WO2025046457A1 - A crystalline form of 2-(3-(2,,5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2h)-yl)-4-methylthiazole-5-sulfonamide - Google Patents

Abstract

The invention relates to a novel crystalline form of a helicase-primase inhibitor compound, as well as to pharmaceutical compositions comprising the same, methods for its production, the use of the crystalline form in a medicament and for the treatment of herpes virus infections.

Description

A CRYSTALLINE FORM OF -(3-(2„5^,-DIFLUORO-[1,T-BIPHENYL]-4-YL)-2-OXOTETRAHYDROPYRIMIDIN-1(2H)-YL)-4-METHYLTHIAZOLE-5-SULFONAMIDE

FIELD OF THE INVENTION

[0001] The present disclosure relates to a novel crystalline form of a certain compound, which is useful in treating and/or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection.

BACKGROUND

[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 Whitlows 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 prodrugs, e.g., valacyclovir and 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] Bl LS- 179 BS has been dosed orally to humans but was suspended in early clinical trials due to adverse events (Ruebsamen et al., (2019) Med. Chem. 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. In a human clinical study, the effect of pritelivir on suppression of genital herpes following oral dosing was studied in 156 individuals (Wald et al., (2014) New England Journal of Medicine 370, p. 201-210). The results of a subsequent phase II clinical study in subjects with recurrent genital HSV-2 were reported in Wald et al., (2016) (J. Am. Med. Assoc. 316(23), p. 2495-2503).

[0015] The present disclosure relates to a novel crystalline form of a certain compound, which is a potent helicase-primase inhibitor. The compound is 2-(3-(2',5'-difluoro-[1 , 1 '-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide and is referred to herein also as ‘Compound T.

SUMMARY OF THE INVENTION

[0016] Provided herein is a novel crystalline form of Compound 1. Compound 1 has the following structure:

Compound 1.

[0017] The compound shown above is 2-(3-(2',5'-difluoro-[1 , 1 '-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (also referred to herein as ‘Compound T) and is a potent helicase-primase inhibitor.

[0018] The present disclosure relates to a certain novel solid form of Compound 1 , which possesses promising and advantageous solid-state and/or biopharmaceutical properties.

[0019] The present disclosure is also directed to pharmaceutical compositions comprising the crystalline form, and to methods for preparing such form. The present disclosure is further directed to the use of the crystalline form in the treatment of HSV infections.

[0020] In a first aspect, the present disclosure provides a crystalline form of Compound 1 , wherein the crystalline form is Form C. [0021] Form C is characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20.

[0022] Form C can also be characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ± 3°C.

[0023] Form C is a non-solvated and anhydrous crystalline form of Compound 1 and has a high melting point. A high melting point means that Form C can be handled at high temperatures without it melting, for example, during size reduction procedures, e.g., micronization and/or the manufacturing of a pharmaceutical dosage form. Furthermore, Form C is non-hygroscopic which is particularly advantageous when handling and storing Form C and pharmaceutical compositions comprising Form C at different humidities.

[0024] Advantageously, Form C has certain characteristics that make it particularly suited to formulation and delivery via certain routes of administration. It is a thermodynamically stable form and provides excellent Compound 1 stability, both chemically and physically, even when subjected to extreme temperature, humidity and light storage conditions. Furthermore, Form C possesses very good resistance to mechanical stress.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1 , wherein the crystalline form is Form C, and a pharmaceutically acceptable carrier, diluent or excipient.

[0026] In a further aspect, the present invention provides a method of treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 , wherein the crystalline form is Form C.

[0027] In a further aspect, the present invention provides a method of treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0028] In another aspect, there is provided a crystalline form of Compound 1 for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.

[0029] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C. [0030] In another aspect, there is provided the use of a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising Compound 1 for the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.

[0031] In another aspect, there is provided the use of a crystalline form of Compound 1 or a pharmaceutical composition comprising a crystalline form of Compound 1 in the manufacture of a medicament for treating a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.

[0032] In another aspect, there is provided a process to prepare a crystalline form of Compound 1 wherein the crystalline form is Form C.

[0033] In another aspect, there is provided a crystalline form of Compound 1 obtainable by the process described herein, wherein the crystalline form is Form C.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 is an overlay XRPD diffractogram of Forms A-G of Compound 1.

[0035] FIG. 2 is an XRPD diffractogram of Form C of the present disclosure.

[0036] FIG. 3 shows a DSC thermogram of Form C. The DSC exhibited a sharp endotherm at an onset of 271.7 °C and a peak of 272.4 °C.

[0037] FIG. 4 shows a TGA thermogram of Form C. The TGA data indicated a weight loss of 0.44% up to 200 °C.

[0038] FIG. 5 shows a DVS of Form C.

[0039] FIG. 6 shows a PLM image of Form C crystals.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0040] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

Definitions

[0041] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0042] As used herein, “Compound 1” refers to 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide. [0043] As used herein, “API” refers to an active pharmaceutical ingredient, e.g., Compound 1.

[0044] Unless the context requires otherwise, throughout this specification and claims, the words "comprise," "comprising" and the like are to be construed in an open, inclusive sense; the words "a" "an" and the like are to be considered as meaning at least one and are not limited to just one; and the term "about" is to be construed as meaning plus or minus 10%. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.

[0045] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals {e.g., dogs, cats, and the like), farm animals e.g., cows, sheep, pigs, horses, and the like) and laboratory animals {e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.

[0046] The term “modulation” includes antagonism {e.g., inhibition), agonism, partial antagonism and/or partial agonism.

