Crystal form of 1-methyl-1h-indazole compound, and preparation method therefor and use thereof

Abstract

Disclosed are a crystal form of a 1-methyl-1H-indazole compound, and a preparation method therefor and the use thereof. The present invention specifically relates to a crystal form of the compound of formula (I) and a preparation method therefor.

Description

Crystal forms, preparation methods and applications of 1-methyl-1H-indazole compounds Technical Field

[0001] This invention relates to the crystal forms of 1-methyl-1H-indazole compounds, their preparation methods and applications, and specifically to the crystal forms of compounds of formula (I) and their preparation methods. Background Technology

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is highly expressed in tissues such as the lungs, kidneys, liver, and spleen. DPP1 is a lysosomal cysteine ​​protease composed of a tetramer of four identical subunits, each consisting of a heavy chain, a light chain, and an exclusive domain. The main physiological function of DPP1 is to activate pro-inflammatory neutrophil serine proteases (NSPs, including neutrophil elastase, protease 3, and cathepsin G) in the bone marrow by cleaving the N-terminal dipeptide. NSPs are closely related to inflammation regulation, can activate various cytokines, and play an important role in clearing pathogenic microorganisms. Studies have shown that patients with chronic obstructive pulmonary disease (COPD) or bronchiectasis often exhibit persistent inflammatory responses and excessive activation of NSPs in the airways, leading to the degradation of pulmonary elastin and other proteins, further causing lung tissue damage and bronchial wall destruction. DPP1 inhibitors can inhibit the activation of pro-inflammatory neutrophil proteases at the source, thereby suppressing the inflammatory response and airway damage caused by neutrophils in the airway.

[0003] While the activity of DPP1 inhibitors in solution is usually assessed first, solid-state properties (such as polymorphism) are also important. The numerous crystalline forms of pharmaceutical raw materials (such as DPP1 inhibitors) can possess different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly impact the processing or manufacturing capabilities of both the pharmaceutical raw material and the finished product. Summary of the Invention

[0004] In one aspect, this document describes the crystal forms of compounds of formula (I), wherein the crystal form is A, B, C, D or E. The X-ray powder diffraction pattern of crystal form A, measured using Cu(Kα) radiation, exhibits diffraction peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; the X-ray powder diffraction pattern of crystal form B, measured using Cu(Kα) radiation, exhibits diffraction peaks at the following 2θ angles: 8.954±0.200°, 13.530±0.200°, 15.480±0.200°, and 18.122±0.200°. The X-ray powder diffraction pattern of the C-type crystal, measured using Cu(Kα) radiation, exhibits diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200°, and 19.812±0.200°; the X-ray powder diffraction pattern of the D-type crystal, measured using Cu(Kα) radiation, exhibits diffraction peaks at the following 2θ angles: 9.105±0.200°, 15.206±0.200°, and 16.904±0.200°; the X-ray powder diffraction pattern of the E-type crystal, measured using Cu(Kα) radiation, exhibits diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, and 15.214±0.200°.

[0005] In some implementations, the crystal form is A crystal form.

[0006] In some embodiments, the X-ray powder diffraction pattern of the crystal form measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 20.673±0.200°, and 24.134±0.200°.

[0007] In some embodiments, the X-ray powder diffraction pattern of the crystal form measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 20.673±0.200°, and 24.134±0.200°.

[0008] In some embodiments, the X-ray powder diffraction pattern of the crystal form measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 19.863±0.200°, 20.673±0.200°, 23.025±0.200°, 23.513±0.200°, and 24.134±0.200°.

[0009] In some embodiments, the crystal form A has one or more features selected from the group consisting of: an XRPD pattern substantially as shown in Figure 1; a DSC pattern substantially as shown in Figure 2; and / or a TGA pattern substantially as shown in Figure 3.

[0010] In some embodiments, the crystal form A has one or more features selected from the group consisting of: a differential scanning calorimeter with an endothermic peak at 141.01±3 °C; and / or a thermogravimetric analysis curve showing a weight loss of up to 0.040% at 150.0±3 °C.

[0011] In one aspect, the crystal form of the compound of formula (I) is described herein, wherein the crystal form is A crystal form; The A-type crystal is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; and one or two of the following: a differential scanning calorimetry curve with an endothermic peak at 141.01±3℃; or a thermogravimetric analysis curve showing a weight loss of up to 0.040% at 150.0±3℃.

[0012] In some embodiments, the crystal form A is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; and a differential scanning calorimetry curve with an endothermic peak at 141.01±3 °C.

[0013] In some embodiments, the crystal form A is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; and a thermogravimetric analysis curve showing a weight loss of up to 0.040% at 150.0±3 °C.

[0014] In one aspect, the crystal form of the compound of formula (I) is described herein, wherein the crystal form is A crystal form; The A-type is characterized by having an XRPD pattern as shown in Figure 1; a DSC pattern as shown in Figure 2; and / or a TGA pattern as shown in Figure 3.

[0015] In some embodiments, the crystal form A is characterized by having an XRPD pattern essentially as shown in Figure 1; and a DSC pattern essentially as shown in Figure 2.

[0016] In some embodiments, the crystal form A is characterized by having an XRPD pattern essentially as shown in Figure 1; and a TGA pattern essentially as shown in Figure 3.

[0017] In a further aspect, this document describes a pharmaceutical composition comprising: a crystalline form of the compound of formula (I), and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is a solid form pharmaceutical composition. In some embodiments, the solid form pharmaceutical composition is a tablet, pill, or capsule. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form A. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form A, which substantially does not contain any other crystalline form of the compound of formula (I). In some embodiments, the crystalline form of the compound of formula (I) is crystalline form B. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form C. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form D. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form E.

[0018] In one aspect, this document describes the use of the crystal form of the compound of formula (I) or a pharmaceutical composition comprising the crystal form of the compound of formula (I) in the preparation of a DPP1 inhibitor or a medicament for the prevention or treatment of DPP1-related diseases.

[0019] In one aspect, this document describes a method for preparing a crystal form of the compound of formula (I), the method comprising the steps of: stirring the compound of formula (I) in a mixed solvent of isopropanol and water until a solid precipitates, filtering, and drying at 20-45°C (preferably 30-40°C) to obtain crystal form A.

[0020] This document also describes the use of the crystal form of the compound of formula (I) in the treatment of inflammatory diseases of the human airways. This document also describes the use of pharmaceutical compositions comprising the crystal form of the compound of formula (I) in the treatment of inflammatory diseases of the human airways. In some embodiments, the crystal form of the compound of formula (I) is crystal form A. In some embodiments, the crystal form of the compound of formula (I) is crystal form A, which is substantially free of other crystal forms of the compound of formula (I). In some embodiments, the crystal form of the compound of formula (I) is crystal form B. In some embodiments, the crystal form of the compound of formula (I) is crystal form C. In some embodiments, the crystal form of the compound of formula (I) is crystal form D. In some embodiments, the crystal form of the compound of formula (I) is crystal form E.

[0021] In some implementations, the airway inflammatory disease is chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, acute respiratory distress syndrome, exercise-induced bronchoconstriction (EIB), chronic bronchitis, emphysema, α1-antitrypsin deficiency, pulmonary fibrosis with emphysema (CPFE), or asthma-COPD overlap syndrome (ACOS).

