0.5 mL aliquot of the test article was withdrawn for assay and the vial was stoppered, capped, and crimped. Characterisation of suspension:

[00211] The concentration of Compound 1 in the suspension was measured by UPLC and found to be 20.11 mg / mL.

[00212] Analysis was carried out using a Waters Acquity UPLC system, BEH C18 1.7pm, 2.1 x 100 mm (Acquity UPLC) column, with a 5 pL injection volume and a diluent composed of 50% (v / v) 0.1% TFA in water, 50% (v / v) Methanol. Sample preparation was carried out as follows: 1) Suspension was diluted 10-fold in pure methanol (100 pL of suspension and 900 pL of methanol). 2) The mixture produced in 1) was diluted 40-fold in diluent composed of 50% (v / v) 0.1% TFA in water, 50% (v / v) Methanol. Specifically, 25 pL of the mixture produced in 1) was diluted with 975 pL of diluent before analysis was performed. EXAMPLE 5: Preparation of 100 mq / mL Compound 1 oil suspension

[00213] An oil-based suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N at a concentration of 100 mg / mL was prepared as follows: 1) 234.94 mg of Compound 1 free base Form I, prepared as described in Example 3, was weighed in a 6 mL sterile PK vial. 2) 2.35 mL of Miglyol® 812 N was added slowly and mixed using a vortex mixer. This produced a fine white suspension. 3) The suspension was sonicated for 20 mins to break up larger particles and produce a very fine white suspension. 4) Syringeability of the suspension was tested using a 23-gauge needle and no issues were observed. 5) An aliquot of the test article was withdrawn for a concentration assay check and the vial was labelled, capped, and crimped. Characterisation of suspension:

[00214] The concentration of Compound 1 in the suspension was measured by LIPLC and found to be 97.63 mg / mL. Details of the UPLC method are provided in Table 6. Table 6. UPLC Method for Compound 1 quantification in suspension formulation Instrument Waters Column Acquity UPLC BEH C18 1.7|jm, 2.1 x50 mm Detection 254 nm Flow rate 0.4 mL / min Run time 7.5 min Post run time 3 min Injection Volume 2 |jL Sample Concentration 60 |jg / mL Column temperature 40 °C Autosampler temperature 25 °C Mobile Phase A Water + 0.1% TFA Mobile Phase B Acetonitrile + 0.1% TFA Gradient Program Time (min) %A %B 0.0 95 5 0.5 95 5 6.5 0 100 7.5 0 100 8.1 95 5 13.5 95 5 EXAMPLE 6: Stability of 20 mg / mL Compound 1 oil suspension

[00215] Two oil-based suspensions of crystalline Compound 1 free base Form I in Miglyol® 812 N at concentrations of 20 mg / mL were prepared as follows: Formulation 1: 1) 20.37 mg of Compound 1 free base Form I, prepared as described in Example 3, was weighed in a 4 mL dram vial. 2) 1.018 mL of Miglyol® 812 N was added slowly and mixed using a vortex mixer for 90 seconds at 3000 RPM. 3) The contents of the vial was sonicated for 5 mins. 4) The contents were mixed again for 2.5 min at 3000 RPM using a vortex mixer. After mixing, the suspension appeared milky. Small particulates were observed in the suspension. 5) The contents of the vial were sonicated for an additional 20 min to provide a homogenous suspension. Formulation 2: 1) 29.95 mg of Compound 1 free base Form I, prepared as described in Example 3, was weighed in a 4 mL dram vial. 2) 1.50 mL of Miglyol® 812 N was added slowly and mixed using a vortex mixer for 90 seconds at 3000 RPM. 3) The contents of the vial was sonicated for 5 mins. 4) The contents were mixed again for 2.5 min at 3000 RPM using a vortex mixer. After mixing, the suspension appeared milky. Small particulates were observed in the suspension. 5) The contents of the vial were sonicated for an additional 20 min to provide a homogenous suspension. Stability study