[0047] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0048] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0049] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. A therapeutically effective amount of Compound 1 is the quantity required to achieve a desired therapeutic and/or prophylactic effect. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. [0050] It is to be appreciated that references to “treat”, "treating" or "treatment" includes: (1) delaying or reducing the likelihood of the appearance of clinical symptoms of the disease or disorder developing in a subject that may be afflicted with the disease or disorder but does not yet experience or display clinical or subclinical symptoms of the disease or disorder, (2) inhibiting the disease or disorder, i.e., arresting, reducing or delaying the progression of the disease or disorder 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 or disorder, i.e., causing regression of the disease, disorder or condition or at least one of its clinical or subclinical symptoms. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in improvement of the disease (e.g., via binding to the viral heterotrimeric complex and inhibiting the helicase and primase activity of the virus).

[0051] 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 sub-combination 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.

[0052] 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.

[0053] A "crystalline form" is a solid material wherein the constituents of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice which extends in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms and/or hydrated crystalline forms.

[0054] "Polymorphism" is when a solid material can exist in more than one crystalline form.

[0055] As used herein, the term "amorphous" refers to a solid material having no long-range order in the position of its molecules. Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. [0056] A "hydrate" is a compound that exists in a solid composition with water molecules. The composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e. , a Compound 1 in water solution, while it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and water form part of the crystal lattice.

[0057] A "solvate" is a similar composition to a hydrate except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a Compound 1 in solvent solution, while it may be solvated, is not a solvate as the term is used herein. Solvates may be crystalline, wherein both the compound and solvent form part of the crystal lattice.

[0058] "Anhydrous" means the solid form of the compound does not have water incorporated into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystal structure. The skilled person would be aware of techniques which can be used to quantify the amount of water associated with a solid. For example, water content can be determined by either Karl Fischer Titration or Thermogravimetric Analysis (TGA). Suitably, an anhydrous solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 , about 0.05, or about 0.01 % by weight of water.

[0059] "Un-solvated" or "non-solvated" means the solid form of the compound does not have solvent(s) incorporated into its structure. For example, an un-solvated crystalline form does not have solvent(s) forming part of the crystal structure. The skilled person would be aware of techniques which can quantify the amount of solvent associated with a solid. For example, solvent content can be determined by Gas Chromatography (GC). Suitably, an un-solvated or nonsolvated solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 , about 0.05, or about 0.01 % by weight of solvent.

[0060] Herein, where a composition is said to "consist essentially of" a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to "consist essentially of" a particular component consists of said component save for one or more trace components.

[0061] The phrase "substantially as shown in figure" refers to an X-ray powder diffraction pattern or DSC thermogram with at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% or at least 99% of its features appearing in the figure. [0062] The term “relative volumes” refers to the volume of a liquid (in mL) used relative to the mass of Compound 1 (in g). For example, 10 relative volumes of solvent equates to 10 mL for every gram of Compound 1 .

[0063] The phrase “FIG.” is short for Figure.

Compound 1

[0064] Compound 1 is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1 (2H)- yl)-4-methylthiazole-5-sulfonamide shown below.

[0001] Compound 1 is a potent helicase-primase inhibitor and has an in-vitro EC50 value of approximately 0.019 iM against HSV-1 and 0.011 iM against 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. 297-299). The in-vitro EC50 value can also be determined in accordance with the assays described in the Examples section of the present application.

[0065] Generally, Compound 1 can be prepared, isolated or obtained by any method apparent to those of skill in the art. An exemplary method of preparation is described in Example 1 below.

Crystalline Form of Compound 1

[0066] In a first aspect, the present disclosure provides a crystalline form of Compound 1. Specifically, there is provided a novel crystalline form of Compound 1 described and characterized herein as Form C.

[0067] The present disclosure is also directed to pharmaceutical compositions comprising the crystalline Form C, and to methods for preparing such form. The present disclosure is further directed to the use of Form C in the treatment or prevention of HSV infections.

[0068] There are a number of analytical methods one of ordinary skill in the art in solid-state chemistry can use to characterize solid forms. The term "characterize" as used herein means to obtain information about the solid-state structure of solid forms. For example, powder X-ray diffraction (PXRD/XRPD) is a suitable technique for differentiating amorphous solid forms from crystalline solid forms and for characterizing and identifying particular crystalline solid forms of a compound. [0069] Due to differences in X- Ray diffraction instruments, samples, and sample preparation, peak values are often reported with the modifier "± 0.2 °20" or "± 0.1 °20". This is common practice in the solid-state chemical arts because of the variation inherent in peak values. Variability in peak intensity is a result of how individual crystals are oriented in the sample container with respect to the external X-ray source (known as "preferred orientation"). This orientation effect does not provide structural information about the crystal.

[0070] When the modifiers “± 0.2 °20" and "± 0.1 °20" are used at the end of a list of X-Ray diffraction peaks, it is to be understood that the modifier applies to each peak specified in that list.

[0071] X-ray powder diffraction is just one of several analytical techniques one may use to characterize and/or identify crystalline solid forms. Differential scanning calorimetry (DSC) may be used to characterize and/or identity crystalline solid forms. A typical variability for a value associated with a differential scanning calorimetry onset temperature is of the order of ± 3°C, or more preferably ± 2°C.

[0072] It should be noted that unless noted otherwise, thermal data (DSC and TGA) presented herein were acquired using a heating rate of 10°C/min. Furthermore, DSC data was acquired using aluminum punched pans.

