Heteroaryl compounds, solid forms, methods of preparation and uses thereof

Abstract

The present invention relates to heteroaryl compounds, solid forms, methods of preparation and uses thereof. In particular, provided herein are crystalline free forms, crystalline salt forms, and pharmaceutical compositions thereof of Compound 1 having the following formula. Also provided herein are methods of making and using the same, e.g., for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202310732317.3, application date June 20, 2023, and invention name “Heteroaryl compounds, solid form, preparation method and use thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to Chinese patent application No. CN202210700943.X filed on June 20, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] In various embodiments, the present disclosure generally relates to novel crystalline forms of Heteroaryl Compounds, compositions comprising the same, methods of making the same, and methods of using the same, e.g., for inhibiting kinases and / or for treating various diseases or disorders, e.g., the autoimmune diseases described herein. Background Art

[0005] The Janus kinase (JAK) family is a small family of receptor-associated tyrosine kinases that are crucial for signaling cascades downstream of type I and type II cytokine receptors. Type I and type II cytokine receptors—which comprise a family of receptors that bind to more than 50 cytokines, interleukins, interferons (IFNs), colony-stimulating factors (CSFs), and hormones—share unique intracellular signaling pathways mediated by JAKs, which bind directly to the intracellular domains of type I and type II cytokine receptors, rather than to cytokine receptors of other classes. JAK-dependent cytokines are major contributors to immunopathology. The dependence of type I and type II cytokines on JAKs has been established in a variety of genetic models, from mutagenic cell lines and knockout mice to humans. Polymorphisms in JAK and signal transducer and activator of transcription (STAT) genes have been associated with autoimmunity, and loss-of-function mutations result in immunodeficiency due to the inability of type I and type II cytokines to signal through their receptors. The critical role of JAKs in type I and type II cytokine signaling suggests that interfering with the activity of these kinases may yield a new class of immunomodulatory drugs.

[0006] New compounds and novel crystalline and salt forms thereof capable of modulating cytokines and / or interferons (e.g., IL-12, IL-23, and / or IFN) provide pharmacological responses that advantageously treat one or more of the conditions described herein and may provide substantial therapeutic benefit to a variety of patients in need thereof. Summary of the Invention

[0007] International application No. PCT / CN2021 / 140271 filed on December 22, 2021 (the contents of which are incorporated herein by reference in their entirety) describes compound 1 having the following formula, which can regulate the function of IL-12, IL-23 and / or IFN.

[0008]

[0009] In various embodiments, the present disclosure relates to Compound 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which can be present, for example, in isolated form, substantially pure form, and / or solid form. Further provided are pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, methods of preparing the same, and methods of using the same.

[0010] Certain embodiments of the present disclosure relate to compound 1, which can be, for example, in substantially pure form and / or solid form. In some embodiments, compound 1 can be amorphous. In some embodiments, compound 1 can be in a crystalline form, such as Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or salt Forms A, B, C, D, E, F, G, H, J, K, or L as described herein. In some embodiments, compound 1 can be substantially pure.

[0011] The compounds of the present disclosure can be used to prepare pharmaceutical compositions. In some embodiments, the pharmaceutical compositions can include one or more compounds of the present disclosure (e.g., Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII of Compound 1, or Forms A, B, C, D, E, F, G, H, J, K, and L, or any combination thereof).

[0012] The pharmaceutical compositions described herein can be formulated for any suitable route of administration. In some embodiments, the pharmaceutical compositions can be formulated for oral administration. For example, in some embodiments, the pharmaceutical compositions can be tablets or capsules.

[0013] In some embodiments, the present disclosure provides a method of inhibiting the function of IL-23, IL-12 and / or IFN-α in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K or L of a salt of Compound 1) or a pharmaceutical composition described herein. Exemplary diseases or conditions that can be treated with the methods described herein include, but are not limited to, those proliferative, metabolic, allergic, autoimmune and / or inflammatory diseases or conditions described herein.

[0014] The compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments, the method for treating IL-23-, IL-12- and / or IFN-related diseases or conditions can include administering the compounds of the present disclosure alone or in combination with each other and / or in combination with other suitable therapeutic agents, which can be used to treat these conditions. Examples of such other suitable therapeutic agents include corticosteroids, rolipram, calciferol, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyarginine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral drugs such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, ); antimalarial drugs such as hydroxychloroquine; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-inhibitors such as tenidap, anti-tumor necrosis factor antibodies or soluble TNF receptors, and rapamycin (sirolimus or ) or its derivatives.

[0015] Administration herein is not limited to any specific route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, abdominal, subcutaneous, intramuscular, intravenous, rectal, intrathoracic, intrathecal, and parenteral. In some embodiments, administration is oral.

[0016] The dosage regimen, including dosage, can vary and be adjusted depending on the subject being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1a A representative X-ray powder diffraction (XRPD) pattern of Form I of Compound 1 is shown. Figure 1b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form I of Compound 1 are shown.

[0019] Figure 2a A representative X-ray powder diffraction (XRPD) pattern of Form II of Compound 1 is shown. Figure 2b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form II of Compound 1 are shown.

[0020] Figure 3a A representative X-ray powder diffraction (XRPD) pattern of Form III of Compound 1 is shown. Figure 3b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form III of Compound 1 are shown. Figure 3c A representative dynamic moisture sorption (DVS) analysis of Form III of Compound 1 is presented.

[0021] Figure 4a A representative X-ray powder diffraction (XRPD) pattern of Form IV of Compound 1 is shown. Figure 4b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form IV of Compound 1 are shown.

[0022] Figure 5a A representative X-ray powder diffraction (XRPD) pattern of Form V of Compound 1 is shown. Figure 5b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form V of Compound 1 are shown.

[0023] Figure 6a A representative X-ray powder diffraction (XRPD) pattern of Form VI of Compound 1 is shown. Figure 6b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form VI of Compound 1 are shown.

[0024] Figure 7a A representative X-ray powder diffraction (XRPD) pattern of Form VII of Compound 1 is shown. Figure 7b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form VII of Compound 1 are shown.

[0025] Figure 8a A representative X-ray powder diffraction (XRPD) pattern of Form VIII of Compound 1 is shown. Figure 8bRepresentative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form VIII of Compound 1 are shown.

[0026] Figure 9a A representative X-ray powder diffraction (XRPD) pattern of Form IX of Compound 1 is shown. Figure 9b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form IX of Compound 1 are shown.

[0027] Figure 10a A representative X-ray powder diffraction (XRPD) pattern of Form X of Compound 1 is shown. Figure 10b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form X of Compound 1 are shown.

[0028] Figure 11a A representative X-ray powder diffraction (XRPD) pattern of Form XI of Compound 1 is shown. Figure 11b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XI of Compound 1 are shown.

[0029] Figure 12a A representative X-ray powder diffraction (XRPD) pattern of Form XII of Compound 1 is shown. Figure 12b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XII of Compound 1 are shown.

[0030] Figure 13a A representative X-ray powder diffraction (XRPD) pattern of Form XIII of Compound 1 is shown. Figure 13b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XIII of Compound 1 are shown.

[0031] Figure 14a A representative X-ray powder diffraction (XRPD) pattern of Form XIV of Compound 1 is shown. Figure 14b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XIV of Compound 1 are shown.

[0032] Figure 15a A representative X-ray powder diffraction (XRPD) pattern of Form XV of Compound 1 is shown. Figure 15b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XV of Compound 1 are shown.

[0033] Figure 16a A representative X-ray powder diffraction (XRPD) pattern of Form XVI of Compound 1 is shown. Figure 16bRepresentative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XVI of Compound 1 are shown.

[0034] Figure 16c A representative X-ray powder diffraction (XRPD) spectrum of Form XVII of Compound 1 is shown. Figure 16d Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form XVII of Compound 1 are shown. Figure 16e A representative representation of Form XVII of Compound 1 is shown. 1 H-NMR spectrum.

[0035] Figure 17a A representative X-ray powder diffraction (XRPD) pattern of the crystalline sulfate salt of Compound 1, Form A, is shown. Figure 17b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline sulfate salt of Compound 1, Form A, are shown. Figure 17c A representative dynamic moisture sorption / desorption (DVS) analysis of the crystalline sulfate salt of Compound 1, Form A, is presented.

[0036] Figure 18a A representative X-ray powder diffraction (XRPD) pattern of the crystalline sulfate salt of Compound 1, Form B, is shown. Figure 18b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline sulfate salt of Compound 1, Form B, are shown. Figure 18c A representative dynamic moisture sorption / desorption (DVS) analysis of the crystalline sulfate salt of Compound 1, Form B, is presented.

[0037] Figure 19a A representative X-ray powder diffraction (XRPD) pattern of the crystalline sulfate salt of Compound 1, Form C, is shown. Figure 19b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline sulfate salt of Compound 1, Form C, are shown.

[0038] Figure 20a A representative X-ray powder diffraction (XRPD) pattern of the crystalline besylate salt Form D of Compound 1 is shown. Figure 20b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline besylate salt of Compound 1, Form D, are shown.

[0039] Figure 21a A representative X-ray powder diffraction (XRPD) pattern of Form E of the crystalline phosphate salt of Compound 1 is shown. Figure 21b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline phosphate salt of Compound 1, Form E, are shown. Figure 21cA representative dynamic moisture sorption (DVS) analysis of the crystalline phosphate salt of Compound 1, Form E, is presented.

[0040] Figure 22a A representative X-ray powder diffraction (XRPD) pattern of the crystalline mesylate salt Form F of Compound 1 is shown. Figure 22b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline mesylate salt Form F of Compound 1 are shown.

[0041] Figure 23a A representative X-ray powder diffraction (XRPD) pattern of the crystalline mesylate salt Form G of Compound 1 is shown. Figure 23b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline mesylate salt Form G of Compound 1 are shown. Figure 23c The representativeness of the crystalline mesylate salt form G of compound 1 and its free form is given. 1 Comparison of H-NMR spectra.

[0042] Figure 24a A representative X-ray powder diffraction (XRPD) pattern of the crystalline potassium salt of Compound 1, Form H, is shown. Figure 24b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline potassium salt of Compound 1, Form H, are shown.

[0043] Figure 25a A representative X-ray powder diffraction (XRPD) pattern of Form J of the crystalline potassium salt of Compound 1 is shown. Figure 25b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline potassium salt of Compound 1, Form J, are shown.

[0044] Figure 26a A representative X-ray powder diffraction (XRPD) pattern of the crystalline choline salt of Compound 1, Form K, is shown. Figure 26b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of Form K, the choline salt of Compound 1, are shown. Figure 26c A representative dynamic moisture sorption / desorption (DVS) analysis of the crystalline choline salt of Compound 1, Form K, is presented.

[0045] Figure 27a A representative X-ray powder diffraction (XRPD) pattern of the crystalline choline salt of Compound 1, Form L, is shown. Figure 27b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline choline salt of Compound 1, Form L, are shown. Figure 27c A representative example of the crystalline choline salt of compound 1, Form L, is given. 1 H-NMR spectrum. DETAILED DESCRIPTION

[0046] In various embodiments, the present disclosure relates to Compound 1 or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, which may be, for example, in isolated form, substantially pure form and / or solid form. As shown in the Examples section, various polymorphic forms of Compound 1 have been discovered. Among these polymorphic forms, Form III of Compound 1 has been found to be stable and, compared to other crystalline forms, may be used for various pharmaceutical applications. Compound 1 has the following molecular formula:

[0047]

[0048] As described in International Application No. PCT / CN2021 / 140271 filed on December 22, 2021, the contents of which are incorporated herein by reference in their entirety. As tested in the aforementioned patent application, the IC of HEK BlueIL23 of Compound 1 50 The present invention has a pharmacokinetics value of 2.5 nM and has advantages in, for example, human liver microsomal stability, rat pharmacokinetics and selectivity of TYK2 relative to JAK1, and thus it can be used to treat various diseases or conditions, such as those described herein, such as autoimmune and / or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and / or scleroderma.

