heteroaryl compounds, solid form, preparation methods and uses

Abstract

This invention relates to heteroaryl compounds, their solid forms, methods of preparation, and uses. Specifically, this invention provides crystalline free forms, crystalline salt forms, and pharmaceutical compositions thereof of compound 1 having the following formula. This invention also provides methods of preparation and use thereof, for example, for inhibiting kinases and / or for treating various diseases or conditions, such as autoimmune diseases.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202310732317.3, filed on June 20, 2023, entitled "Heteroaryl Compounds, Solid Form, Preparation Method and Use Thereof".

[0002] Cross-references 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, this disclosure relates in its entirety to novel crystalline forms of heteroaryl compounds, compositions comprising the same, methods of their preparation, and methods of using the same, for example, for inhibiting kinases and / or for treating various diseases or conditions, such as the autoimmune diseases described herein. Background Technology

[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—comprising a family of over 50 receptors for cytokines, interleukins, interferons (IFNs), colony-stimulating factors (CSFs), and hormones—share a unique intracellular signaling pathway mediated by JAKs. These receptors bind directly to the intracellular domains of type I and type II cytokine receptors, rather than to other classes of cytokine receptors. JAK-dependent cytokines are major contributors to immunopathology. JAK dependence on type I and type II cytokines has been established in various genetic models, from mutagenic cell lines and knockout mice to humans. Polymorphisms in JAK and signal transducer and activator of transcription (STAT) genes are associated with autoimmunity, and loss of function due to the inability of type I and type II cytokines to transmit signals through their receptors leads to immunodeficiency. The critical role of JAKs in type I and type II cytokine signaling suggests that interfering with the activity of these kinases could potentially lead to a new class of immunomodulatory drugs.

[0006] Novel compounds capable of modulating cytokines and / or interferons (e.g., IL-12, IL-23, and / or IFN), along with their novel crystal and salt forms, provide favorable pharmacological responses for the treatment of one or more of the conditions described herein and may offer substantial therapeutic benefits to a wide range of patients in need. Summary of the Invention

[0007] International application number 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 modulate the function of IL-12, IL-23 and / or IFN.

[0008]

[0009] In various embodiments, this disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof or a hydrate or solvation thereof, which may 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 solvation thereof, methods of their preparation, and methods of using thereof.

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

[0011] The compounds disclosed herein can be used to prepare pharmaceutical compositions. In some embodiments, the pharmaceutical composition may comprise one or more of the compounds disclosed herein (e.g., crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII of compound 1, or salt crystal 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 may be tablets or capsules.

[0013] In some embodiments, this disclosure provides a method for inhibiting the function of IL-23, IL-12, and / or IFN-α in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of compound 1, or salt crystal forms A, B, C, D, E, F, G, H, J, K, or L of compound 1) or a pharmaceutical composition described herein. Example 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 disclosed herein can be used as monotherapy or in combination therapy. In some embodiments, methods of treating IL-23-, IL-12-, and / or IFN-related diseases or conditions may include administration of the compounds of this disclosure alone or in combination with each other and / or in combination with other suitable therapeutic agents that can be used to treat these conditions. Examples of such other suitable therapeutic agents include corticosteroids, rolipram, calcifosine, cytokine-suppressing 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; and antiproliferative agents such as methotrexate, leflunomide, and FK506 (tacrolimus). Antimalarial drugs, such as hydroxychloroquine; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF inhibitors such as tenidapril, anti-tumor necrosis factor antibodies or soluble TNF receptors, and rapamycin (sirolimus or...). ) or its derivatives.

[0015] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, administration may be made orally, nasally, transdermally, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally, and parenterally. In some embodiments, administration is orally.

[0016] Dosing regimens, 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 administered concurrently.

[0017] It should be understood that the above overview and the following detailed description are illustrative and explanatory only, and are not restrictive. Attached Figure Description

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

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

[0020] Figure 3a The representative X-ray powder diffraction (XRPD) pattern of crystal form III of compound 1 is shown. Figure 3b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of crystal form III of compound 1 are shown. Figure 3c Representative dynamic water adsorption-desorption (DVS) analysis of crystal form III of compound 1 is presented.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0034] Figure 16c The representative X-ray powder diffraction (XRPD) spectrum of crystal form XVII of compound 1 is shown. Figure 16d Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of crystal form XVII of compound 1 are shown. Figure 16e This shows the representativeness of the crystal form XVII of compound 1. 1 H-NMR spectrum.

[0035] Figure 17a The representative X-ray powder diffraction (XRPD) pattern of the crystalline sulfate form A of compound 1 is shown. Figure 17b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline sulfate form A of compound 1 are shown. Figure 17c Representative dynamic water adsorption-desorption (DVS) analysis of the crystalline sulfate form A of compound 1 is presented.

[0036] Figure 18a The representative X-ray powder diffraction (XRPD) pattern of the crystalline sulfate form B of compound 1 is shown. Figure 18b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline sulfate form B of compound 1 are shown. Figure 18c Representative dynamic water adsorption-desorption (DVS) analysis of the crystalline sulfate form B of compound 1 is presented.

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

[0038] Figure 20a The representative X-ray powder diffraction (XRPD) pattern of crystal form D of crystalline benzenesulfonate of compound 1 is shown. Figure 20b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline benzenesulfonate crystal form D of compound 1 are shown.

[0039] Figure 21a The representative X-ray powder diffraction (XRPD) pattern of the crystalline phosphate form E of compound 1 is shown. Figure 21b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline phosphate form E of compound 1 are shown. Figure 21cRepresentative dynamic water adsorption-desorption (DVS) analysis of the crystalline phosphate form E of compound 1 is presented.

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

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

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

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

[0044] Figure 26a The representative X-ray powder diffraction (XRPD) pattern of the crystalline choline salt K of compound 1 is shown. Figure 26b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the choline salt crystal form K of compound 1 are shown. Figure 26c Representative dynamic water adsorption-desorption (DVS) analysis of the crystalline choline salt K of compound 1 is presented.