[00216] Physical Form stability of the two formulations was evaluated by XRPD. Freshly prepared Formulation 1 was used as a To reference. Formulation 2 was evaluated 10 days post preparation. Samples were analysed as follows: 1) Approximately 1 mL of the suspension in a micro centrifuge tube was centrifuged at 15000 RPM for 5 min. 2) The supernatant was carefully transferred to another micro centrifuge tube. 3) The residual solids were transferred to an XRPD sample holder and analysed. XRPD details Instrument: Empyrean Cu LFF HR X-Ray Wavelength: Cu, Ka, Ka 1(A):1.540598, Ka2(A):1.544426 Ka2: Ka1 intensity ratio:0.50 Radius : 240.0 mm X-Ray Tube Setting: 45 kV, 40.0 mA, Scan Mode: Continuous Focus type : line, length 12.0 mm, width 0.4 mm, take-off angle 7.6° Scan Range (2 Theta): 2.0000°-39.9990°, Start position 2.0066°, End position 39.9925°, Step Size (2 Theta): 0.0131° with No. of points 2894 and Counting time 69.870 seconds Scan Speed (2 Theta) 10° / min. Scan axis: Gonio. Results

[00217] The XRPD pattern of the freshly prepared Formulation 1, i.e. the To reference, is shown in FIG. 5 and the XRPD pattern of Formulation 2, i.e. the formulation at 10 days post preparation, is shown in FIG. 6. An overlay of the two XRPD patterns is shown in FIG. 7. As shown in FIG.7, no change in Compound 1 form was observed after 10 days. EXAMPLE 7: Compound 1 PK Study in Rat following IV administration Formulation

[00218] A sterile aqueous solution of 1 mg / mL of Compound 1 in a vehicle containing 15% v / v dimethylacetamide, 55% v / v polyethylene glycol 300, and 30% v / v water-for-injection was used for this study. Animal Dosing - Rat

[00219] The purpose of the study was to assess the plasma pharmacokinetics following intravenous infusion (IV) administration to Sprague-Dawley (SD) rats. Animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources. The protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC). Male SD rats weighing approximately 0.24 to 0.31 kg were used for in-life portion of the studies. The animals were not fasted overnight prior to dosing. The animals were administered with the test compound at 1 mg / kg via IV. The test article for IV administration is a sterile aqueous solution of 1 mg / mL of Compound 1 in vehicle containing 15% v / v dimethylacetamide, 55% v / v polyethylene glycol 300, and 30% v / v water-for-injection. Approximately 0.3 mL blood samples were collected from each animal over 24-hour sampling period. Blood samples were analysed for test compound concentrations. For LC-MS / MS analysis, plasma samples were prepared through protein precipitation extraction and analysed on a Sciex API 6500+ Qtrap LC-MS / MS instrument (Framingham, MA). Analyte was eluted on a 2.6 pm 50 x 2.1 mm Phenomenex KinetexXBC HPLC column (Torrance, CA) using mobile phases containing 0.1% formic acid and a linear gradient from 5% to 80% acetonitrile at a flow rate of 1 mL / min. Noncompartmental pharmacokinetic parameters were calculated using Phoenix 32 (Certara, Princeton, NJ). Results

[00220] The mean plasma concentration profiles (n=3) after intravenous (IV) injection of Compound 1 solution in rat can be found in FIG. 8 and estimated PK parameters are summarised in Table 7. Table 7. Plasma Pharmacokinetic Parameter Estimates for Compound 1 Following IV Administration to SD Rats Parameters IV T1 / 2 (h) 3.31 ± 0.878 Tmax (h) 0.547 ± 0.0577 Cmax (MM) 6.04 ± 1.24 AUCo-t (pM*h) 22.3 ± 13.7 Abbreviations: t1 / 2 Terminal half-life calculated as natural log(2) / kei tmax Time to reach observed peak plasma concentration Cmax:      Maximum observed peak concentration AUCo t:     Area under the concentration-time curve from 0 h to the last quantified value over the dosing interval kei:         Elimination rate constant (1 / h) determined by linear regression analysis of selected time points in the apparent terminal phase of the log plasma concentration vs. time curve (not reported) EXAMPLE 8: Compound 1 PK Study in Rat at dosing concentration of 200 mg / kg Formulation

[00221] The 100 mg / mL oil-based suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N described in Example 5 was used in this study. Animal Dosing

