Polymorphism of HDAC inhibitor and manufacturing method and applications thereof

Abstract

The present disclosure generally relates to solid state forms of an histone deacetylases (HDACs) inhibitor and pharmaceutical compositions comprising the solid state crystalline forms and pharmaceutically acceptable excipients, and methods for preparing and using the solid state forms and the pharmaceutical compositions thereof.

Description

PATENT ATTORNEY DOCKET NO.: 296567-0 POLYMORPHISM OF HDAC INHIBITOR AND MANUFACTURING METHOD AND APPLICATIONS THEREOF Field of the Present Disclosure

[0001] The present disclosure generally relates to solid state crystalline forms of histone deacetylases (HDACs) inhibitors having activities in anti-tumor activities and anti- neurodegenerative activities. Background of the Present Disclosure

[0002] Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation / deacetylation alters chromatin structure and affects transcription. Histone deacetylase 6 (HDAC6) is a cytoplasmic class II histone deacetylase (HDAC) that, in contrast to the other HDACs, has a specificity for non-histone proteins, including α-tubulin. HDAC6 regulates multiple intracellular processes, such as protein degradation, cell motility, and cell-cell interaction. HDAC6 has been implicated in the regulation of mitochondrial transport. HDAC6 inhibition could increase α-tubulin acetylation and promote mitochondrial transport in hippocampal neurons.

[0003] Peripheral neuropathies are a heterogeneous group of diseases that are characterized by a progressive, ascending loss of nerve function arising from the peripheral regions of the limbs. The phenotypic overlap between different types of hereditary and acquired peripheral neuropathies indicates that similar pathophysiological processes are at play. Many downstream pathways in peripheral neurons, such as axonal transport, protein degradation, and interactions with Schwann cells, organelle damage, channelopathies, and neuroinflammatory signaling, have been proposed and each affects peripheral nerves in a negative way. Histone deacetylase 6 (HDAC6) plays an important role at the intersection of these converging pathogenic pathways. The enzymatic deacetylase activity of HDAC6 is upregulated in neurodegenerative disorders and typically results in downstream neuronal stress.

[0004] WO 2021 / 252475 A1 discloses compounds acting as inhibitors of HDAC6, as well as agents for the prevention and treatment of neuropathy-related diseases. (E)-3-(3-(2,6- dimethylphenyl)-2-ethyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide (herein referred to as a compound of “Formula (I)”):PATENT ATTORNEY DOCKET NO.: 296567-0 , which is disclosed a molecular weight of381.40 Da, acts as an (I) and its effects of showing neuron protection effect in paclitaxel-induced neuropathy through promoting neurite outgrowth, reversing cisplatin-induced neuropathy, prevention and treatment of pulmonary fibrosis, etc., are disclosed in WO 2021 / 252475 A1, the disclosures of which are hereby incorporated by reference in their entireties.

[0005] Polymorphism refers to the occurrence of different solid state crystalline forms of the same molecule, and is a property of some molecules and molecular complexes. A single molecule may exhibit various polymorphs having distinct crystal structures and physical characteristics such as melting point, which can be characterized by using techniques conventionally used in the art, such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TG), etc. The crystalline structural features may be characterized by spectrometric parameters, such as X-ray diffraction (XRPD), infrared absorption (FT-IR), and solid state NMR spectrum (SS-NMR), etc. One or more of these techniques may be used to distinguish between different polymorphic forms of a molecule.

[0006] In order to develop materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms, persons of ordinary skill in the art may discover new solid state crystalline forms of a pharmaceutical product. Improvements of the performance characteristics of a pharmaceutical product may be likely achieved by new solid state crystalline forms of a pharmaceutically useful compound. However, whether new solid state crystalline forms of a specific compound exist or can be produced or whether they provide desired effects are generally unpredictable.

[0007] Accordingly, there is a need to understand and develop the solid state crystalline forms of a compound of Formula (I), particularly when used in therapy, such as in the treatment of HDAC-associated diseases or disorders.PATENT ATTORNEY DOCKET NO.: 296567-0 Summary of the Present Disclosure

[0008] The present disclosure relates to new crystalline forms of a compound of Formula (I): .

[0009] In onecrystalline form of a compound of Formula (I) (Form 3), wherein the crystalline form exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at the diffraction angles (2θ) of 7.48, 13.10, and 27.34 degrees, ± 0.2 degrees for each peak, wherein said XRPD pattern is obtained using copper K-alpha 1 X-rays at a wavelength of 1.5406 Angstroms (Å). In one embodiment, the crystalline form exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at the diffraction angles (2θ) of 7.48, 13.10, 26.90 and 27.34 degrees, ± 0.2 degrees for each peak, wherein said XRPD pattern is obtained using copper K-alpha 1 X-rays at a wavelength of 1.5406 Angstroms (Å).

[0010] In any preceding embodiment of Form 3, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.02, 14.90, 16.54, 17.34, 18.42, 19.56, and 21.16, and 28.60 degrees, ± 0.2 degrees; preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.90, 16.54, 17.34, 18.42, 19.56, 21.16, and 28.60 degrees, ± 0.2 degrees; preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.02, 14.90, 16.54, 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees; more preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.02, 14.90, 17.34, 18.42, 19.56, 21.16 and 28.60 degrees, ± 0.2 degrees; further preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.90, 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees.PATENT ATTORNEY DOCKET NO.: 296567-0

[0011] In any preceding embodiments of Form 3, the crystalline form exhibits an XRPD pattern comprising a peak at the diffraction angle (2θ) of 14.90 degrees, ± 0.2 degrees 2θ.

[0012] In any preceding embodiment of Form 3, the crystalline form exhibits an XRPD pattern comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 17.34, 21.16, and 28.60 degrees, ± 0.2 degrees 2θ; preferably, the crystalline form exhibits an XRPD pattern comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 17.34 and 21.16 degrees, ± 0.2 degrees 2θ.

[0013] In any preceding embodiments of Form 3, the crystalline form exhibits an XRPD pattern comprising at least three peaks at the diffraction angles (2θ) selected from the group consisting of 14.02, 16.54, 17.34, 18.42, 19.56, 21.16, and 28.60 degrees, ± 0.2 degrees 2θ for each peak; preferably, the crystalline form exhibits an XRPD pattern comprising at least three peaks at the diffraction angles (2θ) selected from the group consisting of 16.54, 17.34, 18.42, 19.56, 21.16, and 28.60 degrees, ± 0.2 degrees 2θ for each peak; preferably, the crystalline form exhibits an XRPD pattern comprising at least three peaks at the diffraction angles (2θ) selected from the group consisting of 14.02, 17.34, 18.42, 19.56, 21.16 and 28.60 degrees, ± 0.2 degrees 2θ for each peak; preferably, the crystalline form exhibits an XRPD pattern comprising at least three peaks at the diffraction angles (2θ) selected from the group consisting of 14.02, 16.54, 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees 2θ for each peak; more preferably, the crystalline form exhibits an XRPD pattern comprising at least three peaks at the diffraction angles (2θ) selected from the group consisting of 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees 2θ for each peak.

[0014] In any preceding embodiments of Form 3, the XRPD pattern further comprises a peak at the diffraction angle (2θ) of 26.90 ± 0.2 degrees 2θ, a peak at the diffraction angle (2θ) of 28.60 ± 0.2 degrees 2θ, or two peaks at the diffraction angle (2θ) of 26.90 and 28.60 ± 0.2 degrees 2θ. In any preceding embodiments of Form 3, the crystalline form exhibits an XRPD pattern substantially the same as shown in Figure 1 or 45.

[0015] In any preceding embodiments of Form 3, the crystalline form shows an exothermic peak at about 227 °C in the differential scanning calorimetry (DSC) thermogram.

[0016] In any preceding embodiments of Form 3, the crystalline form shows an exothermic event in the initial heat at onset about 224 °C.

[0017] In any preceding embodiments of Form 3, the crystalline form substantially contains no organic solvent molecules.PATENT ATTORNEY DOCKET NO.: 296567-0

[0018] In any preceding embodiments of Form 3, the crystalline form is an anhydrous crystalline form.

[0019] In one embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) (Form 1), wherein the crystalline form exhibits an X-ray powder diffraction (XRPD) pattern comprising the peaks at the diffraction angles (2θ) of 11.50, 13.72, 23.84, and 26.86 degrees, ± 0.2 degrees 2θ for each peak, wherein said XRPD pattern is obtained using copper K-alpha 1 X-rays at a wavelength of 1.5406 Angstroms (Å).

[0020] In any preceding embodiment of Form 1, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 12.72, 13.12, 15.76 and 19.32 degrees, ± 0.2 degrees 2θ; preferably, the crystalline form exhibits an XRPD pattern comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 13.12, 15.76 and 19.13.

