Crystalline form of pde4b inhibitor and pharmaceutical use thereof

Abstract

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Description

A crystal form of a PDE4B inhibitor and its use in medicine Technical Field

[0001] The present invention relates to a crystal form of a compound and a salt thereof, a preparation method and application thereof, and specifically to a PDE4B inhibitor compound and a crystal form of a salt thereof, a preparation method thereof and application thereof in preparing drugs for treating PDE4B-mediated related diseases, belonging to the field of medicinal chemistry. Background Art

[0002] PDE4 inhibitors produce antidepressant effects in humans and animals by enhancing cAMP signaling in the brain. PDE4 inhibitors also play an important role in the treatment of other central nervous system diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, stroke, and Huntington's disease. Significant progress has also been made in the research and development of PDE4 inhibitors for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. The rationale behind the development of these drugs stems from the role of PDE4 in inhibiting the functions of a range of inflammatory cells and resident cells, which is believed to be involved in the pathogenesis of these diseases. Numerous clinical studies have demonstrated that cyclic adenosine monophosphate (cAMP) can block the proliferation and chemotaxis of inflammatory cells and inhibit the release of inflammatory and cytotoxic mediators in the lungs. Furthermore, PDE4 is particularly abundant in immune cells, inflammatory cells, and smooth muscle cells.

[0003] PDE4 inhibitors primarily exert their anti-inflammatory effects by inhibiting PDE4 hydrolysis, increasing cAMP levels in the body, suppressing the release of inflammatory factors, and promoting the production of anti-inflammatory mediators. Roflumilast is clinically used to treat COPD and has significant anti-inflammatory effects, inhibiting the release of inflammatory mediators such as TNF-α, interleukins, and chemokines by monocytes, macrophages, and T cells. However, these inhibitors are commonly associated with serious side effects such as nausea and vomiting, which limits their clinical application. Numerous studies have shown that in humans, isoform B of phosphodiesterase 4 (PDE4B) is involved in inflammatory responses and participates in the release of various inflammatory mediators, while isoform D is closely associated with side effects such as nausea and vomiting. This provides new insights into the identification of PDE4 inhibitors with reduced side effects. Designing PDE4B inhibitors may reduce the impact of these side effects and promote further clinical application.

[0004] Phosphodiesterase 4 (PDE4A), a phosphodiesterase (PDE4B), is highly selective for cAMP and has four isoforms: PDE4A, 4B, 4C, and 4D, with at least 25 splice variants. The protein sequences of the catalytic domains of the four PDE4 isoforms are highly homologous, and inhibitors targeting the catalytic domain do not exhibit isoform selectivity. However, most reported classical PDE4 inhibitors target the catalytic domain. In recent years, novel modes of action of PDE4 inhibitors have been reported, in which inhibitors interact simultaneously with both the catalytic domain and regulatory sequences, enabling the regulatory sequences to stabilize the protein's closed conformation, preventing cAMP entry and exerting inhibitory effects. Studies have revealed amino acid differences between PDE4B and 4D in these regulatory sequences, which can be exploited to design inhibitors that exhibit isoform selectivity. Therefore, targeting the two amino acid differences (Leu674 in PDE4B and Gln594 in PDE4D) within the downstream regulatory sequence CR3 (Conserved Region 3) offers the potential to achieve selectivity for isoform B, while maintaining activity and minimizing inhibitor side effects.

[0005] The behavior of drug polymorphs or salt forms is crucial in pharmacy and pharmacology. Polymorphs or salt forms have different physical properties, which influence pharmaceutical parameters such as storage stability, compressibility, and density (which are important for formulation and product manufacturing), as well as dissolution rate (a key factor in determining bioavailability). Therefore, the discovery of polymorphs or salt forms with excellent activity, high safety, and minimal side effects holds great promise for clinical development.

[0006] PCT / CN2023 / 112061 describes a compound of formula (I) which has a good inhibitory effect on PDE4B. Summary of the Invention

[0007] The present invention provides a small molecule compound having PDE4B inhibitory activity or a crystalline form of a pharmaceutically acceptable salt thereof. The compound is represented by formula (I) and has high activity, low toxic side effects, excellent pharmacokinetic characteristics and high bioavailability.

[0008] The crystalline form of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has advantages including, but not limited to, ease of processing and crystallization, convenient handling, ease of purification, ease of industrialization, good fluidity, ease of micronization, high solubility, good pharmacokinetic properties and good stability, and is suitable for the preparation of pharmaceutical preparations.

[0009] The present invention provides a crystalline form of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate, or glutarate;

[0011] In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate;

[0012] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate, hydrochloride, p-toluenesulfonate;

[0013] In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride;

[0014] In some embodiments, the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:0.5 to 1:3.5;

[0015] In some embodiments, the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:1;

[0016] In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride, and the molar ratio of the compound represented by formula (I): hydrochloric acid is 1:1;

[0017] In some embodiments, the pharmaceutically acceptable salt is selected from p-toluenesulfonate, and the molar ratio of the compound represented by formula (I): p-toluenesulfonic acid is 1:2 or 1:1;

[0018] In some embodiments, the pharmaceutically acceptable salt is selected from methanesulfonate, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2;

[0019] The present invention provides a hydrochloride crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 20.27°±0.2°, 21.82°±0.2°, and 26.50°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 19.84°±0.2°, 20.27°±0.2°, 21.82°±0.2°, 22.65°±0.2°, 25 .23°±0.2°, 26.50°±0.2°; in some embodiments, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 19.06°±0.2°, 19.84°±0.2°, 20.27°±0.2°, 21.45°±0.2°, 21.82°±0.2°, 22.65°±0.2°, 23.04°±0.2°, 23.63°±0.2°, 25.23°±0.2°, 26.50°±0.2°, 28.21°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 1. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperature is 196.13°C; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 0.37% before 175°C; its isothermal adsorption curve shows that there is a 0.431% weight gain in the 0-80% RH range, and it is slightly hygroscopic; its differential scanning calorimetry analysis curve, thermogravimetric analysis curve and isothermal adsorption curve are shown in Figures 2-4.

