Solid forms of hbv core protein allosteric modulator compounds

Abstract

There is provided a physically stable form of Compound (I) (3 - [(8aS) - 7 - [[(4S) - 5-ethoxycarbonyl-4 - (3-fluoro-2-methyl-phenyl) - 2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl] methyl] - 3-oxo - 568, 8a - tetrahydro-imidazo [1, 5-a] pyrazin-2-yl] - 2, 2-dimethyl-propanoic acid). 1H.SOLUTION: Novel solid forms of Compound (I) are provided. Preferably, it is a solid form, which is Form D, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2 θ at 6.8 ° ± 0.2 °, 13.0 ° ± 0.2 °, 20.3 ° ± 0.2 °, 27.1 ° ± 0.2 °, 27.4 ° ± 0.2 °, 28.8 ° ± 0.2 ° and 29.1 ° ± 0.2 °.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compound (I) [ka] The present disclosure relates to novel solid forms of 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic acid, and pharmaceutical compositions comprising the solid forms disclosed herein, which can be used as HBV capsid inhibitors (or HBV core protein allosteric modulators) or for the treatment or prevention of viral diseases in patients with HBV infection or diseases caused by HBV infection. [Background technology]

[0002] HBV is a member of the Hepadnaviridae family of viruses. HBV is a serious societal health problem worldwide, with over 400 million people chronically infected with this small, enveloped DNA virus, particularly in the Asia-Pacific region. While most individuals appear to recover from acute infection, 15–40% of HBV patients will ultimately develop clinical disease during their lifetime, most notably hepatitis, cirrhosis, and hepatocellular carcinoma. Each year, 500,000–1 million people die from end-stage liver disease caused by HBV infection.

[0003] HBV capsid protein plays an essential role in HBV replication. HBV has an icosahedral core containing 240 capsid (or core) proteins. The most important biological function of capsid protein is to act as a structural protein for encapsidating pregenomic RNA to form immature capsid particles in the cytoplasm. This step is a prerequisite for viral DNA replication. Several capsid-related anti-HBV inhibitors have been reported. For example, AT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), as well as phenylpropenamide derivatives, such as those listed in the Valeant R&D has shown that a class of thiazolidin-4-ones (WO2006 / 033995) inhibits pgRNA packaging. Recent studies suggest that phenylpropenamides are indeed accelerators of HBV capsid assembly, leading to the formation of empty capsids. These highly intriguing results demonstrate the importance of this kinetic pathway in normal viral assembly.

[0004] Heteroaryldihydropyrimidines (HAPs), including compounds designated Bay 41-4109, Bay 38-7690, and Bay 39-5493, were discovered in tissue culture-based screening (Deres K. et al. Science 2003, 893). These HAP analogs act as synthetic allosteric activators, inducing aberrant capsid formation that results in core protein degradation. HAP analogs also reorganized core protein from preassembled capsids into non-capsid polymers, likely through interaction of HAP with dimers liberated during capsid "breathing," i.e., when individual intersubunit bonds are temporarily disrupted. Administration of Bay 41-4109 to genetically engineered or humanized mouse models infected with HBV demonstrated in vivo efficacy by reducing HBV DNA (Deres K. et al. Science 2003, 893; Brezillon N. et al. PLoS ONE 2011, e25096). BisANS, a small molecule, has also been shown to act as a molecular "wedge" to interfere with normal capsid-protein geometry and capsid formation (Zlotnick A. et al. J. Virol. 2002, 4848-4854).

[0005] 3-[(8aS)-7-[[(4S)-5-Ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic acid (compound (I)) has been disclosed in WO2015 / 132276 as an HBV capsid inhibitor (or HBV core protein allosteric modulator).

[0006] It has been discovered that Form D of Compound (I) is physically unstable, resulting in morphological changes that make it unsuitable for further drug development. As one of the objects of this patent, several novel solid forms have been identified and characterized that exhibit significantly improved stability compared to Form D of Compound (I). It is one of the objects of the present invention to develop novel forms of Compound (I) that have good processability or acceptable water solubility. Several novel solid forms will drastically enhance the developability of Compound (I).

[0007] The present disclosure relates generally to novel solid forms of Compound (I) and methods for making them.

[0008] The physical stability of a drug substance is an essential part of a systematic evaluation of drug stability due to its potential impact on the chemical stability performance and safety of the drug. Higher stability may equate to a longer shelf life. Therefore, the accelerated and long-term stability tests used in this invention can be used to predict shelf life.

[0009] Generally speaking, amorphous drugs are significantly more soluble but less stable than their crystalline counterparts. In another embodiment, the amorphous form of Compound (I) surprisingly exhibits significantly improved stability compared to Form D of Compound (I).

[0010] In another embodiment, sodium salt Form J of Compound (I) exhibited improved stability compared to Form D of Compound (I) and improved solubility compared to some of the other crystalline forms of the parent Compound (I). In vivo PK studies showed that Form J of Compound (I) exhibited a much slower absorption rate until Cmax was reached. Therefore, sodium salt Form J is suitable for formulation as a sustained-release oral dosage form. Although Form J was rapidly converted to the HCl salt, its apparent solubility in FaSSIF increased over time. Therefore, sodium salt Form J may avoid conversion in SGF for better absorption. and could be developed as an enteric release formulation to achieve higher solubility in the intestinal environment.

[0011] In another embodiment, Form H of Compound (I) is a monohydrate and has shown improved stability compared to Form D of Compound (I). Generally speaking, hydrated crystalline forms exhibit the lowest thermodynamic solubility in water. Form H unexpectedly exhibits higher solubility in water than Form A. Due to acceptable solid form stability, Form H of Compound (I) is more preferred for oral suspension formulations. Summary of the Invention

[0012] The present invention relates to polymorphs, salts, solvates, co-crystals, or combinations thereof of 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic acid, and methods for the synthesis and production of the solid forms.

[0013] One embodiment provided herein is an amorphous or solid form of Compound (I), or a solvate or combination thereof.

[0014] Another embodiment provided herein is an amorphous or solid form of Compound (I), wherein the solid form is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V, Form W, Form X, or a combination thereof.

[0015] In another embodiment, the solid form of Compound (I) is Form D, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 6.8°±0.2°, 13.0°±0.2°, 20.3°±0.2°, 27.1°±0.2°, 27.4°±0.2°, 28.8°±0.2°, and 29.1°±0.2°.

[0016] In a further embodiment, the solid form of Compound (I) is Form D, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0017] In another embodiment, the solid form of Compound (I) is Form A, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 10.0°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 19.4°±0.2°, 21.1°±0.2°, and 23.2°±0.2°.

[0018] In a further embodiment, the solid form of Compound (I) is Form A exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following degrees 2θ: 10.0°±0.2°, 12.3°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.5°±0.2°, and 26.8°±0.2°.

[0019] In a further embodiment, the solid form of Compound (I) is Form A, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0020] In a further embodiment, the solid form of Compound (I) is an amorphous form exhibiting the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0021] In another embodiment, the solid form of Compound (I) is Form B, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 3.9°±0.2°, 4.8°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 10.7°±0.2°, 15.6°±0.2°, and 19.5°±0.2°.

[0022] In a further embodiment, the solid form of Compound (I) is Form B exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 3.9°±0.2°, 4.8°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 10.7°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 16.4°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 21.7°±0.2°.

[0023] In a further embodiment, the solid form of Compound (I) is Form B, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0024] In another embodiment, the solid form of Compound (I) is Form C, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.1°±0.2°, 10.6°±0.2°, 10.8°±0.2°, 12.1°±0.2°, 13.6°±0.2°, and 13.9°±0.2°, expressed in degrees 2θ.