[0049] Compound 1

[0050] In some embodiments, the present disclosure relates to Compound 1 or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof. Compound 1 should be understood to be in its free state, thereby distinguishing it from salts formed by external acids or bases. Unless otherwise apparent from the context, Compound 1 should be understood to be in the free state in question.

[0051] Compound 1 can be synthesized by the method described in International Application No. PCT / CN2021 / 140271 filed on December 22, 2021, the contents of which are incorporated herein by reference in their entirety. The present disclosure provides an improved method for preparing Compound 1, comprising the following steps:

[0052] Step 1: Compound 1-1 reacts with (2,4-dimethoxyphenyl)methylamine to produce compound 1-2;

[0053]

[0054] Step 2: Compound 1-2 reacts with cyclopropanecarbonyl chloride to produce compound 1-3;

[0055]

[0056] Step 3: Compound 1-3 is oxidized to produce compound 1-4;

[0057]

[0058] Step 4: Compound 1-4 is treated by removing the (2,4-dimethoxyphenyl)methylene group to produce compound 1;

[0059]

[0060] Each step in the above synthesis method is easy to carry out and can achieve high yields, resulting in a high overall yield. The resulting product has a high purity of greater than 99% and is low in impurities. Therefore, this novel synthesis method is suitable for large-scale production.

[0061] In some embodiments, step 1 can be performed using cesium fluoride in N-methylpyrrolidone. In some embodiments, step 2 can be performed at a temperature of about 50-80° C., preferably about 60-70° C., and more preferably about 65° C. In some embodiments, step 3 can be performed using potassium peroxodisulfate as an oxidizing agent. In some embodiments, step 4 can be performed using an acid, such as trifluoroacetic acid.

[0062] In some embodiments, compound 1 can be a solid form, such as an amorphous form, a crystalline form, or a combination thereof. In some embodiments, compound 1 can be an amorphous form. In some embodiments, compound 1 can be a crystalline form (e.g., in any one or more crystalline forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, as described herein). As used herein, when compound 1 is said to exist or to exist in a specific solid form (e.g., crystalline form), it should be understood that in certain embodiments, the compound can exist mainly in this specific form. However, in some embodiments, the compound can also exist in a specific form, in a mixture (including amorphous form) with one or more other solid forms. For example, when Compound 1 is said to exist or be in Form III, Compound 1 may exist primarily in Form III, e.g., greater than 80% by weight, greater than 90% by weight, or greater than 95% by weight of Compound 1 is in Form III, or no other solid forms can be identified, e.g., by XRPD; or, in some embodiments, Compound 1 may exist in a mixture of Form III and one or more solid forms, such as an amorphous form.

[0063] Compound 1 herein is generally in a substantially pure form. For example, in some embodiments, compound 1 can have a purity greater than 70%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, greater than 98.5%), by weight, by HPLC area, or both. In some embodiments, compound 1 is characterized in that the purity by weight and / or HPLC area is about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99% or any range between the specified values. For example, in some embodiments, compound 1 is characterized in that the purity by HPLC area is about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99% or any range between the specified values. Substantially pure compound 1 can be a solid form (e.g., crystalline free or salt form, amorphous form, or a combination thereof as described herein) or a solution, suspension, or other form. In some embodiments, substantially pure compound 1 can be Form III. For the avoidance of doubt, a composition comprising substantially pure Compound 1 herein and one or more other ingredients should be understood as a mixture of substantially pure Compound 1 herein and one or more other ingredients, for example, such a composition can be obtained directly or indirectly by mixing substantially pure Compound 1 with one or more other ingredients, such as a solvent, a pharmaceutically acceptable excipient, etc.

[0064] In some embodiments, Compound 1 is in crystalline form. In some embodiments, Compound 1 is Form I. The characteristics of Form I include any of those described herein. In some embodiments, Form I can be characterized by: (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.5°, 11.7°, 20.9°, 22.3°, 23.6°, 24.8°, 25.3°, 26.5°, 27.0°, and 30.2° (2θ, ±0.2°); (2) an XRPD pattern having peaks at 2θ, ±0.2°, and 30.2° (2θ); Figure 1a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 1b or any combination thereof (e.g., (1) and (3), or (2) and (3)). In some embodiments, Form I may be characterized by having Figure 1a Or the characteristic peaks of the XRPD pattern shown in Table 1 (e.g., relative intensity of 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more) (2θ, ±0.2°). It should be understood that when it is said that the XRPD pattern of Form I has Figure 1a or the characteristic peaks in Table 1 or Figure 1aIt does not require the XRPD pattern to be substantially the same as Figure 1a or the same relative intensities as the corresponding peaks shown in Table 1 (if applicable). The XRPD pattern includes the peaks corresponding to Figure 1a or peaks at the corresponding diffraction angles (2θ, ±0.2°) of the peaks shown in Table 1 (if applicable) are sufficient, regardless of their relative intensities. Similar expressions concerning other crystalline forms herein should be understood in a similar manner.

[0065] In some embodiments, Compound 1 is in Form II, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.1°, 7.7°, 11.1°, 12.3°, 20.4°, 21.7°, 22.7°, 24.7°, 26.9°, and 27.5° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 2a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 2b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0066] In some embodiments, Compound 1 is in Form III, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.0°, 9.7°, 14.1°, 14.5°, 17.2°, 18.2°, 19.6°, 21.3°, 24.1°, and 27.0° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 1.5° (e.g., 2.5° (e.g., ... Figure 3a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 3b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0067] In some embodiments, Form III of Compound 1 can be obtained by slurrying Form I in acetone, preferably slurrying in acetone at 35-75° C. for 1 hour to 2 days. Alternatively, Form III of Compound 1 can be obtained by first slurrying Compound 1 in tetrahydrofuran, and then slurrying in ethanol and water. Preferably, the Form III is obtained by first slurrying Compound 1 in tetrahydrofuran at 55-75° C. for 0.5 to 5 hours, and then slurrying in ethanol and water at 60-80° C. for 6 to 48 hours.

[0068] In some embodiments, Compound 1 is in Form IV, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 5.6°, 7.6°, 11.3°, 15.2°, 21.0°, 21.7°, 22.8°, 24.0°, and 26.8° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 1.5° (e.g., 2.5° (e.g., ... Figure 4a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 4b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0069] In some embodiments, Compound 1 is in Form V, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 4.8°, 8.7°, 9.7°, 12.6°, 14.7°, 17.6°, 20.8°, 24.6°, 25.5°, and 27.6° (2θ, ±0.2°); and (2) an XRPD pattern having a peak of 4.8°, 8.7°, 9.7°, 12.6°, 14.7°, 17.6°, 20.8°, 24.6°, 25.5°, and 27.6° (2θ, ±0.2°). Figure 5a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 5b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0070] In some embodiments, Compound 1 is in Form VI, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 13.3°, 14.5°, 17.8°, 21.9°, 22.2°, 24.6°, 25.0°, 27.1°, and 27.4° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 100 nm (e.g., 200 nm) and ... Figure 6a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 6b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0071] In some embodiments, Compound 1 is in Form VII, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.1°, 6.6°, 6.9°, 7.5°, 9.4°, 13.9°, 18.7°, 20.9°, 22.7°, and 27.6° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 7a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 7b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0072] In some embodiments, Compound 1 is in Form VIII, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.7°, 7.4°, 9.4°, 13.6°, 18.7°, 19.0°, 20.8°, 21.9°, 23.6°, and 35.7° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 8a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 8b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0073] In some embodiments, Compound 1 is in Form IX, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 7, or 8) of the following peaks: 6.2°, 7.2°, 12.6°, 18.9°, 19.2°, 21.2°, 22.0°, and 23.1° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 9a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 9b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0074] In some embodiments, Compound 1 is in Form X, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 7.4°, 7.9°, 9.4°, 11.7°, 20.7°, 22.0°, 22.6°, 23.6°, and 26.4° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 100 nm (2θ) and ... Figure 10a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 10b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0075] In some embodiments, Compound 1 is Form XI, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.6°, 6.0°, 6.4°, 7.5°, 11.3°, 12.2°, 19.0°, 22.7°, 24.3°, and 25.0° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 1.5° (e.g., 2.5° (e.g., ... Figure 11a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 11bare substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0076] In some embodiments, Compound 1 is in Form XII, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.9°, 6.4°, 8.7°, 11.0°, 11.9°, 13.5°, 19.3°, 19.5°, 24.0°, and 24.9° (2θ, ±0.2°); (2) an XRPD pattern having a peak at or below 5.9°, 6.4°, 8.7°, 11.0°, 11.9°, 13.5°, 19.3°, 19.5°, 24.0°, and 24.9° (2θ, ±0.2°); Figure 12a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 12b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0077] In some embodiments, Compound 1 is in Form XIII, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) of the following peaks: 7.4°, 7.8°, 9.7°, 15.6°, 20.8°, 22.2°, and 22.6° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 13a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 13b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0078] In some embodiments, Compound 1 is Form XIV, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.5°, 8.6°, 10.3°, 11.1°, 15.6°, 17.5°, 19.8°, 20.8°, 23.1°, and 26.4° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 14a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 14b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0079] In some embodiments, Compound 1 is in Form XV, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, or 6) of the following peaks: 7.5°, 7.8°, 9.3°, 20.5°, 21.5°, and 22.4° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 15a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 15bare substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0080] In some embodiments, Compound 1 is Form XVI, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.9°, 7.2°, 7.9°, 9.4°, 15.9°, 16.7°, 20.4°, 21.1°, 22.5°, and 26.0° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 16a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 16b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0081] In some embodiments, Compound 1 is Form XVII, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.1°, 8.8°, 12.0°, 14.7°, 17.7°, 19.1°, 19.5°, 20.9°, 22.7°, and 24.3° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 16c (3) Differential Scanning Calorimetry (DSC) spectra and Figure 16d are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0082] In some embodiments, Compound 1 is a crystalline salt form. Representative salts of Compound 1 include, but are not limited to, water-soluble and water-insoluble salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, bromide, butyrate, calcium salt, chloride, choline, citrate, salicylate, fumarate, gluconate, gluconic acid, glutamate, hydrobromide, hydrochloride, lauryl sulfate, malate, maleate, mandelate, methanesulfonate, palmitate, pantothenate, phosphate, potassium salt, propionate, p-toluenesulfonate, salicylate, sodium salt, stearate, succinate, and sulfate.

[0083] In some embodiments, Compound 1 is a crystalline sulfate salt, Form A, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) of the following peaks: 7.2°, 18.9°, 21.2°, 22.0°, 23.0°, 25.3°, and 26.7° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 1.5°, 2.5°, 3.0°, 4.5°, 5.0°, and 7.0° (2θ, ±0.2°); Figure 17a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 17b substantially the same as shown in (1) and (3), or (2) and (3).

[0084] In some embodiments, Compound 1 is crystalline sulfate Form B characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.3°, 10.2°, 11.6°, 12.8°, 14.8°, 20.6°, 22.3°, 22.7°, 23.4°, and 25.8° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 18a substantially the same as shown in (1) and (3), or (2) and (3). Figure 18b substantially the same as shown in (1) and (3), or (2) and (3).