[0073] In a first aspect, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C. In one embodiment, Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20.

[0074] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A =

1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.2 °20.

[0075] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A =

1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20 and further comprising peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.2 °20.

[0076] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A =

1.5406 A) radiation comprising peaks at 15.1, 25.3 and 30.5 °20 ± 0.1 °20.

[0077] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A =

1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.1 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± O.1 °20. [0078] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.1 °20 and further comprising peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.1 °20.

[0079] In one embodiment, there is provided an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20, suitably 15.1 , 25.3 and 30.5 °20 ± 0.1 °20, and wherein Form C is un-solvated and anhydrous. Suitably, Form C comprises less than about 2% by weight solvent and/or water, such as less than about 1.5% by weight, less than about 1 %, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1 % by weight. Suitably, Form C comprises less than about 2% by weight water, such as less than about 1.5% by weight, less than about 1 %, less than about 0.5, less than about 0.4, less than about 0.3, or less than about 0.2 % by weight water. The skilled person would know of suitable analytical techniques which can quantify the amount of solvent/water associated with a solid. For example, water content can be determined by Karl Fischer Titration. Residual solvents can be determined by Gas Chromatography. Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure). In one embodiment, Form C is anhydrous. Suitably, Form C is anhydrous and un-solvated.

[0080] In one embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20 and further comprising at least two, five, ten, or fifteen peaks selected from the group consisting of the additional peaks in Table A in °20 ± 0.2 °20. In one embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.1 °20 and further comprising at least two, five, ten, or fifteen peaks selected from the group consisting of the additional peaks in Table A in °20 ± 0.1 °20.

Table A - Additional XRPD peak positions for Form C

[0081] In one embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in Figure 2.

[0082] In one embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ± 3°C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 100 °C and an endothermic event with an onset temperature of 269 °C ± 3°C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 269 °C ± 2°C In an embodiment, the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 260 °C ± 2°C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 269 °C ± 3°C.

[0083] In an embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 268 °C ± 2°C, 269 °C ± 2°C, or 270 °C ± 2°C. In an alternative embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 272 °C ± 2°C.

[0084] In an embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ± 3°C. In an embodiment, there is provided a crystalline form of Compound 1 , wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1 , 25.3 and 30.5 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 272 °C ± 2°C.

[0085] In one embodiment, there is provided a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by a DSC thermogram substantially the same as depicted in Figure 3.

[0086] In one embodiment, Form C is substantially pure.

[0087] When it is stated herein that the specification relates to a crystalline form of Compound 1 , the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.

[0088] In one embodiment, Form C is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of Compound 1 contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of Compound 1 , including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured by XRPD. Thus, substantially pure Form C as described herein would be understood to contain 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 crystalline Form C of Compound 1 . Suitably, there is provided Form C wherein when Form C is characterized by a solid-state technique, such as by X-Ray Powder diffraction, no other solid forms (amorphous and/or other crystalline forms) are detected. Suitably, there is provided a crystalline form of Compound 1 essentially consisting of Form C. Suitably, there is provided a crystalline form of Compound 1 consisting of Form C.

Pharmaceutical Compositions and Kits

[0089] In another aspect, the present disclosure provides pharmaceutical compositions comprising a crystalline form of Compound 1 as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0090] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 wherein the crystalline form is Form C; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 wherein the crystalline form is pure or substantially pure Form C; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 wherein Compound 1 consists essentially of crystalline Form C. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 , wherein Compound 1 consists of crystalline Form C.

[0091] When it is stated herein that the pharmaceutical composition relates to a crystalline form of Compound 1 , the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight of Form C. [0092] The pharmaceutical composition of the present invention include those suitable for oral, rectal, topical, buccal, parenteral, rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

[0093] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, which contains Compound 1 in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. Compound 1 may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. Compound 1 is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the progress or condition of the disease (e.g. HSV infection).

[0094] Suitably, there is provided a pharmaceutical composition comprising an aqueous suspension of Compound 1 Form C. Suitably, the pharmaceutical composition is suitable for administration via injection (such as via subcutaneous or intramuscular injection). Suitably, there is provided an injectable pharmaceutical composition comprising an aqueous based suspension of Compound 1 Form C. Suitably, there is provided a solid dosage form (e.g. a tablet) for oral administration.

[0095] In an additional aspect, the invention also provides kits for use by e.g., a consumer in need of HSV infection treatment. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent HSV infection. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [0096] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

Methods of Treatment

[0097] In one aspect, there is provided crystalline Compound 1 Form C for use as a medicament.

[0098] In one aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, for use as a medicament.

[0099] In one aspect, there is provided crystalline Compound 1 Form C for use in therapy.

[0100] In one aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, for use in therapy.

[0101] In one aspect, there is provided a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C. In another aspect, there is provided a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0102] In one embodiment, there is provided a method for inhibiting HSV replication in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C. In one embodiment, there is provided a method for inhibiting HSV replication in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C. [0103] In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C. In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HSV infection in the subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0104] In one embodiment, there is provided 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 to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C. In one embodiment, there is provided 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 to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0105] In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C. In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.

[0106] In a particular embodiment, Compound 1 Form C according to the present invention, or the pharmaceutical compositions according to the present 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.

[0107] In one embodiment, Compound 1 Form C according to the present invention, or the pharmaceutical compositions according to the present 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. [0108] In another aspect, there is provided a crystalline form of Compound 1 for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C. In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.