[0025] In a further embodiment, the solid form of Compound (I) is Form C, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0026] In another embodiment, the solid form of Compound (I) is Form E, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 4.0°±0.2°, 5.1°±0.2°, 5.4°±0.2°, 10.2°±0.2°, 13.3°±0.2°, 15.5°±0.2°, and 20.2°±0.2°.

[0027] In a further embodiment, the solid form of Compound (I) is Form E exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 4.0°±0.2°, 5.1°±0.2°, 5.4°±0.2°, 10.2°±0.2°, 10.5°±0.2°, 11.8°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.5°±0.2°, 19.5°±0.2°, 20.2°±0.2°, and 21.9°±0.2°.

[0028] In a further embodiment, the solid form of Compound (I) is Form E, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0029] In another embodiment, the solid form of Compound (I) is Form F, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 4.0°±0.2°, 4.9°±0.2°, 7.1°±0.2°, 15.8°±0.2°, 20.3°±0.2°, and 21.9°±0.2°.

[0030] In a further embodiment, the solid form of Compound (I) is Form F exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2θ: 4.0°±0.2°, 4.9°±0.2°, 7.1°±0.2°, 7.4°±0.2°, 7.9°±0.2°, 10.6°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 15.8°±0.2°, 20.3°±0.2°, 21.0°±0.2°, and 21.9°±0.2°.

[0031] In a further embodiment, the solid form of Compound (I) is Form F, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0032] In another embodiment, the solid form of Compound (I) is Form G, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 3.7°±0.2°, 4.1°±0.2°, 5.0°±0.2°, 6.2°±0.2°, 7.7°±0.2°, 8.2°±0.2°, and 17.1°±0.2°.

[0033] In a further embodiment, the solid form of Compound (I) is Form G exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.7°±0.2°, 4.1°±0.2°, 5.0°±0.2°, 6.2°±0.2°, 7.7°±0.2°, 8.2°±0.2°, 11.3°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.5°±0.2°, 16.3°±0.2°, 17.1°±0.2°, 19.3°±0.2°, 21.1°±0.2°, and 23.3°±0.2°, expressed in degrees 2θ.

[0034] In a further embodiment, the solid form of Compound (I) is Form G, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0035] In another embodiment, the solid form of Compound (I) is Form J, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following degrees 2θ: 7.7°±0.2°, 9.7°±0.2°, 14.7°±0.2°, 15.9°±0.2°, 22.0°±0.2°, and 23.4°±0.2°.

[0036] In a further embodiment, the solid form of Compound (I) is Form J exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2θ: 7.7°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 19.0°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 24.5°±0.2°, and 25.3°±0.2°.

[0037] In a further embodiment, the solid form of Compound (I) is Form J, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0038] In a further embodiment, the solid form of Compound (I) is Form J, and Form J is the sodium salt of Compound (I).

[0039] In another embodiment, the solid form of Compound (I) is Form H, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 8.0°±0.2°, 9.7°±0.2°, 14.6°±0.2°, 15.7°±0.2°, 15.9°±0.2°, and 24.1°±0.2°.

[0040] In a further embodiment, the solid form of Compound (I) is Form H exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 6.8°±0.2°, 8.0°±0.2°, 9.7°±0.2°, 11.6°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 22.7°±0.2°, 24.1°±0.2°, 24.5°±0.2°, and 26.0°±0.2°.

[0041] In a further embodiment, the solid form of Compound (I) has an X-ray powder diffraction (XR) profile as shown in FIG. This is form H, which exhibits a PD) pattern.

[0042] In another embodiment, the solid form of Compound (I) is Form I, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.4°±0.2°, 7.8°±0.2°, 9.9°±0.2°, 11.6°±0.2°, 16.2°±0.2°, and 22.1°±0.2°, expressed in degrees 2θ.

[0043] In a further embodiment, the solid form of Compound (I) is Form I exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.4°±0.2°, 7.8°±0.2°, 9.6°±0.2°, 9.9°±0.2°, 11.6°±0.2°, 13.0°±0.2°, 14.5°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 18.3°±0.2°, 22.1°±0.2°, 23.0°±0.2°, 24.3°±0.2°, and 27.2°±0.2°, expressed in degrees 2θ.

[0044] In a further embodiment, the solid form of Compound (I) is Form I, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0045] In another embodiment, the solid form of Compound (I) is Form K, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4°±0.2°, 13.3°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 18.0°±0.2°, and 22.7°±0.2°, expressed in degrees 2θ.

[0046] In a further embodiment, the solid form of Compound (I) is Form K exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following degrees 2θ: 5.4°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 18.0°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 21.7°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.1°±0.2°, and 28.0°±0.2°.

[0047] In a further embodiment, the solid form of Compound (I) is Form K, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0048] In a further embodiment, the solid form of Compound (I) is Form K, and Form K is the hydrochloride salt of Compound (I).

[0049] In another embodiment, the solid form of Compound (I) is Form L, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.0°±0.2°, 11.8°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 18.3°±0.2°, and 24.4°±0.2°, expressed in degrees 2θ.

[0050] In a further embodiment, the solid form of Compound (I) is Form L exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.0°±0.2°, 11.2°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.7°±0.2°, 22.5°±0.2°, 23.8°±0.2°, 24.4°±0.2°, 25.7°±0.2°, and 27.7°±0.2°, expressed in degrees 2θ.

[0051] In a further embodiment, the solid form of Compound (I) is Form L, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0052] In a further embodiment, the solid form of Compound (I) is Form L, and Form L is the hydrochloride salt of Compound (I).

[0053] In another embodiment, the solid form of Compound (I) is Form M, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 5.3°±0.2°, 7.7°±0.2°, 10.7°±0.2°, 17.6°±0.2°, 19.0°±0.2°, and 19.2°±0.2°.

[0054] In a further embodiment, the solid form of Compound (I) is Form M, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 5.3°±0.2°, 7.7°±0.2°, 9.4°±0.2°, 10.7°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.2°±0.2°, 19.8°±0.2°, and 24.4°±0.2°.

[0055] In a further embodiment, the solid form of Compound (I) is Form M, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0056] In a further embodiment, the solid form of Compound (I) is Form M, and Form M is a sulfate salt of Compound (I).

[0057] In another embodiment, the solid form of Compound (I) is Form N, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 5.3°±0.2°, 10.7°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.5°±0.2°, and 24.7°±0.2°.

[0058] In a further embodiment, the solid form of Compound (I) is Form N, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0059] In a further embodiment, the solid form of Compound (I) is Form N, which is a sulfate salt of Compound (I).

[0060] In another embodiment, the solid form of Compound (I) is Form 0, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at degrees 2θ: 4.9°±0.2°, 10.6°±0.2°, 14.3°±0.2°, 22.4°±0.2°, and 22.9°±0.2°.

[0061] In a further embodiment, the solid form of Compound (I) is Form 0, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 4.9°±0.2°, 10.6°±0.2°, 13.2°±0.2°, 14.3°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 24.4°±0.2°.

[0062] In a further embodiment, the solid form of Compound (I) is Form O, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0063] In a further embodiment, the solid form of Compound (I) is Form O, which is a besylate salt of Compound (I).

[0064] In another embodiment, the solid form of Compound (I) has an angle of 3.9°±0.2° in degrees 2θ, Form P exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.7°±0.2°, 15.3°±0.2°, 21.5°±0.2°, 27.5°±0.2°, and 31.8°±0.2°.

[0065] In a further embodiment, the solid form of Compound (I) is Form P, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0066] In a further embodiment, the solid form of Compound (I) is Form P, and Form P is the potassium salt of Compound (I).

[0067] In another embodiment, the solid form of Compound (I) is Form Q, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.9°±0.2°, 8.7°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 21.8°±0.2°, 26.3°±0.2°, and 29.3°±0.2°.

