2-(3-(2,5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4- methylthiazole-5-sulfonamide

Abstract

The present invention relates to a novel crystalline form of a helicase-primase inhibitor compound, and to pharmaceutical compositions comprising the novel crystalline form, to methods of production of the novel crystalline form, to the crystalline form in medicine and for use in the treatment of herpes viral infections.

Description

Technical Field

[0001] This disclosure relates to a novel crystalline form of a compound that can be used to treat and / or inhibit the development or progression of diseases or conditions caused by or related to herpesvirus infection. Background Technology

[0002] Human herpesviruses are large enveloped, double-stranded DNA viruses characterized by the ability to establish lifelong infection in humans. This is achieved through their ability to exist in the host as an asymptomatic latent infection (where the virus is in a dormant state) or as a lytic infection with associated symptoms after activation. These viral infections are widespread throughout the world, and notably, over 90% of all human infections are long-term infections with more than one human herpesvirus.

[0003] Human herpesviruses are classified into three subfamilies (α, β, and γ) based on their biological characteristics, and the family consists of eight members: herpes simplex virus subtypes 1 and 2 (HSV1, HSV2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6-8 (HHV 6-8).

[0004] HSV1 and HSV2 infections can cause disease in immunocompetent individuals. Both subtypes cause cutaneous genital / anal and oral / nasal lesions (herpes labialis), but HSV2 is more commonly associated with the former, while HSV1 is associated with the latter. It is believed that >80% of genital infections are caused by HSV2. More than 500 million people worldwide have genital herpes infection, and approximately 50% to 80% of the world's population has oral HSV infection, which is the leading cause of herpes labialis. HSV, and especially HSV1, can also cause lesions on the fingers (whitlows) and other areas of the skin.

[0005] The vast majority of individuals infected with HSV will not experience any noticeable symptoms. However, some will experience recurrent (and often severe) outbreaks of infection. In the United States, 20% to 40% of the population will develop recurrent HSV lesions of the lips. Notably, herpes labialis and whitlow provide a very easy route for the virus to spread to other individuals, which can lead to rarer but more serious HSV-related pathologies. For example, HSV-associated keratitis is a leading cause of blindness, and HSV can also cause encephalitis in newborns, a life-threatening condition. Other conditions believed to be caused by HSV include traumatic herpes, Mollaret's meningitis, and possible Bell's palsy.

[0006] Primary infection or reactivation of existing herpesvirus infection can be a major cause of disease in immunocompromised individuals. Key risk groups include patients who have received solid organ or stem cell transplants, patients undergoing cancer treatment, individuals with HIV / AIDS, and ICU patients.

[0007] Currently, there is no cure for HSV. Drugs have been developed that can reduce the occurrence of outbreaks and / or shorten their duration to some extent, but improvements in treatment are needed.

[0008] Currently, nucleoside analogs, such as acyclovir and its prodrugs (e.g., valacyclovir and famciclovir), are used as agents against herpesviruses such as HSV. To exert their effects, these nucleoside analogs must be phosphorylated by viral thymidine kinase (TK) and subsequently converted to nucleoside triphosphates by cellular kinases, which inhibit the activity of viral DNA polymerase. If the virus lacks functionally active TK, as is the case with resistant HHV1 mutants or TK-negative viruses, the nucleoside analogs cannot function.

[0009] Nucleoside analogs are administered clinically at very high doses, typically ranging from several hundred milligrams to several grams daily. Even at these high doses, often administered over extended periods of treatment, these drugs do not completely prevent recurrent outbreaks of HSV infection symptoms. Nucleoside analogs also offer little solution to viral shedding, which can asymptomatically facilitate HSV transmission to more individuals. Some nucleoside analogs, particularly at high doses, also raise safety concerns. For example, their mutagenicity is a concern because these agents can be incorporated into the host's genomic DNA via host DNA polymerases, as documented with the nucleoside analog ganciclovir (Aoki, Chapter 45, in Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases (8th Edition), 2015).

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

[0011] One class of compounds currently under investigation is helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with novel mechanisms of action. They inhibit the viral heterotrimeric complex, which consists of helicases, primases, and cofactor subunits essential for viral DNA replication. These agents are not nucleoside analogs and do not require TK phosphorylation to inhibit HSV replication; therefore, they have potential activity against TK-deficient HSV, which, as mentioned above, is the primary mechanism by which TK-deficient HSV exhibits resistance to nucleoside analogs.

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

[0013] BILS-179 BS was previously used for oral administration in 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 thiazolidinamide derivative with the chemical name N-methyl-N-(4-methyl-5-aminosulfonyl-1,3-thiazolyl-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide. This compound is disclosed in WO 2001 / 47904. In a human clinical study, the effect of pritelivir on the suppression of genital herpes following oral administration was investigated in 156 individuals (Wald et al., (2014) New England Journal of Medicine 370, pp. 201-210). 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), pp. 2495-2503).

[0015] This disclosure relates to a novel crystalline form of a compound that is an effective helicase-primase inhibitor. The compound is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazolyl-5-sulfonamide, and is also referred to herein as "Compound 1". Summary of the Invention

[0016] This article presents a novel crystalline form of compound 1. Compound 1 has the following structure: Compound 1. The compound shown above is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidine-1(2H)-yl)-4-methylthiazol-5-sulfonamide (also referred to as "compound 1" in this document) and is a potent helicase-primase inhibitor.

[0017] This disclosure relates to a novel solid form of compound 1, which has promising and advantageous solid-state and / or biopharmaceutical properties.

[0018] This disclosure also relates to pharmaceutical compositions comprising the crystalline form, and methods for preparing such forms. This disclosure further relates to the use of the crystalline form in the treatment of HSV infection.

[0019] In a first aspect, this disclosure provides a crystalline form of compound 1, wherein the crystalline form is form C.

[0020] Form C is characterized by X-ray powder diffraction (XRPD) patterns measured using Cu Kα (λ=1.5406Å) radiation, which include peaks at 15.1°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 30.5°2θ±0.2°2θ.

[0021] Form C can also be characterized by the fact that the DSC thermogram includes an endothermic event with an initial temperature of 269℃±3℃.

[0022] Form C is the non-solventized and anhydrous crystalline form of compound 1 and has a high melting point. The high melting point means that form C can be handled at high temperatures without melting, for example, during pharmaceutical dosage form reduction processes, such as micronization and / or manufacturing. Furthermore, form C is non-hygroscopic, which is particularly advantageous when handling and storing form C and pharmaceutical compositions containing form C under varying humidity conditions.

[0023] Advantageously, form C possesses certain properties that make it particularly suitable for formulation and delivery via certain routes of administration. It is a thermodynamically stable form and provides excellent chemical and physical stability of compound 1 even under extreme temperature, humidity, and light storage conditions. Furthermore, form C exhibits very good resistance to mechanical stress.

[0024] In another aspect, this 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.

[0025] In another aspect, the present invention provides a method for treating a subject with a herpes virus (conveniently HSV) infection, 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.

[0026] In another aspect, the present invention provides a method for treating a subject with a herpes virus (conveniently HSV) infection, 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.

[0027] On the other hand, a crystalline form of compound 1 is provided for treating herpes virus (conveniently HSV) infection, wherein the crystalline form is form C.

[0028] On the other hand, a pharmaceutical composition for treating herpes virus (conveniently HSV) infection is provided, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is form C.

[0029] On the other hand, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising compound 1 for treating herpes virus (conveniently HSV) infection is provided, wherein the crystalline form is form C.

[0030] On the other hand, 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 herpes virus (conveniently HSV) infection is provided, wherein the crystalline form is form C.

[0031] On the other hand, a method for preparing the crystalline form of compound 1, wherein the crystalline form is form C, is provided.