[0085] In some embodiments, Compound 1 is crystalline sulfate Form C characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.5°, 8.9°, 14.0°, 14.5°, 17.6°, 18.0°, 19.5°, 21.7°, 23.4°, and 24.6° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 19a substantially the same as shown in (1) and (3), or (2) and (3). Figure 19b substantially the same as shown in (1) and (3), or (2) and (3).

[0086] In some embodiments, Compound 1 is crystalline besylate Form D characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.3°, 6.9°, 7.7°, 8.2°, 9.7°, 12.7°, 13.9°, 14.7°, 18.6°, and 21.2° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 20a substantially the same as shown in (1) and (3), or (2) and (3). Figure 20b substantially the same as shown in (1) and (3), or (2) and (3).

[0087] In some embodiments, Compound 1 is a crystalline phosphate salt, Form E, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 9.8°, 11.2°, 12.6°, 14.5°, 18.0°, 19.8°, 21.8°, 22.5°, and 25.3° (2θ, ±0.2°); (2) an XRPD pattern having a peak of Figure 21a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 21b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0088] In some embodiments, Compound 1 is a crystalline mesylate salt, Form F, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 7, or 8) of the following peaks: 6.9°, 7.3°, 8.5°, 13.8°, 17.2°, 22.3°, 22.6°, and 27.8° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 100 nm (2θ) and ... Figure 22a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 22b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0089] In some embodiments, Compound 1 is a crystalline mesylate salt, Form G, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 7.1°, 8.5°, 13.9°, 14.1°, 17.5°, 20.6°, 21.4°, 22.2°, and 28.7° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 100 nm (2θ, ±0.2°); Figure 23a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 23b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0090] In some embodiments, Compound 1 is a crystalline potassium salt, Form H, characterized in that (1) an X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.7°, 7.9°, 10.4°, 16.0°, 17.5°, 21.9°, 22.5°, 22.8°, 23.0°, and 23.4° (2θ, ±0.2°); (2) an XRPD pattern having a peak of 1.5°, 2.5°, 2.8°, 2.3°, and 2.5° (2θ, ±0.2°); Figure 24a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 24bsubstantially the same as shown in (1) and (3), or (2) and (3).

[0091] In some embodiments, Compound 1 is a crystalline potassium salt Form J characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 10.0°, 11.9°, 16.2°, 19.1°, 20.8°, 21.9°, 22.5°, 23.5°, and 26.9° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 25a substantially the same as shown in (1) and (3), or (2) and (3). Figure 25b substantially the same as shown in (1) and (3), or (2) and (3).

[0092] In some embodiments, Compound 1 is a crystalline choline salt Form K characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.4°, 11.3°, 12.9°, 17.9°, 19.8°, 21.2°, 22.7°, 23.8°, 24.2°, 25.0°, and 26.0° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 26a substantially the same as shown in (1) and (3), or (2) and (3). Figure 26b substantially the same as shown in (1) and (3), or (2) and (3).

[0093] In some embodiments, Compound 1 is a crystalline choline salt Form L characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 9.9°, 11.1°, 13.2°, 16.8°, 19.9°, 21.9°, 23.2°, 23.6°, and 25.5° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 27a substantially the same as shown in (1) and (3), or (2) and (3). Figure 27b substantially the same as shown in (1) and (3), or (2) and (3).

[0094] In some embodiments, the present disclosure also provides solid forms of Compound 1, which can be prepared by any applicable method described in the Examples section.

[0095] In some embodiments, the present disclosure also relates to any products made by any of the methods herein, as well as methods of using such products.

[0096] The present application provides the following embodiments:

[0097] 1. A compound of the formula:

[0098]

[0099] 2. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, in solid form, e.g., an amorphous form, a crystalline form, or a combination thereof.

[0100] 3. The compound according to embodiment 1, which is crystalline Form I, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.5°, 11.7°, 20.9°, 22.3°, 23.6°, 24.8°, 25.3°, 26.5°, 27.0°, and 30.2° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 1a ; (3) a differential scanning calorimetry (DSC) pattern substantially the same as shown in Figure 1b ; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0101] and / or

[0102] which is crystalline Form II, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.1°, 7.7°, 11.1°, 12.3°, 20.4°, 21.7°, 22.7°, 24.7°, 26.9°, and 27.5° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 2a ; (3) a differential scanning calorimetry (DSC) pattern substantially the same as shown in Figure 2b ; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0103] and / or

[0104] which is crystalline Form III, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.0°, 9.7°, 14.1°, 14.5°, 17.2°, 18.2°, 19.6°, 21.3°, 24.1°, and 27.0° (2Θ, ±0.2°); (2) an XRPD pattern substantially the same as shown in Figure 3a ; (3) a differential scanning calorimetry (DSC) pattern substantially the same as shown in Figure 3bare substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0105] and / or

[0106] It is Form IV, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 5.6°, 7.6°, 11.3°, 15.2°, 21.0°, 21.7°, 22.8°, 24.0°, and 26.8° (2θ, ±0.2°); (2) the XRPD pattern is Figure 4a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 4b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0107] and / or

[0108] It is Form V, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 4.8°, 8.7°, 9.7°, 12.6°, 14.7°, 17.6°, 20.8°, 24.6°, 25.5°, and 27.6° (2θ, ±0.2°); (2) the XRPD pattern is Figure 5a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 5b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0109] and / or

[0110] It is Form VI, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 13.3°, 14.5°, 17.8°, 21.9°, 22.2°, 24.6°, 25.0°, 27.1°, and 27.4° (2θ, ±0.2°); (2) the XRPD pattern is Figure 6a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 6b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0111] and / or

[0112] It is Form VII, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.1°, 6.6°, 6.9°, 7.5°, 9.4°, 13.9°, 18.7°, 20.9°, 22.7°, and 27.6° (2θ, ±0.2°); (2) the XRPD pattern is Figure 7a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 7b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0113] and / or

[0114] It is Form VIII, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.7°, 7.4°, 9.4°, 13.6°, 18.7°, 19.0°, 20.8°, 21.9°, 23.6°, and 35.7° (2θ, ±0.2°); (2) the XRPD pattern is Figure 8a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 8b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0115] and / or

[0116] It is Form IX, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 7, or 8) of the following peaks: 6.2°, 7.2°, 12.6°, 18.9°, 19.2°, 21.2°, 22.0°, and 23.1° (2θ, ±0.2°); (2) the XRPD pattern is Figure 9a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 9b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0117] and / or

[0118] It is Form X, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 7.4°, 7.9°, 9.4°, 11.7°, 20.7°, 22.0°, 22.6°, 23.6°, and 26.4° (2θ, ±0.2°); (2) the XRPD pattern is Figure 10a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 10bare substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0119] and / or

[0120] It is Form XI, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.6°, 6.0°, 6.4°, 7.5°, 11.3°, 12.2°, 19.0°, 22.7°, 24.3°, and 25.0° (2θ, ±0.2°); (2) the XRPD pattern is Figure 11a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 11b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0121] and / or

[0122] It is Form XII, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.9°, 6.4°, 8.7°, 11.0°, 11.9°, 13.5°, 19.3°, 19.5°, 24.0°, and 24.9° (2θ, ±0.2°); (2) the XRPD pattern is Figure 12a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 12b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0123] and / or

[0124] It is Form XIII, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) of the following peaks: 7.4°, 7.8°, 9.7°, 15.6°, 20.8°, 22.2°, and 22.6° (2θ, ±0.2°); (2) the XRPD pattern is Figure 13a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 13b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0125] and / or

[0126] It is Form XIV, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 5.5°, 8.6°, 10.3°, 11.1°, 15.6°, 17.5°, 19.8°, 20.8°, 23.1°, and 26.4° (2θ, ±0.2°); (2) the XRPD pattern is Figure 14a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 14b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0127] and / or

[0128] It is Form XV, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, or 6) of the following peaks: 7.5°, 7.8°, 9.3°, 20.5°, 21.5°, and 22.4° (2θ, ±0.2°); (2) the XRPD pattern is Figure 15a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 15b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0129] and / or

[0130] It is Form XVI, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.9°, 7.2°, 7.9°, 9.4°, 15.9°, 16.7°, 20.4°, 21.1°, 22.5°, and 26.0° (2θ, ±0.2°); (2) the XRPD pattern is Figure 16a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 16b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0131] and / or

[0132] It is Form XVII, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.1°, 8.8°, 12.0°, 14.7°, 17.7°, 19.1°, 19.5°, 20.9°, 22.7°, and 24.3° (2θ, ±0.2°); (2) the XRPD pattern is substantially the same as that shown in FIG16B-a; (3) the differential scanning calorimetry (DSC) pattern is substantially the same as that shown in FIG16B-b; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0133] 4. The compound according to embodiment 1, which is a sulfate salt crystalline form A, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) of the following peaks: 7.2°, 18.9°, 21.2°, 22.0°, 23.0°, 25.3°, and 26.7° (2θ, ±0.2°); (2) the XRPD pattern is Figure 17a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 17b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0134] and / or

[0135] It is sulfate salt form B, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.3°, 10.2°, 11.6°, 12.8°, 14.8°, 20.6°, 22.3°, 22.7°, 23.4°, and 25.8° (2θ, ±0.2°); (2) the XRPD pattern is Figure 18a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 18b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0136] and / or

[0137] It is a sulfate salt crystal form C, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.5°, 8.9°, 14.0°, 14.5°, 17.6°, 18.0°, 19.5°, 21.7°, 23.4°, and 24.6° (2θ, ±0.2°); (2) the XRPD pattern is Figure 19a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 19bare substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0138] and / or

[0139] It is a benzenesulfonate salt form D, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.3°, 6.9°, 7.7°, 8.2°, 9.7°, 12.7°, 13.9°, 14.7°, 18.6°, and 21.2° (2θ, ±0.2°); (2) the XRPD pattern is Figure 20a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 20b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0140] and / or

[0141] It is a phosphate crystal form E, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 9.8°, 11.2°, 12.6°, 14.5°, 18.0°, 19.8°, 21.8°, 22.5°, and 25.3° (2θ, ±0.2°); (2) the XRPD pattern is Figure 21a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 21b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0142] and / or

[0143] It is a mesylate salt crystalline form F, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) of the following peaks: 6.9°, 7.3°, 8.5°, 13.8°, 17.2°, 22.3°, 22.6°, and 27.8° (2θ, ±0.2°); (2) the XRPD pattern is Figure 22a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 22b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0144] and / or

[0145] It is a mesylate salt form G, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 7.1°, 8.5°, 13.9°, 14.1°, 17.5°, 20.6°, 21.4°, 22.2°, and 28.7° (2θ, ±0.2°); (2) the XRPD pattern is Figure 23a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 23b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0146] and / or

[0147] It is a potassium salt crystal form H, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.7°, 7.9°, 10.4°, 16.0°, 17.5°, 21.9°, 22.5°, 22.8°, 23.0°, and 23.4° (2θ, ±0.2°); (2) the XRPD pattern is Figure 24a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 24b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0148] and / or

[0149] It is a potassium salt crystal form J, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 10.0°, 11.9°, 16.2°, 19.1°, 20.8°, 21.9°, 22.5°, 23.5°, and 26.9° (2θ, ±0.2°); (2) the XRPD pattern is Figure 25a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 25b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0150] and / or

[0151] It is a choline salt crystal form K, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, 10, or 11) of the following peaks: 7.4°, 11.3°, 12.9°, 17.9°, 19.8°, 21.2°, 22.7°, 23.8°, 24.2°, 25.0°, and 26.0° (2θ, ±0.2°); (2) the XRPD pattern is Figure 26a(3) Differential Scanning Calorimetry (DSC) spectra and Figure 26b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0152] and / or

[0153] It is a choline salt crystal form L, characterized in that (1) the X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.2°, 9.9°, 11.1°, 13.2°, 16.8°, 19.9°, 21.9°, 23.2°, 23.6°, and 25.5° (2θ, ±0.2°); (2) the XRPD pattern is Figure 27a (3) Differential Scanning Calorimetry (DSC) spectra and Figure 27b are substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)).