[0068] In a further embodiment, the solid form of Compound (I) is Form Q exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.9°±0.2°, 8.7°±0.2°, 10.5°±0.2°, 11.0°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 16.8°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.5°±0.2°, 21.2°±0.2°, 21.8°±0.2°, 26.3°±0.2°, 26.7°±0.2°, and 29.3°±0.2°.

[0069] In a further embodiment, the solid form of Compound (I) is Form Q, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0070] In a further embodiment, the solid form of Compound (I) is Form Q, and Form Q is the potassium salt of Compound (I).

[0071] In another embodiment, the solid form of Compound (I) is Form R, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.5°±0.2°, 7.8°±0.2°, 9.9°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 15.7°±0.2°, and 22.2°±0.2°.

[0072] In a further embodiment, the solid form of Compound (I) is Form R exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.5°±0.2°, 7.8°±0.2°, 8.8°±0.2°, 9.9°±0.2°, 11.2°±0.2°, 11.7°±0.2°, 12.4°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 22.2°±0.2°, and 26.3°±0.2°.

[0073] In a further embodiment, the solid form of Compound (I) is Form R, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0074] In a further embodiment, the solid form of Compound (I) is Form R, and Form R is the potassium salt of Compound (I).

[0075] In another embodiment, the solid form of Compound (I) is Form S, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3°±0.2°, 8.7°±0.2°, 13.7°±0.2°, 15.8°±0.2°, 18.0°±0.2°, and 21.7°±0.2°, expressed in degrees 2θ.

[0076] In a further embodiment, the solid form of Compound (I) is Form S exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.3°±0.2°, 8.7°±0.2°, 11.0°±0.2°, 11.2°±0.2°, 13.4°±0.2°, 13.7°±0.2°, 15.8°±0.2°, 16.6°±0.2°, 18.0°±0.2°, 20.9°±0.2°, 21.7°±0.2°, 24.5°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.6°±0.2°, expressed in degrees 2θ.

[0077] In a further embodiment, the solid form of Compound (I) is Form S, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0078] In a further embodiment, the solid form of Compound (I) is Form S, and Form S is the potassium salt of Compound (I).

[0079] In another embodiment, the solid form of Compound (I) is Form T exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ at 8.0°±0.2°, 10.8°±0.2°, 11.1°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 21.5°±0.2°, and 31.6°±0.2°.

[0080] In a further embodiment, the solid form of Compound (I) is Form T, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0081] In a further embodiment, the solid form of Compound (I) is Form T, and Form T is the calcium salt of Compound (I).

[0082] In another embodiment, the solid form of Compound (I) is Form U, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.5°±0.2°, 10.1°±0.2°, 10.6°±0.2°, 13.7°±0.2°, 18.9°±0.2°, 20.3°±0.2°, and 21.0°±0.2°.

[0083] In a further embodiment, the solid form of Compound (I) is Form U, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.5°±0.2°, 9.6°±0.2°, 10.1°±0.2°, 10.6°±0.2°, 11.9°±0.2°, 12.6°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 16.2°±0.2°, 17.8°±0.2°, 18.9°±0.2°, 20.3°±0.2°, and 21.0°±0.2°.

[0084] In a further embodiment, the solid form of Compound (I) is Form U, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0085] In a further embodiment, the solid form of Compound (I) is Form U, and Form U is a calcium salt of Compound (I).

[0086] In another embodiment, the solid form of Compound (I) is Form V, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 5.6°±0.2°, 8.5°±0.2°, 14.2°±0.2°, 16.2°±0.2°, 21.9°±0.2°, and 22.4°±0.2°.

[0087] In a further embodiment, the solid form of Compound (I) is Form V, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0088] In a further embodiment, the solid form of Compound (I) is Form V, and Form V is an ammonium salt of Compound (I).

[0089] In another embodiment, the solid form of Compound (I) is Form W, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2°±0.2°, 7.5°±0.2°, 7.8°±0.2°, 11.4°±0.2°, 15.8°±0.2°, and 21.4°±0.2°, expressed in degrees 2θ.

[0090] In a further embodiment, the solid form of Compound (I) is Form W exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.2°±0.2°, 6.6°±0.2°, 7.5°±0.2°, 7.8°±0.2°, 9.5°±0.2°, 9.8°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 15.8°±0.2°, 19.8°±0.2°, 21.4°±0.2°, 22.5°±0.2°, 24.0°±0.2°, and 26.5°±0.2°, expressed in degrees 2θ.

[0091] In a further embodiment, the solid form of Compound (I) is Form W, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0092] In a further embodiment, the solid form of Compound (I) is Form W, which is an ammonium salt of Compound (I).

[0093] In another embodiment, the solid form of Compound (I) is Form X, which exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 8.6°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 16.3°±0.2°, and 22.0°±0.2°.

[0094] In a further embodiment, the solid form of Compound (I) is Form X exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2θ: 7.6°±0.2°, 8.6°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 12.6°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 16.3°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 22.0°±0.2°, and 23.2°±0.2°.

[0095] In a further embodiment, the solid form of Compound (I) is Form X, which exhibits the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0096] In a further embodiment, the solid form of Compound (I) is Form X, which is an ammonium salt of Compound (I).

[0097] Another embodiment provided herein is a pharmaceutical composition comprising a solid form disclosed herein and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

[0098] Another embodiment provided herein is the use of a solid form or pharmaceutical composition disclosed herein for the manufacture of a medicament for the treatment or prevention of a viral disease in a patient.

[0099] In another embodiment, the viral disease disclosed herein is HBV infection or a disease caused by HBV infection.

[0100] Another embodiment provided herein is a method for treating or preventing HBV infection or a disease caused by HBV infection, comprising administering a therapeutically effective amount of a solid form or pharmaceutical composition disclosed herein.

[0101] Abbreviations ACN Acetonitrile C max Highest observed concentration DSC Differential Scanning Calorimetry EtOAc ethyl acetate FaSSIF fasting artificial intestinal fluid IPA Isopropanol IPAc Isopropyl acetate IPE Diisopropyl Ether Pos.Pos. Rel.Int Relative Intensity RT room temperature SGF artificial gastric fluid TGA thermogravimetric analysis T max Maximum concentration (C max ) was observed XRPD X-ray powder diffraction [Brief explanation of the drawings]

[0102] [Figure 1] 1 is the X-ray powder diffraction pattern for Form D. [Figure 2] 1 is an X-ray powder diffraction pattern for Form A. [Figure 3] FIG. 1 shows the X-ray crystal structure of Form A. [Figure 4] 1 is an X-ray powder diffraction pattern for the amorphous form. [Figure 5] 1 is the X-ray powder diffraction pattern for Form B. [Figure 6] 1 is the X-ray powder diffraction pattern for Form C. [Figure 7] 1 is the X-ray powder diffraction pattern for Form E. [Figure 8] 1 is the X-ray powder diffraction pattern for Form F. [Figure 9] 1 is the X-ray powder diffraction pattern for Form G. [Figure 10] 1 is an X-ray powder diffraction pattern for sodium salt Form J. [Figure 11] FIG. 1 shows the X-ray crystal structure of sodium salt form J. [Figure 12] 1 is the X-ray powder diffraction pattern for Form H. [Figure 13] 1 is a DSC thermogram of Form H. [Figure 14] 1 is a TGA diagram of Form H. [Figure 15] 1 is an X-ray powder diffraction pattern for Form I. [Figure 16] FIG. 1 shows the X-ray crystal structure of HCl salt form K. [Figure 17] 1 is the X-ray powder diffraction pattern for HCl salt Form L. [Figure 18] FIG. 1 shows the X-ray crystal structure of HCl salt form L. [Figure 19] 1 is an X-ray powder diffraction pattern for H2SO4 salt form M. [Figure 20]1 is an X-ray powder diffraction pattern for H2SO4 salt form N. [Figure 21] 1 is an X-ray powder diffraction pattern for besylate salt form O. [Figure 22] 1 is an X-ray powder diffraction pattern for potassium salt Form P. [Figure 23] 1 is an X-ray powder diffraction pattern for potassium salt form Q. [Figure 24] 1 is an X-ray powder diffraction pattern for potassium salt Form R. [Figure 25] 1 is an X-ray powder diffraction pattern for potassium salt Form S. [Figure 26] 1 is an X-ray powder diffraction pattern for calcium salt Form T. [Figure 27] 1 is an X-ray powder diffraction pattern for calcium salt Form U. [Figure 28] 1 is an X-ray powder diffraction pattern for ammonium salt Form V. [Figure 29] 1 is an X-ray powder diffraction pattern for ammonium salt Form W. [Figure 30] 1 is an X-ray powder diffraction pattern for ammonium salt Form X. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0103] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0104] HPLC method and assay testing for chemical purity The HPLC conditions are disclosed herein in Table 1. [Table 1]