[0032] In another respect, a crystalline form of compound 1, which can be obtained by the methods described herein, is provided, wherein the crystalline form is form C. Attached Figure Description

[0033] Figure 1 This is a superimposed XRPD diffraction pattern of compound 1 in the form of AG.

[0034] Figure 2 This is the XRPD diffraction pattern of form C of this disclosure.

[0035] Figure 3 The DSC thermogram of form C is shown. The DSC exhibits a sharp endothermic effect at an onset of 271.7 °C and a peak at 272.4 °C.

[0036] Figure 4The TGA thermogram for form C is shown. The TGA data indicate a weight loss of 0.44% at temperatures up to 200°C.

[0037] Figure 5 The DVS of form C is shown.

[0038] Figure 6 A PLM image of a C-type crystal is shown. Detailed Implementation

[0039] The features and other details of this disclosure will now be described in more detail. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are focused here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0040] definition Unless otherwise stated, the following terms used in the specification and claims have the same meanings as stated below.

[0041] As used herein, “Compound 1” refers to 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidine-1(2H)-yl)-4-methylthiazolyl-5-sulfonamide.

[0042] As used in this article, “API” refers to an active pharmaceutical ingredient, such as compound 1.

[0043] Unless the context otherwise requires, throughout the specification and claims, the words “comprising,” “including,” etc., shall be interpreted in an open, inclusive sense; the words “a,” “an,” etc., shall be considered to mean at least one and not limited to one; and the term “about” shall be interpreted to mean plus or minus 10%. Terms not explicitly defined herein shall be given the meaning that a person skilled in the art would give them based on this disclosure and the context.

[0044] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of this disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). Ideally, the mammals treated in the methods of this disclosure are those desiring to be treated for HBV infection.

[0045] The term “regulation” includes antagonistic effects (e.g., inhibitory effects), agonistic effects, partial antagonistic effects, and / or partial agonistic effects.

[0046] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic and absorption-retarding agents, fillers, etc., compatible with drug administration. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0047] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0048] As used herein, the term "therapeutic effective amount" or "effective amount" refers to the amount of a subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) that is sought by an investigator, veterinarian, physician, or other clinician. Therapeutic effective amount of compound 1 is the amount required to achieve the desired therapeutic and / or preventative effect. "Therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0049] It should be understood that references to “treatment” include: (1) delaying or reducing the likelihood of the onset of clinical symptoms of a disease or condition developing in a subject who may have the disease or condition but has not yet experienced or shown clinical or subclinical symptoms of the disease or condition; (2) suppressing the disease or condition, i.e., preventing, reducing or delaying the progression of the disease or condition or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom of the disease or condition; or (3) alleviating or slowing the disease or condition, i.e. causing the resolution of the disease, condition or symptom or at least one clinical or subclinical symptom of the disease or condition. The term “treatment” includes any action that results in improvement of the disease, such as alleviating, reducing, moderating or eliminating (e.g., by binding to the viral heterotrimeric complex and inhibiting the helicase and primase activity of the virus).

[0050] Throughout this specification, values ​​are disclosed in the form of groups or ranges. It is expressly intended that this specification include all individual sub-combinations of the members of such groups and ranges, as well as any combination of the endpoints of such groups or ranges. For example, integers in the range 0 to 40 are expressly intended to be disclosed individually as 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 integers in the range 1 to 20 are expressly intended to be disclosed individually as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0051] The use of any and all embodiments or exemplary language (e.g., "such as", "including", or "for example") herein is intended only to better illustrate the teachings of the invention and does not constitute a limitation on the scope of the invention as otherwise claimed.

[0052] A “crystalline form” is a solid material in which its components are arranged in a highly ordered microstructure, thereby forming a lattice extending in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms, and / or hydrated crystalline forms.

[0053] "Polymorphism" refers to the fact that a solid material can exist in more than one crystalline form.

[0054] As used herein, the term "amorphous" refers to a solid material in which there is no long-range order in the positions of its molecules. An amorphous solid is a substance in which molecules are arranged in a random manner, such that there is no definite arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are typically isotropic, meaning they exhibit similar properties in all directions and do not have a definite melting point. For example, an amorphous material is a solid material in which there are no sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline, as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids.

[0055] A "hydrate" is a compound present in a solid composition along with water molecules. The composition may include stoichiometric amounts of water, such as monohydrate or dihydrate, or may include random amounts of water. As used herein, the term "hydrate" refers to the solid form in which the solution is aqueous (i.e., compound 1), although it can be hydrated, but not as a hydrate as used herein. A hydrate may be crystalline, in which both the compound and water form part of a crystal lattice.

[0056] A "solvent" is a composition similar to a hydrate, in which a solvent other than water is used instead of water. For example, methanol or ethanol can form an "alcohol," which can be stoichiometric or non-stoichiometric. As used herein, the term "solvent" refers to a solid form in the form of a solvent solution (i.e., compound 1), although it can be solvated, but is not a solvate as used herein. Solvents can be crystalline, in which both the compound and the solvent form part of a crystal lattice.

[0057] "Anhydrous" means that the solid form of the compound contains no water incorporated into its structure. For example, the anhydrous crystalline form contains no water forming part of its crystalline structure. Those skilled in the art will know techniques that can be used to quantify the amount of water associated with the solid. For example, the water content can be determined by Karl Fischer titration or thermogravimetric analysis (TGA). Suitably, the anhydrous solid form of the compound contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% by weight, such as less than about 0.5% by weight, about 0.4% by weight, about 0.3% by weight, about 0.2% by weight, about 0.1% by weight, about 0.05% by weight, or about 0.01% by weight of water.

[0058] "Unsolvated" or "non-solvated" means that the solid form of the compound has no solvent incorporated into its structure. For example, the unsolvated crystalline form has no solvent forming part of its crystal structure. Those skilled in the art will know techniques to quantify the amount of solvent associated with the solid. For example, the solvent content can be determined by gas chromatography (GC). Suitably, the unsolvated or non-solvated solid form of the compound contains less than about 2% by weight, such as less than about 1.5% by weight, less than about 1% by weight, such as less than about 0.5% by weight, about 0.4% by weight, about 0.3% by weight, about 0.2% by weight, about 0.1% by weight, about 0.05% by weight, or about 0.01% by weight of solvent.

[0059] In this document, when a composition is referred to as "consisting substantially of a particular component," the composition suitably comprises at least 70% by weight of the component, suitably at least 80% by weight of the component, suitably at least 90% by weight of the component, suitably at least 95% by weight of the component, and most preferably at least 99% by weight of the component. Suitably, a composition referred to as "consisting substantially of a particular component" consists of the component, in addition to one or more trace components.

[0060] The phrase “basically as shown” means that 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 the features in the X-ray powder diffraction pattern or DSC thermograph appear in the pattern.

[0061] The term "relative volume" refers to the volume (in mL) of liquid used relative to the mass (in grams) of compound 1. For example, 10 relative volumes of solvent are equivalent to 10 mL per gram of compound 1.

[0062] The phrase "FIG." is an abbreviation for "Figure."

[0063] Compound 1 Compound 1 is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidine-1(2H)-yl)-4-methylthiazolyl-5-sulfonamide, as shown below.

[0064] Compound 1. Compound 1 is a potent helicase-primase inhibitor, and its in vitro EC50 activity is significantly reduced. 50 The values ​​were approximately 0.019 µM for HSV-1 and 0.011 µM for HSV-2. In vitro ECGs for HSV-1 and / or HSV-2... 50The value can be determined according to methods known to those skilled in the art, such as those disclosed in Field et al. (2013, Antiviral Res. 100, pp. 297-299). In vitro EC 50 The value can also be determined according to the determination method described in the Embodiments section of this application.

[0065] Generally, compound 1 can be prepared, isolated, or obtained by any method that is obvious to those skilled in the art. Exemplary preparation methods are described in the following Example 1.