[0154] 5. The compound according to any one of embodiments 1-4, which is substantially pure.

[0155] 6. A pharmaceutical composition comprising the compound according to any one of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, and optionally a pharmaceutically acceptable excipient.

[0156] 7. A method for modulating the function of IL-12, IL-23 and / or interferon alpha and / or treating or preventing a proliferative, metabolic, allergic, autoimmune and / or inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0157] 8. The method of embodiment 7, wherein the disease or condition is cancer, an autoimmune disease, an inflammatory disease and / or a metabolic disease, such as type 2 diabetes or atherosclerosis; preferably selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome and scleroderma.

[0158] 9. A method for preparing compound 1, comprising:

[0159] Step 4: Deprotection of compound 1-4 to produce compound 1

[0160]

[0161] and / or

[0162] It includes:

[0163] Step 3: Oxidation of compound 1-3 to produce compound 1-4

[0164]

[0165] and / or

[0166] It includes:

[0167] Step 2: Acylation of compound 1-2 with cyclopropanecarbonyl chloride to produce compound 1-3;

[0168]

[0169] and / or

[0170] It includes:

[0171] Step 1: reacting compound 1-1 with (2,4-dimethoxyphenyl)methanamine to produce compound 1-2;

[0172]

[0173] 10. The method according to embodiment 9, wherein step 4 comprises deprotecting compound 1-4 with an acid (such as trifluoroacetic acid);

[0174] and / or

[0175] Wherein step 3 comprises using potassium persulfate complex salt as an oxidant to oxidize compound 1-3;

[0176] and / or

[0177] wherein step 2 is carried out at a temperature of about 50-80° C., preferably about 60-70° C., and more preferably about 65° C.;

[0178] and / or

[0179] Wherein step 1 is carried out in N-methylpyrrolidone in the presence of cesium fluoride.

[0180] Pharmaceutical composition

[0181] In various embodiments, the present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, such as Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1 as described herein, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, and optionally a pharmaceutically acceptable excipient. Non-limiting suitable excipients include, for example, encapsulating materials or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, fillers, fillers, flavorings, wetting agents, lubricants, fragrances, preservatives, propellants, release agents, sterilants, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st ed., AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; herein incorporated by reference in its entirety), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0182] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, or any combination thereof), for example, in a therapeutically effective amount. In any embodiment described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof.

[0183] The pharmaceutical composition may also be formulated for administration by any known delivery route including, but not limited to, oral, parenteral, inhalation, and the like.

[0184] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be presented as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients used to prepare compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, peanut oil, hydroxypropyl methylcellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0185] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous injection or intramuscular injection). Parenteral formulations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, glucose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0186] In some embodiments, the pharmaceutical composition is formulated for inhalation. For example, the inhalable formulation can be formulated as a nasal spray, a dry powder, or an aerosol that can be administered by a metered dose inhaler. Excipients for preparing inhalation formulations are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, as well as mixtures of these substances. Sprays may also contain propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0187] Pharmaceutical compositions can include various amounts of the compounds of the disclosure, depending on various factors, such as the intended use and potency and selectivity of the compound. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the disclosure (e.g., a crystalline form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or a salt crystalline form A, B, C, D, E, F, G, H, J, K, or L thereof, or in any combination). In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the disclosure is an amount effective to treat a disease or disorder described herein, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s disease, Sjogren’s syndrome, and / or scleroderma, which can depend on the subject being treated, the disease or disorder being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of the treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0188] For veterinary use, the compounds of the disclosure can be administered as appropriate acceptable formulations in accordance with normal veterinary practice. The veterinarian can determine the optimum dosage regimen and route of administration most appropriate for a particular animal.

[0189] In some embodiments, all of the necessary components for treating a disease or disorder mediated by IL-12, IL-23, and / or interferon-alpha (INF-alpha), using a compound of the disclosure, whether used alone or in combination with another drug or intervention traditionally used to treat such a disease, can be packaged into a kit. Specifically, in some embodiments, the present application provides a kit for a disease treatment intervention, comprising a set of packaged medicaments, including a compound disclosed herein, and buffers and other components for preparing the medicaments in deliverable form, and / or devices for delivering such medicaments, and / or any agents to be used in conjunction with the compound of the disclosure for treatment, and / or disease treatment instructions packaged with the medicaments. The instructions can be fixed in any tangible medium, e.g., printed paper, or computer-readable media, or the instructions can be fixed on a computer data signal, e.g., a web page custom designed for the intended recipient. The instructions can be fixed in any tangible medium, e.g., printed paper, or computer-readable media, or the instructions can be fixed on a computer data signal, e.g., a web page custom designed for the intended recipient.

[0190] Methods of treatment

[0191] The compounds of the present disclosure can be used to treat disorders associated with modulation of the function of IL-23, IL-12, and / or IFN-a. These disorders include IL-23-, IL-12-, and / or IFN-a-associated diseases, where the pathogenic mechanism is mediated by these cytokines, including any of those known in the art and those described herein.

[0192] In some embodiments, the present disclosure provides a method of inhibiting the function of IL-23, IL-12, and / or IFN-a in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0193] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder associated with IL-23, IL-12, and / or IFN-a, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof). Suitable diseases or disorders associated with IL-23, IL-12, and / or IFN-a that can be treated using the methods herein include any of those known in the art and exemplary diseases or disorders associated with IL-23, IL-12, and / or IFN-a that can be treated using the methods described herein also include, but are not limited to, those proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or disorders described herein.

[0194] In some embodiments, the present disclosure provides a method of treating or preventing a proliferative, metabolic, allergic, autoimmune, and / or inflammatory disease or disorder, e.g., as described herein, in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0195] In some embodiments, the present disclosure provides methods of treating or preventing autoimmune and / or inflammatory diseases or conditions, such as those described herein, in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, or any combination thereof).

[0196] In some embodiments, the present disclosure provides methods of treating or preventing a metabolic disease or disorder, such as those described herein, such as type 2 diabetes or atherosclerosis, in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, or any combination thereof).

[0197] In some embodiments, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, or any combination thereof).

[0198] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 of crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt crystalline Form A, B, C, D, E, F, G, H, J, K, or L thereof, or any combination thereof), wherein the disease or disorder can be one or more diseases or disorders selected from the group consisting of: inflammatory diseases, such as Crohn’s disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases, such as Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; autoinflammatory diseases including CAPS, TRAPS, FMF, adult onset still’s disease (AOSD), systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone diseases, such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma related bone disease; proliferative diseases, such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic diseases, such as angiogenic diseases, including solid tumors, ocular neovascularization, and infantile hemangioma; infectious diseases, such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury, neoplastic and viral diseases such as metastatic melanoma, Kaposi sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS.

[0199] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 of crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt crystalline Form A, B, C, D, E, F, G, H, J, K, or L thereof, or any combination thereof), wherein the disease or disorder that can be treated with the method includes, but is not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, graft vs. host disease, inflammatory reactions to endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter’s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, induced by pancreatitis B cells disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary fibrosis, bone resorption diseases, allograft rejection, fever and myalgias due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, sepsis, septic shock and Shwachman’s syndrome; Alzheimer’s disease, Parkinson’s disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; angiogenic diseases including solid tumors, ocular neovascularization and infantile haemangioma; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemic stroke, ischemia, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxic shock and / or toxic shock syndrome, diseases associated with prostaglandin endoperoxidase syndrome-2 and pemphigus vulgaris.

[0200] In some preferred embodiments, the present disclosure provides a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof), wherein the disease or condition is one or more diseases or conditions selected from Crohn’s disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.

[0201] In some preferred embodiments, the present disclosure provides a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof), wherein the disease or condition is ischemia-reperfusion injury caused by stroke (including cerebral ischemia-reperfusion injury) and myocardial ischemia-reperfusion injury caused by myocardial infarction.

[0202] In some preferred embodiments, the present disclosure provides a method of treating or preventing multiple myeloma in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0203] In some preferred embodiments, the present disclosure provides a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in crystalline Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt Form thereof, Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof), wherein the disease or condition is one or more diseases or conditions selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s disease, Sjogren’s syndrome, and scleroderma.

[0204] In some preferred embodiments, the present disclosure provides a method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in Form I, II, III, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt thereof in Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0205] In some preferred embodiments, the present disclosure provides a method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K or L of its salt, or any combination thereof).

[0206] In some preferred embodiments, the present disclosure provides a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K or L of its salt, or any combination thereof).

[0207] In some preferred embodiments, the present disclosure provides a method of treating systemic lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of its salt, or any combination thereof).

[0208] In some preferred embodiments, the present disclosure provides a method of treating psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of its salt, or any combination thereof).

[0209] In some preferred embodiments, the present disclosure provides a method of treating psoriatic arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of its salt, or any combination thereof).

[0210] In some preferred embodiments, the present disclosure provides a method of treating Crohn's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K or L of its salt, or any combination thereof).

[0211] In some preferred embodiments, the present disclosure provides a method of treating Sjögren's syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt thereof in Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0212] In some preferred embodiments, the present disclosure provides a method of treating scleroderma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Compound 1 in Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a salt thereof in Form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof).

[0213] In some embodiments, the present disclosure also provides the use of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of its salt, or any combination thereof) for treating or preventing any disease or condition described herein, e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma.

[0214] In some embodiments, the present disclosure also provides the use of one or more compounds of the present disclosure (e.g., Form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of Compound 1, or Form A, B, C, D, E, F, G, H, J, K, or L of a salt thereof, or any combination thereof) in the manufacture of a medicament for treating or preventing any disease or condition described herein, e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma.

[0215] The compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments, the method for treating IL-23-, IL-12 and / or IFN related diseases or conditions can include administering the compounds of the present disclosure alone or in combination with each other and / or in combination with other suitable therapeutic agents, which can be used to treat these conditions. Examples of such other suitable therapeutic agents include corticosteroids, rolipram, calcifestin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyarginine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral drugs such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, ); antimalarial drugs such as hydroxychloroquine; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-inhibitors such as tenidap, anti-tumor necrosis factor antibodies or soluble TNF receptors, and rapamycin (sirolimus or ) or its derivatives.

[0216] Administration herein is not limited to any specific route of administration. For example, in some embodiments, oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, peritoneal, subcutaneous, intramuscular, intravenous, rectal, intrathoracic, intrathecal and parenteral administration are available. In some embodiments, the administration is oral.

[0217] The dosage regimen, including dosage, can vary and be adjusted depending on the subject being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0218] definition

[0219] As used herein, "compound(s) of the present disclosure" refers to Compound 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, an isolated form, a substantially pure form thereof, including a crystalline form, an amorphous form, a solid form of a hydrate and / or a solvate.

[0220] As used herein, the term "about" modifies a quantity related to the present invention to indicate that variations in the numerical amount may occur, for example, through routine testing and processing; through inadvertent errors in such testing and processing; through differences in the manufacture, origin, or purity of the components used in the present invention, etc. As used herein, "about" a particular value also includes that particular value, for example, about 10% includes 10%. Whether or not modified by the word "about", the claims include equivalents of the recited quantities. In one embodiment, the term "about" refers to within 20% of the reported value.

