Improved solid-state form of triazine compound, preparation method therefor, pharmaceutical composition, and use

Abstract

The present invention relates to an improved solid-state form of a triazine compound, a preparation method therefor, a pharmaceutical composition, and a use. The present invention provides a solid-state form of a compound represented by formula 1, which is a crystalline form. The solid-state form of the compound represented by formula 1 provided in the present invention has good stability and good pharmacokinetic properties, and is suitable for pharmaceutical research and development.

Description

Modified solid forms of triazine compounds, their preparation methods, pharmaceutical compositions, and uses.

[0001] This application claims priority to Chinese Patent Application No. 202510367713X, filed on March 26, 2025, and Chinese Patent Application No. 2025103799688, filed on March 28, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to modified solid forms of triazine compounds, their preparation methods, pharmaceutical compositions, and uses. Background Technology

[0003] Inflammasomes are protein complexes that recognize intracellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Assembly of inflammasomes triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1 and converting the cytokine precursors pro-IL-1β and pro-IL-18 into mature, biologically active IL-1β and IL-18, respectively. This process regulates the expression of inflammation-related genes, leading to various biological effects. As receptors for the body's innate immunity, inflammasome activation can resist pathogen infection and stress damage; however, uncontrolled activation can amplify inflammatory effects and cause organ damage. Currently, research on inflammasomes containing pyrin domain-containing protein 3 (NLRP3), a member of the nucleotide-binding oligomerization domain (NOD)-like receptor family, is the most popular.

[0004] The NLRP3 inflammasome consists of a sensor (NLRP3), an adapter (ASC, also known as PYCARD), and an effector (caspase 1). Classical NLRP3 inflammasome activation is triggered by the co-stimulation of two signals. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting NF-κB nuclear translocation, inducing the production of precursors such as IL-1β and IL-18, and inducing post-translational modifications of NLRP3. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. Upon activation, ASC polymerizes with apoptosis-associated specklike protein containing a caspase activation and recruitment domain. ASC then interacts with cysteine ​​protease caspase-1 to form a complex called the inflammasome. The precursor form of pro-caspase-1 self-cleaves into its activated form. Activated caspase-1 cleaves the precursor forms of pro-inflammatory cytokines IL-1β and IL-18, converting them into their active forms and releasing them extracellularly. This recruits inflammatory cells, amplifying the inflammatory response. ASC specklike protein can also recruit and activate caspase-8, cleaving the precursor forms of IL-1β and IL-18 into their mature forms and inducing pyroptosis. Non-classical NLRP3 inflammasome activation does not depend on TLR4 signaling pathway activation. Instead, it is initiated by caspase-11 directly recognizing intracellular LPS, which promotes the activation and release of Gasdermin D, thereby mediating cell death.

[0005] Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, neurological diseases, autoimmune diseases and / or autoinflammatory diseases, cancer, chronic metabolic diseases, and neurological diseases. Examples include cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke. NLRP3 is located upstream of cytokines and can block inflammation at its source, therefore developing new NLRP3 inflammasome inhibitors has high research value.

[0006] Although some compounds with NLRP3 inhibitory activity have been reported in this field, such as WO2024193703A1, the physicochemical properties of their solid-state form often become a key limiting factor in the conversion of these compounds into drugs. For example, an undesirable solid-state form may lead to problems such as poor solubility, low chemical or physical stability, high hygroscopicity, poor flowability, or low bioavailability. These defects directly affect drug formulation development, manufacturing processes, shelf life, and clinical efficacy. Therefore, optimizing and screening the solid-state forms of known NLRP3 inhibitors with potential therapeutic value to obtain crystalline or other solid forms with superior and stable physicochemical properties is crucial for promoting their development into usable drugs. Summary of the Invention

[0007] This invention provides an improved solid-state form of triazine compounds, its preparation method, pharmaceutical composition, and uses. The solid-state form of the triazine compounds provided by this invention exhibits good stability and favorable pharmacokinetic properties, making it suitable for drug research and development.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a solid form of a compound represented by Formula 1, which is a crystalline form, wherein the crystalline form has at least one pharmaceutically relevant property superior to the amorphous form of the free base compound of Formula 1, the pharmaceutically relevant property being selected from: chemical stability, hygroscopicity, flowability, and compressibility.

[0010] In some embodiments of the invention, the compound comprising Formula 1 is in solid form, wherein the crystalline form is the free base of the compound comprising Formula 1 or its hydrochloride, sulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, maleate or gentianate crystalline form.

[0011] In some embodiments of the invention, the compound comprising Formula 1 is in solid form, wherein the crystalline form is the free base of the compound comprising Formula 1 or its maleate or gentianate in crystalline form.

[0012] Preferably, the crystalline form of the maleate or gentianate is wherein the molar ratio of the compound represented by Formula 1 to maleic acid or gentianic acid is 1:1.

[0013] In some embodiments of the present invention, the solid form of the compound represented by Formula 1, wherein the crystalline form is crystal form I of the free base of the compound represented by Formula 1, crystal form I of the maleate of the compound represented by Formula 1, or crystal form I of the gentianate, wherein the X-ray powder diffraction pattern of crystal form I of the free base of the compound represented by Formula 1, expressed in 2θ angle, has diffraction peaks at 11.60±0.20°, 16.69±0.20°, 18.70±0.20°, and 24.57±0.20°;

[0014] The maleate crystal form I has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 9.94±0.20°, 13.40±0.20°, 18.34±0.20° and 20.16±0.20°;

[0015] The gentianate crystal form I has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 7.67±0.20°, 11.32±0.20°, 17.15±0.20° and 17.66±0.20°.

[0016] In this invention, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed at an angle of 2θ, may also have diffraction peaks at one or more of the following locations: 6.89±0.20°, 9.93±0.20°, 12.19±0.20°, 13.58±0.20°, 13.94±0.20°, 19.95±0.20°, 21.41±0.20°, 22.06±0.20°, 22.81±0.20°, 23.82±0.20°, 25.79±0.20°, 27.40±0.20°, 28.43±0.20°, 29.34±0.20°, 30.14±0.20°, and 36.31±0.20°.

[0017] Preferably, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed at an angle of 2θ, has diffraction peaks at 6.89±0.20°, 11.60±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20° and 24.57±0.20°.

[0018] More preferably, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed at an angle of 2θ, has diffraction peaks at 6.89±0.20°, 11.60±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20°, 19.95±0.20°, 22.81±0.20°, 24.57±0.20°, 25.79±0.20° and 28.43±0.20°.

[0019] In some embodiments of the invention, the X-ray powder diffraction pattern of crystal form I of the free base of compound of formula 1, expressed at an angle of 2θ, is at 6.89±0.20°, 9.93±0.20°, 11.60±0.20°, 12.19±0.20°, 13.58±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20°, and 19.95±0.20°. Diffraction peaks are observed at 0.20°, 21.41±0.20°, 22.06±0.20°, 22.81±0.20°, 23.82±0.20°, 24.57±0.20°, 25.79±0.20°, 27.40±0.20°, 28.43±0.20°, 29.34±0.20°, 30.14±0.20°, and 36.31±0.20°.

[0020] In one aspect of the present invention, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed at a 2θ angle, has the diffraction peaks and relative intensities shown in Table 1 (the relative peak intensity of diffraction peaks at the same position is allowed to have an error of ±5%, and the order of intensity of the diffraction peaks is consistent):

[0021] Table 1. XRD data of crystal form I of the free base of compound 1.

[0022] In one aspect of the present invention, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, represented by an angle of 2θ, is basically as shown in Figure 1.

[0023] In this invention, the X-ray powder diffraction pattern can be obtained using Cu-Kα radiation spectroscopy.

[0024] In this invention, the thermogravimetric analysis curve of the free base of the compound of Formula 1 in crystal form I shows a weight loss of 0.26% at room temperature to 200±3℃.

[0025] In one aspect of the present invention, the thermogravimetric analysis curve of the free base of the compound of formula 1 in crystal form I is basically as shown in Figure 2.

[0026] In this invention, the differential scanning spectroscopy curve of crystal form I of the free base of the compound of formula 1 has an endothermic peak at 206.6±3℃. Further, the endothermic peak reaches its peak at 209.7±3℃. Even further, the enthalpy change between 206.6±3℃ and 209.7±3℃ is 29.7 J / g.

[0027] In one aspect of the present invention, the differential scanning spectral density curve of the free base of the compound of formula 1 in crystal form I is basically as shown in Figure 2.

[0028] In some embodiments of the present invention, the hygroscopic weight gain of crystal form I of the free base of compound 1 at 95% RH is 0.98%, and the hygroscopic weight gain of crystal form I of the free base of compound 1 at 80% RH is 0.44%; preferably, the dynamic moisture adsorption spectrum of crystal form I of the free base of compound 1 is basically as shown in Figure 4.