[0066] Crystalline form of compound 1 In a first aspect, this disclosure provides a crystalline form of compound 1. Specifically, a novel crystalline form of compound 1 described and characterized herein as form C is provided.

[0067] This disclosure also relates to pharmaceutical compositions comprising crystalline form C, and methods for preparing such form. This disclosure further relates to the use of form C in the treatment or prevention of HSV infection.

[0068] Many analytical methods exist that can be used by those skilled in the art of solid-state chemistry to characterize solid forms. As used herein, the term "characterization" means obtaining information about the solid structure of a solid form. For example, powder X-ray diffraction (PXRD / XRPD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, as well as for characterizing and identifying specific crystalline solid forms of compounds.

[0069] Due to variations in X-ray diffraction instruments, samples, and sample preparation, peak values ​​are often reported with the modifiers "±0.2°2θ" or "±0.1°2θ". This is common practice in solid-state chemistry due to the inherent variability in peak values. The variability in peak intensity is a result of how the individual crystals are oriented relative to the external X-ray source within the sample container (referred to as "preferred orientation"). This orientation effect does not provide information about the crystal's structure.

[0070] When the modifiers “±0.2°2θ” and “±0.1°2θ” are used at the end of the X-ray diffraction peak list, it should be understood that the modifiers apply to each peak specified in the list.

[0071] X-ray powder diffraction is just one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. Differential scanning calorimetry (DSC) can also be used to characterize and / or identify crystalline solid forms. Typical variability of values ​​related to the onset temperature of differential scanning calorimetry is about ±3 °C, or more preferably ±2 °C.

[0072] It should be noted that, unless otherwise specified, the thermal data (DSC and TGA) presented herein were obtained using a heating rate of 10 °C / min. Furthermore, DSC data were obtained using an aluminum perforated disk.

[0073] In a first aspect, a crystalline form of compound 1 is provided, wherein the crystalline form is form C. In one embodiment, form C is characterized by XRPD spectra measured using Cu Kα (λ=1.5406Å) radiation including peaks at 15.1°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 30.5°2θ±0.2°2θ.

[0074] In one embodiment, an XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) is provided, which includes peaks at 15.1°2θ ± 0.2°2θ, 25.3°2θ ± 0.2°2θ, and 30.5°2θ ± 0.2°2θ, and also includes at least one, two, three, four, or five specific peaks selected from those at 7.3°2θ ± 0.2°2θ, 8.5°2θ ± 0.2°2θ, 21.8°2θ ± 0.2°2θ, 36.7°2θ ± 0.2°2θ, and 37.0°2θ ± 0.2°2θ.

[0075] In one embodiment, an XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) is provided, which includes peaks at 15.1°2θ ± 0.2°2θ, 25.3°2θ ± 0.2°2θ, and 30.5°2θ ± 0.2°2θ, and also includes peaks at 7.3°2θ ± 0.2°2θ, 8.5°2θ ± 0.2°2θ, 21.8°2θ ± 0.2°2θ, 36.7°2θ ± 0.2°2θ, and 37.0°2θ ± 0.2°2θ.

[0076] In one embodiment, an XRPD spectrum measured using Cu Kα (λ=1.5406Å) radiation is provided, which includes peaks at 15.1°2θ±0.1°2θ, 25.3°2θ±0.1°2θ, and 30.5°2θ±0.1°2θ.

[0077] In one embodiment, an XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) is provided, which includes peaks at 15.1°2θ ± 0.1°2θ, 25.3°2θ ± 0.1°2θ, and 30.5°2θ ± 0.1°2θ, and also includes at least one, two, three, four, or five specific peaks selected from those at 7.3°2θ ± 0.1°2θ, 8.5°2θ ± 0.1°2θ, 21.8°2θ ± 0.1°2θ, 36.7°2θ ± 0.1°2θ, and 37.0°2θ ± 0.1°2θ.

[0078] In one embodiment, an XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) is provided, which includes peaks at 15.1°2θ ± 0.1°2θ, 25.3°2θ ± 0.1°2θ, and 30.5°2θ ± 0.1°2θ, and also includes peaks at 7.3°2θ ± 0.1°2θ, 8.5°2θ ± 0.1°2θ, 21.8°2θ ± 0.1°2θ, 36.7°2θ ± 0.1°2θ, and 37.0°2θ ± 0.1°2θ.

[0079] In one embodiment, an XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) is provided, the spectrum including peaks at 15.1°2θ ± 0.2°2θ, 25.3°2θ ± 0.2°2θ, and 30.5°2θ ± 0.2°2θ, suitably at 15.1°2θ ± 0.1°2θ, 25.3°2θ ± 0.1°2θ, and 30.5°2θ ± 0.1°2θ, and wherein form C is unsolvated and anhydrous. Suitably, form C contains less than about 2 wt% of solvent and / or water, such as less than about 1.5 wt%, less than about 1 wt%, less than about 0.5 wt%, less than about 0.4 wt%, less than about 0.3 wt%, less than about 0.2 wt%, or less than about 0.1 wt% of solvent and / or water. Suitablely, form C contains less than about 2% by weight of water, such as less than about 1.5% by weight, less than about 1%, less than about 0.5% by weight, less than about 0.4% by weight, less than about 0.3% by weight, or less than about 0.2% by weight. Those skilled in the art will know suitable analytical techniques to quantify the amount of solvent / water associated with the solid. For example, the water content can be determined by Karl Fischer titration. Residual solvent can be determined by gas chromatography. Thermogravimetric analysis (TGA) can also quantify the amount of volatile substances (i.e., solvent and water) associated with the solid (surface-bound or incorporated into the crystal structure). In one embodiment, form C is anhydrous. Suitablely, form C is anhydrous and unsolvated.

[0080] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) includes peaks at 15.1°2θ ± 0.2°2θ, 25.3°2θ ± 0.2°2θ, and 30.5°2θ ± 0.2°2θ, and further includes at least two, five, ten, or fifteen additional peaks selected from Table A and denoted as °2θ ± 0.2°2θ. In another embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the XRPD spectrum measured using Cu Ka (λ = 1.5406 Å) includes peaks at 15.1, 25.3, and 30.5°2θ ± 0.1°2θ, and further includes at least two, five, ten, or fifteen additional peaks selected from Table A and denoted as °2θ ± 0.1°2θ.

[0081] surface A- form C Additional XRPD Peak position

[0082] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation and... Figure 2 The results are basically the same.

[0083] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the DSC thermogram includes an endothermic event with an onset temperature of 269°C ± 3°C. In one embodiment, the DSC thermogram excludes thermal events between 50°C and 100°C but includes an endothermic event with an onset temperature of 269°C ± 3°C. In one embodiment, the DSC thermogram excludes thermal events between 50°C and 200°C but includes an endothermic event with an onset temperature of 269°C ± 2°C. In one embodiment, the DSC thermogram excludes thermal events between 50°C and 200°C but includes an endothermic event with an onset temperature of 260°C ± 2°C. In one embodiment, the DSC thermogram excludes thermal events between 50°C and 200°C but includes an endothermic event with an onset temperature of 269°C ± 3°C.

[0084] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the DSC thermogram includes 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, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the DSC thermogram includes an endothermic event with an onset temperature of 272°C ± 2°C.

[0085] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the XRPD spectrum measured using Cu Kα (λ=1.5406 Å) radiation includes peaks at 15.1° 2θ±0.2°2θ, 25.3° 2θ±0.2°2θ, and 30.5° 2θ±0.2°2θ, and the DSC thermogram includes an endothermic event with an onset temperature of 269°C±3°C. In another embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the XRPD spectrum measured using Cu Kα (λ=1.5406 Å) radiation includes peaks at 15.1° 2θ±0.2°2θ, 25.3° 2θ±0.2°2θ, and 30.5° 2θ±0.2°2θ, and the DSC thermogram includes an endothermic event with an onset temperature of 272°C±2°C.