[0045] Figure 27a The representative X-ray powder diffraction (XRPD) pattern of the crystalline choline salt L of compound 1 is shown. Figure 27b Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analyses of the crystalline choline salt form L of compound 1 are shown. Figure 27c The representative crystal form L of crystalline choline salt of compound 1 is given. 1 H-NMR spectrum. Detailed Implementation

[0046] In various embodiments, this disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof or a hydrate or solvation thereof, which may be, for example, in isolated form, substantially pure form, and / or solid form. Various polymorphic forms of compound 1 have been discovered, as shown in the Examples section. Of these polymorphs, crystal form III of compound 1 has been found to be stable and, compared to other crystal forms, suitable for a wide range of pharmaceutical uses. 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 compound 1 with HEK BlueIL23... 50 With a value of 2.5 nM, and advantages in, for example, human liver microsomal stability, rat pharmacokinetics, and selectivity of TYK2 relative to JAK1, it can be used to treat a variety of 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, this disclosure relates to compound 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvation thereof. Compound 1 should be understood as being in its free state, thereby distinguishing it from salts formed by external acids or bases. Unless obvious from the context, compound 1 should be understood as being 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. This 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: Compounds 1-2 react with cyclopropaneformyl chloride to produce compounds 1-3;

[0055]

[0056] Step 3: Compounds 1-3 are oxidized to produce compounds 1-4;

[0057]

[0058] Step 4: Compounds 1-4 are produced by removing the (2,4-dimethoxyphenyl)methylene group to generate compound 1;

[0059]

[0060] Each step in the above synthetic method is easy to perform and can achieve high yields, resulting in a high overall yield. The obtained product has a high purity of over 99% and few impurities. Therefore, this novel synthetic 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, more preferably about 65°C. In some embodiments, step 3 can be performed using potassium peroxymonosulfate complex salt as an oxidant. In some embodiments, step 4 can be performed using an acid, such as trifluoroacetic acid.

[0062] In some embodiments, compound 1 may be in solid form, such as an amorphous form, a crystalline form, or a combination thereof. In some embodiments, compound 1 may be in an amorphous form. In some embodiments, compound 1 may be in a crystalline form (e.g., in any one or more crystal 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 be present or in a particular solid form (e.g., a crystalline form), it should be understood that in some embodiments, the compound may be present primarily in that particular form. However, in some embodiments, the compound may also be present in a particular form, or in a mixture with one or more other solid forms (including amorphous forms). For example, when compound 1 is said to be present or in crystal form III, compound 1 may be present primarily in crystal form III, for example, more than 80 wt%, more than 90 wt%, or more than 95 wt% of compound 1 is in crystal form III, or no other solid form can be identified, for example by XRPD; or in some embodiments, compound 1 may be present in crystal form III, or as a mixture with one or more solid forms such as amorphous forms.

[0063] Compound 1 as used herein is typically in a substantially pure form. For example, in some embodiments, compound 1 may 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 by a purity by weight and / or HPLC area in any range between about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or a specified value. For example, in some embodiments, compound 1 is characterized by a purity by HPLC area in any range between about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or a specified value. The substantially pure compound 1 may be in solid form (e.g., the crystalline free or salt form, amorphous form, or a combination thereof as described herein) or in solution, suspension, or other form. In some embodiments, the substantially pure compound 1 may be crystal form III. For the avoidance of doubt, a composition comprising substantially pure compound 1 and one or more other ingredients shall be understood as a mixture of substantially pure compound 1 and one or more other ingredients, such as solvents, pharmaceutically acceptable excipients, etc., obtained directly or indirectly by mixing substantially pure compound 1 with one or more other ingredients.

[0064] In some embodiments, compound 1 is in crystalline form. In some embodiments, compound 1 is crystal form I. Crystal form I is characterized by any of those described herein. In some embodiments, crystal form I can be characterized by: (1) X-ray powder diffraction (XRPD) patterns 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) XRPD patterns and Figure 1a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 1b The crystal form I is substantially the same as shown; or any combination thereof (e.g., (1) and (3), or (2) and (3)). In some embodiments, the crystal form I may be characterized by having Figure 1a Or, as shown in Table 1, characteristic peaks of the XRPD spectrum (e.g., relative intensities of 5% or higher, 10% or higher, 20% or higher, 30% or higher, 40% or higher, 50% or higher, 60% or higher, 70% or higher, 80% or higher, or 90% or higher) (2θ, ±0.2°). It should be clarified that when saying that the XRPD spectrum of crystal form I has... Figure 1a Or the characteristic peaks in Table 1 or related to Figure 1aEssentially the same, it does not require the XRPD map to have the same characteristics as... Figure 1a Or the same relative intensity as the corresponding peak shown in Table 1 (if applicable). XRPD spectra include those corresponding to... Figure 1a Peaks at the corresponding diffraction angles (2θ, ±0.2°) shown in Table 1 (if applicable) are sufficient, regardless of their relative intensities. Similar expressions for other crystal forms in this document should be understood in a similar manner.

[0065] In some embodiments, compound 1 is crystal form II, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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) the XRPD pattern is consistent with... Figure 2a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 2b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0066] In some embodiments, compound 1 is crystal form III, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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) the XRPD pattern is consistent with... Figure 3a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 3b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

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

[0068] In some embodiments, compound 1 is crystal form IV, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) peaks at the following θ: 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 consistent with... Figure 4a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 4b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0069] In some embodiments, compound 1 is in crystal 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) peaks of the following: 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 consistent with... Figure 5a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 5b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0070] In some embodiments, compound 1 is in crystal 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) peaks of the following: 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 consistent with... Figure 6a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 6b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0071] In some embodiments, compound 1 is crystal form VII, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 7a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 7b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0072] In some embodiments, compound 1 is crystal form VIII, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 8a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 8b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0073] In some embodiments, compound 1 is crystal form IX, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 7, or 8) peaks of the following: 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 similar to... Figure 9a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 9b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0074] In some embodiments, compound 1 is crystal form X, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) peaks at the following values: 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 consistent with... Figure 10a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 10b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0075] In some embodiments, compound 1 is crystal form XI, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 11a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 11bThe ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0076] In some embodiments, compound 1 is crystal form XII, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 12a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 12b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0077] In some embodiments, compound 1 is crystal form XIII, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) peaks at the following values: 7.4°, 7.8°, 9.7°, 15.6°, 20.8°, 22.2°, and 22.6° (2θ, ±0.2°); (2) the XRPD pattern is consistent with... Figure 13a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 13b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0078] In some embodiments, compound 1 is crystalline form XIV, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 14a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 14b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0079] In some embodiments, compound 1 is crystalline form XV, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, or 6) peaks at the following θ: 7.5°, 7.8°, 9.3°, 20.5°, 21.5°, and 22.4° (2θ, ±0.2°); (2) the XRPD pattern is similar to... Figure 15a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 15bThe ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0080] In some embodiments, compound 1 is crystalline form XVI, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 16a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 16b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0081] In some embodiments, compound 1 is crystal form XVII, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 similar to... Figure 16c The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 16d The ones shown are essentially the same; 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 acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, bromides, butyrates, calcium salts, chlorides, choline, citrates, salicylates, fumarates, gluconates, gluconic acids, glutamates, hydrobromide, hydrochloride, lauryl sulfate, malates, maleates, mandelates, methanesulfonates, palmitates, pantothenates, phosphates, potassium salts, propionates, p-toluenesulfonates, salicylates, sodium salts, stearates, succinates, and sulfates.