[0020] The present invention provides a hydrochloride crystalline form B of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 15.07°±0.2°, 21.85°±0.2°, and 22.03°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 15.07°±0.2°, 19.35°±0.2°, 21.85°±0.2°, 22.03°±0.2°, 23.37°± 0.2°, 25.06°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 10.13±0.2°, 13.39°±0.2°, 15.07°±0.2°, 17.46°±0.2°, 17.64°±0.2°, 19.35°±0.2°, 21.85°±0.2°, 22.03°±0.2°, 22.79°±0.2°, 23.37°±0.2°, 25.06°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 5. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperatures are 198.25°C and 239.10°C, respectively; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 2.84% before 186.67°C and about 5.08% before 186.67-219.16°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 6-7.

[0021] The present invention provides a hydrochloride crystalline form C of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 20.60°±0.2°, 21.88°±0.2°, and 24.38°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 19.93°±0.2°, 20.60°±0.2°, 21.22°±0.2°, 21.88°±0.2°, and 24.38°±0 .2°, 25.72°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 14.96°±0.2°, 16.01°±0.2°, 17.80°±0.2°, 18.90°±0.2°, 19.93°±0.2°, 20.60°±0.2°, 21.22°±0.2°, 21.88°±0.2°, 24.38°±0.2°, 25.08°±0.2°, 25.72°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 8. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperatures are 61.14°C, 154.19°C, and 237.65°C, respectively; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 4.15% before 138.62°C and about 4.00% before 138.62-190.78°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 9-10.

[0022] The present invention provides a p-toluenesulfonate crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.50°±0.2°, 6.33°±0.2°, 7.77°±0.2°, 16.52°±0.2°, and 19.63°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.50°±0.2°, 6.33°±0.2°, 7.77°±0.2°, 12.69°±0.2°, 16.52°±0.2°, 19.63°±0.2°, 20.58°± 0.2°, 22.79°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.50°±0.2°, 6.33°±0.2°, 7.77°±0.2°, 12.69°±0.2°, 15.57°±0.2°, 16.52°±0.2°, 19.63°±0.2°, 20.58°±0.2°, 20.92°±0.2°, 21.84°±0.2°, 22.21°±0.2°, 22.79°±0.2°, 24.15°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 11. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperatures are 122.88°C, 139.30°C, and 183.68°C, respectively; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 4.39% before 170.24°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 12-13.

[0023] The present invention provides a p-toluenesulfonate crystalline form B of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.00°±0.2°, 9.70°±0.2°, 18.16°±0.2°, 19.50°±0.2°, and 23.15°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.62°±0.2°, 8.00°±0.2°, 9.70°±0.2°, 18.16°±0.2°, 18.39°±0.2°, 19.50°±0.2°, and 23.15°±0.2°. 0.2°, 25.01°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.62°±0.2°, 8.00°±0.2°, 9.70°±0.2°, 11.10°±0.2°, 11.91°±0.2°, 18.16°±0.2°, 18.39°±0.2°, 19.01°±0.2°, 19.50°±0.2°, 20.56°±0.2°, 23.15°±0.2°, 25.01°±0.2°, and 26.38°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 14. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperature is 132.56°C; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 4.14% before 165.81°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 15-16.

[0024] The present invention provides a mesylate salt crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.28°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 20.58°±0.2°, and 24.06°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.23°±0.2°, 7.28°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 20.58°±0.2°, 20.81°±0.2°, 21.55°± 0.2°, 24.06°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.23°±0.2°, 7.28°±0.2°, 14.61°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 19.53°±0.2°, 19.85°±0.2°, 20.58°±0.2°, 20.81°±0.2°, 21.55°±0.2°, 21.96°±0.2°, 23.19°±0.2°, 24.06°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 17. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperatures are 117.97°C, 161.11°C, and 238.79°C, respectively; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 3.27% before 166.45°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 18-19.

[0025] The present invention provides a mesylate salt form B of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 22.53°±0.2°, and 23.71°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 9.71°±0.2°, 14.90°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 20.85°±0.2°, 22.53°±0.2°. 0.2°, 23.71°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 9.71°±0.2°, 14.90°±0.2°, 18.33°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 20.33°±0.2°, 20.85°±0.2°, 22.53°±0.2°, 23.71°±0.2°, 25.06°±0.2°, 26.42°±0.2°, 29.71°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 20. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperatures are 47.47°C, 115.97°C, and 154.87°C, respectively; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 1.89% before 90.13°C and about 2.84% before 90.13-150.12°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 21-22.

[0026] The present invention provides a crystalline form A of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 14.96°±0.2°, 17.88°±0.2°, 20.12°±0.2°, 20.54°±0.2°, and 27.07°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 10.60°±0.2°, 12.79°±0.2°, 14.96°±0.2°, 17.88°±0.2°, 20.12°±0.2°, 20.54°±0.2°, and 23.3 4°±0.2°, 27.07°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 10.60°±0.2°, 11.08°±0.2°, 12.79°±0.2°, 14.60°±0.2°, 14.96°±0.2°, 17.88°±0.2°, 19.85°±0.2°, 20.12°±0.2°, 20.54°±0.2°, 23.34±0.2°, 24.03±0.2°, 27.07, 29.54±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 23. In some embodiments, its differential scanning calorimetry analysis curve (DSC) shows that the peak temperature is 220.37°C; its thermogravimetric analysis curve (TGA) shows that the weight loss is about 1.28% before 250°C; its differential scanning calorimetry analysis curve and thermogravimetric analysis curve are shown in Figures 24-25.

[0027] The present invention also provides a method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the method comprises: forming a salt with a compound represented by formula (I) and an acid; in some embodiments, the solvent used is selected from C 1-6 Halogenated alkane solvents, C 2-6 Ester solvents, C 2-6 Ether solvents, C 1-6 One or more of an alcohol solvent or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.

[0028] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of a pharmaceutically acceptable salt of any one of the aforementioned compounds represented by formula (I), and a pharmaceutically acceptable carrier or excipient.

[0029] The present invention belongs to the field of pharmaceutical technology and, more particularly, relates to a small molecule compound with selective PDE4B inhibitory activity, its stereoisomers or pharmaceutically acceptable salts, and its use in the preparation of a medicament for treating related diseases. Furthermore, the PDE4B-mediated disease is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.