[0086] In one embodiment, a crystalline form of compound 1 is provided, wherein the crystalline form is form C, characterized in that the DSC thermogram is consistent with... Figure 3 The descriptions are basically the same.

[0087] In one implementation, form C is essentially pure.

[0088] When this specification refers to the crystalline form of compound 1, the crystallinity is conveniently greater than about 60% by weight, more conveniently greater than about 80%, even more conveniently greater than about 90%, and preferably greater than 95%, 98% or 99%.

[0089] In one embodiment, form C is pure or substantially pure. As used herein, the term "substantially pure" means that the solid 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 any impurities or other solid forms of compound 1, including alternative crystalline forms, hydrates, solvates, or amorphous forms, as measured, for example, by XRPD. Thus, substantially pure form C as described herein will be understood as containing more than about 80% by weight, more than 85% by weight, more than 90% by weight, more than 95% by weight, more than 98% by weight, more than 99% by weight, or more than 99.5% by weight of crystalline form C of compound 1. Suitably, form C is provided in which no other solid forms (amorphous forms and / or other crystalline forms) are detected when form C is characterized by solid-state techniques, such as by X-ray powder diffraction. Suitably, a crystalline form of compound 1 consisting substantially of form C is provided. Suitablely, the crystalline form of compound 1 consisting of form C is provided.

[0090] Pharmaceutical Compositions and Kits In another aspect, this disclosure provides pharmaceutical compositions comprising a crystalline form of compound 1 disclosed herein, formulated with one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the crystalline form is form C.

[0091] In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of compound 1, wherein the crystalline form is form C; and a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, a pharmaceutical composition is provided 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 another embodiment, a pharmaceutical composition comprising compound 1 is provided, wherein compound 1 is substantially composed of crystalline form C. In yet another embodiment, a pharmaceutical composition comprising compound 1 is provided, wherein compound 1 is composed of crystalline form C.

[0092] When the pharmaceutical composition described herein relates to the crystalline form of compound 1, the crystallinity is conveniently greater than about 60% by weight of form C, more conveniently greater than about 80%, even more conveniently greater than about 90%, and preferably greater than 95%, 98% or 99%.

[0093] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical, buccal, parenteral, rectal, vaginal, or aerosol administration, but the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound used.

[0094] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing compound 1 mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. Compound 1 can be compounded with generally non-toxic, pharmaceutically acceptable carriers, such as those used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. Compound 1 is included in the pharmaceutical composition in an amount sufficient to produce a desired effect against the progression or condition of a disease, such as HSV infection.

[0095] Suitably, a pharmaceutical composition comprising an aqueous suspension of compound C in form 1 is provided. Suitably, the pharmaceutical composition is suitable for administration by injection (such as subcutaneous or intramuscular injection). Suitably, an injectable pharmaceutical composition comprising an aqueous suspension of compound C in form 1 is provided. Suitably, a solid dosage form (e.g., tablet) for oral administration is provided.

[0096] In another aspect, the present invention also provides kits for use by consumers, for example, who require treatment for HSV infection. Such kits include suitable dosage forms, such as those described above, and instructions describing methods for mediating, reducing, or preventing HSV infection using such dosage forms. The instructions will instruct consumers or healthcare professionals to administer the dosage form according to administration methods known to those skilled in the art. Such kits can advantageously be packaged and sold as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a sheet of relatively rigid material covered with a foil, preferably a 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 packaged. The tablets or capsules are then placed in the recesses, and the relatively rigid material sheet is sealed to the plastic foil on the side of the foil opposite to the direction in which the recesses are formed. Thus, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the sheet is strong enough that tablets or capsules can be removed from the blister pack by manually applying pressure to the recess, thereby creating an opening in the sheet at the location of the recess. The tablets or capsules can then be removed through said opening.

[0097] It may be desirable to provide memory aids on the kit, for example, in the form of numbers close to the tablets or capsules, whereby these numbers correspond to the number of days of a regimen in which such specified tablets or capsules should be taken. Another example of such memory aids is a calendar printed on a card, such as: "Week 1, Monday, Tuesday, ... etc... Week 2, Monday, Tuesday, ... etc." Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several tablets or capsules taken on a given day. Furthermore, the daily dose of a first compound may consist of one tablet or capsule, while the daily dose of a second compound may consist of several tablets or capsules, and vice versa. Memory aids should reflect this.

[0098] Treatment In one respect, crystalline compound 1 in form C is provided for use as a drug.

[0099] In one aspect, a pharmaceutical composition is provided for use as a medicament, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0100] In one aspect, a crystalline compound in form C is provided for therapeutic purposes.

[0101] In one aspect, a pharmaceutical composition for treatment is provided, the 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 aspect, a method is provided for treating a subject with a herpesvirus (conveniently HSV) infection, 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, a method is provided for treating a subject with a herpesvirus (conveniently HSV) infection, 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, a method for inhibiting HSV replication in a subject of need is provided, 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 embodiment, a method for inhibiting HSV replication in a subject of need is provided, 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.

[0104] In one embodiment, a method for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need is provided, 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 embodiment, a method for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need is provided, 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, a method is provided for inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need, 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 embodiment, a method is provided for inhibiting the development or progression of a disease or condition caused by or related to HSV infection in a subject of need, 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 one embodiment, a method is provided for treating or preventing a disease or condition caused by or related to HSV infection in a subject of need, 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 embodiment, a method is provided for treating or preventing a disease or condition caused by or related to HSV infection in a subject of need, 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.

[0107] In one particular embodiment, compound 1 form C according to the invention or the pharmaceutical composition according to the invention can reduce the time for lesions caused by HSV infection to heal (e.g., the time for complete recovery of lesions) and the duration of symptoms in diseases or conditions such as cold sores or genital herpes. The time for lesion healing can be defined as the complete epithelialization of HSV lesions on the skin and mucous membranes during the treatment period without the appearance of new lesions, for example, as assessed by a physician.

[0108] In one embodiment, compound 1 form C according to the invention, or pharmaceutical composition according to the invention, can reduce pain or pain intensity (e.g., at the site of lesion) caused by HSV infection in diseases or conditions such as cold sores or genital herpes.

[0109] In another aspect, a crystalline form of compound 1 is provided for treating herpesvirus (conveniently HSV) infection, wherein the crystalline form is form C. In another aspect, a pharmaceutical composition for treating herpesvirus (conveniently HSV) infection is provided, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0110] In one embodiment, a crystalline form of compound 1 for inhibiting HSV replication in a subject is provided, wherein the crystalline form is form C. In another embodiment, a pharmaceutical composition for inhibiting HSV replication in a subject is provided, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0111] In one embodiment, a crystalline form of compound 1 is provided for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need, wherein the crystalline form is form C. In another embodiment, a pharmaceutical composition is provided for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0112] In one embodiment, a crystalline form of compound 1 is provided for inhibiting the development or progression of a disease or condition caused by or associated with HSV infection in a subject of need, wherein the crystalline form is form C. In another embodiment, a pharmaceutical composition is provided for inhibiting the development or progression of a disease or condition caused by or associated with HSV infection in a subject of need, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0113] In one embodiment, a crystalline form of compound 1 for treating or preventing diseases or conditions caused by or related to HSV infection in a subject of need is provided, wherein the crystalline form is form C. In another embodiment, a pharmaceutical composition for treating or preventing diseases or conditions caused by or related to HSV infection in a subject of need is provided, the pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is form C.

[0114] On the other hand, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 for treating herpes virus (conveniently HSV) infection is provided, wherein the crystalline form is form C.

[0115] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 for inhibiting HSV replication in a subject is provided, wherein the crystalline form is form C.

