Novel crystalline forms

Abstract

The invention relates to novel crystalline forms of a compound, as well as to pharmaceutical compositions comprising the same, methods for their production, the use of the crystalline forms in medicaments and for the treatment of diseases or disorders caused by, or associated with hepatitis B virus (HBV) and / or hepatitis D virus (HDV). Compound (1)

Description

NOVEL CRYSTALLINE FORMSFIELD OF THE INVENTION

[0001] The present disclosure relates to novel crystalline forms 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, hepatitis B virus (HBV) and / or hepatitis D virus (HDV).BACKGROUND

[0002] Hepatitis B virus (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 296 million people were chronically infected in 2019 according to the World Health Organization website, and every year HBV infection causes more than one half million deaths. HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV-positive mothers may also be infected, unless vaccinated at birth.

[0003] The HBV particle is composed of a lipid envelope studded with the hepatitis B surface antigen (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After capsid assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA- filled viral core.

[0004] At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g., entecavir) that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleos(t)ide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance.

[0005] The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon a can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients is likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment.

[0006] Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.

[0007] Another form of viral hepatitis is hepatitis D virus (HDV), a defective RNA virus that causes chronic viral hepatitis and eventual cirrhosis. However, the HDV life cycle is dependent on the presence of HBsAg for viral particle assembly. Thus, in a small set of patients infected with HBV, HDV presents as coinfection / superinfection with HBV. See for example, Sagnelli et al., Life (Basel). 2021 Feb; 11 (2): 169; published online February 22, 2021. doi: 10.3390 / life11020169, herein incorporated by reference with regard to such background teaching. For patients already infected with HBV, coinfection / superinfection with HDV can further exacerbate the symptoms of HBV, increasing the likelihood of complications, rapid disease progression and / or death. Chronic HBV / HDV infection is also associated with the development of hepatocellular carcinoma (HCC). Like HBV, treatment options for HDV infection or HBV / HDV coinfection, are limited and include those used to treat HBV. Thus, there is a need for effective therapeutic options for the treatment of HDV infection or HBV / HDV coinfection / superinfection.

[0008] WO 2022 / 253997 relates to 1 ,5-benzothiazepine and 1 ,2,5-benzothiadiazepine derivatives. These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and / or liver bile acid transport (LBAT) inhibitory activity. WO 2022 / 253997 also relates to pharmaceutical compositions comprising these compounds, and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.

[0009] WO 2023 / 237728 relates to methods for treating hepatitis B and / or D with an Na+ / taurocholate co-transporting polypeptide (NTCP) inhibitor, such as 1 ,5-benzothiazepine and 1 ,2,5-benzothiadiazepine derivatives.

[0010] NTCP functions as a cellular receptor for viral entry of HBV and HDV, which in turn is the major cause of liver disease and HCC. There is a need for additional bile acid modulating compounds that have an improved profile with respect to potency, safety, selectivity and / or bioavailability.

[0011] The present disclosure relates to novel crystalline forms and novel crystalline salt forms of a certain compound. The compound is 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1 ,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid and is referred to herein also as ‘Compound T.SUMMARY OF THE INVENTION

[0012] Provided herein are novel crystalline forms and novel crystalline salt forms of Compound 1. Compound 1 has the following structure:Compound 1.

[0013] The compound shown above is 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1 ,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (also referred to herein as ‘Compound T) and is a hepatitis D virus (HDV) entry inhibitor.

[0014] Compound 1 was first disclosed in PCT application PCT / US2024 / 016495, published as WO 2024 / 177984, as Example 10b.

[0015] The present disclosure relates to certain novel crystalline forms of the free acid and salts of Compound 1 , which possess promising and advantageous solid-state and / or biopharmaceutical properties.

[0016] The present disclosure is also directed to pharmaceutical compositions comprising the crystalline forms, and to methods for preparing such forms. The present disclosure is further directed to the use of the crystalline forms in the treatment of HBV and HDV infections.

[0017] In a first aspect, the present disclosure provides a crystalline form of Compound 1 free acid.

[0018] In one embodiment, the crystalline form of Compound 1 free acid is Form C (described and characterized herein as “Compound 1 free acid Form C”). Compound 1 free acid Form C is a non-solvated and anhydrous crystalline form of Compound 1 free acid.

[0019] Compound 1 free acid Form C is characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 7.1 and 11.3 °20 ± 0.2 °20.

[0020] Compound 1 free acid Form C can also be characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 149°C ± 2°C.

[0021] Compound 1 free acid Form C is a non-solvated and anhydrous crystalline form of Compound 1 free acid and has a high melting point. A high melting point means that Compound 1 free acid 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.

[0022] Advantageously, Compound 1 free acid Form C has certain characteristics that make it particularly suited to formulation and delivery via certain routes of administration. For example, Compound 1 free acid Form C is highly crystalline, non-hygroscopic, is chemically and physically stable under accelerated and stressed stability conditions, and has reasonable solubility in biorelevant media.

[0023] In another aspect, further crystalline forms of Compound 1 free acid are provided.

[0024] In one embodiment, the present disclosure provides a crystalline form of Compound 1 free acid wherein the form is Form A (described and characterized herein as “Compound 1 free acid Form A”). Compound 1 free acid Form A is a non-solvated and anhydrous crystalline form of Compound 1 free acid.

[0025] In one embodiment, the present disclosure provides a crystalline form of Compound 1 free acid wherein the form is Form B (described and characterized herein as “Compound 1 free acid Form B”). Compound 1 free acid Form B is a non-solvated and anhydrous crystalline form of Compound 1 free acid.

[0026] In one embodiment, the present disclosure provides a crystalline form of Compound 1 free acid wherein the form is Form D (described and characterized herein as “Compound 1 free acid Form D”). Compound 1 free acid Form D is a crystalline DMSO solvate of Compound 1 free acid.

[0027] In one embodiment, the present disclosure provides a crystalline form of Compound 1 free acid wherein the form is Form E (described and characterized herein as “Compound 1 free acid Form E”). Compound 1 free acid Form E is a crystalline non-stoichiometric mixed ethyl acetate and heptane solvate of Compound 1 free acid.

[0028] In one embodiment, the present disclosure provides a crystalline form of Compound 1 free acid wherein the form is Form F (described and characterized herein as “Compound 1 free acid Form F”). Compound 1 free acid Form F is a crystalline MTBE solvate of Compound 1 free acid.

[0029] In one aspect, the present disclosure provides a crystalline form of a salt of Compound 1.

[0030] In another aspect, a crystalline form of a tert-butylamine salt of Compound 1 (Compound 1 tert-butylamine salt) is provided.

[0031] In one embodiment, the present disclosure provides a crystalline form of a ferf- butylamine salt of Compound 1 wherein the form is Form A (described and characterized herein as “Compound 1 ferf-butylamine salt Form A”). Form A of the ferf-butylamine salt of Compound 1 is non-solvated and anhydrous. The salt formation ratio is 1 :1 , i.e., for every one molecule of Compound 1 there is one ferf-butylamine molecule present in the salt.

[0032] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient.

[0033] In a further aspect, the present invention provides a method of treating a HBV 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 free acid or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt.

[0034] In a further aspect, the present invention provides a method of treating a HBV 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 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient.

[0035] In another aspect, there is provided a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for use in the treatment of a HBV infection.

[0036] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a HBV infection.

[0037] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for the treatment of a HBV infection.

[0038] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or a pharmaceutical composition comprising a crystalline form of Compound 1free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in the manufacture of a medicament for treating a HBV infection.

[0039] In a further aspect, the present invention provides a method of treating a HDV 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 free acid or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt.

[0040] In a further aspect, the present invention provides a method of treating a HDV 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 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient.

[0041] In another aspect, there is provided a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt for use in the treatment of a HDV infection.

[0042] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a HDV infection.

[0043] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1, such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for the treatment of a HDV infection.

[0044] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1, such as a tert- butylamine salt, or a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in the manufacture of a medicament for treating a HDV infection.

[0045] In another aspect, there is provided a process to prepare Compound 1 free acid Form C.

[0046] In another aspect, there is provided Compound 1 free acid Form C obtainable by the process described herein.

[0047] In another aspect, there is provided a process to prepare Compound 1 ferf-butylamine salt Form A.

[0048] In another aspect, there is provided Compound 1 tert-butylamine salt Form A obtainable by the process described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG. 1 is an XRPD diffractogram of Compound 1 free acid Form A.

[0050] FIG. 2 shows the DSC and TGA thermograms of Compound 1 free acid Form A.

[0051] FIG. 3 shows a PLM image of Compound 1 free acid Form A crystals.

[0052] FIG. 4 is an XRPD diffractogram of Compound 1 free acid Form B.

[0053] FIG. 5 shows the DSC and TGA thermograms of Compound 1 free acid Form B.

[0054] FIG. 6 shows a PLM image of Compound 1 free acid Form B crystals.

[0055] FIG. 7 is an XRPD diffractogram of Compound 1 free acid Form C.

[0056] FIG. 8 shows the DSC and TGA thermograms of Compound 1 free acid Form C.

[0057] FIG. 9 shows a PLM image of Compound 1 free acid Form C crystals.

[0058] FIG. 10 is an XRPD diffractogram of Compound 1 free acid Form D.

[0059] FIG. 11 shows the DSC and TGA thermograms of Compound 1 free acid Form D.

[0060] FIG. 12 shows a PLM image of Compound 1 free acid Form D crystals.

[0061] FIG. 13 is an XRPD diffractogram of Compound 1 free acid Form E.

[0062] FIG. 14 shows the DSC and TGA thermograms of Compound 1 free acid Form E.

[0063] FIG. 15 shows a PLM image of Compound 1 free acid Form E crystals.

[0064] FIG. 16 is an overlay XRPD diffractogram of Compound 1 free acid Forms A-E of Compound 1.

[0065] FIG. 17 shows a DVS of Compound 1 free acid Form C.

[0066] FIG. 18 shows the conversion relationship for Compound 1 free acid Forms A, B, C and E.

[0067] FIG. 19 shows the heat-cooling cycles of DSC curves of Compound 1 free acid Form B

[0068] FIG. 20 shows the heat-cooling cycles of DSC curves of Compound 1 free acid Form C

[0069] FIG. 21 is an XRPD diffractogram of Compound 1 free acid Form F

[0070] FIG. 22 shows the DSC and TGA thermograms of Compound 1 free acid Form F.

[0071] FIG. 23 shows a PLM image of Compound 1 free acid Form F crystals.

[0072] FIG. 24 is an XRPD diffractogram of the sodium salt of Compound 1 Form A.

[0073] FIG. 25 shows the DSC and TGA thermograms of the sodium salt of Compound 1 FormA.

[0074] FIG. 26 shows a PLM image of sodium salt of Compound 1 Form A crystals.

[0075] FIG. 27 is an XRPD diffractogram of the potassium salt of Compound 1 Form A.

[0076] FIG. 28 shows the DSC and TGA thermograms of the potassium salt of Compound 1 Form A.

[0077] FIG. 29 shows a PLM image of potassium salt of Compound 1 Form A crystals.

[0078] FIG. 30 is an XRPD diffractogram of Compound 1 tert-butylamine salt Form A.

[0079] FIG. 31 shows the DSC and TGA thermograms of Compound 1 tert-butylamine salt FormA.

[0080] FIG. 32 shows a PLM image of Compound 1 tert-butylamine salt Form A crystals.

[0081] FIG. 33 is an XRPD diffractogram of Compound 1 tert-butylamine salt Form B.

[0082] FIG. 34 shows the DSC and TGA thermograms of Compound 1 tert-butylamine salt FormB.

[0083] FIG. 35 shows a PLM image of Compound 1 tert-butylamine salt Form B crystals.

[0084] FIG. 36 is an XRPD diffractogram of Compound 1 tert-butylamine salt Form C.

[0085] FIG. 37 shows the DSC and TGA thermograms of Compound 1 tert-butylamine salt FormC.

[0086] FIG. 38 shows a PLM image of Compound 1 tert-butylamine salt Form C crystals.

[0087] FIG. 39 shows a DVS of sodium salt of Compound 1 Form C.

[0088] FIG. 40 shows XRPD diffractograms of sodium salt of Compound 1 Form C pre- and post-DVS.

[0089] FIG. 41 shows a DVS of Compound 1 tert-butylamine salt Form A.

[0090] FIG. 42 shows XRPD diffractograms of Compound 1 tert-butylamine salt Form A pre- and post-DVS.DETAILED DESCRIPTION OF THE DISCLOSURE

[0091] 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

[0092] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0093] As used herein, “Compound 1” refers to 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1 ,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid.

[0094] As used herein, “API” refers to an active pharmaceutical ingredient, e.g., Compound 1.

[0095] 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.

[0096] 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.

[0097] The term “modulation” includes antagonism {e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0098] The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] "Polymorphism" is when a solid material can exist in more than one crystalline form.

[0107] 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.

[0108] 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., 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.

[0109] A "solvate" is a similar composition to a hydrate except that a solvent other than 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., 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.

[0110] "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 %, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01% by weight of water.

[0111] "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) or Nuclear Magnetic Resonance (NMR) spectroscopy. Suitably, an un-solvated or non-solvated solid form of the compound comprisesless than about 2% by weight, such as less than about 1.5%, less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1 %, less than about 0.05%, or less than about 0.01% by weight of solvent.

[0112] 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.

[0113] 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. In one embodiment, the features are the peaks of the X-Ray powder diffraction powder pattern or the thermic event(s) in the DSC thermogram.

[0114] 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 .

[0115] The phrase “FIG.” is short for Figure.Compound 1

[0116] Compound 1 is 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1 ,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid shown below.

[0117] Compound 1 has a half-maximal inhibitory concentration (IC50) of approximately 7.3 and 2400 nM versus human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC50 / NTCP IC50) of >350 fold. Furthermore, Compound 1 also prevented HBV infection of human hepatoma cells with an EC50 of 4.2 nM without affecting cell viability. The in-vitro EC50 and IC50values 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 and IC50 values can also be determined in accordance with the assays described in Example 2 of the present application.

[0118] 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 Forms of Compound 1 Free Acid

[0119] In one aspect, the present disclosure provides a crystalline form of Compound 1 free acid. Specifically, there are provided novel crystalline forms of Compound 1 free acid described and characterized herein as Compound 1 free acid Form A, B, C, D, E or F.

[0120] The present disclosure is also directed to pharmaceutical compositions comprising each crystalline form, and to methods for preparing such forms. The present disclosure is further directed to the use of the crystalline forms in the treatment or prevention of HBV or HDV infection, or HBV / HDV coinfections.

[0121] 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.

[0122] Due to differences in 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.

[0123] 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.

[0124] 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 ± 2°C.

[0125] 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 aluminium punched pans.Form C

[0126] In a first aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Form C. In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) radiation comprising peaks at 7.1 and 11.3 °20 ± 0.2 °20.

[0127] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.1 and 11.3 °20 ± 0.2 °20 and further comprising at least one, two or three specific peaks selected from peaks at 11.8, 13.1 and 14.6 °20 ± 0.2 °20.

[0128] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.1 and 11.3 °20 ± 0.2 °20 and further comprising peaks at 11.8, 13.1 and 14.6 °20 ± 0.2 °20.

[0129] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 7.1 and 11.3 °20 ± 0.1 °20.

[0130] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 7.1 and 11.3 °20 ± 0.1 °20 and further comprising at least one, two or three peaks selected from peaks at 11.8, 13.1 and 14.6 °20 ± 0.1 °20.

[0131] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 7.1 and 11.3 °20 ± 0.1 °20 and further comprising peaks at 11.8, 13.1 and 14.6 °20 ± 0.1 °20.

[0132] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 2-theta values of 7.1 and 11.3 °20 ± 0.2 °20, suitably 7.1 and 11.3 °20 ± 0.1 °20, and wherein Compound 1 free acid Form C is unsolvated and anhydrous. Suitably, Compound 1 free acid 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%, or less than about 0.2 % by weight. 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). Suitably, Compound 1 free acid Form C is anhydrous and un-solvated.

[0133] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 7.1 and 11.3 °20 ±0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five or thirty further peaks selected from the group consisting of the additional peaks in Table 1 in °20 ± 0.2 °20.Table 1 - Additional XRPD peak positions for Compound 1 free acid Form C

[0134] In one embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 7.

[0135] In one embodiment, Compound 1 free acid Form C is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 149°C ± 2°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 130°C, such as between 50 and 100°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 130°C, such as between 50 and 100°C, and an endothermic event with an onset temperature of 149°C ± 2°C.

[0136] In an embodiment, Compound 1 free acid Form C is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 7.1 and 11.3 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 149°C ± 2°C.

[0137] In one embodiment, Compound 1 free acid Form C is characterized by a DSC thermogram substantially the same as depicted in FIG. 8.Form A

[0138] In a further aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Form A. In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) radiation comprising peaks at 7.9 and 10.3 °20 ± 0.2 °20.

[0139] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.9 and 10.3 °20 ± 0.2 °20 and further comprising at least one, two or three specific peaks selected from peaks at 18.1 , 19.7 and 20.4 °20 ± 0.2 °20.

[0140] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.9 and 10.3 °20 ± 0.2 °20 and further comprising peaks at 18.1 , 19.7 and 20.4 °20 ± 0.2 °20.

[0141] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 7.9 and 10.3 °20 ± 0.1 °20.

