New crystal morphology

Abstract

The present disclosure generally relates to novel crystalline forms of certain compounds useful as modulators of Hepatitis B virus core protein assembly. The present disclosure also relates to identifying suitable solid state forms with promising solid state properties for clinical development. The disclosed solid state forms can be used in the manufacture of drug products that may have dimer, multimer, and allosteric effector properties against Hepatitis B virus (HBV) core protein (Cp), a protein found as the protein shell of the HBV core. As an example, provided herein are stable crystalline forms that may be useful for treating viral infections such as Hepatitis B.

Description

[Technical Field]

[0001] The present disclosure generally relates to novel crystalline forms of certain compounds useful as modulators of hepatitis B virus core protein assembly. The disclosure also relates to identifying suitable solid-state forms with promising solid-state properties for clinical development. The disclosed solid-state forms can be used in the manufacture of drug products that may have dimers, multimers, and allosteric effector properties against hepatitis B virus (HBV) core protein (Cp), a protein found as the protein shell of the HBV core. As an example, provided herein are stable crystalline forms that may be useful for treating viral infections, such as hepatitis B. [Background technology]

[0002] Hepatitis B (HBV) causes viral hepatitis, which further leads to chronic liver disease and increases the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, approximately 2 billion people are infected with HBV, approximately 360 million are chronically infected, and more than 500,000 people die from HBV infection each year. HBV can be spread through bodily fluids: from mother to child, through sexual contact, and through blood products. Babies born to HBV-positive mothers can also become infected unless vaccinated at birth.

[0003] Hepatitis virus particles consist of a lipid envelope studded with surface proteins (HBsAg) surrounding a viral core. The core is composed of a protein shell, or capsid, assembled from 120 core protein (Cp) dimers, which contains the incomplete double-stranded DNA (relaxed circular DNA (rcDNA)) viral genome and viral and host proteins. In infected cells, the genome is found in the host cell nucleus as a covalently closed circular DNA (cccDNA). The cccDNA is the template for viral RNA and therefore viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (so-called pregenomic RNA, or pgRNA) and viral polymerase (P). After assembly, P reverse-transcribes the pgRNA into rcDNA within the capsid region, generating a DNA-filled viral core.

[0004] Currently, chronic HBV is primarily treated with nucleoside (nucleotide) analogs (e.g., entecavir), which suppress the virus while the patient is receiving treatment but do not eliminate the infection, even after years of treatment. Once patients begin taking nucleoside (nucleotide) analogs, most must continue the treatment or risk a potentially life-threatening immune response due to viral rebound. Furthermore, nucleotide therapy may lead to the emergence of antiviral drug resistance.

[0005] The only FDA-approved alternatives to nucleoside (nucleotide) analogs are treatments with interferon alpha or pegylated interferon alpha. Unfortunately, the adverse events and profile of interferon alpha can be poorly tolerated, and many patients fail to complete the therapy. Furthermore, only a small percentage of patients appear to have a sustained clinical response to a course of interferon therapy, meaning that only a small percentage of patients are likely to be suitable for interferon therapy. As a result, only a small percentage of all diagnosed patients who elect treatment use interferon-based therapy.

[0006] Therefore, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress viral production and treat symptoms, but the infection remains. Interferon-α has severe side effects, is poorly tolerated by patients, and has only been a successful limited treatment strategy in a minority of patients. Clearly, there is an ongoing need for more effective treatments for HBV infection.

[0007] The present disclosure relates to novel crystalline forms of certain compounds, which were first disclosed in PCT / US2021 / 028323, the entire contents of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0008] One embodiment of the present disclosure is Compound I

[0009] [ka] It is a crystalline form of

[0010] One embodiment of the present disclosure is a crystalline form of Compound I, the crystalline form being Compound I(a):

[0011] [ka] It is a crystalline form of

[0012] The present disclosure relates to certain novel crystalline solid forms of Compound I, preferably Compound I(a), that have promising and advantageous solid-state and / or biopharmaceutical properties.

[0013] The present disclosure is also directed to pharmaceutical compositions comprising the crystalline form or mixtures of crystalline forms, and methods for preparing such forms. The present disclosure is further directed to the use of the crystalline forms in the treatment of HBV infection.

[0014] It is understood that there are multiple analytical methods that those skilled in the art of solid-state chemistry can use to analyze solid forms.The term "analyze" used herein means to obtain information about the solid-state structure of solid forms.For example, powder X-ray diffraction (PXRD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, and characterizing and identifying specific crystalline solid forms of compounds.

[0015] Due to differences in instruments, samples, and sample preparation, PXRD peak values ​​are often reported with the modifier "±0.2° 2θ." This is common practice in solid-state chemistry due to the inherent variability in peak values. The variability in peak intensities is a result of how individual crystals are oriented in the sample container relative to the external X-ray source (known as "preferred orientation"). This orientation effect does not provide structural information about the crystals.

[0016] It should be noted that unless otherwise stated, the X-ray powder diffraction patterns disclosed herein were obtained using Cu Kα (1.5406 Å) radiation.

[0017] It is also understood that PXRD is only one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. For example, differential scanning calorimetry (DSC) can also be used to characterize and / or identify crystalline solid forms. Typical variability associated with the differential scanning calorimetry onset temperature is on the order of plus or minus 2°C.

[0018] It should be noted that unless otherwise noted, the thermal data (DSC and TGA) presented herein were obtained using a heating rate of 10°C / min. Furthermore, the DSC data were obtained using an aluminum crimped pan, while the TGA data were obtained using a platinum open pan.

[0019] In one aspect of the invention, the crystalline form is Form 1. Form 1 is an anhydrous crystalline form. In one embodiment, Form 1 is an anhydrous crystalline form of Compound I, where Compound I is Compound I(a).

[0020] In one embodiment, crystalline Form 1 is characterized by the XRPD pattern of Figure 24. In one embodiment, crystalline Form 1 is characterized by an XRPD pattern having at least one of the 2θ peaks from Table 1.

[0021] [Table 1]

[0022] In one embodiment, crystalline Form 1 is characterized by at least two of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least three of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least four of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least five of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least six of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least seven of the 2θ peaks from Table 1. In one embodiment, crystalline Form 1 is characterized by at least eight of the 2θ peaks from Table 1.

[0023] In one embodiment, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ). In a further embodiment, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least one or two specific peaks selected from peaks at 2-theta values ​​of 16.4 and 17.6 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0024] In one aspect, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least 2, 5, 10, 15, or 20 additional peaks selected from the group consisting of the peaks in Table 2 at °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0025] [Table 2]

[0026] In one embodiment, crystalline Form 1 is anhydrous and characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ). In one embodiment, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ), wherein Form 1 contains less than 2% water by weight. In one embodiment, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ), wherein Form 1 contains less than 1.5% water by weight. In a further aspect, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least one or two specific peaks selected from peaks at 2-theta values ​​of 16.4 and 17.6 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), wherein Form 1 contains less than 2% water by weight. In a further aspect, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least one or two specific peaks selected from peaks at 2-theta values ​​of 16.4 and 17.6 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), wherein Form 1 contains less than 1.5% water by weight.

[0027] In one embodiment, crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0028] In one embodiment, crystalline Form 1 contains less than 2% by weight of water, e.g., less than 1.5% or less than 1.0%. Those skilled in the art will be aware of suitable analytical techniques that can quantify the amount of water associated with a solid. For example, water content can be determined by Karl Fischer titration. Thermogravimetric analysis (TGA) can also quantify the amount of volatile material (i.e., water) associated with a solid (either surface-bound or incorporated into the crystalline structure).

[0029] In one embodiment, crystalline Form 1 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C). In one embodiment, crystalline Form 1 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C) without a thermal event between 50 and 100°C.

[0030] In one embodiment, crystalline Form 1 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 2B.

[0031] In one embodiment, crystalline Form 1 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 from other forms. In one embodiment, crystalline Form 1 is free from other forms.

[0032] In one aspect of the invention, the crystalline form is Form 2. Form 2 is a hydrated crystalline form. In one embodiment, Form 2 is the crystalline trihydrate form of Compound I, where Compound I is Compound I(a). In one aspect, crystalline Form 2 is characterized by the XRPD pattern of Figure 25. In one aspect, crystalline Form 2 is characterized by an XRPD pattern having at least one of the 2θ peaks from Table 3:

[0033] [Table 3]

[0034] In one embodiment, crystalline Form 2 is characterized by at least two of the 2θ peaks from Table 3. In one embodiment, crystalline Form 2 is characterized by at least three of the 2θ peaks from Table 3. In one embodiment, crystalline Form 2 is characterized by at least four of the 2θ peaks from Table 3. In one embodiment, crystalline Form 2 is characterized by five 2θ peaks from Table 3.

[0035] In one embodiment, crystalline Form 2 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 5.6 and 8.5 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ). In one embodiment, crystalline Form 2 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 5.6 and 8.5 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least 2, 5, 10, 15, or 20 additional peaks selected from the group consisting of the peaks in Table 4 at °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0036] [Table 4]

[0037] In one embodiment, crystalline Form 2 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0038] In one embodiment, crystalline Form 2 contains 5-12% water by weight, for example 7-11% by weight. In one embodiment, crystalline Form 2 contains about 9% water by weight.

[0039] In one embodiment, crystalline Form 2 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 212° C.±2° C. (preferably ±1° C.).

[0040] In one embodiment, crystalline Form 2 is characterized by a DSC thermogram comprising an endothermic event between 50 and 120°C and an endothermic event with an onset temperature of 212°C ± 2°C (preferably ± 1°C).

[0041] In one embodiment, crystalline Form 2 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 4B.

[0042] In one embodiment, crystalline Form 2 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 from other forms. In one embodiment, crystalline Form 2 is free from other forms.

[0043] In one aspect of the invention, the crystalline form is Form 3. Form 3 is a hydrated crystalline form. In one embodiment, Form 3 is a crystalline monohydrate of Compound I. In one embodiment, Form 3 is a crystalline monohydrate of Compound I, and Compound I is Compound I(a).

[0044] In one embodiment, crystalline Form 3 is characterized by the XRPD pattern of Figure 26. In one embodiment, crystalline Form 3 is characterized by an XRPD pattern having at least one of the 2θ peaks from Table 5:

[0045] [Table 5]

[0046] In one embodiment, crystalline Form 3 is characterized by at least two of the 2θ peaks from Table 5. In one embodiment, crystalline Form 3 is characterized by three 2θ peaks from Table 5.

[0047] In one embodiment, crystalline Form 3 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 6.4 and 7.1 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ). In one embodiment, crystalline Form 3 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 6.4 and 7.1 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and further comprising at least one or two particular peaks selected from peaks at 2-theta values ​​of 9.7, 14.2, and 14.9 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0048] In one aspect, crystalline Form 3 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 6.4 and 7.1 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and at least 2, 5, 10, or 15 additional peaks selected from the group consisting of the peaks in Table 6 at °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0049] [Table 6]

[0050] In one embodiment, crystalline Form 3 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0051] In one embodiment, crystalline Form 3 contains 2-4% water by weight. In one embodiment, crystalline Form 3 contains about 3% water by weight.