[0022] In some implementations, the asthma is allergic asthma, aspirin-induced asthma, cough-variant asthma, exercise-induced asthma, nocturnal asthma, steroid-resistant asthma, occupational asthma, eosinophilic asthma, neutrophilic asthma, or mixed eosinophilic and neutrophilic asthma.

[0023] In some implementations, the airway inflammatory disease is chronic obstructive pulmonary disease (COPD).

[0024] In some implementations, the airway inflammatory disease is bronchiectasis.

[0025] This document also describes a method for treating inflammatory airway diseases in humans, the method comprising administering a therapeutically effective amount of a crystalline form of the compound of formula (I) to a person in need. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form A. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form A, which is substantially free of other crystalline forms of the compound of formula (I). In some embodiments, the crystalline form of the compound of formula (I) is crystalline form B. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form C. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form D. In some embodiments, the crystalline form of the compound of formula (I) is crystalline form E. In some embodiments, the therapeutically effective amount of the crystalline form is administered in the form of a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is a tablet, pill, or capsule.

[0026] In some implementations, the airway inflammatory disease is chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, acute respiratory distress syndrome, exercise-induced bronchoconstriction (EIB), chronic bronchitis, emphysema, α1-antitrypsin deficiency, pulmonary fibrosis with emphysema (CPFE), or asthma-COPD overlap syndrome (ACOS).

[0027] In some implementations, the asthma is allergic asthma, aspirin-induced asthma, cough-variant asthma, exercise-induced asthma, nocturnal asthma, steroid-resistant asthma, occupational asthma, eosinophilic asthma, neutrophilic asthma, or mixed eosinophilic and neutrophilic asthma.

[0028] In some implementations, the airway inflammatory disease is chronic obstructive pulmonary disease (COPD).

[0029] In some implementations, the airway inflammatory disease is bronchiectasis.

[0030] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed descriptions. However, it should be understood that while the detailed descriptions and specific examples indicate particular embodiments, they are given for illustrative purposes only, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from these detailed descriptions. Attached Figure Description

[0031] Figure 1: XRPD pattern of compound A of formula (I).

[0032] Figure 2: DSC spectrum of crystal form A of compound (I).

[0033] Figure 3: TGA spectrum of crystal form A of compound (I).

[0034] Figure 4: XRPD pattern of compound B of formula (I).

[0035] Figure 5: DSC spectrum of crystal form of compound B of formula (I).

[0036] Figure 6: TGA spectrum of crystal form of compound B of formula (I).

[0037] Figure 7: XRPD pattern of the C crystal form of compound (I).

[0038] Figure 8: DSC spectrum of the C crystal form of compound (I).

[0039] Figure 9: TGA spectrum of the C crystal form of compound (I).

[0040] Figure 10: XRPD pattern of crystal form D of compound (I).

[0041] Figure 11: DSC spectrum of crystal form D of compound (I).

[0042] Figure 12: TGA spectrum of crystal form D of compound (I).

[0043] Figure 13: XRPD pattern of crystal form E of compound (I).

[0044] Figure 14: DSC spectrum of crystal form E of compound (I).

[0045] Figure 15: TGA spectrum of crystal form E of compound (I).

[0046] Figure 16: DVS spectrum of crystal form A of compound (I). Detailed Implementation

[0047] In airway inflammatory conditions, activated neutrophils are a significant disease driver because they release tissue-damaging neutrophil serine proteases (NSPs) that promote airway inflammation, mucus plugging, and worsening of the lungs. Dipeptidyl peptidase-1 (DPP1, also known as cathepsin C) enzymatically activates NSPs, including neutrophil elastase (NE), protease 3 (PR3), and cathepsin G (CatG), during neutrophil maturation in the bone marrow; therefore, DPP1 inhibitors may reduce systemic NSP levels. NSPs in the airways reduce ciliary beating frequency, hinder the clearance of apoptotic cells, and promote sputum production. NSPs also degrade extracellular matrix components, leading to alveolar destruction and chronic airway remodeling, and degrade antimicrobial peptides, resulting in increased bacterial colonization and lung infections.

[0048] Neutrophils require DPP1 to activate NSPs, such as NE, CatG, and PR3, which are key drivers of disease in airway inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and bronchiectasis. Excessive NSPs promote airway inflammation, mucus plugging, and exacerbations (i.e., symptom flare-ups). Neutrophils and NSPs further increase during exacerbations, perpetuating a positive feedback loop in the pathology. Therefore, drugs that block or reduce NSPs hold therapeutic potential for controlling inflammatory lung diseases, representing a significant unmet need in COPD.

[0049] COPD is a chronic inflammatory disease affecting the airways and alveoli. It contributes to a significant disease burden and is the third leading cause of death worldwide (see the 2025 Global Initiative for Chronic Obstructive Lung Disease [GOLD] Report). Patients with COPD develop chronic bronchitis and emphysema and are prone to frequent bacterial infections. The pathophysiology of COPD includes airflow limitation and impaired gas exchange, which may be accompanied by excessive mucus secretion and airway epithelial ciliary dysfunction. Smoking and environmental exposure to particulate matter and harmful gases are the most common causes of COPD.

[0050] While existing treatments for COPD (e.g., inhaled short-acting bronchodilators (short-acting β2 receptor agonists, SABA and short-acting muscarinic receptor agonists, SAMA), long-acting bronchodilators / muscarinic receptor agonists (LABA / LAMA), inhaled corticosteroids (ICS), phosphodiesterase 3 (PDE3) and PDE4 inhibitors, dupilumab, mepolizumab) can reduce exacerbation rates and improve quality of life, they have little impact on COPD progression and mortality. Therefore, there is an urgent need for new drugs with novel mechanisms of action or new routes of administration to address unmet medical needs in COPD control. The inhibition of DPP1 by compounds of formula (I) represents a promising therapeutic strategy for reducing NSP activity levels and improving COPD outcomes, supported by the approval of the DPP1 inhibitor brenscotib for the treatment of bronchiectasis (an airway inflammatory disease similar to COPD).

[0051] Noncystic fibrotic bronchiectasis (NCFBE), also known as bronchiectasis, is caused by recurrent purulent infections of various etiologies. These infections lead to repeated damage and / or obstruction of small and medium-sized bronchi and destruction of bronchial structure, resulting in persistent, abnormal bronchiectasis. Its etiologies are complex and diverse, including persistent bacterial infection, immune dysregulation, dysfunction of the mucociliary clearance system, abnormal bronchiectasis caused by airway mucus obstruction, and chronic inflammation. Clinical manifestations include persistent or recurrent cough and sputum production, sometimes accompanied by hemoptysis, which can lead to respiratory dysfunction and chronic cor pulmonale.

[0052] Bronchiectasis is a common chronic respiratory condition with a long course and irreversible damage. It can severely impair lung tissue and function, affecting patients' quality of life and imposing a heavy socioeconomic burden. The co-occurrence of bronchiectasis with other lung conditions is also a significant concern. Approximately 15% to 30% of patients with chronic bronchitis or COPD also have bronchiectasis, and up to 50% of patients with bronchiectasis have severe COPD.