[0221] As used herein, the term "treating" and synonyms refer to eliminating, reducing or ameliorating a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the term "treating" and the like may include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or condition, or the likelihood of recurrence of a previously controlled disease or condition, in a subject who does not have a disease or condition but has a risk or susceptibility to the disease or condition, a disease or condition redevelopment, or a disease or condition recurrence. The term "treating" and synonyms contemplate administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment.

[0222] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent (e.g., one or more compounds of the present disclosure) sufficient to result in an improvement in one or more diseases or conditions (e.g., those that are proliferative, metabolic, allergic, autoimmune, and / or inflammatory diseases or conditions), or to prevent the appearance or progression of a disease or condition, or to result in the regression or cure of a disease or condition.

[0223] The term "subject" (also referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. In any of the embodiments described herein, the subject can be a human.

[0224] Examples

[0225] General methods

[0226] Materials: Starting materials, reagents, solvents and the like can be obtained through commercial sources.

[0227] 1 H nuclear magnetic resonance spectroscopy (H NMR): H NMR was performed using a Bruker Advance 400 equipped with an autosampler (B-ACS 120). 1 1 H NMR.

[0228] Powder X-ray Diffraction (XRPD) analysis: Solid samples were examined using an X-ray diffractometer (Bruker D8 advance). The system was equipped with a LynxEye detector. The X-ray wavelength was 1.5418 A. The samples were scanned from 3 to 40° (2q) with a step of 0.02° (2q). The tube voltage and current were 40 KV and 40 mA, respectively.

[0229] Thermogravimetric analysis (TGA): TGA was performed on a Discovery TGA 55 (TA Instruments, USA). The sample was placed in an open deremped aluminum pan, automatically weighed, and then inserted into the TGA furnace. The sample was heated from room temperature (RT) to a final temperature at a rate of 10 °C / min.

[0230] Differential scanning calorimetry (DSC): DSC was performed using a Discovery DSC 250 (TA Instruments, USA). The sample was placed in an aluminum pin-holed sealed pan and the weight was accurately recorded. The sample was heated from 25 °C to a final temperature at a rate of 10 °C / min.

[0231] Dynamic vapor sorption (DVS) analysis: Moisture sorption / desorption data were collected on a DVS Intrinsic PLUS (SMS, UK). The sample was placed in a deremped sample chamber and automatically weighed. The sample was dried at 40 °C until dm / dt was less than 0.002% and cooled to 25 °C.

[0232] High performance liquid chromatography (HPLC): A representative HPLC method is shown below, which can be used, for example, to analyze the purity, solubility and stability of Compound 1 herein.

[0233] ​

[0234] Preparation and solid-state characterization of compound 1

[0235]

[0236] Compound 1-1 has been prepared starting from 2-amino-5-chloropyridine through multiple synthetic steps by following the known process described in international application No. PCT / CN2021 / 140271 filed on December 22, 2021, the contents of which are incorporated herein by reference in their entirety.

[0237] Step 1: Under nitrogen, compound 1-1 (200 g), (2,4-dimethoxyphenyl)methylamine (290 g) and cesium fluoride (88 g) were added to N-methylpyrrolidone (1000 mL) and reacted at 120 ° C for 3 hours. The reaction mixture was then cooled to room temperature, quenched with water and filtered. The filter cake was rinsed with water and collected. At 65 ° C, the crude product was slurried with a mixed solvent of tetrahydrofuran and isopropanol (V / V, 1 / 1) to obtain compound 1-2 (white solid, 251 g, yield 91%). LCMS: 478.1 [M+1] + .

[0238] Step 2: Under nitrogen, compound 1-2 (200 g) and N, N-diisopropylethylamine (81 g) were added to tetrahydrofuran (1200 mL) and heated to 65 ° C. A solution of cyclopropanecarbonyl chloride (52.6 g) in THF (500 mL) was added dropwise and reacted for 2 hours. The reaction mixture was cooled to 25 ° C, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, concentrated under reduced pressure, and isopropanol was added and slurried at 80 ° C for 1 hour to obtain compound 1-3 (pale yellow solid, 196 g, yield 87%). LCMS: 546.2 [M+1] + . 1 H NMR: (400MHz, CDCl3); δ: 12.20 (s, 1H), 9.08 (s, 1H), 8.45 (s, 1H), 8.06, (d, 1H, J = 4.0Hz), 7.62 (d, 1H, J = 4.0Hz), 7.27 (d, 1H, J = 12.0Hz), 6.43 (dd, 1H, J=4.0,12.0Hz),6.36(d,1H,J=4.0Hz),5.24(s,2H),3.77(s,3H),3.62(s, 3H),2.55(s,3H),1.80-1.71(m,1H),1.20-1.16(m,2H),0.84-0.78(m,2H).

[0239] Step 3: Under nitrogen, compound 1-3 (160 g) was added to 1,4-dioxane (1600 mL). At a temperature below 30 ° C, a solution of potassium persulfate complex salt (325 g) in water (700 mL) was added and reacted at 30 ° C for 24 hours. The reaction mixture was filtered and washed with dichloromethane. The filtrate was washed with 5% sodium sulfite aqueous solution and water, respectively. After the organic phase was concentrated, methanol was added and slurried at 65 ° C for 1 hour to obtain compound 1-4 (white solid, 121 g, yield 72%). 1 HNMR: (400MHz, DMSO-d6); δ: 12.25 (s, 1H), 9.45 (s, 1H), 8.75 (d, 1H, J = 4.8Hz), 8.58, (d, 1H, J = 2.4Hz), 8.25 (d, 1H, J = 2.4Hz), 7.10 (d, 1H, J =8.0Hz),6.48-6.44(m,2H),5.04(s,2H),3.72(s,3H),3.60(s,3H),3.41(s,3H),1.80-1.74(m,1H),0.96-0.91(m,2H),0.81-0.76(m,2H).

[0240] Step 4: Under nitrogen, compound 1-4 (105 g) was added to trifluoroacetic acid (TFA, 330 mL) and reacted at 35 ° C for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was added to anhydrous ethanol, stirred for 30 minutes, and then filtered. The filter cake was first slurried in tetrahydrofuran at 65 ° C for 1 hour, and then slurried in ethanol and water at 70 ° C for 12 hours to obtain compound 1 (white solid, 67 g, yield 86%). LCMS: 428.2 [M+1] + ; 1 H NMR: (400MHz, DMSO-d6); δ: 12.14(s,1H),11.44(s,1H),9.36(s,1H),9.19,(s,1H),8.65( d,1H,J=2.4Hz),8.23(d,1H,J=2.4Hz),3.38(s,3H),2.12-2.09(m,1H),0.86-0.84(m,4H).

[0241] Example 1: Preparation and Characterization of Form I of Compound 1

[0242] 33g of compound 1 was added to 900mL of DMSO, heated to 110°C to dissolve and clarify, cooled to 80-90°C, and filtered while hot. While stirring, 1500mL of pure water was added to the filtrate, stirred for 1 hour, filtered, and the filter cake was rinsed with 500mL of pure water. The filter cake was added to 1000mL of pure water, heated to 60-70°C, stirred for 1 hour, cooled to 40-50°C, filtered, and the filter cake was rinsed with 500mL of pure water. The filter cake was collected and dried at 60°C for 30 hours.

[0243] The obtained solid was characterized by XRPD, DSC and TGA. Figure 1a The main diffraction peaks and their relative intensities are shown in Table 1. The DSC and TGA spectra are shown in Table 1. Figure 1b The DSC spectrum shows a small exothermic peak at 250°C and a strong endothermic peak at 319°C. The TGA spectrum shows that Form I has no obvious weight loss from room temperature to 220°C.

[0244] Table 1: XRPD peak table of Form I of Compound 1.

[0245] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 7.5 100.0 23.6 16.0 11.3 2.3 24.8 15.2 11.7 10.9 25.3 9.7 13.7 0.7 26.5 21.4 14.9 4.4 27.0 5.1 15.3 3.4 27.8 2.0 18.1 4.4 28.9 1.7 18.9 4.5 30.2 5.5 20.3 2.0 31.0 3.0 20.9 35.5 32.8 1.6 21.4 2.7 35.0 2.6 22.3 18.4 36.7 2.2 22.8 4.6

[0246] Example 2: Preparation and Characterization of Form II of Compound 1

[0247] Form I was weighed into a sample bottle, and then 50V isopropanol was added and slurried at 50°C for 1 day. The solid was filtered, collected and dried at 50°C overnight.

[0248] The obtained solid was characterized by XRPD, DSC and TGA. Figure 2a The main diffraction peaks and their relative intensities are shown in Table 2. The DSC and TGA spectra are shown in Table 2. Figure 2b The DSC spectrum shows relatively strong endothermic peaks at 310°C and 317°C. The TGA spectrum shows that Form II has no obvious weight loss in the temperature range from RT to 275°C.

[0249] Table 2: XRPD peak table of Form II of Compound 1.

[0250] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.3 2.1 23.6 1.4 7.1 100.0 24.2 3.7 7.7 48.9 24.5 9.4 11.1 7.1 24.7 24.6 12.3 15.4 26.1 0.9 14.4 4.0 26.9 4.9 15.6 4.2 27.5 7.6 17.8 2.3 28.9 1.0 19.6 4.6 29.1 4.0 20.4 30.2 30.5 1.8 21.1 2.8 31.6 3.9 21.7 5.6 33.9 1.7 22.7 34.0 34.4 1.3

[0251] Example 3: Preparation and Characterization of Form III of Compound 1

[0252] Form I was weighed into a sample bottle, then slurried in 50V acetone at 50°C for 1 day. The solid was collected by filtration and dried at 50°C overnight. Alternatively, Form III can be directly obtained through the purification process described in Step 4 of the synthesis above.

[0253] The obtained solid was characterized by XRPD, DSC, TGA and DVS. The XRPD pattern is shown in FIG. Figure 3a The main diffraction peaks and their relative intensities are shown in Table 3. The DSC and TGA spectra are shown in Table 3. Figure 3b The DSC spectrum shows a weak endothermic peak at 272°C and stronger endothermic peaks at 310°C and 318°C. The TGA spectrum shows that Form III has no obvious weight loss in the temperature range of RT to 250°C. Figure 3c The DVS results in FIG1 show that at 90% RH, the moisture absorption weight gain of Form III is 0.13%.

[0254] Table 3: XRPD peak table of Form III of Compound 1.

[0255] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.9 3.8 24.1 24.7 7.0 84.6 25.3 2.9 8.5 4.4 25.7 3.2 9.7 100.0 26.0 11.3 14.1 32.2 27.0 29.3 14.5 19.2 28.0 1.5 16.0 7.4 28.5 6.1 17.2 17.3 29.0 3.2 17.7 4.2 29.3 9.6 18.2 33.1 29.8 3.1 19.3 4.3 30.8 0.9 19.6 13.4 31.5 1.8 19.9 3.9 32.4 1.5 20.5 2.4 33.8 1.7 21.3 49.1 34.7 1.5 21.6 4.9 35.0 1.9 22.1 5.2 35.7 3.1 22.9 10.1 36.6 2.4 23.2 2.5 37.0 10.2 23.9 5.3

[0256] Example 4: Preparation and Characterization of Form IV of Compound 1

[0257] Form I was weighed into a sample bottle, and then 50V of acetonitrile was added and slurried at 50°C for 1 day. The solid was filtered, collected, and dried under vacuum at 50°C for 6 hours.

[0258] The obtained solid was characterized by XRPD, DSC and TGA. Figure 4a The main diffraction peaks and their relative intensities are shown in Table 4. The DSC and TGA spectra are shown in Table 4. Figure 4b The DSC spectrum shows a weak exothermic peak at 216°C and a strong endothermic peak at 319°C. The TGA spectrum shows that Form IV has no obvious weight loss in the temperature range from RT to 275°C.