[0030] The present invention also provides a method for treating a disease in a mammal or human, comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any of the foregoing schemes. The disease is preferably cancer or COPD, idiopathic pulmonary fibrosis, or interstitial lung disease. Preferably, the therapeutically effective amount is 1-1500 mg. In some embodiments, the mammal described in the present invention does not include humans.

[0031] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0032] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0033] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, solvate, or pharmaceutically acceptable salt;

[0034] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of a compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as a "preparation specification"). In some embodiments, the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg , 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg of a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0035] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0036] A method for treating a disease in a mammal or a human comprises administering a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100 -1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0037] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0038] "Preparation specifications" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.

[0039] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit comprises a pharmaceutically acceptable salt or co-crystal of the compound of the present invention, and the amount of the pharmaceutically acceptable salt or co-crystal of the compound of the present invention is the same as that in the above-mentioned pharmaceutical composition.

[0040] The crystal form of the compound represented by formula (I) of the present invention has excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, and high humidity resistance. For example, the crystal form of the present invention can significantly reduce the filtration time during the preparation process, shorten the production cycle, and save costs. The crystal form of the present invention also has good light stability, thermal stability, and moisture stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not need to be specially packaged to prevent the influence of light, temperature, and humidity, thereby reducing costs. The crystal form will not be degraded due to the influence of light, high temperature, and high humidity, thereby improving the safety of the preparation and the effectiveness after long-term storage. Patients taking the crystal form will not worry about the preparation producing photosensitivity reactions due to exposure to sunlight.

[0041] The crystalline form of the compound represented by formula (I) of the present invention undergoes minimal or minimal degradation when stored or transported at ambient temperature, has good thermal stability, can be maintained stably for a long time, and is suitable for standard formulation production processes.

[0042] The crystal form of the compound represented by formula (I) described in the present invention is suitable and convenient for large-scale preparation. The preparation prepared using the aforementioned crystal form can reduce irritation and improve absorption, thereby solving the problem of metabolic rate, significantly reducing toxicity, improving safety, and effectively ensuring the quality and efficacy of the preparation.

[0043] It can be understood that the expressions such as “preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2θ position” or “more preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2θ position” described in the present invention mean that on the basis of having a characteristic diffraction peak at the aforementioned 2θ position, there is further a characteristic diffraction peak at the aforementioned “following 2θ position”.

[0044] It is understood that the numerical values ​​described and protected by the present invention are approximate values. Variations in the numerical values ​​may be due to equipment calibration, equipment errors, crystal purity, crystal size, sample size and other factors.

[0045] The crystalline 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 (XRD), ion chromatography (IC), differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0046] It is understood that the crystal form of the present invention is not limited to the characteristic spectra that are exactly the same as the characteristic spectra described in the drawings disclosed in the present invention, such as XRD, DSC, and TGA. Any crystal form having characteristic spectra that are substantially the same or essentially the same as those described in the drawings falls within the scope of the present invention.

[0047] It is understood that, as is well known in the art 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 compound of the present invention is characterized by a DSC pattern having characteristic peak positions, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ±3°C.

[0048] Unless otherwise stated, the technology and scientific terms used herein have the same meaning as those skilled in the art to which the present invention pertains. If there is a contradiction, the definition provided herein shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically disclosing any scope by combining any pair of upper range limits or preferred values ​​with any lower range limit or preferred values, without considering whether the scope is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include all integers and fractions (decimals) within the endpoints and range of the range.

[0049] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0050] The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.

[0051] When used with a numerical variable, the terms "about" and "approximately" are used herein to refer to the numerical value of the variable and all numerical values ​​of the variable within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified numerical value, or a wider range.

[0052] Unless otherwise indicated, percentages, parts, etc. herein are by weight.

[0053] As used herein, "amorphous" refers to any solid material that is not three-dimensionally ordered. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As described below, an amorphous solid produces an XRPD pattern lacking distinct characteristic diffraction peaks.

[0054] As used herein, a "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, as opposed to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0055] The "seed crystals" mentioned in the present invention refer to the crystal nuclei formed by adding insoluble additives in the crystallization method, which accelerate or promote the growth of enantiomer crystals with the same crystal form or stereo configuration.

[0056] The "pharmaceutical composition" of the present invention refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts and other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and excipients.

[0057] The "carrier" mentioned in the present invention refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

[0058] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, and the like.

[0059] The "1C50" mentioned in the present invention refers to the half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0060] The "ether solvent" described in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.

[0061] The "alcohol solvent" of the present invention refers to one or more "hydroxyl" substituted "C 1-6 The group is derived from one or more hydrogen atoms on the "alkyl" group, the "hydroxyl" and "C 1-6 "Alkyl" is as defined above, and specific examples include but are not limited to methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.

[0062] The "ester solvent" mentioned in the present invention refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to ethyl acetate, isopropyl acetate or butyl acetate.

[0063] The "ketone solvent" described in the present invention refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. Depending on the different hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, and 4-methyl-2-pentanone.

[0064] The "nitrile solvent" of the present invention refers to one or more "cyano" substituted "C 1-6 The group derived from one or more hydrogen atoms on the "alkyl" group, the "cyano" and "C 1-6 "Alkyl" is as defined above, and specific examples include but are not limited to acetonitrile or propionitrile.

[0065] The "halogenated hydrocarbon solvent" of the present invention refers to one or more "halogen atoms" replacing "C 1-6 The group derived from one or more hydrogen atoms on the "alkyl", the "halogen atom" and "C 1-6 "Alkyl" is as defined above, and specific examples include but are not limited to: dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.

[0066] The "crystal of the present invention", "crystal form of the present invention", "polymorph of the present invention" and the like described in the present invention can be used interchangeably.

[0067] The "room temperature" mentioned in the present invention generally refers to 4-30°C, preferably 20±5°C.

[0068] The drying temperature of the present invention is generally 20-100° C., preferably 25-70° C., and can be dried under normal pressure or reduced pressure (vacuum drying). Preferably, the drying is carried out under reduced pressure.

[0069] As used herein, an "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or a parameter, data, or value derived therefrom. An XRPD pattern is typically characterized by peak positions (on the abscissa) and / or peak intensities (on the ordinate).