[0116] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 for reducing the likelihood of HSV infection or the severity of symptoms in a subject in need is provided, wherein the crystalline form is form C.

[0117] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 in inhibiting the development or progression of a disease or condition caused by or associated with HSV infection in a subject of need is provided, wherein the crystalline form is form C.

[0118] In one embodiment, the use of a crystalline form of compound 1 or a pharmaceutical composition comprising a crystalline form of compound 1 in the treatment or prevention of a disease or condition caused by or related to HSV infection is provided, wherein the crystalline form is form C.

[0119] On the other hand, 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 herpes virus (conveniently HSV) infection is provided, wherein the crystalline form is form C.

[0120] In one embodiment, use is provided in the manufacture of a crystalline form of compound 1 or a pharmaceutical composition comprising the 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.

[0121] In one embodiment, 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 reducing the likelihood of HSV infection or the severity of symptoms in a subject in need is provided, wherein the crystalline form is form C.

[0122] In one embodiment, 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 inhibiting the development or progression of a disease or condition caused by or associated with HSV infection in a subject of need, wherein the crystalline form is form C.

[0123] In one embodiment, 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 or preventing a disease or condition caused by or related to HSV infection in a subject in need, wherein the crystalline form is form C.

[0124] In one particular implementation, the disease or condition caused by or associated with HSV infection is selected from herpes labialis (e.g., oral herpes or whitlow), genital herpes, HSV-associated keratitis, HSV-associated encephalitis, traumatic herpes, primary HSV gingivostomatitis, Morales meningitis, and Bell's palsy.

[0125] In one particular implementation, the disease or condition caused by or associated with HSV infection is selected from herpes labialis (e.g., oral herpes labialis or whitlow) or genital herpes. In one implementation, the disease or condition is recurrent herpes labialis or recurrent genital herpes. An individual with a history of multiple recurrences of herpes labialis or recurrent genital herpes (e.g., HSV recurring six or more times per year) may be considered to have recurrent HSV.

[0126] In one implementation, the herpes virus being treated is HSV2. In another implementation, the herpes virus being treated is HSV2, and the subject requiring treatment has recurrent genital herpes with HSV2.

[0127] In one implementation, the herpesvirus being treated is HSV1. In yet another implementation, both HSV-1 and HSV-2 are treated.

[0128] In one embodiment, the herpesvirus being treated or prevented is resistant to nucleoside antiviral therapy. In one embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

[0129] In one embodiment, the treated herpesvirus is resistant to nucleoside antiviral therapy, such as an anti-acyclovir mucosal HSV infection. In another embodiment, the treated HSV infection is a mucosal HSV infection resistant to antiviral therapy using nucleoside analogs such as acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir.

[0130] In one particular implementation, the subject requiring 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 genetic immunodeficiency.

[0131] In one particular implementation, the subjects for whom the methods disclosed herein are required are newborns or infants.

[0132] In one particular implementation, the subject is a herpes-positive patient.

[0133] In one particular implementation, the subject requiring the methods disclosed herein has an acyclovir-resistant mucocutaneous HSV infection. This subject may have been diagnosed with the condition based on clinical failure, for example, failure to improve after at least 7 days of administration of an approved oral or intravenous dose of acyclovir.

[0134] In one particular implementation, the subject requiring the methods disclosed herein has a primary genital HSV-associated herpes infection. In another aspect, the subject requiring the methods disclosed herein has a severe or progressive genital HSV-associated herpes infection.

[0135] For the intended use in this area, the appropriate dosage is expected to vary depending on factors such as the mode of administration, the nature and severity of the infection to be treated, and the specific infection to be treated, and is within the authority of the attending physician. Generally, the indicated dosage may be in the range of about 0.1 μg / kg to about 1000 μg / kg of body weight.

[0136] In one 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 once a week, twice a month, once a month, once every two months, once every three months, once every six months, or once a year.

[0137] Suitablely, the crystalline form of the present invention or a pharmaceutical composition comprising the crystalline form of the present invention may be administered to a subject in need once every three months, once every six months, or once a year.

[0138] 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 by injection. In a convenient embodiment, the pharmaceutical composition is a solid dosage form for oral administration. The pharmaceutical composition of the present invention may suitably be an aqueous 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.

[0139] In some embodiments, the subjects being treated are humans. In addition to its use in human treatment, the crystalline form of the invention can also be used in veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. Conveniently, such animals include horses, dogs, and cats.

[0140] combination The pharmaceutical compositions of the present invention can be administered alone as the sole therapy, or in combination with one or more other substances and / or treatments. Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[0141] This document also considers methods including the administration of a second active agent. For example, in addition to HSV infection, the subject or patient may also suffer from HSV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or contributed to by HSV infection. This document also considers disclosed pharmaceutical compositions in combination with at least one other agent previously shown to treat these HSV infection-related symptoms. Such combination therapy can be achieved independently (by administering the individual components of treatment simultaneously, sequentially, or separately) and / or by the pharmaceutical compositions of the present invention comprising a second active agent.

[0142] Therefore, this article provides a method for treating or preventing HSV infection in subjects in need, the method comprising administering a therapeutically effective amount of a crystalline form of compound 1, and co-administering a therapeutically effective amount of an additional therapeutic agent to the subject, wherein the crystalline form is form C.

[0143] Additionally, this article provides a method for treating or preventing HSV infection in a subject in need, 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.

[0144] In one implementation, the additional therapeutic agent is selected from one or more of the following pharmaceutical agents: i. Nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir, and ganciclovir; ii. Pyrophosphate polymerase inhibitors, such as phosphonic acid; iii. Saturated aliphatic alcohols, such as docosanool; iv. Pharmaceuticals such as idoxuridine, trifluuridine, and vidarabine; v. corticosteroids; and vi. Other helicase-primase inhibitors, such as amonexvir.

[0145] In some cases, the crystalline form of compound 1 according to the first aspect of the invention may be administered as part of a combination therapy in a first amount together with one or more antiviral agents, including nucleoside analogs such as acyclovir, phosphonoformic acid, ganciclovir or penciclovir or corresponding prodrugs such as valacyclovir or famciclovir, which may be administered in a second amount.

[0146] In some implementations, the first and second amounts together constitute a pharmaceutically effective amount. The first, second, or both amounts may be the same, more, or less than the effective amount of each compound administered as a monotherapy. The therapeutically effective amount of the disclosed compounds and the antiviral agent may be administered to the subject concurrently, i.e., simultaneously or separately, in any given order and via the same or different routes of administration. In some cases, it may be advantageous to begin administration of compound 1 first, for example, one or more days or one or more weeks before initiating administration of the antiviral agent. Furthermore, additional medications may be administered in conjunction with the aforementioned combination therapy.

[0147] Suitablely, in the combination therapy described above, the crystalline form of compound (I) is form C.

[0148] Method for preparing form C In one aspect of the invention, a method for preparing a crystalline form of compound 1 is provided, wherein the crystalline form is form C.

[0149] In one embodiment, the method for preparing form C includes the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Add a second solvent system to the solution from step a); c) Stir the mixture obtained from step b), optionally stirring for at least 1 hour; d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated from step d).

[0150] 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 mg / mL, 75 mg / mL, 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 substantially of DMSO. Suitably, the first solvent system consists of DMSO. Suitably, compound 1 is dissolved in 1 to 10 relative volumes, such as 1 to 5 relative volumes, of the first solvent system. Suitably, compound 1 is dissolved in 1 to 10 relative volumes of DMSO, such as 1 to 5 or 2 to 4 relative volumes of DMSO.

[0151] Suitablely, step a) is performed at 50°C to 100°C. Suitablely, step a) is performed at 60°C to 90°C, such as 65°C to 85°C, 75°C to 85°C, or 70°C to 80°C.