[0142] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.9 and 10.3 °20 ± 0.1 °20 and further comprising at least one, two or three specific peaks selected from peaks at 18.1 , 19.7 and 20.4 °20 ± O.1 °20.

[0143] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 7.9 and 10.3 °20 ± 0.1 °20 and further comprising peaks at 18.1 , 19.7 and 20.4 °20 ± 0.1 °20.

[0144] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 2-theta values of 7.9 and 10.3 °20 ± 0.2 °20, suitably 7.9 and 10.3 °20 ± 0.1 °20, and wherein Compound 1 Form A is un-solvated and anhydrous. Suitably, Compound 1 free acid Form A 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%, or less than about 0.2% by weight. 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 KarlFischer 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). Suitably, Compound 1 free acid Form A is anhydrous and un-solvated.

[0145] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 7.9 and 10.3 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five or fifty further peaks selected from the group consisting of the additional peaks in Table 2 in °20 ± 0.2 °20.Table 2 - Additional XRPD peak positions for Compound 1 free acid Form A

[0146] In one embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 1.

[0147] In one embodiment, Compound 1 free acid Form A is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 162°C ± 2°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 140°C, such as between 50 and 100°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 140°C, such as between 50 and 100°C, and an endothermic event with an onset temperature of 162°C ± 2°C.

[0148] In an embodiment, Compound 1 free acid Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 7.9 and 10.3 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 162°C ± 2°C.

[0149] In one embodiment, Compound 1 free acid Form A is characterized by a DSC thermogram substantially the same as depicted in FIG. 2.Form B

[0150] In a further aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Compound 1 free acid Form B. In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.4 and 20.7 °20 ± 0.2 °20.

[0151] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.4 and 20.7 °20 ± 0.2 °20 and further comprising at least one or two peaks selected from peaks at 5.5 and 8.1 °20 ± 0.2 °20.

[0152] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.4 and 20.7 °20 ± 0.2 °20 and further comprising peaks at 5.5 and 8.1 °20 ± 0.2 °20.

[0153] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) radiation comprising peaks at 9.4 and 20.7 °20 ± 0.1 °20.

[0154] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.4 and 20.7 °20 ± 0.1 °20 and further comprising at least one or two specific peaks selected from peaks at 5.5 and 8.1 °20 ± 0.1 °20.

[0155] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.4 and 20.7 °20 ± 0.1 °20 and further comprising peaks at 5.5 and 8.1 °20 ± 0.1 °20.

[0156] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 9.4 and 20.7 °20 ± 0.2 °20, suitably 9.4 and 20.7 °20 ± 0.1 °20, and wherein Compound 1 free acid Form B is un-solvated and anhydrous. Suitably, Compound 1 free acid Form B 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%, or less than about 0.2 % by weight. 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). Suitably, Compound 1 free acid Form B is anhydrous and un-solvated.

[0157] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 9.4 and 20.7 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, fifty or fifty-five further peaks selected from the group consisting of the additional peaks in Table 3 in °20 ± 0.2 °20.Table 3 - Additional XRPD peak positions for Compound 1 free acid Form B

[0158] In one embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 4.

[0159] In one embodiment, Compound 1 free acid Form B is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 148°C ± 2°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 130°C, such as between 50 and 100°C. In an embodiment, the DSC thermogram comprises no thermal events between 40 and 130°C, such as between 50 and 100°C and an endothermic event with an onset temperature of 148°C ± 2°C.

[0160] In an embodiment, Compound 1 free acid Form B is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.4 and 20.7 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 148°C ± 2°C.

[0161] In one embodiment, Compound 1 free acid Form B is characterized by a DSC thermogram substantially the same as depicted in FIG. 5.Form D

[0162] In a further aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Compound 1 free acid Form D. In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.7 and 11.6 °20 ± 0.2 °20.

[0163] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.7 and 11.6 °20 ± 0.2 °20 and further comprising at least one or two peaks selected from peaks at 19.3 and 20.5 °20 ± 0.2 °20.

[0164] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) comprising peaks at 9.7 and 11.6 °20 ± 0.2 °20 and further comprising peaks at 19.3 and 20.5 °20 ± 0.2 °20.

[0165] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.7 and 11.6 °20 ± 0.1 °20.

[0166] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.7 and 11.6 °20 ± 0.1 °20 and further comprising at least one or two specific peaks selected from peaks at 19.3 and 20.5 °20 ± 0.1 °20.

[0167] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.7 and 11.6 °20 ± 0.1 °20 and further comprising peaks at 19.3 and 20.5 °20 ± 0.1 °20.

[0168] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 9.7 and 11.6 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty or thirty- five further peaks selected from the group consisting of the additional peaks in Table 4 in °20 ± 0.2 °20.Table 4 - Additional XRPD peak positions for Compound 1 free acid Form D

[0169] In one embodiment, Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 10.

[0170] In one embodiment, Compound 1 free acid Form D is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 106°C ± 2°C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 90 °C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 90 °C and an endothermic event with an onset temperature of 106°C ± 2°C.

[0171] In an embodiment Compound 1 free acid Form D is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.7 and 11.6 °20 ± 0.2 °20,and a DSC thermogram comprising an endothermic event with an onset temperature of 106 °C ± 2°C.

[0172] In one embodiment, Compound 1 free acid Form D is characterized by a DSC thermogram substantially the same as depicted in FIG. 11.

[0173] In one embodiment, Compound 1 free acid Form D comprises at least 8.0% by weight of DMSO. In one embodiment, Compound 1 free acid Form D comprises approximately 10.5% by weight of DMSO.Form E

[0174] In a further aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Compound 1 free acid Form E. In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 6.7 and 10.0 °20 ± 0.2 °20.

[0175] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 6.7 and 10.0 °20 ± 0.2 °20 and further comprising at least one or two peaks selected from peaks at 16.8 and 21.1 °20 ± 0.2 °20.

[0176] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 6.7 and 10.0 °20 ± 0.2 °20 and further comprising peaks at 16.8 and 21.1 °20 ± 0.2 °20.

[0177] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 6.7 and 10.0 °20 ± 0.1 °20.

[0178] In one embodiment Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 6.7 and 10.0 °20 ± 0.1 °20 and further comprising at least one or two specific peaks selected from peaks at 16.8 and 21.1 °20 ± 0.1 °20.

[0179] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 6.7 and 10.0 °20 ± 0.1 °20 and further comprising peaks at 16.8 and 21.1 °20 ± 0.1 °20.

[0180] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 6.7 and 10.0 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, fifty or fifty-five further peaks selected from the group consisting of the additional peaks in Table 5 in °20 ± 0.2 °20.Table 5 - Additional XRPD peak positions for Compound 1 free acid Form E

[0181] In one embodiment, Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 13.

[0182] In one embodiment, Compound 1 free acid Form E is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 87°C ± 2°C.

[0183] In an embodiment Compound 1 free acid Form E is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 6.7 and 10.0 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 87°C ± 2°C.

[0184] In one embodiment Compound 1 free acid Form E is characterized by a DSC thermogram substantially the same as depicted in FIG. 14.

[0185] In one embodiment, Compound 1 free acid Form E comprises at least 3.0% by weight of ethyl acetate. In one embodiment, Compound 1 free acid Form E comprises approximately 4.5% by weight of ethyl acetate. In one embodiment, Compound 1 free acid Form E comprises at least0.1 % by weight of heptane. In one embodiment Compound 1 free acid Form E comprises approximately 0.5% by weight of heptane. In one embodiment, Compound 1 free acid Form E comprises at least 3.0% by weight of ethyl acetate and at least 0.1 % by weight of heptane. In one embodiment Compound 1 free acid Form E comprises approximately 4.5% by weight of ethyl acetate and approximately 0.5% by weight of heptane.Form F

[0186] In a further aspect, there is provided a crystalline form of Compound 1 free acid, wherein the crystalline form is Compound 1 free acid Form F. In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1 .5406 A) radiation comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.2 °20.

[0187] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.2 °20 and further comprising at least one, two, three or four peaks selected from peaks at 9.5, 9.7, 10.1 and 18.9 °20 ± 0.2 °20.

[0188] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.2 °20 and further comprising peaks at 9.5, 9.7, 10.1 and 18.9 °20 ± 0.2 °20.

[0189] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.1 °20.

[0190] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.1 °20 and further comprising at least one, two, three or four specific peaks selected from peaks at 9.5, 9.7, 10.1 and 18.9 °20 ± 0.1 °20.

[0191] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.1 °20 and further comprising peaks at 9.5, 9.7, 10.1 and 18.9 °20 ± 0.1 °20.

[0192] In one embodiment, Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 10.8, 18.3 and 19.4 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty- five, forty or forty-five further peaks selected from the group consisting of the additional peaks in Table 6 in °20 ± 0.2 °20.Table 6 - Additional XRPD peak positions for Compound 1 free acid Form F

[0193] In one embodiment Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 21.

[0194] In one embodiment, Compound 1 free acid Form F is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 78°C ± 2°C.

[0195] In an embodiment Compound 1 free acid Form F is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 10.8, 18.3 and 19.4 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 78 °C ± 2°C.

[0196] In one embodiment, Compound 1 free acid Form F is characterized by a DSC thermogram substantially the same as depicted in FIG. 22.

[0197] Compound 1 free acid Form F is an MTBE solvate. In one embodiment, Compound 1 free acid Form F comprises at least 8.0% by weight of MTBE. In one embodiment, Compound 1 free acid Form F comprises approximately 11% by weight of MTBE.

[0198] In one embodiment, Compound 1 free acid Forms A, B, C, D, E or F are substantially pure. In one embodiment, Compound 1 free acid Form C is substantially pure.

[0199] When it is stated herein that the specification relates to a crystalline form of Compound 1 free acid, 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.

[0200] In one embodiment, Compound 1 free acid 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, salt or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 free acid 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 Compound 1 free acid Form C. Suitably, there is provided Compound 1 free acid Form C wherein when Compound 1 free acid 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 Compound 1 free acid Form C. Suitably, there is provided a crystalline form of Compound 1 free acid consisting of Compound 1 free acid Form C.

[0201] In one embodiment, Compound 1 free acid Form A, Form B, Form D, Form E or Form F 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, salt or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 free acid Form A, Form B, Form D, Form E or Form F 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 Compound 1 free acid Form A, Form B, Form D, Form E or Form F. Suitably, there is provided Compound 1 free acid Form A, Form B, Form D, Form E or Form F wherein when Compound 1 free acid Form A, Form B, Form D, Form E or Form F 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 Compound 1 free acid Form A, Form B, Form D, Form E or1Form F. Suitably, there is provided a crystalline form of Compound 1 consisting of Compound 1 free acid Form A, Form B, Form D, Form E or Form F.Crystalline Form of Compound 1 tert-butylamine salt

[0202] In one aspect, the present disclosure provides a crystalline form of Compound 1 tert- butylamine salt. Specifically, there is provided a novel crystalline form of a tert-butylamine salt of Compound 1 described and characterized herein as Compound 1 tert-butylamine salt Form A.

[0203] The present disclosure is also directed to pharmaceutical compositions comprising each crystalline form, and to methods for preparing such forms. The present disclosure is further directed to the use of the crystalline forms in the treatment or prevention of HBV or HDV infection, or HBV / HDV coinfections.

[0204] In a first aspect, there is provided a crystalline form of Compound 1 tert-butylamine salt, wherein the crystalline form is Compound 1 tert-butylamine salt Form A. In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.1 and 10.5 °20 ± 0.2 °20.

[0205] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.1 and 10.5 °20 ± 0.2 °20 and further comprising at least one or two specific peaks selected from peaks at 11.7 and 17.5 °20 ± 0.2 °20.

[0206] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.1 and 10.5 °20 ± 0.2 °20 and further comprising peaks at 11.7 and 17.5 °20 ± 0.2 °20.

[0207] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.1 and 10.5 °20 ± O.1 °20.

[0208] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.1 and 10.5 °20 ± 0.1 °20 and further comprising at least one or two peaks selected from peaks at 11.7 and 17.5 °20 ± 0.1 °20.

[0209] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 9.1 and 10.5 °20 ± 0.1 °20 and further comprising peaks at 11.7 and 17.5 °20 ± 0.1 °20.

[0210] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 9.1 and 10.5 °20 ± 0.2 °20, suitably 9.1 and 10.5 °20 ± 0.1 °20, and wherein Compound 1 tert-butylamine salt Form A is un-solvated and anhydrous. Suitably, Compound 1 tert-butylamine salt Form A 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%, or less than about 0.2% by weight. 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). Suitably, Compound 1 tert-butylamine salt Form A is anhydrous and un-solvated.

[0211] In one embodiment, Compound 1 tert-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) comprising peaks at 2-theta values of 9.1 and 10.5 °20 ± 0.2 °20 and further comprising at least two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five or forty further peaks selected from the group consisting of the additional peaks in Table 7 in °20 ± 0.2 °20.Table 7 - Additional XRPD peak positions for Compound 1 tert-butylamine salt Form A

[0212] In one embodiment, Compound 1 ferf-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in FIG. 30.

[0213] In one embodiment, Compound 1 ferf-butylamine salt Form A is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 151 °C ± 2 °C. In an embodiment, the DSC thermogram comprises no thermal events between 50 and 100°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 151 °C ± 2 °C. In another embodiment, the DSC thermogram further comprises an endothermic event with an onset temperature of 180 °C ± 2 °C. In another embodiment, the DSC thermogram comprises endothermic events with onset temperatures of 151 °C ± 2 °C and 180 °C ± 2 °C.

[0214] In an embodiment, Compound 1 ferf-butylamine salt Form A is characterized by an XRPD pattern measured using Cu Ka (A = 1.5406 A) radiation comprising peaks at 9.1 and 10.5 °20 ± 0.2 °20, and a DSC thermogram comprising an endothermic event with an onset temperature of 151 °C ± 2°C.

[0215] In one embodiment, Compound 1 ferf-butylamine salt Form A is characterized by a DSC thermogram substantially the same as depicted in FIG. 31.

[0216] When it is stated herein that the specification relates to a crystalline form of Compound 1 ferf-butylamine salt, 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.

[0217] In one embodiment, Compound 1 terf-butylamine salt Form A is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form 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, salt or amorphous forms, for example as measured by XRPD. Thus, substantially pure Compound 1 ferf-butylamine salt Form A 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 Compound 1 ferf-butylamine salt Form A. Suitably, there is provided Compound 1 ferf-butylamine salt Form A wherein when 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 Compound 1 terf-butylamine salt FormA. Suitably, there is provided a crystalline form of Compound 1 consisting of Compound 1 tert- butylamine salt Form A.Pharmaceutical Compositions and Kits

[0218] In another aspect, the present disclosure provides pharmaceutical compositions comprising a crystalline form of Compound 1 free acid as disclosed herein or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient.

[0219] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1 free acid (Form A, B, C, D, E or F) or a crystalline form of Compound 1 terf-butylamine salt (Form A) and a pharmaceutically acceptable carrier, diluent or excipient.

[0220] In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid Form C and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising pure or substantially pure crystalline Compound 1 free acid Form C and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid wherein the Compound 1 free acid consists essentially of crystalline Compound 1 free acid Form C. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid, wherein the Compound 1 free acid consists of Compound 1 free acid crystalline Form C.

[0221] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of Compound 1 terf-butylamine salt and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form of Compound 1 free acid is Form A, B, D, E or F and the crystalline form of Compound 1 tert- butylamine salt is Form A. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of Compound 1 tert- butylamine salt and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form of Compound 1 free acid is pure or substantially pure Compound 1 free acid Form A, B, D, E or F and the crystalline form of the ferf-butylamine salt of Compound 1 is pure or substantially pure Compound 1 terf-butylamine salt Form A.

[0222] In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid wherein the Compound 1 free acid consists essentially of crystalline Compound 1 free acid Form A, B, D, E or F. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid, wherein the Compound 1 free acid consists of crystalline Compound 1 free acid Form A, B, D, E or F.

[0223] In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 tert-butylamine salt wherein the Compound 1 tert-butylamine salt consists essentially of crystalline Compound 1 tert-butylamine salt Form A. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 tert-butylamine salt, wherein the Compound 1 terf-butylamine salt consists of crystalline Compound 1 tert-butylamine salt Form A.

[0224] 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 that crystalline form.

[0225] The pharmaceutical composition of the present invention include those suitable for oral, rectal, topical, buccal, parenteral, 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.

[0226] 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. HBV or HDV infection, or HBV / HDV coinfection).

[0227] In an additional aspect, the invention also provides kits for use by e.g., a consumer in need of HBV or HDV infection, or HBV / HDV coinfection 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 HBV or HDV infection, or HBV / HDV coinfection. 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 betweenthe 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.

[0228] 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

[0229] In one aspect, there is provided crystalline Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use as a medicament.

[0230] In embodiment, there is provided Compound 1 free acid Form A, B, C, D, E or F or Compound 1 terf-butylamine salt Form A for use as a medicament. In one embodiment, there is provided Compound 1 free acid Form C for use as a medicament.

[0231] In one aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1, such as terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use as a medicament. In one embodiment, there is provided a pharmaceutical composition comprising Compound 1 free acid Form A, B, C, D, E or F or Compound 1 tert- butylamine salt Form A, and a pharmaceutically acceptable carrier, diluent or excipient for use as a medicament. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0232] In one aspect, there is provided crystalline Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in therapy. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0233] In one aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluentor excipient for use in therapy. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free-acid is Form C.