[0083] In some embodiments, compound 1 is a crystalline sulfate form A, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 3, 4, 5, 6, or 7) peaks at the following values: 7.2°, 18.9°, 21.2°, 22.0°, 23.0°, 25.3°, and 26.7° (2θ, ±0.2°); (2) the XRPD pattern is consistent with... Figure 17a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 17b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0084] In some embodiments, compound 1 is a crystalline sulfate form B, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 18a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 18b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0085] In some embodiments, compound 1 is a crystalline sulfate form C, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks at the following θ: 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 consistent with... Figure 19a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 19b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0086] In some embodiments, compound 1 is a crystalline benzenesulfonate crystal form D, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 20a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 20b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0087] In some embodiments, compound 1 is a crystalline phosphate crystal form E, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks at the following values: 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 consistent with... Figure 21a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 21b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0088] In some embodiments, compound 1 is a crystalline methanesulfonate crystal form F, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 7, or 8) peaks at the following values: 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 consistent with... Figure 22a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 22b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0089] In some embodiments, compound 1 is a crystalline methanesulfonate crystal form G, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) peaks at the following θ: 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 consistent with... Figure 23a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 23b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0090] In some embodiments, compound 1 is a crystalline potassium salt of form H, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 24a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 24bThe ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0091] In some embodiments, compound 1 is a crystalline potassium salt crystal form J, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 9) peaks at the following values: 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 consistent with... Figure 25a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 25b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0092] In some embodiments, compound 1 is a crystalline choline salt of form K, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 26a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 26b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0093] In some embodiments, compound 1 is a crystalline choline salt of form L, characterized in that (1) its X-ray powder diffraction (XRPD) pattern has one or more (e.g., 2, 4, 6, 8, or 10) peaks of the following: 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 consistent with... Figure 27a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 27b The ones shown are essentially the same; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0094] In some embodiments, this disclosure also provides compound 1 in solid form, which can be prepared by any applicable method described in the Examples section.

[0095] In some embodiments, this disclosure also relates to any product prepared by any of the methods described herein, and methods of using such products.

[0096] This application provides the following implementation scheme:

[0097] 1. A compound having the following formula, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

[0098]

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

[0100] 3. The compound according to embodiment 1, which is of crystal form I, is 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°, 11.7°, 20.9°, 22.3°, 23.6°, 24.8°, 25.3°, 26.5°, 27.0° and 30.2° (2θ, ±0.2°); (2) the XRPD pattern and Figure 1a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 1b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0101] and / or

[0102] It is crystal form II, 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: 7.1°, 7.7°, 11.1°, 12.3°, 20.4°, 21.7°, 22.7°, 24.7°, 26.9° and 27.5° (2θ, ±0.2°); (2) the XRPD pattern and Figure 2a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 2b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0103] and / or

[0104] It is crystal form III, 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: 7.0°, 9.7°, 14.1°, 14.5°, 17.2°, 18.2°, 19.6°, 21.3°, 24.1° and 27.0° (2θ, ±0.2°); (2) the XRPD pattern and Figure 3a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 3bThe ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0105] and / or

[0106] It is crystal 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 and Figure 4a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 4b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0107] and / or

[0108] It is crystal 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 and Figure 5a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 5b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0109] and / or

[0110] It is crystal 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 and Figure 6a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 6b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0111] and / or

[0112] It is crystal 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 and Figure 7a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 7b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0113] and / or

[0114] It is crystal 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 and Figure 8a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 8b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0115] and / or

[0116] It is crystal 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) peaks of the following: 6.2°, 7.2°, 12.6°, 18.9°, 19.2°, 21.2°, 22.0° and 23.1° (2θ, ±0.2°); (2) the XRPD pattern and Figure 9a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 9b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0117] and / or

[0118] It is crystal 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) peaks of the following: 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 and Figure 10a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 10bThe ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0119] and / or

[0120] It is crystal 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 and Figure 11a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 11b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0121] and / or

[0122] It is crystal 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 and Figure 12a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 12b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0123] and / or

[0124] It is crystal 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) peaks of the following: 7.4°, 7.8°, 9.7°, 15.6°, 20.8°, 22.2° and 22.6° (2θ, ±0.2°); (2) the XRPD pattern and Figure 13a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 13b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0125] and / or

[0126] It is crystal 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 and Figure 14a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 14b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0127] and / or

[0128] It is of crystal 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) peaks of the following: 7.5°, 7.8°, 9.3°, 20.5°, 21.5° and 22.4° (2θ, ±0.2°); (2) the XRPD pattern and Figure 15a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 15b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0129] and / or

[0130] It is of crystal 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 and Figure 16a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 16b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0131] and / or

[0132] It is crystal 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) peaks below: 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 Figure 16B-a; (3) the differential scanning calorimetry (DSC) pattern is substantially the same as that shown in Figure 16B-b; or any combination thereof (e.g. (1) and (3), or (2) and (3)).

[0133] 4. The compound according to embodiment 1, which is sulfate crystal form A, is 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 and Figure 17a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 17b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0134] and / or

[0135] It is sulfate crystal 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 and Figure 18a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 18b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0136] and / or

[0137] It is sulfate 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 and Figure 19a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 19bThe ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0138] and / or

[0139] It is a benzenesulfonate crystal 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 and Figure 20a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 20b The ones shown are substantially the same; 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 and Figure 21a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 21b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0142] and / or

[0143] It is a methanesulfonate crystal 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 and Figure 22a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 22b The ones shown are substantially the same; or any combination thereof (e.g., (1) and (3), or (2) and (3));

[0144] and / or

[0145] It is a methanesulfonate crystal 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 and Figure 23a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 23b The ones shown are substantially the same; 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 and Figure 24a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 24b The ones shown are substantially the same; 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) peaks of the following: 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 and Figure 25a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 25b The ones shown are substantially the same; 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 and Figure 26aThe results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 26b The ones shown are substantially the same; 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 and Figure 27a The results are basically the same; (3) Differential scanning calorimetry (DSC) spectra are the same as those shown. Figure 27b The ones shown are essentially the same; 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 a compound or pharmaceutically acceptable salt or its hydrate or solvate according to any one of embodiments 1-5, and optionally a pharmaceutically acceptable excipient.