[0109] In one embodiment, there is provided a crystalline form of Compound 1 for use in the inhibition of HSV replication in a subject, wherein the crystalline form is Form C. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of HSV replication in a subject, wherein the crystalline form is Form C.

[0110] In one embodiment, there is provided a crystalline form of Compound 1 for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.

[0111] In one embodiment, there is provided a crystalline form of Compound 1 for use in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.

[0112] In one embodiment, there is provided a crystalline form of Compound 1 for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.

[0113] In another aspect, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C. [0114] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for the inhibition of HSV replication in a subject, wherein the crystalline form is Form C.

[0115] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.

[0116] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.

[0117] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in treating or preventing a disease or disorder caused by, or associated with, HSV infection, wherein the crystalline form is Form C.

[0118] In another aspect, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for treating a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.

[0119] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for inhibiting HSV replication in a subject, wherein the crystalline form is Form C.

[0120] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.

[0121] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.

[0122] In one embodiment, there is provided the use of a crystalline form of Compound 1 , or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.

[0123] In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s), genital herpes, HSV-related ocular keratitis, HSV-related encephalitis, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis and Bell's palsy.

[0124] In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (e.g., 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.

[0125] 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.

[0126] In one embodiment, the herpes virus being treated is HSV1. In yet a further embodiment, both herpes virus HSV-1 and HSV-2 are being treated.

[0127] In one embodiment, the herpes virus being treated or prevented is resistant to nucleosidic anti-viral therapy. In one embodiment, the nucleosidic antiviral therapy is selected from therapy with the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[0128] In one embodiment, the herpes virus 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.

[0129] 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 and chronic glucocorticoid use or a genetic immunodeficiency.

[0130] In a particular embodiment, the subject in need of the methods disclosed herein, is a neonate or an infant.

[0131] In a particular embodiment, the subject is a herpes-positive patient. [0132] 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 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.

[0133] In a particular embodiment, the subject in need of the methods disclosed herein, has a primary genital HSV-related herpes infection. In one aspect, the subject in need of the methods disclosed herein, has severe or progressive genital HSV-related herpes infection.

[0134] For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the mode of administration, and the nature and severity of the infection to be treated as well as the specific 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.

[0135] In an embodiment, the crystalline form of the present invention, or a pharmaceutical composition comprising the crystalline form of the present invention, is administered to a subject in need thereof once a week, twice a month, once a month, once every two months, once every three months, once every six months, or once every year.

[0136] Suitably, the crystalline form of the present invention, or a pharmaceutical composition comprising the crystalline form of the present invention, is administered to a subject in need thereof once every three months, once every six months, or once every year.

[0137] In a convenient embodiment, the crystalline form of the present invention, or a pharmaceutical composition comprising the crystalline form of the present invention, is administered orally, or via injection. In a convenient embodiment, the pharmaceutical composition is a solid dosage form administered orally. A pharmaceutical composition of the present invention may suitably be an aqueous based suspension of Compound 1 Form C to be administered by intramuscular or subcutaneous injection. In a convenient embodiment, the pharmaceutical composition is administered by subcutaneous injection. In a convenient embodiment, the pharmaceutical composition is administered by intramuscular injection.

[0138] In an embodiment, the subject being treated in a human. Besides being useful for human treatment, the crystalline form of the present 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.

Combinations

[0139] 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.

[0140] Also contemplated herein are methods that include administering a second 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.

[0141] 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 a crystalline form of Compound 1 , and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent, wherein the crystalline form is Form C.

[0142] Also, provided herein is a method for treating or preventing HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0143] 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. [0144] In some cases, a crystalline form of Compound 1 according to the first aspect of the invention may be administered in a first amount as part of a combination therapy in conjunction with one or more antivirals, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir or the respective prodrugs valacyclovir or famciclovir, which antiviral agents may be administered in a second amount.

[0145] 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.

[0146] Suitably, in the combination therapies described hereinabove, the crystalline form of Compound (I) is Form C.

Process to prepare Form C

[0147] In one aspect of the present invention, there is provided a process to prepare a crystalline form of Compound 1 wherein the crystalline form is Form C.

[0148] In one embodiment, the process to prepare Form C comprises the steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture obtained from step b), optionally for at least 1 hour; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0149] In one embodiment, the first solvent system comprises a solvent wherein Compound 1 has a solubility of at least 25 mg/mL at room temperature, such as at least 50, 75, or 100 mg/mL. Suitably, the first solvent system comprises DMSO or DMF. Suitably, the first solvent system comprises DMSO. Suitably, the first solvent system consists essentially of DMSO. Suitably, the first solvent system consists of DMSO. Suitably Compound 1 is dissolved in 1-10 relative volumes of the first solvent system, such as 1-5 relative volumes. Suitably Compound 1 is dissolved in 1- 10 relative volumes of DMSO, such as 1-5, or 2-4 relative volumes of DMSO.

[0150] Suitably, step a) is performed at 50 to 100 °C. Suitably, step a) is performed at 60 to 90 °C, such as 65 to 85 °C, 75 to 85 °C or 70 to 80 °C. [0151] Suitably Compound 1 is dissolved in 1-5 relative volumes of DMSO (such as 2-4 relative volumes of DMSO) at a temperature of 60 to 90 °C (such as 70 to 80 °C).