[0105] Example 1 Preparation of Form D of Compound (I) A solution of 10 mg of Compound (I) in 5 mL of n-propanol was placed at room temperature and evaporated to dryness.

[0106] A solid was obtained and characterized by XRPD. The XRPD pattern of Compound (I) Form D is shown in Figure 1. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0107] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 2]

[0108] Example 2 Alternative Preparation of Form D of Compound (I) A solution of 10 mg of compound (I) in 5 mL of a mixture of n-propanol and 2-butanol (2:8, v:v) was placed at room temperature and evaporated to dryness.

[0109] The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table 2, confirming that it was Form D of Compound (I).

[0110] Example 3 Preparation of Form A of Compound (I) A solution of 10 mg of Compound (I) in 10 mL of acetone was placed at room temperature and evaporated to dryness.

[0111] The XRPD pattern of Compound (I) Form A is shown in Figure 2. The major peaks in the XRPD pattern and associated intensities are shown in the table below.

[0112] Experimental conditions XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4-40. The step size was 0.053° at a scan rate of 10.504° / min. [Table 3]

[0113] Figure 3 shows the X-ray structure of Form A. Single crystal X-ray intensity data were collected at 296 K using a Bruker SMART APEX II with Cu-Kα radiation (1.54 Å). Structure solution and refinement were performed using ShelXTL software (Bruker AXS, Karlsruhe). The crystal data and structure refinement are shown in Table 4. [Table 4]

[0114] Example 4 Alternative Preparation of Form A of Compound (I) A solution of 10 mg of Compound (I) in 1 mL of ethyl acetate was placed at room temperature and evaporated to dryness.

[0115] The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table 3, confirming that it was Form A of Compound (I).

[0116] Example 5 Alternative Preparation of Form A of Compound (I) A solution of 10 mg of Compound (I) in 2 mL of isopropyl acetate was placed at room temperature and evaporated to dryness.

[0117] The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table 3, confirming that it was Form A of Compound (I).

[0118] Example 6 Alternative Preparation of Form A of Compound (I) A solution of 10 mg of Compound (I) in 4 mL of acetonitrile was placed at room temperature and evaporated to dryness.

[0119] The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table 3. and was confirmed to be Form A of Compound (I).

[0120] Example 7 Preparation of amorphous forms of Compound (I) A solution of 500 mg of Compound (I) in 10 mL of dichloromethane was quickly evaporated using a rotary evaporator. The solid was dried overnight at 30° C. The solid was analyzed by XRPD. The results are shown in FIG. 4.

[0121] Characterization method XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4 to 40 degrees 2θ. The step size was 0.053° at a scan rate of 10.504° / min.

[0122] Example 8 Alternative Preparation of Amorphous Form of Compound (I) A solution of 10 mg of Compound (I) in 1 mL of methanol was placed at room temperature and evaporated to dryness.

[0123] The solid was collected for XRPD analysis, and the XRPD pattern of the solid was the same as that in Figure 4, confirming the amorphous form of Compound (I).

[0124] Example 9 Alternative Preparation of Amorphous Form of Compound (I) A solution of 10 mg of Compound (I) in 1 mL of a mixed solvent of methanol and dichloromethane (50:50, v:v) was placed at room temperature and evaporated to dryness.

[0125] The solid was collected for XRPD analysis, and the XRPD pattern of the solid was the same as that in Figure 4, confirming the amorphous form of Compound (I).

[0126] Example 10 Preparation of Form B of Compound (I) Approximately 50 mg of the amorphous form of Compound (I) prepared in Example 7 was weighed and transferred to a glass vial. 0.4 mL of ethanol was added to form a suspension. The vial was placed on a shaker and continued to shake at 1200 rpm at 25°C for 3 minutes.

[0127] The XRPD pattern of Compound (I) Form B is shown in Figure 5. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0128] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 5]

[0129] Example 11 Preparation of Form C of Compound (I) Approximately 50 mg of the amorphous form of Compound (I) prepared in Example 7 was weighed and transferred to a glass vial. 0.5 mL of a mixture of ethanol and methylcyclohexane (1:4, v:v) was added to form a suspension. The suspension was stirred for 10 minutes.

[0130] The solid was collected for XRPD analysis. The XRPD pattern of Compound (I) Form C is shown in Figure 6. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0131] Characterization method XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4 to 40 degrees 2θ. The step size was 0.026° at a scan rate of 3.348° / min. [Table 6]

[0132] Example 12 Preparation of Form E of Compound (I) Approximately 10 mg of the amorphous form of Compound (I) prepared in Example 7 was weighed and transferred to a centrifuge tube. The tube was placed in a sealed container, filled with n-heptane, and left for 16 hours.

[0133] The solid was collected and analyzed by XRPD. The XRPD pattern of Compound (I) Form E is shown in Figure 7. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0134] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 7]

[0135] Example 13 Preparation of Form F of Compound (I) Approximately 20 mg of the amorphous form of Compound (I) prepared in Example 7 was weighed and transferred to a mortar. 0.1 mL of n-propanol was added. The mixture was manually ground for 3 minutes.

[0136] The solid was collected for XRPD analysis. The XRPD pattern of Compound (I) Form F is shown in Figure 8. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0137] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 8]

[0138] Example 14 Preparation of Form G of Compound (I) Approximately 15 mg of Compound (I) Form A prepared in Example 3 was weighed and transferred to a glass vial. 2 mL of an ethanol / n-heptane mixture (1:1, v:v) was added and gently sonicated to ensure complete dissolution. Approximately 2 mg of PEG 6000 was added. The solution was evaporated to dryness at room temperature.

[0139] The solid was collected for XRPD analysis. The XRPD pattern of Compound (I) Form G is shown in Figure 9. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0140] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 9]

[0141] Example 15 Preparation of the sodium salt form J of compound (I) 1.0 g of Compound (I) Form A, prepared in Example 3, was weighed into a vial and dissolved in 13 mL of ethanol. The solution was stirred in a water bath at 40°C for 5 minutes. 73.19 mg of sodium hydroxide (1.1 eq.) was added to the solution, and stirring was applied for 1 minute. The solution became clear, then cloudy, and then gel-like. 2.0 mL of ethanol was added, and the mixture was stirred at room temperature until the solution became fluid. After stirring at room temperature for 5 hours, the product was isolated by vacuum filtration. The wet cake was washed with a small amount of ethanol and dried in an air-blow oven at 40°C for 16 hours.