[0053] Current standards of clinical care for bronchiectasis include non-pharmacological, pharmacological, and surgical treatments. Despite recommended treatments outlined in guidelines, patients with bronchiectasis still experience recurrent acute exacerbations. Therefore, there is an urgent need for new treatment strategies aimed at slowing disease progression, reducing the frequency of acute exacerbations, and improving lung function.

[0054] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have, for the first time, provided a new crystal form of compound (I), its preparation method, and its applications. Based on this, the present invention was completed. Compound (I)

[0055] Compound (I) is an orally effective small molecule inhibitor of dipeptidyl peptidase-1 (DPP1). Compared to other classes of drugs used to treat airway inflammation, compound (I) shows promise in avoiding the problems of antibiotic resistance and the safety risks associated with corticosteroids. In some implementations, administration of compound (I) reduces the frequency of acute exacerbations seen in COPD and bronchiectasis, slows the progression of airway dilatation, improves patients' clinical symptoms and quality of life, and is expected to fill the gap in long-term treatments for these indications.

[0056] The object of the present invention is to provide a new crystal form of the compound of formula (I), wherein the crystal form is A, B, C, D or E.

[0057] The present invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200° and 20.673±0.200°;

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 20.673±0.200° and 24.134±0.200°.

[0059] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 20.673±0.200° and 24.134±0.200°.

[0060] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 20.673±0.200°, and 24.134±0.200°.

[0061] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 20.673±0.200°, 23.513±0.200°, and 24.134±0.200°.

[0062] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 19.863±0.200°, 20.673±0.200°, 23.025±0.200°, 23.513±0.200°, and 24.134±0.200°.

[0063] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.672±0.200°, 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550± 0.200°, 18.110±0.200°, 18.484±0.200°, 19.863±0.200°, 20.673±0.200°, 23.025±0.200°, 23.513±0.200°, 24.134±0.200°, 25.621±0.200° and 26.924±0.200°.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.672±0.100°, 10.267±0.100°, 11.716±0.100°, 13.822±0.100°, 15.236±0.100°, 16.899±0.100°, 17.550± 0.100°, 18.110±0.100°, 18.484±0.100°, 19.863±0.100°, 20.673±0.100°, 23.025±0.100°, 23.513±0.100°, 24.134±0.100°, 25.621±0.100° and 26.924±0.100°.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.889±0.200°, 6.954±0.200°, 7.672±0.200°, 9.110±0.200°, 10.267±0.200°, 11.716±0.200°, 13.367±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, and 18.484±0.2. 00°, 18.813±0.200°, 19.863±0.200°, 20.673±0.200°, 21.748±0.200°, 22.433±0.200°, 23.025±0.200°, 23.513±0.200°, 24.134±0.200°, 24.563±0.200°, 25.621±0.200°, 26.403±0.200°, 26.924±0.200°, 27.775±0.200°, 28.336±0.200°, 29.197±0.200°, 30 0.076±0.200°, 30.822±0.200°, 31.926±0.200°, 33.208±0.200°, 33.423±0.200°, 34.209±0.200°, 34.748±0.200°, 35.427±0.200°, 36.157±0.200°, 36.701±0.200°, 37.391±0.200°, 38.174±0.200°, 38.426±0.200°, 39.734±0.200°, 39.988±0.200°, 40.731±0 .200°, 41.079±0.200°, 42.194±0.200°, 43.590±0.200°, 44.030±0.200°, 44.489±0.200°, 45.700±0.200°, 46.652±0.200°, 46.968±0.200°, 48.017±0.200°, 49.638±0.200°, 50.604±0.200°, 54.563±0.200°, 55.180±0.200°, 56.460±0.200°, 57.287±0.200°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.889±0.100°, 6.954±0.100°, 7.672±0.100°, 9.110±0.100°, 10.267±0.100°, 11.716±0.100°, 13.367±0.100°, 13.822±0.100°, 15.236±0.100°, 16.899±0.100°, 17.550±0.100°, 18.110±0.100°, and 18.484±0.1. 00°, 18.813±0.100°, 19.863±0.100°, 20.673±0.100°, 21.748±0.100°, 22.433±0.100°, 23.025±0.100°, 23.513±0.100°, 24.134±0.100°, 24.563±0.100°, 25.621±0.100°, 26.403±0.100°, 26.924±0.100°, 27.775±0.100°, 28.336±0.100°, 29.197±0.100°, 30 0.076±0.100°, 30.822±0.100°, 31.926±0.100°, 33.208±0.100°, 33.423±0.100°, 34.209±0.100°, 34.748±0.100°, 35.427±0.100°, 36.157±0.100°, 36.701±0.100°, 37.391±0.100°, 38.174±0.100°, 38.426±0.100°, 39.734±0.100°, 39.988±0.100°, 40.731±0 0.100°, 41.079±0.100°, 42.194±0.100°, 43.590±0.100°, 44.030±0.100°, 44.489±0.100°, 45.700±0.100°, 46.652±0.100°, 46.968±0.100°, 48.017±0.100°, 49.638±0.100°, 50.604±0.100°, 54.563±0.100°, 55.180±0.100°, 56.460±0.100°, 57.287±0.100°.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and / or 20.673±0.200°, and / or 5.889±0.200°, and / or 6.954±0.200°, and / or 7.672±0.200°, and / or 9.110±0.200°, and / or 10.267±0.200°, and / or 11.716±0.200°, and / or 13.367±0.200°, and / or 17.550±0.200°, and / or 18.110±0.200°. °, and / or 18.484±0.200°, and / or 18.813±0.200°, and / or 19.863±0.200°, and / or 21.748±0.200°, and / or 22.433±0.200°, and / or 23.025±0.200°, and / or 23.513±0.200°, and / or 24.134±0.200°, and / or 24.563±0.200°, and / or 25.621±0.200°, and / or 26.403±0.200°, and / or 26.924±0.200°, and / or 27.775±0.200°, and / or 28.336±0.200°, and / or 29.19 7±0.200°, and / or 30.076±0.200°, and / or 30.822±0.200°, and / or 31.926±0.200°, and / or 33.208±0.200°, and / or 33.423±0.200°, and / or 34.209±0.200°, and / or 34.748±0.2 00°, and / or 35.427±0.200°, and / or 36.157±0.200°, and / or 36.701±0.200°, and / or 37.391±0.200°, and / or 38.174±0.200°, and / or 38.426±0.200°, and / or 39.734±0.200°, and / or 39.988±0.200°, and / or 40.731±0.200°, and / or 41.079±0.200°, and / or 42.194±0.200°, and / or 43.590±0.200°, and / or 44.030±0.200°, and / or 44.489±0.200°, and / or 45. 700±0.200°, and / or 46.652±0.200°, and / or 46.968±0.200°, and / or 48.017±0.200°, and / or 49.638±0.200°, and / or 50.604±0.200°, and / or 54.563±0.200°, and / or 55.180±0.200°, and / or 56.460±0.200°, and / or 57.287±0.200°.