[0052] In one embodiment, crystalline Form 3 is characterized by a DSC thermogram containing endothermic events with onset temperatures of 192 and 212°C ± 2°C (preferably ± 1°C).

[0053] In one embodiment, crystalline Form 3 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 7B.

[0054] In one embodiment, crystalline Form 3 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 from other forms. In one embodiment, crystalline Form 3 is free from other forms.

[0055] In one aspect of the invention, the crystalline form is Form 4. Form 4 is a hydrated crystalline form. In one embodiment, Form 4 is a crystalline sesquihydrate of Compound I. In one embodiment, Form 4 is a crystalline sesquihydrate of Compound I, and Compound I is Compound I(a).

[0056] In one embodiment, crystalline Form 4 is characterized by the XRPD pattern of Figure 27. In one embodiment, crystalline Form 4 is characterized by an XRPD pattern having at least one of the 2θ peaks from Table 7:

[0057] [Table 7]

[0058] In one embodiment, crystalline Form 4 is characterized by at least two of the 2θ peaks from Table 7. In one embodiment, crystalline Form 4 is characterized by at least three of the 2θ peaks from Table 7. In one embodiment, crystalline Form 4 is characterized by at least four of the 2θ peaks from Table 7. In one embodiment, crystalline Form 4 is characterized by five 2θ peaks from Table 7.

[0059] In one embodiment, crystalline Form 4 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 5.1 and 17.6 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ). In one embodiment, crystalline Form 4 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation comprising peaks at 2-theta values ​​of 5.1 and 17.6 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ), and further comprising a peak at a 2-theta value of 8.3 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ).

[0060] In one aspect, crystalline Form 4 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 5.1 and 17.6 °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ), and at least 2, 5, 10, 15, or 20 additional peaks selected from the group consisting of the peaks in Table 8 at °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0061] [Table 8]

[0062] In one embodiment, crystalline Form 4 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0063] In one embodiment, crystalline Form 4 contains 4-6% water by weight. In one embodiment, crystalline Form 4 contains about 4.5% water by weight.

[0064] In one embodiment, crystalline Form 4 is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C). In one embodiment, crystalline Form 4 is characterized by a DSC thermogram comprising an endothermic event between 75-110°C ± 2°C (preferably ± 1°C) and an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C).

[0065] In one embodiment, crystalline Form 4 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 8B.

[0066] In one embodiment, crystalline Form 4 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 from other forms. In one embodiment, crystalline Form 4 is free from other forms.

[0067] In one aspect of the invention, the crystalline form is Form 5. Form 5 is a solvated crystalline form. In one embodiment, Form 5 is a crystalline monodichloromethane solvate of Compound I. In one embodiment, Form 5 is a crystalline monodichloromethane solvate of Compound I, where Compound I is compound I(a).

[0068] In one embodiment, crystalline Form 5 is characterized by the XRPD pattern of Figure 28. In one embodiment, crystalline Form 5 is characterized by an XRPD pattern having at least one of the 2θ peaks from Table 9:

[0069] [Table 9]

[0070] In one embodiment, crystalline Form 5 is characterized by two 2θ peaks from Table 9.

[0071] In one embodiment, crystalline Form 5 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 6.7 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ). In one embodiment, crystalline Form 5 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes peaks at 2-theta values ​​of 6.7 and 18.9 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ).

[0072] In one aspect, crystalline Form 5 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation that includes a peak at a 2-theta value of 6.79 °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ) and at least 2, 5, 10, 15, or 20 additional peaks selected from the group consisting of the peaks in Table 10 at °2θ±0.2 °2θ (preferably °2θ±0.1 °2θ).

[0073] [Table 10]

[0074] In one embodiment, crystalline Form 5 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0075] In one embodiment, crystalline Form 5 contains 11-15% by weight of dichloromethane. In one embodiment, crystalline Form 5 contains about 13% by weight of dichloromethane.

[0076] In one embodiment, crystalline Form 5 is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C). In one embodiment, crystalline Form 5 is characterized by a DSC thermogram comprising an endothermic event between 70-110°C ± 2°C (preferably ± 1°C), an exothermic event between 160-200°C ± 2°C (preferably ± 1°C), and an endothermic event with an onset temperature of 210°C ± 2°C (preferably ± 1°C).

[0077] In one embodiment, crystalline Form 5 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 9B.

[0078] In one embodiment, crystalline Form 5 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 from other forms. In one embodiment, crystalline Form 5 is free from other forms.

[0079] In one aspect of the invention, the crystalline form is Form 8. Form 8 is an anhydrous crystalline form. In one embodiment, Form 8 is an anhydrous crystalline form of Compound I, and Compound I is Compound I(a).

[0080] Form 8 was surprisingly produced during a drug substance manufacturing campaign. A manufacturing batch intended to produce a different form yielded trace amounts of another crystalline form, which was later characterized as a new solid-state form, Form 8. Form 8 had not previously been observed during numerous crystallization experiments described in Example 2.

[0081] Applicants have characterized Form 8 and found it to be the most thermodynamically stable form discovered to date.

[0082] In one embodiment, crystalline Form 8 is characterized by an XRPD pattern measured using Cu Kα (λ=1.5406 Å) radiation of Figure 29. In one embodiment, crystalline Form 8 is characterized by an XRPD pattern measured using Cu Kα (λ=1.5406 Å) radiation comprising peaks at 2-theta values ​​of 9.4, 15.4, and 16.7 °2θ±0.2 °2θ (preferably °±0.1 °2θ).

[0083] In one aspect, crystalline Form 8 is characterized by an XRPD pattern measured using Cu Kα (λ=1.5406 Å) radiation that includes peaks at 2-theta values ​​of 9.4, 15.4, and 16.7 °2θ ± 0.2 °2θ (preferably °± 0.1 °2θ), and at least 2, 5, 10, 15, or 20 additional peaks selected from the group consisting of the peaks in Table 11 at °2θ ± 0.2 °2θ (preferably °2θ ± 0.1 °2θ).

[0084] [Table 11]

[0085] In one embodiment, crystalline Form 8 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

[0086] In one embodiment, crystalline Form 8 contains less than 2% water by weight, such as less than 1.5% or less than 1.0%.

[0087] In one embodiment, crystalline Form 8 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 212°C ± 2°C (preferably ± 1°C). In one embodiment, crystalline Form 8 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 212°C ± 2°C (preferably ± 1°C) and no thermal event between 50 and 100°C.

[0088] In one embodiment, crystalline Form 8 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in FIG.

[0089] In one embodiment, crystalline Form 8 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 from other forms. In one embodiment, crystalline Form 8 is free from other forms.

[0090] In one embodiment, the crystalline form of the present disclosure is stereochemically pure. In one embodiment, the crystalline form of the present disclosure is stereochemically pure Compound I(a):

[0091] [ka] It is a crystalline form of

[0092] The term "stereochemically pure" with respect to compound I(a) means that the crystalline form of compound I(a) is dominated by one diastereomer, e.g., less than about 20% by weight, e.g., less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of the other diastereomer (e.g., compounds I(b), I(c), and / or I(d)). Preferably, the crystalline form of compound I(a) consists essentially of a single diastereomer. Preferably, the crystalline form of compound I(a) consists of a single diastereomer. In one aspect, the crystalline form of the present disclosure is compound I(a).

[0093] When the present specification refers to a crystalline form of compound I(a), the degree of crystallinity is advantageously greater than about 60% by weight, more advantageously greater than about 80% by weight, even more advantageously greater than about 90% by weight, and preferably greater than 95%, 98%, or 99% by weight.

[0094] In one aspect, Form 1 is pure or substantially pure. As used herein, the term "substantially pure" means that the solid-state form of Compound I(a) 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 I(a), including alternative crystalline forms, hydrates, solvates, or amorphous forms, as measured, for example, by XRPD. Thus, substantially pure Form 1 as described herein will be understood to include greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, or greater than 99.5% by weight of crystalline Form 1 of Compound I(a). Preferably, Form 1 is provided in which no other solid forms (amorphous and / or other crystalline forms) are detectable when Form 1 is analyzed by solid-state techniques such as X-ray powder diffraction. Preferably, there is provided a crystalline form of Compound I(a) which consists essentially of Form 1. Preferably, there is provided a crystalline form of Compound I(a) which consists of Form 1. Preferably, there is provided a crystalline form of Compound I(a) which is Form 1 and which does not include Form 2, Form 3, Form 4, Form 5, or Form 8.

[0095] In one embodiment, Form 8 is pure or substantially pure. As used herein, the term "substantially pure" means that the solid-state form of Compound I(a) 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 I(a), including alternative crystalline forms, hydrates, solvates, or amorphous forms, as measured, for example, by XRPD. Thus, substantially pure Form 8 as described herein will be understood to include greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, or greater than 99.5% by weight of crystalline Form 8 of Compound I(a). Preferably, Form 8 is provided in which no other solid forms (amorphous and / or other crystalline forms) are detectable when Form 8 is analyzed by solid-state techniques such as X-ray powder diffraction. Preferably, there is provided a crystalline form of Compound I(a) which consists essentially of Form 8. Preferably, there is provided a crystalline form of Compound I(a) which consists of Form 8. Preferably, there is provided a crystalline form of Compound I(a) which is Form 8 and which does not include Form 1, Form 2, Form 3, Form 4, or Form 5.

[0096] In one embodiment, Form 2, Form 3, or Form 4 is pure or substantially pure. As used herein, the term "substantially pure" means that the solid-state form of Compound I(a) 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 I(a), including alternative crystalline forms, hydrates, solvates, or amorphous forms, as measured, for example, by XRPD. Thus, substantially pure Form 2, Form 3, or Form 4 described herein will be understood to include greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, or greater than 99.5% by weight of crystalline Form 2, Form 3, or Form 4 of Compound I(a). Preferably, Form 2, Form 3, or Form 4 is provided in which no other solid forms (amorphous and / or other crystalline forms) are detectable when Form 2, Form 3, or Form 4 is analyzed by solid-state techniques such as X-ray powder diffraction. Preferably, a crystalline form of Compound I(a) is provided that consists essentially of Form 2, Form 3, or Form 4. Preferably, a crystalline form of Compound I(a) is provided that consists of Form 2, Form 3, or Form 4.

[0097] One embodiment of the present disclosure includes a pharmaceutical composition comprising a crystalline form or forms according to the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. Preferably, the pharmaceutical composition comprises a single crystalline form according to the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0098] One embodiment of the present disclosure includes a method of treating hepatitis B (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form according to the present disclosure.