[0152] Suitablely, at a temperature of 60°C to 90°C (such as 70°C to 80°C), compound 1 is dissolved in 1 to 5 relative volumes of DMSO (such as 2 to 4 relative volumes of DMSO).

[0153] 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 mg / mL 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 to 40 relative volumes of the second solvent system are added to the solution from step a), such as 5 to 20, 10 to 18, or 12 to 16 relative volumes of ethanol. Suitably, 5 to 40 relative volumes of ethanol are added to the solution from step a), such as 5 to 20, 10 to 18, or 12 to 16 relative volumes of ethanol.

[0154] Suitablely, the first solvent system contains DMSO and the second solvent system contains ethanol.

[0155] Suitablely, the second solvent system is an antisolvent system.

[0156] Suitably, in step b), the second solvent system is added at 40°C to 90°C, such as 40°C to 80°C, 55°C to 80°C, or 40°C to 70°C. Suitably, in step b), the second solvent system is added at 50°C to 65°C, such as 50°C to 60°C, 55°C to 60°C, or 60°C.

[0157] Suitable, the second solvent system from step b) is added dropwise to the solution from step a).

[0158] Suitably, the second solvent is added in step b) over a 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 second solvent is added in step b) over a period of about 5 hours. Suitably, the second solvent is added in step b) over a period of about 7 hours. Suitably, the second solvent is added in step b) over a period of about 8 hours. Suitably, the second solvent is added in step b) over a period of 8 to 10 hours.

[0159] Suitably, the addition of the second solvent system in step b) is performed in two parts. Suitably, 0.5 to 2 relative volumes, such as 1 to 2 relative volumes, of the second solvent system (e.g., ethanol) are added in the first part, and 10 to 20 relative volumes, such as 10 to 15 relative volumes, of the second solvent system (e.g., ethanol) are added in the second part. Suitably, the first part of the second solvent system is added over 30 to 60 minutes. In one embodiment, the first part of the second solvent system is added to the stirred mixture at 40°C to 90°C, such as 40°C to 80°C, 40°C to 70°C, 65°C to 85°C, 70°C to 80°C, 50°C to 60°C, or 50°C to 55°C. In one embodiment, the first part of the second solvent system is added to the stirred mixture at the same temperature as in step a). In one embodiment, the second part of the second solvent system is added to the stirred mixture at 50°C to 65°C, such as 55°C to 60°C, 57°C to 62°C, or about 60°C. Suitably, after adding the second solvent system, the mixture is stirred at 57°C to 62°C for 1 to 2 hours. Suitably, after adding the second solvent system, the mixture is stirred at 55°C to 60°C for 1 to 2 hours.

[0160] In one embodiment, step b) further includes an additional step (step b2) of adding seed crystals of compound 1 in form C to the solution. Suitably, 0.01% to 10% by weight of seed crystals are added relative to the amount of compound 1 present in the solution in step a). Suitably, 0.1% to 5% by weight of seed crystals are added, such as about 2% by weight. Suitably, step b2) is performed after the first portion of the second solvent system is added to the mixture. Suitably, step b2) is performed before the second portion of the second solvent system is added to the mixture.

[0161] Suitablely, the stirring in step c) is carried out at room temperature. Suitablely, the stirring in step c) is carried out at 18°C ​​to 22°C.

[0162] Suitably, the stirring in step c) is carried out 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 carried out for at least 1 hour.

[0163] Suitablely, step d) includes separating the solids by filtration.

[0164] Suitably, step e) includes drying the solid at a temperature above room temperature, such as above 30°C or above 40°C. Suitably, step e) includes drying the solid at a temperature of about 50°C.

[0165] The present invention is illustrated by the following non-limiting embodiments.

[0166] Example The following abbreviations are used in this specification: ACN: Acetonitrile DCM: Dichloromethane DMAc: Dimethylacetamide DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DSC: Differential Scanning Calorimetry DVS: Dynamic Vapor Adsorption eq: equivalent EtOAc: Ethyl acetate hr: hours HPLC: High Performance Liquid Chromatography KF: Karl Fischer titration MeOH: Methanol min: minutes NMP: N-methylpyrrolidone PLM: Polarizing Microscopy RH: Relative Humidity RT: Room temperature (approximately 22°C) TBAB: Tetrabutylammonium bromide TGA: Thermogravimetric Analysis THF: Tetrahydrofuran TLC: Thin-layer chromatography Vol: Volume XRPD: X-ray powder diffraction Instruments and methods Polarized light microscopy (PLM): Photographs were collected using an Olympus BX53 polarized light microscope. The sample was dispersed on a glass slide with methyl silicone oil.

[0167] X-ray powder diffraction (XRPD): XRPD diffraction patterns were acquired using Cu, Kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 radiation at a Kα2:Kα1 intensity ratio of 0.50 on a Rigaku Smartlab MiniFlex 600C diffractometer. The X-ray tube was set to 40 kV, 15 mA, and scan mode 1D. The scan range (2θ) was 3°–40°, the step size (2θ) was 0.02°, and the scan speed (2θ) was 10° / min.

[0168] Differential Scanning Calorimetry (DSC): DSC was performed using a TA Instruments DSC2500 differential scanning calorimeter with a temperature ramp from 30°C to 300°C and a heating rate of 10°C / min. The purge gas was N2 (>99.999%). A perforated aluminum disk was used.

[0169] Thermogravimetric analysis (TGA): TGA was performed using a TA Instruments TGA500 differential scanning calorimeter with a temperature ramp from 25°C to 300°C and a heating rate of 10°C / min. The purge gas was N2 (>99.999%). An open aluminum pan was used.

[0170] Dynamic vapor adsorption (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 were collected at 25°C. Two cycles were performed for each analysis. An N2 gas flow (200 sccm) was used.

[0171] Karl Fischer (KF) water content: KF was collected using a volumetric method on a 915 KF Ti-Touch Metrohm titrator. 100 mg of sample was used, diluted with 1:1 NMP:MeOH.

[0172] HPLC methods: The HPLC method conditions used to measure sample stability are summarized in Table 1.

[0173] Table 1 - HPLC Methods Example 1: Synthesis of Compound 1 Step 1: 1-(4-methylthiazolyl-2-yl)tetrahydropyrimidine 2(1 H Synthesis of )-ketone (intermediate 1-1) A mixture of 2-amino-4-methylthiazole (6 g, 52.632 mmol) and 1-chloro-3-isocyanopropane (6.26 g, 52.632 mmol) in THF (60 mL) was heated at 70 °C for 6 h. TBAB (1.7 g, 5.263 mmol) and K₂CO₃ (18.15 g, 131.58 mmol) were added fractionally to the resulting solution, maintaining the same temperature and stirring at 70 °C for 16 h. After the reaction was complete (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 give intermediate 1-1 (5.1 g, 49.22%) as a grayish-white solid. TLC: 70% EtOAc / heptane (R f (0.5). For the chemical formula: C8H 11 N3OS calculated MS value: 197.06; measured value: 198.17 [M+1] + . 1 H NMR (400MHz, DMSO-) d 6 ) δ 7.30 (s, 1H), 6.60 (s, 1H), 3.99 (t, J = 5.4Hz, 2H), 3.20 -3.19 (m, 2H), 2.28 (s, 3H), 1.99 - 1.89 (m, 2H).

[0174] Step 1A: Synthesis of 4'-bromo-2,5-difluoro-1,1'-biphenyl (intermediates 1-2) (2,5-Difluorophenyl)boronic acid (3.07 g, 19.441 mmol) and K3PO4 (7.5 g, 35.348 mmol) were added to a stirred solution of 1-bromo-4-iodobenzene (5 g, 17.674 mmol) in 1,4-dioxane:H2O (50:5 mL), and the reaction mixture was purged under nitrogen for 10 min. PdCl2 (dppf) (1.29 g, 1.767 mmol) was added to the resulting solution under nitrogen. The reaction mixture was heated at 80 °C for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, 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 subjected to CombiFlash chromatography (eluting with 100% heptane) to give intermediate 1-2 (2.3 g, 48.62%) as a grayish-white solid. TLC: 100% heptane (R f : 0.5). 1 H NMR (400MHz, CDCl3) δ 7.58 (d, J = 8.3Hz, 2H), 7.40 (d, J = 7.3Hz, 2H), 7.15-7.06 (m, 2H), 7.05-6.97 (m, 1H).