[0142] The solid was collected for XRPD analysis. The XRPD pattern of the sodium salt form J of Compound (I) is shown in Figure 10. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0143] Experimental conditions XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4 to 40 degrees 2θ. The step size was 0.053° at a scan rate of 10.504° / min. [Table 10]

[0144] Figure 11 shows the X-ray structure of sodium salt form J. Single crystal X-ray intensity data at 293(2) K were collected using a Bruker SMART APEX II with Mo-Kα radiation (0.71 Å). Structure solution and refinement were performed using ShelXTL software (Bruker AXS, Karlsruhe). The crystal data and structure refinement are shown in Table 11. [Table 11]

[0145] Example 16 Preparation of Form H of Compound (I) 200 mg of the sodium salt form J of Compound (I), prepared in Example 15, was weighed into a vial, and 20 mL of FaSSIF solution was added thereto to form a suspension. The resulting suspension was stirred at 25° C. for 16 hours. The solid was then collected by filtration and dried under air blow at 40° C. for 16 hours. The solid was collected for XRPD analysis, DSC analysis, and TGA analysis.

[0146] The XRPD pattern of Compound (I) Form H is shown in Figure 12. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0147] Characterization method XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4 to 40 degrees 2θ. The step size was 0.026° at a scan rate of 3.348° / min.

[0148] DSC analysis: TA Q2000, 25~250℃, heating rate 10℃ / min.

[0149] TGA analysis: TA Q5000, 25~300℃, heating rate 10℃ / min. [Table 12]

[0150] The DSC and TGA results shown in Figures 13 and 14 indicate that Compound (I) Form H has a dehydration temperature around 60°C.

[0151] Example 17 Preparation of Form I of Compound (I) 10 mg of Compound (I) Form H, prepared in Example 16, was weighed into a variable temperature chamber. The sample was placed at 60° C. for 5 minutes.

[0152] The solid was collected for XRPD analysis. The XRPD pattern of Form I of Compound (I) is shown in Figure 15. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0153] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 30 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 13]

[0154] Example 18 Preparation of Hydrochloride Form K of Compound (I) 400 mg of Compound (I) Form A, prepared in Example 3, and 9.0 mL of acetone were added to a vial in a water bath at 45°C, and the mixture was stirred to obtain a clear solution. 74.4 mg of concentrated hydrochloric acid (1.1 eq.) in 1.0 mL of acetone was added to the solution, which immediately turned cloudy. After stirring at room temperature for 1 hour, the mixture became sticky and solidified. After adding 2.0 mL of acetone, the mixture became fluid. The suspension was stirred for an additional 5 hours at room temperature, and the solid was collected by vacuum filtration, washed with a small amount of acetone, and dried in an air-blow oven at 40°C for 16 hours. The solid was collected for XRPD analysis.

[0155] The XRPD pattern of the hydrochloride salt form K of Compound (I) is shown in Figure 16. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0156] Experimental conditions XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4-40 degrees 2θ. The step size was 0.026° at a scan rate of 3.348° / min. It was. [Table 14]

[0157] Example 19 Preparation of the hydrochloride salt form L of compound (I) 150 mg of Compound (I) hydrochloride salt Form K, prepared in Example 18, was placed in a sealed high relative humidity chamber at room temperature and 100% RH for 3 days.

[0158] The solid was collected for XRPD analysis. The XRPD pattern of the hydrochloride salt form L of Compound (I) is shown in Figure 17. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0159] Experimental Method XRPD: PANalytical EMPYREAN X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 4 to 40 degrees 2θ. The step size was 0.026° at a scan rate of 3.348° / min. [Table 15]

[0160] Figure 18 shows the X-ray structure of the hydrochloride salt form L. G using Mo-Kα radiation (0.71 Å). Single crystal X-ray intensity data were collected at 100.08 K using an emini. Structure analysis and refinement were performed using Olex2 software. The crystal data and structure refinement are shown in Table 16. [Table 16]

[0161] Example 20 Preparation of sulfate form M of compound (I) 9.98 mg of Compound (I) Form A, prepared in Example 3, was added to 1.5 mL of IPA, and 1.8 mg of sulfuric acid (1.1 eq.) was added to obtain a clear solution. The solvent was evaporated to 0.2 mL, and the remainder was stirred for an additional 16 hours to produce a suspension. The solid was collected by centrifugation and dried in a vacuum oven at 40°C for 16 hours.

[0162] The solid was collected for XRPD analysis. The XRPD pattern of the sulfate salt Form M of Compound (I) is shown in Figure 19. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0163] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 17]

[0164] Example 21 Preparation of sulfate form N of compound (I) 401 mg of Compound (I) Form A, prepared in Example 3, and 8.0 mL of IPA were added to a vial and heated to 60°C in a water bath. The solution became clear after stirring and then slightly cloudy upon cooling to room temperature. 76.6 mg of sulfuric acid (approximately 1.1 eq.) diluted in 1.0 mL of IPA was added, resulting in a clear solution. The solution was stirred at room temperature for 0.5 hours and then at 10°C for 16 hours, but no precipitation occurred. The solvent was evaporated to 2-3 mL, and the mixture was stirred at 10°C. The solution became very cloudy within 2 minutes, and continued stirring at 10°C resulted in a suspension (which became oily after exposure to air). 5.0 mL of IPE was added dropwise at 10°C, after which the mixture was heated to room temperature and stirred for 16 hours. The solid was isolated by vacuum filtration and air-dried at room temperature. 200 mg of the resulting solid was added to 1.0 mL of EtOAc, which was stirred at room temperature for 24 hours, and the solid was collected by filtration, washed with a small amount of EtOAc, and dried in an air-blow oven at 40° C. for 24 hours.

[0165] The solid was collected for XRPD analysis. The XRPD pattern of the sulfate salt Form N of Compound (I) is shown in Figure 20. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0166] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 18]

[0167] Example 22 Preparation of besylate form O of compound (I) 401 mg of Compound (I) Form A prepared in Example 3 and 12.0 mL of ethyl acetate were added to a vial at 65° C. and stirred until the solution became clear. The solution became slightly cloudy when cooled to room temperature. 122.64 mg of benzenesulfonic acid (1.2 eq.) in 0.5 mL of IPA was added to the solution, which became clear again. The solution was stirred at room temperature for 0.5 hours, then at 10° C. for 16 hours, during which precipitation occurred. The suspension was kept stirring at room temperature for 3 days. The cream solid was collected by filtration and dried at room temperature.

[0168] The solid was collected for XRPD analysis. The XRPD pattern of the besylate salt form O of Compound (I) is shown in Figure 21. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0169] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 19]

[0170] Example 23 Preparation of the potassium salt form P of compound (I) 10.02 mg of Compound (I) Form A, prepared in Example 3, was dissolved in 0.3 mL of MeOH. 1.22 mg of potassium hydroxide (1.1 eq.) was added to the solution and stirred to obtain a clear solution. After stirring for an additional 16 hours, the solvent was then reduced to 0.2 mL, and stirring was continued at 10°C for an additional 16 hours. 3.0 mL of n-heptane was added to the solution, at which time a small amount of solid precipitated. The solid was collected by centrifugation and dried under reduced pressure at 40°C for 24 hours.

[0171] The solid was collected for XRPD analysis. The XRPD pattern of the potassium salt form P of Compound (I) is shown in Figure 22. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0172] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 20]

[0173] Example 24 Preparation of potassium salt form Q of compound (I) 705.70 mg of Compound (I) Form A, prepared in Example 1, was dissolved in 50 mL of ethyl acetate. The solution in the vial was placed in a 40°C water bath and stirred to ensure complete dissolution. 218.28 mg of potassium phthalimide (1.0 eq.) was then added, causing the solution to become slightly cloudy. The solution was stirred at room temperature for 16 hours, at which point it became significantly cloudy. The solid was collected by filtration, washed with 10 mL of ethyl acetate, and dried in an air-blow oven at 40°C for 5 hours.