[0068] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 13.822±0.100°, 15.236±0.100°, 16.899±0.100°, and / or 20.673±0.100°, and / or 5.889±0.100°, and / or 6.954±0.100°, and / or 7.672±0.100°, and / or 9.110±0.100°, and / or 10.267±0.100°, and / or 11.716±0.100°, and / or 13.367±0.100°, and / or 17.550±0.100°, and / or 18.110±0.100°. °, and / or 18.484±0.100°, and / or 18.813±0.100°, and / or 19.863±0.100°, and / or 21.748±0.100°, and / or 22.433±0.100°, and / or 23.025±0.100°, and / or 23.513±0.100°, and / or 24.134±0.100°, and / or 24.563±0.100°, and / or 25.621±0.100°, and / or 26.403±0.100°, and / or 26.924±0.100°, and / or 27.775±0.100°, and / or 28.336±0.100°, and / or 29.19 7±0.100°, and / or 30.076±0.100°, and / or 30.822±0.100°, and / or 31.926±0.100°, and / or 33.208±0.100°, and / or 33.423±0.100°, and / or 34.209±0.100°, and / or 34.748±0.1 00°, and / or 35.427±0.100°, and / or 36.157±0.100°, and / or 36.701±0.100°, and / or 37.391±0.100°, and / or 38.174±0.100°, and / or 38.426±0.100°, and / or 39.734±0.100°, and / or 39.988±0.100°, and / or 40.731±0.100°, and / or 41.079±0.100°, and / or 42.194±0.100°, and / or 43.590±0.100°, and / or 44.030±0.100°, and / or 44.489±0.100°, and / or 45. 700±0.100°, and / or 46.652±0.100°, and / or 46.968±0.100°, and / or 48.017±0.100°, and / or 49.638±0.100°, and / or 50.604±0.100°, and / or 54.563±0.100°, and / or 55.180±0.100°, and / or 56.460±0.100°, and / or 57.287±0.100°.

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.889°, 6.954°, 7.672°, 9.110°, 10.267°, 11.716°, 13.367°, 13.822°, 15.236°, 16.899°, 17.550°, 18.110°, 18.484°, 18.813°, 19.863°, 20.673°, 21.748°, 22.433°, 23.025°, 23.513°, 24.134°, 24.563°, 25.621°, 26.403°, 26.924°, 27.775°, 28.336°, 2 9.197°, 30.076°, 30.822°, 31.926°, 33.208°, 33.423°, 34.209°, 34.748°, 35.427°, 36.157°, 36.701°, 37.391°, 38.174°, 38.426°, 39.734°, 39.988° 40.731°, 41.079°, 42.194°, 43.590°, 44.030°, 44.489°, 45.700°, 46.652°, 46.968°, 48.017°, 49.638°, 50.604°, 54.563°, 55.180°, 56.460°, and 57.287°.

[0070] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned A-form are shown in Table 1. Table 1 XRPD analysis data of the A-form of compound (I)

[0071] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A crystal form is basically as shown in Figure 1.

[0072] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned A crystal form has a peak value of an endothermic peak at 141.01±3℃.

[0073] In some embodiments of the present invention, the DSC spectrum of the above-mentioned A crystal form is basically as shown in Figure 2.

[0074] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned A crystal form shows a weight loss of 0.040% at 150.0±3℃.

[0075] In some embodiments of the present invention, the TGA spectrum of the above-mentioned A crystal form is basically as shown in Figure 3.

[0076] In some embodiments of the present invention, the A-crystal form of the compound of formula (I) substantially does not contain other solid forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the B, C, D, and / or E-crystal forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the B-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the C-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the D-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the E-crystal form of the compound of formula (I). In some embodiments, the above-mentioned A crystal form of the compound of formula (I) comprises less than 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.0%, 1.5%, 2%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% (w / w) of the B, C, D, and / or E crystal forms of the compound of formula (I). In some embodiments, the above-mentioned A crystal form of the compound of formula (I) comprises less than 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, or 1.0% (w / w) of the B, C, D, and / or E crystal forms of the compound of formula (I). In some embodiments, the aforementioned A crystal form of the compound of formula (I) comprises no more than 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.0%, 1.5%, 2%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% (w / w) of the B, C, D, and / or E crystal forms of the compound of formula (I). In some embodiments, the aforementioned crystal form A of the compound of formula (I) comprises no more than 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, or 1.0% (w / w) of crystal forms B, C, D, and / or E of the compound of formula (I). In some embodiments, detection is performed by XRPD, DSC, TGA, etc.

[0077] In some embodiments of the present invention, the A-crystal form of the compound of formula (I) substantially does not contain other solid forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the B, C, D, and / or E-crystal forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the B-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the C-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the D-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) substantially does not contain the E-crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain detectable amounts of the B, C, D, and / or E-crystal forms of the compound of formula (I). In some embodiments, detection is performed by XRPD, DSC, TGA, etc.

[0078] In some embodiments of the present invention, the A-crystal form of the compound of formula (I) does not contain other solid forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain the B, C, D, and / or E crystal forms of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain the B crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain the C crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain the D crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain the E crystal form of the compound of formula (I). In some embodiments, the A-crystal form of the compound of formula (I) does not contain detectable amounts of the B, C, D, and / or E crystal forms of the compound of formula (I). In some embodiments, detection is performed by XRPD, DSC, TGA, etc.

[0079] In some embodiments of the present invention, the above-mentioned crystal form A is amorphous.

[0080] The present invention also provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.954±0.200°, 13.530±0.200°, 15.480±0.200° and 18.122±0.200°;

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.396±0.200°, 7.598±0.200°, 8.954±0.200°, 9.987±0.200°, 13.530±0.200°, 15.054±0.200°, 15.480±0.200°, 17.549±0.200°, 18.122±0.200°, 19.604±0.200°, 22.535±0.200°, 27.395±0.200°, 31.079±0.200°, 35.470±0.200°, and 36.859±0.200°.

[0082] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.954±0.200°, 13.530±0.200°, and / or 15.480±0.200°, and / or 18.122±0.200°, and / or 4.396±0.200°, and / or 7.598±0.200°, and / or 9.987 ±0.200°, and / or 15.054±0.200°, and / or 17.549±0.200°, and / or 19.604±0.200°, and / or 22.535±0.200°, and / or 27.395±0.200°, and / or 31.079±0.200°, and / or 35.470±0.200°, and / or 36.859±0.200°.

[0083] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.396°, 7.598°, 8.954°, 9.987°, 13.530°, 15.054°, 15.480°, 17.549°, 18.122°, 19.604°, 22.535°, 27.395°, 31.079°, 35.470°, and 36.859°.

[0084] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned B crystal form are shown in Table 2. Table 2 XRPD analysis data of the B crystal form of compound (I)

[0085] In some embodiments of the present invention, the XRPD pattern of the B crystal form is basically as shown in Figure 4.

[0086] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has a peak value of endothermic peak at 221.82±3℃.

[0087] In some embodiments of the present invention, the DSC pattern of the B crystal form is basically as shown in Figure 5.

[0088] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned B crystal form shows a weight loss of 1.056% at 100.00±3℃.

[0089] In some embodiments of the present invention, the TGA spectrum of the B crystal form is basically as shown in Figure 6.

[0090] The present invention also provides the C crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200° and 19.812±0.200°;

[0091] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200°, 13.988±0.200°, 15.873±0.200°, 19.812±0.200°, and 22.076±0.200°.

[0092] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.200°, 9.557±0.200°, 11.606±0.200°, 13.120±0.200°, 13.988±0.200°, 15.873±0.200°, 16.314±0.200°, 19.812±0.200°, 20.416±0.200°, and 22.076±0.200°.