[0175] Step 2: 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-3-(4-methylthiazolyl-2-yl)tetrahydropyrimidine-2 (1 H Synthesis of )-ketones (intermediates 1-3) Intermediate 1-2 (8.16 g, 30.456 mmol) and K₂CO₃ (8.75 g, 63.45 mmol) were added to a stirred solution of intermediate 1-1 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL), followed by CuI (0.96 g, 5.076 mmol). The resulting reaction mixture was purged under nitrogen for 20 min. 1,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added to the resulting reaction mixture under nitrogen. The reaction mixture was heated in a sealed tube at 120 °C for 24 h. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc, followed by extraction with brine. 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 30%-40% EtOAc in heptane) to give intermediates 1-3 (4.1 g, 41.96%) as a grayish-white solid. TLC: 50% EtOAc / heptane (R f (0.5). For chemical formula: C 20 H17 Calculated MS value for F2N3OS: 385.11; Measured value: 385.90 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 7.61 (d, J = 7.8Hz, 2H),7.54 - 7.35 (m, 4H), 7.35 - 7.21 (m, 1H), 6.70 (s, 1H), 4.17 (t, J = 5.6Hz, 2H), 3.81 (t, J = 4.9Hz, 2H), 2.26 (s, 3H), 2.24 - 2.21 (m, 2H).

[0176] Step 3: 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidine-1(2 H )-base)-4- Synthesis of methylthiazole-5-sulfonic acid (intermediates 1-4) Chlorosulfonic acid (2.07 mL, 31.168 mmol) was added to a stirred solution of intermediates 1-3 (4 g, 10.389 mmol) in anhydrous DCM (40 mL) at 0 °C under an inert atmosphere. The resulting reaction mixture was slowly heated to room temperature and stirred for 12 h. After the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by grinding with diethyl ether. The obtained solid was filtered off and dried under vacuum to give intermediates 1-4 (3.35 g, crude product) as a grayish-white solid. TLC: 100% EtOAc (R f (0.2). For chemical formula: C 20 H 17 MS calculation value of F2N3O4S2: 465.06; Measured value: 466 [M+ 1] + .

[0177] Step 4: 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidine-1(2 H )-base)-4- Synthesis of methylthiazole-5-sulfonamide (compound 1) Intermediates 1-4 (3.3 g, 7.096 mmol) were allowed to be stirred in POCl3 (33 mL) at 90 °C for 5 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in THF (66 mL), and ammonia (33 mL) was added at -5 °C, followed by stirring at room temperature for another 12 h. After the reaction was complete, 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 give the desired product, compound 1 (1.1 g, 44.64%), as a white solid. 1 H NMR (400MHz, DMSO-) d6 ) δ 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, 1H), 4.17 (t, J = 6.1Hz, 2H), 3.82 (t, J =5.6Hz, 2H), 2.45 (s, 3H), 2.29-2.18 (m, 2H).

[0178] Example 2: Bioassay data of compound 1 Cell culture Vero cells were cultured in DMEM (Durbeco Modified Igor Medium) supplemented with 10% fetal bovine serum and 100 units / mL penicillin and streptomycin. Cells were passaged 2-3 times per week to maintain sub-confluence density.

[0179] HSV-1 antiviral assay Vero cells were planted at a density of 2.5 × 10⁶ cells per well. 3 Cells were seeded at a density of 100 μL into 96-well plates and allowed to attach overnight. After attachment, the medium was replaced with 50 µL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 U / mL penicillin and streptomycin). The compound was then added to the culture using an 8-point 3-fold serial dilution format with a Tecan D300e digital dispenser. For all treatments, the DMSO concentration was normalized to 0.5%. After compound addition, 50 µL of DMEM containing 80 TCID45 was added to the culture. 50 HSV-1 infection medium was added to the cells and incubated at 37°C for 4 days. After incubation, the plate was equilibrated to room temperature, the medium was removed, and 60 µL of a 1:1 diluted Cell titer glow and phosphate-buffered saline solution was added to the cells. Cell viability was quantified by measuring the glow intensity using a Tecan Infinite M1000 Pro microplate reader after 5 minutes of incubation.

[0180] HSV-2 antiviral assay Vero cells were planted at a density of 1.0 × 10⁶ cells per well. 4Cells were seeded at a density of 100 μL into 96-well plates and allowed to attach overnight. After attachment, the medium was replaced with 50 µL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 U / mL penicillin and streptomycin). The compound was then added to the culture using an 8-point 3-fold serial dilution format with a Tecan D300e digital dispenser. For all treatments, the DMSO concentration was normalized to 0.5%. After compound addition, 50 µL of DMEM containing 160 TCID45 was added to the culture. 50 Infection medium containing HSV-2 G strain was added to the cells and incubated at 37°C for 5 days. After incubation, 10 µL / well of WST-8 chromogenic reagent was added, and the plates were incubated at 37°C for 3 hours. Cell viability was quantified by measuring absorbance at 460 nm and 620 nm using a Tecan Infinite M1000Pro microplate reader.

[0181] In the HSV-1 antiviral assay, the EC50 of compound 1 was... 50 The concentration was 0.019 µM (n=22). In the HSV-2 antiviral assay, the EC50 of compound 1 was... 50 It is 0.011µM (n=35).

[0182] Example 3: Generation of Crystallized Form Numerous crystallization experiments were conducted on compound 1 using various techniques in multiple solvent systems (slurrying at room temperature and 50°C, slow evaporation, and addition of antisolvent). Table 2 provides a summary of the obtained crystalline forms.

[0183] Table 2 - Summary of crystal forms of compound 1

[0184] ND = Undetermined Figure 1 A superimposed view of XRPD diffraction patterns of forms A to G is shown.

[0185] Competitive Slurry Research Table 3 summarizes the results of competitive slurry experiments on forms A, B, and C, mixed in a 1:1:1 ratio with three different solvent mixtures at 25°C or 50°C. Samples were taken, filtered, and analyzed by XRPD after 24 or 72 hours of slurrying.

[0186] Table 3 - Summary of Competitive Slurry Studies for Forms A, B, and C

[0187] Competitive slurry studies show that form C is more thermodynamically stable than forms A and B at 25°C and 50°C.

[0188] Example 4: Formation and Characterization of Form C In a first reactor at 75°C–85°C, crude compound 1 (4.0 kg) prepared according to Example 1 was stirred in DMSO (12 L, 3 relative volumes) to form a solution. The solution was then filtered through a 0.2 µm filter into a second preheated (75°C–85°C) reactor, followed by rinsing the first reactor with DMSO (2 L, 0.5 relative volumes) and transferring the rinse to the second reactor. The contents of the second reactor were stirred at 75°C–85°C for 30–60 minutes, then cooled at a rate of 8°C–12°C / hour to obtain a batch temperature of 50°C–55°C. The mixture was stirred at 50°C–55°C for 1–2 hours. Ethanol (4 L, 1 relative volume) was then slowly added over 60–90 minutes while maintaining the batch temperature at 50°C–55°C. The internal batch temperature was then increased to 57°C–62°C and ethanol (52 L, 13 relative volumes) was slowly added over 7.0–7.5 hours. The contents were stirred at 57°C to 62°C for 1 to 2 hours, and then cooled at a rate of 8°C to 12°C / hour to obtain a final batch temperature of 18°C ​​to 22°C. The mixture was stirred at 18°C ​​to 22°C for 8 to 12 hours, then filtered, washed with ethanol (8 L, 2 volumes), and the filter cake was dried at 45°C to 55°C for 20 to 24 hours to give 3.6 kg (90% yield) of compound 1 as a grayish-white to pale yellow solid with an HPLC purity of 99.7%. 1 H NMR (400MHz, d6-DMSO, ppm): 7.39ppm (ddd, J = 10.0 / 9.2 / 4.7Hz, 1 H), 7.27ppm (m, 1 H), 7.45ppm (ddd, J = 9.3 / 6.2 / 3.2Hz, 1 H), 2 x 7.63ppm (dd, J = 8.6 / 1.5Hz, 1 H), 2 x7.51ppm (d, J = 8.6Hz, 1 H), 3.83ppm (t, 5.7Hz, 2 H), 2.24ppm (quin, 5.8Hz, 2H), 4.17ppm (t, 5.9Hz, 2 H), 2.46ppm (s, 3 H), 7.59ppm (s, 2 H); HR-MS (ESI positive): [M+H]+ =465.09.