[0259] Table 4: XRPD peak table of Form IV of Compound 1.

[0260]

[0261]

[0262] Example 5: Preparation and Characterization of Form V of Compound 1

[0263] Form I was heated to 300°C.

[0264] The obtained solid was characterized by XRPD, DSC and TGA. Figure 5a The main diffraction peaks and their relative intensities are shown in Table 5. The DSC and TGA spectra are shown in Table 5. Figure 5b The DSC spectrum shows a strong endothermic peak at 319°C. The TGA spectrum shows that when heated to 275°C, Form V does not lose weight significantly.

[0265] Table 5: XRPD peak table of Form V of Compound 1.

[0266] 2 theta o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 4.8 9.9 22.1 3.6 7.1 2.0 22.5 3.3 8.7 91.4 23.4 1.0 9.7 100.0 24.6 20.5 10.3 3.7 24.9 4.5 12.6 11.0 25.5 15.0 13.6 3.0 26.5 4.4 14.7 11.6 27.4 7.2 17.6 23.0 27.6 8.6 17.8 4.2 28.1 5.8 18.6 2.3 29.4 1.6 19.6 4.0 31.6 1.7 20.8 57.5 36.0 1.1 21.7 2.0 36.4 1.9

[0267] Example 6: Preparation and Characterization of Form VI of Compound 1

[0268] Form I was weighed into a sample bottle, and then 50V of water was added and slurried at 50°C for 1 day. The solid was filtered, collected and dried at room temperature.

[0269] The obtained solid was characterized by XRPD, DSC and TGA. Figure 6a The main diffraction peaks and their relative intensities are shown in Table 6. The DSC and TGA spectra are shown in Table 6. Figure 6b The DSC spectrum showed two strong endothermic peaks at 49°C and 318°C, respectively. The TGA spectrum showed a weight loss of approximately 7.3% in the temperature range of 30°C to 70°C. Form VI may be a dihydrate of Compound 1 (theoretical water content is 7.8%).

[0270] Table 6: XRPD peak table of Form VI of Compound 1.

[0271] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.8 4.8 24.6 8.0 7.2 100.0 25.0 5.7 11.0 7.6 26.1 0.7 13.3 12.5 26.8 5.6 14.5 14.1 27.1 10.3 17.8 6.6 27.4 11.2 20.2 1.1 28.5 1.5 20.8 1.6 29.1 3.0 21.1 0.8 29.4 5.2 21.7 6.1 32.7 2.3 21.9 10.3 33.4 3.6 22.2 41.8 35.0 1.5 23.6 3.2 35.9 0.9 23.9 0.7 39.8 2.7

[0272] Example 7: Preparation and Characterization of Form VII of Compound 1

[0273] Form I was weighed into a sample bottle, and then 50V of ethyl acetate was added and slurried at 50°C for 1 day. The solid was filtered, collected, and dried under vacuum at 50°C overnight.

[0274] The obtained solid was characterized by XRPD, DSC and TGA. Figure 7a The main diffraction peaks and their relative intensities are shown in Table 7. The DSC and TGA spectra are shown in Table 7. Figure 7b The DSC spectrum shows multiple endothermic / exothermic peaks, with the exothermic peak at 135°C and endothermic peaks at 72°C, 237°C, 283°C, and 318°C. The TGA spectrum shows a weight loss of approximately 2.6% over the temperature range from RT to 130°C.

[0275] Table 7: XRPD peak table of Form VII of Compound 1.

[0276] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.1 100.0 20.9 15.4 6.6 63.6 22.0 12.6 6.9 47.2 22.7 26.4 7.5 22.8 23.1 7.8 9.4 22.0 23.7 13.2 12.2 7.9 24.6 4.4 13.5 7.0 26.4 11.3 13.9 16.7 27.3 11.5 16.5 7.5 27.6 22.0 16.9 7.1 28.2 5.4 17.3 6.4 30.0 6.9 18.1 9.6 31.0 3.7 18.7 15.8 31.7 3.3 19.6 3.9 35.4 4.8

[0277] Example 8: Preparation and Characterization of Form VIII of Compound 1

[0278] Form VII was heated to 200°C.

[0279] The solid was characterized by XRPD, DSC and TGA. The XRPD pattern is shown in FIG. 6, and the major diffraction peaks and their relative intensities are listed in Table 5. The DSC and TGA patterns are shown in FIGS. 7 and 8, respectively. The DSC pattern shows an endothermic peak at 303 °C and a strong endothermic peak at 319 °C. The TGA pattern indicates no significant weight loss in the temperature range from room temperature to 130 °C. Figure 8a Figure 8b

[0280] Table 5: XRPD peak table of crystalline Form VII of compound 1.

[0281] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.7 100.0 18.7 6.3 7.4 22.8 19.0 5.8 9.4 67.6 20.8 20.4 13.6 22.4 21.9 6.0 14.3 4.6 23.6 9.2 15.4 3.7 35.7 5.6 17.3 5.3

[0282] Example 9: Preparation and characterization of crystalline Form IX of compound 1

[0283] About 40 mg of Form I was weighed and dissolved in dimethyl sulfoxide (DMSO) at 50 °C. The solution was filtered and allowed to cool crystallize at room temperature. The solid was filtered, collected and vacuum dried at 50 °C for 6 hours.

[0284] The solid was characterized by XRPD, DSC and TGA. The XRPD pattern is shown in FIG. 11, and the major diffraction peaks and their relative intensities are listed in Table 9. The DSC and TGA patterns are shown in FIGS. 12 and 13, respectively. The DSC pattern shows two endothermic peaks at 138 °C and 319 °C, respectively. The TGA pattern shows about 15.2% weight loss in the temperature range from 50 °C to 170 °C. Form IX can be a mono-DMSO solvate of compound 1 (theoretical DMSO content is 15.4%). Figure 9a Figure 9b

[0285] Table 9: XRPD peak table of crystalline Form IX of compound 1.

[0286] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.2 5.1 22.0 17.8 7.2 100.0 22.2 2.8 9.5 3.0 23.1 11.1 11.4 1.4 24.7 0.9 12.6 6.0 25.4 4.5 14.5 0.6 25.7 1.5 16.7 3.1 26.6 1.7 17.2 0.5 29.0 1.0 18.9 8.9 30.8 2.6 19.2 5.0 31.9 1.1 19.9 1.4 37.3 2.2 21.2 11.4

[0287] Example 10: Preparation and characterization of crystalline Form X of compound 1

[0288] Form IX was heated to 200 °C.

[0289] The solid was characterized by XRPD, DSC and TGA. The XRPD pattern is shown in FIG. 14, and the major diffraction peaks and their relative intensities are listed in Table 10. The DSC and TGA patterns are shown in FIGS. 15 and 16, respectively. The DSC pattern shows endothermic peaks at 300 °C and 319 °C. The TGA pattern indicates no significant weight loss when heated to 250 °C. Figure 10a Figure 10b

[0290] Table 10: XRPD peak table of crystalline Form X of compound 1.​​​​​​

[0291] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 7.4 100.0 22.0 4.9 7.9 42.6 22.6 6.1 9.4 6.7 23.6 13.7 11.7 16.3 26.4 6.4 20.7 16.6

[0292] Example 11: Preparation and characterization of crystalline Form XI of Compound 1

[0293] About 20 mg of Form I was dissolved in 1 mL of dimethylformamide at 50 °C. 4 mL of isopropanol was added gradually until solids precipitated. The solids were slurried at 50 °C overnight, then filtered, collected and vacuum dried at 50 °C overnight.

[0294] The resulting solids were characterized by XRPD, DSC and TGA. The XRPD pattern is shown in FIG. 6, and the major diffraction peaks and their relative intensities are shown in Table 11. The DSC and TGA patterns are shown in FIGS. 7 and 8, respectively. The DSC pattern showed an exothermic peak at 211 °C and endothermic peaks at 104 °C and 319 °C. The TGA pattern showed a weight loss of about 4.1% when heated to 140 °C. Figure 11a Figure 11b

[0295] Table 11: XRPD peak table for crystalline Form XI of Compound 1.

[0296]

[0297]

[0298] Example 12: Preparation and characterization of crystalline Form XII of Compound 1

[0299] About 20 mg of Form I was dissolved in 1 mL of dimethylformamide at 50 °C. 4 mL of acetone was added gradually until solids precipitated. The solids were slurried at 50 °C overnight, then filtered, collected and vacuum dried at 50 °C overnight.

[0300] The resulting solids were characterized by XRPD, DSC and TGA. The XRPD pattern is shown in FIG. 9, and the major diffraction peaks and their relative intensities are shown in Table 12. The DSC and TGA patterns are shown in FIGS. 10 and 11, respectively. The DSC pattern showed an exothermic peak at 205 °C and endothermic peaks at 124 °C and 319 °C. The TGA pattern showed a weight loss of about 4.1% when heated to 120 °C; a further weight loss of about 2.1% over the temperature range of greater than 120 °C to 230 °C. Figure 12a Figure 12b

[0301] Table 12: XRPD peak table for crystalline Form XII of Compound 1.

[0302] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.9 100.0 19.5 62.9 6.4 83.7 20.2 21.8 7.0 21.7 21.3 12.0 8.7 33.3 22.2 7.8 9.3 3.2 23.2 7.4 11.0 23.7 24.0 32.0 11.9 26.8 24.5 18.5 12.8 5.5 24.9 24.8 13.5 23.6 26.1 9.6 14.1 7.4 27.4 7.5 15.6 12.8 28.1 7.7 16.2 21.7 32.9 3.7 19.3 46.8 34.7 4.2

[0303] Example 13: Preparation and characterization of crystalline Form XIII of Compound 1​​​​

[0304] Form I was weighed into a sample bottle, and then slurried in 50V methanol at room temperature for 3 days. The solid was filtered, collected and dried.

[0305] The obtained solid was characterized by XRPD, DSC and TGA. Figure 13a The main diffraction peaks and their relative intensities are shown in Table 13. The DSC and TGA spectra are shown in Table 13. Figure 13b The DSC spectrum shows an endothermic peak at 319°C. The TGA spectrum shows no obvious weight loss when heated to 250°C.

[0306] Table 13: XRPD peak table of Form XIII of Compound 1.

[0307]

[0308]

[0309] Example 14: Preparation and Characterization of Form XIV of Compound 1

[0310] Form I was weighed into a sample bottle and then slurried in 50V isopropanol at room temperature for 3 days. The solid was filtered, collected and dried.

[0311] The obtained solid was characterized by XRPD, DSC and TGA. Figure 14a The main diffraction peaks and their relative intensities are shown in Table 14. The DSC and TGA spectra are shown in Table 14. Figure 14b The DSC spectrum shows two endothermic peaks at 237°C and 319°C. The TGA spectrum shows no obvious weight loss when heated to 250°C.

[0312] Table 14: XRPD peak table of Form XIV of Compound 1.

[0313] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.5 29.1 20.8 100.0 8.6 25.5 23.1 5.9 10.3 9.1 23.4 4.2 11.1 36.1 25.1 2.7 12.4 4.4 26.4 9.6 15.6 8.5 27.9 3.3 16.9 3.5 30.8 2.6 17.5 16.4 31.5 4.6 19.8 8.1 33.1 4.9

[0314] Example 15: Preparation and Characterization of Form XV of Compound 1

[0315] Form I was weighed into a sample bottle, and then 50V tetrahydrofuran was added and slurried at room temperature for 3 days. The solid was filtered, collected and dried.