[0021] In any preceding embodiments of Form 1, the crystalline form exhibits an XRPD pattern comprising at least two peaks at the diffraction angles (2θ) selected from those at 12.72, 13.12, 14.32, 15.76 and 19.32 degrees, ± 0.2 degrees 2θ for each peak; preferably, the crystalline form exhibits an XRPD pattern comprising at least two peaks at the diffraction angles (2θ) selected from those at 13.12, 14.32, 15.76 and 19.32.

[0022] In any preceding embodiments of Form 1, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 18.10, 24.78, 27.46, 29.74, and 30.32 degrees, ± 0.2 degrees 2θ; preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 24.78, 27.46, 29.74, and 30.32 degrees, ± 0.2 degrees 2θ; preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 18.10, 27.46, 29.74, and 30.32 degrees, ± 0.2 degrees 2θ; preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 18.10, 24.78, 27.46 and 29.74; more preferably, the crystalline form exhibits an XRPD pattern further comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of 27.46 and 29.74 degrees, ± 0.2 degrees 2θ.

[0023] In any preceding embodiments of Form 1, the crystalline form exhibits an XRPD pattern substantially the same as shown in Figure 5.PATENT ATTORNEY DOCKET NO.: 296567-0

[0024] In any preceding embodiments of Form 1, the crystalline form shows an endothermic peak at about 64 °C and an exothermic peak at about 218 °C in the differential scanning calorimetry (DSC) thermogram.

[0025] In any preceding embodiments of Form 1, the crystalline form shows an endothermic event in the initial heat at onset about 44 °C and an exothermic event in the initial heat at onset about 213 °C.

[0026] In any preceding embodiments of Form 1, the crystalline form substantially contains no organic solvent molecules.

[0027] In any preceding embodiments of Form 1, the crystalline form contains an water content of about 3.48±0.5 wt.% (determined via Karl Fischer titration).

[0028] In various embodiments, the present disclosure provides various crystalline forms of a compound of Formula (I), e.g., Forms 2, 4, 5, 6, 7 and 8 as described herein. In one embodiment, the crystalline Form 3 is converted from the crystalline Form 1.

[0029] The present disclosure also provides a pharmaceutical composition comprising any one of the crystalline forms as described herein, and a pharmaceutically acceptable carrier.

[0030] The present disclosure also provides a method for treating an HDAC-associated disease or disorder in a subject in need thereof, comprising administering an effective amount of a crystalline form or a pharmaceutical composition as described herein to the subject. Preferably, the HDAC-associated disease or disorder is neuropathic related diseases. More preferably, the neuropathic related diseases are selected from the group consisting of diabetic neuropathy, post- herpes zoster pain, postherpetic neuralgia from shingles, and chemotherapy-induced peripheral neuropathy. In one embodiment, the chemotherapy is platinum-based chemotherapy, alkaloid- based, or taxane-based chemotherapy.

[0031] In one embodiment, the present disclosure also provides a method for promoting neurite outgrowth in a subject in need thereof, wherein said subject is administered with an effective amount of a crystalline form or a pharmaceutical composition as described herein. The present disclosure also provides a method for enhancing tubulin hyperacetylation of cells in a subject, wherein said subject is treated with a crystalline form or a pharmaceutical composition as described herein.

[0032] The present disclosure also provides a method for the prevention or treatment of fibrosis of a subject, wherein said subject is administered with an effective amount of a crystallinePATENT ATTORNEY DOCKET NO.: 296567-0 form or a pharmaceutical composition as described herein. In one embodiment, the fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis. In one embodiment, the pulmonary fibrosis is associated with increased expression of IL-1, TNF-α, TL-6 or Collagens in said subject. In one embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis.

[0033] The present disclosure also provides a method of decreasing expression of IL-1, TNF-α, IL-6 or Collagens in a subject in need, wherein said subject is administered with an effective amount of a crystalline form or a pharmaceutical composition as described herein.

[0034] The present disclosure also provides a method of treating or ameliorating cytokine-induced inflammatory conditions in a subject in need, wherein said cytokine comprises IL-1, TNF-α, TL-6, M-CSF, VCAM-1, or MCP-1, and said subject is administered with an effective amount of a crystalline form or a pharmaceutical composition as described herein. In one embodiment, the conditions are selected from a group consisting of coronavirus-induced pulmonary inflammation, acute respiratory distress syndrome, acute pulmonary inflammation, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

[0035] The present disclosure also provides a method for preparing a crystalline form of a compound of Formula (I) as described herein. Brief Description of the Drawings

[0036] FIG. 1 depicts an X-ray powder diffraction (XRPD) pattern of a compound of formula (I) Form 3.

[0037] FIG.2 depicts a thermogravimetric analysis (TGA) thermogram of a compound of formula (I) Form 3.

[0038] FIG. 3 depicts a differential scanning calorimetry (DSC) thermogram of a compound of formula (I) Form 3.

[0039] FIG.4 depicts a1H NMR spectrum of a compound of formula (I) Form 3.

[0040] FIG.5 depicts an XRPD pattern of a compound of formula (I) Form 1.

[0041] FIG.6 depicts a TGA thermogram of a compound of formula (I) Form 1.

[0042] FIG.7 depicts a DSC thermogram of a compound of formula (I) Form 1.

[0043] FIG.8 depicts a1H NMR spectrum of a compound of formula (I) Form 1.

[0044] FIG.9 depicts an XRPD pattern of a compound of formula (I) Form 2.

[0045] FIG.10 depicts a TGA thermogram of a compound of formula (I) Form 2.

[0046] FIG.11 depicts a1H NMR spectrum of a compound of formula (I) Form 2.PATENT ATTORNEY DOCKET NO.: 296567-0

[0047] FIG.12 depicts an XRPD pattern of a compound of formula (I) Form 4.

[0048] FIG.13 depicts a TGA thermogram of a compound of formula (I) Form 4.

[0049] FIG.14 depicts a DSC thermogram of a compound of formula (I) Form 4.

[0050] FIG.15 depicts a1H NMR spectrum of a compound of formula (I) Form 4.

[0051] FIG.16 depicts an XRPD pattern of a compound of formula (I) Form 5.

[0052] FIG.17 depicts a thermogram of a compound of formula (I) Form 5.

[0053] FIG.18 depicts a DSC thermogram of a compound of formula (I) Form 5.

[0054] FIG.19 depicts a1H NMR spectrum of a compound of formula (I) Form 5.

[0055] FIG.20 depicts an XRPD pattern of a compound of formula (I) Form 6.

[0056] FIG.21 depicts a TGA thermogram of a compound of formula (I) Form 6.

[0057] FIG.22 depicts a DSC thermogram of a compound of formula (I) Form 6.

[0058] FIG.23 depicts a1H NMR spectrum of a compound of formula (I) Form 6.

[0059] FIG.24 depictsXRPD pattern of a compound of formula (I) Form 7.

[0060] FIG.25 depicts a TGA thermogram of a compound of formula (I) Form 7.

[0061] FIG.26 depicts a DSC thermogram of a compound of formula (I) Form 7.

[0062] FIG.27 depicts a1H NMR spectrum of a compound of formula (I) Form 7.

[0063] FIG.28 depicts an XRPD pattern of a compound of formula (I) Form 8.

[0064] FIG.29 depicts a TGA thermogram of a compound of formula (I) Form 8.

[0065] FIG.30 depicts a DSC thermogram of a compound of formula (I) Form 8.

[0066] FIG.31 depicts a1H NMR spectrum of a compound of formula (I) Form 8.

[0067] FIG.32 depictspatterns of a compound of formula (I) Forms 1 to 8.

[0068] FIG. 33 depicts the conversion between different crystalline forms of a compound of formula (I).

[0069] FIG. 34 depicts XRPD patterns of a compound of formula (I) from Form 7 to Form 4 obtained in a conversion procedure.

[0070] FIG. 35 depicts XRPD patterns of a compound of formula (I) from Form 4 to Form 3 obtained in a conversion procedure.

[0071] FIG. 36 depicts XRPD patterns of a compound of formula (I) from Form 8 to Form 2 obtained in a conversion procedure.

[0072] FIG. 37 depicts XRPD patterns of a compound of formula (I) from Form 2 to Form 1 obtained in a conversion procedure.PATENT ATTORNEY DOCKET NO.: 296567-0

[0073] FIGs. 38 and 39 depict microscopic images of a compound of formula (I) between Form 3 and Form 1 obtained by polarized light microscopy (PLM).

[0074] FIGs. 40 and 41 depict the dynamic vapour sorption (DVS) profiles of a compound of formula (I) Form 3 and Form 1.