[0234] In one aspect, there is provided a method for treating a HBV infection in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0235] In another aspect, there is provided a method for treating a HBV infection in a subject in need thereof is provided, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0236] In one aspect, there is provided a method for treating a HDV infection in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0237] In another aspect, there is provided a method for treating a HDV infection in a subject in need thereof is provided, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0238] With regard to HBV / HDV coinfection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of theHDV virions. See, for example, Negro, Cold Spring Harb. Perspect. Med. 2014 Nov 3;4(11):a021550. doi: 10.1101 / cshperspect.a021550; herein incorporated by reference with regard to such background teaching. Thus, because HDV infection is dependent on the presence of an existing HBV infection, strategies for treating HBV / HDV coinfection may focus on targeting HBV alone, HDV alone or both viruses together.

[0239] Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV / HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0240] In another embodiment, a method for treating an HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0241] Without being bound by any theory, methods of treatment may be facilitated by various mechanisms of action. One possibility for treatment involves targeting machinery involved in viral particle assembly. In the case of HBV, inhibiting assembly of the HBV envelope or core by targeting HBsAg would disrupt assembly of the HBV particles. A second strategy would be to inhibit viral replication of HBV and / or HDV. Existing antiviral therapies may apply this approach in the form of replication inhibitors that target, for example, a specific viral RNA polymerase.

[0242] In one embodiment, there is provided a method for inhibiting HBV and / or HDV viral replication in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0243] In one embodiment, there is provided a method for inhibiting HBV and / or HDV viral replication in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form ofCompound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0244] Methods of treatment may further include targeting the network of bile acid transport proteins that are believed to be the “gateway” of entry for HBV or HDV infection into the hepatocyte. See for example, Slijepcevic et al., Digestive Diseases, 2017; 35:251-258; herein incorporated by reference with regard to such background teaching. The bile acid transport system comprising the sodium taurocholate co-tra ns porting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) are a set of receptors that ensure effective bile acid transport between the ileum and hepatocyte. HBV / HDV coinfection of hepatocytes is believed to be mediated via the NTCP receptor, making it a possible target for treatment. Without being bound by any theory, an “entry inhibitor” may target any of the possible bile acid transport receptors, including, but not limited to the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) to prevent entry of either HBV or HDV virus into the cells. Such entry inhibitors may target all or a portion of the transport receptors to inhibit viral entry.

[0245] In one embodiment, there is provided a method of inhibiting viral entry in hepatocytes in a subject in need thereof, comprising administering to a subject an effective amount of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0246] In another embodiment, there is provided a method of inhibiting viral entry in hepatocytes in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 , or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0247] Regardless of the mechanism targeted, treatment for patients dealing with HBV or HDV infection or HBV / HDV coinfection may be measured by seroconversion of any of the viralantigens, including but not limited to HBsAg or HBeAg, or maintenance of undetectable levels of these antigens.

[0248] For use in accordance with the aspects described herein, the appropriate dosage of the compounds described herein is expected to vary depending on, for example, the particular compound employed, 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. In some cases, the administration dose of the compound may be less than 400 pg / kg body weight. In other cases, the administration dose may be less than 200 pg / kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 pg / kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.

[0249] A compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g., in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).

[0250] For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate.

[0251] Preparations for oral administration may also be suitably formulated to give controlled- release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.

[0252] A disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and / or dispersing agents. Alternatively, the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0253] In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0254] In one embodiment, there is provided a method for reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0255] In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1, such as a tert-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0256] In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1, such as a terf-butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0257] In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0258] In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0259] In another aspect, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in the treatment of a HBV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0260] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier,diluent or excipient for use in the treatment of a HBV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0261] In another aspect, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in the treatment of a HDV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0262] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a HDV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0263] In another aspect, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in the treatment of a HBV or HDV infection, or HBV / HDV coinfection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0264] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a HBV or HDV infection, or HBV / HDV coinfection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0265] In another aspect, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in the inhibition of HBV and / or HDV replication in a subject. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0266] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of HBV and / or HDV replication in a subject. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0267] In one embodiment, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in the inhibition of viral entry in hepatocytes in a subject. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0268] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of viral entry in hepatocytes in a subject. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0269] In one embodiment, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0270] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0271] In one embodiment, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in inhibiting the development or progression of a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0272] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, 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, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0273] In one embodiment, there is provided a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, for use in treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0274] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a pharmaceutically acceptable carrier, diluent or excipient for use in treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0275] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of Compound 1 salt, such as a terf-butylamine salt, for the treatment of a HBV infection. In one embodiment, the crystalline form of Compound 1 freeacid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0276] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for the treatment of a HDV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0277] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for the treatment of a HBV or HDV infection, or HBV / HDV coinfection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0278] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for the inhibition of HBV and / or HDV replication in a subject. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0279] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for inhibiting viral entry in hepatocytes in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0280] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, for reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0281] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in inhibiting the development or progression of a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0282] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0283] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in the manufacture of a medicament for treating a HBV infection. In one embodiment, the crystalline form is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0284] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt 1 , or the use of a pharmaceutical composition comprising a crystalline form ofCompound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, in the manufacture of a medicament for treating a HDV infection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0285] In another aspect, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, in the manufacture of a medicament for treating a HBV or HDV infection, or HBV / HDV coinfection. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0286] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, in the manufacture of a medicament for inhibiting HBV and / or HDV replication in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 tert- butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0287] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, in the manufacture of a medicament for inhibiting viral entry in hepatocytes in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0288] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, in the manufacture of a medicament for reducing the likelihood or severity of symptoms of a HBV or HDV infection, or HBV / HDV coinfection in a subject in needthereof, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0289] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in the manufacture of a medicament for inhibiting the development or progression of a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 terf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0290] In one embodiment, there is provided the use of a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 free acid, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a ferf-butylamine salt, in the manufacture of a medicament for treating or preventing a disease or disorder caused by, or associated with, HBV or HDV infection, or HBV / HDV coinfection, in a subject in need thereof. In one embodiment, the crystalline form of Compound 1 free acid is Form A, B, C, D, E or F and the crystalline form of the Compound 1 ferf-butylamine salt is Form A. In one embodiment, the crystalline form of Compound 1 free acid is Form C.

[0291] 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.

[0292] 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 twice daily, once daily, once every two, three, four, five, or six days, 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.

[0293] 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 twice daily, once daily, once every two, three, four, five, or six days, or once a week, such as once daily dosing.

[0294] 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

[0295] 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.

[0296] Also contemplated herein are methods that include administering a second active agent. For example, in addition to being infected with HBV and / or HDV, a subject or patient can further have HBV and / or HDV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV and / or HDV. Contemplated herein are also disclosed pharmaceutical compositions in combination with at least one other agent that has previously been shown to treat these HBV- and / or HDV- 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.

[0297] Therefore, provided herein is a method for treating or preventing HBV or HDV infection, or HBV / HDV coinfection in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of Compound 1 free acid, or a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0298] In some cases, a disclosed crystalline form of Compound 1 free acid, or a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, may be administered as part of a combination therapy in conjunction with one or more antivirals. Example antivirals include nucleoside analogs, interferon a, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4- fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1 ,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, provided herein is a method of treating a patient suffering from hepatitis B infection comprising administering to the patient a first amount of a disclosed crystalline form of Compound 1 free acid, or a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a terf-butylamine salt, and a second amount of an antiviral, or other anti HBV agent, for example a second amount of a second compound selected from the group consisting of:(i) an HBV capsid assembly promoter - for example, GLS4, BAY 41-4109, AT-130, DVR-23 (as depicted below),NVR 3-778, NVR1221 (by code), and N890 (as depicted below):(ii) other capsid inhibitors such as those disclosed in the following patent applications hereby incorporated by reference: WO 2014 / 037480, WO 2014 / 184328, WO 2013 / 006394, WO 2014 / 089296, WO 2014 / 106019, WO 2013 / 102655, WO 2014 / 184350, WO 2014 / 184365, WO 2014 / 161888, WO 2014 / 131847, WO 2014 / 033176, WO 2014 / 033167, and WO 2014 / 033170;(iii) nucleos(t)ide analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and:(iv) viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives;(v) HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below:and BM601 as depicted below:(vi) disruptors of nucleocapsid formation or integrity such as NZ-4 / W28F:(vii) cccDNA formation inhibitors such as BSBI-25, CCC-0346, CCC-0975 (as depicted below):(viii) HBc directed transbodies, such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at / / dx.doi.org / 10.1016 / j.intimp.2015.01.028;(ix) antiviral core protein mutant (such as Cp183-V124W and related mutations as described in WO 2013 / 010069, WO 2014 / 074906, each incorporated by reference);(x) inhibitors of HBx-interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid based polymer: (REP 2139-Ca);(xi) immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda 1a and PEG IFN lambda 1a, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1);(xii) non-lnterferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) and Interleukin- 7 (CYT107);(xiii) TLR-7 / 9 agonists such as GS-9620, CYT003, Resiquimod;(xiv) cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs;(xv) HBV vaccines such as GS-4774, TG1050, Core antigen vaccine;(xvi) SMAC mimetics such as birinapant and other lAP-antagonists;(xvii) epigenetic modulators such as KMT inhibitors (EZH1 / 2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists;(xviii) kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors;(xix) STING Agonists;(xx) FXR agonists (such as GW 4064 and Fexaramin);(xxi) antibodies, therapeutic proteins, gene therapy, and biologies directed against viral components or interacting host proteins; and(xxii) other agents selected from ribavirin, N-acetyl cysteine, NOV-205 (BAM205), Nitazoxanide (Alinia), Tizoxanide, SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH), DV-601 , and Arbidol.

[0299] In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from one of the disclosed crystalline forms of Compound 1 free acid, or disclosed crystalline forms of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed crystalline form of Compound 1 free acid, or a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, and administering another HBV therapeutic.

[0300] In some embodiments, the disclosure further provides a method of treating HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof, comprising administering a firstcompound selected from one of the disclosed crystalline forms of Compound 1 free acid, or one of the disclosed crystalline forms of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, and one or more other antivirals (including HDV therapies) and one or more HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a HBV or HBV infection or HBV / HDV coinfection in a patient in need thereof, comprising administering a first amount of a disclosed crystalline form of Compound 1 free acid, or a first amount of a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, and administering a second amount of another HBV therapeutic, or an HDV therapeutic.

[0301] 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 crystalline form of Compound 1 free acid or a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert- butylamine salt, 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 a disclosed crystalline form of Compound 1 free acid or a disclosed crystalline form of a pharmaceutically acceptable salt of Compound 1 , such as a tert-butylamine salt, 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.

[0302] In another embodiment, a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of a disclosed compound), with a detection moiety, for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and / or upon photon excitation). Contemplated fluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety may be used in e.g., a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo, and / or methods of assessing new compounds for biological activity.

[0303] Suitably, in the combination therapies described hereinabove, the crystalline form of Compound 1 free acid is Form C. Suitably, in the combination therapies described hereinabove, the crystalline form of a pharmaceutically acceptable salt of Compound 1 is Compound 1 tert- butylamine salt Form A.Process to prepare Compound 1 Free Acid Form C

[0304] In one aspect of the present invention, there is provided a process to prepare Compound 1 free acid Form C.

[0305] In one embodiment, the process to prepare Compound 1 free acid Form C comprises the steps of: a) providing a solution of Compound 1 free acid 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) for at least 10 minutes; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0306] In one embodiment, the first solvent system comprises a first solvent wherein Compound 1 free acid has a solubility of at least 25 mg / mL at room temperature, such as at least 50, 75, or 100 mg / mL. Suitable solvents for the first solvent include ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether (MTBE), THF and 2- methylTHF.

[0307] Suitably, the first solvent system comprises MTBE. Suitably, the first solvent system comprises MTBE and a second solvent. Suitably, Compound 1 free acid has a solubility of less than 20 mg / mL at room temperature, such as less than 10 mg / mL in the second solvent. Suitable solvents for the second solvent include water and a (C5-C12)alkane. Suitably, the second solvent is a (C5-C10)alkane, such as heptane.

[0308] In one embodiment, Compound 1 free acid has a solubility of at least 25 mg / mL at room temperature, such as at least 50, 75, or 100 mg / mL in the first solvent system.

[0309] Suitably, the first solvent system comprises MTBE and heptane. Suitably, the first solvent system comprises heptane and MTBE, wherein the heptane:MTBE ratio is >1 :1 (V / V), such as about 5:4 (V / V).

[0310] Suitably, the first solvent system comprises ethanol. Suitably, the first solvent system consists essentially of ethanol. Suitably, the first solvent system consists of ethanol.

[0311] Suitably, in step a) Compound 1 free acid is dissolved in 1-10 relative volumes of the first solvent system, such as 5-10 relative volumes. Suitably, in step a) a solution of Compound 1 free acid in 1-10 relative volumes of the first solvent system, such as 5-10 relative volumes, is provided.

[0312] Suitably, Compound 1 free acid is dissolved in 1-10 relative volumes of heptane:MTBE, such as 5-10, wherein the heptane:MTBE ratio is >1 :1 (V / V), such as about 5:4 (V / V). Suitably, in step a) a solution of Compound 1 free acid in 1-10 relative volumes of heptane: MTBE, such as 5- 10, wherein the heptane:MTBE ratio is >1 :1 (V / V), such as about 5:4 (V / V), is provided.

[0313] Suitably, Compound 1 free acid is dissolved in 1-10 relative volumes of ethanol, such as 5-10 relative volumes. Suitably, in step a) a solution of Compound 1 free acid in 1-10 relative volumes of ethanol, such as 5-10, is provided.

[0314] Suitably, step a) is performed at 25 to 75 °C. Suitably, step a) is performed at 40 to 60 °C. Suitably, step a) is performed at about 50 °C.

[0315] Suitably, in step a) Compound 1 free acid is dissolved in 5-10 relative volumes of the first solvent system. Suitably, in step a) Compound 1 free acid is dissolved in 5-10 relative volumes of the first solvent system at a temperature of 25 to 75 °C (such as 40 to 60 °C).

[0316] Suitably, in step a) Compound 1 free acid is dissolved in 5-10 relative volumes of heptane: MTBE (such as 7-9 relative volumes) at a temperature of 25 to 75 °C (such as 40 to 60 °C), wherein the heptane:MTBE ratio is >1 :1 (V / V), such as about 5:4 (V / V).

[0317] Suitably, in step a) Compound 1 free acid is dissolved in 5-10 relative volumes of ethanol. Suitably, in step a) Compound 1 free acid is dissolved in 5-10 relative volumes (such as 6-8 relative volumes) of ethanol at a temperature of 25 to 75 °C (such as 40 to 60 °C).

[0318] Suitably, step a) comprise an additional step (step a2)) of adding seeds of Compound 1 free acid Form C to the solution. Suitably, 0.05% to 5% by weight of seed relative to the amount of Compound 1 free acid present in the solution in step a) is added. Suitably, 1% to 3% by weight of seed is added, such as about 2% by weight. Suitably step a2) is carried out at the same temperature as step a), such as at 25-75 °C (suitably at 40 to 60°C or more suitably at about 50°C).

[0319] Suitably, the process comprises an additional step (step a3)) of ageing the solution from step a) or step a2) for 20 to 120 minutes, such as for about 60 minutes. Suitably, step a3) is carried out at the same temperature as step a), such as at 25 to 75 °C, (suitably at 40 to 60 °C, more suitably at about 50°C).

[0320] Steps a2) and / or a3) may provide a suspension of Compound 1 free acid in the first solvent system, therefore, step b) may comprise adding a second solvent system to the suspension resulting from step a2) or step a3).

[0321] Suitably, step a) comprises steps a2) and a3).

[0322] Suitably, the second solvent system comprises a solvent wherein Compound 1 free acid has a solubility of less than 20 mg / mL at room temperature, such as less than 10 mg / mL. Suitable solvents for the second solvent system include water and a (C5-C12)alkane.

[0323] Suitably, the second solvent system comprises a (C5-C10)alkane, such as heptane. Suitably, the second solvent system comprises heptane. Suitably, the second solvent system consists essentially of heptane. Suitably, the second solvent system consists of heptane.

[0324] Suitably, the second solvent system comprises water. Suitably, the second solvent system consists essentially of water. Suitably, the second solvent system consists of water.

[0325] Suitably, 1-40 relative volumes of the second solvent system are added to the solution or suspension from step a), such as 1-10, 5-20, 5-15 or 8-12 relative volumes.

[0326] Suitably, 5-40 relative volumes of heptane are added to the solution or suspension from step a), such as 5-30 or 8-20 relative volumes of heptane.

[0327] Suitably, in step b) the combination of the first and second solvent systems provides a heptane:MTBE ratio of about 6:1 (V / V),

[0328] Suitably, 1 — 10 relative volumes of water, such as 1-5 relative volumes, are added to the solution or suspension from step a).

[0329] Suitably, the first solvent system comprises MTBE and the second solvent system comprises heptane.

[0330] Suitably, the first solvent system comprises ethanol and the second solvent system comprises water.

[0331] Suitably, the second solvent system is an anti-solvent system.

[0332] In an embodiment, the first solvent system comprises a water-miscible organic solvent such as ethanol, isopropanol, acetone, and / or acetonitrile, and the second solvent system comprises water.

[0333] Suitably, in step b) the second solvent system is added at 40 to 70 °C. Suitably, in step b) the second solvent system is added at 40 to 60 °C, such as about 50 °C.