[0070] The term "2θ or 2θ angle" as used herein refers to the diffraction angle, where θ is the Bragg angle, which is a peak position expressed in degrees (°) based on an X-ray diffraction experiment, and is typically the horizontal coordinate unit in a diffraction pattern. If the incident beam is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2θ. It should be understood that the specific 2θ value of a specific crystal form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2θ is ±0.3, which may be ±0.3, ±0.2, or ±0.1.

[0071] As used herein, "substantially the same" means that variations in representative peak positions and intensities are taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) can exhibit some variation, typically as much as 0.1 to 0.2 degrees, and that the instrument used to measure diffraction can also introduce some variation. Furthermore, one skilled in the art will appreciate that relative peak intensities can vary due to instrumental differences, as well as the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art, and should be considered merely qualitative measurements.

[0072] The "differential scanning calorimetry or DSC" mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature, so as to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0073] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2020 edition of the Chinese Pharmacopoeia,

[0074] Deliquescent: Absorbs sufficient water to form a liquid;

[0075] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0076] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0077] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0078] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0079] The crystal form disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:

[0080] 1. The volatilization experiment is to evaporate the clear sample solution at different temperatures until the solvent is dry.

[0081] 2. The slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids present) at a certain temperature in different solvent systems.

[0082] 3. The antisolvent test is to dissolve the sample in a good solvent, add an antisolvent, stir the precipitated solid for a short time and then filter it immediately.

[0083] 4. The cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.

[0084] 5. The polymer template experiment is to add different types of polymer materials to the sample clear solution and leave it open at room temperature to evaporate until the solvent is dry.

[0085] 6. The thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool it to room temperature.

[0086] 7. The water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] FIG1 is an X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound represented by formula (I).

[0088] FIG2 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form A of the compound represented by formula (I).

[0089] FIG3 is a thermogravimetric analysis curve of the hydrochloride crystal form A of the compound represented by formula (I).

[0090] FIG4 is an isothermal adsorption curve of the hydrochloride crystal form A of the compound represented by formula (I).

[0091] FIG5 is an X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound represented by formula (I).

[0092] FIG6 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form B of the compound represented by formula (I).

[0093] FIG7 is a thermogravimetric analysis curve of the hydrochloride crystal form B of the compound represented by formula (I).

[0094] FIG8 is an X-ray powder diffraction pattern of Form C of the hydrochloride salt of the compound represented by formula (I).

[0095] FIG9 is a differential scanning calorimetry analysis spectrum of the hydrochloride salt form C of the compound represented by formula (I).

[0096] FIG10 is a thermogravimetric analysis curve of Form C of the hydrochloride salt of the compound represented by formula (I).

[0097] FIG11 is an X-ray powder diffraction pattern of Form A of the p-toluenesulfonate salt of the compound represented by formula (I).

[0098] FIG12 is a differential scanning calorimetry analysis spectrum of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).

[0099] FIG13 is a thermogravimetric analysis curve of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).

[0100] FIG14 is an X-ray powder diffraction pattern of Form B of the p-toluenesulfonate salt of the compound represented by formula (I).

[0101] FIG15 is a differential scanning calorimetry analysis spectrum of the p-toluenesulfonate crystalline form B of the compound represented by formula (I).

[0102] FIG16 is a thermogravimetric analysis curve of the p-toluenesulfonate crystalline form B of the compound represented by formula (I).

[0103] FIG17 is an X-ray powder diffraction pattern of Form A of the mesylate salt of the compound represented by formula (I).

[0104] FIG18 is a differential scanning calorimetry analysis spectrum of the mesylate salt form A of the compound represented by formula (I).

[0105] FIG19 is a thermogravimetric analysis curve of Form A of the mesylate salt of the compound represented by formula (I).

[0106] FIG20 is an X-ray powder diffraction pattern of Form B of the mesylate salt of the compound represented by formula (I).

[0107] FIG21 is a differential scanning calorimetry analysis spectrum of the mesylate salt form B of the compound represented by formula (I).

[0108] FIG22 is a thermogravimetric analysis curve of Form B of the mesylate salt of the compound represented by formula (I).

[0109] FIG23 is an X-ray powder diffraction pattern of Form A of the compound represented by formula (I).

[0110] FIG24 is a differential scanning calorimetry analysis spectrum of Form A of the compound represented by formula (I).

[0111] FIG25 is a thermogravimetric analysis curve of Form A of the compound represented by formula (I).

[0112] FIG26 is a graph showing the anti-TNF-α secretion activity test results of the compound represented by formula (I) in the LPS-induced mouse lung inflammation model.

[0113] FIG27 is a microscope image of Form A of the hydrochloride salt of the compound of formula (I).

[0114] FIG28 is a microscope image of Form A of the compound of formula (I). DETAILED DESCRIPTION

[0115] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance 111 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0116] MS was measured using (Ag1lent 6120B (ES1) and Ag1lent 6120B (APC1)).

[0117] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Eclipse Plus C18, 150×4.6 mm).

[0118] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0119] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0120] Example 1: Preparation of compound of formula (I)

[0121] Step 1: Dissolve compound A (1.0 g, 3.63 mmol) in 1,4-dioxane (30 mL), add compound A-1 (880 mg, 4.36 mmol) and N,N-diisopropylethylamine (1.40 g, 10.86 mmol), and stir overnight at 90°C under nitrogen. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5) to yield compound B (1.6 g, 94%).

[0122] LC-MS (ESI): m / z = 441.6 [M+H] +

[0123] Step 2: Dissolve compound B (1.6 g, 3.63 mmol) in dichloromethane (5 mL), add trichloroacetyl isocyanate (820 mg, 4.36 mmol) under ice-cooling, and stir under ice-cooling for one hour. The reaction mixture is concentrated to obtain compound C (2.28 g, 100%).

[0124] Step 3: Dissolve compound C (2.28 g, 3.63 mmol) in methanol (20 mL). Add potassium carbonate (1.51 g, 10.89 mmol) and water (20 mL) under ice-cooling, and stir at room temperature for 2.5 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried, filtered, and concentrated. Chiral separation by SFC affords compound (I) (1.3 g, 74%).

[0125] 1H NMR(400MHz,DMSO-d6)δ8.54(s,2H),7.19(d,1H),6.70-6.40(m,3H),4.46(s,2H),4.30(s,2H),4.00(t,2H),3.48-3.38(m,1H),3.28- 3.23(m,1H),3.01-2.92(m,1H),2.92-2.82(m,1H),2.67(s,2H),1.98-1.88(m,1H),1.46(d,6H),1.10-0.96(m,2H),0.91-0.77(m,2H).