[0093] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.478±0.200°, 8.069±0.200°, 9.557±0.200°, 11.606±0.200°, 13.120±0.200°, 13.988±0.200°, 15.873±0.200°, 16.314±0.200°, 17.312±0.200°, 17.900±0.200°, 18.287±0.200°, 19.349±0.200°. 0.200°, 19.812±0.200°, 20.416±0.200°, 21.116±0.200°, 22.076±0.200°, 22.673±0.200°, 23.464±0.200°, 23.807±0.200°, 24.271±0.200°, 24.637±0.200°, 26.569±0.200°, 26.988±0.200°, 28.326±0.200°, 30.416±0.200° and 33.799±0.200°.

[0094] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.478±0.100°, 8.069±0.100°, 9.557±0.100°, 11.606±0.100°, 13.120±0.100°, 13.988±0.100°, 15.873±0.100°, 16.314±0.100°, 17.312±0.100°, 17.900±0.100°, 18.287±0.100°, 19.349±0.100°. 0.100°, 19.812±0.100°, 20.416±0.100°, 21.116±0.100°, 22.076±0.100°, 22.673±0.100°, 23.464±0.100°, 23.807±0.100°, 24.271±0.100°, 24.637±0.100°, 26.569±0.100°, 26.988±0.100°, 28.326±0.100°, 30.416±0.100° and 33.799±0.100°.

[0095] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200°, and / or 6.478±0.200°, and / or 9.557±0.200°, and / or 13.988±0.200°, and / or 15.873±0.200°, and / or 16.314±0.200°, and / or 17.312±0.200°, and / or 17.900±0.200°, and / or 18.287±0.200°, and / or 19.349±0.200°, and / Or 19.812±0.200°, and / or 20.416±0.200°, and / or 21.116±0.200°, and / or 22.076±0.200°, and / or 22.673±0.200°, and / or 23.464±0.200°, and / or 23.807±0.200°, and / or 24.271±0.200°, and / or 24.637±0.200°, and / or 26.569±0.200°, and / or 26.988±0.200°, and / or 28.326±0.200°, and / or 30.416±0.200°, and / or 33.799±0.200°.

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.100°, 11.606±0.100°, 13.120±0.100°, and / or 6.478±0.100°, and / or 9.557±0.100°, and / or 13.988±0.100°, and / or 15.873±0.100°, and / or 16.314±0.100°, and / or 17.312±0.100°, and / or 17.900±0.100°, and / or 18.287±0.100°, and / or 19.349±0.100°, and / Or 19.812±0.100°, and / or 20.416±0.100°, and / or 21.116±0.100°, and / or 22.076±0.100°, and / or 22.673±0.100°, and / or 23.464±0.100°, and / or 23.807±0.100°, and / or 24.271±0.100°, and / or 24.637±0.100°, and / or 26.569±0.100°, and / or 26.988±0.100°, and / or 28.326±0.100°, and / or 30.416±0.100°, and / or 33.799±0.100°.

[0097] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.478°, 8.069°, 9.557°, 11.606°, 13.120°, 13.988°, 15.873°, 16.314°, 17.312°, 17.900°, 18.287°, 19.349°, 19.812°, 20.416°, 21.116°, 22.076°, 22.673°, 23.464°, 23.807°, 24.271°, 24.637°, 26.569°, 26.988°, 28.326°, 30.416°, and 33.799°.

[0098] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned C-form are shown in Table 3. Table 3 XRPD analysis data of the C-form of compound (I)

[0099] In some embodiments of the present invention, the XRPD pattern of the C crystal form is basically as shown in Figure 7.

[0100] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned C crystal form have endothermic peaks at 78.70±3℃ and 140.29±3℃.

[0101] In some embodiments of the present invention, the DSC pattern of the above-mentioned C crystal form is basically as shown in Figure 8.

[0102] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned C crystal form shows a weight loss of 6.495% at 100.00±3℃.

[0103] In some embodiments of the present invention, the TGA pattern of the above-mentioned C crystal form is basically as shown in Figure 9.

[0104] In some embodiments of the present invention, the above-mentioned C crystal form is an ethanol solvate crystal form.

[0105] The present invention also provides the D crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.105±0.200°, 15.206±0.200° and 16.904±0.200°;

[0106] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 9.105±0.200°, 9.751±0.200°, 13.745±0.200°, 15.206±0.200°, 16.904±0.200° and 18.075±0.200°.

[0107] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.105±0.200°, 9.751±0.200°, 13.745±0.200°, 14.031±0.200°, 15.206±0.200°, 16.904±0.200°, 17.316±0.200°, 18.075±0.200°, 18.381±0.200°, 22.434±0.200°, and 22.659±0.200°.

[0108] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.105±0.100°, 9.751±0.100°, 13.745±0.100°, 14.031±0.100°, 15.206±0.100°, 16.904±0.100°, 17.316±0.100°, 18.075±0.100°, 18.381±0.100°, 22.434±0.100°, and 22.659±0.100°.

[0109] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.105±0.200°, 9.751±0.200°, 11.830±0.200°, 13.745±0.200°, 14.031±0.200°, 15.206±0.200°, 16.171±0.200°, 16.904±0.200°, 17.316±0.200°, 18.075±0.200°, 18.381±0.200°, 18.825±0.200°, 22.434±0.200°, 22.659±0.200°, and 27.269±0.200°.

[0110] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.105±0.100°, 9.751±0.100°, 11.830±0.100°, 13.745±0.100°, 14.031±0.100°, 15.206±0.100°, 16.171±0.100°, 16.904±0.100°, 17.316±0.100°, 18.075±0.100°, 18.381±0.100°, 18.825±0.100°, 22.434±0.100°, 22.659±0.100°, and 27.269±0.100°.

[0111] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.477±0.200°, 7.374±0.200°, 8.218±0.200°, 9.105±0.200°, 9.751±0.200°, 10.371±0.200°, 11.830±0.200°, 12.113±0.200°, 13. 351±0.200°, 13.745±0.200°, 14.031±0.200°, 15.206±0.200°, 15.361±0.200°, 16.171±0.200°, 16.672±0.200°, 16.904±0.200°, 17.316±0.200°, 18.075±0.200°, 18.381±0.200°, 18 0.825±0.200°, 19.690±0.200°, 20.141±0.200°, 20.449±0.200°, 21.349±0.200°, 22.434±0.200°, 22.659±0.200°, 23.294±0.200°, 23.692±0.200°, 24.482±0.200°, 25.049±0.200°, 2 5.805±0.200°, 26.062±0.200°, 26.812±0.200°, 27.269±0.200°, 28.229±0.200°, 28.586±0.200°, 30.933±0.200°, 32.633±0.200°, 33.574±0.200°, 34.384±0.200° and 39.672±0.200°.

[0112] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.477±0.100°, 7.374±0.100°, 8.218±0.100°, 9.105±0.100°, 9.751±0.100°, 10.371±0.100°, 11.830±0.100°, 12.113±0.100°, 13. 351±0.100°, 13.745±0.100°, 14.031±0.100°, 15.206±0.100°, 15.361±0.100°, 16.171±0.100°, 16.672±0.100°, 16.904±0.100°, 17.316±0.100°, 18.075±0.100°, 18.381±0.100°, 18 0.825±0.100°, 19.690±0.100°, 20.141±0.100°, 20.449±0.100°, 21.349±0.100°, 22.434±0.100°, 22.659±0.100°, 23.294±0.100°, 23.692±0.100°, 24.482±0.100°, 25.049±0.100°, 2 5.805±0.100°, 26.062±0.100°, 26.812±0.100°, 27.269±0.100°, 28.229±0.100°, 28.586±0.100°, 30.933±0.100°, 32.633±0.100°, 33.574±0.100°, 34.384±0.100° and 39.672±0.100°.