[0334] 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, at least 4 hours or at least 5 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 2 hours. Suitably, the addition of the second solvent in step b) is over a time period of about 5 hours.

[0335] Suitably, the addition of the second solvent system in step b) is carried out in two portions. Suitably, 5-15 relative volumes of the second solvent system (e.g. heptane) are added in the first portion and 5-15 relative volumes of the second solvent system (e.g. heptane) are added in the second portion. In an embodiment, the first portion of the second solvent system isadded to the mixture / suspension being stirred at 40 to 60 °C. In an embodiment, the second portion of the second solvent system is added to the mixture / suspension being stirred at 40 to 60 °C, such as 45 to 55 °C. Suitably, after the addition of the second solvent system, the mixture is stirred at 45 to 55 °C for 0.5-4 hours, such as 0.5-2 hours.

[0336] Suitably, step b) comprises an additional step (step b2)) of cooling the mixture or suspension to 10-50 °C, such as to about 45°C or to about 20°C, after the second solvent system has been added. Suitably, the cooling is over a period of at least 1 hour, such as at least 2, at least 4 hours or for about 6 hours. Suitably, step b2) further comprises stirring the mixture / suspension for at least 1 hour, such as at least 2 hours, at least 4 hours or for about 5 hours.

[0337] Suitably, step b) comprise an additional step (step b3)) of adding seeds of Compound 1 free acid Form C to the mixture or suspension. Suitably, 0.05% to 5% by weight of the seed relative to the amount of Compound 1 free acid present in the solution in step a) is added. Suitably, 1 % to 3% by weight of seed is added, such as about 2% by weight. Suitably step b3) is carried out at the same temperature as step b2), such as at 30-50°C, or more suitably at about 45°C.

[0338] Steps b), b2) and / or b3) may provide a suspension of Compound 1 free acid in the first and second solvent systems, therefore, step c) may comprise stirring the suspension resulting from steps b), b2) and / or b3).

[0339] Suitably, the stirring in step c) is performed at room temperature, such as about 20°C. Suitably, step c) further comprises cooling the mixture or suspension from step b) to less than 40°C, such as less than 30°C, such as to about 20°C. Suitably, the cooling is over a period of at least 1 hour, such as at least 2 hours, at least 4 hours, for about 5 hours or for about 6 hours.

[0340] 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 5 hours, at least 6 hours, at least 10 hours. Suitably, the stirring in step c) is performed for about 12 hours at 20°C.

[0341] Suitably, step d) comprises isolating the solids by filtration.

[0342] 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.

[0343] In one embodiment, the process to prepare Compound 1 free acid Form C comprises the steps of: a) providing a solution of Compound 1 free acid in a first solvent system (suitably comprising ethanol); b) adding a second solvent system (suitably comprising water) to the solution from step a); b3) adding seeds of Compound 1 free acid Form C to the mixture or suspension from step b);c) stirring the mixture or suspension obtained from step b3) for at least 10 minutes; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0344] In another embodiment, the process to prepare Compound 1 free acid Form C comprises the steps of: a) providing a solution of Compound 1 free acid in a first solvent system (suitably, the first solvent comprises heptane and MTBE); a2) adding seeds of Compound 1 free acid Form C to the solution from step a); b) adding a second solvent system (suitably comprising heptane) to the mixture or suspension from step a2); c) stirring the mixture or suspension obtained from step b) for at least 10 minutes; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0345] In an aspect of the present invention, there is provided a crystalline form of Compound 1 free acid Form C obtainable by the process described above.Process to prepare Compound 1 tert-butylamine salt Form A

[0346] In one aspect of the present invention, there is provided a process to prepare Compound 1 tert-butylamine salt Form A.

[0347] In one embodiment, the process to prepare Compound 1 tert-butylamine salt Form A comprises the steps of: a) providing a solution of Compound 1 free acid in a first solvent system; b) adding tert-butylamine in a second solvent system to the solution from step a); c) stirring the mixture obtained from step b) for at least 10 minutes; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

[0348] In one embodiment, the first solvent system comprises a solvent wherein Compound 1 free acid has a solubility of at least 25 mg / mL at room temperature, such as at least 50, 75, or 100 mg / mL. Suitable solvents for the first solvent system include ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether (MTBE), THF and 2- methylTHF. Suitably, the first solvent system comprises ethanol, acetonitrile or isopropanol. Suitably, the first solvent system comprises ethanol. Suitably, in step a) a solution of Compound 1 free acid in 1-10 relative volumes of the first solvent system, such as 1-5 relative volumes, is provided. Suitably, in step a) Compound 1 free acid is dissolved in 1-10 relative volumes of the first solvent system, such as 1-5 relative volumes. Suitably, in step a) a solution of Compound 1 free acid in 1-10 relative volumes of ethanol, such as 1-5, 2-4 or about 3 volumes of ethanol, isprovided. Suitably, in step a) Compound 1 free acid is dissolved in 1-10 relative volumes of ethanol, such as 1-5, 2-4 or about 3 volumes of ethanol.

[0349] Suitably, step a) is performed at 10 to 50°C. Suitably, step a) is performed at 15 to 30°C, 15 to 25°C, or about 20°C.

[0350] Suitably, the second solvent system comprises a solvent in which tert-butylamine is soluble at ambient temperature. Suitable solvents for the second solvent system include ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether (MTBE), THF and 2-methylTHF. Suitably, the second solvent system comprises ethanol, acetonitrile or isopropanol. Suitably, the second solvent system comprises ethanol. Suitably, the second solvent system comprises the same solvent as the first solvent system. Suitably, 1.0 to 1.5, such as 1.0 to 1.2, or about 1.1 molar equivalents of tert-butylamine are used in step b). Suitably, in step b) tert-butylamine is dissolved in 1-10 relative volumes of the second solvent system, such as 1-5 relative volumes. Suitably, in step b) tert-butylamine in 1-10 relative volumes of the second solvent system, such as 1-5 relative volumes, is provided. Suitably, tert-butylamine is dissolved in 1-10 relative volumes of ethanol, such as 1-5, 2-4 or about 3 volumes of ethanol. Suitably, in step b) tert-butylamine in 1-10 relative volumes of ethanol, such as 1-5, 2-4 or about 3 volumes of ethanol, is provided.

[0351] Suitably, in step b) the tert-butylamine in the second solvent system is added to the solution from step a) at 10 to 50°C. Suitably, step b) is performed at 15 to 30°C, 15 to 25°C, or about 20°C.

[0352] Suitably, the stirring in step c) is performed at 20 to 70°C, 30 to 65°C, 40 to 60°C, or about 50°C, such as about 50°C.

[0353] Suitably, the stirring in step c) is performed for at least 1 hour, such as at least 2 hours, at least 4 hours, or at least 5 hours. Suitably, the stirring in step c) is performed at 40 to 60°C, such as about 50°C, for about 2 hours, or until a suspension has formed. Suitably, the stirring in step c) comprises an additional period of stirring after a suspension has formed; suitably this additional period of stirring comprises cooling the mixture to ambient temperature. Suitably, this additional period of stirring comprises cooling the mixture to 20°C over a period of at least 1 hour, such as at least 2 hours, or over 2 to 4 hours, such as over about 3 hours.

[0354] Suitably, step d) comprises isolating the solids by filtration or centrifugation.

[0355] Suitably, step e) comprises drying the solids at 15 to 30°C, 15 to 25°C, or about 20°C. Suitably, step e) comprises drying the solids at 15 to 30°C, 15 to 25°C, or about 20°C under vacuum.

[0356] In an aspect of the present invention there is provided a crystalline form of Compound 1 tert-butylamine salt Form A obtainable by the process described above.

[0357] The invention is illustrated below by the following non-limiting examples.EXAMPLES

[0358] The following abbreviations are used within this specification:ACN: AcetonitrileCOSY: Homonuclear correlation spectroscopyDCM: DichloromethaneDMF: DimethylformamideDMSO: Dimethyl sulfoxideDSC: Differential Scanning CalorimetryDVS: Dynamic Vapor SorptionEA, EtOAc: Ethyl acetateEtOH: EthanolFaSSIF: Fasted State Simulated Intestinal FluidFeSSIF: Fed State Simulated Intestinal FluidHATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium hr: HoursHMBC: Heteronuclear multiple bond correlationHPLC: High Performance Liquid ChromatographyHSQC Heteronuclear single quantum coherence□HMDS: Lithium bis(trimethylsilyl)amideMeOH: Methanol min: MinutesMS: Mass spectrometryMTBE: Methyl tert-butyl etherNBS: N-BromosuccinimideNFSI: N-FluorobenzenesulfonimideNMP: N-Methyl PyrrolidoneNMR: Nuclear magnetic resonanceNOESY: Nuclear Overhauser effect spectroscopyPE: Petroleum etherPLM: Polarized light microscopyRH: Relative Humidity rt: Room Temperature (~22°C)SFC: Supercritical Fluid ChromatographySGF: Simulated Gastric FluidTEA: TriethylamineTGA: Thermogravimetric analysisTHF: Tetra hydrofuranVol, V: VolumeXRPD: X-Ray Powder DiffractionINSTRUMENTATION AND METHODSPolarized-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 either: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 1 D. The scan range (2 theta) was 3-40°, step size (2 theta) of 0.02° with scan speed (2 theta) of 107min; orInstrument Rigaku Smartlab SE using a X-Ray Wavelength: Cu, Ka, Ka1 (A): 1.540598, Ka2 (A): 1.544426 with a Ka2: Ka1 intensity ratio:0.50. X-Ray Tube Setting was 40 kV, 40 mA, Scan Model D. The scan Range (2 Theta): 3°-40°, Step Size (2 Theta): 0.02° with Scan Speed (2 Theta) 107minDifferential 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 aluminium 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 aluminium 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. 1 cycle was performed per analysis. Gas flow of N2 (200 seem) was used.NMR method:1H NMR spectra were collected on a Bruker AVANCE NEO 400MHz spectrometer with the following conditions: PROBHD: 5 mm PABBO BB / ; NS:16; DS: 2; D1 : 1.0000 sec; and solvent: DMSO-D6.HPLC method: The HPLC method conditions used for measuring stability samples for Compound 1 are summarized in Table 8.Table 8 - HPLC method for Compound 1

[0359] The HPLC method conditions used for measuring stability samples for the salts of Compound 1 are summarized in Table 9.Table 9 - HPLC method for salts of Compound 1EXAMPLE 1 : SYNTHESIS OF COMPOUND 1Intermediate 11b (trans- racemate)Intermediate 14bStep 1 : Synthesis of methyl 5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (Intermediate 1)

[0360] To a stirred solution of methyl 5,5-difluoro-2-(hydroxymethyl)hexanoate (100 g, 509.70 mmol) and TEA (154.73 g, 1529.10 mmol) in DCM (1000 mL) was added MsCI (70.06 g, 611.64 mmol) dropwise at 0°C. After stirring at rt for 2 hr, the reaction mixture was added H2O (500 mL) at 0°C. The resulting mixture was extracted with DCM (1000 mL x 2). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous Na2SC>4, and concentrated.The residue was dried in vacuo to give Intermediate 1 (110 g, 79%) as a brown liquid, which was used for the next step without further purification.Step 2: Synthesis of methyl 2-(bromomethyl)-5,5-difluorohexanoate (Intermediate 2)

[0361] To a stirred solution of Intermediate 1 (110 g, 401.05 mmol) in acetone (500 mL) was added lithium bromide (104.48 g, 1203.15 mmol) in portions at rt. After stirring at 60 °C for 3 hr, the mixture was allowed to cool down to rt and added H2O (200 mL) at rt. The resulting mixture was extracted with EA (300 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give Intermediate 2 (100 g, 96%) as a brown liquid, which was used in the next step without further purification.1H NMR (300 MHz, CDCh): 5 3.77 (s, 3H), 3.56 (qd, J = 10.2, 6.4 Hz, 2H), 2.94 - 2.81 (m, 1 H), 2.02 - 1.80 (m, 4H), 1.62 (t, J = 18.4 Hz, 3H) ppm.Step 3: Synthesis of methyl 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5- difluorohexanoate (Intermediate 3)

[0362] To a stirred solution of 2-amino-5-methoxybenzenethiol (60 g, 386.55 mmol) and CS2CO3 (151.60 g, 463.85 mmol) in ACN (500 mL) was added Intermediate 2 (100.15 g, 386.56 mmol) dropwise at rt. After stirring at rt for 4 hr, the reaction mixture was added water (50 mL) at rt. The resulting mixture was extracted with EA (500 mL x 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 4 / 1 (v / v) to give Intermediate 3 (80 g, 62%) as a brown liquid. MS (ESI): calcd. for C15H21F2NO3S: 333.1 ; Found: 334.1 [M + 1]+.Step 4: Synthesis of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5-difluorohexanoic acid (Intermediate 4)

[0363] To a stirred solution of Intermediate 3 (94 g, 281.95 mmol) in dioxane (800 mL) and H2O (200 mL) was added LiOH (20.26 g, 845.87 mmol) at rt. The resulting mixture was stirred at rt for 2 hr. The mixture was acidified with 2 N aq. HCI solution to pH ~ 6. The resulting mixture was extracted with EA (100 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. This residue was dried in vacuo to give Intermediate 4 (80 g, 89%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C14H19F2NO3S: 319.1 ; Found: 320.1 [M + 1]+.Step 5. Synthesis of 3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin- 4(5H)-one (Intermediate 5)

[0364] To a stirred solution of Intermediate 4 (80 g, 250.49 mmol) and HATU (104.77 g, 275.54 mmol) in DCM (1000 mL) was added DIEA (38.85 g, 300.59 mmol) dropwise at rt. The reaction mixture was stirred at rt for 2 hr and then added H2O (50 mL). The resulting mixture was extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (50 mL), driedover anhydrous Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 7 / 3 (v / v) to give Intermediate 5 (67 g, 89%) as a yellow solid. MS (ESI): calcd. for C14H17F2NO2S: 301.1 ; Found: 302.1 [M + 1]+.Step 6. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (Intermediate 6)

[0365] To a stirred solution of Intermediate 5 (32 g, 106.18 mmol) in DCM (200 mL) and ACN (200 mL) was added NBS (20.79 g, 116.80 mmol) in portions at rt. The resulting mixture was stirred at rt for 4 hr and then added H2O (100 mL) at rt. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by trituration with PE / EA = 1 / 1 (v / v) (300 mL). The precipitated solid was collected by filtration, washed with PE / EA = 1 / 1 (v / v) (100 mL), and dried in vacuo to give Intermediate 6 (22 g, 54%) as a white solid. MS (ESI): calcd. for Ci4Hi6BrF2NO2S: 379.0; Found: 380.0 [M + 1]+.1H NMR (300 MHz, CDCh): 5 7.39 (s, 1 H), 7.34 (s, 1 H), 7.14 (s, 1 H), 3.94 (s, 3H), 3.53 (dd, J = 11.3, 6.0 Hz, 1 H), 3.02 (t, J = 11.9 Hz, 1 H), 2.68 (ddd, J = 16.4, 9.3, 5.2 Hz, 1 H), 2.17 - 2.00 (m, 1 H), 2.04 - 1.70 (m, 1 H), 1.68 - 1.47 (m, 5H) ppm.Step 7. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (Intermediate 7)

[0366] A solution of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1 ,4]- thiazepin-4(5H)-one (Intermediate 6) (20 g, 52.60 mmol), (4-fluorophenyl)boronic acid (14.72 g, 105.19 mmol), and Et3N (15.97 g, 0.16 mol) in DMF (300 mL) was treated with Cu(OAc)2 (14.33 g, 78.90 mmol) at room temperature. The resulting mixture was stirred at 80°C for 16 h under oxygen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (300 mL) and sat. aq. NH4CI solution (900 mL). The resulting solution was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL x 3) and brine (300 mL), dried over anhydrous Na2SO4, and concentrated. Thie residue was dried in vacuo to give crude Intermediate 7 (25 g) as a black solid, which was used in the next step without purification. MS (ESI): calcd. for C2oHi9BrF3N02S: 473.0; Found: 473.9 [M + 1]+.1H NMR (300 MHz, CDCh): 6 7.22 (s, 1 H), 7.19 (s, 1 H), 7.18 - 7.13 (m, 2H), 7.11 - 7.04 (m, 2H), 3.96 (s, 3H), 3.51 (dd, J = 11.1 , 6.0 Hz, 1 H), 3.10 - 2.95 (m, 1 H), 2.88 - 2.77 (m, 1 H), 2.15 (m, 1 H), 2.05 - 1.86 (m, 1 H), 1.86 - 1.74 (m, 1 H), 1.61 (t, J = 18.6 Hz, 4H) ppm.Step 8. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1 -dioxide (Intermediate 8)

[0367] To a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1 ,4]thiazepin-4(5H)-one (Intermediate 7) (25 g, 52.71 mmol) in THF (500 mL) and H2O (500 mL) was added Oxone® (107 g, 0.31 mol) in portions at rt. The resulting mixturewas stirred at rt for 16 h. The resulting mixture was filtered. The filtrate was concentrated to remove organic solvent, and the residue was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude Intermediate 8 (24 g) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C2oHi9BrF3N04S: 505.0; Found: 506.0 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 6 7.47 (s, 1 H), 7.42 (s, 1 H), 7.38 - 7.24 (m, 4H), 4.00 (s, 3H), 4.09 - 3.88 (m, 1 H), 3.75 (dd, J = 13.6, 12.0 Hz, 1 H), 2.99 (dd, J = 12.0, 5.7 Hz, 1 H), 2.01 - 1.80 (m, 4H), 1.58 (t, J = 18.9 Hz, 3H) ppm.Step 9. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2, 3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Intermediate 9)