[0029] In some embodiments of the present invention, the X-ray powder diffraction pattern of the maleate crystal form I, expressed at an angle of 2θ, also shows diffraction peaks at one or both of 26.98±0.20° and 28.00±0.20°.

[0030] Preferably, the X-ray powder diffraction pattern of the maleate crystal form I, expressed at an angle of 2θ, also includes 13.92±0.20°, 14.65±0.20°, 15.30±0.20°, 16.22±0.20°, 17.88±0.20°, 19.20±0.20°, 19.52±0.20°, 21.48±0.20°, 22.10±0.20°, 22.40±0.20°, and 23... Diffraction peaks are present at one or more of the following locations: 0.63±0.20°, 24.79±0.20°, 26.60±0.20°, 27.62±0.20°, 29.01±0.20°, 29.76±0.20°, 30.64±0.20°, 31.37±0.20°, 31.99±0.20°, 33.23±0.20°, 37.63±0.20°, and 38.24±0.20°.

[0031] More preferably, the X-ray powder diffraction pattern of the maleate crystal form I, expressed at a 2θ angle, shows the diffraction peaks and relative intensities as shown in Table 2 (the relative peak intensity of diffraction peaks at the same position is allowed to have an error of ±5%, and the order of intensity of the diffraction peaks is consistent):

[0032] Table 2 shows the XRD data of maleate crystal form I of compound formula 1.

[0033] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of maleate crystal form I shows a weight loss of 0.38% at 25±5°C to 100±3°C.

[0034] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the maleate crystal form I has an endothermic peak with an onset temperature of 221.6 ± 3 °C.

[0035] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the maleate crystal form I has an endothermic peak with a peak temperature of 225.9 ± 3 °C.

[0036] In some embodiments of the present invention, the crystalline form I of the maleate has a moisture absorption weight gain of 0.58% to 0.75% at 80% to 95% RH.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form I of the gentianate, expressed at an angle of 2θ, also shows a diffraction peak at 23.27±0.20°.

[0038] Preferably, the X-ray powder diffraction pattern of the gentianate crystal form I, expressed at a 2θ angle, is also at 9.19±0.20°, 12.64±0.20°, 13.56±0.20°, 13.89±0.20°, 14.20±0.20°, 15.10±0.20°, 15.41±0.20°, 16.42±0.20°, 18.41±0.20°, and 18.77±0. Diffraction peaks are present at one or more of the following locations: 20°, 19.26±0.20°, 20.22±0.20°, 21.52±0.20°, 22.54±0.20°, 22.87±0.20°, 24.16±0.20°, 25.50±0.20°, 26.01±0.20°, 27.96±0.20°, 28.68±0.20°, and 29.75±0.20°.

[0039] More preferably, the X-ray powder diffraction pattern of the crystal form I of the gentianate, expressed at a 2θ angle, shows the diffraction peaks and relative intensities as shown in Table 3 (the relative peak intensity of diffraction peaks at the same position is allowed to have an error of ±5%, and the order of intensity of the diffraction peaks is consistent):

[0040] Table 3 shows the XRD data of crystal form I of the gentianate of compound formula 1.

[0041] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of crystal form I of the gentianate shows a weight loss of 0.22% at 25±5°C to 100±3°C.

[0042] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of crystal form I of the gentianate has an endothermic peak with an onset temperature of 208.2 ± 3 °C.

[0043] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of crystal form I of the gentianate salt has an endothermic peak with a peak temperature of 213.1 ± 3 °C.

[0044] In some embodiments of the present invention, the crystalline form I of the gentianate salt has a moisture absorption weight gain of 0.67% to 0.91% at 80% to 95% RH.

[0045] In some embodiments of the present invention, the XRPD pattern of the maleate crystal form I is basically as shown in Figure 5.

[0046] In some embodiments of the present invention, the X-ray powder diffraction pattern is obtained using Cu-Kα radiation spectroscopy.

[0047] In some embodiments of the present invention, the thermogravimetric analysis curve of the maleate crystal form I is basically as shown in Figure 6.

[0048] In some embodiments of the present invention, the differential scanning calorimeter of the maleate crystal form I is basically as shown in Figure 6.

[0049] In some embodiments of the present invention, the dynamic water adsorption spectrum of maleate crystal form I is basically as shown in Figure 7.

[0050] In some embodiments of the present invention, the XRPD pattern of crystal form I of the gentianate is basically as shown in Figure 8.

[0051] In some embodiments of the present invention, the thermogravimetric analysis curve of crystal form I of the gentianate is basically as shown in Figure 9.

[0052] In some embodiments of the present invention, the differential scanning calorimeter of crystal form I of the gentianate is basically as shown in Figure 9.

[0053] In some embodiments of the present invention, the dynamic water adsorption spectrum of crystal form I of the gentianate is basically as shown in Figure 10.

[0054] In a second aspect, the present invention provides a method for preparing a solid form of a compound containing Formula 1 as described above, wherein when the solid form of the compound containing Formula 1 is crystal form I of the free base of the compound of Formula 1, it is any one of the following methods one to four.

[0055] Method 1 includes the following steps: at 40-60℃, the suspension of the compound of Formula 1 is stirred and crystallized to obtain crystal form I of the free base of the compound shown in Formula 1. The solvent of the suspension is an alcohol, ester, ketone, nitrile, ether, alkanes, aromatic hydrocarbons, cycloalkanes or water.

[0056] In this invention, the alcohol solvent may be methanol, ethanol, isopropanol or n-butanol.

[0057] In this invention, the ester solvent may be ethyl acetate, isopropyl acetate, or methyl acetate.

[0058] In this invention, the ketone solvent may be acetone or butanone.

[0059] In this invention, the nitrile solvent may be acetonitrile.

[0060] In this invention, the ether solvent may be methyl tert-butyl ether or 2-methyltetrahydrofuran.

[0061] In this invention, the alkane solvent may be n-heptane.

[0062] In this invention, the aromatic hydrocarbon solvent may be toluene.

[0063] In this invention, the cycloalkane solvent may be cyclohexane.

[0064] In this invention, the mass-to-volume ratio of the compound of Formula 1 to the solvent in the suspension can be 1g:(8-20)mL, for example 1g:8mL, 1g:10mL or 1g:20mL.

[0065] In this invention, the stirring temperature can be 50°C.

[0066] In this invention, the stirring time can be 3-7 days, for example, 3 days or 7 days.

[0067] Method 2 includes the following steps: stirring and crystallizing a suspension of the compound of Formula 1 to obtain crystal form I of the free base of the compound shown in Formula 1, wherein the solvent of the suspension is a mixture of a polar solvent and water or a mixture of a polar solvent and a non-polar solvent.

[0068] In this invention, the polar solvent may be methanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, acetone or tetrahydrofuran.

[0069] In this invention, the nonpolar solvent may be n-heptane.

[0070] In this invention, the volume ratio of the polar solvent to water in the mixture of polar solvent and water can be 1:1 or 1:4.

[0071] In this invention, the volume ratio of the polar solvent to the non-polar solvent in the mixture of polar solvent and non-polar solvent can be 1:2.

[0072] In this invention, the mass-to-volume ratio of the compound of Formula 1 to the solvent in the suspension can be 3g:100mL.

[0073] In this invention, the stirring temperature can be 20-60℃, for example 20-30℃ or 50℃.

[0074] In this invention, the stirring time can be 3-7 days, for example, 3 days or 7 days.

[0075] Method 3 includes the following steps: at 40-60°C, the solution of compound 1 is cooled and crystallized to obtain crystal form I of the free base of the compound shown in Formula 1, wherein the solvent of the solution is an ether, ketone, ester or nitrile.

[0076] In this invention, the ether solvent may be 1,4-dioxane or tetrahydrofuran.

[0077] In this invention, the ketone solvent may be acetone.

[0078] In this invention, the ester solvent may be methyl acetate.

[0079] In this invention, the nitrile solvent may be acetonitrile.

[0080] In this invention, the mass-to-volume ratio of the compound of Formula 1 to the solvent in the solution can be 3g:(80-400)mL, for example 3g:80mL, 3g:90mL, 3g:240mL, 3g:360mL or 3g:400mL.

[0081] In this invention, the dissolution temperature of the solution can be 50°C.

[0082] In this invention, the cooling method can be rapid cooling or slow cooling.

[0083] In this invention, the cooling temperature can be 0-30°C, for example 4°C or 20-30°C.