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

[0157] 8. The method according to 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: Deprotect compounds 1-4 to produce compound 1

[0160]

[0161] and / or

[0162] It includes:

[0163] Step 3: Oxidize compounds 1-3 to produce compounds 1-4

[0164]

[0165] and / or

[0166] It includes:

[0167] Step 2: Acylate compound 1-2 with cyclopropaneformyl chloride to produce compound 1-3;

[0168]

[0169] and / or

[0170] It includes:

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

[0172]

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

[0174] and / or

[0175] Step 3 includes using potassium peroxymonosulfate complex salt as an oxidant to oxidize compounds 1-3;

[0176] and / or

[0177] Step 2 is performed at a temperature of approximately 50-80°C, preferably approximately 60-70°C, and more preferably approximately 65°C.

[0178] and / or

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

[0180] Pharmaceutical Composition

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

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

[0183] The pharmaceutical composition can also be formulated for administration via any known route of delivery, including but not limited to oral, parenteral, and inhalation.

[0184] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Oral formulations may be presented in discrete units, such as capsules, pills, buffers, lozenges, or tablets, each containing a predetermined amount of the active compound; as 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. Suitable excipients, without limitation, include, for example, agar, alginate, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, 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 carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearate fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl ethanol, 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). The parenteral formulation may be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for preparing the parenteral formulation are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, glucose, wheat 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, inhalable formulations may be formulated as nasal sprays, dry powders, or aerosols that can be administered via a metered-dose inhaler. Excipients used to prepare inhaled formulations are known in the art. Suitable, non-limiting excipients include, for example, lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, as well as mixtures of these substances. The spray may also contain propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0187] Pharmaceutical compositions may include various amounts of the compounds disclosed herein, depending on various factors such as the intended use, potency, and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein (e.g., crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII of compound 1, or its salt crystal forms A, B, C, D, E, F, G, H, J, K, or L, or in any combination thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein and pharmaceutically acceptable excipients. As used herein, a therapeutically effective amount of the disclosed compounds is an effective amount for treating the diseases or conditions described herein, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and / or scleroderma. This may depend 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, and whether another drug is co-administered.

[0188] For veterinary use, the compounds disclosed herein can be administered as appropriate and acceptable formulations in accordance with normal veterinary practice. Veterinarians can readily determine the dosing regimen and route of administration best suited for a particular animal.

[0189] In some embodiments, all necessary components for treating diseases or conditions mediated by IL-12, IL-23, and / or interferon-α (INF-α), using the compounds of this disclosure, whether used alone or in combination with another medicine or intervention conventionally used to treat such diseases, can be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for a disease treatment intervention comprising a packaged group of medicines, including the compounds disclosed herein, as well as buffers and other components for preparing said medicines in a deliverable form, and / or a device for delivering such medicines, and / or any reagents for treatment in combination with the compounds of this disclosure, and / or disease treatment instructions packaged with the medicines. These instructions may be affixed to any tangible medium, such as printed paper, or computer-readable magnetic or optical media, or may be instructions referencing a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0190] Treatment

[0191] The compounds disclosed herein may be used to treat conditions associated with the functional regulation of IL-23, IL-12, and / or IFN-α. These conditions include IL-23-, IL-12-, and / or IFN-α-related diseases, wherein the pathogenic mechanism is mediated by these cytokines, including any known in the art and those described herein.

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

[0193] In some embodiments, this disclosure provides a method for treating or preventing diseases or conditions associated with IL-23, IL-12, and / or IFN-α, the method comprising administering to a subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof). Suitable diseases or conditions associated with IL-23, IL-12, and / or IFN-α that can be treated using the methods described herein include any diseases or conditions known in the art. Exemplary diseases or conditions associated with IL-23, IL-12, and / or IFN-α 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 conditions described herein.

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

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

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

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

[0198] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof), wherein the disease or condition may be one or more diseases or conditions selected from: inflammatory diseases, such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic 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 include CAPS, TRAPS, FMF, adult-onset autoimmune diseases (AOSD), systemic juvenile idiopathic arthritis, gout, and gouty arthritis; metabolic diseases include type 2 diabetes, atherosclerosis, and myocardial infarction; destructive bone diseases such as osteoporosis, osteoarthritis, osteoporosis, and multiple myeloma-associated bone diseases; proliferative diseases such as acute myeloid leukemia and chronic myeloid leukemia; angiogenic diseases such as solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigella infection; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; tumors and viral diseases such as metastatic melanoma, Kaposi's sarcoma, and multiple myeloma; as well as HIV infection and CMV retinitis, and AIDS.

[0199] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject of need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof), wherein the disease or condition that can be treated by this method includes, but is not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, etc. Obstructive lung disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenic purpura, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-host disease, inflammatory response caused by endotoxins, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rheumatoid arthritis. Rheumatoid arthritis, acute synovitis, pancreatic B-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritis diseases, cerebral malaria, chronic inflammatory lung diseases, silicosis, pulmonary sarcoidosis, osteoporosis, allogeneic rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and Shigella infection; Alzheimer's disease, Parkinson's disease. Kimberly's disease, a neurodegenerative disease caused by cerebral ischemia or traumatic injury; angiogenic diseases, including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases, including acute hepatitis infections (including hepatitis A, hepatitis B, and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC, or malignant tumors, and herpes; stroke, myocardial ischemia, ischemic heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, diseases associated with prostaglandin endothelial oxidase syndrome-2, and pemphigus vulgaris.

[0200] In some preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal 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, allogeneic rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.

[0201] In some preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject of need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal 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 (including cerebral ischemia-reperfusion injury) caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction.

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

[0203] In some preferred embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal 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, Sjögren's syndrome, and scleroderma.