[0126] LC-MS (ESI): m / z = 484.2 [M+H] +

[0127] Example 2: Preparation of Hydrochloride Form A of the Compound of Formula (I)

[0128] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial. 209 μL of an ethanol solution containing 9 μL of hydrochloric acid (1.1 eq.) was added to the sample and the suspension was stirred at room temperature for 3 days. The mixture was centrifuged and the solid was vacuum-dried at 50°C to obtain Form A of the hydrochloride salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 1 . Its differential scanning calorimetry (DSC) curve showed a peak temperature of 196.13°C; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 0.37% before 175°C; its isothermal adsorption curve showed a weight gain of 0.431% in the 0-80% RH range, indicating slight hygroscopicity. Its differential scanning calorimetry curve, thermogravimetric analysis curve, and isothermal adsorption curve are shown in Figures 2-4 .

[0129] Ion chromatography (IC) detection results showed that the salt ratio was 1:1.

[0130] Example 3: Preparation of Hydrochloride Form B of the Compound of Formula (I)

[0131] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial. 209 μL of an acetonitrile solution containing 9 μL of hydrochloric acid (1.1 eq.) was added to the sample and the mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged and the solid was vacuum-dried at 50°C to obtain Form B of the hydrochloride salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 5 . Its differential scanning calorimetry (DSC) curve showed peak temperatures of 198.25°C and 239.10°C, respectively. Its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 2.84% before 186.67°C and a weight loss of approximately 5.08% between 186.67°C and 219.16°C. Its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 6-7 .

[0132] Example 4: Preparation of Hydrochloride Form C of the Compound of Formula (I)

[0133] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial. 209 μL of an MTBE solution containing 9 μL of hydrochloric acid (1.1 eq.) was added to the sample and the mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged and the solid was vacuum-dried at 50°C to obtain Form C, the hydrochloride salt of the compound of formula (I). Its X-ray powder diffraction pattern is shown in Figure 8 . Its differential scanning calorimetry (DSC) curve showed peak temperatures of 61.14°C, 154.19°C, and 237.65°C, respectively. Its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 4.15% before 138.62°C and a weight loss of approximately 4.00% between 138.62°C and 190.78°C. Its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 9-10 .

[0134] Example 5: Preparation of p-toluenesulfonate Form A of the compound of formula (I)

[0135] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, 0.2 mL of ethanol was added, and 1.1 eq. of p-toluenesulfonic acid was added. The mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged, and the solid was vacuum-dried at 50°C to obtain Form A of the p-toluenesulfonate salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 11. Its differential scanning calorimetry (DSC) curve showed peak temperatures of 122.88°C, 139.30°C, and 183.68°C, respectively; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 4.39% before 170.24°C; its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 12-13.

[0136] Example 6: Preparation of p-toluenesulfonate Form B of the compound of formula (I)

[0137] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, 0.2 mL of acetonitrile was added, and 1.1 eq. of p-toluenesulfonic acid was added. The mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged, and the solid was vacuum-dried at 50°C to obtain Form B of the p-toluenesulfonate salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 14 . Its differential scanning calorimetry (DSC) curve showed a peak temperature of 132.56°C; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 4.14% before 165.81°C; its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 15-16 .

[0138] Example 7: Preparation of Form A of the Methanesulfonate Salt of the Compound of Formula (I)

[0139] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, and 207 μL of an ethanol solution containing 7 μL of methanesulfonic acid (1.1 eq.) was added. The mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged, and the solid was vacuum-dried at 50°C to obtain Form A of the methanesulfonate salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 17 . Its differential scanning calorimetry (DSC) curve showed peak temperatures of 117.97°C, 161.11°C, and 238.79°C, respectively; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 3.27% before 166.45°C; its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 18-19 .

[0140] Example 8: Preparation of Form B of the Methanesulfonate Salt of the Compound of Formula (I)

[0141] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, and 207 μL of an acetonitrile solution containing 7 μL of methanesulfonic acid (1.1 eq.) was added. The mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged, and the solid was vacuum-dried at 50°C to obtain Form B of the methanesulfonate salt of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 20. Its differential scanning calorimetry (DSC) curve showed peak temperatures of 47.47°C, 115.97°C, and 154.87°C, respectively; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 1.89% before 90.13°C and a weight loss of approximately 2.84% between 90.13°C and 150.12°C; its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 21-22.

[0142] By analyzing the peak shift of 1H NMR (400 MHz, DMSO) δ, the chemical shift of the compound of formula (I) at 8.56 (2H) is the -Ch peak at positions 28 and 30, and the -CH3 peak of methanesulfonic acid at position 2.35 (4H), and the ratio is 1:2. Therefore, it can be analyzed that the ratio of the compound of formula (I) to methanesulfonic acid is 1:0.7.

[0143] Example 8: Preparation of Form A of the Compound of Formula (I)

[0144] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, 200 μL of acetonitrile solution was added, and the mixture was suspended and slurried at room temperature for 3 days. The mixture was centrifuged, and the solid was vacuum-dried at 50°C to obtain Form A of the compound of formula (I). Using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 23 . Its differential scanning calorimetry (DSC) curve showed a peak temperature of 220.37°C; its thermogravimetric analysis (TGA) curve showed a weight loss of approximately 1.28% before 250°C; its differential scanning calorimetry and thermogravimetric analysis curves are shown in Figures 24-25 .

[0145] X-ray powder diffractometer (XRD) / DSC / TGA / DVS / 1C testing

[0146] The XRD / DSC / TGA / DVS test parameters are detailed in Table 1, and the XRD data of the relevant crystal forms are shown in Tables 2 to 8.