[0099] One embodiment of the present disclosure includes a method of treating hepatitis B (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0100] One embodiment includes a crystalline form according to the present disclosure for use in the treatment of HBV infection.

[0101] One embodiment includes a pharmaceutical composition of the present disclosure for use in the treatment of HBV infection.

[0102] One embodiment includes the use of a crystalline form or pharmaceutical composition according to the present disclosure for the treatment of HBV infection.

[0103] One embodiment includes the use of a crystalline form according to the present disclosure in the manufacture of a medicament for treating HBV infection.

[0104] One embodiment includes a process for preparing crystalline Compound I, preferably Compound I(a), wherein the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8.

[0105] In one embodiment, a process for preparing a crystalline form of Compound I, preferably Compound I(a), is provided, wherein the crystalline form is Form 8.

[0106] One embodiment comprises crystalline Compound I obtainable by the processes described herein [preferably Compound I(a)], wherein the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. [Brief explanation of the drawings]

[0107] [Figure 1] FIG. 1 is an XRPD overlay of Forms 1, 2, 3, 4, and 5 of the present disclosure. [Figure 2A] Figure 2A illustrates the characterization of Form 1. XRPD showed that Form 1 was crystalline. [Figure 2B] Figure 2B illustrates the characterization of Form 1. TGA data showed a two-step weight loss of 1.33% up to 235°C. DSC showed a sharp endotherm with an onset at 210.7°C. PLM showed irregularly shaped birefringent particles. [Figure 3]Figure 3 is a GC graph of Form 1. GC showed 0.02% EtOAc and EtOH, suggesting the presence of residual solvent in the solid. KF showed a water content of 0.83%. [Figure 4A] Figure 4A illustrates the characterization of Form 2. XRPD showed that Form 2 was crystalline. [Figure 4B] Figure 4B illustrates the characterization of Form 2. TGA data showed a weight loss of 11.6% up to 200°C. DSC thermograms showed endotherms at 78.1, 93.6, and 212.9°C (peak temperatures). PLM showed irregularly shaped birefringent particles. [Figure 5] Figure 5 illustrates the characterization of Form 2 from a slurry at 5 °C using THF:HO. Upon drying, TGA showed a weight loss of 6.8%. Similarly, KF showed a water content of 7.10%. [Figure 6A] Figure 6A illustrates the DVS of Form 2 from a slurry using THF:HO at 5 °C. Form 2 showed a moisture content of 9.2% at 80% RH by DVS, indicating that the sample is a trihydrate and is stable between 30 and 95% RH. [Figure 6B] Figure 6B shows the XPRD diffractograms for Form 2 before DVS and for the material obtained after DVS. A change in morphology to a lower hydrate was observed after DVS. [Figure 7A] Figure 7A illustrates the characterization of Form 3. Form 3 was prepared by keeping Form 2 at 0% RH for 3 days. XRPD showed that Form 3 was crystalline. [Figure 7B] Figure 7B illustrates the characterization of Form 3. TGA shows a weight loss of 0.75% up to 150°C. The DSC thermogram shows endotherms at 111, 192.4, and 211.5°C (onset). PLM showed irregularly shaped birefringent particles. KF was 3.02%, indicating that Form 3 is a monohydrate. The discrepancy between KF and TGA weight loss is likely due to insufficient time given for the sample to equilibrate at room temperature prior to TGA analysis. [Figure 8A]Figure 8A illustrates the characterization of Form 4. XRPD showed that Form 4 was crystalline. [Figure 8B] Figure 8B illustrates the characterization of Form 4. TGA showed a 6.4% weight loss up to 150°C. DSC thermogram showed an endotherm at 84.9°C corresponding to the TGA weight loss and a melting event at 209.8°C (onset temperature). PLM showed irregularly shaped birefringent particles. [Figure 9A] Figure 9A is the characterization of Form 5. XRPD showed that Form 5 was crystalline. [Figure 9B] Figure 9B illustrates the characterization of Form 4. TGA showed a two-step weight loss of 12.1% up to 150°C. DSC thermogram showed an endotherm at 80.6°C corresponding to the TGA weight loss, followed by a recrystallization event at 179.9°C and a simultaneous melt at 207.5°C (onset temperature). PLM showed irregularly shaped birefringent particles. KF was 2.26%, indicating that Form 5 is a mono-DCM solvate. [Figure 10] Figures 10A, 10B, and 10C are illustrative of the characterization of the amorphous material from rotary evaporation. Baseline characterization was performed for the amorphous form. XRPD showed the material to be amorphous, and the DSC thermogram showed a glass transition at 46.9 °C, followed by a recrystallization event at 124.3 °C, and melting with an onset of 200.7 °C. TGA showed a weight loss of 5.8% up to 175 °C. [Figure 11] Figure 11 is an illustration of the characterization of a slurry conversion experiment from an amorphous form. The XRPD pattern of a room temperature slurry conversion experiment using amorphous material is shown. [Figure 12] 12A and 12B are illustrations of XRPD patterns of temperature cycling experiments using amorphous material. [Figure 13] FIG. 13 illustrates the XRPD pattern of the product obtained from a filtered anti-solvent addition experiment using crystalline starting material. [Figure 14]14A and 14B are illustrations of XRPD patterns of products obtained from antisolvent addition experiments using crystalline starting material. [Figure 15] 15A and 15B are illustrative XRPD patterns of the product obtained from the slurry in room temperature experiments using crystalline starting material. [Figure 16] 16A and 16B are illustrations of the XRPD patterns of the products obtained from slurry conversion experiments at 60° C. using crystalline starting material. [Figure 17] FIG. 17 is an illustration of the XRPD pattern of the product from the solid vapor diffusion experiment. [Figure 18] FIG. 18 is an illustration of the XRPD pattern of the product from the liquid vapor diffusion experiment. [Figure 19] FIG. 19 is an illustration of the XRPD pattern of the product from the filtered slow cooling experiment. [Figure 20] Figures 20A and 20B are illustrations of the XRPD patterns of the products from the slow cooling experiments. [Figure 21] FIG. 21 is an illustration of the XRPD pattern of the product from the slow evaporation experiment. [Figure 22] 22A and 22B are illustrations of the XRPD patterns of the products from the temperature cycling experiments. [Figure 23] Figure 23A is the DVS of Compound I, Form 1. Form 1 showed a moisture content of 0.67% at 80% RH by DVS, indicating the sample was slightly hygroscopic. [Figure 23] Figure 23B shows that no morphological changes were observed after DVS. KF showed a moisture content of 1.02%. [Figure 24] FIG. 24 is an XRPD of Compound I, Form 1, showing 2θ peak characterization. [Figure 25] FIG. 25 is an XRPD of Compound I, Form 2, showing 2θ peak characterization. [Figure 26] FIG. 26 is an XRPD of Compound I, Form 3, showing 2θ peak characterization. [Figure 27] FIG. 27 is an XRPD of Compound I, Form 4, showing 2θ peak characterization. [Figure 28] FIG. 28 is an XRPD of Compound I, Form 5, showing 2θ peak characterization. [Figure 29] FIG. 29 is an XRPD of Compound I, Form 8, showing 2θ peak characterization. [Figure 30] FIG. 30 is the DSC and TGA thermograms of Compound I, Form 8. [Figure 31] FIG. 31 is the DVS of compound I, type 8. [Figure 32] FIG. 32 is a PLM of compound I, type 8. [Figure 33] FIG. 33 shows the absolute structure of Compound I. [Figure 34] FIG. 34 shows the XRPD of Form 1, Form 8, and the material obtained by preparation. DETAILED DESCRIPTION OF THE INVENTION

[0108] The features and other details of the present disclosure will now be more particularly described. Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read as understood by those skilled in the art in light of the remainder of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0109] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings provided below.

[0110] As used herein, "Compound I" refers to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.

[0111] As used herein, "Compound I(a)" refers to N-(3-chloro-4-fluorophenyl)-4-((2s,3aR,5r,6aS)-5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.

[0112] As used herein, "API" refers to the active pharmaceutical ingredient, e.g., Compound I.

[0113] Unless the context requires otherwise, throughout this specification and claims, words like "comprise," "comprising," and the like are to be interpreted in an open and inclusive sense; words like "a," "an," and the like are to be construed to mean at least one, and not limited to only one; and the term "about" is to be interpreted to mean plus or minus 10%. Terms not specifically defined herein should be given the meaning given to them by one of ordinary skill in the art in light of this disclosure and the context.

[0114] In certain cases, the substituents shown may contribute to optical or stereoisomerism. Compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of each other are termed "diastereomers," and those that are non-superimposable mirror images of each other are termed "enantiomers." A single diastereomeric compound may form an aspect of the present disclosure. More specifically, solid state forms of a single diastereomeric compound may form an aspect of the present disclosure.

[0115] When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are designated as (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: 657-668) or can be characterized by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory [i.e., (+)- or (-)-isomer, respectively]. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0116] The compounds of the present disclosure may exist as stereoisomers. The term "stereoisomer," as used herein, consists of all enantiomers or diastereomers. As noted, these compounds may be designated by the symbols "(+)," "(-)," "R," or "S," depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, although the skilled artisan will recognize that structures may imply chiral centers.

[0117] The compounds of the present disclosure may contain one or more double bonds and, therefore, may exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.

[0118] [ka] means a bond which may be a single bond, a double bond, or a triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be designated as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. Compounds of the present disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be designated "cis" or "trans," where the term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are disposed on both the same and opposite sides of the plane of the ring are designated "cis / trans."

[0119] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing an asymmetric or stereogenic center, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These methods of resolution are exemplified by (1) coupling of the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting mixture of diastereomers, and liberation of the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; (3) direct separation of a mixture of optical antipodes on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms an unbalanced mixture of stereoisomers while creating a new stereocenter or while converting a pre-existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0120] The compounds of the present disclosure may contain one or more double bonds and, therefore, may exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.

[0121] [ka] means a bond which may be a single bond, a double bond, or a triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be designated as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. Compounds of the present disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be designated "cis" or "trans," where the term "cis" refers to substituents on the same side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are disposed on both the same and opposite sides of the plane of the ring are designated "cis / trans."

[0122] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, farm animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment of HBV infection is desired.

[0123] The term "modulation" includes antagonism (eg, inhibition), agonism, partial antagonism, and / or partial agonism.

[0124] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal, or a human, as appropriate. For human administration, preparations must meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0125] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, compatible with pharmaceutical administration. The use of such media and agents with pharmaceutical active substances is well known in the art. The compositions may also include other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0126] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0127] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound used in the composition. Compounds included in the present composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, etc. phosphate), isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the present compositions that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present compositions that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0128] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of a compound of interest that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the 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 being treated.