[0174] The solid was collected for XRPD analysis. The XRPD pattern of potassium salt form Q of Compound (I) is shown in Figure 23. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0175] Experimental conditions XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 21]

[0176] Example 25 Preparation of potassium salt form R of compound (I) 5.0 mg of the potassium salt form Q of Compound (I), prepared in Example 24, was suspended in 0.5 mL of IPAc. The suspension was stirred at room temperature for 3 days.

[0177] The solid was collected for XRPD analysis. The XRPD pattern of the potassium salt form R of Compound (I) is shown in Figure 24. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0178] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 22]

[0179] Example 26 Preparation of potassium salt form S of compound (I) 10 mg of the potassium salt form Q of Compound (I), prepared in Example 24, was weighed into a variable temperature chamber. The sample was placed at 120° C. for 5 minutes.

[0180] The solid was collected for XRPD analysis. The XRPD pattern of the potassium salt Form S of Compound (I) is shown in Figure 25. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0181] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 30 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 23]

[0182] Example 27 Preparation of the calcium salt form T of compound (I) 20.04 mg of the sodium salt form J of Compound (I), prepared in Example 15, was dissolved in 0.7 mL of water at room temperature, and 4.10 mg of calcium chloride anhydrous (1.1 eq.) in 0.1 mL of water was added to form an emulsion-like white suspension. An additional 0.4 mL of water was added, and the suspension was stirred at room temperature for 1.5 hours. The solid was collected by centrifugation and dried in a vacuum oven at 40°C for 16 hours.

[0183] The solid was collected for XRPD analysis. The XRPD pattern of the calcium salt of Compound (I), Form T, is shown in Figure 26. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0184] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 24]

[0185] Example 28 Preparation of the calcium salt form U of compound (I) 304.32 mg of sodium salt form J of Compound (I), prepared in Example 15, was dissolved in 10 mL of water at room temperature using sonication. Approximately 59.90 mg of calcium chloride anhydrous (1.1 eq.) in 1.0 mL of water was added dropwise to the solution, and the solution immediately became cloudy. After stirring at room temperature for 1 hour, the suspension became viscous and solidified. After adding 4.0 mL of water while stirring at room temperature for 16 hours, it became fluid, and the solid was collected by vacuum filtration, washed with a small amount of water, and dried in an air-blowing oven at 40°C for 16 hours.

[0186] The solid was collected for XRPD analysis. The XRPD pattern of the calcium salt form U of Compound (I) is shown in Figure 27. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0187] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 25]

[0188] Example 29 Preparation of the ammonium salt form V of compound (I) 10.34 mg of Compound (I) Form A, prepared in Example 3, was dissolved in 0.3 mL of methanol at room temperature. 2.66 mg of ammonia solution (1.1 eq., 25%-28%) was added to the solution. The mixture was clear, but after stirring for 16 hours, precipitation occurred. After removing all the solvent, an oil was obtained. 0.05 mL of acetonitrile and 0.4 mL of IPE were added to the residue, forming a solid, which was collected by filtration and dried in a vacuum oven for 16 hours.

[0189] The solid was collected for XRPD analysis. XRPD of the ammonium salt form V of compound (I) The PD pattern is shown in Figure 28. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0190] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 26]

[0191] Example 30 Preparation of the ammonium salt form W of compound (I) 10.47 mg of Compound (I) Form A, prepared in Example 3, was dissolved in 1.0 mL of acetonitrile at 50°C, and then the solution was cooled to room temperature. 2.69 mg of ammonia solution (1.1 eq., 25%-28%) was added to the solution. The mixture was clear, and after stirring for 16 hours, precipitation occurred. The amount of solvent was reduced to 0.2 mL, and stirring was continued at 10°C for 3 days. The solid was collected by filtration and dried in a vacuum oven for 16 hours.

[0192] The solid was collected for XRPD analysis.

[0193] The XRPD pattern of the ammonium salt form W of Compound (I) is shown in Figure 29. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0194] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 27]

[0195] Example 31 Preparation of the ammonium salt form X of compound (I) 400.46 mg of Compound (I) Form A, prepared in Example 3, was dissolved in 30 mL of ACN at 65° C. and cooled to room temperature. 100.35 mg of ammonia solution (1.1 eq., 25%-28%) was added to the solution with stirring, and the solution immediately became cloudy. The suspension was stirred at room temperature for 17 hours. The solid was collected by filtration, washed with a small amount of acetonitrile, and dried in a vacuum oven for 5 hours.

[0196] The solid was collected for XRPD analysis. The XRPD pattern of the ammonium salt Form X of Compound (I) is shown in Figure 30. The major peaks and associated intensities in the XRPD pattern are shown in the table below.

[0197] Characterization method XRPD: Bruker D8 Advance X-ray powder diffractometer using Cu-Kα radiation. The tube voltage was 40 KV and the tube current was 40 mA. The scan range was 3 to 40 degrees 2θ. The step size was 0.02° at a scan rate of 6° / min. [Table 28]

[0198] Example 33 Solid form stability 40 mg of Compound (I) in different solid forms was stored in a stability chamber where the temperature and humidity were controlled at 40°C and 75%RH, respectively. After one month, the samples were analyzed by XRPD to confirm the solid form and compare it with the initial solid form. According to the results shown in Table 29, Form D and sodium salt Form J showed better solid form stability than the initial Form D prepared in Example 1. [Table 29]

[0199] Example 34 Apparent solubility studies The apparent solubilities were determined by suspending 5 mg of Compound (I) in different biorelevant media, including pH buffer (50 mM). The suspensions were equilibrated at 25°C for 24 hours. The suspensions were then filtered through 0.22 μm PVDF filters into 2 mL HPLC vials. Quantification of the filtrates was performed by HPLC with reference to standard solutions. The solubility results of selected novel solid forms of this invention are shown in Table 30. The novel solid forms of this invention, Form H, Form J, and Form Q, exhibited higher solubilities than Form A at pH 7 and pH 9. [Table 30]

[0200] Example 35 Solubility and stability studies of Form H The apparent solubility in water was determined by suspending 5 mg of Compound (I) in purified water. The suspension was equilibrated at 25°C for 24 hours. The suspension was then filtered through a 0.22 μm PVDF filter into a 2 mL HPLC vial. Quantitation of the filtrate was performed by HPLC with reference to a standard solution. The solid was analyzed by XRPD. The results of the solubility studies of selected novel solid forms in this invention are shown in Table 31. [Table 31]

[0201] Surprisingly, monohydrate form H exhibits significantly higher aqueous solubility than anhydrous form A.

[0202] 20 mg of Compound (I) in different solid forms was stored in a stability chamber where the temperature and humidity were controlled at 25°C and 60%RH. After one month, the sample was analyzed by XRPD to confirm the solid form and compare it with the initial solid form. Form H showed better stability than the initial Form D prepared in Example 1. [Table 32]

[0203] Due to its unexpectedly high aqueous solubility and acceptable solid form stability, solubility-limited absorption of Compound (I) Form H could be further developed into a solid dosage form to better improve absorption.

Claims

1. Solid forms of compound (I) 【Chemistry 1】 or a salt, solvate, or combination thereof.

2. 2. The solid form of claim 1, which is an amorphous form, form A, form B, form C, form D, form E, form F, form G, form H, form I, form J, form K, form L, form M, form N, form O, form P, form Q, form R, form S, form T, form U, form V, form W, or form X; or a combination thereof.

3. 3. The solid form of claim 1 or 2, wherein the solid form is Form D, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.8°±0.2°, 13.0°±0.2°, 20.3°±0.2°, 27.1°±0.2°, 27.4°±0.2°, 28.8°±0.2°, and 29.1°±0.2°.