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

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

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

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

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

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

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

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

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

[0213] In some embodiments, this disclosure also provides the use of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof) for the treatment or prevention of any disease or condition described herein, such as 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, this disclosure also provides the use of one or more compounds of this disclosure (e.g., compound 1 of crystal form I, II, III, IV, V, VI, VIII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or its salt crystal form A, B, C, D, E, F, G, H, J, K, or L, or any combination thereof) in the manufacture of a medicament for the treatment or prevention of any of the diseases or conditions described herein, such as 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 disclosed herein can be used as monotherapy or in combination therapy. In some embodiments, methods of treating IL-23-, IL-12-, and / or IFN-related diseases or conditions may include administration of the compounds of this disclosure alone or in combination with each other and / or in combination with other suitable therapeutic agents that can be used to treat these conditions. Examples of such other suitable therapeutic agents include corticosteroids, rolipram, calcifosine, cytokine-suppressing 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; and antiproliferative agents such as methotrexate, leflunomide, and FK506 (tacrolimus). Antimalarial drugs, such as hydroxychloroquine; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF inhibitors such as tenidapril, anti-tumor necrosis factor antibodies or soluble TNF receptors, and rapamycin (sirolimus or...). ) or its derivatives.

[0216] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, administration may be made orally, nasally, transdermally, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally, and parenterally. In some embodiments, the administration is orally.

[0217] Dosing regimens, 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 administered concurrently.

[0218] definition

[0219] As used herein, “(one or more) compounds of the present disclosure” means compound 1 or a pharmaceutically acceptable salt thereof or a hydrate or solvation thereof, in its isolated form or substantially pure form, including crystalline form, amorphous form, hydrated and / or solvated solid form.

[0220] As used herein, the term "about" modifying a quantity relating to the invention refers to variations in a numerical quantity that can occur, such as through routine testing and processing; through unintentional errors in such testing and processing; through differences in the manufacture, origin, or purity of the ingredients used in the invention, etc. As used herein, "about" also includes a specific value, for example, about 10% includes 10%. The claims include the equivalent of the enumerated quantity, whether or not modified by the word "about". In one embodiment, the term "about" refers to less than 20% of the reported value.

[0221] As used herein, the term "treatment" and its synonyms refer to the elimination, reduction, or improvement of a disease or condition and / or symptoms associated with it. While not excluding, treating a disease or condition does not require the complete elimination of the associated disease, condition, or symptoms. As used herein, the term "treatment," etc., may include "preventive 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 subjects who do not have a disease or condition but are at risk or susceptible to it, or whose disease or condition is recurrent or developing. The term "treatment" and its synonyms contemplate administering a therapeutically effective amount of the disclosed compound to a subject who requires such treatment.

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

[0223] As used herein, the term "subject" (or "patient") refers to an animal, preferably a mammal, and most preferably a human, that is a subject of treatment, observation, or experimentation. In any of the embodiments described herein, the subject may be a human.

[0224] Example

[0225] General Method

[0226] Materials: Starting materials, reagents, solvents, etc., can be obtained from commercial sources.

[0227] 1 H nuclear magnetic resonance spectroscopy ( 1 H NMR: Performed using a Bruker Advance400 equipped with an automated sampler (B-ACS120). 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 [wavelength value missing]. The sample was scanned from 3 to 40° (2θ) with a step size of 0.02° (2θ). 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, peeled aluminum pan, automatically weighed, and then inserted into the TGA furnace. The sample was heated from room temperature (RT) to the 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 pinhole sealed container, and the weight was accurately recorded. The sample was heated from 25°C to the final temperature at a rate of 10°C / min.

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

[0232] High-performance liquid chromatography (HPLC): The following shows a representative HPLC method that can be used, for example, to analyze the purity, solubility, and stability of compound 1 in this paper.

[0233]

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

[0235]

[0236] Compound 1-1 was prepared from 2-amino-5-chloropyridine by a number of synthetic steps following a 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 atmosphere, 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 washed with water and collected. The crude product was slurried at 65 °C with a mixed solvent of tetrahydrofuran and isopropanol (V / V, 1 / 1) to give compound 1-2 (white solid, 251 g, yield 91%). LCMS: 478.1 [M+1] + .

[0238] Step 2: Under nitrogen atmosphere, compounds 1-2 (200 g) and N,N-diisopropylethylamine (81 g) were added to tetrahydrofuran (1200 mL) and heated to 65 °C. A solution of cyclopropaneformyl chloride (52.6 g) in THF (500 mL) was added dropwise, and the reaction was allowed to proceed 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 slurried with isopropanol at 80 °C for 1 hour to give compounds 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 atmosphere, compound 1-3 (160 g) was added to 1,4-dioxane (1600 mL). A solution of potassium peroxymonosulfate complex salt (325 g) in water (700 mL) was added at a temperature below 30 °C, and the reaction was carried out at 30 °C for 24 hours. The reaction mixture was filtered and washed with dichloromethane. The filtrate was washed with a 5% sodium sulfite aqueous solution and water, respectively. After concentrating the organic phase, methanol was added and the mixture was stirred 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 atmosphere, compounds 1-4 (105 g) were 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 give 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 crystal form I of compound 1

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

[0243] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 1a As shown, its main diffraction peaks and their relative intensities are listed in Table 1. The DSC and TGA spectra are as follows: Figure 1b As shown in the figure. The DSC spectrum shows a small exothermic peak at 250℃ and a strong endothermic peak at 319℃. The TGA spectrum shows that crystal form I does not exhibit significant weight loss from room temperature to 220℃.

[0244] Table 1: XRPD peak table of crystal 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 crystal form II of compound 1

[0247] Weigh crystal form I into a sample vial, then add 50V isopropanol and slurry at 50°C for 1 day. Filter the solid, collect it, and dry it at 50°C overnight.

[0248] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 2a As shown, its main diffraction peaks and their relative intensities are listed in Table 2. The DSC and TGA spectra are as follows: Figure 2b As shown in the figure. The DSC spectrum shows relatively strong endothermic peaks at 310℃ and 317℃. The TGA spectrum indicates that crystal form II does not exhibit significant weight loss in the temperature range from RT to 275℃.

[0249] Table 2: XRPD peak table of crystal 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 crystal form III of compound 1

[0252] Crystal form I was weighed into a sample vial, and then 50V acetone was added and stirred at 50°C for 1 day. The solid was filtered, collected, and dried at 50°C overnight. Alternatively, crystal form III can also be obtained directly through the purification process described in step 4 of the above synthesis.