[0084] Method 4 includes the following steps: adding an antisolvent to a solution of the compound of Formula 1; or adding a solution of the compound of Formula 1 to an antisolvent; wherein the solvent of the solution of the compound of Formula 1 is a haloalkane, alcohol, ether, ketone, amide, sulfoxide, or pyrrolidone; wherein the antisolvent is an ester, ether, alkane, cycloalkanes, or water; wherein the volume ratio of the solvent to the antisolvent of the solution of the compound of Formula 1 is 1:(5-20); wherein the mass-volume ratio of the solvent to the compound of Formula 1 is 10-150 mg / mL.

[0085] When the solid form of the compound shown in Formula 1 is the maleate crystal form I of the compound shown in Formula 1, the preparation method of maleate crystal form I includes the following steps: in a solvent, the compound shown in Formula 1 reacts with maleic acid to obtain maleate crystal form I; the solvent is a ketone solvent, an ester solvent, an epoxy solvent, a nitrile solvent, or an alcohol solvent and water.

[0086] When the solid form of the compound shown in Formula 1 is crystal form I of the gentianate of the compound shown in Formula 1, the preparation method of crystal form I of the gentianate includes the following steps: in a solvent, the aforementioned compound shown in Formula 1 reacts with gentic acid to obtain crystal form I of the gentianate; the solvent is a ketone solvent or a nitrile solvent.

[0087] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the alkyl haloide in the solvent may be dichloromethane.

[0088] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the alcohol in the solvent may be methanol.

[0089] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the ether in the solvent can be tetrahydrofuran or 1,4-dioxane.

[0090] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the ketone in the solvent may be acetone.

[0091] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the amide in the solvent may be N,N-dimethylformamide.

[0092] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the sulfoxide in the solvent may be dimethyl sulfoxide.

[0093] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the pyrrolidone in the solvent may be N-methylpyrrolidone.

[0094] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the ester in the antisolvent may be isopropyl acetate.

[0095] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the ether in the antisolvent can be methyl tert-butyl ether.

[0096] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the alkane in the antisolvent can be n-heptane.

[0097] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the cycloalkanes in the antisolvent may be cyclohexane.

[0098] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the mass-to-volume ratio of the solvent in the solution of the compound of Formula 1 to the compound of Formula 1 can be 15-130 mg / mL, for example 20 mg / mL, 25 mg / mL, 40 mg / mL, 46 mg / mL, 80 mg / mL or 120 mg / mL.

[0099] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, the dissolution temperature of the solution of the compound of Formula 1 can be 20-60℃, for example 20-30℃ or 50℃.

[0100] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, when an antisolvent is added to the solution of the compound of Formula 1, the volume ratio of the solvent to the antisolvent can be 1:(8-15), for example 1:10.

[0101] In the method for preparing crystal form I of the free base of the compound shown in Formula 1, when the solution of the compound of Formula 1 is added to the antisolvent, the volume ratio of the solvent to the antisolvent can be 1:(0.5-20), for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:9 or 1:10.

[0102] In the method for preparing crystal form I of the maleate of the compound shown in Formula 1, the ketone solvent is acetone, methyl ethyl ketone (MEK) or cyclohexanone, for example, acetone.

[0103] In the method for preparing maleate crystal form I, the ester solvent is ethyl acetate, isopropyl acetate, butyl acetate, or dimethyl phthalate; for example, ethyl acetate.

[0104] In the method for preparing maleate crystal form I, the epoxy solvent is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene oxide, or 1,4-dioxane, preferably tetrahydrofuran.

[0105] In the method for preparing maleate crystal form I, the nitrile solvent is acetonitrile, propionitrile, or butyronitrile; preferably acetonitrile.

[0106] In the method for preparing maleate crystal form I, the alcohol solvent is methanol, ethanol, or isopropanol; preferably ethanol.

[0107] In the preparation method of maleate crystal form I, the volume molar ratio of the alcohol solvent to water is preferably 40-60:1, and more preferably 49:1.

[0108] In the preparation method of maleate crystal form I, the preparation temperature is 25±5℃.

[0109] In the preparation method of maleate crystal form I, the volume-to-mass ratio of the solvent to the compound shown in Formula 1 is 20-30 mg / mL, for example 25 mg / mL.

[0110] In the preparation method of maleate crystal form I, the molar ratio of the compound shown in Formula 1 to maleic acid is 1:(1-1.2), for example 1:1.1.

[0111] In the method for preparing crystal form I of the gentian salt of the compound shown in Formula 1, the ketone solvent is acetone, methyl ethyl ketone (MEK) or cyclohexanone, for example, acetone.

[0112] In the preparation method of crystal form I of the gentianate, the nitrile solvent is acetonitrile, propionitrile, or butyronitrile; preferably acetonitrile.

[0113] In the preparation method of crystal form I of the gentianate, the preparation temperature is 25±5℃.

[0114] In the method for preparing crystal form I of the gentianate, the volume-to-mass ratio of the solvent to the compound shown in Formula 1 is 20-30 mg / mL, for example, 25 mg / mL.

[0115] The molar ratio of the compound shown in Formula 1 to gentic acid is 1:(1-1.2), for example, 1:1.1.

[0116] Thirdly, the present invention provides a pharmaceutical composition comprising, as described above, a compound of Formula 1 in solid form and pharmaceutically acceptable excipients.

[0117] In this invention, the dosage form of the pharmaceutical composition may be tablets, capsules, powders, granules, ointments, solutions, suspensions, injections, inhalers, gels, microspheres, or aerosols.

[0118] Fourthly, the present invention provides the use of the solid form of the compound of Formula 1 as described above or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing NLRP3-related diseases.

[0119] In this invention, the NLRP3-related diseases may be inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0120] In this invention, the NLRP3-related diseases may include cryptothermal protein-related cycle syndrome, Muker-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.

[0121] In this invention, the asthma is preferably bronchial asthma.

[0122] Fifthly, the present invention provides the use of a solid form of a compound of Formula 1 as described above or a pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0123] In this invention, the drug can be used to treat and / or prevent cryptothermal protein-related cycle syndrome, Mukel-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory diseases, familial Mediterranean fever, non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.

[0124] In this invention, the asthma is preferably bronchial asthma.

[0125] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is a good solvent, and the one with lower solubility is a bad solvent.

[0126] The X-ray powder diffraction or DSC pattern and TGA pattern disclosed in this invention, which are substantially the same, also fall within the scope of this invention.

[0127] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0128] As used in this invention, "crystal of the present invention", "crystal form of the present invention", "crystal form of the present invention" and the like are interchangeable.

[0129] The "room temperature" mentioned in this invention generally refers to 25±5℃.

[0130] The crystal structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0131] The X-ray powder diffraction pattern testing parameters for each crystal form in this invention were obtained using Cu-Kα radiation.

[0132] The "2θ or 2θ angle" mentioned in this invention refers to the peak position, expressed in degrees (°), based on the setup in an X-ray diffraction experiment, and is typically the horizontal axis unit in a diffraction pattern. If the incident beam is diffracted when it forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for a particular crystal form mentioned herein are intended to represent 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0133] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0134] The reagents and raw materials used in this invention are all commercially available.

[0135] The positive and progressive effects of this invention are as follows: The free base of Formula 1 provided by this invention has stable crystal form I properties and can be prepared by heating and suspending in a single solvent, suspending in a mixed solvent, cooling and crystallizing, and dissolution and crystallization. Crystal form I of the free base is slightly hygroscopic, which meets the requirements for formulation development. It has low solubility in FaSSIF and water (0.15–0.3 mg / mL), higher solubility in FeSSIF (3–5 mg / mL), and the highest solubility in FaSSGF (7–9 mg / mL). After 30 days under light, high humidity, and high temperature conditions, the crystal form and purity do not change significantly, maintaining stable physical and chemical properties, which meets the requirements for formulation development. Crystal form I of the free base exhibits good pharmacokinetic properties in rats, including good oral bioavailability, exposure, half-life, and clearance. The salt form improves the solubility and solid stability of the product, reduces storage costs, extends the product cycle, and simultaneously improves the product's bioavailability. Attached Figure Description

[0136] Figure 1 shows the X-ray powder diffraction pattern of crystal form I of the free base of compound of formula 1.

[0137] Figure 2 shows the DSC and TGA spectra of crystal form I of the free base of compound 1.

[0138] Figure 3 shows the amorphous X-ray powder diffraction pattern of the compound of Formula 1.

[0139] Figure 4 shows the dynamic water adsorption curve (DVS) of crystal form I of the free base of compound of formula 1, where 1 in Figure 4 represents the first adsorption curve and 2 represents the first desorption curve.

[0140] Figure 5 shows the X-ray powder diffraction pattern of maleate of Formula 1, crystal form I.

[0141] Figure 6 shows the DSC and TGA spectra of crystal form I of compound maleate of formula 1.