[0075] FIG.42 depicts XRPD patterns of a compound of formula (I) between Forms 1 and 3 obtained in competition tests.

[0076] FIGs.43 and 44 depict XRPD patterns of a compound of formula (I) Form 3 and Form 1 obtained in stability tests.

[0077] FIG.45 depicts XRPD patterns of a compound of formula (I) Form 3 obtained in a long-term stability test.

[0078] FIG.46 provides a representative 2θ values and peak intensity of a compound of formula (I) Form 3.

[0079] FIG. 47 depicts a dissolution profile of a tablet comprising a compound of formula (I) Form 3.

[0080] FIG.48 depicts pharmacokinetic (PK) profile of administration of Form 3 in an animal model. Detailed Description of the Invention

[0081] Definitions

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for describing particular embodiments only and is not intended to limit the present disclosure.

[0083] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit—unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms, in which case each carbon atom number falling within the range is provided)—is between the upper and lower limit of that range, and any other stated or intervening value in that stated range is encompassed within the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the present disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present disclosure.PATENT ATTORNEY DOCKET NO.: 296567-0

[0084] The articles "a" and "an" as used herein and in the appended claims are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0085] The term "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically listed in the "and / or" phrase, whether related or unrelated to those elements specifically identified.

[0086] The term “about” as used herein means ± 20% of the stated value and in more specific embodiments means ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% of the stated value.

[0087] As used herein, a compound of “Formula (I)” refers to the compound having the following chemical structure: , and a chemical7-fluoro-4-oxo-3,4- dihydroquinazolin-6-yl)-N-hydroxyacrylamide. Preparation of a compound of Formula (I) and its use is disclosed in WO 2021 / 252475 A1. The compound of Formula (I) is used in the methods and uses described herein.

[0088] A solid state form of a compound of Formula (I), such as a crystalline form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, X-ray powder diffractograms, DSC thermograms, or NMR spectrums. As is well-known in the art, such graphical data may provide additional technical information to further define the respective solid state form which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may present smallPATENT ATTORNEY DOCKET NO.: 296567-0 variations, e.g., in peak relative intensities and / or peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, persons of ordinary skill in the art would readily be capable of comparing the graphical data in the figures disclosed herein with graphical data generated for an unknown crystalline form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different ones. A solid state form of a compound of Formula (I) referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a figure will thus be understood to include any solid state forms of a compound of Formula (I) characterized with the graphical data having such small variations, as are well known to persons of ordinary skill in the art, in comparison with the figure.

[0089] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 3”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 3”, “a compound of Formula (I) Form 3” or “Form 3” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.1.

[0090] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 1”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 1”, “a compound of Formula (I) Form 1” or “Form 1” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.5.

[0091] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 2”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 2”, “a compound of Formula (I) Form 2” or “Form 2” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.9.

[0092] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 4”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 4”, “a compound of Formula (I) Form 4” or “Form 4” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.12.PATENT ATTORNEY DOCKET NO.: 296567-0

[0093] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 5”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 5”, “a compound of Formula (I) Form 5” or “Form 5” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.16.

[0094] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 6”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 6”, “a compound of Formula (I) Form 6” or “Form 6” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.20.

[0095] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 7”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 7”, “a compound of Formula (I) Form 7” or “Form 7” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.24.

[0096] As used herein, “solid state form of a compound of Formula (I) designated as a compound of Formula (I) Form 8”, “solid state form of a compound of Formula (I) referred to herein as a compound of Formula (I) Form 8”, “a compound of Formula (I) Form 8” or “Form 8” refers to the solid state form of a compound of Formula (I) which may be identified in a composition by detecting the peaks of the X-ray powder diffraction pattern as depicted in FIG.28.

[0097] As used herein, the term “solvent” refers to a liquid component that can be mixed with a compound of Formula (I) or a solid state form thereof to form a slurry, a dispersion or a solution. As used herein, the term “soluble” in reference to solid state forms of a compound of Formula (I) corresponds to the compound or a solid state form thereof having a solubility of at least 1 mg / mL at room temperature when being mixed with a solvent, and the solvent can also be referred to as a “good solvent.” As used herein, the term “highly soluble” in reference to solid state forms of a compound of Formula (I) corresponds to the compound or a solid state form thereof having a solubility of at least 10 mg / mL at room temperature. On the other hand, if said solubility is less than 1 mg / mL, the solvent can also be referred to as an “anti-solvent.” In an embodiment, the solvents include, but are not limited to, water, alkanes, (hetero)cycloalkanes, alcohols, ketones, ethers, esters, sulfoxides, amides, or mixtures thereof, e.g., water, methanol (MeOH), ethanolPATENT ATTORNEY DOCKET NO.: 296567-0 (EtOH), isopropanol (IPA), acetonitrile (ACN), acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), toluene, n-heptane, cyclohexane, 1,4-dioxane dichloromethane (DCM), dimethylsulfoxide (DMSO), dimethylformamide (DMF), a mixture of MeOH and water, a mixture of acetone and water, etc. In one embodiment, the good solvents include, but are not limited to, MeOH, EtOH, IPA, ACN, acetone, MEK, MIBK, EtOAc, iPrOAc, THF, 1,4-dioxane, DMSO, DMF, etc. In one embodiment, the anti-solvents include, but are not limited to, water, MTBE, n-heptane, toluene, DCM, etc.

[0098] As used herein, the term “overnight” is used for describing a long time interval in which a process or step may be carried out. This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is at least 12 hours, e.g., about 12-24 hours, about 12-22 hours, about 14-22 hours, about 14-20 hours, or about 12-20 hours, etc.

[0099] “Pharmaceutically acceptable excipient“ includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which is understood as being acceptable for use in humans or domestic animals.

[0100] As used herein, the phrase “substantially free“ can be used to refer to a particular solid state form of a compound of Formula (I) that contains 20% (w / w) or less, preferably 10% (w / w) or less, more preferably 5% (w / w) or less and most preferably 1% (w / w) or less of any other solid state forms of a compound of Formula (I) or of a specified solid state form of a compound of Formula (I). In one embodiment, the solid state Form 3 of a compound of Formula (I) is substantially free of one or more other solid state forms, including Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, and Form 8. In one embodiment, the solid state Form 1 of a compound of Formula (I) is substantially free of one or more other solid state forms, including Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, and Form 8.

[0101] As used herein, the term “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgusPATENT ATTORNEY DOCKET NO.: 296567-0 monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0102] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

[0103] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a neuropathy-related disorder. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0104] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0105] In an alternate embodiment, the present invention contemplates administration of the solid state crystalline form of a compound of Formula (I) as described herein, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound or its solid state crystalline form is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound or its solid state crystalline form means an amount of a therapeutic agent, alone or in combination with other agents, which provides aPATENT ATTORNEY DOCKET NO.: 296567-0 prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0106] As used herein, the term “under vacuum,” “in vacuo” or “reduced pressure” refers to a pressure that is less than atmospheric pressure.

[0107] Solid State Crystalline Forms

[0108] In one embodiment, Form 3 is characterized by the XRPD diagram as substantially depicted in FIG.1. In one embodiment, the XRPD diagram exhibits the peak values and relative density as provided in FIG.46.

[0109] In one embodiment, Form 1 is characterized by the XRPD diagram as substantially depicted in FIG.5.

[0110] In one embodiment, Form 2 is characterized by the XRPD diagram as substantially depicted in FIG.9.

[0111] In one embodiment, Form 4 is characterized by the XRPD diagram as substantially depicted in FIG.12.

[0112] In one embodiment, Form 5 is characterized by the XRPD diagram as substantially depicted in FIG.16.

[0113] In one embodiment, Form 6 is characterized by the XRPD diagram as substantially depicted in FIG.20

[0114] In one embodiment, Form 7 is characterized by the XRPD diagram as substantially depicted in FIG.24.

[0115] In one embodiment, Form 8 is characterized by the XRPD diagram as substantially depicted in FIG.28.

[0116] In some embodiments, a solid state crystalline form of a compound of Formula (I) (e.g., Form 3, Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, and Form 8) contains 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, 0.2% (w / w) or less, or 0.1% (w / w) or less of any other solid state crystalline forms of aPATENT ATTORNEY DOCKET NO.: 296567-0 compound of Formula (I) disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein.

[0117] In other embodiments, a solid state crystalline form of a compound of Formula (I) (e.g., Form 3, Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, and Form 8) contains from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of any other solid state crystalline forms of a compound of Formula (I) disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein.

[0118] In other embodiments, a solid state crystalline form of a compound of Formula (I) (e.g., Form 3, Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, and Form 8) contains from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of any other solid state crystalline forms of a compound of Formula (I) disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein.