[0368] To a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1 ,4]thiazepin-4(5H)-one 1 ,1-dioxide (Intermediate 8) (24 g, 47.40 mmol) in THF (120 mL) was added 10 M BH3*Me2S in THF (48 mL) dropwise at rt. The resulting mixture was stirred at 60°C for 16 hr. The reaction was quenched by the addition of H2O (100 mL) at rt. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 2 / 1 (v / v) as eluent to give Intermediate 9 (20 g, 85.7%) as a brown solid. MS (ESI): calcd. for C2oH2iBrF3N03S: 491.0; Found: 492.0 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 57.61 (s, 1 H), 7.52 (s, 1 H), 7.02 (t, J = 8.8 Hz, 2H), 6.64 (dd, J = 8.6, 4.4 Hz, 2H), 4.21 (d, J = 15.1 Hz, 1 H), 3.98 (s, 3H), 3.60 (dd, J = 14.9, 3.4 Hz, 1 H), 3.42 - 3.28 (m, 1 H), 3.16 (s, 1 H), 2.27 (s, 1 H), 2.15 - 1.93 (m, 2H), 1.70 - 1.39 (m, 5H) ppm.Step 10. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Intermediate 10)

[0369] To a solution of 7-bromo-3-(3, 3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2, 3,4,5- tetrahydrobenzo[b][1 ,4]thiazepine 1 ,1-dioxide (Intermediate 9) (2.5 g, 5.07 mmol) in tetrahydrofuran (50 mL) was added dropwise LiHMDS (1 mol / L in THF) (2.8 mL, 10.15 mmol) at -78°C under N2atmosphere. The reaction mixture was stirred at -78°C for 30 mins. Then a solution of NFSI (1.60 g, 5.07 mmol) in tetrahydrofuran (5 mL) was added dropwise and the mixture was stirred at -78°C for 30 mins. The reaction was quenched with sat. aq. NH4CI solution (50 mL), and then the mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as eluent to give Intermediate 10 (1.5 g, 57.9%) as a brown solid. MS (ESI): calcd. for C2oH2oBrF4N03S: 509.0; Found: 510.0 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 5 7.66 (s, 1 H), 7.54 (s, 1 H), 7.11 -6.96 (m, 2H), 6.66 (m, 2H), 6.12 - 5.77 (m, 1 H), 4.22 - 4.11 (m, 1 H), 4.05 - 3.95 (m, 3H), 3.27 - 3.12 (m, 1 H), 2.68 - 2.36 (m, 1 H), 2.33 - 1.90 (m, 3H), 1.73 - 1.38 (m, 4H) ppm.Step 11. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1 -dioxide (Intermediate 11a) and rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1 -dioxide (Intermediate 11 b)

[0370] To a stirred solution of rac-7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepine 1 ,1 -dioxide (Intermediate 10) (170 g, 0.33 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (384 g, 2 mol) in DMF (3.4 L) was added CuBr (95.57 g, 0.67 mol) in portions at rt under N2 atmosphere. The resulting mixture was stirred at 130°C for 16 h under N2 atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (10 L) at rt. The resulting mixture was extracted with EA (3 L x 2). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as eluent to give Intermediate 11a (60 g, 36.1 %, cis- racemate) as a yellow solid and Intermediate 11 b (45 g, 27.1 %, trans- racemate) as a yellow solid, respectively.

[0371] Intermediate 11a: MS (ESI): calcd. for C21H20F7NO3S: 499.1 ; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 6 7.73 (s, 1 H), 7.67 (s, 1 H), 7.10 - 7.02 (m, 23H), 6.71 - 6.60 (m, 2H), 6.10 (d, J = 44.4 Hz, 1 H), 4.19 (d, J = 15.6 Hz, 1 H), 4.06 (s, 3H), 3.22 (dd, J = 15.9, 11.4 Hz, 1 H), 2.76 - 2.44 (m, 1 H), 2.30 - 1.96 (m, 3H), 1 .74 - 1 .56 (m, 4H) ppm.

[0372] Intermediate 11 b: MS (ESI): calcd. for C21H20F7NO3S: 499.1 ; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 6 7.71 (s, 1 H), 7.45 (s, 1 H), 7.10 (t, J = 8.7 Hz, 2H), 6.89 (s, 2H), 5.95 (dd, J = 44.1 , 6.9 Hz, 1 H), 4.03 (s, 3H), 4.01 - 3.59 (m, 2H), 2.45 - 2.39 (m, 1 H), 2.14 - 1.89 (m, 2H), 1.86 - 1.71 (m, 1 H), 1.70 - 1.55 (m, 1 H), 1.49 (t, J = 18.9 Hz, 3H) ppm.Step 12. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1 -dioxide (Intermediate 12)

[0373] A mixture of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepine 1 ,1 -dioxide (60 g, 0.12 mol) (Intermediate 11a) in DMSO (600 mL) was added LiCI (50.5 g, 1.21 mol) at room temperature. After stirring at 140°C for 16 h under nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL x 4), dried over anhydrous Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 8 / 1 (v / v) as eluent to give Intermediate 12 (43 g, 73.7%, cis-racemate) as a yellow oil. MS (ESI): calcd. for C20H18F7NO3S: 485.1 ; Found: 486.3 [M + 1]+.1H NMR (300 MHz, DMSO-cfe): 5 11.68 (s, 1 H), 7.70 (s, 1 H), 7.56 (s, 1 H), 7.03 (t, J = 9.0 Hz, 2H), 6.62 (dd, J = 9.3, 4.5 Hz, 2H), 6.03 (d, J = 44.4 Hz, 1 H), 4.15 (d, J = 15.9 Hz, 1 H), 3.20 (dd, J = 15.9, 11.4 Hz, 1 H), 2.69 - 2.60 (m, 1 H), 2.22 - 2.06 (m, 2H), 1.61 (t, J = 18.9 Hz, 5H) ppm.Step 13. Synthesis of rac-methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (Intermediate 13)

[0374] To a stirred solution of rac-(2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepine 1 ,1 -dioxide (Intermediate 12) (1.20 g, 2.47 mmol) and Cs2CO3(2.42 g, 7.41 mmol) in DMF(50 mL) were added KI (1.23 g, 7.41 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (1.04 g, 4.94 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 h. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (150 mL) at rt. The resulting mixture was extracted with EA (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc = 2 / 1 (v / v) to give Intermediate 13 (800 mg, 54.0%) as a brown solid. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+.Step 14. Synthesis of methyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoate (Intermediate 14a) and methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]- thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (Intermediate 14b)

[0375] The product rac-methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1 ,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1 ,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoate (Intermediate 13) (800 mg) was purified by Prep-SFC with the following conditions: Column: (R, R)-WHELK-O, 3 x 25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 20% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wavelength: 220 nm; RT1 (min): 3.8; RT2 (min): 6.5; Sample Solvent: MeOH; Injection Volume: 9 mL. The collected fractions were concentrated, and the residue was dried in vacuo to give Intermediate 14a (260 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) and Intermediate 14b (240 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+.Step 15. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Compound 1)

[0376] A solution of Intermediate 14b (240 mg, 0.40 mmol) and LiOH (28.85 mg, 1.20 mmol) in 1 ,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 h. The mixture was acidified to pH 4 with 2 N aq. HCI solution and extracted with EA (10 mL x 2). Subsequently, the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5pm 30 x 150 mm Column; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 1 .87. The collected solution was concentrated under vacuum to remove ACN and the resulting solution was lyophilized to give Compound 1 (163 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1 ; Found: 586.2 [M + 1]+.1H NMR (300 MHz, CD3OD): 5 7.79 (s, 1 H), 7.57 (s, 1 H), 7.02 - 6.96 (m, 2H), 6.75 - 6.70 (m, 2H), 5.70 (d, J = 45.3 Hz, 1 H), 4.29 - 4.18 (m, 3H), 3.38 - 3.34 (m, 1 H), 2.80 - 2.66 (m, 1 H), 2.20 - 2.06 (m, 2H), 1.79 - 1.57 (m, 5H), 1.37 (s, 6H) ppm.Relative stereochemistry determination of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Compound 1).

[0377] 1H,13C,19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of Compound 1.

[0378] 1H NMR (300 MHz, CD3OD): 5 7.79 (s, 1 H, H13), 7.57 (s, 1 H, H9), 7.06 - 6.91 (m, 2H, H33&H31), 6.78 - 6.65 (m, 2H, H34&H30), 5.69 (d, J = 45.2 Hz, 1 H, H18), 4.27 (d, J = 8.6 Hz, 1 H, H20’), 4.23 (d, J = 8.6 Hz, 1 H, H20”), 4.26 - 4.15 (m, 1 H, H6’), 3.31 (dd, J = 16.0, 11.2 Hz, 1 H, H6”), 2.82-2.62 (m, 1 H, H5), 2.28 - 1 .99 (m, 2H, H3), 1.81 - 1 .65 (m, 2H, H4), 1 .65 (t, J = 18.5 Hz, 3H, H1), 1.37 (s, 6H, H28&H29) ppm.13C NMR (75 MHz, CD3OD): 5 177.77 (C23), 156.90 (d, J = 237.4 Hz, C32), 154.84 (C11), 142.37 (C21), 140.35 (C14), 138.30 (C8), 129.17 (q, J = 4.6 Hz, C9), 124.97 (q, J = 31.9 Hz, C10), 123.79 (t, J = 237.6 Hz, C2), 127.33 - 116.85 (m, C36), 116.16 (d, J = 7.7 Hz, C34&C30), 115.31 (d, J = 22.7 Hz, C31&C33), 114.27 (C13), 101.98 (d, J = 219.9 Hz, C18), 75.47 (C20), 47.68 (C6), 42.65 (C22), 37.61 (d, J = 18.5 Hz, C5), 34.36 (t, J = 25.9 Hz, C3), 22.12 (t, J = 27.7 Hz, C1), 21.59 - 21.30 (m, C4), 21.19 (C28&C29).19F NMR (282 MHz, CD3OD): 6 -64.47 (F37, F38&F39), -92.72 (d, J= 10.9 Hz, F26&F27), -127.48 (F35), -199.65 (F19) ppm. F-H NOESY NMR data suggested F19 has correlation with H4 but not with H5.EXAMPLE 2: BIOLOGICAL ASSAY DATA FOR COMPOUND 1HepG2-NTCP HBV infection protocol

[0379] HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture using DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 pg / mL G418 (Alfa Aesar, Cat# J62671), 50 U / mL penicillinstreptomycin (Invitrogen, Cat# 15140-122), and 0.5 pg / mL blasticidin (Sigma, Cat# 15205). Prior to infection, the cells were washed twice with 1 x DPBS (Invitrogen, Cat# 14190-136) and treated with 3 mL of 0.05% trypsin (Invitrogen, Cat# 25200-056) to dissociate the cells. Following dissociation, 10 mL of HepG2-NTCP growth medium was added to the cells to neutralize the trypsin and the cells were then counted and centrifuged at 1 ,300 rpm for 5 minutes. Following centrifugation, the cells were resuspended in DMEM supplemented with 5% FBS, 50 U / mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1 % DMSO (Sigma, Cat# D4540) to a density of 8 x 105cells / mL and infected with HBV at an MOI of 50. Immediately after infection, 50 pL of the cell / HBV mixture was added to a 96-well plate containing 50 pL of compound and incubated at 37°C for 24 hours (2% final DMSO concentration). After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50 U / mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 72 hours. At the end of the incubation, the plates were spun at 1 ,800 rpm for 8 minutes and the supernatant was removed for HBeAg quantification using electrochemiluminescence enzyme-linked immunosorbent assays (ECL-ELISA).

[0380] To conduct the HBeAg ECL-ELISA, Lumitrack high-binding 96-well plates (Greiner, Cat# 655074) were treated with 625 ng / mL HBeAg mAb (Biocheck, Cat# 70426) in 1 x DPBS for 2 hours at 25°C with shaking. The HBeAg mAb solution was then removed and the plates treated with 1 x DPBS containing 0.5% bovine serum albumin (BSA) (Sigma, Cat# A7030-100g) for 2 hours at 25°C with shaking. The HBeAg-coated plates were then washed 4 times with 1 x DPBS containing 0.05% Tween 20 (DPBS-T) (Thermo Fisher Scientific, Cat# J61544-K2). Following the wash, 90 pL of HRP-conjugated antibody (Fitzgerald, Cat# 61 -H1 OK), diluted 1 :8,000 in 1 x DPBS- T containing 0.5% BSA, was added to the HBeAg-coated plates along with 15 pL of each sample. The plates were then incubated for 2 hours at 25 °C with shaking. Following the incubation, the sample was then removed and 200 pL of 1 x PBS-T was added and the plates were incubated for 10 minutes at 25°C with shaking. The plates were then washed 6 times with 1 x PBS-T and blotted dry. 80 pL of ECL substrate (Millipore, Cat# WBKLS0500) was then added to the plate and the luminescence was measured using a Tecan M1000 Pro plate reader.

[0381] Other assays are known in the art, see for example, Lempp et al., Nature Communications, 2019, 10:2265, https: / / doi.org / 10.1038 / s41467-019-10211-2; or Grosser et al., Frontiers in Molecular Biosciences, 2021 , 8: doi: 10.3389 / fmolb.2021.689757.HepG2-NTCP HDV infection protocol

[0382] HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture in DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 pg / mL G418 (Alfa Aesar, Cat# J62671), 50 U / rnL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 pg / mL blasticidin (Sigma, Cat# 15205). 10,000 HepG2- NTCP cells were seeded in 96-well plate in 50 pL DMEM supplemented with 5% FBS, 50U / mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1 % DMSO (Sigma, Cat# D4540). After cell seeding, compounds were dispensed using a Tecan D300e dispenser in the wells in a serial dilution (4-fold, 8 doses) followed by infection with 50 pL HDV inoculum at an MOI of 20 vge / cell. Cells were then incubated at 37 °C in 5% CO2 for 24 hrs. After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50 U / rnL penicillin-streptomycin, and 1% DMSO and incubated for an additional 96 hrs. To conduct an HDAg in-cell ELISA, at the end of the incubation, the supernatant was removed, cells washed with PBS, fixed for 30 minutes at room temperature, washed with PBS, and permeabilized for 15 minutes at room temperature followed by a PBS wash and blocking for 45 minutes at room temperature. After aspiration of the supernatant, a primary mouse anti-HDAg antibody was added, incubated at 4 °C overnight followed by multiple PBS-T washes and addition of a secondary anti-mouse IRDye800CW antibody. After 1 hr incubation at room temperature, cells were washed multiple times with PBS-T prior to readout. For HDAg readout, the plates were scanned on the LiCoR Odyssey CLX infrared scanner. Bulevirtide and DMSO treated cells were used as positive and negative controls in the assay, respectively.NTCP assay protocol

[0383] 50,000 HEK293 cells were seeded in 96-well plate in 100 pL Eagle’s Minimum Essential Medium (EMEM) supplemented with 10% FBS and a transfection mix (Lipofectamine 3000) containing human NTCP-expression DNA plasmids. The cells were incubated at 37 °C in 5% CO2 for 24 h. After incubation, compounds were dispensed to the wells using a Tecan D300e dispenser in a serial dilution (4-fold, 8 doses) and the cells were incubated at 37 °C in 5% CO2 for 1 h. After incubation, 2 pM bile acid 3-a-nitrobenzoxadiazole (NBD)-Taurocholic acid (TCA) was added to each well and incubated at 37 °C in 5% CO2 for 50 minutes, followed by aspiration of supernatants from the wells and reading the plates in a Tecan M1000 plate reader to measure the NBD (490ex / 520em) fluorescence intensity. Bulevirtide and DMSO treated cells were used positive and negative controls, respectively.Statistical Analysis

[0384] Percentage inhibitions were calculated with respect to the assay controls. Further data analysis was performed using validated statistical software (GraphPad Prism) to calculate the average EC50 or IC50 value from at least three experiments for the test compound.ASBT assay protocol

[0385] 20,000 HEK293T cells stably overexpressing human apical sodium-dependent bile salt transporter (ASBT) were seeded in a 96-well plate in 100 pL DMEM / High glucose with L- glutamine medium supplemented with 10% FBS containing puromycin (0.9 mg / mL) and incubated at 37 °C in 5% CO2 in the presence of serially diluted compounds (3-fold serial dilution in DMSO, 8 concentrations) in DMEM (with 10% FBS) for 30 minutes. After incubation, 2 pM bile acid 3-a- nitrobenzoxadiazole (NBD)-Taurocholic acid (TCA) was added and incubated 2 minutes at 37 °C in 5% CO2 followed by centrifugation at 500 RCF for 5 minutes at room temperature. After centrifugation, supernatant was carefully aspirated and 100 pL PBS / well added. Subsequently, plates were centrifuged at 500 RCF for 5 minutes at room temperature, followed by supernatant removal and adding 175 pL PBS / well and cells were resuspended thoroughly. For analysis, an Attune NxT Flow Cytometer (Invitrogen) was used, and NBD’s fluorescence intensity was measured at 488 nm excitation. Linerixibat and DMSO treated cells were used as positive and negative controls, respectively.Statistical Analysis

[0386] Percentage inhibitions were calculated cells respect to the assay controls. Further data analysis was performed using validated statistical software (GraphPad Prism) to calculate the average EC50 or IC50 value from at least three experiments for the test compound.