[0253] The obtained solid was characterized by XRPD, DSC, TGA, and DVS. The XRPD spectrum is shown below. Figure 3a As shown, its main diffraction peaks and their relative intensities are listed in Table 3. The DSC and TGA spectra are as follows: Figure 3b As shown in the figure. The DSC spectrum shows a weak endothermic peak at 272 °C, and stronger endothermic peaks at 310 °C and 318 °C. The TGA spectrum indicates that crystal form III does not exhibit significant weight loss in the temperature range from RT to 250 °C. Figure 3c The DVS results showed that, at 90% RH, the moisture absorption weight gain of crystal form III was 0.13%.

[0254] Table 3: XRPD peak table of crystal 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 crystal form IV of compound 1

[0257] Weigh crystal form I into a sample vial, then add 50V acetonitrile and slurry at 50℃ for 1 day. Filter the solid, collect it, and vacuum dry it at 50℃ for 6 hours.

[0258] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 4a As shown, its main diffraction peaks and their relative intensities are listed in Table 4. The DSC and TGA spectra are as follows: Figure 4b As shown in the figure. The DSC spectrum shows a weak exothermic peak at 216 °C and a strong endothermic peak at 319 °C. The TGA spectrum indicates that crystal form IV does not exhibit significant weight loss in the temperature range from RT to 275 °C.

[0259] Table 4: XRPD peak table of crystal form IV of compound 1.

[0260]

[0261]

[0262] Example 5: Preparation and characterization of crystal form V of compound 1

[0263] Heat crystal form I to 300°C.

[0264] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 5a As shown, its main diffraction peaks and their relative intensities are shown in Table 5. The DSC and TGA spectra are as follows: Figure 5b As shown in the figure. The DSC spectrum shows a strong endothermic peak at 319 °C. The TGA spectrum indicates that crystal form V does not exhibit significant weight loss when heated to 275 °C.

[0265] Table 5: XRPD peak table of crystal form V of compound 1.

[0266] <![CDATA[2θ( 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 crystal form VI of compound 1

[0268] Weigh crystal form I into a sample vial, then add 50V of water and slurry at 50°C for 1 day. Filter the solid, collect it, and dry it at room temperature.

[0269] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 6a As shown, its main diffraction peaks and their relative intensities are listed in Table 6. The DSC and TGA spectra are as follows: Figure 6b As shown. The DSC spectrum shows two strong endothermic peaks at 49℃ and 318℃, respectively. The TGA spectrum shows a weight loss of approximately 7.3% in the temperature range of 30℃ to 70℃. Crystal form VI can be a dihydrate of compound 1 (theoretical water content is 7.8%).

[0270] Table 6: XRPD peak table of crystal 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 crystal form VII of compound 1

[0273] Weigh crystal form I into a sample vial, then add 50V of ethyl acetate and slurry at 50°C for 1 day. Filter the solid, collect it, and vacuum dry it overnight at 50°C.

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

[0275] Table 7: XRPD peak table of crystal 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 crystal form VIII of compound 1

[0278] Heat crystal form VII to 200°C.

[0279] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 8a As shown, its main diffraction peaks and their relative intensities are listed in Table 8. The DSC and TGA spectra are as follows: Figure 8b As shown in the figure. The DSC spectrum shows an exothermic peak at 303℃ and a strong endothermic peak at 319℃. The TGA spectrum indicates no significant weight loss in the temperature range of room temperature to 130℃.

[0280] Table 8: XRPD peak table of crystal form VIII 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 crystal form IX of compound 1

[0283] Weigh approximately 40 mg of crystal form I and dissolve it in dimethyl sulfoxide (DMSO) at 50°C. Filter the solution and allow it to cool and crystallize at room temperature. Filter the solid, collect it, and dry it under vacuum at 50°C for 6 hours.

[0284] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 9a As shown, its main diffraction peaks and their relative intensities are listed in Table 9. The DSC and TGA spectra are as follows: Figure 9b As shown. The DSC spectrum shows two endothermic peaks at 138 °C and 319 °C, respectively. The TGA spectrum shows a weight loss of approximately 15.2% in the temperature range of 50 °C to 170 °C. Crystal form IX can be a mono-DMSO solvate of compound 1 (theoretical DMSO content is 15.4%).

[0285] Table 9: XRPD peaks of crystal 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 crystal form X of compound 1

[0288] Heat crystal form IX to 200°C.

[0289] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 10a As shown, its main diffraction peaks and their relative intensities are listed in Table 10. The DSC and TGA spectra are as follows: Figure 10b As shown in the figure. The DSC spectrum shows endothermic peaks at 300℃ and 319℃. The TGA spectrum indicates that there is no significant weight loss when heated to 250℃.

[0290] Table 10: XRPD peak table of crystal 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 crystal form XI of compound 1

[0293] Dissolve approximately 20 mg of crystal form I in 1 mL of dimethylformamide at 50 °C. Gradually add 4 mL of isopropanol until a solid precipitates. Pulverize the solid at 50 °C overnight, then filter, collect, and vacuum dry at 50 °C overnight.

[0294] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 11a As shown, its main diffraction peaks and their relative intensities are listed in Table 11. The DSC and TGA spectra are as follows: Figure 11b As shown in the figure. The DSC spectrum shows an exothermic peak at 211 °C and endothermic peaks at 104 °C and 319 °C. The TGA spectrum shows a weight loss of approximately 4.1% when heated to 140 °C.

[0295] Table 11: XRPD peak table of crystal form XI of compound 1.

[0296]

[0297]

[0298] Example 12: Preparation and characterization of crystal form XII of compound 1

[0299] Approximately 20 mg of crystal form I was dissolved in 1 mL of dimethylformamide at 50 °C. 4 mL of acetone was gradually added until a solid precipitated. The solid was pulped at 50 °C overnight, then filtered, collected, and vacuum dried at 50 °C overnight.

[0300] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 12a As shown, its main diffraction peaks and their relative intensities are shown in Table 12. The DSC and TGA spectra are as follows: Figure 12b As shown in the figure. The DSC spectrum shows an exothermic peak at 205 °C and endothermic peaks at 124 °C and 319 °C. The TGA spectrum shows that there is a weight loss of about 4.1% when heated to 120 °C; and a further weight loss of about 2.1% in the temperature range above 120 °C to 230 °C.

[0301] Table 12: XRPD peak table of crystal 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 crystal form XIII of compound 1

[0304] Weigh crystal form I into a sample vial, then add 50V methanol and slurry at room temperature for 3 days. Filter, collect, and dry the solid.