[0119] In other embodiments, a solid state crystalline form of a compound of Formula (I) (e.g., Form 3, Form 1, Form 2, Form 4, Form 5, Form 6, Form 7 or Form 8) contains from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), from 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of any other solid state crystalline forms of a compound of Formula (I) disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein.

[0120] In other embodiments, a solid state crystalline form of a compound of Formula (I) (e.g., Form 3, Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, and Form 8) contains from 0.1% to 5% (w / w), from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w),PATENT ATTORNEY DOCKET NO.: 296567-0 from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of any other solid state crystalline forms of a compound of Formula (I) disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein.

[0121] In some embodiments, a solid state crystalline form of a compound of Formula (I) contains Form 3 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid state crystalline forms of a compound of Formula (I) in total disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein, such as Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, Form 8 or a combination of these. In a specific embodiment, a solid state crystalline form of a compound of Formula (I) contains Form 3 and Form 1.

[0122] In some embodiments, a solid state crystalline form of a compound of Formula (I) contains Form 1 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, 0.2% (w / w) or less, or 0.1% (w / w) or less of all other solid state crystalline forms of a compound of Formula (I) in total disclosed herein, or of a specified solid state crystalline form of a compound of Formula (I) disclosed herein, such as Form 3, Form 2, Form 4, Form 5, Form 6, Form 7, Form 8 or a combination of these. In a specific embodiment, a solid state crystalline form of a compound of Formula (I) contains Form 1 and Form 3.

[0123] Process of Manufacturing Solid State Crystalline Forms

[0124] The present disclosure also provides processes of manufacturing solid state crystalline forms of a compound of Formula (I).

[0125] In one embodiment, a method called “slurry method” is provided, the slurry method comprising at least the following steps: providing a solvent and a compound of Formula (I); mixing the solvent with a sufficient amount of the compound of Formula (I) to form a slurry,PATENT ATTORNEY DOCKET NO.: 296567-0 preferably wherein the amount of the compound of Formula (I) is present in a level higher than the solubility of the compound of Formula (I) in said solvent, preferably at least 1 mg / mL; stirring the slurry at room temperature or an elevated temperature (e.g., 50°C or less); collecting wet precipitates from the slurry; and optionally drying the wet precipitates to give a solid state crystalline form of a compound of Formula (I); wherein the step of "drying the wet precipitates" is included in the slurry method for preparing Form 1, Form 2, Form 3, Form 4, and Form 8; wherein the step of "drying the wet precipitates" is omitted from the slurry method for preparing Form 7. In one embodiment, the solid state crystalline form of a compound of Formula (I) prepared by a slurry method as described herein comprises at least one of Form 1, Form 2, Form 3, Form 4, Form 7 and Form 8, preferably at least one of Form 1, Form 2 and Form 3.

[0126] In one embodiment, the slurry method comprises the following steps: mixing a compound of Formula (I) with a solvent or solvent mixture selected from the group consisting of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate, methyl tert-butyl ether, toluene and acetone / water (at least 9:1, v / v) at room temperature or a temperature of 50°C to form a slurry, with the proviso that when toluene is used as the solvent, the mixing is conducting at 50°C; stirring the slurry for at least one day; centrifuging the slurry and collecting wet precipitates; and drying the wet precipitates under a reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 3. In one embodiment, the slurry method comprises the following steps: mixing a compound of Formula (I) with a solvent or solvent mixture selected from the group consisting of water, methanol, ethyl acetate, toluene, n-heptane, cyclohexane and acetone / water (1:1, v / v) at room temperature or a temperature of 50°C to form a slurry, with the proviso that when toluene is used as the solvent, the mixing is conducting at room temperature; stirring the slurry for at least one day; centrifuging the slurry and collecting wet precipitates; and drying the wet precipitates under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 1.

[0127] In one embodiment, a method called “solvent evaporation method” is provided, the solvent evaporation method comprising at least the following steps: providing a solvent and a compound of Formula (I); mixing the solvent with a sufficient amount of the compound of Formula (I) to form a solution, preferably wherein the amount of the compound of Formula (I) is present inPATENT ATTORNEY DOCKET NO.: 296567-0 a level no more than the solubility of the compound of Formula (I) in said solvent; stirring the solution at room temperature; allowing the solution to evaporate the solvent; collecting wet precipitates from the slurry; and drying the wet precipitates to give a solid state crystalline form of a compound of Formula (I). In one embodiment, the solid state crystalline form of a compound of Formula (I) prepared by a solvent evaporation method as described herein comprises at least one of Form 1, Form 2 and Form 3.

[0128] In one embodiment, the solvent evaporation method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of ethanol, isopropanol, acetone, methyl ethyl ketone and methyl isobutyl ketone at room temperature to form a solution; placing the solution in a container for evaporating the solvent at room temperature for at least five days; filtering and then collecting wet precipitates; and drying the wet precipitates under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 3. In one embodiment, the solvent evaporation method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of methanol and tetrahydrofuran at room temperature to form a solution; placing the solution in a container for evaporating the solvent at room temperature for at least three days; collecting wet precipitates; and drying the wet precipitates under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 1.

[0129] In one embodiment, a method called “heating-cooling method” is provided, the heating-cooling method comprising at least the following steps: providing a solvent and a compound of Formula (I); mixing the solvent with a sufficient amount of the compound of Formula (I) to form a saturated solution at an elevated temperature (e.g., 50°C or above); cooling the saturated solution to a temperature lower than room temperature (e.g., 4°C or -20°C), preferably the cooling rate being 10°C / h or higher; allowing the solution stand for a period (e.g., at least 1 day); collecting wet precipitates from the solution; and drying the wet precipitates to give a solid state crystalline form of a compound of Formula (I). In one embodiment, the solid state crystalline form of a compound of Formula (I) prepared by a heating-cooling method as described herein comprises at least one of Form 1 and Form 3.PATENT ATTORNEY DOCKET NO.: 296567-0

[0130] In one embodiment, the heating-cooling method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone and isopropanol acetate at 55°C to form a saturated solution; (i) immediately cooling the saturated solution using a -20°C bath, or (ii) cooling the saturated solution to 4°C at a rate of 10°C / h; centrifuging the solution and collecting wet precipitates; and drying the wet precipitates under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 3. In one embodiment, the heating- cooling method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of methanol and methyl ethyl ketone at 55°C to form a saturated solution; (i) immediately cooling the saturated solution using a -20°C bath, or (ii) cooling the saturated solution to 4°C at a rate of 10°C / h; centrifuging the solution and collecting wet precipitates; and drying the wet precipitates under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 1.

[0131] In one embodiment, a method called “anti-solvent method” is provided, the anti- solvent method comprising at least the following steps: providing a solvent and a compound of Formula (I); mixing the solvent with a sufficient amount of the compound of Formula (I) to form a saturated solution, preferably wherein the solvent is a “good solvent” as described herein; adding an anti-solvent dropwise to the saturated solution; collecting (wet) precipitates from the solution; and drying the wet precipitates to give a solid state crystalline form of a compound of Formula (I). In one embodiment, the method further comprises a step of solvent evaporation to follow the step of addition of the anti-solvent. In one embodiment, the solid state crystalline form of a compound of Formula (I) prepared by an anti-solvent method as described herein comprises at least one of Form 1, Form 3, Form 5 and Form 6, preferably at least one of Form 1 and Form 3.

[0132] In one embodiment, the anti-solvent method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of isopropanol, tetrahydrofuran and dimethylformamide at room temperature to form a saturated solution; adding an anti-solvent dropwise to the saturated solution, wherein: when isopropanol is used as the solvent, the anti-solvent is selected from the group consisting of water, methyl tert-butyl ether and n- heptane, when tetrahydrofuran is used as the solvent, the anti-solvent is selected from the groupPATENT ATTORNEY DOCKET NO.: 296567-0 consisting of toluene and dichloromethane, and when dimethylformamide is used as the solvent, the anti-solvent is water; then, (i) if precipitates are formed, centrifuging the solution and collecting wet precipitates, or (ii) if no precipitates are formed, removing the solvent by drying and collecting the solid contents; and drying the wet precipitates or the solid contents under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 3. In one embodiment, the anti-solvent method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of isopropanol and tetrahydrofuran at room temperature to form a saturated solution; adding an anti-solvent dropwise to the saturated solution, wherein: when isopropanol is used as the solvent, the anti-solvent is selected from the group consisting of toluene and dichloromethane, and when tetrahydrofuran is used as the solvent, the anti-solvent is selected from the group consisting of water, methyl tert-butyl ether and n-heptane; then, (i) centrifuging the solution and collecting wet precipitates if precipitates are formed, or (ii) removing the solvent by drying and collecting the solid contents if no precipitates are formed; and drying the wet precipitates or the solid contents under reduced pressure at 40°C for at least 12 hours to form the crystalline form of a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 1.