[00222] The purpose of the study was to assess the plasma pharmacokinetics following subcutaneous (SC) administration to Sprague-Dawley (SD) rats. Animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources. The protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC). Male SD rats weighing approximately 0.24 to 0.31 kg were used for in-life portion of the studies. The animals were not fasted overnight prior to dosing. The animals were administered with the test compound at 200 mg / kg via SC. The test article for SC administration is the 100 mg / mL oil-based suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N described in Example 5 and the dose administered was about 0.5 mL / animal. The suspension was sociated for 5 mins before administration. Approximately 0.3 mL blood samples were collected from each animal over 1344-hour sampling period. Blood samples were analysed for test compound concentrations. For LC-MS / MS analysis, plasma samples were prepared through protein precipitation extraction and analysed on a Sciex API 6500+ Qtrap LC-MS / MS instrument (Framingham, MA). Analyte was eluted on a 2.6 pm 50 x 2.1 mm Phenomenex KinetexXBC HPLC column (Torrance, CA) using mobile phases containing 0.1% formic acid and a linear gradient from 5% to 80% acetonitrile at a flow rate of 1 mL / min. Noncompartmental pharmacokinetic parameters were calculated using Phoenix 32 (Certara, Princeton, NJ). Results

[00223] The mean plasma concentration profiles (n=3) after SC injection of Compound 1 solution in rat can be found in FIG. 9. Individual PK profiles can be found in FIG. 10 and PK parameters are summarised in Table 8. Prolonged exposure out to at least 56 days was achieved. Variability in plasma concentrations was low. Table 8. Plasma Pharmacokinetic Parameter Estimates for Compound 1 Following SC Administration to SD Rats at 200 mg / kg Parameters SC T1 / 2 (h) 851 ±113 Tmax (h) 152 ±121 Cmax (MM) 1.91 ±0.560 AUCo-t (pM*h) 1280 ±443 Abbreviations: t1 / 2 Terminal half-life calculated as natural log(2) / kei tmax Time to reach observed peak plasma concentration Cmax:      Maximum observed peak concentration AUCo t:     Area under the concentration-time curve from 0 h to the last quantified value over the dosing interval kei:         Elimination rate constant (1 / h) determined by linear regression analysis of selected time points in the apparent terminal phase of the log plasma concentration vs. time curve (not reported) EXAMPLE 9: Compound 1 PK Study in Rat at dosing concentration of 100 mg / kg Formulation

[00224] The 20 mg / mL oil-based suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N described in Example 4 was used in this study. Animal Dosing

[00225] The purpose of the study was to assess the plasma pharmacokinetics following subcutaneous (SC) administration to Sprague-Dawley (SD) rats. Animals were housed and handled in accordance with the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources. The protocols were reviewed and approved by the Institutional Animal Care and Use Committees (IACUC). Male SD rats weighing approximately 0.24 to 0.31 kg were used for in-life portion of the studies. The animals were not fasted overnight prior to dosing. The animals were administered with the test compound at 100 mg / kg via SC. The test article for SC administration is the 20 mg / mL oilbased suspension of crystalline Compound 1 free base Form I in Miglyol® 812 N described in Example 4 and the dose administered was 5 mL / kg. The suspension was sociated for 5 mins before administration. Approximately 0.3 mL blood samples were collected from each animal over 168-hour sampling period. Blood samples were analysed for test compound concentrations. For LC-MS / MS analysis, plasma samples were prepared through protein precipitation extraction and analysed on a Sciex API 6500+ Qtrap LC-MS / MS instrument (Framingham, MA). Analyte was eluted on a 2.6 pm 50 x 2.1 mm Phenomenex Kinetex XBC HPLC column (Torrance, CA) using mobile phases containing 0.1% formic acid and a linear gradient from 5% to 80% acetonitrile at a flow rate of 1 mL / min. Noncompartmental pharmacokinetic parameters were calculated using Phoenix 32 (Certara, Princeton, NJ). Results

[00226] The PK parameters derived from the study are summarised in Table 9. An overlay of the mean plasma concentration profile (n=3) after SC injection of Compound 1 suspension in rat at 100 mg / kg from this study and the mean plasma concentration profile (n=3) after SC injection of Compound 1 suspension in rat at 200 mg / kg (from the study described in Example 8) over a 168 hour period can be found in FIG. 11. Table 9. Plasma Pharmacokinetic Parameter Estimates for Compound 1 Following SC Administration to SD Rats at 100 mg / kg Parameters SC Ti / 2 (h) NA Tmax (h) 6.00 ± 3.46 C (pM) max vr 7 6.50 ± 6.04 AUCo-t (pM*h) 208 ± 67.4 Abbreviations: t1 / 2 Terminal half-life calculated as natural log(2) / kei tmax Time to reach observed peak plasma concentration Cmax:      Maximum observed peak concentration AUCo t: Area under the concentration-time curve from 0 h to the last quantified value over the dosing interval 5 kei:         Elimination rate constant (1 / h) determined by linear regression analysis of selected time points in the apparent terminal phase of the log plasma concentration vs. time curve (not reported) NA:        Not applicable due to insufficient data set

Claims

1. A long-acting injectable depot pharmaceutical composition comprising a compound (Compound 1) represented by:or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

2. A composition according to claim 1, wherein the composition is a subcutaneous or intramuscular long-acting injectable depot pharmaceutical composition.