[0113] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200°, and / or 6.478±0.200°, and / or 9.557±0.200°, and / or 13.988±0.200°, and / or 15.873±0.200°, and / or 16.314±0.200°, and / or 17.312±0.200°, and / or 17.900±0.200°, and / or 18.287±0.200°, and / or 19.349±0.200°, and / Or 19.812±0.200°, and / or 20.416±0.200°, and / or 21.116±0.200°, and / or 22.076±0.200°, and / or 22.673±0.200°, and / or 23.464±0.200°, and / or 23.807±0.200°, and / or 24.271±0.200°, and / or 24.637±0.200°, and / or 26.569±0.200°, and / or 26.988±0.200°, and / or 28.326±0.200°, and / or 30.416±0.200°, and / or 33.799±0.200°.

[0114] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.069±0.100°, 11.606±0.100°, 13.120±0.100°, and / or 6.478±0.100°, and / or 9.557±0.100°, and / or 13.988±0.100°, and / or 15.873±0.100°, and / or 16.314±0.100°, and / or 17.312±0.100°, and / or 17.900±0.100°, and / or 18.287±0.100°, and / or 19.349±0.100°, and / or Or 19.812±0.100°, and / or 20.416±0.100°, and / or 21.116±0.100°, and / or 22.076±0.100°, and / or 22.673±0.100°, and / or 23.464±0.100°, and / or 23.807±0.100°, and / or 24.271±0.100°, and / or 24.637±0.100°, and / or 26.569±0.100°, and / or 26.988±0.100°, and / or 28.326±0.100°, and / or 30.416±0.100°, and / or 33.799±0.100°.

[0115] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.477°, 7.374°, 8.218°, 9.105°, 9.751°, 10.371°, 11.830°, 12.113°, 13.351°, 13.745°, 14.031°, 15.206°, 15.361°, 16.171°, 16.672°, 16.904°, 17.316°, 18.075°, 1 8.381°, 18.825°, 19.690°, 20.141°, 20.449°, 21.349°, 22.434°, 22.659°, 23.294°, 23.692°, 24.482°, 25.049°, 25.805°, 26.062°, 26.812°, 27.269°, 28.229°, 28.586°, 30.933°, 32.633°, 33.574°, 34.384°, and 39.672°.

[0116] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned D crystal form are shown in Table 4. Table 4 XRPD analysis data of the D crystal form of compound (I)

[0117] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form is basically as shown in Figure 10.

[0118] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned D crystal form have endothermic peaks at 88.63±3℃ and 140.53±3℃.

[0119] In some embodiments of the present invention, the DSC pattern of the above-mentioned D crystal form is basically as shown in Figure 11.

[0120] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned D crystal form shows a weight loss of 2.273% at 120.00±3℃.

[0121] In some embodiments of the present invention, the TGA pattern of the above-mentioned D crystal form is basically as shown in Figure 12.

[0122] In some embodiments of the present invention, the above-mentioned D crystal form is a hydrate.

[0123] The present invention also provides the E crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200° and 15.214±0.200°;

[0124] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, 15.214±0.200°, 15.988±0.200°, and 16.749±0.200°.

[0125] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, 15.214±0.200°, 15.988±0.200°, 16.749±0.200°, and 20.522±0.200°.

[0126] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, 13.671±0.200°, 15.214±0.200°, 15.988±0.200°, 16.749±0.200°, 17.932±0.200°, and 20.522±0.200°.

[0127] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.876±0.200°, 9.331±0.200°, 10.126±0.200°, 12.051±0.200°, 13.671±0.200°, 15.214±0.200°, 15.988±0.200°, 16.749±0.200°, 17.932±0.200°, 20.522±0.200°, 22.933±0.200°, and 23.443±0.200°.

[0128] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.539±0.200°, 8.876±0.200°, 9.331±0.200°, 10.126±0.200°, 11.566±0.200°, 12.051±0.200°, 13.169±0.200°, 13.671±0.200°, 15.214±0.200°, 15.988±0.200°, 16.749±0.200°, 17.398±0.200°, 17.932±0.200°, 18.823±0.200°, 19.722±0.200°, 2 0.522±0.200°, 20.819±0.200°, 21.288±0.200°, 22.933±0.200°, 23.443±0.200°, 24.005±0.200°, 24.364±0.200°, 24.861±0.200°, 26.357±0.200° 27.064±0.200°, 27.606±0.200°, 28.189±0.200°, 29.117±0.200°, 29.932±0.200°, 30.932±0.200°, 32.265±0.200°, 33.273±0.200° and 34.094±0.200°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.539±0.100°, 8.876±0.100°, 9.331±0.100°, 10.126±0.100°, 11.566±0.100°, 12.051±0.100°, 13.169±0.100°, 13.671±0.100°, 15.214±0.100°, 15.988±0.100°, 16.749±0.100°, 17.398±0.100°, 17.932±0.100°, 18.823±0.100°, 19.722±0.100°, 2 0.522±0.100°, 20.819±0.100°, 21.288±0.100°, 22.933±0.100°, 23.443±0.100°, 24.005±0.100°, 24.364±0.100°, 24.861±0.100°, 26.357±0.100° 27.064±0.100°, 27.606±0.100°, 28.189±0.100°, 29.117±0.100°, 29.932±0.100°, 30.932±0.100°, 32.265±0.100°, 33.273±0.100° and 34.094±0.100°.

[0130] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, 15.214±0.200°, and / or 7.539±0.200°, and / or 8.876±0.200°, and / or 10.126±0.200°, and / or 11.566±0.200°. °, and / or 13.169±0.200°, and / or 13.671±0.200°, and / or 15.988±0.200°, and / or 16.749±0.200°, and / or 17.398±0.200°, and / or 17.932±0.200°, and / or 18.823±0.200°, and / or 19.722±0.200°, and / or 20.522± 0.200°, and / or 20.819±0.200°, and / or 21.288±0.200°, and / or 22.933±0.200°, and / or 23.443±0.200°, and / or 24.005±0.200°, and / or 24.364±0.200°, and / or 24.861±0.200°, and / or 26.357±0.200°, and / or 27 0.064±0.200°, and / or 27.606±0.200°, and / or 28.189±0.200°, and / or 29.117±0.200°, and / or 29.932±0.200°, and / or 30.932±0.200°, and / or 32.265±0.200°, and / or 33.273±0.200°, and / or 34.094±0.200°.