[0152] Suitably, the second solvent system comprises a solvent wherein Compound 1 has a solubility of less than 50 mg/mL at room temperature, such as less than 20, or less than 10 mg/mL. Suitably, the second solvent system comprises ethanol. Suitably, the second solvent system consists essentially of ethanol. Suitably, the second solvent system consists of ethanol. Suitably 5-40 relative volumes of the second solvent system are added to the solution from step a), such as 5-20, 10-18, or 12-16 relative volumes. Suitably 5-40 relative volumes of ethanol are added to the solution from step a), such as 5-20, 10-18, or 12-16 relative volumes of ethanol.

[0153] Suitably, the first solvent system comprises DMSO and the second solvent system comprises ethanol.

[0154] Suitably, the second solvent system is an anti-solvent system.

[0155] Suitably, in step b) the second solvent system is added at 40 to 90 °C, such as 40 to 80 °C, 55 to 80 °C, or 40 to 70 °C. Suitably, in step b) the second solvent system is added at 50 to 65 °C, such as 50 to 60°C, 55 to 60 °C or 60 °C.

[0156] Suitably, the second solvent system in step b) is added dropwise to the solution from step a).

[0157] Suitably, the addition of the second solvent system in step b) is over a time period of at least 1 hour, such as at least 2 hours, such as at least 5 hours or such as at least 8 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 5 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 7 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 8 hours. Suitably, the addition of the second solvent in step b) is over a time period of 8 to 10 hours.

[0158] Suitably, the addition of the second solvent system in step b) is carried out in two portions. Suitably, 0.5-2 relatives volumes, such as 1-2 relative volumes, of the second solvent system (e.g. ethanol) are added in the first portion and 10-20 relative volumes, such as 10-15 relative volumes, of the second solvent system (e.g. ethanol) are added in the second portion. Suitably, the first portion of the second solvent system is added over 30 to 60 minutes. In an embodiment, the first portion of the second solvent system is added to the mixture being stirred at 40 to 90 °C, such as 40 to 80 °C, 40 to 70 °C, 65 to 85 °C, 70 to 80 °C, 50 to 60 °C, or 50 to 55 °C. In an embodiment, the first portion of the second solvent system is added to the mixture being stirred at the same temperature step a) was performed. In an embodiment, the second portion of the second solvent system is added to the mixture being stirred at 50 to 65 °C, such as 55 to 60 °C, 57 to 62 °C, or about 60 °C. Suitably, after the addition of the second solvent system, the mixture is stirred at 57 to 62 °C for 1-2 hours. Suitably, after the addition of the second solvent system, the mixture is stirred at 55 to 60 °C for 1-2 hours.

[0159] In one embodiment, step b) further comprises an additional step (step b2)) of adding a seed of Compound 1 Form C to the solution. Suitably, 0.01 to 10% by weight of the seed relative to the amount of Compound 1 present in the solution in step a) is added. Suitably, 0.1 to 5% by weight of seed is added, such as about 2% by weight. Suitably step b2) is carried out after the first portion of the second solvent system is added to the mixture. Suitably step b2) is carried out before the second portion of the second solvent system is added to the mixture.

[0160] Suitably, the stirring in step c) is performed at room temperature. Suitably, the stirring in step c) is performed at 18 to 22 °C.

[0161] Suitably, the stirring in step c) is performed for at least 1 hour, such as at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 22 hours, or at least 24 hours. Suitably, the stirring in step c) is performed for at least 1 hour.

[0162] Suitably, step d) comprises isolating the solids by filtration.

[0163] Suitably, step e) comprises drying the solids at a temperature greater than room temperature, such as greater than 30°C, or greater than 40°C. Suitably, step e) comprises drying the solids at a temperature of about 50 °C.

[0164] The invention is illustrated below by the following non-limiting examples.

EXAMPLES

[0165] The following abbreviations are used within this specification:

ACN: Acetonitrile

DCM: Dichloromethane

DMAc: Dimethylacetamide

DMF: Dimethylformamide

DMSO: Dimethyl sulfoxide

DSC: Differential Scanning Calorimetry

DVS: Dynamic Vapor Sorption eq: Equivalents

EtOAc: Ethyl acetate hr: Hours

HPLC: High Performance Liquid Chromatography

KF: Karl Fischer titration

MeOH: Methanol min: Minutes

NMP: N-Methyl Pyrrolidone PLM: Polarized light microscopy

RH: Relative Humidity

RT: Room Temperature (~22°C)

TBAB: Tetrabutylammonium bromide

TGA: Thermogravimetric analysis

THF: Tetrahydrofuran

TLC: Thin Layer Chromatography

Vol: Volume

XRPD: X-Ray Powder Diffraction

INSTRUMENTATION AND METHODS

Polarized-Light Microscopy (PLM): The photomicrographs were collected using Olympus BX53 polarized-light microscope. The sample was dispersed with methyl silicone oil on a glass slide.

X-Ray Powder Diffraction (XRPD): XRPD diffractograms were acquired on Rigaku Smartlab MiniFlex 600C diffractometer using Cu, Ka, Ka 1(A): 1.540598, Ka2(A): 1.544426 radiation with a Ka2:Ka1 intensity ratio of 0.50. X-Ray tube setting was 40 kV, 15 mA, Scan Mode 1D. The scan range (2 theta) was 3-40°, step size (2 theta) of 0.02° with scan speed (2 theta) of 107min.

Differential Scanning Calorimetry (DSC): DSC was conducted with a TA Instruments DSC2500 differential scanning calorimeter using temperature ramp of 30 to 300°C with a heating rate of 10°C/min. The purge gas was N2 (>99.999%). Punched aluminum pans were used.