[0129] References to "treat," "treating," or "treatment" should be understood to include (1) delaying or reducing the likelihood of the onset of clinical symptoms of a developing disease or disorder in a subject who may be afflicted with the disease or disorder but who has not yet experienced or developed clinical or subclinical symptoms of the disease or disorder; (2) inhibiting the disease or disorder, i.e., halting, alleviating, or delaying the progression of the disease or disorder, or its recurrence (in the case of maintenance therapy), or at least one clinical or subclinical symptom thereof; or (3) alleviating or attenuating the disease or disorder, i.e., causing regression of at least one condition of the disease, disorder, or its clinical or subclinical symptom. The term "treating" includes any effect, e.g., alleviating, reducing, modulating, or eliminating, mediated by disruption of HBV core protein assembly that results in amelioration of disease. "Disruption" includes inhibition of HBV viral assembly and infection. The crystalline compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, and it is intended that the present disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0130] The present disclosure also includes isotopically labeled compounds of the present disclosure identical to those enumerated herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0131] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavy isotopes, such as H, may confer some therapeutic advantage resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those disclosed in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0132] The term "prodrug" refers to a compound that is converted in vivo to provide the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The conversion may occur at various sites (e.g., in the intestinal lumen or during intestinal transit, in the blood, or in the liver) and by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative metabolism, or reductive metabolism). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0133] In certain embodiments of the present disclosure, the compounds disclosed herein are "stereochemically pure." A stereochemically pure compound has a level of stereochemical purity recognized by those of skill in the art as "pure." Of course, this level of purity can be less than 100%. In certain embodiments, "stereochemically pure" designates a compound that is substantially free of alternative isomers, i.e., at least about 85% or more free of alternative isomers. In certain embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% free of other isomers.

[0134] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of substituents around the stereogenic carbon atom, although one of ordinary skill in the art will recognize that the structure may imply a chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the nomenclature "(±)", although one of ordinary skill in the art will recognize that the structure may imply a chiral center.

[0135] At various places throughout this specification, values ​​are disclosed in groups or ranges, and it is specifically intended that the description include all individual subcombinations of the members of such groups and ranges, and any combination of the various endpoints of such groups or ranges. For example, integers in the range of 0 to 40 are specifically intended to 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 individually; and integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 individually.

[0136] The use of any and all examples or exemplary language herein, such as "such as," "including," or "for example," is intended merely to better illustrate the present teachings and does not pose a limitation on the scope of the invention unless claimed.

[0137] A "crystalline form" is a solid material in which the components of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice that extends in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms, and / or hydrated crystalline forms.

[0138] "Polymorphism" is the ability of a solid material to exist in more than one crystalline form.

[0139] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. An amorphous solid is a substance in which the molecules are arranged in a random manner, without a well-defined arrangement, e.g., molecular packing, and without long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peaks 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 amorphous solids.

[0140] A "hydrate" is a compound that exists in a solid composition with water molecules. The composition may contain water in a stoichiometric amount, such as a monohydrate or dihydrate, or may contain water in random amounts. As used herein, the term "hydrate" refers to a solid form; i.e., a compound in an aqueous solution may be hydrated but not a hydrate as the term is used herein. Hydrates may be crystalline, in which both the compound and water form part of the crystal lattice.

[0141] A "solvate" is a composition similar to a hydrate, except that a solvent other than water is substituted for water. For example, methanol or ethanol can form "alcoholates," which can also be stoichiometric or non-stoichiometric. As the term is used herein, "solvate" refers to a solid form; i.e., a compound in solution in a solvent may be solvated but is not a solvate as the term is used herein. Solvates may be crystalline, in which both the compound and the solvent form part of the crystal lattice.

[0142] "Anhydrous" means that the solid form of a compound does not have water incorporated into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystalline structure. Those skilled in the art will be aware of techniques that can be used to quantify the amount of water associated with a solid. For example, water content can be determined by Karl Fischer titration or thermogravimetric analysis (TGA). Preferably, the anhydrous solid form of a compound contains less than about 2% by weight of water, e.g., about 1.5%, less than about 1%, e.g., about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or less than about 0.01% by weight.

[0143] "Unsolvated" or "nonsolvated" means that the solid form of a compound does not have solvent incorporated into its structure. For example, an unsolvated crystalline form does not have solvent forming part of the crystalline structure. Those skilled in the art will be aware of techniques that can quantify the amount of solvent associated with a solid. For example, solvent content can be determined by gas chromatography (GC). Suitably, an unsolvated or nonsolvated solid form of a compound contains less than about 2% by weight of solvent, e.g., about 1.5%, less than about 1%, e.g., about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, or less than about 0.01% by weight.

[0144] As used herein, when a composition is said to "consist essentially of" a particular component, the composition preferably comprises at least 70 wt% of the component, preferably at least 80 wt% of the component, preferably at least 90 wt% of the component, preferably at least 95 wt% of the component, and most preferably at least 99 wt% of the component. Preferably, a composition said to "consist essentially of" a particular component consists of the component except for one or more minor components.

[0145] The phrase "substantially as shown in the figure" refers to an X-ray powder diffraction pattern or DSC thermogram in which 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 are apparent in the figure.

[0146] The word "FIG." is an abbreviation for Figure.

[0147] compound In general, the compounds of the invention may be prepared, isolated, or obtained by any method apparent to one skilled in the art. Exemplary methods of preparation are illustrated by the following schemes and descriptions.

[0148] Example 55 of PCT / US2021 / 028323, which is incorporated herein by reference, provides one embodiment for preparing compound I: N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.

[0149] Example 55, PCT'323

[0150] [ka]

[0151] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgBr (3 M in DEE, 0.59 mL, 1.78 mmol) was added slowly to a stirred solution of ethyl 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)acetate (0.5 g, 0.89 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by CombiFlash column chromatography followed by preparative HPLC to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.501 g, 61%) as an off-white solid. TLC: 5% MeOH (R f :0.4); 1 H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.40 (t, J = 9.6 Hz, 1H), 5.52 (s, 1H), 5.23 (s, 1H), 4.53 (s, 1H), 3.75-3.70 (m, 5H), 3.67 (s, 3H), 3.26-3.20 (m, 1H), 2.50-2.44 (m, 2H), 2.20-2.06 (m, 4H), 1.90-1.80 (m, 4H), 1.13 (s, 6H) ppm.C27 H 33 MS calculated for ClFN5O4: 545.2; found: 546.3 [M+1] + .

[0152] The product of Example 55 is referred to herein as Compound I:

[0153] [ka] It is also sometimes called.

[0154] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Compound I). Alternative naming conventions may result in different chemical names.

[0155] As will be appreciated by those skilled in the art, Compound I is a mixture of diastereomers. Thus, stereomerically enriched or stereomerically purified compounds encompassed by the phrase "stereochemically pure" as used hereinabove may form an aspect of the present disclosure. Diastereomers of Compound I include:

[0156] [ka] Includes.

[0157] As described herein, the present disclosure relates to novel solid-state forms of Compound I, as well as novel solid-state forms of each of Compounds Ia, Ib, Ic, and Id.

[0158] Suitably, the present disclosure relates to novel solid state forms of compound I(a).

[0159] Pharmaceutical compositions and kits In another aspect, the present disclosure provides novel pharmaceutical compositions comprising a crystalline form of Compound I, or a mixture of a crystalline form of Compound I and a pharmaceutically acceptable carrier, diluent, or excipient. Preferably, the pharmaceutical composition comprises a crystalline form of Compound I, preferably a crystalline form of Compound I(a), and a pharmaceutically acceptable carrier, diluent, or excipient. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0160] Suitably, the pharmaceutical composition comprises a crystalline form of Compound I(a) or a mixture of a crystalline form of Compound I(a) and a pharmaceutically acceptable carrier, diluent, or excipient.

[0161] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable mode of administration in any given case will depend on the severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compounds can be formulated as a unit dose and / or can be formulated for oral or subcutaneous administration.

[0162] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, e.g., solid, semisolid, or liquid forms, which contain one or more compounds of the present disclosure as an active ingredient in admixture with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. The active ingredient can be compounded with conventional non-toxic pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active ingredient is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of a disease.

[0163] When preparing solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0164] In solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, and the like), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerin; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) sorbitols, such as acetyl alcohol. (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, for example.

[0165] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets can be produced by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets, as well as other solid dosage forms such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation arts.

[0166] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0167] Suspensions may contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0168] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0169] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0170] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0171] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0172] Alternatively, the compositions and compounds of the present disclosure can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can be used to minimize exposure of the drug to shear, which can result in degradation of the compounds contained in the composition. Typically, aqueous aerosols are produced by formulating an aqueous solution or suspension of the composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0173] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0174] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0175] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising Compound I and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluids at a specific pH. The small intestine is the portion of the gastrointestinal tract (gastrointestinal tract) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.

[0176] The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5. Thus, the enteric material is not soluble until the pH is, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate, and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, and copal collophorium. collophorium), as well as some commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric).

[0177] The solubility of each of the above materials is known or readily determinable in vitro. While the foregoing is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of this disclosure.

[0178] Advantageously, the present disclosure also provides kits for use by consumers in need of treatment for, for example, HBV infection. Such kits include suitable dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, mitigate, or prevent HBV infection. The instructions would instruct the consumer or medical professional to administer the dosage forms according to modes of administration known to those skilled in the art. Such kits can be advantageously 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 widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). 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 packaged. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil with the side of the plastic foil opposite the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, forming holes in the sheet at the locations of the recesses. The tablets or capsules can then be removed through said holes.

[0179] For example, it may be desirable to provide a memory aid in the kit in the form of numbers next to the tablets or capsules, the numbers corresponding to the days of the regimen on which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, e.g., "Week 1, Monday, Tuesday, etc. Week 2, Monday, Tuesday, etc." Other variations of memory aids will be readily apparent. A "daily dose" can be one tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

[0180] Treatment methods In a further aspect, a method for treating hepatitis B infection in a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a crystalline form of Compound I, preferably a crystalline form of Compound I(a). In another embodiment, a method for treating hepatitis B infection in a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound I, preferably a crystalline form of Compound I(a), and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 1 or Form 8. Preferably, the crystalline form is Form 8.

[0181] In another aspect, there is provided a crystalline form of Compound I, preferably a crystalline form of Compound I(a), for use in treating HBV infection. In one embodiment, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0182] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of Compound I (preferably a crystalline form of Compound I(a)) and a pharmaceutically acceptable carrier, diluent, or excipient for use in treating HBV infection. In one embodiment, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0183] In another aspect, there is provided the use of a crystalline form of Compound I (preferably a crystalline form of Compound I(a)) or a pharmaceutical composition comprising a crystalline form of Compound I (preferably a crystalline form of Compound I(a)) for the treatment of HBV infection. In one embodiment, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0184] In another aspect, there is provided the use of a crystalline form of Compound I (preferably a crystalline form of Compound I(a)) or a pharmaceutical composition comprising a crystalline form of Compound I (preferably a crystalline form of Compound I(a)) in the manufacture of a medicament for treating HBV infection. In one embodiment, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0185] The pharmaceutical compositions according to the invention can be administered orally, sublingually / buccally, rectally, parenterally, intravenously, intramuscularly, subcutaneously, intraventricularly, transdermally, topically, by inhalation, and / or intranasally. In an advantageous embodiment, the pharmaceutical compositions according to the invention are administered orally.