[0131] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.331±0.100°, 12.051±0.100°, 15.214±0.100°, and / or 7.539±0.100°, and / or 8.876±0.100°, and / or 10.126±0.100°, and / or 11.566±0.100°. °, and / or 13.169±0.100°, and / or 13.671±0.100°, and / or 15.988±0.100°, and / or 16.749±0.100°, and / or 17.398±0.100°, and / or 17.932±0.100°, and / or 18.823±0.100°, and / or 19.722±0.100°, and / or 20.522± 0.100°, and / or 20.819±0.100°, and / or 21.288±0.100°, and / or 22.933±0.100°, and / or 23.443±0.100°, and / or 24.005±0.100°, and / or 24.364±0.100°, and / or 24.861±0.100°, and / or 26.357±0.100°, and / or 27 0.064±0.100°, and / or 27.606±0.100°, and / or 28.189±0.100°, and / or 29.117±0.100°, and / or 29.932±0.100°, and / or 30.932±0.100°, and / or 32.265±0.100°, and / or 33.273±0.100°, and / or 34.094±0.100°.

[0132] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.539°, 8.876°, 9.331°, 10.126°, 11.566°, 12.051°, 13.169°, 13.671°, 15.214°, 15.988°, 16.749°, 17.398°, 17.932°, 18.823°. 19.722°, 20.522°, 20.819°, 21.288°, 22.933°, 23.443°, 24.005°, 24.364°, 24.861°, 26.357°, 27.064°, 27.606°, 28.189°, 29.117°, 29.932°, 30.932°, 32.265°, 33.273° and 34.094°.

[0133] In some embodiments of the present invention, the XRPD spectral analysis data of the above-mentioned E-crystal form are shown in Table 5. Table 5 XRPD analysis data of the E-crystal form of compound (I)

[0134] In some embodiments of the present invention, the E crystal form of the compound of formula (I) above has an XRPD spectrum that is basically as shown in Figure 13.

[0135] In some embodiments of the present invention, the E crystal form of the compound of formula (I) above has a peak value of exothermic at 96.78±3℃ and a peak value of endothermic at 140.12±3℃ in its differential scanning calorimetry curve.

[0136] In some embodiments of the present invention, the E crystal form of the compound of formula (I) above has a DSC spectrum that is basically as shown in Figure 14.

[0137] In some embodiments of the present invention, the E crystal form of the compound of formula (I) above has a thermogravimetric analysis curve showing a weight loss of 0.293% at 100.00±3℃.

[0138] In some embodiments of the present invention, the E crystal form of the compound of formula (I) above has a TGA spectrum that is basically as shown in Figure 15.

[0139] In some embodiments of the present invention, the E crystal form of the compound of formula (I) is an anhydrous hydrate.

[0140] In a second aspect, the present invention provides a pharmaceutical composition comprising: a crystal form according to any one or more of the present invention, and a pharmaceutically acceptable carrier.

[0141] In some embodiments of the present invention, the crystal form is crystal form A.

[0142] On the other hand, the present invention also provides the application of the crystal form of the above-mentioned compound (I) in the preparation of DPP1 inhibitors.

[0143] On the other hand, the present invention also provides the application of the A crystal form of the above-mentioned compound (I) in the preparation of DPP1 inhibitors.

[0144] On the other hand, the present invention also provides the use of the crystal form of the compound of formula (I) in the preparation of a medicament for the prevention or treatment of diseases related to DPP1.

[0145] In some embodiments of the present invention, the disease associated with DPP1 is chronic obstructive pulmonary disease.

[0146] On the other hand, the present invention also provides the use of the A crystal form of the above-mentioned compound (I) in the preparation of a medicament for the prevention or treatment of diseases related to DPP1.

[0147] On the other hand, the present invention also provides a method for preventing or treating DPP1-related diseases in subjects who require it, comprising providing the subjects with an effective dose of the crystal form of the compound of formula (I) above.

[0148] On the other hand, the present invention also provides a method for preventing or treating DPP1-related diseases in subjects who require it, comprising providing the subjects with an effective dose of the A crystal form of the compound of formula (I) above.

[0149] On the other hand, the present invention also provides the use of the crystal form of the compound of formula (I) in the prevention or treatment of diseases related to DPP1.

[0150] On the other hand, the present invention also provides crystal form A of the compound of formula (I) above for the prevention or treatment of DPP1-related diseases.

[0151] On the other hand, the present invention also provides a method for preparing the A crystal form of the compound of formula (I), characterized by comprising the steps of: stirring the compound of formula (I) in a mixed solvent of isopropanol and water until a solid precipitates, filtering, and drying at 20-45°C (preferably 30-40°C) to obtain the A crystal form.

[0152] In another preferred embodiment, the stirring is carried out at 40-55°C (preferably 45-50°C) for 1-6 hours (preferably 2-4 hours), and then cooled to 15-30°C (preferably 20-25°C) and stirred for 0.5-3 hours (preferably 1-2 hours).

[0153] In another preferred embodiment, the drying is vacuum drying.

[0154] In another preferred embodiment, the volume ratio of isopropanol to water in the mixed solvent is 10-20:1, more preferably 14-16:1.

[0155] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I) to the mixed solvent is 20-100 g / L, more preferably 30-80 g / L, and even more preferably 50-70 g / L.

[0156] On the other hand, the present invention also provides a method for preparing the B crystal form of the compound of formula (I), characterized by comprising the steps of: stirring the compound of formula (I) in ethyl acetate until a solid precipitates, filtering, and purging the obtained solid with nitrogen gas (2-6 h) to obtain the B crystal form.

[0157] In another preferred embodiment, the stirring is carried out at 40-55°C (preferably 45-50°C) for 1-5 days (preferably 2-4 days).

[0158] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I) to ethyl acetate is 20-80 g / L, more preferably 30-60 g / L, and even more preferably 40-50 g / L.

[0159] On the other hand, the present invention also provides a method for preparing the C crystal form of the compound of formula (I), characterized by comprising the steps of: providing an ethanol solution of the compound of formula (I), cooling it to -8 to -20°C (preferably -10 to -15°C) and stirring until a solid precipitates, filtering, and purging the obtained solid with nitrogen gas (2-6 h) to obtain the C crystal form.

[0160] In another preferred embodiment, the stirring time is 10-30 hours, preferably 16-24 hours.

[0161] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I) to ethanol is 20-80 g / L, more preferably 30-60 g / L, and even more preferably 40-50 g / L.

[0162] On the other hand, the present invention also provides a method for preparing the D crystal form of the compound of formula (I), characterized by comprising the steps of: providing a methanol solution of the compound of formula (I), and then slowly evaporating it at 15-30°C (preferably 18-22°C) to obtain the D crystal form.

[0163] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I) to methanol is 10-80 g / L, more preferably 20-60 g / L, and even more preferably 30-40 g / L.

[0164] On the other hand, the present invention also provides a method for preparing the E crystal form of the compound of formula (I), characterized by comprising the steps of: providing an ethanol solution of the compound of formula (I), cooling it to -8 to 20°C (preferably -10 to 15°C) until a solid precipitates, filtering it, and drying the obtained solid at 40 to 55°C (preferably 30 to 40°C) to obtain the E crystal form.

[0165] In another preferred embodiment, the stirring time is 10-30 hours, preferably 16-24 hours.

[0166] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I) to ethanol is 20-80 g / L, more preferably 20-60 g / L, and even more preferably 30-40 g / L.

[0167] A method for preparing crystal form E, characterized by comprising the step of drying crystal form C at 40-55℃ (preferably 30-40℃) to obtain crystal form E. It should be understood that, within the scope of this invention, the above-mentioned technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to constitute new or preferred technical solutions. Due to space limitations, they will not be elaborated upon here. Certain terms...