Thermogravimetric Analysis (TGA): TGA was conducted with a TA Instruments TGA500 differential scanning calorimeter using temperature ramp of 25 to 300°C with a heating rate of 10°C/min. The purge gas was N2 (>99.999%). Open aluminum pans were used.

Dynamic Vapor Sorption (DVS): DVS analysis was performed on an Adventure DVS instrument, using a partial pressure range of 0-90%, with a step size of 10% and dm/dt = 0.002. DVS data was collected at 25 °C. 2 cycles were performed per analysis. Gas flow of N2 (200 seem) was used.

Karl Fischer (KF) water content: KF was collected on 915 KF Ti-Touch Metrohm titrator using the volumetric method. 100 mg samples were used with 1:1 NMP:MeOH as diluent.

HPLC method: The HPLC method conditions used for measuring stability samples are summarized in Table 1.

Table 1 - HPLC method

EXAMPLE 1 : SYNTHESIS OF COMPOUND 1

Step 3 Step 4

Step 1 : Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (Intermediate 1- 1)

[0166] A mixture of 2-amino-4-methylthiazole (6 g, 52.632 mmol) and 1-chloro-3- isocyanatopropane (6.26 g, 52.632 mmol) in THF (60 mL) was heated at 70 °C for 6 h. To the resulting solution, TBAB (1.7 g, 5.263 mmol) and K2CO3 (18.15 g, 131.58 mmol) were added portion wise maintaining the same temperature and stirring continued at 70 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 60-70% EtOAc in heptane) to afford Intermediate 1-1 (5.1 g, 49.22%) as an off-white solid. TLC: 70% EtOAc/heptane (R_f: 0.5). MS calcd. for Chemical Formula: C₈HnN₃OS: 197.06; Found: 198.17 [M + 1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 5 7.30 (s, 1 H), 6.60 (s, 1 H), 3.99 (t, J = 5.4 Hz, 2H), 3.20 - 3.19 (m, 2H), 2.28 (s, 3H), 1.99 - 1.89 (m, 2H).

Step 1A: Synthesis of 4'-bromo-2,5-difluoro-1,1 '-biphenyl (Intermediate 1-2)

[0167] To a stirred solution of 1-bromo-4-iodobenzene (5 g, 17.674 mmol) in 1 ,4 dioxane: H2O (50:5 mL) were added (2,5-difluorophenyl) boronic acid (3.07 g, 19.441 mmol) and K3PO4 (7.5 g, 35.348 mmol) and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution PdCh(dppf) (1.29 g, 1.767 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 100% heptane) to afford Intermediate 1-2 (2.3 g, 48.62%) as an off-white solid. TLC: 100% heptane (R_f: 0.5). ¹H NMR (400 MHz, CDCI3) 6 7.58 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.15-7.06 (m, 2H), 7.05-6.97 (m, 1 H).

Step 2: Synthesis of 1-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl) tetrahydropyrimidin-2(1H)-one (Intermediate 1-3)

[0168] To a stirred solution of Intermediate 1-1 (5 g, 25.380 mmol) in 1 ,4-dioxane (100 mL) were added Intermediate 1-2 (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol) followed by Cui (0.96 g, 5.076 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture, 1 ,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 120 °C for 24 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through Celite bed and washed with ethyl acetate. The filtrate was diluted with water and, extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography (eluting with 30-40% EtOAc in heptane) to afford Intermediate 1-3 (4.1 g, 41.96%) as an off-white solid. TLC: 50% EtOAc/Heptane (R 0.5). MS calcd. for Chemical Formula: C20H17F2N3OS: 385.11 ; Found: 385.90 [M + 1]⁺. ¹H NMR (400 MHz, DMSO-d₆) 5 7.61 (d, J = 7.8 Hz, 2H), 7.54 - 7.35 (m, 4H), 7.35 - 7.21 (m, 1 H), 6.70 (s, 1 H), 4.17 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 4.9 Hz, 2H), 2.26 (s, 3H), 2.24 - 2.21 (m, 2H).

Step 3: Synthesis of 2-(3-(2',5'-difluoro-[1,1^,-biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonic acid (Intermediate 1-4)

[0169] To a stirred solution of Intermediate 1-3 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0 °C in an inert atmosphere, chlorosulfuric acid (2.07 mL, 31.168 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to afford Intermediate 1-4 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (R_f: 0.2). MS calcd. for Chemical Formula: C20H17F2N3O4S2: 465.06; Found: 466 [M + 1]⁺.

Step 4: Synthesis of 2-(3-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonamide (Compound 1)

[0170] A stirred solution of Intermediate 1-4 (3.3 g, 7.096 mmol) in POCI3 (33 mL) was allowed to stir at 90 °C for 5 h. The reaction mixture was concentrated under reduced pressure to dryness. The resulting residue obtained was dissolved in THF (66 mL), and aqueous ammonia (33 mL) was added at -5 °C and stirring continued at room temperature for another 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 100% EtOAc) to afford the desired product Compound 1 (1.1 g, 44.64%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 5 7.65-7.59 (m, 2H), 7.55 (br s, 2H), 7.53-7.48 (m, 2H), 7.48-7.36 (m, 2H), 7.31-7.25 (m, 1 H), 4.17 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.29- 2.18 (m, 2H).

EXAMPLE 2: BIOLOGICAL ASSAY DATA FOR COMPOUND 1

Cell culture

[00166] Vero cells were cultured in Dulbecco’s Modified Eagle Medium (DM EM) supplemented with 10% foetal bovine serum and 100 units/mL penicillin and streptomycin. The cells were passaged 2-3 times per week to maintain sub-confluent densities.