[0186] When used according to this embodiment, suitable dosages are expected to vary depending, for example, on the particular crystalline form of Compound I used, the mode of administration, and the nature and severity of the infection being treated, as well as the particular infection being treated, and are within the purview of the treating physician. Typically, the prescribed dosage may range from about 0.01 to about 20 mg / kg body weight. In some cases, the dosage of the compound may be less than 10 mg / kg body weight. In other cases, the dosage may be less than 5 mg / kg body weight. In still other cases, the dosage may range from about 0.01 to about 3 mg / kg body weight.

[0187] The dose can conveniently be administered once daily or in divided doses, for example, twice daily or up to four times daily, or in sustained release form. In a convenient embodiment, the pharmaceutical composition is administered daily, such as once daily. In an embodiment, a therapeutically effective amount of the crystalline form of Compound I (preferably the crystalline form of Compound I(a)) is about 5-1000 mg (e.g., about 25-300 mg) administered to a subject daily.

[0188] In embodiments, there is provided a method of treating HBV, comprising administering a pharmaceutical composition described herein, wherein the composition is orally administered with a meal (fed) or any time between meals (fasted). Advantageously, the composition is orally administered to a subject in a fasting state.

[0189] In a preferred embodiment, the unit dosage form of the pharmaceutical composition contains about 1 mg to about 500 mg (e.g., about 2 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg, about 10 mg, or about 50 mg) of the crystalline form of Compound I (preferably the crystalline form of Compound I(a)). In a most preferred embodiment, the unit dosage form of the pharmaceutical composition is a tablet, and the tablet contains about 1 mg to about 500 mg (e.g., about 2 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg, about 10 mg, or about 50 mg) of the crystalline form of Compound I (preferably the crystalline form of Compound I(a)).

[0190] In an embodiment, a subject in need of treatment with a crystalline form of Compound I according to the invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the invention is treatment naive and HBeAg (Hepatitis B e-antigen) positive prior to treatment. In an embodiment, a subject in need of treatment with a crystalline form of Compound I according to the invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the invention is virologically suppressed and HBeAg positive prior to treatment. In an embodiment, a subject in need of treatment with a crystalline form of Compound I according to the invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the invention is virologically suppressed and HBeAg negative prior to treatment.

[0191] In embodiments, a subject in need of treatment with a crystalline form of Compound I according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention has been virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment. In embodiments, a subject in need of treatment with a crystalline form of Compound I or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention has been virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment, and the subject has been previously treated with a nucleoside (nucleotide) inhibitor. In embodiments, a subject in need of treatment with a crystalline form of Compound I or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention has been previously treated with a nucleoside (nucleotide) inhibitor for at least 2 months prior to treatment with a composition of the present invention.

[0192] In embodiments, a crystalline form of Compound I of the present invention or a pharmaceutical composition comprising a crystalline form of Compound I of the present invention is administered to a subject for a treatment period of at least 12 weeks (e.g., at least 24 weeks, 28 weeks, 32 weeks, 40 weeks, 12 months, 18 months, 24 months, or 36 months). In alternative embodiments, a crystalline form of Compound I of the present invention or a pharmaceutical composition comprising a crystalline form of Compound I of the present invention is administered to a subject until the subject's HBeAg and / or HBsAg (hepatitis B surface antigen) levels are reduced. In embodiments, after at least 12 weeks of daily administration of a crystalline form of Compound I of the present invention or a pharmaceutical composition comprising a crystalline form of Compound I of the present invention, an HBeAg-positive subject experiences a sustained loss of <0.11 PEI units / mL. In embodiments, after at least 12 weeks of daily administration of a crystalline form of Compound I of the present invention or a pharmaceutical composition comprising a crystalline form of Compound I of the present invention, a subject experiences a reduction in HBsAg to ≦100 IU / mL. In embodiments, after daily administration of a crystalline form of Compound I of the present invention or a pharmaceutical composition comprising a crystalline form of Compound I of the present invention for at least 12 weeks, the subject experiences a reduction in HBV DNA or HBV RNA.

[0193] The compounds of the present disclosure can be administered by any conventional route, particularly enterally, topically, orally, nasally, for example, in the form of tablets or capsules, via suppositories, or parenterally, for example, in the form of an injectable solution or suspension for intravenous, intramuscular, subcutaneous, or intraperitoneal injection.Suitable formulations and pharmaceutical compositions include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any known, commercially available, or currently used in clinical practice.Therefore, the compounds can be formulated into a form suitable for oral, buccal, topical, parenteral, rectal, or transdermal administration, or for administration by inhalation or insufflation (oral or nasal).

[0194] For oral administration, the pharmaceutical compositions may take the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, including, but not limited to, one or more of the following: binders (e.g., pregelatinized 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); wetting agents (e.g., sodium lauryl sulfate); pH adjusters (e.g., adipic acid, tartaric acid, sodium bicarbonate, or potassium citrate); complexing agents (e.g., cyclodextrins, phosphates, phosphonates, polycarboxylates, and zeolites); and precipitation inhibitors (Eudragit, PEG, or PEI). Tablets may be coated by methods known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be provided as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid). The preparations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents as needed.

[0195] Preparations for oral administration may also be suitably formulated to give controlled or sustained release of the active compound over an extended period of time. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner known to those skilled in the art.

[0196] In an advantageous embodiment, the pharmaceutical composition is administered orally.

[0197] In an advantageous embodiment, the unit dosage form of the pharmaceutical composition is a tablet. Most advantageously, the pharmaceutical composition is an orally administered tablet.

[0198] The disclosed compounds can also be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Preparations for injection can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain additives such as suspending, stabilizing, and / or dispersing agents. Alternatively, the compounds can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds can also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides.

[0199] Suitably, the crystalline form of Compound (I) is the crystalline form of Compound (Ia). In one embodiment, the crystalline form of Compound I(a) is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0200] combination Also contemplated herein are methods and compositions comprising or administering a second active agent. For example, in addition to being infected with HBV, a subject or patient may also have comorbidities associated with HBV infection, i.e., diseases and other adverse health conditions associated with, exacerbated by, or caused by HBV infection. Contemplated herein are pharmaceutical compositions comprising the disclosed crystalline forms of Compound I of the present invention, or a crystalline form of Compound I of the present invention, in combination with at least one other agent previously shown to treat these HBV infection-related conditions.

[0201] In some cases, the disclosed compounds can be administered as part of a combination therapy in conjunction with one or more antiviral agents. Exemplary antiviral agents include nucleoside analogs, interferon alpha, and other assembly effectors, such as 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 for treating a patient suffering from a hepatitis B infection, comprising administering to the patient a first amount of a crystalline form of Compound I according to the present invention and a second amount of an antiviral agent, or other anti-HBV agent, such as a second amount of a second compound selected from the group consisting of: i. HBV capsid assembly promoter (e.g., GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as shown below)),

[0202] [ka] NVR 3-778, NVR1221 (by code); and N890 (shown below):

[0203] [ka] ii. Other core protein allosteric modulators (CpAMs), such as those disclosed in the following patent applications, which are incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and WO2014033170; iii. Nucleoside (nucleotide) analogs that interfere with viral polymerases, such as entecavir (Baraclude), lamivudine, (Epivir-HBV), telbivudine [Tyzeka, Sebivo], adefovir dipivoxil (Hepsera), tenofovir (Viread), tenofovir alafenamide (Vemlidy), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g., AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir):

[0204] [ka] and active site polymerase inhibitor nucleotides (ASPINs), such as those disclosed in WO2016099982; 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 amphiphilic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15, as shown below:

[0205] [ka] and BM601 shown below:

[0206] [ka] vi. Nucleocapsid formation or integrity disruptors, such as NZ-4 / W28F:

[0207] [ka] vii. cccDNA formation inhibitors, such as BSBI-25, CCC-0346, CCC-097 (shown below):

[0208] [ka] 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) (published at http: / / dx.doi.org / 10.1016 / j.intimp.2015.01.028); antiviral core protein mutants (such as Cp183-V124W and related mutants described in WO / 2013 / 010069 and WO2014 / 074906, each of which is incorporated by reference); ix. Inhibitors of HBx interaction, such as RNAi, antisense and nucleic acid-based polymers targeting HBV RNA, for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid-based polymers: (REP 2139-Ca); x. Immunostimulants, such as lymphotoxin beta agonists such as interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys® (peginterferon alpha 2a), pegylated IFN2b, IFN lambda 1a and PEGIFN lambda 1a, Wellferon, Roferon, Infergen, CBE11 and BS1; xi. Non-interferon immune enhancers such as thymosin alpha 1 (Zadaxin) and interleukin-7 (CYT107); xii. TLR-7 / 9 agonists such as GS-9620, CYT003, or resiquimod; xiii. Cyclophilin inhibitors such as NVP018, OCB-030, SCY-635, alisporivir, NIM811, and related cyclosporine analogues; xiv. Vaccines such as GS-4774, TG1050, and core antigen vaccines; xv. Second mitochondria-derived activator of caspases (SMAC) mimetics, such as birinapant and other IAP antagonists; xvi. Epigenetic modulators, such as KMT inhibitors (EZH1 / 2 inhibitors, G9a inhibitors, SETD7 inhibitors, 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; xvii. Kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM and ATR kinase inhibitors; xviii.STING agonists; xix. A drug selected from ribavirin, N-acetylcysteine, NOV-205 (BAM205), nitazoxanide (Alinia), tizoxanide, SB 9200 small molecule nucleic acid hybrid (SMNH), DV-601, arbidol, and an FXR agonist (such as GW 4064 and fexaramin); xx. Antibodies, therapeutic proteins, gene therapies, and biologics directed against viral components or interacting host proteins.

[0209] In some embodiments, the disclosure provides methods of treating hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed crystalline forms of Compound I and one or more other HBV agents, each selected from the group consisting of an HBV capsid assembly promoter, an HBF viral polymerase-interfering nucleoside, a viral entry inhibitor, an HBsAg secretion inhibitor, a nucleocapsid formation disruptor, a cccDNA formation inhibitor, an antiviral core protein mutant, an HBc-directed transbody, an RNAi targeting HBV RNA, an immunostimulant, a TLR-7 / 9 agonist, a cyclophilin inhibitor, an HBV vaccine, a SMAC mimetic, an epigenetic modulator, a kinase inhibitor, and a STING agonist. In some embodiments, the disclosure provides methods of treating hepatitis B infection in a patient in need thereof, comprising administering an amount of the disclosed crystalline form of Compound I and administering another HBV capsid assembly promoter. Preferably, the crystalline form is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8, more preferably Form 8.