4. 4. The solid form of claim 3, which is Form D, exhibiting the X-ray powder diffraction (XRPD) pattern shown in FIG.

5. 3. The solid form of claim 1 or 2, wherein the solid form is Form A, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 10.0°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 19.4°±0.2°, 21.1°±0.2°, and 23.2°±0.2°.

6. 6. The solid form of claim 5, wherein the solid form is Form A, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 10.0°±0.2°, 12.3°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 16.4°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 21.6°±0.2°, 23.2°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.5°±0.2°, and 26.8°±0.2°.

7. 7. The solid form of claim 5 or 6, which is Form A, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 2.

8. 3. The solid form of claim 1 or 2, which is an amorphous form exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 4.

9. 3. The solid form of claim 1 or 2, wherein the solid form is Form B, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 3.9°±0.2°, 4.8°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 10.7°±0.2°, 15.6°±0.2°, and 19.5°±0.2°.

10. 10. The solid form of claim 9, wherein the solid form is Form B, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 3.9°±0.2°, 4.8°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 10.7°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 16.4°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 21.7°±0.2°.

11. 11. The solid form of claim 9 or 10, which is Form B, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 5.

12. 3. The solid form of claim 1 or 2, wherein the solid form is Form C, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.1°±0.2°, 10.6°±0.2°, 10.8°±0.2°, 12.1°±0.2°, 13.6°±0.2°, and 13.9°±0.2°.

13. 13. The solid form of claim 12, which is Form C, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 6.

14. 3. The solid form of claim 1 or 2, wherein the solid form is Form E, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 4.0°±0.2°, 5.1°±0.2°, 5.4°±0.2°, 10.2°±0.2°, 13.3°±0.2°, 15.5°±0.2°, and 20.2°±0.2°.

15. 15. The solid form of claim 14, wherein the solid form is Form E, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 4.0°±0.2°, 5.1°±0.2°, 5.4°±0.2°, 10.2°±0.2°, 10.5°±0.2°, 11.8°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.5°±0.2°, 19.5°±0.2°, 20.2°±0.2°, and 21.9°±0.2°.

16. 16. The solid form of claim 14 or 15, which is Form E, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 7.

17. 3. The solid form of claim 1 or 2, wherein the solid form is Form F, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 4.0°±0.2°, 4.9°±0.2°, 7.1°±0.2°, 15.8°±0.2°, 20.3°±0.2°, and 21.9°±0.2°.

18. 18. The solid form of claim 17, wherein the solid form is Form F, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks in degrees 2-theta at 4.0°±0.2°, 4.9°±0.2°, 7.1°±0.2°, 7.4°±0.2°, 7.9°±0.2°, 10.6°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 15.8°±0.2°, 20.3°±0.2°, 21.0°±0.2°, and 21.9°±0.2°.

19. 19. The solid form of claim 17 or 18, which is form F, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 8.

20. 3. The solid form of claim 1 or 2, wherein the solid form is Form G, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 3.7°±0.2°, 4.1°±0.2°, 5.0°±0.2°, 6.2°±0.2°, 7.7°±0.2°, 8.2°±0.2°, and 17.1°±0.2°.

21. 21. The solid form of claim 20, wherein the solid form is Form G, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 3.7°±0.2°, 4.1°±0.2°, 5.0°±0.2°, 6.2°±0.2°, 7.7°±0.2°, 8.2°±0.2°, 11.3°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.5°±0.2°, 16.3°±0.2°, 17.1°±0.2°, 19.3°±0.2°, 21.1°±0.2°, and 23.3°±0.2°.

22. 22. The solid form of claim 20 or 21, which is Form G, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 9.

23. 3. The solid form of claim 1 or 2, wherein the solid form is Form J, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following degrees 2-theta: 7.7°±0.2°, 9.7°±0.2°, 14.7°±0.2°, 15.9°±0.2°, 22.0°±0.2°, and 23.4°±0.2°.

24. 24. The solid form of claim 23, wherein the solid form is Form J, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 7.7°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 13.0°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 19.0°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 24.5°±0.2°, and 25.3°±0.2°.

25. 25. The solid form of claim 23 or 24, which is Form J, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 10.

26. 26. The solid form of any one of claims 23 to 25, wherein Form J is the sodium salt of Compound (I).

27. 3. The solid form of claim 1 or 2, wherein the solid form is Form H, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 8.0°±0.2°, 9.7°±0.2°, 14.6°±0.2°, 15.7°±0.2°, 15.9°±0.2°, and 24.1°±0.2°.

28. 28. The solid form of claim 27, wherein the solid form is Form H, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.8°±0.2°, 8.0°±0.2°, 9.7°±0.2°, 11.6°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 22.7°±0.2°, 24.1°±0.2°, 24.5°±0.2°, and 26.0°±0.2°.

29. 29. The solid form of claim 27 or 28, which is form H, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 12.

30. 3. The solid form of claim 1 or 2, wherein the solid form is Form I, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.4°±0.2°, 7.8°±0.2°, 9.9°±0.2°, 11.6°±0.2°, 16.2°±0.2°, and 22.1°±0.2°.

31. 31. The solid form of claim 30, wherein the solid form is Form I, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.4°±0.2°, 7.8°±0.2°, 9.6°±0.2°, 9.9°±0.2°, 11.6°±0.2°, 13.0°±0.2°, 14.5°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 18.3°±0.2°, 22.1°±0.2°, 23.0°±0.2°, 24.3°±0.2°, and 27.2°±0.2°.

32. 32. The solid form of claim 30 or 31, which is Form I, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 15.

33. 3. The solid form of claim 1 or 2, wherein the solid form is Form K, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.4°±0.2°, 13.3°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 18.0°±0.2°, and 22.7°±0.2°.

34. 34. The solid form of claim 33, wherein the solid form is Form K, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 5.4°±0.2°, 13.3°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 18.0°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 21.7°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.1°±0.2°, and 28.0°±0.2°.

35. 35. The solid form of claim 33 or 34, which is form K, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 16.

36. 36. The solid form of any one of claims 33 to 35, wherein Form K is the hydrochloride salt of Compound (I).

37. 3. The solid form of claim 1 or 2, wherein the solid form is Form L, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.0°±0.2°, 11.8°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 18.3°±0.2°, and 24.4°±0.2°.

38. 38. The solid form of claim 37, wherein the solid form is Form L, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.0°±0.2°, 11.2°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.7°±0.2°, 22.5°±0.2°, 23.8°±0.2°, 24.4°±0.2°, 25.7°±0.2°, and 27.7°±0.2°.

39. 39. The solid form of claim 37 or 38, which is form L, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 17.

40. 40. The solid state drug of any one of claims 37 to 39, wherein Form L is the hydrochloride salt of compound (I). Body form.

41. 3. The solid form of claim 1 or 2, wherein the solid form is Form M, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.3°±0.2°, 7.7°±0.2°, 10.7°±0.2°, 17.6°±0.2°, 19.0°±0.2°, and 19.2°±0.2°.

42. 42. The solid form of claim 41, wherein the solid form is Form M, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.3°±0.2°, 7.7°±0.2°, 9.4°±0.2°, 10.7°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 19.2°±0.2°, 19.8°±0.2°, and 24.4°±0.2°.

43. 43. The solid form of claim 41 or 42, which is form M, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 19.

44. 44. The solid form of any one of claims 41 to 43, wherein Form M is a sulfate salt of Compound (I).

45. 3. The solid form of claim 1 or 2, wherein the solid form is Form N, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.3°±0.2°, 10.7°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.5°±0.2°, and 24.7°±0.2°.