[0387] In the HBeAg assay, Compound 1 had an EC50 of 4.2 nM. Following the described HepG2-NTCP HDV infection protocol, Compound 1 had an EC50 between 10 and 100 nM. In the NTCP assay, Compound 1 had an IC50 of 7.3 nM. In the ASBT assay, Compound 1 had an IC50 of 2400 nM.EXAMPLE 3: GENERATION OF CRYSTALLINE FORMS OF COMPOUND 1 FREE ACID

[0388] A number of crystallization experiments were conducted on Compound 1 free acid using different techniques (slurry at RT and 50°C, slow evaporation, cooling crystallization and antisolvent addition) in a variety of solvent systems.Input material:

[0389] Amorphous Compound 1 free acid, Purity of 99.46%. Prepared using the methodology in Example 1.Crystallization Methods:Anti-solvent Addition Method at 25 / 50 °C

[0390] About 10 mg of Compound 1 free acid was added into 2 mL glass vial, followed by the addition of corresponding various positive solvents (3V for 25 °C or 2V for 50 °C) to obtain clear solution (Table 10). Then a suitable amount of anti-solvent was added into the corresponding clear solution drop by drop under stirring until a suspension was formed. If oil was formed, antisolvent was added up to total volume of 30V (V / V=1 :9, solvent vs antisolvent) at 25 °C or 20V (V / V=1 :9, solvent vs antisolvent, V / V=1 :14 for EtOH / Heptane solvent system) at 50 °C, and then slurry for two days. For the methylcyclohexane solvent system, 30V was added at 25 °C and 20V was added at 50 °C directly, and the system was kept in suspension state. A portion of solids was tested by PLM to identify the crystalline state. For the DMSO / H2O system at 25 °C, the sample was isolated and fully characterized by XRPD, DSC, TGA and1H NMR.Equilibrium with Solvent at 25 / 50 °C for 14 days

[0391] For the experiments of adding anti-solvent at 25 / 50 °C, further research was carried out on the suspension system. For the oily system, the experiment was stopped here. For the suspension system, another 20 mg Compound 1 free acid was added into vial (total 30 mg), and corresponding mixed solvents were added to 30V for 25 °C and 20V for 50 °C. After stirring for another 12 days (total 14 days), a portion of solids were collected and dried at 25 / 50 °C under vacuum for 24 h for characterization, e.g., XRPD, DSC, TGA and1H NMR.Slow Evaporation at 25 °C

[0392] The filtrate from the experiments (Equilibrium with solvent at 25 °C for 14 days) was used for evaporation (slow). The sample vials were placed at ambient condition (20-25 °C) under N2 protection and sealed with a sealing film. Solvent was allowed to evaporate spontaneously after puncturing with a needle. The samples were collected prior to completing dryness and examined by XRPD.Cooling Crystallization

[0393] The filtrate from the experiments (Equilibrium with solvent at 50 °C for 14 days) used for the cooling crystallization experiments. The solution (sealed with a sealing film) was cooled to ambient condition (20-25 °C) and placed in the refrigerator (2-8 °C) for 72 h. Precipitation was separated by centrifugation and the filter cake was dried, and then was tested by XRPD.Results of Crystallization Experiments and Solid-State Characterization

[0394] Table 10 provides a summary of the results obtained from the crystallization experiments. Furthermore, Compound 1 free acid Forms A, B, C, D and E were characterized by XRPD, DSC, TGA and PLM.Table 10 - summary of solid forms obtained from the crystallization experiments.Compound 1 free acid - Form A

[0395] In the crystallization experiments, Compound 1 free acid Form A was first obtained in the EA / heptane solvent system through equilibrium at 25 °C for 14 days, but later it could only stably exist at 70 °C in the ACN / H2O solvent system. However, it transformed into Compound 1 free acid Form C after long-term equilibrium at 25°C (see section titled “Conversion Relationship of the Forms”).

[0396] Compound 1 free acid Form A is an anhydrate with good crystallinity. FIG.1 shows the XRPD diffractogram obtained for Compound 1 free acid Form A. Compound 1 free acid Form A exhibits a simple thermal event with a single endothermic peak at 161.75 °C with an enthalpy value of 37.86 J / g and no weight loss before 160.00 °C (see FIG.2). FIG.3 shows a PLM image of Compound 1 free acid Form A crystals. Peak positions present in the XRPD diffractogram acquired for Compound 1 free acid Form A are presented in Table 11.Table 11 - XRPD peak positions for Compound 1 free acid Form ACompound 1 free acid - Form B

[0397] In the crystallization experiments, Compound 1 free acid Form B was obtained in many solvent systems through equilibrium at 25 °C for 14 days. Interestingly, treated by 3 heat-cooling cycles (from 30 °C to 150 °C, at a rate of 2 °C / min) through DSC, the melting point of Compound 1 free acid Form B disappeared and the melting point of Compound 1 free acid Form A appeared (see section titled “Conversion Relationship of the Forms”), which means Compound 1 free acid Form B can convert to Compound 1 free acid Form A though heating treatment. It was also proved by XRPD result, i.e. , after heated at 150 °C for 1 h, that the crystal form of sample was transformed into Compound 1 free acid Form A.

[0398] Compound 1 free acid Form B is a metastable anhydrate with good crystallinity. FIG. 4 is an XRPD diffractogram of Compound 1 free acid Form B. Compound 1 free acid Form B exhibits a simple thermal event with a single endothermic peak at 147.80 °C with an enthalpy value of 43.72 J / g and 0.05% weight loss before 150 °C (see FIG.5). FIG.6 shows a PLM image of Compound 1 free acid Form B crystals. Peak positions present in the XRPD diffractogram acquired for Compound 1 free acid Form B are presented in Table 12.Table 12 - XRPD peak positions for Compound 1 free acid Form BCompound 1 free acid - Form C

[0399] In the crystallization experiments, Compound 1 free acid Form C can be obtained in most solvent systems through equilibrium at 50 °C for 14 days. Compound 1 free acid Form C can be converted to Compound 1 free acid Form A through heat treatment (see section titled “Conversion Relationship of the Forms”). Compound 1 free acid Form A and Compound 1 free acid B can convert to Compound 1 free acid Form C in competitive slurries.

[0400] Compound 1 free acid Form C is an anhydrate with good crystallinity. FIG.7 is an XRPD diffractogram of Compound 1 free acid Form C. Form C exhibits a simple thermal event with a single endothermic peak at 149.31 °C with an enthalpy value of 46.74 J / g and no weight loss before 150 °C (see FIG.8). FIG.9 shows a PLM image of Compound 1 free acid Form C crystals. Peak positions present in the XRPD diffractogram acquired for Compound 1 free acid Form C are presented in Table 13.Table 13 - XRPD peak positions for Compound 1 free acid Form CCompound 1 free acid - Form D

[0401] In the crystallization experiments, Compound 1 free acid Form D was obtained in DMSO / H2O solvent system by equilibrium at 25 °C / 50 °C for 14 days.

[0402] Compound 1 free acid Form D is a mono-DMSO solvate with good crystallinity. FIG.10 is an XRPD diffractogram of Compound 1 free acid Form D. Compound 1 free acid Form D exhibits a simple thermal event with a single endothermic peak at 106.26 °C with an enthalpy value of 61.27 J / g and 11.11% weight loss before 240 °C, which corresponds to the weight loss of one DMSO solvent molecule (see FIG.11). FIG.12 shows a PLM image of Compound 1 free acid Form D crystals. Peak positions present in the XRPD diffractogram acquired for Compound 1 free acid Form D are presented in Table 14.Table 14 - XRPD peak positions for Compound 1 free acid Form DCompound 1 free acid - Form E

[0403] Compound 1 free acid Form E was found during the preparation of Compound 1 free acid Form C in EA / Heptane system. Once solid was precipitated, the pattern of the sample was Compound 1 free acid Form E, and slowly turned to Compound 1 free acid Form C after equilibrium at 25 °C for 8 days (see section titled “Conversion Relationship of the Forms”).

[0404] Compound 1 free acid Form E is a non-stoichiometric solvate with moderate crystallinity. FIG.13 is an XRPD diffractogram of Compound 1 free acid Form E. Compound 1 free acid Form E exhibits a simple thermal event with only one endothermic peak at 86.94 °C with an enthalpy value of 26.61 J / g and 5.02% weight loss before 130 °C (see FIG.14). The weight loss corresponds to the loss of residual solvent of EA and Heptane, with approximately 4.5% corresponding to EA and approximately 0.5% corresponding to heptane. FIG.15 shows a PLM image of Compound 1 free acid Form E crystals. Peak positions present in the XRPD diffractogram acquired for Form E are presented in Table 15.Table 15 - XRPD peak positions for Compound 1 free acid Form E

[0405] Table 16Table provides a summary of the crystalline forms obtained and FIG.16 is an overlay XRPD diffractogram of Forms A-E of Compound 1 free acid.Table 16 - Summary of Crystal Forms of Compound 1 free acidN.D. = not determinedPreparation of Compound 1 free acid Forms A, B and C (Scale-up)Procedure for Compound 1 free acid Form A

[0406] (1) Input material (500 mg, amorphous free acid) and ACN / H2O=2:12 (V / V, 20 V) were charged into a 20 mL glass reactor, and an oil state was obtained at 70 °C and kept stirring at 70 °C. The system did not disperse well after ultrasound. (2) After stirring for 3 h, the oil turned slowly into a sticky solid, but with poor dispersion. (3) The system was kept stirring at 70 °C for another 15 h, the system turned to a suspension but the product aggregated into a spherical mass. (4) The precipitation was filtered and the filter cake was dried at 20 °C under vacuum for 18 h. The solid samples were collected for XRPD, DSC, TGA, PLM, HPLC and1H NMR.Procedure for Compound 1 free acid Form B

[0407] (1) 30 V Methylcyclohexane and 2 wt% seed were charged into a 2 mL glass reactor, and obtained a suspension at 20°C. (2) Input material (30 mg, amorphous free acid) was charged into a 2 mL glass reactor, and obtained a suspension at 20 °C. (3) The suspension was kept stirring at 20 °C for 15 h. (4) The precipitation was filtered and the filter cake was washed with 4*1 V Methylcyclohexane, and then dried at 20 °C under vacuum for 18 h. The solid samples were collected for XRPD, DSC, TGA, PLM, HPLC and1H NMR.Procedure for Compound 1 free acid Form C

[0408] (1) Input material (1 g, amorphous free acid) and MTBE (4 V) were charged into a reactor, and obtained a clear solution at 20 °C. (2) 5V Heptane was added into the solution in 20 min and 2 wt% seed was added, then the crystallisation mixture was aged for 2 h. (3) 7 V Heptane was added into the suspension within 4 h and the suspension was kept at 20 °C for 10 h. (4) The precipitate was filtered and the filter cake was washed twice with 2 V Heptane. (5) The filter cake was dried under vacuum at 20 °C for 18 h. (6) The solid samples were collected for XRPD, DSC & TGA, PLM, HPLC and1H NMR.Results

[0409] Compound 1 free acid Forms A, B and C were successfully prepared according to the methods described above.Competitive Slurrying Experiments - Compound 1 Free Acid

[0410] Compound 1 free acid Form A (20 mg), Compound 1 free acid Form B (20 mg) and Compound 1 free acid Form C (20 mg) were charged into 2 mL glass vial. Mixed saturated solvent was added into vial to obtain suspension with a magnetic stirring (500 rpm) at 25 °C or 50 °C. A small amount of solid was isolated at 10 min, 1 d and 3 d and tested by XRPD. Preparation method of saturated solution: About 1 mL mixed solvent was charged into a 2 mL vial and a certain amount of free acid (amorphous) was added to prepare suspension. The seven systems were prepared as follows:(1) For the EtOH / H2O=2:1 (V / V) solvent system, about 20 mg free acid was added to prepare suspension at 25°C;(2) For the EtOH / H2O=2:1 (V / V) solvent system, about 50 mg free acid was added to prepare suspension at 50°C;(3) For the IPA / H2O=2:1 (V / V) solvent system, about 45 mg free acid was added to prepare suspension at 25°C;(4) For the MTBE / Heptane=1 :2(V / V) solvent system, about 35 mg free acid was added to prepare suspension at 25°C;(5) For the MTBE / Heptane=1 :2(V / V) solvent system, about 80 mg free acid was added to prepare suspension at 50°C;(6) For the IPAC / Heptane=1 :3(V / V) solvent system, about 45 mg free acid was added to prepare suspension at 25°C;(7) For the IPAC / Heptane=1 :4.2(V / V) solvent system, about 80 mg free acid was added to prepare suspension at 50°C . The suspension was kept stirring at 25 / 50°C for about 10 min and then filtered. The filtrate was the saturated solution.Results

[0411] Compound 1 free acid Form C was the dominant form. A summary of the results is provided in Table 17.Table 17 - Results of competitive experimentsHygroscopicity assessment of Compound 1 free acid Form CMethod of Hygroscopicity Test by DVS

[0412] Compound 1 free acid Form C (~20 mg) was used for DVS, and the XRPD was characterized after the test was completed.Results

[0413] As shown in FIG.17, the DVS result showed Compound 1 free acid Form C was almost non-hygroscopic. The crystal form remained as Compound 1 free acid Form C after the DVS test.Conversion Relationship of the Forms

[0414] The conversion relationship is summarized in FIG.18.Heat Treatment by DSC

[0415] Procedure: the materials (Compound 1 free acid Form B or Compound 1 free acid C) were treated by heat-cooling cycles from 30-150 °C with a rate of 2 °C / min for 3 times and then were heated to 250 °C using DSC.

[0416] Results: For Compound 1 free acid Form B and Compound 1 free acid Form C treated by DSC heat-cooling cycles the previous melting points disappeared and the melting point of Compound 1 free acid Form A appeared, see FIG.19-20.Heat Treatment by TGA

[0417] Procedure: the materials (Compound 1 free acid Form B or Compound 1 free acid Form C) were heated to 150 °C with a rate of 10 °C / min and kept for 1 h. The residue was tested by XRPD.

[0418] Results: For Compound 1 free acid Form B and Compound 1 free acid Form C treated by TGA the crystal form of the residue turned to Compound 1 free acid Form A.Crystal Transformation between Compound 1 free acid Form A and Compound 1 free acid Form C

[0419] Procedure: (1) Input material and ACN (2 V) were charged into a 2 mL glass vial, and obtained a clear solution at 50°C. (2) Water (18 V) was added into the solution and then the solution turned to oil. (3) Kept at 50°C for 15 h (crystal form: Compound 1 free acid Form A (major) + Compound 1 free acid Form C (minor)). (4) Heated to 70 °C and kept stirring for another 39 h (crystal form: Compound 1 free acid Form A). (5) Cooled down to 25°C and kept stirring for another 24 h (crystal form: Compound 1 free acid Form C (major) + Compound 1 free acid Form A (minor)). (6) Kept stirring for another 72 h (crystal form: Compound 1 free acid Form C).

[0420] Results: Compound 1 free acid Form A and Compound 1 free acid Form C seem to be in enantiotropic system. Compound 1 free acid Form A stably existed at 70 °C in the ACN / H2O solvent system, however it can be converted to Compound 1 free acid Form C by slurrying at 50 °C or 25 °C.Crystal Transformation between Compound 1 free acid Form B and Compound 1 free acid C

[0421] Procedure: (1) Input material and Methylcyclohexane (30 V) were charged into a 2 mL glass vial, and obtained a suspension at 25°C. (2) Kept stirring at 25°C for 15 h (crystal form: Compound 1 free acid Form B). (3) Divided into two parts, one was kept stirring for another 39 h (crystal form: Compound 1 free acid Form B). (4) The other was heated to 70°C and kept stirring for another 39 h (crystal form: Compound 1 free acid Form C).

[0422] Results: Small scale of Compound 1 free acid Form B was prepared in methylcyclohexane at 25 °C, but it turned to Compound 1 free acid Form C when heated to 70 °C.Crystal Transformation between Compound 1 free acid Form E and Compound 1 free acid Form C

[0423] Procedure: The material was charged into 2 mL glass vial, and 20 V EA / Heptane=1 :9 (V / V) was added to obtain gel with a magnetic stirring (500 rpm). The system was kept stirring at 25°C and sampled at different times.

[0424] Results: Compound 1 free acid Form E can turn into Compound 1 free acid Form C through equilibrium in EA / Heptane for 8 days.Solubility determination of Compound 1 free acidMethod of Equilibrium Solubility Test in Different pH Vehicles

[0425] Tests were conducted using 5 mg / mL as the target concentration (i.e., 20 mg Compound 1 free acid was dispersed into 4 mL medium). The specific method was as follows: Compound 1 free acid Form C (20 mg) was accurately weighed and charged into a 20 mL glass vial, and then 4 mL pH buffer solutions (pH = 1.0, 4.5 and 7.4, which were prepared according to the USP. pH 1.0 buffer is hydrochloric acid aqueous solution; pH 4.5 is acetate buffer with a concentration of 0.050 mol / L; pH 7.4 is phosphate buffer with a concentration of 0.050 mol / L) were added into the vials. The vials were sealed and transferred to a thermostatic shaker and kept at a shaking rate of 200 rpm for 48 h at 25°C. After 48 h, about 1 mL filtrate was separated by centrifugation and then filtered again using a 0.22 pm PTFE membrane. The content of the filtrate was detected by HPLC, and the filter cake was collected to detect the change in crystal form by XRPD, and the pH of the system was determined using a pH meter.