[0210] 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 as, greater than, or less than the effective amount of each compound administered as a monotherapy. The therapeutically effective amounts of the disclosed compound and the antiviral agent can be co-administered to a subject, i.e., administered simultaneously or separately in any given order, by the same or different routes of administration. In some cases, it may be advantageous to start administering the disclosed compound first, for example, one or more days or weeks before starting administration of the antiviral agent. Furthermore, additional drugs may be given in conjunction with the above-mentioned combination therapy.

[0211] In a preferred embodiment, the method further comprises co-administering a therapeutically effective amount of a nucleoside (nucleotide) inhibitor to the subject. Advantageously, the nucleoside (nucleotide) inhibitor is selected from entecavir, tenofovir, tenofovir alafenamide, and tenofovir disoproxil fumarate. In a preferred embodiment, the nucleoside (nucleotide) inhibitor is administered orally. In a preferred embodiment, the nucleoside (nucleotide) inhibitor is administered daily, such as once daily.

[0212] In a preferred embodiment, the method further comprises co-administering a therapeutically effective amount of pegylated interferon alpha, e.g., pegylated interferon alpha 2a, to the subject. In a preferred embodiment, the pegylated interferon alpha is administered by subcutaneous injection. In a preferred embodiment, the pegylated interferon alpha is administered weekly, e.g., once weekly. In a preferred embodiment, the therapeutically effective amount of pegylated interferon alpha is about 100-300 μg, e.g., about 180 μg.

[0213] In a preferred embodiment, the method further comprises co-administering a therapeutically effective amount of an HBV siRNA inhibitor to the subject. In a preferred embodiment, the siRNA inhibitor is administered by subcutaneous injection. In a preferred embodiment, the siRNA inhibitor is administered once every 4 to 12 weeks, for example, once every 8 weeks. In a preferred embodiment, the therapeutically effective amount of the siRNA inhibitor is about 20 to 100 mg, for example, about 60 mg.

[0214] In a preferred embodiment, the method further comprises co-administering a therapeutically effective amount of ASPIN to the subject. In a preferred embodiment, ASPIN is administered orally. In a preferred embodiment, ASPIN is administered daily, such as once daily. In a preferred embodiment, the therapeutically effective amount of ASPIN is about 10 to 100 mg, for example, about 25 mg or about 50 mg.

[0215] In embodiments, there is provided a method of treating hepatitis B in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound I according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention, and co-administering to the subject a therapeutically effective amount of a nucleoside (nucleotide) inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of pegylated interferon alpha (such as pegylated interferon alpha 2a).

[0216] In embodiments, there is provided a method of treating hepatitis B in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound I according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention, and co-administering to the subject a therapeutically effective amount of a nucleoside (nucleotide) inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of an HBV siRNA inhibitor.

[0217] In embodiments, there is provided a method of treating hepatitis B in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound I according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention, and co-administering to the subject a therapeutically effective amount of a nucleoside (nucleotide) inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of ASPIN.

[0218] Suitably, the crystalline form of Compound (I) is the crystalline form of Compound (Ia). In one embodiment, the crystalline form of Compound I(a) is Form 1, Form 2, Form 3, Form 4, Form 5, or Form 8. In one embodiment, the crystalline form is Form 8. Preferably, the crystalline form is Form 1 or Form 8.

[0219] Process for preparing type 8 In one embodiment, a process for preparing a crystalline form of Compound I(a) is provided, wherein the crystalline form is Form 8.

[0220] In one embodiment, the process for preparing Form 8 comprises: a) providing a solution of compound I(a) in a solvent system; b) cooling the solution from step a) to a temperature below 20°C; c) stirring the mixture from step b); d) optionally isolating the solid formed from step c); and e) optionally drying the solid isolated from step d).

[0221] In one embodiment, the solvent system comprises a solvent in which compound I(a) has a solubility of at least 0.1 mg / mL, e.g., at least 1 mg / mL or at least 2 mg / mL, at room temperature. Preferably, the solvent system comprises a solvent in which compound I(a) has a solubility of less than 200 mg / mL, e.g., less than 100 mg / mL, less than 50 mg / mL, less than 20 mg / mL, or less than 10 mg / mL, at room temperature. Preferably, the solvent system comprises ethyl acetate, methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether, and / or water. Preferably, the solvent system comprises ethyl acetate. Preferably, the solvent system consists essentially of ethyl acetate. Preferably, the solvent system consists of ethyl acetate.

[0222] In one embodiment, the cooling in step b) is to a temperature below 20° C., such as below 15° C. or 10° C. Suitably the temperature is between 0 and 15° C., such as between 5 and 10° C.

[0223] In one embodiment, the stirring in step c) is carried out for at least 1 hour, such as at least 2, 5, or 10 hours. Suitably, the stirring in step c) is carried out for 8 to 30 hours, such as 10 to 24 hours.

[0224] Suitably, step d) comprises isolating the solid by filtration.

[0225] Suitably, step e) comprises drying the solid at a temperature above room temperature, for example above 30° C. or above 40° C. Suitably, step e) comprises drying the solid at a temperature of about 50° C.

[0226] The invention is illustrated below by the following non-limiting examples. [Example]

[0227] The following abbreviations are used herein: ACN: acetonitrile API: Active ingredient a w :Water activity DCM: dichloromethane DMF: dimethylformamide DMSO: dimethyl sulfoxide DSC: Differential scanning calorimetry eq: equivalent EtOAc: ethyl acetate h: time KF: Karl Fischer titration IPA: 2-propanol MeOH: Methanol MIBK: Methyl isobutyl ketone MTBE: t-butyl ether NMT: ~ or less PLM: Polarized Light Microscope PXRD: Powder X-ray diffraction RT: Room temperature (about 22℃) TGA: Thermogravimetric analysis THF: tetrahydrofuran Vol: Capacity XRPD: X-ray powder diffraction

[0228] The procedures disclosed herein can be carried out in multiple ways based on the teachings contained herein and synthetic procedures known in the art. In the description of synthetic methods below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental time, and work-up procedures, can be selected to be standard conditions for the reaction unless otherwise indicated. Those skilled in the art of organic synthesis will understand that the functionality present on various portions of the molecule must be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. Starting materials in the examples are commercially available or readily prepared by standard methods from known materials. For example, at least some compounds identified as intermediates as part of the synthetic schemes disclosed herein are contemplated as compounds of the present invention.

[0229] As previously described, the present disclosure relates to alternative and novel methods for synthesizing the compounds disclosed in PCT / US2021 / 028323 (PCT'323), which is incorporated herein by reference in its entirety.

[0230] In the procedures described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio, or carboxyl groups) to prevent their undesired participation in the reactions. The incorporation of such groups and the methods necessary for their introduction and removal are known to those skilled in the art (see, for example, Greene, Wuts, Protective Groups in Organic Synthesis. 4th Ed. (2007)). The deprotection step may be the final step of the synthesis, such that removal of the protecting group yields the compound of the disclosed process. The starting materials used in the schemes below can be purchased, prepared by methods described in the chemical literature, or prepared by adapting methods known to those skilled in the art. The order in which the steps are performed may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0231] Certain reactions of the disclosed processes may be carried out in the presence of a base. Examples of such bases may include, but are not limited to, carbonates and hydrates thereof, such as LiCO, NaCO, KCO, RbCO, CsCO, MgCO, CaCO, SrCO, BaCO, hydroxides and hydrates thereof, such as LiOH, NaOH, KOH, Ca(OH), NHOH, and amines, such as methylamine, trimethylamine, diisopropylethylamine, morpholine, and morpholine derivatives.

[0232] Certain reactions of the disclosed processes, including coupling an amino moiety with a carboxylic acid moiety to form an amide, may be carried out in the presence of an activator. Examples of such activators include, but are not limited to, carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and carbonyldiimidazole (CDI); and triazoles such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt). Other activators may include, but are not limited to, HBTU, HATU, HCTU, TBTU, and PyBOP.

[0233] Analysis methodology XRPD XRPD is a Panalytical X'Pert 3 Powder XRPD was used and run on a Si zero background holder. 2θ positions were calibrated against Panalytical Si reference standard discs. The parameters used for both crystalline and amorphous material are listed in Table 12.

[0234] [Table 12]

[0235] TGA and DSC: TGA data was collected using a TA Discovery 550 TGA from TA Instrument. The TGA was calibrated using a nickel reference standard. DSC was performed using a TA D2500 DSC from TA Instrument. The DSC was calibrated using an indium reference standard. The detailed parameters used are listed in Table 13.

[0236] [Table 13]

[0237] PLM Polarized light micrographs were captured at room temperature with a Nikon DS-Fi2 upright microscope.

[0238] KF To determine the moisture content of the samples, Karl Fischer titrations (KF) were collected on a C30S coulometric KF titrator using a DO308 oven (Mettler Toledo). To validate the coulometric KF titrator using a DO308 oven, a 5.55% oven moisture standard was used as the standard.

[0239] HPLC method The HPLC method conditions used to measure the solubility and stability of the samples are summarized in Table 14.

[0240] [Table 14] [Example 1]

[0241] Synthesis of Compound I Example 55 of PCT / US2021 / 028323, which is incorporated herein by reference, discloses the racemic compound Compound I: N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide:

[0242] [ka] One embodiment is provided for preparing

[0243] General Procedure for Alkylation, Method A To a stirred solution of Ar-OH (1 equiv.) and halo compound (2 equiv.) in acetonitrile / DMF (4 mL / mmol) was added K2CO3 (2 equiv.) and KI (0.5 equiv.). The reaction mixture was stirred at 60-80 °C for 1216 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography or preparative HPLC to give the desired compound.

[0244] General Procedure for Alkylation, Method B To a stirred solution of Ar-OH (1 equiv.) and halo compound (2 equiv.) in DMF / ACN (6 mL / mmol) was added Cs2CO3 (2.5 equiv.). The reaction mixture was stirred at room temperature / 60 °C for 2-4 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography or preparative HPLC to give the desired compound.

[0245] [ka]

[0246] 1-Methyl-3-nitro-1H-pyrazole. NaOtBu (19.11 g, 199.1 mmol) was added to a stirred solution of 3-nitro-1H-pyrazole (15 g, 132.7 mmol) in DMF (150 mL) at 0° C., and the reaction was stirred for 20 minutes. Then, MeI (9.91 mL, 159.24 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 1-methyl-3-nitro-1H-pyrazole (10 g, 59%) as an off-white solid. TLC: 20% EtOAc / hexane (R f :0.2). 1 H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H) ppm.