[0133] In one embodiment, a method called “reverse anti-solvent method” is provided, the reverse anti-solvent method comprising at least the following steps: providing a solvent and a compound of Formula (I); mixing the solvent with a sufficient amount of the compound of Formula (I) to form a saturated solution, preferably wherein the solvent is a “good solvent” as described herein; adding the saturated solution dropwise to an anti-solvent; collecting (wet) precipitates from the solution; and drying the wet precipitates to give a solid state crystalline form of a compound of Formula (I). In one embodiment, the method further comprises a step of solvent evaporation to follow the step of addition of the saturated solution. In one embodiment, the solid state crystalline form of a compound of Formula (I) prepared by an anti-solvent method as described herein comprises at least one of Form 1, Form 3, Form 5 and Form 6.

[0134] In one embodiment, the reverse anti-solvent method comprises the following steps: mixing a compound of Formula (I) with a solvent selected from the group consisting of isopropanol, tetrahydrofuran and dimethylsulfoxide at room temperature to form a saturated solution; adding the saturated solution dropwise to an anti-solvent selected from water and methylPATENT ATTORNEY DOCKET NO.: 296567-0 tert-butyl ether, with the proviso that only when tetrahydrofuran is used as the solvent, methyl tert- butyl ether can be used as the anti-solvent; then, (i) centrifuging the solution and collecting wet precipitates if precipitates are formed, or (ii) removing the solvent by drying and collecting the solid contents if no precipitates are formed; and drying the wet precipitates or the solid contents under reduced pressure at 40°C for at least 12 hours to form the a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 3. In one embodiment, the reverse anti-solvent method comprises the following steps: mixing a compound of Formula (I) with tetrahydrofuran at room temperature to form a saturated solution; adding the saturated solution dropwise to the methyl tert-butyl ether; then, (i) centrifuging the solution and collecting wet precipitates if precipitates are formed, or (ii) removing the solvent by drying and collecting the solid contents if no precipitates are formed; and drying the wet precipitates or the solid contents under reduced pressure at 40°C for at least 12 hours to form the a compound of Formula (I); preferably the crystalline form of a compound of Formula (I) comprises Form 1.

[0135] In one embodiment, the crystalline Form 1 or Form 3 of a compound of Formula (I) has improved stability compared with Form 2, Form 4, Form 5, Form 6, Form 7, or Form 8 using the stability testing methods as described herein or known in the art.

[0136] Pharmaceutical Compositions / Pharmaceutical Combinations

[0137] In another aspect, the present disclosure provides a pharmaceutical composition or pharmaceutical combination comprising a compound of a Formula (I), or a pharmaceutically acceptable salt, hydrate, stereoisomer, solvate, or prodrug thereof, together with a pharmaceutically acceptable carrier.

[0138] To prepare the pharmaceutical compositions or pharmaceutical combinations of the present disclosure, the solid state crystalline form of a compound of Formula (I) as described herein as the active ingredient may be thoroughly admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral, such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gel caps and tablets, suitable carriers and additives include starches,PATENT ATTORNEY DOCKET NO.: 296567-0 sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients may be included, for example, for purposes such as aiding solubility or for preservation. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.

[0139] The liquid forms in which the novel compositions of the present disclosure may be incorporated for administration orally or by injection include: aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include: synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0140] Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g., polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate). In one embodiment, at least one of the following excipients is used for manufacturing tablets containing a solid state crystalline form of a compound of Formula (I): mannitol, microcrystalline cellulose, sodium lauryl sulfate, povidones (e.g., povidone K30), carboxymethylcelluose sodium and magnesium stearate. In one embodiment, the tablet comprises at least 20 wt.% of a solid state crystalline form of a compound of Formula (I), preferably at least 25 wt.%, at least 30 wt.% or at least 35 wt.%.

[0141] The oral solid compositions can be prepared by conventional methods of blending, filling or tableting. The blending operation can be repeated to distribute the activePATENT ATTORNEY DOCKET NO.: 296567-0 principle throughout compositions containing large quantities of fillers. Such operations are conventional.

[0142] For parenteral administration, fluid unit dosages can be prepared containing the compound and a sterile vehicle. The compound can be either suspended or dissolved, depending on the vehicle and concentration. The parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilizing by filtration, filling suitable vials and sealing. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle. To increase stability, the composition can be frozen after having filled the vials and removed the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by using radiation sterilization (e.g., gamma-ray sterilization), thermal sterilization, or chemical sterilization before suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the application.

[0143] A pharmaceutical preparation for administration by inhalation can be delivered from an insufflator or a nebulizer pressurized pack.

[0144] Therapeutic Applications

[0145] In one embodiment, the present disclosure provides a method for promoting neurite outgrowth in a subject in need thereof, wherein said subject is administered with an effective amount of a crystalline form or the pharmaceutical composition as described herein.

[0146] In one embodiment, the present disclosure provides a method of treating an HDAC-associated disease or disorder in a subject in need thereof, comprising administering an effective amount of a crystalline form or the pharmaceutical composition as described herein to the subject.

[0147] In any preceding embodiment, the HDAC-associated disease or disorder is neuropathic related diseases.

[0148] In any preceding embodiment, the neuropathic related diseases are selected from the group consisting of diabetic neuropathy, post-herpes zoster pain, postherpetic neuralgia from shingles, fiber muscle pain, peripheral neuropathic pains and central neuropathic pains, painful diabetic neuropathy, complex regional pain syndrome, nerve damage induced by chemotherapy, cancer pain, HIV-associated sensory neuropathy, HIV-associated myelopathy, phantom limb pain,PATENT ATTORNEY DOCKET NO.: 296567-0 trigeminal neuralgia, postherpetic neuralgia, painful radiculopathy, central post-stroke pain, sciatic neuralgia, orofacial pain, acute or chronic inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, carpal tunnel syndrome, knuckle pain, snapping finger, iatrogenic nerve damage, neurothlipsia by tumor or nerve damage by infiltration, post radiation nerve damage, toxic peripheral neuropathy, post-traumatic peripheral nerve injury pain, glossopharyngeal neuralgia, autoimmune nerve damage, acute, chronic or intractable muscle and fascia pain, postapoplectic pain, post-traumatic spinal cord injury pain, pain accompanying multiple sclerosis or Parkinson's disease, spinal canal stenosis or hernia pain, so-called low back pain, pain resulting from cervical spondylosis or ligamentum osteosis, pain of stomatitis, perishoulder arthritis, rheumatoid arthritis or osteoarthritis, nociceptive pain, pain of incised wound, abrasion, bone fracture, or bruise, pain caused by insertion of dialysis needle or pain resulting from dialysis at the time of dialysis, senile or nervous itch, itch of scalp, atopic dermatitis, restless legs syndrome, numbness of hand and foot, pain after odontectomy, postoperative pain, pain prophylaxis by preoperative administration, and chemotherapy-induced peripheral neuropathy.

[0149] In any preceding embodiments, the chemotherapy is platinum-based chemotherapy, alkaloid-based, or taxane-based chemotherapy.

[0150] In one embodiment, the present disclosure provides a method for enhancing tubulin hyperacetylation of cells in a subject, wherein said subject is treated with an effective amount of a crystalline form or the pharmaceutical composition as described herein to the subject.

[0151] In one embodiment, the present disclosure provides a method for the prevention or treatment of fibrosis of a subject, wherein said subject is administered with an effective amount of a crystalline form or the pharmaceutical composition as described herein to the subject.

[0152] In any preceding embodiment, the fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis.

[0153] In any preceding embodiments, the pulmonary fibrosis is associated with increased expression of IL-1, TNF-α, TL-6 or Collagens in said subject.

[0154] In any preceding embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis.

[0155] In one embodiment, the present disclosure provides a method of decreasing expression of IL-1, TNF-α, IL-6 or Collagens in a subject in need, wherein said subject isPATENT ATTORNEY DOCKET NO.: 296567-0 administered with an effective amount of a crystalline form or the pharmaceutical composition as described herein to the subject.

[0156] In one embodiment, the present disclosure provides a method of treating or ameliorating cytokine-induced inflammatory conditions in a subject in need, wherein said cytokine comprises IL-1, TNF-α, TL-6, M-CSF, VCAM-1, or MCP-1, and said subject is administered with an effective amount of a crystalline form or the pharmaceutical composition as described herein to the subject.