[0316] The obtained solid was characterized by XRPD, DSC and TGA. Figure 15a The main diffraction peaks and their relative intensities are shown in Table 15. The DSC and TGA spectra are shown in Table 15. Figure 15bThe DSC profile shows a weak exothermic peak at 253 °C and endothermic peaks at 285 °C and 319 °C. The TGA profile shows a weight loss of about 0.7% when heated to 250 °C.

[0317] Table 15: XRPD Peak Table for Form XV of Compound 1.

[0318] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.6 2.8 17.6 1.4 7.5 13.8 19.8 3.6 7.8 100.0 20.5 6.2 9.3 14.1 21.5 11.1 11.2 1.7 22.4 14.8 12.9 3.2 24.3 2.6 15.1 1.1 26.5 3.1 15.8 2.6 35.8 2.2 16.2 1.5

[0319] Example 16: Preparation and Characterization of Form XVI of Compound 1

[0320] Form IV was heated to 230 °C.

[0321] The resulting solid was characterized by XRPD, DSC and TGA, the XRPD pattern is shown in Figure 16a , and the major diffraction peaks and their relative intensities are shown in Table 16. The DSC and TGA profiles are shown in Figure 16b . The DSC profile shows a weak exothermic peak at 137 °C and endothermic peaks at 259 °C and 319 °C. The TGA profile shows no significant weight loss when heated to 250 °C.

[0322] Table 16: XRPD Peak Table for Form XVI of Compound 1.

[0323]

[0324]

[0325] Example 16B: Preparation and Characterization of Form XVII of Compound 1

[0326] Fifteen mg of Form III was dissolved in 1 mL of dichloromethane containing 10% acetic acid. It was shaken at room temperature for 24 hours. The solid was collected by centrifugation and dried in an oven at 60 °C for 3 hours.

[0327] The resulting solid was characterized by XRPD, DSC, TGA and 1 H-NMR, where the XRPD pattern is shown in Figure 16c , and the major diffraction peaks and their relative intensities are listed in Table 16B. The DSC and TGA results are shown in Figure 16d . The DSC profile shows a significant endothermic peak at 156.6 °C. The TGA profile shows a weight loss of about 12.0% when heated from room temperature to 180 °C. Figure 16e 1 The H-NMR spectrum shows a molar ratio of Compound 1 to acetic acid of about 1 : 1. Since the theoretical acetic acid content of a mono-acetic acid solvate is 12.3%, Form XVII is likely a mono-acetic acid solvate of Compound 1. ​

[0328] Table 16B: XRPD peak table of Form XVII of Compound 1.

[0329] 2 theta o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.1 40.3 20.9 38.2 7.3 22.0 22.2 21.1 8.8 33.1 22.7 100.0 10.4 18.2 23.6 7.4 12.0 97.4 24.3 37.1 14.7 24.1 24.6 21.3 15.5 4.8 25.2 14.6 16.4 16.0 25.6 22.0 17.7 25.2 26.7 23.9 18.4 10.0 27.9 6.8 19.1 26.6 28.7 3.2 19.5 24.3 29.9 12.1 19.9 7.2 30.5 8.1

[0330] Example 17: Preparation and Characterization of Sulfate Form A of Compound 1

[0331] The crystal form I was weighed into a sample bottle, and 120V ethanol and 1 equivalent (eq) sulfuric acid were added, and the mixture was slurried at room temperature for 1 day. The solid was filtered, collected and dried.

[0332] The obtained solid was characterized by XRPD, DSC, TGA, IC and DVS. The XRPD pattern is shown in FIG. Figure 17a The main diffraction peaks and their relative intensities are shown in Table 17. The DSC and TGA spectra are shown in Table 17. Figure 17b The DSC spectrum showed two endothermic peaks at 198°C and 226°C, respectively. The TGA spectrum showed a weight loss of approximately 1.6% when heated to 176°C. Ion chromatography (IC) results showed that the sulfate content was 16.7%. Figure 17c The DVS results shown in Figure 3 show that the sulfate salt form A absorbs moisture and increases in weight by approximately 10% at 90% RH. It is speculated that the molar ratio of compound 1 to sulfuric acid in the sulfate salt form A is 1:1.

[0333] Table 17: XRPD peak table of sulfate salt form A of compound 1.

[0334]

[0335]

[0336] Example 18: Preparation and Characterization of Compound 1 Sulfate Salt Form B

[0337] Form I was weighed into a sample bottle and 120 V acetone was added to form a suspension. 1 eq of sulfuric acid was added and the suspension was stirred at room temperature for 3 days. The solid was collected by filtration and dried under vacuum at 50 °C.

[0338] The obtained solid was characterized by XRPD, DSC, TGA, IC and DVS. The XRPD pattern is shown in FIG. Figure 18a The main diffraction peaks and their relative intensities are shown in Table 18. The DSC and TGA spectra are shown in Table 18. Figure 18b The DSC spectrum shows a clear endothermic peak at 250°C. The TGA spectrum shows no significant weight loss when heated to 200°C. The IC results show that the sulfate content is 18.7%. Figure 18cThe DVS results shown in Figure 2 show that the moisture absorption weight gain of sulfate Form B at 90% RH is 1.0%. It is speculated that the molar ratio of compound 1 and sulfuric acid in sulfate Form B is 1:1.

[0339] Table 18: XRPD peak table of sulfate salt Form B of Compound 1.

[0340] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.9 18.0 22.7 24.7 6.6 7.5 23.4 38.2 7.3 100.0 25.8 74.1 10.2 30.0 26.6 7.8 11.6 52.4 27.0 8.8 11.9 31.5 27.2 10.2 12.8 49.5 28.6 1.3 13.4 7.0 29.1 1.4 14.8 69.9 29.5 0.8 17.0 6.1 30.0 2.4 17.9 3.3 31.2 1.3 18.6 12.7 32.1 2.4 19.1 3.1 32.9 14.4 19.9 1.9 33.9 6.8 20.1 4.0 34.9 1.4 20.6 52.2 36.4 1.5 21.1 4.7 37.0 1.1 22.3 65.7 39.5 2.2

[0341] Example 19: Preparation and Characterization of Compound 1 Sulfate Salt Form C

[0342] The samples were collected after DVS testing of Form A sulfate salt.

[0343] The obtained solid was characterized by XRPD, DSC and TGA. Figure 19a The main diffraction peaks and their relative intensities are shown in Table 19. The DSC and TGA spectra are shown in Table 19. Figure 19b The DSC spectrum shows endothermic peaks at 111°C, 196°C, and 230°C, and an exothermic peak at 209°C. The TGA spectrum indicates a weight loss of approximately 3.3% upon heating to 177°C. It is speculated that the molar ratio of compound 1 to sulfuric acid in sulfate Form C is 1:1.

[0344] Table 19: XRPD peak table of sulfate salt form C of compound 1.

[0345] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 4.4 18.5 20.3 18.8 7.5 27.3 21.3 29.8 8.9 55.5 21.7 31.2 9.7 12.8 21.9 25.1 11.7 11.0 22.8 26.9 13.2 14.4 23.4 43.6 13.5 15.5 23.8 22.8 14.0 47.7 24.6 34.5 14.5 54.2 25.4 25.7 16.0 12.7 27.3 17.5 16.6 7.9 28.2 21.4 17.6 44.1 29.5 20.0 18.0 31.9 31.2 9.4 18.8 5.6 32.4 9.8 19.5 100.0 32.8 6.0

[0346] Example 20: Preparation and Characterization of Compound 1 Benzenesulfonate Form D

[0347] Form I was weighed into a sample bottle and 120 V acetone was added to form a suspension. 1 eq of benzenesulfonic acid was added and the suspension was stirred at room temperature for 20 hours. The solid was collected by filtration and dried under vacuum at 50°C.

[0348] The obtained solid was characterized by XRPD, DSC and TGA. Figure 20a The main diffraction peaks and their relative intensities are shown in Table 20. The DSC and TGA spectra are shown in Table 20. Figure 20b The DSC spectrum shows two strong endothermic peaks in the range of 124-142°C. The TGA spectrum shows a weight loss of approximately 5.8% when heated to 170°C. It is speculated that the molar ratio of compound 1 to benzenesulfonic acid in benzenesulfonate salt form D is 1:1.

[0349] Table 20: XRPD peak table of Form D of benzenesulfonate salt of Compound 1.

[0350] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.9 7.3 18.6 12.7 6.3 38.5 19.5 1.8 6.9 11.2 20.3 2.5 7.7 100.0 21.2 8.3 8.2 79.1 24.1 1.8 9.7 18.7 24.8 5.2 12.7 18.8 25.1 6.7 13.9 16.0 26.0 2.6 14.7 17.4 26.5 1.9 16.6 2.7 28.6 4.2 17.7 6.3 38.9 2.2 18.3 4.7

[0351] Example 21: Preparation and Characterization of Phosphate Form E of Compound 1

[0352] Form I was weighed into a sample bottle and 120 V acetone was added to form a suspension. 1 eq of phosphoric acid was added and the suspension was stirred at room temperature for 20 hours. The solid was collected by filtration and dried under vacuum at 50°C.

[0353] The obtained solid was characterized by XRPD, DSC, TGA and DVS. The XRPD pattern is shown in FIG. Figure 21a The main diffraction peaks and their relative intensities are shown in Table 21. The DSC and TGA spectra are shown in Table 21. Figure 21b The DSC spectrum shows two endothermic peaks at 241°C and 259°C, respectively. The TGA spectrum shows no obvious weight loss when heated to 210°C. Figure 21c The DVS results shown in Figure 3 show that the phosphate crystal form E absorbs moisture and increases in weight by approximately 0.92% at 90% RH. It is speculated that the molar ratio of compound 1 to phosphoric acid in the phosphate crystal form E is 1:1.

[0354] Table 21: XRPD peak table of phosphate salt form E of compound 1.

[0355] 2 theta o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 5.6 4.3 21.8 46.3 6.5 1.0 22.5 27.1 7.2 100.0 24.6 5.7 9.8 6.4 25.3 34.7 11.2 66.1 25.7 4.2 12.6 32.1 26.8 1.9 13.1 0.8 28.5 4.3 14.5 43.7 29.2 6.0 16.2 2.2 29.7 1.0 17.0 1.3 32.4 2.3 18.0 12.2 33.3 2.8 19.8 24.1 34.2 2.6

[0356] Example 22: Preparation and Characterization of Form F of the Methanesulfonate Salt of Compound 1

[0357] Form I was weighed into a sample bottle, and 120V ethanol was added to form a suspension. 1 eq of methanesulfonic acid was added, and the suspension was stirred at room temperature for 20 hours. The solid was collected by filtration and dried under vacuum at 50°C.

[0358] The obtained solid was characterized by XRPD, DSC and TGA. Figure 22a The main diffraction peaks and their relative intensities are shown in Table 22. The DSC and TGA spectra are shown in Table 22. Figure 22b The DSC spectrum showed two strong endothermic peaks at 120°C and 257°C, and two weak exothermic peaks at 183°C and 221°C. The TGA spectrum indicated a weight loss of approximately 5.9% upon heating to 140°C. It is speculated that the molar ratio of compound 1 to methanesulfonic acid in mesylate Form F is 1:1.

[0359] Table 22: XRPD peak table of Form F of the mesylate salt of Compound 1.