[0426] Preparation methods for different buffer solutions (according to the USP):• pH 1.0: Measure 0.45 mL of HCI (12 mol / L) and weigh 37.5 mg of KCI, diluted with water to 50 mL.• pH 4.5: Measure 0.7 mL of 2 mol / L CH3COOH and weigh 0.15 g of NaC2H3C>2-3H2O, dilute with water to 50 mL.• pH 7.4: Measure 9.77 mL of 0.2 mol / L NaOH and 12.5 mL of 0.2 mol / L potassium dihydrogen phosphate, diluted with water to 50 mL.Method of Kinetic Solubility Test in Different Bio-relevant Vehicles

[0427] The specific method was as follows: Compound 1 free acid Form C (20 mg) was accurately weighed and charged into a 20 mL glass vial, and then 4 mL bio-relevant vehicles (SGF, FaSSIF and FeSSIF) were added into the vials. The vials were sealed and transferred toa thermostatic shaker and kept at a shaking rate of 200 rpm at 37°C. The dissolution of the sample vials was recorded at 0.5 h, 2 h and 24 h, the suspension was centrifuged and filtered for about 1 mL and then filtered using a 0.22 pm PTFE membrane, the content of the filtrate was detected by HPLC, and the filter cake was collected to detect the change in crystal form by XRPD, and the pH of the system was determined using a 5 pH meter.

[0428] Preparation methods for different bio-relevant vehicles:• SGF (pH 1.2): Measure 21 .25 mL of 0.2 mol / mL HCI and weigh 99.95 mg of NaCI, diluted with water to 50 mL.• FaSSIF (pH 6.5): Weigh 21 mg of NaOH, 171 .9 mg of NaH2PO4and 309.3 mg of NaCI, dilute with water to 50 mL. The pH of the solution was adjusted to 6.5 and 112 mg of FaSSIF / FeSSIF / FaSSGF powder was added.• FeSSIF (pH 5.0): Weigh 593.7 mg of NaCI, 202 mg of NaOH and 412.3 pL of Acetic acid, dilute with water to 50 mL. The pH of the solution was adjusted to 5.0 and 560 mg of FaSSIF / FeSSIF / FaSSGF powder was added.Results of Solubility Tests

[0429] As summarized in Table 18 and Table 19, the solubility in SGF was below the limit of detection, and the solubility in FeSSIF and FaSSIF were about 30-45 pg / mL. The equilibrium solubility results showed that the solubility in pH 1.0 and pH 4.5 were below the limit of detection, and the solubility in pH 7.4 was about 22 pg / mL. The results suggest the compound has poor solubility. The crystal form of residue remained Compound 1 free acid Form C after solubility test.Table 18 - Kinetic solubility of Compound 1 free acid Form CLOD = limit of detection (0.5 pg / mL) [All samples were directly injected without dilution]Table 19 - Equilibrium Solubility of Compound 1 free acid Form CLOD = limit of detection (0.5 pg / mL); ML = mother liquor [All samples were directly injected without dilution]Stability StudiesMethods of Bulk Stability and Accelerated Stability Test

[0430] Bulk stability test: Compound 1 free acid Form C (70 mg) was weighed separately in a glass dish. The glass dishes were placed in different chambers with different conditions:• irradiation: 4500 ± 500 Lux (opened) (Under the condition of illumination of 4500 1ux ± 500 1 ux, and the total illumination of the light source should not be less than 1.2x106 lux ■ hr, and the energy of the near ultraviolet lamp should not be less than 200 W- hr / m2 according to Pharmacopoeia);• high temperature: 60°C (capped);• high humidity: 25°C, 90 ± 5% RH (opened).

[0431] Data were collected on the appearance, crystal form, and HPLC purity of the samples after 5 and 11 days.

[0432] Accelerated stability test: About 20 mg of Compound 1 free acid Form C (the sample has been exposed to the condition of 90% ± 5% RH for 5 days) was put at 40°C and 75% ± 5% RH (Opened) for 30 days. Data were collected on the appearance, crystal form, and HPLC purity of the samples for 30 days.Results of Bulk Stability Tests

[0433] Compound 1 free acid Form C exhibits good physical and chemical stability under high temperature (60°C) (capped), high humidity conditions (90% ± 5% RH) (opened) and accelerated condition (40°C and 75% RH) (opened). As shown in the Tables 20 and 21 , the color, crystal form and purity of the samples only changed after light exposure; after 11 days of illumination, the color darkened and purity decreased by 0.5%.Table 20 - Result of Bulk Stability Study of Compound 1 free acid Form CAll samples were solid and needed to be dissolved in ACN / H2O and diluted before injection at a concentration of about 0.5 mg / mL.Table 21 - Result of Accelerated Stability Study of Compound 1 free acid Form CThe sample was solid and needed to be dissolved in ACN / H2O and diluted before injection at a concentration of about 0.5 mg / mL.Method of Solution Stability Test

[0434] The following seven vehicles were prepared, and the solution stability tests at 50°C with Compound 1 concentration of 0 mg / mL (blank) and 0.5 mg / mL were investigated, respectively. The pH, purity and assay of the samples were tested at 0, 1 and 2 days, respectively. The sample was covered with aluminum foil and the blank solution was only sampled at 0 and 2 days. The vehicles used in the solution stability tests are presented in Table 22.Table 22 - Vehicles used in Solution Stability TestsResults of Solution Stability Tests

[0435] Compound 1 exhibits good solution stability under the acid and base conditions, i.e., in 1 :1 (v:v) 0.1 N HCI: ACN, 1 :1 (v:v) 10 mM Phosphate Buffer: ACN and 0.01 N NaOH solutions, there was no significant change in pH value, purity, and assay after 2 days. However, in the vehicles containing H2O2 and AIBN, the stability of the compound was relatively poor, with a few impurities appearing up to a level of 3-9%. The data is shown in Table 23.85Table 23 - Results of Solution Stability study of Compound 1 free acidote: All samples were diluted twice with ACN / H2O=1 :1 (V / V) before injection to a concentration of 0.25 mg / mConclusion

[0436] Five crystal forms of Compound 1 free acid have been identified during the crystallisation experiments, with Compound 1 free acid Forms A, B, and C being anhydrous forms, and Form D and E being solvates. After investigation of the conversion relationship among all forms, Compound 1 free acid Form C has shown to be stable and easily prepared. Compound 1 free acid Form C was almost non-hygroscopic and the increase in mass was less than 0.1% when tested over the range from 10 to 80% RH. The compound exhibited good bulk and solution stability. For the bulk stability, the appearance, purity and crystal form of the samples were unchanged under most conditions, except for a darkening of the color with impurities increasing by 1% when exposed to light for 11 days. For the solution stability, the compound was stable in acid and base conditions, although under the systems containing H2O2 and Al BN the impurities increased by 3-9% after 2 days at 50°C. The compound showed poor solubility with a maximum value of less than 45 pg / mL in FaSSIF.EXAMPLE 4: COMPOUND 1 FREE ACID - FORM F

[0437] During manufacturing of Compound 1 free acid Form C, a new crystalline form of Compound 1 free acid (designated Form F) was found during the final crystallization step of the process. Compound 1 free acid Form F was determined to be a MTBE solvate from NMR and TGA analysis.

[0438] The procedure in which Compound 1 free acid Form F was first discovered is as follows:1. Input material (Compound 1 free acid Form C, total 508 g) and MTBE (4 V) were charged into a jacketed reactor, and filtered to obtain a clear solution at RT.2. 4 V Heptane was added into the solution immediately (clear solution) and another 1 V Heptane was slowly added.3. 2 wt% seed (Compound 1 free acid Form C) was added into the above clear solution, then the mixture was aged for 2 h.4. 11 V Heptane was added into the suspension within 6 h and kept at RT for 8 h (the system maintained a good suspension state).5. The suspension was stirred at 20°C for another 18 h.6. The suspension was filtered and filter cake was washed twice with 2 V Heptane.7. The filtrate cake was dried under vacuum at 20°C for 18 h.8. Solid samples were collected for XRPD, DSC, TGA, PLM and HPLC.

[0439] Compound 1 free acid Form F was discovered at Step 4 of the above original process. The process was adapted to introduce an additional stage of warming the batch up to 50°C after heptane addition; this updated procedure, with new steps 5 and 6, is illustrated as follows:1. Input material (Compound 1 free acid Form C, total 1.35 g) and MTBE (4 V) were charged into a 50 mL jacket reactor, and filtered to obtain a clear solution at RT.2. 4 V Heptane was added into the solution immediately (clear solution) and another 1 V Heptane was slowly added in 20 min.3. 2 wt% seed (Compound 1 free acid Form C) was added into the above clear solution, then the crystal was aged for 2 h.4. 11 V Heptane was added into the suspension within 6 h and kept at RT for 8 h (the system maintained a good suspension state).5. The system was heated to 50°C, held at 50°C for 1 h.6. The system was cooled down to 20°C, held at 20°C for 2 h.7. Kept stirring at 20°C for another 18 h.8. Filtered and filter cake was washed twice with 2 V Heptane.9. The filtrate cake was dried under vacuum at 20°C for 18 h.10. The solid samples were collected for XRPD, DSC, TGA, PLM and HPLC.

[0440] In process testing at Steps 5-7 demonstrated that Compound 1 free acid Form C was the crystal form present in the suspension.

[0441] The original crystallization process used to produce Compound 1 free acid Form C uses 1 :1 heptane / MTBE to form the initial crystals, with more heptane added to bring the final ratio to 4:1 heptane / MTBE. Compound 1 free acid Form F has been shown to be more stable than Compound 1 free acid Form C at low heptane / MTBE ratios (<1 :1) and Compound 1 free acid Form C has been shown to more stable than Compound 1 free acid Form F when heptane / MTBE ratio > ~1 :1. Even though the original crystallization process ended with 4:1 heptane / MTBE, Compound 1 free acid Form F was formed because it was being kinetically trapped at RT. Heating to 50°C in 4:1 heptane / MTBE leads to full conversion of Compound 1 free acid Form F to Compound 1 free acid Form C (see Table 25 below).

[0442] Compound 1 free acid Form F can therefore be formed by stirring Compound 1 free acid Form C in 1 :1 heptane / MTBE. Consequently, a new process to prepare Compound 1 free acid Form C has been developed which uses 5:4 heptane / MTBE ratio during initial crystal growth (see Example 5).Solid-state characterization of Compound 1 free acid Form F

[0443] Compound 1 free acid Form F was characterized by XRPD, DSC, TGA and NMR.

[0444] FIG. 21 is an XRPD diffractogram of Compound 1 free acid Form F. Compound 1 free acid Form F has moderate crystallinity and exhibits a simple thermal event with a single endothermic peak with an onset temperature of 78.42°C with an enthalpy value of 71.97 J / g and 11.076% weight loss before 130°C, which corresponds to the weight loss of one MTBE solvent molecule (see FIG.22). Compound 1 free acid Form F contained 112719 ppm of MTBE and 6488 ppm of Heptane as determined by1H NMR analysis. FIG.23 shows a PLM image of Compound 1 free acid Form F crystals. Peak positions present in the XRPD diffractogram acquired for Compound 1 free acid Form F are presented in Table 24.Table 24 - XRPD peak positions for Compound 1 free acid Form FCompetitive Slurry Experiments (Compound 1 free acid Form C and Compound 1 free acid Form F)

[0445] Procedure: Compound 1 free acid Form C and Compound 1 free acid Form F (80 mg each) were charged into 2 mL glass vial, mixed, saturated solvent was added to obtain suspension with a magnetic stirring (500 rpm) at 25°C or 50°C. The small amount of solid was isolated at 10 min and 1.5 d, and tested by XRPD.

[0446] Solvents used were MTBE: Heptane (1 :1), MTBE: Heptane (1 :4).Results

[0447] As shown in Table 25 Compound 1 free acid Form C can be quickly transformed into Compound 1 free acid Form F in MTBE / Heptane=1 :1 (V / V) and Compound 1 free acid Form C was stable in MTBE / Heptane=1 :4 (V / V).Table 25 - Results from competitive slurry experiments of Compound 1 free acid Form C and Compound 1 free acid Form FEXAMPLE 5: PROCESS TO PREPARE COMPOUND 1 FREE ACID FORM C

[0448] Due to the unexpected discovery of Compound 1 free acid Form F during the Compound 1 free acid Form C crystallization process, a new Compound 1 free acid Form C crystallization was developed, which incorporates a slurry at 50°C in MTBE / Heptane 1 :6 V / V (step 5), to ensure any Compound 1 free acid Form F is converted to Compound 1 free acid Form C. This updated process is presented below.1 . Compound 1 free acid input material (445 g) and MTBE (4 V) were charged into a 25 L jacket reactor, and filtered to obtain a clear solution at 30°C .2. 5 V Heptane was added slowly into the solution at 50°C (clear solution; MTBE / Heptane 4:5 V / V (8 V)) [the solubility of Compound 1 free acid in 4:5 V / V MTBE / Heptane is 42-50 mg / mL at 20-25°C]. 2 wt % seed (Form C) was added into the above clear solution.3. After further aging for 1 h, a large amount of solid precipitated out of solution (Suspension; MTBE / Heptane 4:5 V / V (9 V)).4. 11 V Heptane was added into the suspension over 5 h.5. Another 8 V Heptane was added into the suspension over 2 h and the suspension was stirred for about 1 h at 50°C .6. The system was cooled down to 20°C over 6 h and kept stirring at 20°C for 5 h (Suspension; MTBE / Heptane 4:24 V / V (28 V); Assay: 1.1 mg / mL).7. The suspension was filtered and the filter cake was washed twice with 2 V Heptane.8. The filter cake was dried under vacuum at 45°C for 18 h.9. Solid samples were collected for XRPD, DSC, TGA, PLM and HPLC.

[0449] In process testing at steps 3 and 6 confirmed Compound 1 free acid Form C was the solid present in the suspension.EXAMPLE 6 - SALT FORMATION OF COMPOUND 1

[0450] Compound 1 has a carboxylic acid group so it was decided to investigate whether salts of Compound 1 could be prepared. 11 different counter-ions in a number of different solvent systems were investigated. Three different salts were prepared (sodium, potassium and tert- butylamine).Procedure to prepare salts

[0451] The experimental procedure was as follows:(i) Compound 1 free acid (30 mg, amorphous) and solvent (1 mL) were charged into a 2 mL glass vial (R1). The reaction system was stirred at 20 °C to obtain a clear solution system.(ii) The counter-ion (1.1 eq.) and solvent (0.5 mL) were first added to another 2 mL glass vial (R2) to obtain a clarified solution or suspension system under stirring conditions at room temperature, and then the solution or suspension in R2 was slowly added to R1 under stirring conditions.(iii) The reaction system was heated to 50 °C and stirred at 50 °C for 2 h.(iv) The reaction system was cooled to 20 °C at a cooling rate of 10 °C / h and kept stirring for 15 h.(v) Suspended reaction system was separated by centrifugation and filter cake was dried at 20 °C under vacuum for 15 h.(vi) Reaction systems with no solids precipitated were slowly evaporated with nitrogen at 20 °C, and then were slurred with a negative solvent (e.g., Heptane, MTBE, Toluene, IPAC, 2- MeTHF, MEK and DCM) with heat-cooling cycling from 50 °C to 20 °C. The suspension was separated by centrifugation and filter cake was dried at 20 °C under vacuum for 15 h.(vii) Samples were characterized by XRPD, DSC & TGA, PLM,1H NMR and HPLC.