[0157] In any preceding embodiments, the conditions are selected from a group consisting of coronavirus-induced pulmonary inflammation, acute respiratory distress syndrome, acute pulmonary inflammation, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

[0158] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

[0159] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0160] The present disclosure having now been described by way of written description, those of skill in the art will recognize that the present disclosure can be practiced in a variety of embodiments and that the foregoing description and the examples below are for illustrative purposes only and do not limit the claims that follow. Examples

[0161] The compound of Formula (I) can be prepared, e.g., based on the disclosure in WO 2021 / 252475 A1, in particular Example 15. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.PATENT ATTORNEY DOCKET NO.: 296567-0 Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0162] Abbreviations of terms used herein are listed below: Abbreviation Original Term Abbreviation Original Term XRPD X-ray Powder Diffraction MeOH methanol e ntdisclosure are described below:

[0164] XRPD (X-ray Powder Diffractometer)

[0165] The X-ray powder diffraction (XRPD) pattern was obtained on a Shimadzu XRD-6000 instrument. Samples were run on XRPD using below method: Setting Parameters

[0167] Samples of compounds (~1 mg) were tested in a pinhole aluminum pans under nitrogen purge using a ramp rate of 20 °C / min over the range 30 °C to 300 °C Setting ParametersPATENT ATTORNEY DOCKET NO.: 296567-0 Ramp rate 20°C / min over the range 30°C~300°C Nitrogen purge 50 mL / minder nitrogen purge using a ramp rate of 20 °C / min over the range of 30 °C to 350 °C. Setting Parameters Ram rate 20°C / min over the ran e 30°C~300°Cg p p p ion profiles at 25 °C under 0% to 95% to 0% relative humidity (RH) cycle with the following parameters: Setting Parameters °

[0173] Samples dispersed in silicone oil were observed using ocular lens: 10X and objective lens: 10X under crossed polarizers, and recorded by camera / computer system with magnification scale.

[0174] 1HNMR (Nuclear Magnetic Resonance)

[0175] About 3 mg of compound was weighed out into the nuclear magnetic tube and 0.5 mL of deuterated dimethyl sulfoxide or deuterated methanol was added to dissolve the sample completely. In this study, all of the samples were dissolved by deuterated methanol. Put the tube into the rotor, place the rotor on the open position of the automatic sampler and scanned by BRUKER AVANCE III (400M).

[0176] HPLC method for Solubility and StabilityPATENT ATTORNEY DOCKET NO.: 296567-0

[0177] Sample preparation: for Stability: dissolving solid sample in 50% ACN to the concentration of 0.5mg / mL; analyzing the solution using HPLC to determine the amount of impurities. Content Information (stability) Chromatographic Column Waters Xbridge Sheild RP18 3.5µm 150mm*4.6 mm

[0179] Different solvents were used for evaluating solubility of a compound of Formula (I) by the following methods. In particular, the method was conducted by manual dilution with visual observation at room temperature. A typical procedure as follows was used: approximate 4.0 mg of Formula I was weighed into a glass vial (e.g., 4 mL) and the solvent was then added to the vial (the total volume of the solvent was, for example, 200, 500, 1000, 2000, or 4000 μL) until no particles could be observed (i.e., totally dissolved), or up to 4000 μL of the solvent was added if particles still remained (i.e., undissolved). The total amount of the solvent was recorded to calculate the approximate solubility.

[0180] The results are listed in Table 1 below: Table 1 Solvent Solubility(mg / mL) Solvent Solubility(mg / mL)PATENT ATTORNEY DOCKET NO.: 296567-0 Solvent Solubility(mg / mL) Solvent Solubility(mg / mL) EtOH 9.5~10.7 n-heptane <1 on-p g , , p , y . p of Formula (I) can dissolve in alcohols, ketones, and ester solvents and can more easily dissolve in certain polar aprotic solvents such as THF, DMSO, and DMF.

[0182] Example 2

[0183] Different methods of preparing crystalline forms of the compound of Formula (I) were tested and at least eight crystalline forms of a compound of Formula (I) were identified. The methods of preparation and results are summarized in Table 2 below. Table 2 Results usPATENT ATTORNEY DOCKET NO.: 296567-0 Results Crystal P ti TGA DVS Solvent peak of nd ewater content is 3.48%.$The mole ratio between Formula I and solvents was determined by using H peak area in1H-NMR.

[0184] The exemplified XRPD diagrams of each form are shown in FIGs.1, 5, 9, 12, 16, 20, 24 and 28 (Forms 3, 1, 2, 4, 5, 6, 7, 8, respectively). The exemplified TGA thermograms of each form are shown in FIGs. 2, 6, 10, 13, 17, 21, 25 and 29 (Forms 3, 1, 2, 4, 5, 6, 7, 8, respectively). The exemplified DSC diagrams of each form are shown in FIGs.3, 7, 14, 18, 22,26 and 30 (Forms 3, 1, 4, 5, 6, 7, 8, respectively). The exemplified1H NMR spectra of each form are shown in FIGs.4, 8, 15, 19, 23, 27 and 31 (Forms 3, 1, 2, 4, 5, 6, 7, 8, respectively). For the purpose of comparison, the XRPD diagrams of Forms 1 to 8 are presented in parallel in FIG.32.

[0185] Example 3

[0186] The “slurry method” was adopted for preparing solid state crystalline forms of the compound of Formula (I). In particular, about 50 mg of Formula I was suspended in those solvents in which the compound had low solubility (water, ACN, acetone, etc.) to form a slurry.PATENT ATTORNEY DOCKET NO.: 296567-0 The slurry was kept stirring at room temperature (20 to 25°C) (Sample Nos. 1 to 24) or 50°C (Sample Nos. 25 to 43) for 1 to 3 days. After that, the wet solid precipitates were isolated by centrifugation method, and Sample Nos.1 to 15,17 to 21, and 25 to 43 were further dried at 40 °C under reduced pressure condition in vacuum oven for overnight (12 to 24 hours). The dried solid precipitates were analyzed by XRPD, TGA and DSC. The parameters of the method and crystalline forms identified by XRPD are summarized in Table 3 below. Table 3 Experimental phenomenon after the No. Solvents Volume Stirring (mL) Tim slurry being stirred and subsequent FormPATENT ATTORNEY DOCKET NO.: 296567-0 Experimental phenomenon after the No. Solvents Volume Stirring (mL) Time slurry being stirred and subsequent FormPATENT ATTORNEY DOCKET NO.: 296567-0 Experimental phenomenon after the No. Solvents Volume Stirring (mL) Time slurry being stirred and subsequent FormPATENT ATTORNEY DOCKET NO.: 296567-0 Experimental phenomenon after the No. Solvents Volume Stirring (mL) Time slurry being stirred and subsequent Form dwhen the stirring was conducted at room temperature. Three polymorphisms (Forms 1, 2 and 3) obtained after using slurry method when the stirring was conducted at an elevated temperature (50°C).

[0188] Example 4

[0189] The “solvent evaporation method” was adopted for preparing solid state crystalline forms of the compound of Formula (I). In particular, according to the solubility results as shown in Example 1, about 50 mg of Formula I (API) was fully dissolved in a “good solvent” at room temperature. The sample bottles were covered by aluminum foil with pinholes. Then these samples were spontaneously evaporated at room temperature for 1 to 2 weeks. If some solid precipitates are precipitated out after evaporation, it will be further dried at 40 °C under reducing pressure condition overnight (12 to 24 hours). The dried solid precipitates were analyzed by XRPD, TGA and DSC. The parameters of the method and crystalline forms identified by XRPD are summarized in Table 3 below.PATENT ATTORNEY DOCKET NO.: 296567-0 Table 4 Evapo- No. Solvents Volume (mL) ration Experimental phenomenon after evaporation and subsequent processing Form e,MEK, and MIBK, Form 1 was obtained by using solvents of MeOH, and THF, and Form 2 was obtained by using solvent of 1,4-dioxane.

[0191] Example 5

[0192] The “heating-cooling method” was adopted for preparing solid state crystalline forms of the compound of Formula (I). In particular, about 50 mg of Formula I was dissolved completely in selected solvent to form saturated solution at 55°C. After that, the sample was cooling down to lower the temperature to 4 °C slowly (e.g., at a rate of 10°C / h) or immediately using a -20 °C bath. After stored for 3 days, the solid precipitates were isolated by centrifugation method and further dried the solid at 40 ℃ under vacuum condition overnight (12 to 24 hours). The dried solid precipitates were analyzed by XRPD, TGA and DSC. If there is no clear solution after heating at 55 °C, the sample solution will be dried until solvent evaporated. The parameters of the method and crystalline forms identified by XRPD are summarized in Table 5 below. Table 5 Total 1 3 3 3 3PATENT ATTORNEY DOCKET NO.: 296567-0 Total No. Solvents Volume Cooling Program Experimental phenomenon Form 1 3 3 1 3 3 3 3 3 yusing solvents of EtOH, IPA, ACN, acetone, MIBK and iPrOAc, and Form 1 was obtained by using MeOH and MEK.