3. A composition according to claim 2, wherein the composition is for administration twice a month, once a month, once every two months, once every three months, once every six months or once every year.

4. A composition according to any one of claims 1 to 3, wherein Compound 1 is in its free base form.

5. A composition according to claim 4, wherein the free base form is present as a crystalline solid.

6. A composition according to any one of claims 1 to 5, wherein the long-acting injectable depot pharmaceutical composition is an aqueous based depot, an aqueous based suspension depot, a solution in organic solvent based formulation, a suspension in organic solvent based depot, a gel based depot, an in-situ gelling depot formulation, an oil-based depot, an emulsion based depot, a monolithic polymer based depot, a microparticle polymer based depot, or a solid implant depot.

7. A composition according to any one of claims 1 to 6, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of a solvent, co-solvent, wetting or suspending agent, an isotonic agent, a pH adjusting agent, a stabiliser, an emulsifier and a viscosity modifier.

8. A composition according to any one of claims 1 to 7, wherein the long-acting injectable depot pharmaceutical composition is an oil-based depot composition, such as an oilbased suspension.

9. A composition according to claim 8, wherein the oil-based depot composition comprises one or more pharmaceutically acceptable oils selected from castor oil, PEG-60 hydrogenated castor oil, polyoxyl 35 castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides, and long chain triglycerides.

10. A composition according to claim 8 or claim 9, wherein the oil-based depot composition is an oil-based suspension and the free base form of Compound 1 is suspended as a crystalline solid.

11. A composition according to claim 5 or claim 10, wherein the crystalline solid is Form I characterized by an XRPD pattern comprising peaks at 18.0, 21.2 and 23.2° 20 (± 0.2° 20).

12. A composition according to claim 11, wherein the XRPD pattern further comprises at least two, five, ten, fifteen or twenty specific peaks selected from peaks at 12.3, 12.5, 13.3, 14.4, 16.6, 17.3, 18.5, 19.8, 20.3, 22.8, 24.0, 24.6, 25.0, 25.3, 26.5, 27.6, 28.1, 28.7, 29.5, 30.9, 31.5, 32.2, 36.4, and 37.1° 20 (± 0.2° 20).

13. A composition according to any one of claims 1 to 12, wherein the long-acting injectable depot pharmaceutical composition comprises about 2 wt % to about 40 wt % of Compound 1 or a pharmaceutically acceptable salt thereof.

14. A composition according to any one of claims 1 to 13, wherein the long-acting injectable depot pharmaceutical composition comprises about 10 mg to about 1200 mg (such as about 100 mg to about 900 mg) of Compound 1 or a pharmaceutically acceptable salt thereof.

15. A composition according to any one of claims 1 to 13, wherein the long-acting injectable depot pharmaceutical composition comprises about 25 mg to about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

16. A composition of any one of claims 1 to 15, wherein the long-acting injectable depot pharmaceutical composition comprises Compound 1 free form and produces a plasmaconcentration of Compound 1 in the subject after administration of at least 25 ng / mL for at least 80% of the dosing interval, wherein the dosing interval is at least 10 days.

17. A composition according to any one of claims 1 to 16, wherein the composition is stable for at least four weeks.

18. A composition according to any one of claims 1 to 17, for use as a medicament.

19. A pharmaceutical composition according to any one of claims 1 to 17, for use in the treatment of a herpes virus (conveniently a HSV) infection in a subject in need thereof.

20. A method for treating a herpes virus (such as HSV) infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject wherein the Compound 1 or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to any one of claims 1 to 17.

21. The method of claim 20, wherein the pharmaceutical composition is administered twice a month, once a month, once every two months, once every three months, once every six months, or once every year.

22. The method of claim 21, wherein the pharmaceutical composition is administered once every three months, once every six months, or once every year.

23. The method of any one of claims 20 to 22, wherein the pharmaceutical composition is administered by intramuscular or subcutaneous administration.

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