[0189] The obtained crystalline form has the following characteristics: Figure 2 The XRPD pattern shown is named Form C. Table 4 presents the peak positions in the XRPD diffraction pattern obtained for Form C.

[0190] Table 4 - XRPD peak positions in form C

[0191] Further solid-state characterization of form C was performed using DSC, TGA, DVS, and PLM. Form C was identified as the anhydrous crystalline form of compound 1. DSC showed a rapid melting endothermic reaction with an onset temperature of 271.7 °C (see [link to DSC]). Figure 3 TGA showed a 0.44% weight loss at temperatures up to 200°C (see [reference]). Figure 4 DVS analysis showed a groundwater renewal rate of 0.02% at 90% P / Po. Figure 5 The indicator form C is non-hygroscopic. No change in crystal form was observed after the DVS experiment. PLM showed plate-like birefringent crystals of form C ( Figure 6 ).

[0192] Example 5: Solid stability of form C The stability of form C samples was tested for 11 days under high temperature (60°C), high humidity (90% RH at 25°C), or light exposure (4,500 Lux). Samples were taken at 5 and 11 days for visual analysis, HPLC analysis of compound 1 purity, and XRPD solid-state analysis. The results are summarized in Table 5.

[0193] Table 5 - Solid stability studies of compound 1 - form C As shown in Table 5, despite being subjected to extreme temperature, humidity and light storage conditions for at least 11 days, form C was found to be surprisingly stable and did not transform into different solid forms, and the decrease in stability of compound 1 was negligible.

[0194] Example 6: Mechanical stress test of form C Mechanical stress tests were performed on the sample of form C, and then evidence of form changes was analyzed by XRPD.

[0195] A compression test was conducted for 5 minutes under 10 tons of pressure; XRPD testing showed that the sample remained in form C.

[0196] Granulation tests were performed for 3 minutes, including pure grinding and ethanol-assisted grinding; in both cases, XRPD tests showed that the samples remained in form C after the test.

[0197] These results demonstrate that form C exhibits excellent resistance to mechanical stress.

[0198] Example 7: Formation of Form C In a first reactor at 70-80°C, crude compound 1 (approximately 7 kg) was stirred in DMSO (3.5 relative volumes) to form a solution. The solution was then filtered through a 0.2 µm filter into a second preheated reactor (70-80°C), followed by rinsing the first reactor with DMSO (0.5 relative volumes) and transferring the rinse to the second reactor. The mixture was stirred at 70-80°C until clear. Ethanol (1 relative volume) was then slowly added over 30-60 minutes while maintaining the batch temperature at 70-80°C. The internal batch temperature was reduced to 55-60°C (cooling rate of 8-12°C / hour), seed crystals (2 wt%) were added to the reactor, and the mixture was stirred at 55-60°C for 2-3 hours. Ethanol (15 relative volumes) was then slowly added over 8-10 hours. The contents were stirred at 55°C to 60°C for 1 to 2 hours, and then cooled at a rate of 3°C to 7°C / hour to obtain a final batch temperature of 18°C ​​to 22°C. The mixture was stirred at 18°C ​​to 22°C for 12 to 24 hours, then filtered (by centrifugation), washed with ethanol (2 × 4 volumes), and the filter cake was dried at 45°C to 55°C for 12 to 24 hours to obtain approximately 7 kg of compound 1, form C, as a grayish-white to pale yellow solid with an HPLC purity of 99.8%.

[0199] All publications, patents and patent applications cited in this specification are incorporated herein by reference for the purpose of teaching the use of such references.

[0200] Although specific embodiments of the invention have been described and detailed herein, the invention is not limited thereto. The above detailed description is provided as an example of the invention and should not be construed as constituting any limitation on the invention. Modifications will be apparent to those skilled in the art, and all modifications without departing from the spirit of the invention are intended to be included within the scope of the appended claims.

[0201] Unless otherwise indicated, all figures used in the specification and claims to indicate amounts of ingredients, reaction conditions, etc., should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations, which may vary depending on the desired properties sought to be obtained in this disclosure.

Claims

1. A crystalline form of compound 1 Compound 1; The crystalline form mentioned above is form C.

2. The crystalline form according to claim 1, wherein form C is characterized by an XRPD spectrum measured using Cu Kα (λ=1.5406Å) radiation including peaks at 15.1°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 30.5°2θ±0.2°2θ.

3. The crystalline form according to claim 2, wherein the XRPD spectrum measured using Cu Kα (λ=1.5406Å) radiation further includes at least one, two, three, four, or five specific peaks selected from those at 7.3°2θ±0.2°2θ, 8.5°2θ±0.2°2θ, 21.8°2θ±0.2°2θ, 36.7°2θ±0.2°2θ, and 37.0°2θ±0.2°2θ.

4. The crystalline form according to claim 1, wherein the form is characterized in that the XRPD spectrum measured using Cu Ka (λ=1.5406Å) radiation includes at least two, five, ten or fifteen peaks selected from the group of peaks represented in Table 4 as °2θ±0.2°2θ.

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

6. The crystalline form according to claim 1, wherein form C is characterized in that the XRPD pattern measured using Cu Kα (1.5406 Å) radiation is substantially the same as that shown in Figure 2.

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

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

9. The crystalline form according to any one of claims 1 to 8, wherein form C is characterized in that the DSC thermogram includes an endothermic event with an onset temperature of 269°C ± 3°C.

10. The crystalline form according to claim 9, wherein the DSC thermogram does not include thermal events between 50°C and 100°C but includes endothermic events with an initial temperature of 269°C ± 3°C.

11. The crystalline form according to any one of claims 1 to 8, wherein form C is characterized in that the DSC thermogram is substantially the same as the DSC thermogram depicted in FIG3.

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

13. The crystalline form according to 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 according to any one of claims 1 to 11, wherein form C does not contain 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, wherein the crystalline form or the pharmaceutical composition is used as a drug.

17. The crystalline form according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15, wherein the crystalline form or the pharmaceutical composition is used to treat HSV infection.

18. A method for treating a subject with a herpesvirus (such as HSV) infection, the method comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of claims 1 to 14 or a 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 a 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 a year.

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

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

23. 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 method for preparing the crystalline form according to any one of claims 1 to 14, the method comprising the following steps: a) Provide a solution of compound 1 in the first solvent system; b) Add a second solvent system to the solution from step a); c) Stir the mixture obtained from step b), optionally stirring for at least 1 hour; d) Optionally, separate the solid formed in step c); and e) Optionally, dry the solid separated from step d).

25. The method of claim 24, wherein the first solvent system comprises DMSO or DMF, such as DMSO.

26. The method of claim 24 or claim 25, wherein the second solvent system comprises ethanol.

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