46. 46. ​​The solid form of claim 45, which is form N, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 20.

47. 47. The solid form of claim 45 or 46, wherein Form N is a sulfate salt of Compound (I).

48. 3. The solid form of claim 1 or 2, wherein the solid form is Form O, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 4.9°±0.2°, 10.6°±0.2°, 14.3°±0.2°, 22.4°±0.2°, and 22.9°±0.2°.

49. 49. The solid form of claim 48, wherein the solid form is Form O exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 4.9°±0.2°, 10.6°±0.2°, 13.2°±0.2°, 14.3°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.2°±0.2°, 21.1°±0.2°, 22.4°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 24.4°±0.2°.

50. 50. The solid form of claim 48 or 49, which is form O, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 21.

51. 51. The solid form of any one of claims 48 to 50, wherein Form O is a besylate salt of Compound (I).

52. 3. The solid form of claim 1 or 2, wherein the solid form is Form P, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 3.9°±0.2°, 7.7°±0.2°, 15.3°±0.2°, 21.5°±0.2°, 27.5°±0.2°, and 31.8°±0.2°.

53. 53. The solid form of claim 52, which is form P, exhibiting the X-ray powder diffraction (XRPD) pattern shown in FIG.

22.

54. 54. The solid form of claim 52 or 53, wherein Form P is the potassium salt of Compound (I).

55. 3. The solid form of claim 1 or 2, wherein the solid form is Form Q, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 7.9°±0.2°, 8.7°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 21.8°±0.2°, 26.3°±0.2°, and 29.3°±0.2°.

56. 56. The solid form of claim 55, wherein the solid form is Form Q, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 7.9°±0.2°, 8.7°±0.2°, 10.5°±0.2°, 11.0°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 16.8°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.5°±0.2°, 21.2°±0.2°, 21.8°±0.2°, 26.3°±0.2°, 26.7°±0.2°, and 29.3°±0.2°.

57. 57. The solid form of claim 55 or 56, which is form Q, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 23.

58. 58. The solid form of any one of claims 55 to 57, wherein Form Q is the potassium salt of Compound (I).

59. 3. The solid form of claim 1 or 2, wherein the solid form is Form R, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 7.5°±0.2°, 7.8°±0.2°, 9.9°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 15.7°±0.2°, and 22.2°±0.2°.

60. 60. The solid form of claim 59, wherein the solid form is Form R, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 7.5°±0.2°, 7.8°±0.2°, 8.8°±0.2°, 9.9°±0.2°, 11.2°±0.2°, 11.7°±0.2°, 12.4°±0.2°, 14.8°±0.2°, 15.4°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 22.2°±0.2°, and 26.3°±0.2°.

61. 61. The solid form of claim 59 or 60, which is form R, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 24.

62. 62. The solid form of any one of claims 59 to 61, wherein Form R is the potassium salt of Compound (I).

63. 3. The solid form of claim 1 or 2, wherein the solid form is Form S, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 8.3°±0.2°, 8.7°±0.2°, 13.7°±0.2°, 15.8°±0.2°, 18.0°±0.2°, and 21.7°±0.2°.

64. Expressed in 2θ degrees, the angles are 8.3°±0.2°, 8.7°±0.2°, 11.0°±0.2°, 11.2°±0.2°, 13.4°±0.2°, 13.7°±0.2°, 15.8°±0.2°, 16.6°±0.2°, 18.0°±0.2°, 20.9°±0.2°, 21.7°±0.2° 64. The solid form of claim 63, wherein the solid form is Form S, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 24.5°±0.2°, 24.5°±0.2°, 26.2°±0.2°, 26.7°±0.2°, and 28.6°±0.2°.

65. 65. The solid form of claim 63 or 64, which is form S, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 25.

66. 66. The solid form of any one of claims 63 to 65, wherein Form S is the potassium salt of Compound (I).

67. 3. The solid form of claim 1 or 2, wherein the solid form is Form T, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 8.0°±0.2°, 10.8°±0.2°, 11.1°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 21.5°±0.2°, and 31.6°±0.2°.

68. 68. The solid form of claim 67, which is form T, exhibiting the X-ray powder diffraction (XRPD) pattern shown in FIG.

26.

69. 68. The solid form of claim 66 or 67, wherein Form T is the calcium salt of Compound (I).

70. 3. The solid form of claim 1 or 2, wherein the solid form is Form U, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 7.5°±0.2°, 10.1°±0.2°, 10.6°±0.2°, 13.7°±0.2°, 18.9°±0.2°, 20.3°±0.2°, and 21.0°±0.2°.

71. 71. The solid form of claim 70, wherein the solid form is Form U, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 7.5°±0.2°, 9.6°±0.2°, 10.1°±0.2°, 10.6°±0.2°, 11.9°±0.2°, 12.6°±0.2°, 12.9°±0.2°, 13.7°±0.2°, 16.2°±0.2°, 17.8°±0.2°, 18.9°±0.2°, 20.3°±0.2°, and 21.0°±0.2°.

72. 72. The solid form of claim 70 or 71, which is form U, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 27.

73. 73. The solid form of any one of claims 70 to 72, wherein Form U is a calcium salt of Compound (I).

74. 3. The solid form of claim 1 or 2, wherein the solid form is Form V, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 5.6°±0.2°, 8.5°±0.2°, 14.2°±0.2°, 16.2°±0.2°, 21.9°±0.2°, and 22.4°±0.2°.

75. 75. The solid form of claim 74, which is Form V, exhibiting the X-ray powder diffraction (XRPD) pattern shown in FIG.

28.

76. 76. The solid form of claim 74 or 75, wherein Form V is an ammonium salt of Compound (I).

77. 3. The solid form of claim 1 or 2, wherein the solid form is Form W, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 6.2°±0.2°, 7.5°±0.2°, 7.8°±0.2°, 11.4°±0.2°, 15.8°±0.2°, and 21.4°±0.2°.

78. 78. The solid form of claim 77, wherein the solid form is Form W, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.2°±0.2°, 6.6°±0.2°, 7.5°±0.2°, 7.8°±0.2°, 9.5°±0.2°, 9.8°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 15.8°±0.2°, 19.8°±0.2°, 21.4°±0.2°, 22.5°±0.2°, 24.0°±0.2°, and 26.5°±0.2°, expressed in degrees 2-theta.

79. 79. The solid form of claim 77 or 78, which is form W, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 29.

80. 80. The solid form of any one of claims 77 to 79, wherein Form W is an ammonium salt of Compound (I).

81. 3. The solid form of claim 1 or 2, wherein the solid form is Form X, exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following angles in degrees 2-theta: 8.6°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 16.3°±0.2°, and 22.0°±0.2°.

82. 82. The solid form of claim 81, wherein the solid form is Form X, exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at the following angles in degrees 2-theta: 7.6°±0.2°, 8.6°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 12.6°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 16.3°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 22.0°±0.2°, and 23.2°±0.2°.

83. 83. The solid form of claim 81 or 82, which is form X, exhibiting the X-ray powder diffraction (XRPD) pattern shown in Figure 30.

84. 84. The solid form of any one of claims 81 to 83, wherein Form X is an ammonium salt of Compound (I).

85. 85. A pharmaceutical composition comprising the solid form of any one of claims 1 to 84 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

86. 86. Use of a solid form according to any one of claims 1 to 84 or a pharmaceutical composition according to claim 85 for the manufacture of a medicament for the treatment or prevention of a viral disease in a patient.

87. 87. The use of claim 86, wherein the viral disease is HBV infection.

88. A method for the treatment or prevention of HBV infection or a disease caused by HBV infection, comprising administering a therapeutically effective amount of a solid form described in any one of claims 1 to 84 or a pharmaceutical composition described in claim 85.

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