[0142] Figure 7 shows the dynamic water adsorption curve (DVS) of maleate salt of Formula 1, where 1 in Figure 7 represents the first adsorption curve and 2 represents the first desorption curve.

[0143] Figure 8 shows the X-ray powder diffraction pattern of crystal form I of the gentianate of Formula 1.

[0144] Figure 9 shows the DSC and TGA spectra of crystal form I of the gentianate of Formula 1.

[0145] Figure 10 shows the dynamic water adsorption curve (DVS) of crystal form I of the gentianate of Formula 1, where 1 in Figure 10 represents the first adsorption curve and 2 represents the first desorption curve. Detailed Implementation

[0146] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0147] It is understood that the numerical values ​​described and protected in this invention are approximate. Variations within these values ​​may be attributed to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

[0148] It is understood that the crystal forms of the present invention are not limited to those that are exactly the same as the characteristic spectra described in the accompanying drawings, such as XRPD, DSC, and TGA. Any crystal form having a characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings falls within the scope of the present invention.

[0149] It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention have DSC plots with characteristic peak positions that have substantially the same properties as the DSC plots provided in the accompanying drawings of the present invention, with a measurement error tolerance of ±5°C, generally required to be ±3°C.

[0150] The present invention relates to an X-ray powder diffractometer (XRPD) method.

[0151] Testing instrument: Rigaku SmartLab SE;

[0152] Radiation source: Cu-Kα radiation;

[0153] Detection conditions: X-ray tube voltage 40kV, X-ray tube current 40mA, scanning range 3-40° (2θ), step size 0.02°, scan speed 5° / min;

[0154] Testing basis: Appendix IX, X-ray powder diffraction method, of the Pharmacopoeia of the People's Republic of China (2010 Edition, Part II);

[0155] This invention relates to a differential scanning calorimeter (DSC) method.

[0156] Testing instrument: Netzsch STA449F3;

[0157] Detection conditions: Nitrogen gas, 50 mL / min;

[0158] Scanning program: 30~400℃, heating rate: 10℃ / min;

[0159] Sample weight tested: ~3mg (alumina sample dish);

[0160] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis;

[0161] The present invention relates to a thermogravimetric analysis (TGA) method.

[0162] Testing instrument: Netzsch STA449F3;

[0163] Detection conditions: Nitrogen gas, 50 mL / min;

[0164] Scanning program: 30~400℃, heating rate: 10℃ / min;

[0165] Sample weight tested: ~5mg (alumina sample dish);

[0166] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis;

[0167] This invention involves nuclear magnetic resonance spectroscopy analysis ( 1 H-NMR method

[0168] Testing instrument: Nuclear magnetic resonance spectrometer (JMTC-400 / 54 / JJ / YH);

[0169] Detection conditions: 400MHz, deuterated DMSO solution.

[0170] Example 1: Preparation of triazine compounds (compound of formula 1)

[0171] (1) Preparation of intermediate INT1 (2-(4-methoxybenzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane)

[0172] Step 1: CuBr2 (146.5 g, 656 mmol) was added to EtOAc (250 mL), and stirred at 80 °C for 10 minutes. Then, compound INT1a (25.0 g, 164 mmol) was dissolved in chloroform (250 mL) and added to the suspension. The mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was slurried with EtOAc (500 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to obtain the target compound INT1b (46.0 g, 148 mmol, light brown solid, 90% yield). MS: [M+H] + =309.0,311.0,313.0.

[0173] Step 2: Compound INT1b (45.0 g, 145 mmol) and Li₂CO₃ (26.8 g, 363 mmol) were added to DMF (450 mL) and stirred at 100 °C for 6 h. After the reaction was complete, the mixture was filtered, and the filtrate was treated with hydrochloric acid aqueous solution (900 mL, 0.5 N), extracted with EtOAc (400 mL × 2), washed with water (300 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the target compound INT1c (31.0 g, 135 mmol, light brown solid, yield 93%). MS: [MH] - =227.0,229.0.

[0174] Step 3: Compound INT1c (15.0 g, 65.5 mmol) and K2CO3 (18.1 g, 131 mmol) were added to MeCN (150 mL), followed by Me2SO4 (9.9 g, 78.6 mmol). The mixture was stirred overnight at 60 °C under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and silica gel (30 g) was added to the filtrate. The mixture was then concentrated to dryness under reduced pressure and separated by column chromatography (PE:EtOAc = 10:1) to obtain the target compound INTId (13.7 g, 56.4 mmol, white solid, 86% yield). 1 H NMR (400MHz, CDCl3) δ7.51-7.46(m,2H),7.45-7.42(m,2H),4.00(s,3H).

[0175] Step 4: Compound INT1d (13.7 g, 56.4 mmol), bis-pinacol boronic acid ester (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol), and Pd(PPh3)Cl2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL), and the mixture was reacted at 90 °C for 12 h under nitrogen protection. After the reaction, the mixture was filtered, and 30 g of silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and evaporated to dryness. The final product was separated by column chromatography (PE:EtOAc = 30:1) to obtain the target compound INT1 (7.6 g, 26.2 mmol, colorless solid, yield 46%). 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 4.00 (s, 3H), 1.39 (s, 12H).

[0176] (2) Preparation of intermediate INT5 (6-bromo-2-(4-methoxybenzyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione)

[0177] Step 1: Compound int5a (50 g, 260 mmol) and methane (37 g, 260 mmol) were dissolved in ultra-dry DMF (250.0 mL). DIEA (36 g, 281 mmol) was added to the reaction flask, and the reaction was carried out at room temperature for 3 hours. After most of the reactants 1 had reacted completely, the mixture was extracted four times with EA and saturated brine. The organic phase was concentrated and purified by column chromatography (PE / EA 8:1 to 6:1) using silica gel to obtain 39 g of white solid compound int5b.

[0178] Step 2: The reactants INT5b (39 g, 189.3 mmol) and 4-methoxybenzyl chloride (40 g, 265 mmol) were dissolved in ultra-dry DMF (500.0 mL). K2CO3 (52 g, 378.6 mmol) was added to the reaction flask, and the reaction was carried out at room temperature for 8 hours. After the starting material was completely reacted by TLC, the mixture was extracted three times with 200 mL of ethyl acetate and water. The organic phase was washed twice with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain compound INT5. 1 H NMR (400MHz, DMSO-d6) δ7.36-7.20(m,2H),7.00-6.82(m,2H),5.01(s,2H),3.74(s,3H),3.20(s,3H).

[0179] (3) Preparation of compound of formula 1

[0180] Step 1: Compound 1 (4.75 g, 21.8 mmol), paraformaldehyde (1.31 g, 43.6 mmol), and acetic acid (0.26 g, 4.36 mmol) were added to methanol (50 mL), followed by sodium cyanoboronoxide (2.74 g, 43.6 mmol). The mixture was stirred at 50 °C for 1 h. After the reaction was complete, silica gel was added, the mixture was stirred, and the solution was evaporated to dryness. The solution was then purified by column chromatography (DCM:MeOH = 10:1, iodine indicator) to give compound 2 (4.67 g, 20.1 mmol, yield 92%). 1 H NMR (400MHz, CDCl3-d) δ4.92-4.64(m,2H),3.99(s,1H),2.77-2.39(m,3H),2.30(s,3H),1.94-1.80(m,1H),1.45(s,9H); MS / ESI[M+H] + =233.0.

[0181] Step 2: Compound 2 (4.67 g, 20.1 mmol) was dissolved in dioxane (25 mL), and then HCl / dioxane (25 mL, 101 mmol, 4.0 M) was added. The mixture was stirred at 25 °C for 1 h. After the reaction was completed, the product 3 (4.60 g, 22.4 mmol, yield 111%) was obtained by evaporation under reduced pressure. 1 H NMR(400MHz,CD3OD-d4)δ5.37-5.24(m,1H),4.98-4.89(m,1H),3.92-3.77(m,3H),3.51(dd,J =39.2,13.9Hz,1H),3.06(s,3H),2.63-2.55(m,1H),2.15-1.98(m,1H); MS / ESI[M+H]=133.0.

[0182] Step 3: Weigh compound INT5 (3.00 g, 9.20 mmol), compound 3 (1.15 g, 10.1 mmol), Cs₂CO₃ (6.01 g, 18.4 mmol), BINAP (573 mg, 0.92 mmol), and Pd(OA)₂ (208 mg, 0.92 mmol) and add them to dioxane (60 mL). Then, replace the solution with N₂ three times and heat to 110 °C with stirring overnight. After the reaction is complete, evaporate to dryness under reduced pressure using silica gel. Purify by column chromatography (DCM:MeOH = 10:1) to obtain target compound 4 (3.30 g, 9.18 mmol, pale yellow viscous substance, yield 99%). MS / ESI [M+H] + =360.2.