[0305] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 13a As shown, its main diffraction peaks and their relative intensities are listed in Table 13. The DSC and TGA spectra are as follows: Figure 13b As shown in the figure. The DSC spectrum shows an endothermic peak at 319℃. The TGA spectrum shows no significant weight loss when heated to 250℃.

[0306] Table 13: XRPD peak table of crystal form XIII of compound 1.

[0307]

[0308]

[0309] Example 14: Preparation and characterization of crystal form XIV of compound 1

[0310] Weigh crystal form I into a sample vial, then add 50V isopropanol and slurry at room temperature for 3 days. Filter, collect, and dry the solid.

[0311] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 14a As shown, its main diffraction peaks and their relative intensities are listed in Table 14. The DSC and TGA spectra are as follows: Figure 14b As shown in the figure. The DSC spectrum shows two endothermic peaks at 237℃ and 319℃. The TGA spectrum shows no significant weight loss when heated to 250℃.

[0312] Table 14: XRPD peak table of crystal 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 crystal form XV of compound 1

[0315] Weigh crystal form I into a sample vial, then add 50V tetrahydrofuran and slurry at room temperature for 3 days. Filter, collect, and dry the solid.

[0316] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 15a As shown, its main diffraction peaks and their relative intensities are listed in Table 15. The DSC and TGA spectra are as follows: Figure 15bAs shown in the figure. The DSC spectrum shows a weak exothermic peak at 253 °C, and endothermic peaks at 285 °C and 319 °C. The TGA spectrum shows a weight loss of approximately 0.7% when heated to 250 °C.

[0317] Table 15: XRPD peak table of crystal 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 crystal form XVI of compound 1

[0320] Heat crystal form IV to 230°C.

[0321] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 16a As shown, its main diffraction peaks and their relative intensities are shown in Table 16. The DSC and TGA spectra are as follows: Figure 16b As shown in the figure. The DSC spectrum shows a weak exothermic peak at 137℃, and endothermic peaks at 259℃ and 319℃. The TGA spectrum indicates that there is no significant weight loss when heated to 250℃.

[0322] Table 16: XRPD peak table of crystal form XVI of compound 1.

[0323]

[0324]

[0325] Example 16B: Preparation and characterization of crystal form XVII of compound 1

[0326] Dissolve 15 mg of crystal form III in 1 mL of dichloromethane containing 10% acetic acid. Shake at room temperature for 24 hours. Collect the solid by centrifugation and dry it in a 60°C oven for 3 hours.

[0327] Using XRPD, DSC, TGA and 1 The solid obtained by H-NMR characterization, including the XRPD spectrum as shown in the figure Figure 16c As shown, its main diffraction peaks and relative intensities are listed in Table 16B. DSC and TGA results show... Figure 16d The DSC spectrum shows a distinct endothermic peak at 156.6℃. The TGA spectrum shows a weight loss of approximately 12.0% when heated from room temperature to 180℃. Figure 16e In 1 The 1H-NMR spectrum shows that the molar ratio of compound 1 to acetic acid is approximately 1:1. Since the theoretical acetic acid content of the monoacetic acid solvate is 12.3%, crystal form XVII is likely the monoacetic acid solvate of compound 1.

[0328] Table 16B: XRPD peak table of crystal form XVII of compound 1.

[0329] <![CDATA[2θ( 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 crystal form A of compound 1

[0331] Weigh crystal form I into a sample vial, add 120V ethanol and 1 equivalent (eq) sulfuric acid, and slurry at room temperature for 1 day. Filter, collect, and dry the solid.

[0332] The obtained solid was characterized by XRPD, DSC, TGA, IC, and DVS. The XRPD spectrum is shown below. Figure 17a As shown, its main diffraction peaks and their relative intensities are shown in Table 17. The DSC and TGA spectra are as follows: Figure 17b As shown in the figure. The DSC spectrum shows two endothermic peaks at 198 °C and 226 °C, respectively. The TGA spectrum shows a weight loss of approximately 1.6% when heated to 176 °C. Ion chromatography (IC) results indicate a sulfate content of 16.7%. Figure 17c The DVS results shown indicate that sulfate crystal form A gains approximately 10% weight due to moisture absorption at 90% RH. It is speculated that the molar ratio of compound 1 in sulfate crystal form A to sulfuric acid is 1:1.

[0333] Table 17: XRPD peaks of sulfate crystal form A of compound 1.

[0334]

[0335]

[0336] Example 18: Preparation and characterization of sulfate crystal form B of compound 1

[0337] Weigh crystal form I into a sample vial and add 120V acetone to form a suspension. Add 1 eq of sulfuric acid and stir at room temperature for 3 days. Filter the solid, collect it, and vacuum dry it at 50°C.

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

[0339] Table 18: XRPD peaks of sulfate crystal 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 sulfate crystal form C of compound 1

[0342] The samples were collected after DVS testing of sulfate crystal form A.

[0343] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 19a As shown, its main diffraction peaks and their relative intensities are listed in Table 19. The DSC and TGA spectra are as follows: Figure 19b As shown in the figure. The DSC spectrum shows endothermic peaks at 111℃, 196℃, and 230℃, and an exothermic peak at 209℃. The TGA spectrum shows a weight loss of approximately 3.3% when heated to 177℃. It is speculated that the molar ratio of compound 1 (sulfate crystal form C) to sulfuric acid is 1:1.

[0344] Table 19: XRPD peaks of sulfate crystal 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 benzenesulfonate crystal form D of compound 1

[0347] Weigh crystal form I into a sample vial and add 120V acetone to form a suspension. Add 1 eq benzenesulfonic acid and stir at room temperature for 20 hours. Filter the solid, collect it, and vacuum dry it at 50°C.

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

[0349] Table 20: XRPD peak table of benzenesulfonate crystal form D 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 crystal form E of compound 1

[0352] Weigh crystal form I into a sample vial and add 120V acetone to form a suspension. Add 1 eq of phosphoric acid and stir at room temperature for 20 hours. Filter the solid, collect it, and vacuum dry it at 50°C.

[0353] The obtained solid was characterized by XRPD, DSC, TGA, and DVS. The XRPD spectrum is shown below. Figure 21a As shown, its main diffraction peaks and their relative intensities are listed in Table 21. The DSC and TGA spectra are as follows: Figure 21b As shown in the figure. The DSC spectrum shows two endothermic peaks at 241℃ and 259℃, respectively. The TGA spectrum shows no significant weight loss when heated to 210℃. Figure 21c The DVS results shown indicate that phosphate crystal form E exhibits a moisture absorption weight gain of approximately 0.92% at 90% RH. It is speculated that the molar ratio of compound 1 to phosphoric acid in phosphate crystal form E is 1:1.