[0452] The bases and solvents used in this study are presented in Table 26.Table 26 - Bases and Solvents Used in the Study

[0453] All the solids obtained from the experiments were characterized by XRPD. Crystalline samples with new XRPD patterns were subjected to further characterization such as DSC, TGA and PLM. Five salt forms were identified, and characterization of these forms is summarized in Table 27. Results from all the experiments performed is presented in Table 28.Table 27 - Characterization Results of Salt FormsN.D. = Not detectedTable 28 - Results from salt formation experimentsScale- Up Procedure for Preparation of Salt FormsCompound 1 Sodium Salt - Form A

[0454] The sodium salt of Compound 1 Form A was successfully prepared using the following methodology:(i) Input material (amorphous Compound 1 free acid) was dissolved in 4V MTBE and a clear solution was obtained.(ii) The NaOH (1.1 eq.) and 4V MTBE were added into a 2 mL bottle with suspension state, then added 2 wt% seed (Form A sodium salt) and obtained a suspension state.(iii) The MTBE solution of Compound 1 was slowly added into the above suspension.(iv) The suspension was heated to 50°C, 10 minutes later, a large amount of solid precipitated. In order to maintain a good suspension state, another 20V MTBE was added.(v) The system was kept at 50 °C for 2 h and cooled down to 20°C for 10°C / h, and then kept stirring for 15 h.(vi) Suspension was centrifuged and the filter cake was dried at 20°C under vacuum for 24 h.(vii) The solid sample was characterized by XRPD, DSC & TGA, PLM and1H NMR.Compound 1 Potassium Salt - Form A

[0455] The potassium salt of Compound 1 Form A was successfully prepared using the following methodology:(i) Input material (amorphous Compound 1 free acid) and ACN were charged into a 2 mL glass vial (R1). The reaction system was stirred at 20°C to obtain a clear solution.(ii) The KOH (1.1 eq.) and ACN were added to another 2 mL glass vial (R2) to obtain suspension system under stirring conditions at room temperature.(iii) The solution in R1 was slowly added to R2 under stirring conditions.(iv) The reaction system was heated to 50°C and stirred at 50°C for 2 h.(v) The reaction system was cooled to 20°C at a cooling rate of 10 °C / h and kept stirring for 15 h.(vi) The reaction system was treated with nitrogen at 20°C, there was no solids precipitated.After slurring in MTBE with heat-cooling cycling from 50°C to 20°C, a suspended sample was obtained.(vii) Suspension was centrifuged and the filter cake was dried at 20°C under vacuum for 24 h.(viii) The solid sample was characterized by XRPD, DSC & TGA, PLM and1H NMR.Compound 1 tert-butylamine salt - Form A

[0456] The tert-butylamine salt of Compound 1 Form A was successfully prepared using the following methodology:(i) Input material (amorphous Compound 1 free acid) and EtOH (3V) was added into R1. The mixture was magnetic stirred with a rate of 500 rpm to obtain a clear solution at 20°C.(ii) The tert-butylamine (1.1 eq.) and EtOH (3V) were charged into R2 to obtain a clear solution.(iii) The R2 solution was mixed into the R1 under stirring with a rate of 500 rpm.(iv) The mixture was heated and stirred at 50°C for 2 h and it turned to suspension. The system was cooled down to 20°C within 3 h and kept stirring for 15 h.(v) Precipitation was centrifuged, and the filter cake was dried at 20°C under vacuum.(vi) The solid sample was characterized by XRPD, DSC & TGA, PLM and1H NMR.Compound 1 tert-butylamine salt - Form B

[0457] The tert-butylamine salt of Compound 1 Form B was successfully prepared using the following methodology:(i) Input material (amorphous Compound 1 free acid) and EtOH (3V) was added into R1. The mixture was magnetic stirred with a rate of 500 rpm to obtain a clear solution at 20°C.(ii) The tert-butylamine (1.1 eq.) and EtOH / H2O=1 :8 (V / V, 9V) were charged into R2 to obtain a clear solution. The R2 solution was added into the R1 under stirring with a rate of 500 rpm.(iii) The mixture was heated and stirred at 50°C for 2 h and it turned to suspension. The system was cooled down to 20°C within 3 h and kept stirring for 15 h.(iv) Precipitation was centrifuged, and the filter cake was dried at 20°C under vacuum.(v) The solid sample was characterized by XRPD, DSC & TGA, PLM and1H NMR.Compound 1 tert-butylamine salt - Form C

[0458] The tert-butylamine salt of Compound 1 Form C was successfully prepared using the following methodology:(i) Input material (amorphous Compound 1 free acid) and 5V ACN were filled into a 2 mL glass vial (R1). The reaction system was stirred at 20°C to obtain a clear solution.(ii) The tert-butylamine (1.1 eq.) and 5V ACN were added to another 2 mL glass vial (R2) to obtain clear solution, and then the solution in R2 was slowly added to R1 under stirring condition.(iii) The reaction system was heated to 50°C and stirred at 50°C for 2 h, and then the clear solution transformed into a suspension.(iv) The reaction system was cooled to 20°C at a cooling rate of 10°C / h and kept stirring for 15 h.(v) Experiment with precipitation was centrifuged and the filter cake was dried at 20°C under vacuum for 24 h.(vi) The solid sample obtained was characterized by XRPD, DSC & TGA, PLM and1H NMR.Characterization of salt forms

[0459] The sodium, potassium and tert-butylamine salts were characterized by XPRD, DSC, TGA, PLM and1H-NMR.Compound 1 Sodium salt Form A

[0460] The sodium salt of Compound 1 Form A was first discovered under the condition of MTBE slurrying after evaporation in N2, which had good crystallinity. FIG.24 shows the XRPD diffractogram obtained for the sodium salt of Compound 1 Form A. TGA results showed weight loss of 2.79% when heated to 100°C corresponding to the weight loss of one water molecule and DSC results showed two endothermic peaks of 76.85°C and 271.56°C (see FIG.25). PLM results showed that the particles were fine granular (see FIG.26).

[0461] Peak positions present in the XRPD diffractogram acquired for sodium salt of Compound 1 Form A are presented in Table 29.Table 29 = XRPD peak positions for Compound 1 sodium salt Form ACompound 1 Potassium salt Form A

[0462] The potassium salt of Compound 1 Form A was discovered under the condition of MTBE slurrying after evaporation in N2, but it did not achieve good crystallinity by crystallization in different solvents and extending heat-cooling cycling. Potassium salt of Compound 1 Form A was a monohydrate.

[0463] XRPD results showed that the potassium salt of Compound 1 Form A had moderate crystallinity. FIG.27 shows the XRPD diffractogram obtained for the potassium salt of Compound 1 Form A. TGA results showed weight loss of 2.33% when heated to 230°C corresponding to theweight loss of one water molecule and DSC results showed a melting point of 250.31 °C (see FIG.28). PLM results showed that the particles were fine granular (see FIG.29).

[0464] Peak positions present in the XRPD diffractogram acquired for potassium salt of Compound 1 Form A are presented in Table 30.Table 30 = XRPD peak positions for Compound 1 potassium salt Form ACompound 1 tert-butylamine salt Form A

[0465] Compound 1 Terf-butylamine salt Form A can be obtained in EtOH systems.

[0466] XRPD results showed that the terf-butylamine salt of Compound 1 Form A had good crystallinity (see FIG.30). The TGA results showed that there were two stages of weight loss, with a total weight loss of 11.41 % when heated to 260°C, equivalent to the weight loss of one tert- butylamine molecule, and DSC results showed a melting point of 150.68 and 180.28°C (see FIG.31). PLM results showed that the particles were rod-like (see FIG.32).1H NMR results showed that the salt formation ratio is 1 :1.

[0467] Peak positions present in the XRPD diffractogram acquired for terf-butylamine salt of Compound 1 Form A are presented in Table 31.Table 31 = XRPD peak positions for Compound 1 tert-butylamine salt Form ACompound 1 tert-butylamine salt Form B

[0468] Tert-butylamine salt of Compound 1 Form B can be obtained in EtOH / FW systems. XRPD results showed that the tert-butylamine salt of Compound 1 Form B had good crystallinity (see FIG.33). The TGA results showed that there were two stages of weight loss, with a total weight loss of 10.59% when heated to 260°C, equivalent to the weight loss of one tert-butylamine molecule, and DSC results showed a melting point of 149.79 and 183.89°C (see FIG.34). PLM results showed that the particles were rod-like (see FIG.35).1H NMR results showed that the salt formation ratio is 1 :1.

[0469] Peak positions present in the XRPD diffractogram acquired for the tert-butylamine salt of Compound 1 Form B are presented in Table 32.Table 32 = XRPD peak positions for Compound 1 tert-butylamine salt Form BCompound 1 tert-butylamine salt Form C

[0470] Tert-butylamine salt of Compound 1 Form C can be obtained in ACN systems. XRPD results showed that the tert-butylamine salt of Compound 1 Form C had good crystallinity (see FIG.36). The TGA results showed that there were two stages of weight loss with a total weight loss of 11.08% when heated to 260°C, which was owing to the loss of one molecule of tert- butylamine, and DSC results showed a melting point of 148.61 °C (see FIG.37). PLM results showed that the particles were rod-like and small particle (see FIG.38).1H NMR results showed that the salt formation ratio is 1:1.

[0471] Peak positions present in the XRPD diffractogram acquired for tert-butylamine salt of Compound 1 Form C are presented in Table 33.Table 33 = XRPD peak positions for Compound 1 tert-butylamine salt Form CCompetitive Slurry Experiments of Tert-butylamine Salts

[0472] Tert-butylamine salts of Compound 1 Form A (20 mg), Form B (20 mg) and Form C (20 mg) were charged into 2 mL glass vial, mixed saturated solvent was added to obtain suspension with a magnetic stirring (500 rpm) at 25°C or 50°C. A small amount of solid was isolated at 10 min, 1 d and 4 d and tested by XRPD.Preparation method of saturated solvent:

[0473] About 1 mL mixed solvent was charged into a 2 mL vial and a certain amount of tert- butylamine salt of Compound 1 Form A was added to prepare suspension.

[0474] The eight systems were prepared as follows:(1) For the EtOH solvent system, about 50 mg of Compound 1 tert-butylamine salt Form A was added to prepare suspension at 25°C;(2) For the EtOH solvent system, about 100 mg of Compound 1 tert-butylamine salt Form A was added to prepare suspension at 50°C;(3) For the EtOH / H2O=1 :1(V / V) solvent system, about 20 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 25°C ;(4) For the EtOH / H2O=1 :1(V / V) solvent system, about 50 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 50°C ;(5) For the EtOH / H2O=1 :2(V / V) solvent system, about 10 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 25°C ;(6) For the EtOH / H2O=1 :2(V / V) solvent system, about 20 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 50°C ;(7) For the H2O system, about 10 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 25°C ;(8) For the H2O system, about 10 mg Compound 1 tert-butylamine salt Form A was added to prepare suspension at 50°C .

[0475] The suspension was kept stirring at 25°C or 50°C for about 10 min and then filtered. The filtrate was the saturated solution.Results

[0476] As shown in Table 34, Forms B and C of Compound 1 tert-butylamine salt quickly transformed into Form A in the selected solvent systems, except for in H2O system at 25°C. Therefore, Form A is the most stable form of the tert-butylamine salts, while the other two forms are metastable forms in the preparation systems.Table 34 - Results from competitive slurries of tert-butylamine salts of Compound 1“ / / ” = Experiment not performedHygroscopicity analysisMethod

[0477] The Compound 1 sodium salt Form A (~20 mg) and Compound 1 tert-butylamine salt Form A (~20 mg) were used for DVS, and the crystal form was characterized after the test was completed.Results

[0478] As shown in FIG. 39 and FIG. 40, the Compound 1 sodium salt Form A was hygroscopic with water uptake of 14.37% between 0 and 80% RH, and the crystallinity significantly decreased after DVS testing.

[0479] As shown in FIG. 41 and FIG. 42, the Compound 1 tert-butylamine salt Form A was almost non-hygroscopic with a weight gain of -0.15% between 10 and 80% RH, and no change in crystal form was found after DVS test.Solubility assessment of Compound 1 tert-butylamine salt Form AApproximate Solubility Test

[0480] The ferf-butylamine salt of Compound 1 - Form A (30 mg) was charged into a 2 mL glass vial, and water was slowly added to 1 mL with magnetic stirring at RT.Kinetic Solubility Test

[0481] Terf-butylamine salt of Compound 1 - Form A (20 mg) was accurately weighed and transferred to three 20 mL glass vials; 4 mL of the test solutions (SGF, FaSSIF or FeSSIF) was added to each vial separately. The vials were sealed and transferred to a thermostatic shaker and kept at a shaking rate of 200 rpm at 37°C. Samples were taken after 0.5 h, 2 h and 24 h, and separated by centrifugation; about 1 mL of the filtrate was further filtered using a 0.22 pm PTFE membrane. The content of the filtrate was detected by HPLC, and filter cake was collected and tested by XRPD, and the pH of the system was determined using a pH meter.Preparation methods for different bio-relevant vehicles:

[0482] SGF (pH 1.2): Measure 21 .25 mL of 0.2 mol / mL HCI and weigh 99.95 mg of NaCI, and dilute with water to 50 mL.

[0483] FaSSIF (pH 6.5): Weigh 21 mg of NaOH, 171 .9 mg of NaH2PO4and 309.3 mg of NaCI, and dilute with water to 50 mL. The pH of the solution was adjusted to 6.5 and 112 mg of FaSSIF powder was added.

[0484] FeSSIF (pH 5.0): Weigh 593.7 mg of NaCI, 202 mg of NaOH and 412.3 pL of Acetic acid, and dilute with water to 50 mL. The pH of the solution was adjusted to 5.0 and 560 mg of FeSSIF powder was added.Results

[0485] The solubility of Form A of the terf-butylamine salt in water is much higher than 30 mg / mL, however the fluidity is very poor.

[0486] The kinetic solubility results are summarized in Table 35. The salt had poor solubility in SGF and even it is hard to be fully dissociated to free form in the system. In the FaSSIF and FeSSIF systems, the solubility gradually decreased over the 24 hour period, which was owing to the dissociation of salt. The solubility (equivalent to free acid) of Form A of the ferf-butylamine salt after 30 minutes was 260.8 and 169.5 pg / mL in FaSSIF and FeSSIF respectively, which decreased to 83.2 and 60.7 pg / mL after 24 h respectively. The XRPD results showed the salt samples dissociated to the Form C of the free acid of Compound 1 or mixtures of forms. The salt dissociation caused little change in the pH value of the liquors.Table 35 - Results of Kinetic Solubility TestML = Mother liquor; LOD = limit of detection (0.5 pg / mL);1based on free form; / / = insufficient sample to test; ‘Samples were directly injected without dilution; # Samples were diluted twice before injection with ACN / H2O=1 :1 (V / V); ## Samples were diluted 4 times before injection with ACN / H2O=1 :1 (V / V); ### Samples were diluted 6 times before injection with ACN / H2O=1 :1 (V / V).Summary of Compound 1 salt studies

[0487] Three of the bases investigated gave crystalline salt forms - sodium hydroxide, potassium hydroxide and terf-butylamine. Of these the sodium salt is very hygroscopic and the potassium salt is not stable under ambient conditions.

[0488] Three polymorphs of the terf-butylamine salt were identified, of which Form A was shown to be the most stable terf-butylamine salt. Form A of the terf-butylamine salt of Compound 1 is non-hygroscopic and has increased solubility compared to Form C of the free acid.EXAMPLE 7: ALTERNATIVE PROCESS TO PREPARE COMPOUND 1 FREE ACID FORM C

[0489] An alternative process, at a laboratory scale (~20 g scale), to prepare Compound 1 free acid Form C is presented below:1. Charge Compound 1 free acid input material (1.0 eq) into reactor 1.2. Charge EtOH (6.7V) into reactor 1.3. Heat to 50 °C and stir until a clear solution is obtained.4. Charge H2O (3.3V) into reactor 1.5. Cool reactor 1 to 45 °C.6. Charge 2 wt% Form C seeds to reactor 1 and age the crystal for 2-3 h.7. Cool reactor 1 to 20 °C over a period of 5 h.8. Keep stirring for 12 h at 20 °C.9. Filter suspension and collect solids to get Compound 1 free acid Form C.

[0490] The product was analyzed via XRPD, DSC, TGA, PLM, HPLC, chiral HPLC and QNMR.

[0491] Advantageously, this crystallization results in better purging of a des-fluoro impurity (purged from 0.57% to 0.10%, overall HPLC purity improved from 99.07% to 99.80%).

[0492] All other analyses indicated the product given by this process was comparable to that produced by the MTBE / heptane crystallization of Example 5.

[0493] All publications, patents and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used.

[0494] 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.

[0495] 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 1wherein 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 7.1 and 11.3 °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 or three specific peaks selected from peaks at 11.8, 13.1 and 14.6 °20 ± 0.2 °20.

4. 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 additional peaks selected from the group consisting of the peaks in Table 1 in °20 ± 0.2 °20.

5. The crystalline form of any one of claims 1 to 4, wherein Form C is characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in Figure 7.

6. The crystalline form of any one of claims 1 to 5, wherein the crystalline form is anhydrous.

7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form comprises less than 2% by weight of water.

8. The crystalline form of any one of claims 1 to 7, wherein the Form C is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 149 °C ± 2°C.

9. The crystalline form of claim 8, wherein the DSC thermogram comprises no thermal events between 50 and 100 °C and an endothermic event with an onset temperature of 149 °C ± 2°C.

10. The crystalline form of any one of claims 1 to 9 wherein Form C is characterized by a DSC thermogram substantially the same as the DSC thermogram depicted in Figure 8.11 . The crystalline form of any one of claims 1 to 10, wherein the crystalline form is substantially pure.

12. The crystalline form of any one of claims 1 to 11 , 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.

13. The crystalline form of any one of claims 1 to 10, wherein Form C is free from other forms.

14. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, diluent or excipient.

15. A pharmaceutical composition according to claim 14, for use as a medicament.

16. A method for treating a hepatitis B virus (HBV) infection or a hepatitis D virus (HDV) infection, or a HBV / HDV coinfection, in a subject in need thereof, the method comprising administering a therapeutically effective amount of the crystalline form according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14.

17. The method of claim 16, wherein the pharmaceutical composition is administered twice daily, once daily, once every two, three, four, five, or six days, 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.

18. The crystalline form according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14, for use in the treatment of HBV infection or HDV infection, or a HBV / HDV coinfection.

19. The use of the crystalline form according to any one of claims 1 to 13 in the manufacture of a medicament for treating HBV infection or HDV infection, or a HBV / HDV coinfection.

20. A process to prepare the crystalline form according to any one of claims 1 to 13, wherein the process comprises the steps of: a) providing a solution of Compound 1 free acid 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) for at least 10 minutes; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).

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