[0247] [ka]

[0248] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. LDA (2 M in THF, 60 mL, 120 mmol) was added dropwise to a stirred solution of methyl-3-nitro-1H-pyrazole (10.16 g, 80 mmol) in dry THF (100 mL) under an inert atmosphere at −78° C., and the reaction mixture was stirred for 2 hours. To this was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (3 g, 8 mmol) in THF at −78° C. The resulting reaction mixture was stirred at −78° C. for 1 hour. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2 g, 50%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3). 1 H-NMR (DMSO-d6, 400 MHz): δ 10.23 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.66 (s, 1H), 7.59-7.55 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 6.93 (s, 1H), 5.60 (s, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 3.29-3.24 (m, 1H), 2.51-2.49 (m, 2H), 2.30-2.24 (m, 2H), 2.13-2.07 (m, 2H), 1.94-1.85 (m, 4H) ppm;C 23 H 24MS calculated for ClFN6O4: 502.2; found: 503.3 [M+1] + .

[0249] [ka]

[0250] 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. 10% Pd / C (0.5 g) and NaBH4 (1.06 g, 27.88 mmol) were added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (2 g, 3.98 mmol) in MeOH (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1.5 g, 80%) as an off-white solid. TLC: 10% MeOH / DCM (R f :0.1). 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 7.95 (d, J = 4.4 Hz, 1H), 7.76 (s, 1H), 7.58-7.54 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 6.62-5.57 (br s, 2H), 5.39 (s, 1H), 5.17 (s, 1H), 3.69 (s, 6H), 3.32-3.31 (m, 1H, complex), 2.50-2.32 (m, 2H, complex), 2.29-2.11 (m, 4H), 1.85-1.83 (m, 4H) ppm; C 23 H 26 MS calculated value of ClFN6O2: 472.2; measured value: 471.2[M-1] - .

[0251]

change

[0252] 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. Selectfluor (0.149 g, 0.42 mmol) and DIPEA (0.147 mL, 0.84 mmol) were added to a stirred solution of 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.2 g, 0.42 mmol) in ACN (5 mL). The reaction mixture was stirred at 100° C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.02 g, 10%) as an off-white solid. TLC: 10% MeOH (R) in DCM f :0.3). 1 H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H), 7.63 (s, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J = 9.6 Hz, 1H), 5.21 (s, 1H), 4.47 (s, 2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.30-3.14 (m, 1H), 2.50-2.40 (m, 2H, combined), 2.23-2.16 (m, 2H), 2.07-2.04 (m, 2H), 1.96-1.83 (m, 4H).C 23 H 25 MS calculated for ClF2N6O2: 490.2; found: 473.1 [M-H2O+1] + .

[0253] [ka]

[0254] Methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate. n-BuLi (1.19 g, 18.6 mmol) was added to a stirred solution of methyl propiolate (1.56 g, 18.6 mmol) in dry THF (40 mL) at −78° C. under an inert atmosphere, and the reaction mixture was stirred for 30 minutes. To this was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (1 g, 2.66 mmol) in THF at −78° C. The resulting reaction mixture was stirred at −78° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate, an off-white solid, as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.3); 1 H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.55 (m, 1H), 7.40 (t, J = 8.8 Hz, 1H), 5.79 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.28-3.23 (m, 1H), 2.58-2.54 (m, 2H), 2.09-2.06 (m, 4H), 1.80-1.76 (m, 4H) ppm.C 23 H 23MS calculated for ClFN3O4: 459.1; found: 460.2 [M+1] + .

[0255] [ka]

[0256] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. TEA (2 g, 19.82 mmol) and 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate (1.3 g, 2.83 mmol) were added to a stirred solution of methylhydrazine sulfate (2.85 g, 19.82 mmol) in EtOH (20 mL). The reaction mixture was stirred at 50° C. for 24 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.65 g, 49%) as a white solid. TLC: 8% MeOH / DCM (R f :0.2); 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 4.4 Hz, 1H), 7.64 (s, 1H), 7.61-7.55 (m, 1H), 7.39 (t, J = 8.8 Hz, 1H), 5.28 (s, 1H), 5.13 (s, 1H), 3.66 (s, 6H), 3.38-3.18 (m, 1H, combined), 2.60-2.38 (m, 2H, combined), 2.20-2.01 (m, 4H), 1.91-1.75 (m, 4H) ppm.C 23 H 25 MS calculated for ClFN5O3: 473.2; found: 473.9 [M+1] + .

[0257] [ka]

[0258] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-isopropoxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized by alkylation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide using Method A. 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.99-7.94 (m, 1H), 7.64 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 5.47 (s, 1H), 5.20 (s, 1H), 4.61-4.54 (m, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.29-3.18 (m, 1H), 2.48-2.39 (m, 2H), 2.20-2.04 (m, 4H), 1.90-1.78 (m, 4H), 1.21 (d, J = 6.4 Hz, 6H) ppm; TLC: 10% MeOH / DCM (R f : 0.3);C 26 H 31 MS calculated value of ClFN5O3: 515.2; measured value: 516.1[M+1] + .

[0259]

change

[0260] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgBr (3 M in DEE, 0.59 mL, 1.78 mmol) was added slowly to a stirred solution of ethyl 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)acetate (0.5 g, 0.89 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by CombiFlash column chromatography followed by preparative HPLC to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.501 g, 61%) as an off-white solid. TLC: 5% MeOH (R f :0.4); 1 H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.40 (t, J = 9.6 Hz, 1H), 5.52 (s, 1H), 5.23 (s, 1H), 4.53 (s, 1H), 3.75-3.70 (m, 5H), 3.67 (s, 3H), 3.26-3.20 (m, 1H), 2.50-2.44 (m, 2H), 2.20-2.06 (m, 4H), 1.90-1.80 (m, 4H), 1.13 (s, 6H) ppm.C27 H 33 MS calculated for ClFN5O4: 545.2; found: 546.3 [M+1] + .

[0261] Scheme As previously described, the present disclosure relates to alternative and novel methods for synthesizing the compounds disclosed in PCT / US2021 / 028323 (PCT'323), which is incorporated herein by reference in its entirety.

[0262] One route to compound I uses the guidance of PCT '323 as a template.

[0263] [ka]

[0264] Alternative routes exist, including those disclosed in co-pending U.S. Provisional Application No. 63 / 257,697, filed October 20, 2021, which is incorporated herein by reference in its entirety. [Example 2]

[0265] Crystalline morphology generation One embodiment of the present disclosure is a novel solid-state form of Compound I. Multiple crystallization experiments were performed using crystalline starting material or amorphous material in various solvent systems using different techniques (slurry at room temperature and 60°C, slow evaporation, slow cooling, antisolvent addition, slurry thermal cycling, solid vapor diffusion, and liquid vapor diffusion). Only one anhydrous form (starting API) was identified. This form was designated Form 1. A trihydrate form (Form 2) was obtained in THF / water and acetone / water systems. After desorption and absorption, Form 2 converted to Form 3. Form 3 was determined to be the monohydrate form. Another hydrate form (Form 4) was identified in a slurry study in MTBE. A DCM-solvated form (Form 5) was produced in a solid vapor diffusion study in DCM.

[0266] In one embodiment, one or more forms are created by slurry at room temperature or 60° C.: an excess amount of API was suspended in the solvent of choice for 3 days. If the API was completely dissolved at the end of the study, the sample was transferred for slow evaporation.

[0267] In one embodiment, one or more forms are created by slow cooling: an excess of API was suspended in a solvent of choice at 50°C. The suspension was filtered. The filtrate was stored under refrigerated conditions. If no crystals had formed at the end of the study, the sample was transferred for slow evaporation.

[0268] In one embodiment, one or more forms are created by slow evaporation: Near-saturated solutions were prepared in different solvents, the solutions were filtered, and the filtrates were placed in an ambient environment.

[0269] In one embodiment, one or more forms are created by anti-solvent addition: the API was dissolved in a solvent of choice. The solution was filtered and the anti-solvent was slowly introduced.

[0270] In one embodiment, one or more forms are created by liquid vapor diffusion: the study was set up in a two-vial system (small vial inside a larger vial): the filtered API solution was placed in the small vial, while the anti-solvent was placed in the large vial.

[0271] In one embodiment, one or more forms are created by solid vapor diffusion: the study was set up in a two-vial system (a small vial inside a larger vial), where the API was placed in the small vial, while the solvent was placed in the larger vial.

[0272] In one embodiment, one or more forms are created by thermal cycling: an excess of the API is suspended in a solvent of choice, and the suspension is then subjected to an alternating thermal program from 5 to 50°C.

[0273] As indicated, both crystalline API (Type 1) and amorphous API were used in the slurry, thermal cycling, and solid vapor experiments.

[0274] These techniques are known to those skilled in the art.

[0275] Characterization of crystal morphology Table 15 provides a summary of the characterization of the crystalline forms of the present disclosure. Figures 1-9 illustrate the characterization of Forms 1, 2, 3, 4, and 5, as shown.

[0276] [Table 15]

[0277] Tables 16, 17, and 18 provide summaries of the characterization of the crystalline forms of the present disclosure following screening experiments using amorphous forms of Compound I characterized in Figures 10A, 10B, 10C, 11, 12A, and 12B, which illustrate the characterization of Forms 1, 2, 3, 4, and 5, as shown.

[0278] [Table 16]

[0279] [Table 17]

[0280] [Table 18]

[0281] Tables 19-28 below provide summaries of the characterization of the crystalline forms of the present disclosure following screening experiments using crystalline Form 1 of Compound I, respectively. Figures 13-22 illustrate the characterization of Forms 1, 2, 3, 4, and 5, as shown.

[0282] Table 19

[0283] Table 20

[0284] Table 21

[0285] Table 22

[0286] Table 23

[0287] Table 24

[0288] Table 25

[0289] Table 26

[0290] Table 27

[0291] Table 28

[0292] Figure 24 is an XRPD of Compound I, Form 1. Specific characterization peaks present in the XRPD diffractogram of Form 1 are presented in Table 29, in terms of 2θ. Peak positions present in the XRPD diffractogram obtained for Form 1 are presented in Table 30.

[0293] [Table 29]

[0294] [Table 30]

[0295] Figure 25 is an XRPD of Compound I, Form 2. Specific characterization peaks present in the XRPD diffractogram of Form 2 are presented in Table 31, in terms of 2θ. Peak positions present in the XRPD diffractogram obtained for Form 2 are presented in Table 32.

[0296] [Table 31]

[0297] [Table 32]

[0298] Figure 26 is an XRPD of Compound I, Form 3. Specific characterization peaks in the XRPD diffractogram of Form 3 are presented in Table 33 in 2θ. Peak positions present in the XRPD diffractogram obtained for Form 3 are presented in Table 34.