[0183] Step 4: Compound 4 (3.30 g, 9.18 mmol) was dissolved in dichloromethane (30 mL), and TfOH (4.13 g, 27.5 mmol) was slowly added at room temperature, followed by stirring overnight. After the reaction was complete, the pH was adjusted to approximately 8 with ammonia, and the mixture was dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was stirred into silica gel and evaporated to dryness under reduced pressure. The solution was then separated by column chromatography (DCM:MeOH = 5:1) to obtain the target compound 5 (770 mg, 3.22 mmol, pale yellow solid, yield 35%). MS / ESI [M+H] + =240.1.

[0184] Step 5: Add 4 mL of POCl3 to compound 5 (770 mg, 3.22 mmol), heat to 110 °C and stir overnight. After the reaction is complete, evaporate excess POCl3 to dryness to obtain target compound 6 (1.5 g, 3.30 mmol, light brown solid, 100% yield). MS / ESI [M+H] + =258.2.

[0185] Step 6: Weigh compound 6 (1.1 g, 2.42 mmol), INT1 (772 mg, 2.66 mmol), Cs2CO3 (3.94 g, 12.1 mmol), and Pd(dppf)Cl2 (176 mg, 0.24 mmol) and add them to dioxane (20 mL) and water (4 mL). Then, replace the solution with N2 three times and heat to 100 °C with stirring overnight. After the reaction is complete, evaporate to dryness under reduced pressure using silica gel. Purify by column chromatography (DCM:MeOH = 10:1) to obtain target compound 7 (550 mg, 1.43 mmol, pale yellow viscous substance, yield 59%). MS / ESI [M+H] + =386.2.

[0186] Step 7: Compound 7 (550 mg, 1.43 mmol) was dissolved in DCM (5.5 mL), cooled to 0 °C, and then BBr3 (4.29 mL, 4.29 mmol, 1.0 M) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was complete, an appropriate amount of methanol was added to quench the reaction, and the mixture was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was then dissolved in methanol (5 mL) and purified by preparative liquid chromatography (Pre-HPLC) to obtain the target compound of formula 1 (295 mg, 0.79 mmol, pale yellow powder, yield 55%), which was an amorphous solid. MS / ESI[M+H]*=390.0; 1H NMR (400MHz, CDCl3-d)8 7.60(d,J=5.4Hz,1H),7.43-7.31(m,2H),7.19(d,J=8.5Hz,1H),6.17(d,J=8.1Hz,1H),4.90-4.72(m,1H),4.45(s,1H),3.57(s,3H ), 2.91-2.78(m,1H),2.68-2.60(m,1H),2.56-2.48(m,1H),2.46-2.38(m,1H),2.37(s,3H),2.28-2.17(m,1H),1.91-1.81(m,1H).

[0187] Example 2: Preparation of crystal form I of the free base of compound of formula 1

[0188] Method 1: Preparation of crystal form I of the free base of compound formula 1 by heating, suspending, and pulping in a single solvent.

[0189] Approximately 100 mg of compound of formula 1 was weighed into a 4 ml sample vial, and corresponding amounts of different solvents were added to prepare suspensions. The suspensions were then stirred at 50 °C for 3 and 7 days. The supernatant was removed by centrifugation, and the suspensions were vacuum-dried at room temperature for 4 hours before XRPD testing. Only one crystal form was obtained in the 50 °C single-solvent suspension slurry experiment, which was crystal form I of the free base. The results are shown in the table below.

[0190] Method 2: Preparation of free alkali crystal form I by mixing and slurrying with a mixed solvent

[0191] Approximately 30 mg of compound of formula 1 was weighed into a 4 mL sample vial, and corresponding amounts of different solvents were added to prepare suspensions. The suspensions were then stirred at room temperature and 50°C for 3 and 7 days, respectively. The supernatant was removed by centrifugation, and the suspensions were vacuum-dried at room temperature for 4 hours before XRPD testing. Only one crystal form was obtained in the mixed solvent suspension slurry experiment, which was crystal form I of the free base. The results are shown in the table below.

[0192] Method 3: Preparation of free base crystal form I by cooling crystallization

[0193] Based on the preliminary solubility test results, four single solvents and seven mixed solvents were selected for cooling crystallization experiments. 30 mg of compound of formula 1 was weighed and added to the corresponding solvent, stirred at 50°C to dissolve, then filtered. The filtrate was placed in a sample vial and subjected to either rapid cooling (directly placed at room temperature with stirring) or slow cooling (gradual cooling to room temperature with stirring). If no solid precipitated at room temperature, the sample was then placed at 4°C. The solid sample was then collected by centrifugation and vacuum dried at room temperature for 4 hours for XRPD testing. Only one crystal form was obtained in the cooling crystallization experiment, which was crystal form I of the free base. The experimental results are shown in the table below.

[0194] Method 4: Preparation of free base crystal form I by dissolution and crystallization

[0195] Based on the preliminary solubility test results, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetone, dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide were selected as good solvents for the dissolution-crystallization experiment. 30 mg of compound of formula 1 was weighed and added to the corresponding good solvent, and dissolved completely at room temperature or 50°C. The solution was then filtered. Subsequently, the antisolvent was slowly added dropwise to the filtrate at room temperature until a solid precipitated or until 10 times its volume (antisolvent addition), or the filtrate was rapidly added to 10 times its volume of antisolvent (antisolvent addition). After the solid precipitated, the mixture was stirred overnight (~17 h), and the supernatant was removed by centrifugation. The sample was collected, dried under vacuum at room temperature for 4 h, and then the product was characterized accordingly. Only one crystal form was obtained in the dissolution-crystallization experiment, which was crystal form I of the free base. The experimental results are shown in the table below.

[0196] The X-ray powder diffraction pattern of crystal form I of the free base of compound 1 is shown in Figure 1.

[0197] The TGA spectrum of crystal form I of the free base of compound 1 is shown in Figure 2.

[0198] Example 3: Preparation of the maleate crystal form I of compound of formula 1

[0199] Approximately 50 mg of compound 1 was weighed into a sample vial and added to the corresponding solvent at 25±5℃. The mixture remained in a suspended state. Then, 1.1 equivalents of maleic acid were added. Detailed experimental information and results are shown in the table below. Crystal form I and crystal form II of maleate were obtained.

[0200] The DSC spectrum of maleate crystal form I showed an endothermic peak at ~221.6℃, presumably due to melt decomposition. The TGA spectrum showed a weight loss of ~0.38% from 25±5℃ to 100℃. 1 H-NMR showed the presence of 1 equivalent of maleic acid. Based on this, it is inferred that the crystal form I of maleate is amorphous and the salt ratio is 1:1 (base:acid).

[0201] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.70(d,J=5.6Hz,1H),7.65(dd,J=5.6,0.8Hz,1H),7.56(dd,J=8.2,0.8Hz,1H),7.22( d,J=8.2Hz,1H),6.01(s,2H),3.16(s,3H),2.50(p,J=1.9Hz,2H),2.48(d,J=2.6Hz,1H),2.45(s,7H),2.42(p,J=1.8Hz,1H).

[0202] Figure 5 shows the X-ray powder diffraction pattern of maleate of Formula 1, crystal form I.

[0203] Figure 6 shows the DSC and TGA spectra of the maleate crystal form I of compound formula 1.

[0204] Maleate crystal form II 1 H-NMR showed that it contained 1 equivalent of maleic acid, with a salt ratio of 1:1 (base:acid). However, crystal form II had low crystallinity and contained crystallization solvent and water of crystallization, which was not conducive to development.

[0205] Example 4: Preparation of crystal form I of gentianate of compound formula 1

[0206] Approximately 50 mg of compound of formula 1 was weighed into a sample vial and added to the corresponding solvent at 25±5℃. The mixture remained in a suspended state. Then, 1.1 equivalents of gentianic acid were added. Detailed experimental information and results are shown in the table below. The crystal form I of gentianate salt was obtained.

[0207] DSC spectroscopy of gentianate crystal form I showed an endothermic peak at ~208.2℃, presumably due to melt decomposition. TGA spectroscopy showed a weight loss of ~0.22% from 25±5℃ to 100℃. 1H-NMR showed the presence of 1 equivalent of gentianic acid. In conclusion, it is presumed that gentianate crystal form I is amorphous, with a salt-to-acid ratio of 1:1.