[0194] When the solution was cooled at a lower rate, e.g., 10°C / h, Form 3 was obtained by using solvents of EtOH, IPA, ACN, Acetone, and MEK, and Form 1 was obtained by using solvents of MeOH.

[0195] Example 6

[0196] The “anti-solvent method” was adopted for preparing solid state crystalline forms of the compound of Formula (I). In particular, about 50 mg of Formula I was fully dissolved in “good solvent” to form a nearly saturated solution. Then several anti-solvents were added drop- wise, until plenty of solid precipitated out, respectively. The sample solution with no solid precipitated out was dried for solvents evaporation. After that, the solid precipitates were isolated by centrifugation and dried at 40 °C under reducing pressure condition overnight (12 ~ 24 hours).PATENT ATTORNEY DOCKET NO.: 296567-0 Analyze the dried solid precipitates by XRPD, TGA and DSC. The parameters of the method and crystalline forms identified by XRPD are summarized in Table 6 below. Table 6 No. Good Solvents / Anti-Solvents / Volume (mL) Volume (mL) Experimental phenomenon Form 3 3 3 1 1 1 1 1 3 3 5 5 6 3nti- solvents in different solvents.

[0198] Example 7

[0199] The “reverse anti-solvent method” was adopted for preparing solid state crystalline forms of the compound of Formula (I). In particular, about 50 mg of Formula I was fully dissolved in good solvent to form a nearly saturated solution. Then the stock solution was added into 20 mL of anti-solvent in a drop wise manner. The sample solution with no solid precipitated out was dried for solvent evaporation. After that, the solid precipitates were isolated by centrifugation and dried at 40 °C under reducing pressure condition for overnight (12~24 hours).PATENT ATTORNEY DOCKET NO.: 296567-0 Analyze the dried solid precipitates by XRPD, TGA and DSC. The parameters of the method and crystalline forms identified by XRPD are summarized in Table 7 below. Table 7 No. Good Solvents / Anti-Solvents / Volume (mL) Volume (mL) Experimental phenomenon Form 3 3 3 3 1 6 5 6 6 nti-solvents in different solvents.

[0201] Example 8

[0202] The applicant found that the crystalline forms may be converted from one to the other (see FIG.33). For example, Form 7 (obtained by slurring Formula I in DCM without drying process) was converted to Form 4 after drying at 40 °C for 1 to 2 hours. The NMR spectrum indicated a lower DCM peak value after drying, which means that Form 7 (higher DCM peak value) was converted to Form 4 (lower DCM peak value); FIG.34 also indicates this fact. In addition, when Form 4 was heated to 170°C, it was converted to Form 3 (see FIG.35).

[0203] On the other hand, when Form 8 (obtained by slurring Formula I in DCM:dioxane (2:1)) was heating at 80°C, causing the desolvation on DCM, it was converted to Form 2, evidenced by both the NMR spectrum (not shown) and FIG.36.PATENT ATTORNEY DOCKET NO.: 296567-0

[0204] In addition, when Form 2 was suspended in 1 mL of water and kept stirring overnight at room temperature, and the wet solid was isolated by centrifugation method, and further dried in vacuum oven at 40℃ for a few hours, it was converted to Form 1 (see FIG.37).

[0205] Example 9

[0206] As the occurrence of Forms 1 and 3 is higher than other forms and they seem to be more stable, further studies were done to discover their potential in potential future applications.

[0207] PLM images

[0208] FIG.38 depicts the PLM image of Form 3 and FIG.39 depicts the PLM image of Form 1. Form 1 and Form 3 powder exhibited birefringence under PLM, confirming that the samples of Form 1 and Form 3 powder are crystalline materials.

[0209] TGA thermograms

[0210] FIG. 2 depicts a thermogram of Form 3, and only 0.0675% weight loss was observed during heating to 120.0 °C, which indicates that the crystal Form 3 is an anhydrous crystal. FIG.6 depicts a thermogram of Form 1, and 4.0043% weight loss was observed during heating to 120 °C, which indicates the crystal Form 1 including water. The water content determined by Karl Fisher is 3.48%, which indicates that Form 1 is a hydrated crystalline form.

[0211] DVS tests

[0212] DVS tests were conducted in the two forms and the results are shown in FIG.40 (Form 3) and FIG.41 (Form 1).

[0213] Form 1 can absorb 3.560% of water at 30% RH,. On the other hand, Form 3 absorbs 0.0758% of water at 30% RH, which indicates the polymorphism Form 3 is non- hygroscopic.

[0214] Competition tests

[0215] The competition study was conducted in three solvent systems: (1) ethanol, (2) methanol, and (3) DMSO:water (20:80). In particular, about 30 mg of Form 1 and about 30 mg of Form 3 were added to the solvent system to form a suspension mixture. The mixture was kept stirring at room temperature for 3 days. Then, wet solid was isolated by centrifugation and collected for XRPD measurements. The results are depicted in FIG.42.

[0216] The results show that Form 3 may be the dominant form after incubating in ethanol or DMSO:water (20:80), while Form 1 may be the dominant form after incubating in methanol.PATENT ATTORNEY DOCKET NO.: 296567-0

[0217] Storage stability tests

[0218] To evaluate the storage stability, these forms were stored in an open container or in a closed container under different conditions of temperature, relative humidity and storage period. HPLC was used to detect the impurities, qualitatively (based on their relative retention time (RRT)) and quantitatively (based on peak area). The amount of total impurities is the sum of each impurity, and the purity value equals 100% minus total impurities (%). Testing conditions and results are summarized in Table 8 (Form 3) and Table 9 (Form 1) below, and FIGs.43 and 44 depict the XRPD patterns of the solids upon being stored. The term "open" used in Tables 8 and 9 refers to placing the sample in a sample vial without a cap, allowing the sample to equilibrate with the environmental conditions (temperature and humidity). The term "closed" used in Tables 8 and 9 refers to placing the sample in a sealed sample vial with a cap, allowing the sample to equilibrate only with the temperature (excluding humidity). Table 8 – Form 3 Impurities amount (%) Purity / 4 6 1 9 3 9 0 1 9 0 1 9PATENT ATTORNEY DOCKET NO.: 296567-0 Table 9 – Form 1 Impurities amount (%) Purity / RT (min) 4 6 9 8 2 3 8 9 9 9 3 8 esmore than 0.2% at 60°C in 2 months or at 40 °C in 2 months when being stored in an opened container or a container with a closed lip.

[0220] A stability test was conducted on a scaled-up GMP batch (Form 3). In particular, 2 kg of Form 3 was stored at 25°C / 60% RH for 24 months. FIG.45 depicts the XRPD pattern of Form 3 upon being stored.

[0221] The results reveal that both Forms 3 and 1 are stable under thermal stress and high humidity.

[0222] Example 10

[0223] To evaluate the applicability of the forms in pharmaceutical applications, water and different aqueous media were used for evaluating solubility of Form 3 and Form 1. About 15.0 mg of compound was weighed out into each glass vial and then 3.0 ml of medium was added (final concentration was 5 mg / ml). The samples were kept stirring on a magnetic stirrer at a speed of 200 rpm under 37°C. After stirring for 1 hr and 24 hrs, 0.5 ml of sample solution was transferred into 1.5 ml centrifugation tube and centrifuge at 12,000 rpm for 10 min. The supernatant was diluted with 50% ACN and was analyzed by HPLC. The results are summarized in Table 10 below:PATENT ATTORNEY DOCKET NO.: 296567-0 Table 10 Solubility (µg / ml) Sample Aqueous medium Final pH 1h 24h FaSSIF,and FeSSIF is similar. This represents that Forms 1 and 3 are beneficial in various pharmaceutical applications.

[0225] A model pharmaceutical composition of Form 3 was further prepared, as tablets, with the excipients noted below: Ingredient Percent composition (%) API (Form 3) 3947 [0w:

[0227] Sample: Tablet with 150 mg of API (Form 3).

[0228] Medium: 0.5% SLS at pH 6.8 buffer (900mL).

[0229] Temperature: 37°C.

[0230] Apparatus: paddle (type 2) with 75 rpm.

[0231] The dissolution profile was provided in FIG.47. The results reveal that over 80% Form 3 can dissolve in 30 minutes.