[0299] [Table 33]

[0300] [Table 34]

[0301] Figure 27 is an XRPD of Compound I, Form 4. Specific characterization peaks in the XRPD diffractogram of Form 4 are presented in Table 35, in 2θ. Peak positions present in the XRPD diffractogram obtained for Form 4 are presented in Table 36.

[0302] [Table 35]

[0303] [Table 36]

[0304] Figure 28 is an XRPD of Compound I, Form 5. Specific characterization peaks in the XRPD diffractogram of Form 5 are presented in Table 37, in 2θ. Peak positions present in the XRPD diffractogram obtained for Form 5 are presented in Table 38.

[0305] [Table 37]

[0306] [Table 38]

[0307] Solubility experiment The solubility of Compound I, Form 1 (6036531-01-A) in 20 different solvents at room temperature was estimated. Approximately 2 mg of solid was added to a 3 mL glass vial. The solvents in Table 39 were then added stepwise (50 μL per step) to the vial until the solid dissolved or a total volume of 2 mL was reached. The results are summarized in Table 39.

[0308] [Table 39] [Example 3]

[0309] Preparation and characterization of form 8 Form 8 is an anhydrous crystalline form and trace amounts of this form were surprisingly first discovered during a drug substance manufacturing campaign - see Figure 34 for the XRPD obtained from the material resulting from this manufacturing. The XRPD shows that the isolated material is mostly Form 1 with some minor peaks attributed to Form 8.

[0310] Competitive slurry study. Competitive slurry studies using Form 1 and the resulting material (a mixture of Forms 1 and 8) were carried out in THF, EtOH, and EtOAc at 25 and 50° C. The solid form was confirmed by XRPD on days 3 and 7. The results are presented in Table 40.

[0311] [Table 40]

[0312] Competitive slurry studies indicate that at 25 and 50°C, Form 8 is the more thermodynamically stable form.

[0313] Type 8 characterization Solid-state characterization of Form 8 was performed using XRPD, DVS, DSC, TGA, and PLM (Figures 29-32). Form 8 was determined to be an anhydrous crystalline form of Compound I(a) (see Figure 29 for the XRPD diffractogram). XRPD peak positions are presented in Table 41. DSC shows a sharp melting endotherm with an onset temperature of 212°C (see Figure 30), while TGA shows a 0.14% weight loss to 216°C (see Figure 30). DVS analysis shows a 0.1% water update at 80% RH (see Figure 31), indicating that Form 8 is non-hygroscopic. No change in crystalline morphology was observed after the DVS experiment. PLM shows plate-like birefringent particles (Figure 32).

[0314] [Table 41]

[0315] Process for preparing type 8 Form 8 can be prepared as follows. 1. A reactor is charged with N-(3-chloro-4-fluorophenyl)-4-((3aS,5S,6aR)-5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (3.9 kg). 2. Charge THF (146 kg) into the reactor. 3. Charge the reactor with 0.39 kg of 10 wt % Pd / C in 20 kg of THF. 4. Expose the contents to 1 atm of H2. 5. Stir the contents for approximately 25-30 hours until no more than 2.0% N-(3-chloro-4-fluorophenyl)-4-((3aS,5S,6aR)-5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide remains. 6. Filter contents through Celite (wash with THF). 7. Activated carbon is added to the filtrate, and the mixture is stirred at 50°C for 16 hours. 8. Filter through Celite and filter cartridge (wash with THF). 9. Concentrate to 2-5 volumes at 40-50°C and <1.0 MPa over approximately 40 hours. 10. Charge ethyl acetate (8 volumes). 11. Concentrate to 2-3 volumes at 40-50°C and <1.0 MPa over approximately 6-8 hours. 12. Repeat steps 10 and 11 twice. 13. Dilute the mixture with EtOAc (3 volumes). 14. Adjust the process temperature to 5-10°C over approximately 3 hours. 15. Stir the contents for 14-15 hours. 16. Collect the precipitate by filtration (wash with EtOAc). 17. Dry the material at 50°C until the loss on drying is 4.0% or less. [Example 4]

[0316] SINGLE CRYSTAL CULTURE AND STRUCTURE ANALYSIS OF COMPOUND I Single crystals of compound I were grown and analyzed by single crystal X-ray diffraction to determine its absolute structure.

[0317] A single crystal refers to the regular, periodic arrangement of particles in a crystal in three-dimensional space, or simply a single crystal polyhedron. Single crystal analysis is the most direct and convincing method for identifying the absolute structure of a compound. Therefore, single crystal analysis is often used in drug research to confirm or even directly determine the absolute structure of drug molecules.

[0318] Design experiments for single crystal culture Approximate solubility test at room temperature / 50℃ The approximate solubility of the starting material was determined in different solvents at room temperature (approximately 25°C). The specific procedure is as follows: Approximately 5 mg of compound I is placed in a clean glass vial, and then an appropriate amount of solvent is added at room temperature until no particles are visible in the solution (up to 1.5 mL of solvent is added), and the final amount of solvent is recorded for solubility calculation.

[0319] Slow cooling crystallization Approximately 100.0 mg of compound I was placed in a clean glass vial at 55°C, and 1.2 mL of MeOH was added to obtain a clear solution. The system was cooled to 45°C, and a small amount of seeds was added to obtain a suspension. The suspension was filtered through a 0.22 μm filter, and the filtrate was placed in a clean glass vial and sealed. The sample was allowed to stand and slowly cool to room temperature. Methodology and equipment used SCXRD Device type: Bruker APEX-II CCD Type of diffracted radiation: Mo K\a Diffraction ambient temperature: 298K

[0320] Experimental results Approximate solubility The approximate solubility experimental results at room temperature are shown in Table 42.

[0321] [Table 42]

[0322] Slow cooling crystallization The results of the slow cooling crystallization experiments are shown in Table 43.

[0323] [Table 43]

[0324] Suitable plate-shaped single crystals can be grown via slow-cooling crystallization from hot saturated MeOH solution. The single crystal structure of the sample was monoclinic and its space group was P21 / c. The cell parameters were a: 19.5045 Å, b: 10.5123 Å, c: 13.6234 Å, α: 90°, β: 104.549°, γ: 90°, and V: 2703.7 Å. 3 Its absolute structure is shown in Figure 33, and its detailed parameters are shown in Table 44.

[0325] [Table 44]

[0326] The structure of compound I was determined by single crystal X-ray diffraction to be compound I(a):

[0327] [ka] It was decided as follows.

[0328] All publications, patents, and patent applications cited herein are hereby incorporated by reference for the teachings to which such citations are applied.

[0329] The test compounds in the experiments described herein were used in free or salt form.

[0330] The specific response observed may vary according to and depending on the particular active compound selected, or whether or not a carrier is present, as well as the type of formulation and mode of administration used, and such expected variations or differences in results are to be expected in accordance with the practice of the present invention.

[0331] Although specific embodiments of the present invention are illustrated and described in detail herein, the present invention is not limited thereto. The above detailed description is provided as an example of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

[0332] 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 the specification and appended claims are approximations and may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. Compound I 【Chemistry 1】 Crystals.

2. Compound I is compound I(a): 【Chemistry 2】 The crystal of claim 1, wherein

3. The crystal according to claim 1 or 2, which is type 8.

4. 4. The crystal of claim 3, wherein crystalline Form 8 is characterized by an XRPD pattern measured using Cu Kα (λ=1.5406 Å) radiation, comprising peaks at 2-theta values ​​of 9.4, 15.4, and 16.7°2θ±0.2°2θ.

5. 5. The crystal of claim 4, wherein the XRPD pattern measured using Cu Kα (λ=1.5406 Å) radiation further comprises at least 2, 5, 10, 15, or 20 additional peaks °2θ±0.2 °2θ selected from the group consisting of the following peaks: Table 1

6. 4. The crystal of claim 3, wherein Form 8 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in FIG.

7. The crystal of claim 3, which is anhydrous.

8. 8. The crystal of claim 7, containing less than 2% water by weight.

9. 4. The crystal of claim 3, wherein crystalline Form 8 is characterized by a DSC thermogram containing an endothermic event with an onset temperature of 212°C ± 2°C.

10. 10. The crystal according to claim 9, wherein the DSC thermogram does not contain a thermal event between 50 and 100°C and contains an endothermic event with an onset temperature of 212°C ± 2°C.

11. 4. The crystal of claim 3, wherein crystalline Form 8 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 30.

12. The crystal of claim 3, which is substantially pure.

13. The crystal according to claim 1 or 2, which is form 1.

14. 25. The crystal of claim 13, characterized by the XRPD pattern of FIG.

24.

15. 14. The crystal of claim 13, characterized by XRPD having at least one of the following 2θ peaks: Table 2

16. 16. The crystal of claim 15, characterized by at least two, at least three, at least four, at least five, at least six, or at least seven 2θ peaks.

17. 17. The crystal of claim 16, characterized by eight 2θ peaks.

18. 14. The crystal of claim 13, wherein the crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation, comprising peaks at 2-theta values ​​of 12.2, 19.4, and 19.9 °2θ±0.2 °2θ.

19. 19. The crystal of claim 18, wherein the XRPD pattern further comprises at least one or two specific peaks selected from peaks at 2-theta values ​​of 16.4 and 17.6°2θ±0.2°2θ.

20. 20. The crystal of claim 18, wherein the XRPD pattern further comprises at least 2, 5, 10, 15, or 20 additional peaks at °2θ±0.2 °2θ selected from the table below. Table 3

21. 14. The crystal of claim 13, wherein the crystalline Form 1 is characterized by an XRPD pattern measured using Cu Kα (1.5406 Å) radiation substantially identical to that shown in Figure 24.

22. The crystal of claim 13, wherein crystalline form 1 is anhydrous.

23. 14. The crystal of claim 13, containing less than 2% water by weight.

24. 14. The crystal of claim 13, wherein crystalline Form 1 is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 210°C ± 2°C.

25. 25. The crystal of claim 24, wherein the DSC thermogram does not contain a thermal event between 50 and 100°C and contains an endothermic event with an onset temperature of 210°C ± 2°C.

26. 14. The crystal of claim 13, wherein crystalline Form 1 is characterized by a DSC thermogram substantially identical to the DSC thermogram shown in Figure 2B.

27. 14. The crystal of claim 13, wherein Form 1 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 from other crystals.

28. The crystal of claim 13, wherein Form 1 is free of other crystals.

29. 3. The crystal of claim 1 or 2, wherein the compound is stereochemically pure.

30. A pharmaceutical composition comprising the crystal of claim 1 or 2 and a pharmaceutically acceptable carrier, diluent, or excipient.

31. 31. The pharmaceutical composition of claim 30 for use in the treatment of HBV infection.

32. 10. Use of the crystals of claim 1 or 2 in the manufacture of a medicament for treating HBV infection.

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