[0208] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.90(s,1H),7.69(d,J=5.5Hz,1H),7.65(dd,J=5. 6,0.8Hz,1H),7.55(dd,J=8.2,0.8Hz,1H),7.23(d,J=8.2Hz,1H),7.09(d,J=3.1Hz,1H), 6.80(dd,J=8.8,3.1Hz,1H),6.64(d,J=8.8Hz,1H),4.98(d,J=46.7Hz,1H),4.36(s,1H), 3.15(s,3H),2.50(s,1H),2.48(s,1H),2.45(s,3H),2.42(p,J=1.9Hz,1H),2.36(s,3H).

[0209] Figure 8 shows the X-ray powder diffraction pattern of crystal form I of triazine compound gentianate.

[0210] Figure 9 shows the DSC and TGA spectra of gentianate, a triazine compound, crystal form I.

[0211] Example 5: Preparation of amorphous samples

[0212] Method 1: Weigh about 500 mg of compound 1 and add 50 mL of methanol to dissolve it. Then filter the solution and spray dry the filtrate to obtain an amorphous sample.

[0213] Method 2: Weigh approximately 100 mg of compound 1 and add it to a mixed solution of 50 mL dimethyl sulfoxide (0.5 mL) and acetonitrile (2 mL) to dissolve it completely. After purification by preparative liquid chromatography (Pre-HPLC), the solution is lyophilized to obtain an amorphous sample.

[0214] Example 1: Dynamic Water Adsorption Curve (DVS) Analysis of Different Crystalline and Amorphous Forms

[0215] 1. Test method: The moisture absorption weight gain of different crystalline and amorphous forms of the compound containing formula 1 under different humidity conditions was investigated using a dynamic moisture adsorption instrument (DVS INTRINSIC). The humidity program was 0% RH to 95% RH to 0% RH, with a gradient of 10% RH.

[0216] 2. Test Results: The DVS test data for crystal form I of the free base, crystal form I of the maleate, and crystal form I of the gentianate of compound 1 are shown in Figures 4, 7, and 10, respectively. The test results show that crystal form I of the free base, crystal form I of the maleate, and crystal form I of the gentianate of compound 1 are slightly hygroscopic, all meeting the development characteristics of the formulation. In particular, crystal form I of the free base exhibits hygroscopicity comparable to the stable crystal form after salt formation, demonstrating its inherent excellent physical stability. It eliminates the need for salt formation to overcome hygroscopicity, simplifying the process and avoiding the potential risk of introducing other acid radicals. The test data results are shown in the table below:

[0217] Example 2: Solubility Test

[0218] 1. Test Method: Solubility tests were performed on different samples. 30 mg of each sample was placed in a sample vial, and then 3 mL of biological media (FaSSIF, FeSSIF, and FaSSGF) and water were added respectively. All suspensions were shaken at 200 rpm at 37°C. Samples were taken and observed at 0.5, 2, and 24 hours, and the solubility of the filtrate was tested. Furthermore, XRPD tests were performed on the remaining solid sample and filtrate after 24 hours.

[0219] 2. Test Results: The results showed that the free alkali crystal form I had low solubility in FaSSIF and water (0.15–0.3 mg / mL), relatively high solubility in FeSSIF (3–5 mg / mL), and the highest solubility in FaSSGF (7–9 mg / mL). After shaking in FaSSIF, FeSSIF, and water for 24 hours, the crystal form of crystal form I remained unchanged.

[0220] The solubility of maleate crystal form I in FaSSIF, FeSSIF, and FaSSGF ranged from 4 to 7 mg / mL, while its solubility in water was less than 3 mg / mL. XRPD results showed that the sample exhibited multiple peaks in FaSSGF after 24 hours, while the crystal form remained unchanged in the other three media.

[0221] The solubility of gentianate crystal form I in FaSSIF after shaking for 24 hours was approximately 4 mg / mL, a decrease compared to the solubility after 2 hours. Some free base crystal form I was observed in the remaining solid, possibly due to partial decomposition of the sample into free base. The solubility of the sample in FeSSIF after shaking for 24 hours was approximately 7 mg / mL, with the remaining solid forming an oil. The solubility of the sample in FaSSGF was greater than 10 mg / mL. The solubility of the sample in water was between 1 and 4 mg / mL.

[0222] Among the various crystalline forms, crystal form I of the free base exhibits extremely high equilibrium solubility in simulated intestinal fluids (such as FeSSIF and FaSSGF). Specific experimental results are shown in the table below:

[0223] Example 3: Stability Test

[0224] 1. Test Method: Stability was investigated for different samples. 30 mg of sample was placed at 60℃ (closed-door), under light (cool white light, 5000 Lux ± 500 Lux; closed-door), and at 25℃ / 92.5% RH (open-door) for 5 days, 10 days, and 30 days, respectively. The chemical stability of the solid samples after these conditions was analyzed by HPLC.

[0225] 2. Test Results: The results show that the crystal form and purity of the crystalline form did not change significantly after 30 days under light, high humidity, and high temperature conditions, maintaining stable physical and chemical properties, which meets the requirements for formulation development. The amorphous form is unstable under storage conditions, gradually transforming into crystal form I of the free base. Furthermore, under light conditions, its purity decreases significantly, posing a stability risk. Based on the previous preparation examples, it is evident that starting from the amorphous form, the endpoint under various crystallization conditions or long-term storage will be crystal form I of the free base. This indicates that crystal form I of the free base is the thermodynamically most stable form of the compound, and using it as a raw material can better guarantee the drug's shelf life. The test results are shown in the table below:

[0226] Example 4: Pharmacokinetic Evaluation in SD Rats

[0227] 1. Test method: Weigh the samples separately, add a small amount of DMSO to prepare a stock solution containing 50 mg / mL of compound 1 (the salt-containing compound is corrected according to the molecular weight), then add sodium chloride solution for injection to prepare a compound solution of 2 mg / mL for administration.

[0228] Free base crystal form I administration group: 4 male SD rats, 2 rats per group, were administered the drug via rehydration solution at 10 mg / kg intravenously and 10 mg / kg orally. Approximately 0.1 mL of blood was collected at the following sampling times: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The plasma was collected by centrifugation at 3500 rpm for 15 min. 5 μL of plasma was placed in an EP tube, and 50 μL of acetonitrile containing 20 ng / ml internal standard SAHA was added to precipitate the protein. The tube was vortexed for 30 s and centrifuged at 13000 rpm for 15 min. The supernatant was collected and placed in a sample vial for analysis. Standard curve range: 3–10000 ng / ml. The experimental data are shown in the table below. Free base crystal form I exhibits good pharmacokinetic properties in rats, including good oral bioavailability, exposure, half-life, and clearance.

[0229] Maleate and gentianate administration groups: 8 SD rats, 2 rats per group, were administered the drug in solution. Male rats were given 10 mg·kg⁻¹ intravenously and 10 mg·kg⁻¹ orally. Approximately 0.1 mL of blood was collected at the following sampling times: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The plasma was centrifuged at 3500 rpm for 15 min, and the supernatant was collected. 5 μL of plasma was placed in an EP tube, and 50 μL of acetonitrile containing 20 ng·ml⁻¹ internal standard SAHA was added to precipitate the protein. The tube was vortexed for 30 s and centrifuged at 13000 rpm for 15 min. The supernatant was then collected and placed in a sample vial for analysis. Standard curve range: 3–10000 ng·ml⁻¹.

[0230] The experimental data are shown in the table below. Maleate crystal form I and gentic acid crystal form I have good pharmacokinetic properties in rats, including good oral bioavailability, exposure, half-life and clearance.

[0231] In summary, the crystalline form of the compound containing Formula 1 provided by this invention improves the pharmaceutically relevant properties of the amorphous form of the free base. Particularly surprising is that the free base crystalline form I provided by this invention achieves significantly improved physical and chemical stability without sacrificing its solubility; its high solubility in biologically relevant media indicates that this crystalline form possesses an ideal physicochemical basis for becoming a highly effective oral drug.

Claims

1. A solid form of a compound of Formula 1, wherein the solid form is a crystalline form, said crystalline form being crystal form I of the free base of the compound of Formula 1, crystal form I of the maleate salt of the compound of Formula 1, or crystal form I of the gentianate salt, wherein, The X-ray powder diffraction pattern of crystal form I of the free base of the compound of formula 1, expressed in 2θ angle, shows diffraction peaks at 11.60±0.20°, 16.69±0.20°, 18.70±0.20° and 24.57±0.20°. In the crystal form I of maleate and crystal form I of gentianate, the molar ratio of the compound represented by Formula 1 to maleic acid or gentianic acid is 1:

1. The maleate crystal form I has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 9.94±0.20°, 13.40±0.20°, 18.34±0.20° and 20.16±0.20°; The crystal form I of the gentianate has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 7.67±0.20°, 11.32±0.20°, 17.15±0.20° and 17.66±0.20°.