HSV-1 antiviral assay

[00167] Vero cells were seeded into 96-well plates at a density of 2.5 * 10³ cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 .L of infection medium (DMEM supplemented with 2% foetal bovine serum and 100 units/mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 iL of infection medium containing 80 TCID50 HSV-1 was added to the cells and incubated at 37°C for 4 days. After the incubation, the plates were equilibrated to room temperature, the media was removed, and 60 pL of a 1 :1 dilution of Cell titer glow and phosphate buffered saline was added to the cells. Following a 5-minute incubation, cell viability was quantified by measuring luminance using a Tecan Infinite M1000 Pro plate reader.

HSV-2 antiviral assay

[00168] Vero cells were seeded into 96-well plates at a density of 1.0 x 10⁴ cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 iL of infection medium (DMEM supplemented with 2% foetal bovine serum and 100 units/mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 iL of infection medium containing 160 TCID50 HSV-2 G strain was added to the cells and incubated at 37°C for 5 days. After the incubation, 10 pL/well of WST-8 chromogenic reagent was added and the plates incubated at 37°C for 3 hours. Following the incubation, cell viability was quantified by measuring the absorbance at 460 nm and 620 nm using a Tecan Infinite M1000 Pro plate reader.

[00169] In the HSV-1 antiviral assay, Compound 1 had an EC50 of 0.019 iM (n=22). In the HSV- 2 antiviral assay, Compound 1 had an EC50 of 0.011 iM (n=35).

EXAMPLE 3: GENERATION OF CRYSTALLINE FORMS

[00170] A number of crystallization experiments on Compound 1 were conducted using different techniques (slurry at RT and 50°C, slow evaporation and anti-solvent addition) in a variety of solvent systems. Table 2 provides a summary of the crystalline forms obtained.

Table 2 - Summary of Crystal Forms of Compound 1

ND = not determined

[00171] Figure 1 shows an overlay of the XRPD diffractograms for Forms A to G.

COMPETITIVE SLURRY STUDIES

[00172] Table 3 provides a summary of the results of a competitive slurry experiment of Forms A, B and C mixed in a 1 : 1 : 1 ratio in three different solvent mixtures at both 25°C or 50°C. After 24 or 72 hour slurrying a sample was taken, filtered and analysed by XRPD.

Table 3 - Summary of Competitive Slurry Study of Forms A, B & C

[00173] It can be seen from the competitive slurry studies that Form C is more thermodynamically stable than Forms A and B at 25°C and 50°C. EXAMPLE 4: FORMATION & CHARACTERISATION OF FORM C

[00174] Crude Compound 1 prepared according to Example 1 (4.0 kg) was stirred in DMSO (12 L, 3 relative volumes) at 75-85°C in a first reactor to form a solution. The solution was then filtered through a 0.2 pm filter into a second pre-warmed (75 to 85 °C) reactor, the first reactor being subsequently rinsed with DMSO (2 L, 0.5 rel. vol.) and the rinse being transferred to the second reactor. The contents of the second reactor were stirred at 75-85°C in for 30-60 minutes and then cooled at a cooling rate of 8-12°C per hour to give a batch temperature of 50-55°C. The mixture was stirred at 50-55°C for 1-2 hr. Ethanol (4 L, 1 rel. vol.) was then added slowly over a period of 60-90 minutes whilst maintaining the batch temperature at 50-55°C. The internal batch temperature was increased to 57 to 62 °C and ethanol (52 L, 13 rel. vol.) was added slowly over a period of 7.0-7.5 hr. The contents were stirred at 57 to 62 °C for 1 to 2 hours and then cooled at a cooling rate of 8-12°C per hour to give a final batch temperature of 18-22°C. The mixture was stirred at 18-22°C for 8-12 hours and was then filtered, washed with ethanol (8 L, 2 volumes) and the cake dried at 45 to 55°C for 20-24 hr to give 3.6 kg (90% yield) of Compound 1 as an off white to light yellow solid with a purity by HPLC of 99.7%. ¹H NMR (400 MHz, d6-DMSO, ppm): 7.39 ppm (ddd, J = 10.0/9.2/4.7 Hz, 1 H), 7.27 ppm (m, 1 H), 7.45 ppm (ddd, J = 9.3/6.2/3.2 Hz, 1 H), 2 x 7.63 ppm (dd, J = 8.6/1.5 Hz, 1 H), 2 x 7.51 ppm (d, J = 8.6 Hz, 1 H), 3.83 ppm (t, 5.7 Hz, 2 H), 2.24 ppm (quin, 5.8 Hz, 2 H), 4.17 ppm (t, 5.9 Hz, 2 H), 2.46 ppm (s, 3 H), 7.59 ppm (s, 2 H); HR-MS (ESI Positive): [M+H]+ =465.09.

[00175] The crystalline form obtained had an XRPD diffractogram as shown in Figure 2 and was designated as Form C. Peak positions present in the XRPD diffractogram acquired for Form C are presented in Table 4.

Table 4 - XRPD peak positions for Form C

[00176] Further solid state characterization of Form C was performed using DSC, TGA, DVS and PLM. Form C was determined to be an anhydrous crystalline form of Compound 1. DSC shows a sharp melting endothermic with an onset temperature of 271.7 °C (see Figure 3), while TGA shows a weight loss of 0.44% up to 200° C (see Figure 4). DVS analysis showed water update of 0.02% at 90% P/Po (Figure 5) indicating Form C is non-hygroscopic. No change in crystalline form was observed post DVS experiment. PLM shows plate-like birefringent crystals of Form C (Figure 6).