[0147] Table 1 XRD / DSC / TGA / DVS test instruments and parameters

[0148] Table 2: XRD peak list of hydrochloride salt form A of compound of formula (I)

[0149] Table 3: XRD peak list of hydrochloride salt form B of compound of formula (I)

[0150] Table 4: XRD peak list of hydrochloride salt form C of compound of formula (I)

[0151] Table 5: XRD peak list of p-toluenesulfonate salt form A of the compound of formula (I)

[0152] Table 6: XRD peak list of p-toluenesulfonate salt form B of compound of formula (I)

[0153] Table 7: XRD peak list of mesylate salt form A of compound of formula (I)

[0154] Table 8: XRD peak list of mesylate salt form B of compound of formula (I)

[0155] Table 9: XRD peak list of Form A of the compound of formula (I)

[0156] Thermal stability study

[0157] Two 40 mg portions of Form A hydrochloride of the compound of formula (I) were taken, 1 mL of ethanol was added, and the temperature was raised to 50°C and 70°C, respectively. Samples were taken at regular intervals and submitted to HPLC for stability testing. Specific data are shown in the table below. The test results show that the hydrochloride salt has good thermal stability.

[0158] Table 10. Hydrochloride Form A 50°C Stability Data

[0159] Table 11. Hydrochloride Form A 70°C Stability Data

[0160] Aqueous solution stability study

[0161] 100 mg of the hydrochloride crystalline form of the compound of formula (I) was added to 4 mL of water to form a suspension, which was stirred at room temperature. Samples were taken at regular intervals and submitted for HPLC and XRPD analysis to assess stability. Specific data are shown in the table below. The test results showed that the XRD pattern of the hydrochloride of the compound of formula (I) in aqueous solution was consistent with that of the raw material, with no significant impurities formed, indicating good aqueous stability.

[0162] Table 12. Stability of hydrochloride salt form A in aqueous solution

[0163] Study on hygroscopicity of crystal form

[0164] Table 14. Comparison of hygroscopicity of compounds of formula (I)

[0165] Comparative study of crystallinity

[0166] Table 15. Comparison of crystallinity of compounds of formula (I)

[0167] Hydrochloride competition experimental study

[0168] 100 mg of each hydrochloride crystal form A, hydrochloride crystal form B, and hydrochloride crystal form C sample was taken, mixed evenly, and sampled for XRPD characterization; the mixed sample was divided into 3 equal parts, and 0.5 mL of solvent (acetone, methanol, and acetonitrile) was added to each to form a suspension. The suspension was stirred at room temperature for 3 days, and samples were taken for XRPD characterization. The results are shown in Table 16. It can be seen that the three crystal forms of the hydrochloride were mixed and eventually converted into crystal form A in different solvents.

[0169] Table 16. Comparison of crystallinity of compounds of formula (I)

[0170] Experimental study of solid properties

[0171] The sample of the hydrochloride crystal form A of the compound of formula (I) is an irregular sample with uneven size, difficult to prepare, and poor fluidity. The sample of the crystal form A of the compound of formula (I) is a block agglomerated sample with uniform size, simple to prepare, and good fluidity.

[0172] Microscope images of the hydrochloride form A of the compound of formula (I) and the crystalline form A of the compound of formula (I) are shown in Figures 27 and 28, respectively.

[0173] Table 17. Solid-state property research data of compound of formula (I)

[0174] Solid stability studies

[0175] 100 mg of Form A of the compound of Formula (I) was placed under different conditions and tested for relevant data over 1 month, 2 months, 3 months, 6 months, and 9 months. The specific conditions and results for the relevant substances are shown in the table below. The test results show that Form A of the compound of Formula (I) has good stability under all conditions.

[0176] Table 18 Stability of Form A of Compound of Formula (I)

[0177] Biological testing:

[0178] 1. Effects of compounds on PDE4B2 activity

[0179] The effects of compounds on PDE4B2 activity were determined using a Fluorescence Polarization Assay Kit (BPS Bioscience, Catalog #60343). According to the kit instructions, a final concentration of 0.1 μM FAM-Cyclic-3',5'-AMP and 1 ng / well of PDE4B2 were added to each well (negative control wells were treated with PDE buffer). A serial dilution of compound was added (positive control wells were treated with PDE buffer containing 10% DMSO). The mixture was mixed thoroughly and incubated at room temperature for 1 hour. The binding agent was diluted 1:100 with binding agent diluent (cAMP). 50 μl / well of the binding agent diluent was added to the assay plate and incubated at room temperature for 20 minutes with slow shaking. After incubation, FP was detected using Envision (excitation 480 nm, emission 535 nm). FP is typically expressed as mP values.

[0180] I II (S535): Fluorescence intensity in the parallel direction

[0181] I ┴ (P535): Fluorescence intensity in the vertical direction

[0182] G:G factor = 1

[0183] Calculation of inhibition rate (%Inhibition): %Inhibition=[1-(mP (样品) -mP (阴性对照) ) / (mP (阳性对照) -mP (阴性对照) )]x100%

[0184] mP (样品)： mP of the test compound reaction well

[0185] mP (阴性对照)： Negative control well mP

[0186] mP (阳性对照)： Positive control well mP

[0187] According to the calculated inhibition rate at each concentration, the IC of each compound was calculated using GraphPad Prism 8 software. 50 value.

[0188] The IC values ​​of the compounds of the present invention for PDE4B2 50 The value is <300 nM, preferably some compounds are <100 nM, more preferably some compounds are <50 nM, and further preferably some compounds are <10 nM.

[0189] IC of the compounds of the present invention against PDE4B2 50 The value is less than 300nM, and the preferred compound IC 50 The IC values ​​of some specific compounds are less than 100 nM, more preferably less than 50 nM, and even more preferably less than 10 nM. 50 The values ​​are shown in Table 19 below, where A<10nM, 10nM≤B<50nM, and 50nM≤C<100nM.

[0190] Table 19 PDE4B2 activity

[0191] 2. Effects of Compounds on PDE4D2 Activity

[0192] The effects of compounds on PDE4D2 activity were detected using a fluorescence polarization kit (BPS Bioscience, Catalog #60345). The reaction was preincubated at room temperature for 15 minutes with 12.5 μL of serially diluted compound (4% DMSO) at 0.272 ng / well of enzyme (final concentration 0.068 ng / well). The same volume and concentration of enzyme and 12.5 μL of PDE buffer containing 4% DMSO were added to the positive control wells, and 25 μL of PDE buffer containing 2% DMSO was added to the negative control wells. Subsequently, 25 μL of 0.2 μM FAM-Cyclic-3',5'-AMP (final concentration 0.1 μM) was added to each well, mixed thoroughly, and incubated with slow shaking at room temperature for 30 minutes. Dilute the binding agent with Binding Agent Diluent (cAMP) at a ratio of 1:100. Add 100 μl of this dilution to all wells of the assay plate. Incubate at room temperature with slow shaking for 1 hour. After incubation, perform FP detection using a BMG LRBTECH microplate reader at 485 nm excitation and 520 nm emission. FP is typically expressed as mP values.