[0354] Table 21: XRPD peaks of phosphate crystal form E of compound 1.

[0355] <![CDATA[2θ( 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 methanesulfonate form F of compound 1

[0357] Weigh crystal form I into a sample vial and add 120V ethanol to form a suspension. Add 1 eq of methanesulfonic acid and stir at room temperature for 20 hours. Filter the solid, collect it, and vacuum dry it at 50°C.

[0358] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 22a As shown, its main diffraction peaks and their relative intensities are shown in Table 22. The DSC and TGA spectra are as follows: Figure 22b As shown in the figure. The DSC spectrum shows two strong endothermic peaks at 120℃ and 257℃, and two weak exothermic peaks at 183℃ and 221℃. The TGA spectrum shows a weight loss of approximately 5.9% when heated to 140℃. It is speculated that the molar ratio of compound 1 (methanesulfonate form F) to methyl sulfuric acid is 1:1.

[0359] Table 22: XRPD peaks of methanesulfonate form F 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 the methanesulfonate crystal form G of compound 1

[0362] Weigh crystal form I into a sample vial and add 120V acetone to form a suspension. Add 1 eq of methanesulfonic acid and stir at room temperature for 20 hours. Filter the solid, collect it, and vacuum dry it at 50°C.

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

[0364] Table 23: XRPD peaks of the methanesulfonate crystal form G 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 crystal form H of compound 1

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

[0368] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 24a As shown, its main diffraction peaks and their relative intensities are listed in Table 24. The DSC and TGA spectra are as follows: Figure 24b As shown in the figure. The DSC spectrum shows two endothermic peaks at 25 °C and 249 °C, and one exothermic peak at 260 °C. The TGA spectrum shows a weight loss of approximately 2.9% when heated to 120 °C. It is speculated that the molar ratio of compound 1 of potassium salt crystal form H to potassium hydroxide is 1:1.

[0369] Table 24: XRPD peak table of potassium salt crystal form H of compound 1.

[0370] <![CDATA[2θ( 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 potassium salt crystal form J of compound 1

[0372] Weigh crystal form I into a sample vial and add 100V DMSO to form a suspension. Add 1.2eq potassium hydroxide and stir at room temperature for 16 hours. Filter the solid, collect it, and vacuum dry it at 50°C for 3 days.

[0373] The obtained solid was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown below. Figure 25a As shown, its main diffraction peaks and their relative intensities are listed in Table 25. The DSC and TGA spectra are as follows: Figure 25b As shown in the figure. The DSC spectrum shows three endothermic peaks at 29 °C, 154 °C, and 217 °C, respectively. 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 of potassium salt crystal form J to potassium hydroxide is 1:1.

[0374] Table 25: XRPD peak table of potassium salt crystal form J of compound 1.

[0375] <![CDATA[2θ( 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 crystal form K of compound 1

[0377] Weigh crystal form I into a sample vial, add 3 mL of acetone to form a suspension, and then add 1.05 eq of choline to make a clear solution. Filter the solid, collect it, and dry it under vacuum at 50 °C.

[0378] The obtained solid was characterized by XRPD, DSC, TGA, and DVS. The XRPD spectrum is shown below. Figure 26a As shown, its main diffraction peaks and their relative intensities are listed in Table 26. The DSC and TGA spectra are as follows: Figure 26b As shown in the figure. The DSC spectrum shows two strong endothermic peaks at 26℃ and 185℃, respectively. The TGA spectrum shows a weight loss of approximately 6.5% when heated to 161℃. Figure 26c The DVS results shown indicate that choline salt crystal form K gains approximately 23% weight through hygroscopic absorption at 90% RH. It is speculated that the molar ratio of compound 1 to choline in choline salt crystal form K is 1:1.

[0379] Table 26: XRPD peak table of choline salt crystal form K of compound 1.

[0380]

[0381]

[0382] Example 27: Preparation and characterization of choline salt crystal form L of compound 1

[0383] Weigh crystal form I into a sample vial, add 3 mL of tetrahydrofuran to form a suspension, and then add 1.05 eq of choline to make a clear solution. Then add 3 mL of n-heptane and stir overnight at room temperature. Filter the solid, collect it, and dry it under vacuum at 50 °C.

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

[0385] Table 27: XRPD peaks of choline salt crystal 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 crystal forms of compound 1 were obtained and characterized. Among them, crystal forms I, II, III, IV, V, VIII, X, XIII, XIV, XV, XVI, and XVII are anhydrous, crystal forms VI (dihydrate) and VII (channel hydrate) are hydrates, and crystal forms IX, XI, XII, and XVII are solvates. Furthermore, 11 different salt crystal forms of compound 1 were obtained, including sulfates, phosphates, benzenesulfonates, methanesulfonates, potassium salts, and choline salts.

[0388] Interconversion studies were conducted on identified anhydrous hydrates (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VIII, crystal form X, crystal form XIII, crystal form XIV, and crystal form XV) in different organic solvents between RT and 60 °C. The experimental results showed that crystal form III was the most stable anhydrous form between room temperature and 60 °C.

[0389] Water activity experiments were conducted on crystal forms I, III, and VI to determine the critical water activities at 25 °C and 50 °C. The results showed that crystal 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] Crystal form III exhibits low and pH-dependent solubility, but higher solubility was observed in simulated gastric fluid (SGF). Solid stability results showed that crystal form III is physically and chemically stable at 40°C / 75% RH and 60°C for 7 days, and no crystal form transformation was observed after 10 days at 92.5% RH. The physical properties of this dominant crystal form are shown in Table 28.

[0391] Table 28: Physical properties of crystal form III of compound 1.

[0392]

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

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

[0395] The present invention has been described above using 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 can be defined as long as the specific functions and their relationships are properly performed.

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

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

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

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

[0400] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is 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 any document incorporated by reference, the meaning or definition assigned to that term in this document shall prevail.

Claims

1. Compounds having the following formula: ， It is crystal form III, characterized by, Its X-ray powder diffraction pattern has the following peaks at 2θ: 7.0°±0.2°, 9.7°±0.2°, 14.1°±0.2°, 14.5°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 24.1°±0.2° and 27.0°±0.2°.

2. The compound according to claim 1, having the X-ray powder diffraction pattern shown in FIG3a.

Images