2. The solid form of the compound of formula 1 as described in claim 1, characterized in that, It satisfies at least one of the following conditions: (1) The X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed in terms of 2θ angle, also shows diffraction peaks at one or more of the following locations: 6.89±0.20°, 9.93±0.20°, 12.19±0.20°, 13.58±0.20°, 13.94±0.20°, 19.95±0.20°, 21.41±0.20°, 22.06±0.20°, 22.81±0.20°, 23.82±0.20°, 25.79±0.20°, 27.40±0.20°, 28.43±0.20°, 29.34±0.20°, 30.14±0.20° and 36.31±0.20°; (2) The thermogravimetric analysis curve of the free base of the compound of Formula 1 in crystal form I shows a weight loss of 0.26% at 25±5℃ to 200±3℃. (3) The differential scanning calorimetry curve of the free base of the compound of Formula 1 has an endothermic peak at the starting point of 206.6±3℃. (4) The hygroscopic weight gain of the free base I of the compound of Formula 1 at 95% RH is 0.98%; (5) The crystalline form I of the free base of the compound of Formula 1 has a moisture absorption weight gain of 0.44% at 80% RH; (6) The X-ray powder diffraction pattern of the maleate crystal form I, expressed in terms of 2θ angle, also has diffraction peaks at one or both of 26.98±0.20° and 28.00±0.20°. (7) The thermogravimetric analysis (TGA) curve of the maleate crystal form I shows a weight loss of 0.38% at 25±5℃ to 100±3℃; (8) The differential scanning calorimetry (DSC) curve of the maleate crystal form I has an endothermic peak with an onset temperature of 221.6±3℃; (9) The hygroscopic weight gain of the maleate crystal form I at 80%–95% RH is 0.58%–0.75%; (10) The X-ray powder diffraction pattern of the crystal form I of the gentianate, expressed at an angle of 2θ, also shows a diffraction peak at 23.27±0.20°; (11) The thermogravimetric analysis (TGA) curve of crystal form I of the gentianate showed a weight loss of 0.22% from 25±5℃ to 100±3℃; (12) The differential scanning calorimetry (DSC) curve of crystal form I of the gentianate salt has an endothermic peak with an onset temperature of 208.2±3℃; (13) The hygroscopic weight gain of the crystal form I of the gentianate salt at 80% to 95% RH is 0.67% to 0.91%.

3. The solid form of the compound represented by Formula 1 as described in claim 2, characterized in that, It satisfies at least one of the following conditions: (1) The X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed in terms of 2θ angle, shows diffraction peaks at 6.89±0.20°, 11.60±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20° and 24.57±0.20°; Preferably, the X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed at an angle of 2θ, shows diffraction peaks at 6.89±0.20°, 11.60±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20°, 19.95±0.20°, 22.81±0.20°, 24.57±0.20°, 25.79±0.20°, and 28.43±0.20°. More preferably, the X-ray powder diffraction pattern of crystal form I of the free base of compound 1, expressed at an angle of 2θ, is at 6.89±0.20°, 9.93±0.20°, 11.60±0.20°, 12.19±0.20°, 13.58±0.20°, 13.94±0.20°, 16.69±0.20°, 18.70±0.20°, and 19.95±0.20°. Diffraction peaks are observed at 21.41±0.20°, 22.06±0.20°, 22.81±0.20°, 23.82±0.20°, 24.57±0.20°, 25.79±0.20°, 27.40±0.20°, 28.43±0.20°, 29.34±0.20°, 30.14±0.20°, and 36.31±0.20°. For example, the X-ray powder diffraction pattern of crystal form I of the free base of compound 1, expressed at an angle of 2θ, has the diffraction peaks and relative intensities shown in the table below: (2) The thermogravimetric analysis curve of the free base of the compound of Formula 1 in crystal form I is basically shown in Figure 2; (3) The differential scanning quantization curve of the free base of the compound of Formula 1 in crystal form I reaches the peak value of the endothermic peak at 209.7±3℃; preferably, the enthalpy change of the differential scanning quantization curve of the free base of the compound of Formula 1 in crystal form I between 206.6±3℃ and 209.7±3℃ is 29.7J / g. (4) The dynamic water adsorption spectrum of the free base of the compound of Formula 1 in crystal form I is basically shown in Figure 4. (5) The X-ray powder diffraction pattern of the maleate crystal form I, expressed at an angle of 2θ, also shows the following angles: 13.92±0.20°, 14.65±0.20°, 15.30±0.20°, 16.22±0.20°, 17.88±0.20°, 19.20±0.20°, 19.52±0.20°, 21.48±0.20°, 22.10±0.20°, 22.40±0.20°, 23... Diffraction peaks are present at one or more of the following locations: 0.63±0.20°, 24.79±0.20°, 26.60±0.20°, 27.62±0.20°, 29.01±0.20°, 29.76±0.20°, 30.64±0.20°, 31.37±0.20°, 31.99±0.20°, 33.23±0.20°, 37.63±0.20°, and 38.24±0.20°. Preferably, the X-ray powder diffraction pattern of the maleate crystal form I, expressed at a 2θ angle, and the diffraction peaks and relative intensities are shown in the table below: (6) The differential scanning calorimetry (DSC) curve of the maleate crystal form I has an endothermic peak with a peak temperature of 225.9±3℃; (7) The XRPD pattern of the maleate crystal form I is basically shown in Figure 5; (8) The thermogravimetric analysis curve of the maleate crystal form I is basically shown in Figure 6; (9) The differential scanning calorimetry spectrum of the maleate crystal form I is basically shown in Figure 6; (10) The dynamic water adsorption pattern of the maleate crystal form I is basically shown in Figure 7. (11) The X-ray powder diffraction pattern of the crystal form I of the gentianate, expressed at an angle of 2θ, is also at 9.19±0.20°, 12.64±0.20°, 13.56±0.20°, 13.89±0.20°, 14.20±0.20°, 15.10±0.20°, 15.41±0.20°, 16.42±0.20°, 18.41±0.20°, and 18.77±0. Diffraction peaks are present at one or more of the following locations: 20°, 19.26±0.20°, 20.22±0.20°, 21.52±0.20°, 22.54±0.20°, 22.87±0.20°, 24.16±0.20°, 25.50±0.20°, 26.01±0.20°, 27.96±0.20°, 28.68±0.20°, and 29.75±0.20°. Preferably, the X-ray powder diffraction pattern of crystal form I of the gentianate, expressed at a 2θ angle, and the diffraction peaks and relative intensities are shown in the table below: (12) The differential scanning calorimetry (DSC) curve of crystal form I of the gentianate salt has an endothermic peak with a peak temperature of 213.1±3℃; (13) The XRPD pattern of crystal form I of the gentianate is basically shown in Figure 8; (14) The thermogravimetric analysis curve of crystal form I of the gentianate is basically shown in Figure 9; (15) The differential scanning calorimetry spectrum of crystal form I of the gentianate is basically shown in Figure 9; (16) The dynamic water adsorption spectrum of crystal form I of the gentianate is basically shown in Figure 10.

4. The solid form of the compound of formula 1 as described in claim 3, characterized in that, It satisfies at least one of the following conditions: (1) The X-ray powder diffraction pattern of the free base of the compound of Formula 1, expressed in terms of 2θ angle, is basically shown in Figure 1. (2) The differential scanning spectral curve of the free base of the compound of Formula 1 in crystal form I is basically shown in Figure 2; (3) The XRPD pattern of the maleate crystal form I is basically shown in Figure 5; (4) The differential scanning calorimetry spectrum of the maleate crystal form I is basically shown in Figure 6; (5) The XRPD pattern of crystal form I of the gentianate is basically shown in Figure 8; (6) The differential scanning calorimetry spectrum of crystal form I of the gentianate is basically shown in Figure 9.