[0232] Example 11

[0233] Transfer appropriate amounts of sample powder and water into a container. The mixture was stirred for 55 minutes to obtain a white suspension with final concentrations of 0.5, 1.0, 3.0 and 6.0 mg / mL. Twelve Sprague-Dawley rats (approximately 6 to 9 weeks old) werePATENT ATTORNEY DOCKET NO.: 296567-0 divided into four groups (n=3 / group), and the dosing route is oral administration. Animals were food fasted overnight (>12 hours) prior to dosing, and food was withheld until 4 hours post-dose. Animals were administered four different doses (5, 10, 30, and 60 mg / kg), and blood samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-dose for LC MS / MS analysis.

[0234] FIG.48 depicts the pharmacokinetic profile (PK) exhibited in the animal model, and it can be observed that the PK characteristics are similar when different doses are administered, and the Tmax values are consistent. This reveals that the crystalline forms may be potent in therapeutic uses.

[0235] Example 12: Stability comparison of Form 1, Form 3 and amorphous form

[0236] Form 1 and Form 3 are prepared by Slurry method as described herein, and the amorphous form is prepared by spray drying process by BUCHI Spray Dryer S300. To compare the stability of Form 1, Form 3, and the amorphous form, these forms were incubated under 50˚C and 70°C for one week or under strong light for 24 hours. The light chamber RAYONET RPR- 100 equipped with 16 tubes of fluorescent light was used for light stress test. At the designated stability time points, samples were withdrawn and dissolved with diluent solvent (80% acetonitrile in water) to a final concentration of 1 mg / mL for HPLC analysis. The individual impurity of samples were presented by their relative retention time (RRT) and the peak area percentage corresponds to total peak area in HPLC chromatography in Table 11. The amount of total impurities is the sum of each impurity, and the purity value equals 100% minus total impurities (%). The results are shown in Table 11 below. Table 11. Samples Storage Impurity (%) Total conditions Relative retention time (RRT) im uritiesPATENT ATTORNEY DOCKET NO.: 296567-0 Form 3 1 week 0.17 0.04 0.04 0.17 Amorphous 0.05 0.16 0.05 0.08 0.10 0.22 0.56 *Idiid l i it h ( d ith th t l ) 005% i h i bld, , n amorphous sample under 50°C, 70 °C, and light incubation.

[0238] A person of ordinary skill in the art of the subject disclosure should understand that variations and modifications may be made to the teaching and the disclosure of the subject disclosure without departing from the spirit and scope of the subject application. Based on the contents above, the subject application intends to cover any variations and modification thereof with the proviso that the variations or modifications fall within the scope as defined in the appended claims or their equivalents.

Claims

PATENT ATTORNEY DOCKET NO.: 296567-0 What is claimed is:

1. A crystalline form of a compound of Formula (I): , wherein the pattern comprising peaks at the± 0.2 degrees for each peak, wherein 1 X-rays at a wavelength of 1.5406 Angstroms (Å).

2. The crystalline form of Claim 1, wherein the XRPD pattern further comprises at least one peak at the diffraction angle (2θ) selected from the group consisting of 14.90, 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees.

3. The crystalline form of Claim 1, wherein the XRPD pattern comprises a peak at the diffraction angle (2θ) of 14.90 degrees, ± 0.2 degrees 2θ.

4. The crystalline form of Claim 1 or 3, wherein the XRPD pattern comprises at least one peak at the diffraction angle (2θ) selected from the group consisting of 17.34 and 21.16 degrees, ± 0.2 degrees 2θ.

5. The crystalline form of Claim 3, wherein the XRPD pattern comprises at least three peaks at the diffraction angles (2θ) selected from the group consisting of 17.34, 18.42, 19.56, and 21.16 degrees, ± 0.2 degrees 2θ for each peak.

6. The crystalline form of any one of Claims 1-5, wherein the XRPD pattern further comprises a peak at the diffraction angle (2θ) of 26.90 ± 0.2 degrees 2θ, a peak at the diffraction angle (2θ) of 28.60 ± 0.2 degrees 2θ, or two peaks at the diffraction angle (2θ) of 26.90 and 28.60 ± 0.2 degrees 2θ.

7. The crystalline form of Claim 1, wherein the XRPD pattern is substantially the same as shown in Figure 1 or 45.

8. The crystalline form of Claim 1, which shows an exothermic peak at about 227 °C in the differential scanning calorimetry (DSC) thermogram.

9. The crystalline form of Claim 1, which shows an exothermic event in the initial heat at onset about 224 °C.

10. The crystalline form of Claim 1, which substantially contains no organic solvent molecules.PATENT ATTORNEY DOCKET NO.: 296567-0 11. The crystalline form of Claim 1, which is an anhydrous crystalline form.

12. A crystalline form of a hydrate of a compound of Formula (I): , wherein the (XRPD) pattern comprising theand 26.86, degrees, ± 0.2 degrees 2θ using copper K-alpha 1 X-rays at a wavelength of 1.5406 Angstroms (Å).

13. The crystalline form of claim 12, wherein the XRPD pattern further comprises at least one peak at the diffraction angle (2θ) selected from the group consisting of 13.12, 15.76 and 19.32 degrees, ± 0.2 degrees 2θ.

14. The crystalline form of claim 13, wherein the XRPD pattern comprises at least two peaks at the diffraction angles (2θ) selected from those at 13.12, 14.32, 15.76 and 19.32 degrees, ± 0.2 degrees 2θ for each peak.

15. The crystalline form of any one of claims 12 to 14, wherein the XRPD pattern further comprises at least one peak at the diffraction angle (2θ) selected from the group consisting of 27.46, and 29.74 degrees, ± 0.2 degrees 2θ.

16. The crystalline form of claim 12, wherein the XRPD pattern is substantially the same as shown in Figure 5.

17. The crystalline form of claim 12, which shows an endothermic peak at about 64 °C and an exothermic peak at about 218 °C in the differential scanning calorimetry (DSC) thermogram.

18. The crystalline form of claim 12, which shows an endothermic event in the initial heat at onset about 44 °C and an exothermic event in the initial heat at onset about 213 °C.

19. The crystalline form of claim 12, which substantially contains no organic solvent molecules.

20. The crystalline form of claim 12, which contains an water content of about 3.48±0.5 wt.%.

21. A pharmaceutical composition comprising a crystalline form according to any one of Claims 1-11, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a crystalline form according to any one of Claims 11-20, and a pharmaceutically acceptable carrier.PATENT ATTORNEY DOCKET NO.: 296567-0 23. A method for promoting neurite outgrowth in a subject in need thereof, wherein said subject is administered with an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22.

24. A method of treating an HDAC-associated disease or disorder in a subject in need thereof, comprising administering an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22 to the subject.

25. The method of Claim 24, wherein the HDAC-associated disease or disorder is neuropathic related diseases.

26. The method of Claim 25, wherein the neuropathic related diseases are selected from the group consisting of diabetic neuropathy, post-herpes zoster pain, postherpetic neuralgia from shingles and chemotherapy-induced peripheral neuropathy.

27. The method according to claim 26, wherein the chemotherapy is platinum-based chemotherapy, alkaloid-based, or taxane-based chemotherapy.

28. A method for enhancing tubulin hyperacetylation of cells in a subject, wherein said subject is treated with an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22.

29. A method for the prevention or treatment of fibrosis of a subject, wherein said subject is administered with an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22.

30. The method according to claim 29, wherein said fibrosis is pulmonary fibrosis, hepatic fibrosis, or renal fibrosis.

31. The method according to claim 30, wherein said pulmonary fibrosis is associated with increased expression of IL-1, TNF-α, TL-6 or Collagens in said subject.

32. The method according to claim 30, wherein said pulmonary fibrosis is idiopathic pulmonary fibrosis or virus-induced fibrosis.

33. A method of decreasing expression of IL-1, TNF-α, IL-6 or Collagens in a subject in need, wherein said subject is administered with an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22.

34. A method of treating or ameliorating cytokine-induced inflammatory conditions in a subject in need, wherein said cytokine comprises IL-1, TNF-α, TL-6, M-CSF, VCAM-1, or MCP-1, and said subject is administered with an effective amount of a crystalline form according to any one of Claims 1-20 or the pharmaceutical composition of Claim 21 or 22.PATENT ATTORNEY DOCKET NO.: 296567-0 35. The method of claim 34, wherein said conditions are selected from a group consisting of coronavirus-induced pulmonary inflammation, acute respiratory distress syndrome, acute pulmonary inflammation, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

36. A method of preparing a crystalline form according to any one of Claims 1-11, comprising the step of converting another crystalline form of a compound of Formula (I) into the crystalline form according to any one of Claims 1-11.

37. The method of claim 36, wherein the crystalline form according to any one of Claims 1-11 is converted from the crystalline form according to any one of Claims 12-20.

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