EXAMPLE 5: SOLID STABILITY OF FORM C

[00177] Samples of Form C were subjected to stability testing under conditions of high temperature (60 °C), high humidity (90% RH at 25 °C), or illumination (4,500 Lux) for 11 days. Samples were taken after 5 days and 11 days and subjected to visual analysis, HPLC for Compound 1 purity, and XRPD for solid state analysis. The results are summarised in Table 5.

Table 5 - Solid Stability Studies on Compound 1 - Form C

[00178] As the results in Table 5 show, Form C was found to be surprisingly stable with no conversion to a different solid state form and negligible degradation of Compound 1 stability, despite being subjected to extreme temperature, humidity and light storage conditions for at least 11 days.

EXAMPLE 6: MECHANICAL STRESS TESTING OF FORM C

[00179] Samples of Form C were subjected to mechanical stress testing and then analysed by XRPD for evidence of form changes.

[00180] Compression testing was carried out for 5 mins at 10 tons pressure; XRPD testing showed the sample was still Form C. [00181] Granulation testing was carried out for 3 mins, with neat grinding and ethanol-assisted grinding; in both cases XRPD testing showed the samples were still Form C after the tests.

[00182] These results show that Form C exhibits an excellent resistance to mechanical stress.

EXAMPLE 7: FORMATION OF FORM C

[00183] Crude Compound 1 (~7 kg) was stirred in DMSO (3.5 relative volumes) at 70-80°C in a first reactor to form a solution. The solution was then filtered through a 0.2 pm filter into a second pre-warmed (70 to 80 °C) reactor, the first reactor being subsequently rinsed with DMSO (0.5 relative volumes) and the rinse being transferred to the second reactor. The mixture was stirred at 70-80°C until clear. Ethanol (1 rel. vol.) was then added slowly over a period of 30-60 minutes whilst maintaining the batch temperature at 70-80°C. The internal batch temperature was decreased to 55 to 60 °C (cooling rate 8-12 °C per hour), crystal seed (2 wt%) was added to the reactor, and the mixture was stirred at 55-60°C for 2-3 hours. Ethanol (15 rel. vol.) was then added slowly over a period of 8-10 hr. The contents were stirred at 55 to 60 °C for 1 to 2 hours and then cooled at a cooling rate of 3-7°C per hour to give a final batch temperature of 18-22°C. The mixture was stirred at 18-22°C for 12-24 hours and was then filtered (isolated via centrifugation), washed with ethanol (2 x 4 volumes) and the cake dried at 45 to 55°C for 12-24 hr to give ~7 kg of Compound 1 Form C as an off white to light yellow solid with a purity by HPLC of 99.8%.

[00184] All publications, patents and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used.

[00185] Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

[00186] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

THAT WHICH IS CLAIMED IS:

1. A crystalline form of Compound 1

Compound 1; wherein the crystalline form is Form C.

2. The crystalline form of claim 1, wherein Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 15.1, 25.3 and 30.5 °20 ± 0.2 °20.

3. The crystalline form of claim 2, wherein the XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation further comprises at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ± 0.2 °20.

4. The crystalline form of claim 1 , wherein the form is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising at least two, five, ten, or fifteen peaks selected from the group consisting of the peaks in Table 4 in °20 ± 0.2 °20.

5. The crystalline form of claim 2, wherein the XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation further comprises at least two, five, ten, or fifteen peaks selected from the group consisting of the additional peaks in Table A in °20 ± 0.2 °20.

6. The crystalline form of claim 1, wherein Form C is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in Figure 2.

7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form is anhydrous.

8. The crystalline form of any one of claims 1 to 7, wherein the crystalline form comprises less than 2% by weight of water.

9. The crystalline form of any one of claims 1 to 8, wherein Form C is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ± 3°C.

10. The crystalline form of claim 9, wherein the DSC thermogram comprises no thermal events between 50 and 100 °C and an endothermic event with an onset temperature of 269 °C ± 3°C.

11. The crystalline form of any one of claims 1 to 8, wherein Form C is characterized by a DSC thermogram substantially the same as the DSC thermogram depicted in Figure 3.

12. The crystalline form of any one of claims 1 to 11 , wherein the crystalline form is substantially pure.

13. The crystalline form of any one of claims 1 to 12, wherein Form C is at least 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% free of other forms.

14. The crystalline form of any one of claims 1 to 11 , wherein Form C is free from other forms.

15. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier, diluent or excipient.

16. The crystalline form according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, for use as a medicament.

17. The crystalline form according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, for use in the treatment of HSV infection

18. A method for treating a herpes virus (such as HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15.

19. The method of claim 18, wherein the crystalline form or 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.

20. The method of claim 19, wherein the crystalline form or the pharmaceutical composition is administered once every three months, once every six months, or once every year.

21. The method of any one of claims 18-20, wherein the crystalline form or the pharmaceutical composition is administered orally, or via injection.

22. The method of any one of claims 18-21 , wherein the method comprises co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.

23. The use of the crystalline form according to any one of claims 1 to 14 in the manufacture of a medicament for treating HSV infection.

24. A process to prepare the crystalline form according to any one of claims 1 to 14, the process comprising the steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture obtained from step b), optionally for at least 1 hour; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

25. The process according to claim 24, wherein the first solvent system comprises DMSO or DMF, such as DMSO.

26. The process according to claim 24 or claim 25, wherein the second solvent system comprises ethanol.