5. A method for preparing the solid form of a compound of formula 1 as described in any one of claims 1-4, characterized in that, When the solid form of the compound shown in Formula 1 is the crystal form I of the free base of the compound in Formula 1, it is any one of the following methods one to four. Method 1 includes the following steps: at 40-60℃, the suspension of the compound of Formula 1 is stirred and crystallized to obtain crystal form I of the free base of the compound shown in Formula 1. The solvent of the suspension is an alcohol, ester, ketone, nitrile, ether, alkane, aromatic hydrocarbon, cycloalkane or water. Method 2 includes the following steps: stirring and crystallizing a suspension of the compound of Formula 1 to obtain crystal form I of the free base of the compound shown in Formula 1, wherein the solvent of the suspension is a mixture of a polar solvent and water or a mixture of a polar solvent and a non-polar solvent. Method 3 includes the following steps: at 40-60°C, the solution of compound 1 is cooled and crystallized to obtain crystal form I of the free base of the compound shown in Formula 1, wherein the solvent of the solution is an ether, ketone, ester or nitrile. Method four includes the following steps: adding an antisolvent to a solution of compound 1; or adding a solution of compound 1 to an antisolvent; wherein the solvent of the solution of compound 1 is a haloalkane, alcohol, ether, ketone, amide, sulfoxide, or pyrrolidone; wherein the antisolvent is an ester, ether, alkane, cycloalkanes, or water; wherein the volume ratio of the solvent to the antisolvent of the solution of compound 1 is 1:(5-20); wherein the mass-volume ratio of the solvent to the compound 1 solution is 10-150 mg / mL; When the solid form of the compound shown in Formula 1 is the maleate crystal form I of the compound shown in Formula 1, the method for preparing maleate crystal form I includes the following steps: reacting the compound shown in Formula 1 as described in claim 1 with maleic acid in a solvent to obtain maleate crystal form I; the solvent is a ketone solvent, an ester solvent, an epoxy solvent, a nitrile solvent, or an alcohol solvent and water; When the solid form of the compound shown in Formula 1 is crystal form I of the gentianate salt of the compound shown in Formula 1, the preparation method of crystal form I of the gentianate salt includes the following steps: reacting the compound shown in Formula 1 as described in claim 1 with gentic acid in a solvent to obtain crystal form I of the gentianate salt; wherein the solvent is a ketone solvent or a nitrile solvent.

6. The method for preparing the solid form of the compound represented by Formula 1 as described in claim 5, characterized in that, It satisfies at least one of the following conditions: (1) In Method 1, the alcohol solvent is methanol, ethanol, isopropanol or n-butanol; (2) In Method 1, the ester solvent is ethyl acetate, isopropyl acetate or methyl acetate; (3) In Method 1, the ketone solvent is acetone or butanone; (4) In Method 1, the nitrile solvent is acetonitrile; (5) In Method 1, the ether solvent is methyl tert-butyl ether or 2-methyltetrahydrofuran; (6) In Method 1, the alkane solvent is n-heptane; (7) In Method 1, the aromatic hydrocarbon solvent is toluene; (8) In Method 1, the cycloalkane solvent is cyclohexane; (9) In the first method, the mass-to-volume ratio of the compound of formula 1 to the solvent in the suspension is 1g:(8-20)mL, for example 1g:8mL, 1g:10mL or 1g:20mL; (10) In method one, the stirring temperature is 50°C; (11) In the first method, the stirring time is 3-7 days, for example, 3 days or 7 days; (12) In the second method, the polar solvent is methanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, acetone or tetrahydrofuran; (13) In the second method, the non-polar solvent is n-heptane; (14) In the second method, the volume ratio of the polar solvent to water in the mixture of polar solvent and water is 1:1 or 1:

4. (15) In the second method, the volume ratio of the polar solvent to the non-polar solvent in the mixture of polar solvent and non-polar solvent is 1:

2. (16) In the second method, the mass-to-volume ratio of the compound of formula 1 to the solvent in the suspension is 3g:100mL; (17) In the second method, the stirring temperature is 20-60℃, for example 20-30℃ or 50℃; (18) In the second method, the stirring time is 3-7 days, for example, 3 days or 7 days; (19) In method three, the ether solvent is 1,4-dioxane or tetrahydrofuran; (20) In method three, the ketone solvent is acetone; (21) In method three, the ester solvent is methyl acetate; (22) In method three, the nitrile solvent is acetonitrile; (23) In the third method, the mass-volume ratio of the compound of formula 1 to the solvent in the solution is 3g:(80-400)mL, for example 3g:80mL, 3g:90mL, 3g:240mL, 3g:360mL or 3g:400mL; (24) In method three, the dissolution temperature of the solution is 50°C; (25) In the third method, the cooling method is either rapid cooling or slow cooling; (26) In method three, the cooling temperature is 0-30°C, for example 4°C or 20-30°C; (27) In method four, the alkyl haloide in the solvent is dichloromethane; (28) In method four, the alcohol in the solvent is methanol; (29) In the fourth method, the ether in the solvent is tetrahydrofuran or 1,4-dioxane; (30) In method four, the ketone in the solvent is acetone; (31) In the fourth method, the amide in the solvent is N,N-dimethylformamide; (32) In method four, the sulfoxide in the solvent is dimethyl sulfoxide; (33) In the fourth method, the pyrrolidone in the solvent is N-methylpyrrolidone; (34) In the fourth method, the ester in the antisolvent is isopropyl acetate; (35) In method four, the ether in the antisolvent is methyl tert-butyl ether; (36) In the fourth method, the alkane in the antisolvent is n-heptane; (37) In the fourth method, the cycloalkanes in the antisolvent are cyclohexane; (38) In the fourth method, the mass-volume ratio of the solvent of the solution of the compound of formula 1 to the compound of formula 1 is 15-130 mg / mL, for example 20 mg / mL, 25 mg / mL, 40 mg / mL, 46 mg / mL, 80 mg / mL or 120 mg / mL; (39) In the fourth method, the dissolution temperature of the solution of the compound of formula 1 is 20-60℃, for example 20-30℃ or 50℃; (40) In the fourth method, when the antisolvent is added to the solution of the compound of formula 1, the volume ratio of the solvent to the antisolvent is 1:(8-15), for example 1:10; (41) In the fourth method, when the solution of the compound of formula 1 is added to the antisolvent, the volume ratio of the solvent to the antisolvent is 1:(0.5-20), for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:9 or 1:10; (42) In the method for preparing the crystal form I of the maleate, the ketone solvent is acetone, methyl ethyl ketone (MEK) or cyclohexanone, for example, acetone; (43) In the method for preparing the crystal form I of the maleate, the ester solvent is ethyl acetate, isopropyl acetate, butyl acetate or dimethyl phthalate; for example, ethyl acetate; (44) In the method for preparing the crystal form I of the maleate, the epoxy solvent is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene oxide or 1,4-dioxane, preferably tetrahydrofuran; (45) In the method for preparing maleate crystal form I, the nitrile solvent is acetonitrile, propionitrile or butyronitrile; preferably acetonitrile; (46) In the method for preparing maleate crystal form I, the alcohol solvent is methanol, ethanol or isopropanol; preferably ethanol; (47) In the method for preparing maleate crystal form I, the volume molar ratio of the alcohol solvent to water is preferably 40-60:1, preferably 49:1; (48) In the preparation method of maleate crystal form I, the temperature of the preparation method is 25±5℃; (49) In the method for preparing the crystal form I of the maleate, the volume-to-mass ratio of the solvent to the compound shown in Formula 1 is 20-30 mg / mL, for example 25 mg / mL; (50) In the method for preparing the crystal form I of the maleate, the molar ratio of the compound shown in Formula 1 to maleic acid is 1:(1-1.2), for example 1:1.1; (51) In the method for preparing crystal form I of the gentian salt, the ketone solvent is acetone, methyl ethyl ketone (MEK) or cyclohexanone, for example, acetone; (52) In the method for preparing crystal form I of the gentianate, the nitrile solvent is acetonitrile, propionitrile or butyronitrile; preferably acetonitrile; (53) In the preparation method of crystal form I of the gentianate, the temperature of the preparation method is 25±5℃; (54) In the method for preparing crystal form I of the gentian salt, the volume-to-mass ratio of the solvent to the compound shown in Formula 1 is 20-30 mg / mL, for example 25 mg / mL; (55) The molar ratio of the compound shown in Formula 1 to gentic acid is 1:(1-1.2), for example 1:1.

1.

7. A pharmaceutical composition, characterized in that, It includes the solid form of the compound of formula 1 as described in any one of claims 1-4 and pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, characterized in that, The dosage form of the pharmaceutical composition is tablet, capsule, powder, granule, ointment, solution, suspension, injection, inhaler, gel, microsphere or aerosol.

9. Use of a solid form of a compound of formula 1 as described in any one of claims 1-4, or a pharmaceutical composition as described in claim 7 or 8, in the preparation of a medicament for treating and / or preventing NLRP3-related diseases; Preferably, the NLRP3-related diseases are inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases. More preferably, the NLRP3-related diseases are cryptothermal protein-related cycle syndrome, Mukel-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke; The preferred form of asthma is bronchial asthma.

10. The use of a solid form of a compound of formula 1 as described in any one of claims 1-4, or a pharmaceutical composition as described in claim 7 or 8, in the preparation of a medicament for the treatment and / or prevention of inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases; Preferably, the drug is used to treat and / or prevent cryptothermal protein-related cycle syndrome, Mukel-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, nonalcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke. The preferred form of asthma is bronchial asthma.

Images