[0360] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 6.1 3.4 21.2 2.5 6.9 6.4 22.3 8.4 7.3 7.7 22.6 12.3 8.5 100.0 23.2 3.8 11.5 2.2 23.6 1.9 12.2 1.0 23.8 1.8 13.8 11.4 24.3 0.7 14.0 1.6 24.9 1.1 14.3 1.4 26.1 2.3 14.7 1.6 26.3 2.3 15.6 1.1 26.5 1.9 16.3 0.7 27.8 4.6 17.2 6.4 29.1 3.6 17.6 1.0 30.5 0.6 18.1 1.8 31.2 3.2 19.5 1.4 32.7 0.9 20.5 3.7

[0361] Example 23: Preparation and Characterization of Methanesulfonate Form G of Compound 1

[0362] Form I was weighed into a sample bottle and 120 V acetone was added to form a suspension. 1 eq of methanesulfonic acid was added and the suspension was stirred at room temperature for 20 hours. The solid was collected by filtration and dried under vacuum at 50 °C.

[0363] The obtained solid was characterized by XRPD, DSC and TGA. Figure 23a The main diffraction peaks and their relative intensities are shown in Table 23. The DSC and TGA spectra are shown in Table 23. Figure 23b The DSC spectrum shows two weak exothermic peaks at 114°C and 185°C. The TGA spectrum shows that there is a weight loss of about 9.2% when heated to 196°C. Figure 23c shown 1 The H-NMR spectrum showed that the molar ratio of methanesulfonic acid to free base was 1:1.

[0364] Table 23: XRPD peak table of Form G of the mesylate salt of Compound 1.

[0365] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 7.1 100.0 22.2 11.0 8.5 36.6 23.2 2.5 13.9 11.7 24.3 1.9 14.1 4.9 27.5 0.8 17.0 1.6 28.3 3.1 17.5 5.0 28.7 6.3 19.5 0.9 31.2 1.8 20.6 12.5 34.5 2.6 21.4 15.3 36.1 1.1

[0366] Example 24: Preparation and Characterization of Potassium Salt Form H of Compound 1

[0367] Weigh the Form I into a sample bottle, add 120V ethanol to form a suspension, add 1eq potassium hydroxide, and stir at 50°C for 5 hours. Filter, collect the solid, and dry it in vacuo at 50°C.

[0368] The obtained solid was characterized by XRPD, DSC and TGA. Figure 24a The main diffraction peaks and their relative intensities are shown in Table 24. The DSC and TGA spectra are shown in Table 24. Figure 24b The DSC spectrum showed two endothermic peaks at 25°C and 249°C, and an exothermic peak at 260°C. The TGA spectrum indicated a weight loss of approximately 2.9% upon heating to 120°C. It is speculated that the molar ratio of compound 1 to potassium hydroxide in potassium salt Form H is 1:1.

[0369] Table 24: XRPD peak table of potassium salt Form H of Compound 1.

[0370] 2 theta o ) Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 7.7 100.0 22.8 15.0 7.9 60.7 23.0 28.2 9.1 2.8 23.4 6.1 9.9 6.0 23.9 1.4 10.4 15.6 25.6 2.7 13.8 1.5 25.9 4.1 14.1 1.6 26.3 4.8 15.5 3.7 26.6 3.8 16.0 7.3 27.0 1.3 17.5 13.0 27.3 2.9 18.2 2.1 28.4 2.2 18.5 3.0 30.3 1.5 20.0 1.7 31.9 1.4 20.3 1.4 32.2 2.8 20.6 1.0 33.1 1.3 21.2 1.6 34.3 2.4 21.9 5.6 37.7 2.5 22.3 2.1 38.4 3.9 22.5 10.6

[0371] Example 25: Preparation and Characterization of Compound 1 Potassium Salt Form J

[0372] Form I was weighed into a sample bottle and 100 V DMSO was added to form a suspension. 1.2 eq potassium hydroxide was added and the suspension was stirred at room temperature for 16 hours. The solid was collected by filtration and dried under vacuum at 50°C for 3 days.

[0373] The obtained solid was characterized by XRPD, DSC and TGA. Figure 25a The main diffraction peaks and their relative intensities are shown in Table 25. The DSC and TGA spectra are shown in Table 25. Figure 25b The DSC spectrum shows three endothermic peaks at 29°C, 154°C, and 217°C. The TGA spectrum shows a weight loss of approximately 10.4% when heated to 192°C. It is speculated that the molar ratio of compound 1 to potassium hydroxide in potassium salt Form J is 1:1.

[0374] Table 25: XRPD peak table of potassium salt Form J of Compound 1.

[0375] 2 theta o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 10.0 65.3 27.6 1.7 11.6 14.0 28.1 27.5 11.9 31.5 28.5 9.0 14.8 3.5 28.9 5.1 14.9 2.9 29.2 6.8 16.2 24.1 29.5 6.2 18.2 9.8 30.2 4.3 18.7 17.5 30.4 4.5 19.1 100.0 30.8 5.6 19.5 6.2 31.3 5.1 20.2 6.6 31.9 6.5 20.8 22.0 32.1 7.4 21.5 8.6 32.4 3.9 21.9 37.2 32.6 4.5 22.2 17.3 33.6 3.8 22.5 25.1 33.8 4.5 22.8 6.7 34.1 3.2 23.5 46.1 34.7 16.7 23.7 40.9 35.8 2.7 24.0 7.2 36.1 3.6 24.4 9.8 36.5 3.1 24.7 9.2 37.4 6.9 24.9 5.2 38.0 7.3 26.3 5.7 38.8 2.2 26.7 3.6 39.1 7.6 26.9 20.7 39.7 4.7

[0376] Example 26: Preparation and Characterization of Choline Salt Form K of Compound 1

[0377] Form I was weighed into a sample bottle, 3 mL of acetone was added to form a suspension, and 1.05 eq of choline was added to form a clear solution. The solid was filtered, collected, and dried under vacuum at 50°C.

[0378] The obtained solid was characterized by XRPD, DSC, TGA and DVS. The XRPD pattern is shown in FIG. Figure 26a The main diffraction peaks and their relative intensities are shown in Table 26. The DSC and TGA spectra are shown in Table 26. Figure 26b The DSC spectrum shows two strong endothermic peaks at 26°C and 185°C, respectively. The TGA spectrum shows that there is a weight loss of about 6.5% when heated to 161°C. Figure 26c The DVS results shown in Figure 3 indicate that the choline salt form K absorbs moisture and increases in weight by approximately 23% at 90% RH. It is speculated that the molar ratio of compound 1 to choline in the choline salt form K is 1:1.

[0379] Table 26: XRPD peak table of choline salt Form K of Compound 1.

[0380]

[0381]

[0382] Example 27: Preparation and Characterization of Choline Salt Form L of Compound 1

[0383] Form I was weighed into a sample bottle and 3 mL of tetrahydrofuran was added to form a suspension, which was then converted to a clear solution by the addition of 1.05 eq of choline. 3 mL of n-heptane was then added and the suspension was stirred overnight at room temperature. The solid was collected by filtration and dried under vacuum at 50°C.

[0384] The obtained solid was characterized by XRPD, DSC, TGA and DVS. The XRPD pattern is shown in FIG. Figure 27a The main diffraction peaks and their relative intensities are shown in Table 27. The DSC and TGA spectra are shown in Table 27. Figure 27b The DSC spectrum shows two strong endothermic peaks at 55°C and 184°C, respectively. The TGA spectrum shows that there is a weight loss of about 10% when heated to 138°C. Figure 27c shown 1 The H-NMR spectrum showed that the molar ratio of choline to the free base was 1:1. It is speculated that the molar ratio of compound 1 to choline in choline salt form L is 1:1.

[0385] Table 27: XRPD peak table of choline salt Form L of Compound 1.

[0386] <![CDATA[2θ( o )]]> Relative strength (%) <![CDATA[2θ( o )]]> Relative strength (%) 7.2 16.0 22.3 9.6 7.4 14.4 22.5 11.4 7.7 1.5 23.2 29.5 9.9 52.1 23.6 100.0 11.1 18.9 24.1 8.3 12.3 15.8 24.3 7.8 12.8 7.6 24.8 5.2 13.2 24.8 25.3 8.6 13.5 2.3 25.5 21.3 14.2 3.7 25.9 13.3 14.8 4.6 26.4 2.2 15.6 13.7 27.7 11.4 16.0 1.1 29.0 5.5 16.8 27.4 29.2 5.0 17.0 20.4 30.3 5.3 17.7 7.9 31.2 3.7 18.4 12.6 31.7 3.8 18.9 3.4 32.0 2.2 19.9 51.5 32.6 0.9 20.6 15.0 35.0 4.0 20.7 19.6 37.1 1.4 20.9 17.8 37.4 2.7 21.2 12.0 37.9 1.0 21.9 52.3

[0387] In summary, 17 free crystalline forms of compound 1 were obtained and characterized, of which forms I, II, III, IV, V, VIII, X, XIII, XIV, XV, XVI, and XVII are anhydrates, forms VI (dihydrate) and VII (channel hydrate) are hydrates, and forms IX, XI, XII, and XVII are solvates. In addition, 11 different salt forms of compound 1 were obtained, including sulfate, phosphate, benzenesulfonate, methanesulfonate, potassium salt, and choline salt.

[0388] Interconversion studies were conducted on the identified anhydrates (Form I, Form II, Form III, Form IV, Form V, Form VIII, Form X, Form XIII, Form XIV, and Form XV) in various organic solvents between room temperature and 60°C. The results showed that Form III was the most stable anhydrate between room temperature and 60°C.

[0389] Water activity experiments were conducted on Form I, Form III, and Form VI to determine the critical water activities at 25° C. and 50° C. The results showed that Form III was more stable when the water activity was no greater than 0.56 at 25° C. and no greater than 0.83 at 50° C., respectively.

[0390] Form III has low and pH-dependent solubility, with high solubility observed in simulated gastric fluid (SGF). Solid-state stability results indicate that Form III is physically and chemically stable when stored at 40°C / 75% RH and 60°C for 7 days, and no phase transition was observed after storage at 92.5% RH for 10 days. The physical properties of this dominant form are shown in Table 28.

[0391] Table 28: Physical properties of Form III of Compound 1.

[0392]

[0393] Among the crystalline salts, the sulfate salt Form B and the phosphate salt Form E of compound 1 are anhydrates and exhibit better physical properties than other crystalline salts. Similar to the free form III, the sulfate salt Form B and the phosphate salt Form E exhibit low solubility in biologically relevant media (<0.02 mg / mL).

[0394] It should be understood that the "Detailed Description" section, and not the "Abstract" section, is intended to be used to interpret the claims. The Abstract section may set forth one or more, but not all, exemplary embodiments of the present invention as contemplated by the inventor(s) and, therefore, is not intended to limit the present invention and the appended claims in any way.

[0395] The present invention has been described above with reference to functional modules, which illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional modules have been arbitrarily defined herein. Alternative boundaries may be defined so long as the specific functions and their relationships are appropriately performed.

[0396] If an aspect of the invention is described as "comprising" a feature, that embodiment is also considered to consist of or "consist essentially of" the feature.

[0397] The above description of specific embodiments will reveal the general nature of the invention so fully that others can easily modify and / or adapt these specific embodiments for various applications by applying the knowledge of those skilled in the art without undue experimentation and without departing from the general concept of the invention. Therefore, such variations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments based on the teachings and guidance presented herein. It should be understood that the phrases or terms used herein are for descriptive purposes only and not for limiting purposes, and thus the terms or phrases of this specification will be interpreted by those skilled in the art in accordance with the teachings and guidance.

[0398] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0399] The various aspects, embodiments, and options described herein may be combined in any and all variations.

[0400] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims

1. A compound having the following formula or a pharmaceutically acceptable salt thereof: It is a solid form that is an amorphous form, a crystalline form, or a combination thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is in an amorphous form.

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