[0193] I II (S520): Fluorescence intensity in the parallel direction

[0194] I ┴ (P520): Fluorescence intensity in the vertical direction

[0195] G:G factor = 1

[0196] Calculation of inhibition rate (%Inhibition):

[0197] %Inhibition=[1-(mP (样品) -mP(阴性对照) ) / (mP (阳性对照) -mP (阴性对照) )]x100%

[0198] mP (样品)： mP of the test compound reaction well

[0199] mP (阴性对照)： Negative control well mP

[0200] mP (阳性对照)： Positive control well mP

[0201] The IC50 value of each compound was calculated based on the inhibition rate at each concentration using GraphPad Prism 8 software.

[0202] IC of some specific compounds of the present invention 50 The values ​​are shown in Table 20 below, where A<10nM, 10nM≤B<50nM, and 50nM≤C<100nM.

[0203] Table 20 PDE4D2 activity

[0204] 3. Detection of the inhibitory activity of compounds on the release of tumor necrosis factor-α (TNF-α) from human peripheral blood mononuclear cells induced by lipopolysaccharide (LPS) in vitro

[0205] Normal human peripheral blood (citrate anticoagulated) was collected and hPBMCs were prepared using Ficoll-Paque PLUS (Cytiva, Cat#17144002, density 1.077 g / mL). The hPBMC cell concentration was adjusted to 0.25 x 10 6 / mL, and seeded in a 96-well plate with 50,000 cells per well. Subsequently, different concentrations of drugs were added for pre-incubation for 1 hour (the final concentration of DMSO was 0.1%, and the positive and negative control wells were equal volumes of RPMI1640 containing 0.1% DMSO). After the pre-incubation was completed, 100 ng / mL LPS (SIGMA, L2630) was added to the compound and positive control wells, and the negative control wells were equal volumes of RPMI1640 containing 0.1% DMSO. They were cultured in a 37°C, 5% CO2 incubator for 4 hours. The cell supernatant was collected, and the TNF-α content in the supernatant sample was detected using a human TNF-α Elisa quantitative detection kit (Sino Biological, Cat#KIT10602). GraphPad Prism software was used to calculate the IC 50 IC values ​​of some specific compounds of the present invention 50The values ​​are shown in Table 21 below, where A<10nM, 10nM≤B<50nM, and 50nM≤C<100nM.

[0206] Table 21 Inhibitory activity of compounds on LPS-induced TNF-α in vitro

[0207] Re IC 50 : Relative IC 50 .

[0208] 4 Pharmacokinetic test in rats

[0209] 4.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0210] 4.2 Experimental Design: On the day of the experiment, six SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0211] Table 22. Dosing Information

[0212] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Oral administration solvent: 0.5% MC

[0213] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0214] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0215] Table 23. Pharmacokinetic parameters of test compounds in rat plasma

[0216] -:not applicable.

[0217] Conclusion: The compound of formula (I) of the present invention exhibits excellent pharmacokinetic properties in the mouse PK test.

[0218] Detection of anti-TNF-α secretion activity in 5LPS-induced mouse lung inflammation model

[0219] Intratracheal administration of lipopolysaccharides (LPS, Sigma, L2880) can induce elevated TNF-α concentrations in lung tissue in mice. In this study, a number of mice (male, BABL / c, weighing 18-22 g) were randomly divided into 8 groups and orally administered with a dose of the compound of formula (I) (the compound of formula (I) was suspended in 0.5% MC and prepared to a specific concentration, and administered orally at a volume of 10 ml / kg body weight). 0.5 h later, a 0.8 mg / mL dose of LPS was administered intratracheally using a pulmonary quantitative atomization needle at a dose of 2.5 uL / g based on the animal's body weight. 24 h later, the mice were anesthetized intraperitoneally with 20% urethane (10 mL / kg) and sacrificed by cervical dislocation. Lung tissue was then harvested, and the lower half of the left lobe was thoroughly homogenized. The TNF-α content in the homogenate supernatant was assayed using the Mouse TNFα ELISA Kit (RD, SMTA00B).

[0220] The inhibition rate of the test compound on TNF-α level (% Inh) = (model group - test group) / model group * 100%.

[0221] Results and Conclusion: The results are shown in Figure 26, which show that the compound of formula (I) of the present invention has significant anti-TNF-α secretion activity.

Claims

1. A crystalline form, a pharmaceutically acceptable salt and a crystalline form thereof of a compound represented by formula (I), 2. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 1, which is crystalline form A of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 14.96°±0.2°, 17.88°±0.2°, 20.12°±0.2°, 20.54°±0.2°, and 27.07°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 10.60°±0.2°, 12.79°±0.2°, 14.96°±0.2°, 17.88°±0.2°, 20.12°±0.2°, 20.54°±0.2°, and 27.07°±0.2°. 2°, 23.34°±0.2°, 27.07°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 10.60°±0.2°, 11.08°±0.2°, 12.79°±0.2°, 14.60°±0.2°, 14.96°±0.2°, 17.88°±0.2°, 19.85°±0.2°, 20.12°±0.2°, 20.54°±0.2°, 23.34±0.2°, 24.03±0.2°, 27.07±0.2°, 29.54±0.2°; or the X-ray powder diffraction pattern of the crystalline form A is substantially as shown in Figure 23.

3. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 1, wherein the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, fumarate, hydrohalide, sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, tris(o)propionate, t-toluenesulfon ... Phenylacetate, L-proline salt, ferulate salt, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate or glutarate; preferably selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate and oxalate; more preferably selected from hydrochloride.

4. The crystal form, pharmaceutically acceptable salt and crystal form thereof according to claim 3, wherein the molar ratio of the compound represented by formula (I) to the pharmaceutically acceptable salt is 1:0.5 to 1:3.5, preferably 1:1, 1:2 or 1:

3.

5. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is the hydrochloride crystalline form A of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 20.27°±0.2°, 21.82°±0.2°, 26.50°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 19.84°±0.2°, 20.27°±0.2°, 21.82°±0.2°, 22.65°±0.2°. °, 25.23°±0.2°, 26.50°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 9.44°±0.2°, 11.21°±0.2°, 19.06°±0.2°, 19.84°±0.2°, 20.27°±0.2°, 21.45°±0.2°, 21.82°±0.2°, 22.65°±0.2°, 23.04°±0.2°, 23.63°±0.2°, 25.23°±0.2°, 26.50°±0.2°, 28.21°±0.2°; or the X-ray powder diffraction pattern of the hydrochloride form A is substantially as shown in Figure 1.

6. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is a hydrochloride crystalline form B of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 15.07°±0.2°, 21.85°±0.2°, and 22.03°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 15.07°±0.2°, 19.35°±0.2°, 21.85°±0.2°, and 22.03°±0.2°. °, 23.37°±0.2°, 25.06°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 4.46°±0.2°, 7.85°±0.2°, 10.13±0.2°, 13.39°±0.2°, 15.07°±0.2°, 17.46°±0.2°, 17.64°±0.2°, 19.35°±0.2°, 21.85°±0.2°, 22.03°±0.2°, 22.79°±0.2°, 23.37°±0.2°, 25.06°±0.2°; or the X-ray powder diffraction pattern of the hydrochloride salt form B is substantially as shown in Figure 5.

7. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is a hydrochloride crystalline form C of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 20.60°±0.2°, 21.88°±0.2°, and 24.38°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 19.93°±0.2°, 20.60°±0.2°, 21.22°±0.2°, and 21.88°±0.2°. , 24.38°±0.2°, 25.72°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 4.96°±0.2°, 8.86°±0.2°, 14.96°±0.2°, 16.01°±0.2°, 17.80°±0.2°, 18.90°±0.2°, 19.93°±0.2°, 20.60°±0.2°, 21.22°±0.2°, 21.88°±0.2°, 24.38°±0.2°, 25.08°±0.2°, 25.72°±0.2°; or the X-ray powder diffraction pattern of the hydrochloride salt form C is substantially as shown in Figure 8.

8. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.50°±0.2°, 6.33°±0.2°, 7.77°±0.2°, 16.52°±0.2°, and 19.63°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 5.50°±0.2°, 6.33°±0.2°, 7.77°±0.2°, 12.69°±0.2°, 16.52°±0.2°, 19.63°±0.2°, 14.8°±0.2°, 21.77°±0.2°, 22.69°±0.2°, 24.75°±0.2°, 25.91°±0.2°, 26.70°±0.2°, 26.97°±0.2°, 27.79°±0.2°, 28.11°±0.2°, 29.89°±0.2°, 30.71°±0.2°, 31.90°±0.2°, 32.79°±0.2°, 33.91°±0.2°, 34.70°±0.2°, 35.

9. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.00°±0.2°, 9.70°±0.2°, 18.16°±0.2°, 19.50°±0.2°, and 23.15°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 7.62°±0.2°, 8.00°±0.2°, 9.70°±0.2°, 18.16°±0.2°, 18.39°±0.2°, and 19.50°±0.2°. , 23.15°±0.2°, 25.01°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 7.62°±0.2°, 8.00°±0.2°, 9.70°±0.2°, 11.10°±0.2°, 11.91°±0.2°, 18.16°±0.2°, 18.39°±0.2°, 19.01°±0.2°, 19.50°±0.2°, 20.56°±0.2°, 23.15°±0.2°, 25.01°±0.2°, 26.38°±0.2°; or the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B is substantially as shown in Figure 14.

10. The crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to claim 3 or 4, which is a mesylate crystalline form A of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.28°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 20.58°±0.2°, and 24.06°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 6.23°±0.2°, 7.28°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 20.58°±0.2°, and 24.06°±0.2°. °, 21.55°±0.2°, 24.06°±0.2°; more preferably, characteristic diffraction peaks are present at the following 2θ positions: 6.23°±0.2°, 7.28°±0.2°, 14.61°±0.2°, 17.93°±0.2°, 18.51°±0.2°, 19.53°±0.2°, 19.85°±0.2°, 20.58°±0.2°, 20.81°±0.2°, 21.55°±0.2°, 21.96°±0.2°, 23.19°±0.2°, 24.06°±0.2°; or the X-ray powder diffraction pattern of the mesylate salt form A is substantially as shown in Figure 17.

11. The crystal form, pharmaceutically acceptable salt and crystal form thereof according to claim 3 or 4, which is a mesylate crystal form B of the compound represented by formula (I), and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 22.53°±0.2°, and 23.71°±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 9.71°±0.2°, 14.90°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 20.85°±0.2°. °, 22.53°±0.2°, 23.71°±0.2°; more preferably, it has characteristic diffraction peaks at the following 2θ positions: 6.11°±0.2°, 9.71°±0.2°, 14.90°±0.2°, 18.33°±0.2°, 19.51°±0.2°, 19.87°±0.2°, 20.33°±0.2°, 20.85°±0.2°, 22.53°±0.2°, 23.71°±0.2°, 25.06°±0.2°, 26.42°±0.2°, 29.71°±0.2°; or the X-ray powder diffraction pattern of the mesylate salt form B is substantially as shown in Figure 20.

12. A method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), comprising the step of forming a salt with the compound represented by formula (I) and an acid; wherein the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, fumarate, hydrohalide, sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetic acid salt, propionate, valerate, triphenylacetate, L-proline salt, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate or glutarate; preferably selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate and oxalate; more preferably selected from hydrochloride; 13. The preparation method according to claim 12, wherein The solvent used is selected from C 1-6 Halogenated alkane solvents, C 2-6 Ester solvents, C 2-6 Ether solvents, C 1-6 One or more of alcohol solvents or water.

14. The preparation method according to claim 13, wherein The solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.

15. A pharmaceutical composition, wherein The pharmaceutical composition contains a therapeutically effective amount of a crystalline form, a pharmaceutically acceptable salt and a crystalline form thereof of the compound represented by formula (I) according to any one of claims 1 to 11, and a carrier or excipient.

16. Use of the crystalline form, pharmaceutically acceptable salt and crystalline form thereof according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 15 in the preparation of a PDE4B inhibitor drug.