[0168] The chapter titles used in this document are for organizational purposes only and should not be construed as limiting the subject matter.

[0169] Unless otherwise stated, the following terms used in this application have the definitions given below.

[0170] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0171] As used herein, the terms “contain,” “include,” “includes,” or “included” are non-restrictive.

[0172] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0173] Unless otherwise stated, X-ray powder diffraction (XRPD) is a commonly used method for identifying crystals, detecting changes in crystallinity, crystallinity, and crystal structure. The peak positions in XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, for any given crystal form, the relative intensity of diffraction peaks can change due to preferred orientations caused by factors such as crystal morphology, which is well-known in crystallography. Where preferred orientations are present, peak intensities change, but the diffraction peak positions of the crystal cannot be altered. Furthermore, for any given crystal, the peak positions may have slight errors, which is also well-known in crystallography. For example, peak positions can shift due to temperature changes during sample analysis, sample movement, or instrument calibration. The measurement error of the 2θ value is sometimes approximately ±0.2 degrees. The measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples; therefore, the stated 2θ value should not be considered absolute. Therefore, those skilled in the art will understand that this error should be taken into account when determining each crystal structure. Thus, in some embodiments, the crystals of the present invention are characterized by XRPD plots with certain peak positions, which are substantially as shown in the XRPD plots provided in the accompanying drawings.

[0174] DSC determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystalline structure or melting. For the same crystal of the same compound, the error in thermal transition temperature and melting point is typically within about 5°C in consecutive analyses. When we say a compound has a given DSC peak or melting point, we mean that DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline morphologies can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0175] As used herein, the terms “treat,” “treating,” or “treatment” include preventing and / or therapeutically reducing, alleviating, or improving at least one symptom of a disease or condition, preventing other symptoms, suppressing a disease or condition, such as preventing its development, alleviating a disease or condition, causing a disease or condition to subside, preventing the progression of a disease or condition, relieving the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0176] The term “prevention” means administering the compound or preparation of the present invention to prevent one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0177] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0178] In this article, the term “acceptable” as used with respect to formulations, compositions or ingredients means that it will not have a lasting harmful effect on the overall health of the mammal being treated.

[0179] As used herein, the terms “administer,” “administering,” “administration,” etc., refer to methods that deliver a compound or composition to the site of desired biological action. These methods include, but are not limited to, oral administration and parenteral administration (including intravenous, subcutaneous, or infusion). Those skilled in the art are familiar with the administration techniques employed for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0180] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees), and other ape and monkey species. In one respect, the mammal is the human.

[0181] As used herein, the term "effective amount" or "therapeutic effective amount" means an adequate amount of a drug or compound administered that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition containing a compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. In any specific case, the appropriate "effective" amount may optionally be determined using techniques such as dose-escalation studies.

[0182] In some embodiments, a “therapeutic effective amount” refers to an amount of compound of formula (I) administered to a person sufficient or effective to treat (e.g., prevent, slow progression, reduce severity) a disease associated with elevated NSP enzyme activity, including relieving symptoms of such disease or reducing the severity of such symptoms. In some embodiments, a “therapeutic effective amount” refers to an amount of compound of formula (I) administered to a person suffering from an inflammatory airway disease associated with elevated NSP enzyme activity (particularly neutrophil elastase), sufficient or effective to treat (e.g., prevent, slow progression, reduce severity) the inflammatory airway disease, including relieving symptoms of the airway disease or reducing the severity of such symptoms. In some embodiments, a “therapeutic effective amount” refers to an amount of compound of formula (I) administered to a person suffering from COPD or bronchiectasis, sufficient or effective to treat (e.g., prevent, slow progression, reduce severity) COPD or bronchiectasis in the person, including relieving symptoms of COPD or bronchiectasis or reducing the severity of such symptoms.

[0183] The terms "about" or "approximately" refer to an acceptable range of error for a particular value as determined by a person skilled in the art, a range of error that will depend in part on the manner in which the value is measured or determined, such as limitations of the measurement system. Where a particular value is described in this application and claims, the term "about" shall be assumed to refer to an acceptable range of error for that particular value unless otherwise stated. In some embodiments, "about" means ±5%, ±10%, or ±15% of the value. In some embodiments, "about" means ±10% of the value. Active ingredient

[0184] The active ingredient of this invention is a compound of formula (I), particularly a compound of formula (I) existing in the crystalline form of this invention. Such as crystal form A, crystal form B, crystal form C, crystal form D or crystal form E, or combinations thereof.

[0185] The compound of formula (I) is also called (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indazol-6-yl)phenyl)ethyl)-1,4-oxazacycloheptane-2-carboxamide.

[0186] The compound of formula (I) of the present invention is a DPP1 inhibitor, and therefore the crystal form of the present invention can be used to prepare DPP1 inhibitors or drugs for the prevention or treatment of DPP1-related diseases.

[0187] Preferably, in the active ingredient, crystal form A is ≥50 wt%, such as 50-100 wt%, more preferably 80-99.99 wt%, and even more preferably 90-99.99 wt% or 98-99.99 wt%. Pharmaceutical composition

[0188] The present invention also provides a pharmaceutical composition comprising: any one or more crystal forms according to the present invention, and a pharmaceutically acceptable carrier.

[0189] The term "safe and effective amount" refers to an amount of compound (or crystal form) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the crystal form / dosage of the present invention, more preferably, 10-200 mg of the crystal form / dosage of the present invention. Preferably, "one dose" refers to one capsule or tablet.

[0190] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0191] There are no particular limitations on the administration of the crystal form or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral and parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0192] In some embodiments, the pharmaceutical composition is formulated for oral administration to mammals. In some embodiments, the pharmaceutical composition is in the form of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of tablets, pills, or capsules.

[0193] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or compatibilizers, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, sodium carbonate, crospovidone, and crospovidone carboxymethyl cellulose; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0194] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0195] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0196] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0197] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0198] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0199] Dosage forms of the crystal forms of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0200] The crystal form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0201] When using the pharmaceutical composition, a safe and effective amount of the crystalline form of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage at the time of application is a pharmaceutically considered effective dose; for a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 10–500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise. Treatment Methods

[0202] In some embodiments, this document describes a method for treating an airway disease in a mammal, the method comprising administering a compound of formula (I) to the mammal. In some embodiments, this document describes a method for treating an airway disease in a mammal, the method comprising administering a therapeutic amount of a compound of formula (I) to the mammal. In some embodiments, the airway disease is COPD. In some embodiments, the airway disease is bronchiectasis. In some embodiments, the airway disease is noncystic fibrotic bronchiectasis (NCFBE).

[0203] In some embodiments, the compound of formula (I) is used to treat inflammatory airway diseases in humans. In some embodiments, the compound of formula (I) is used to treat neutrophil-driven airway diseases in humans. In some embodiments, the compound of formula (I) is used to treat COPD in humans. In some embodiments, the compound of formula (I) is used to treat bronchiectasis in humans. In some embodiments, the compound of formula (I) is used to treat neutrophilic COPD in humans. In some embodiments, the compound of formula (I) is used to treat NCFBE in humans.

[0204] In some embodiments, this document describes a method for treating an inflammatory airway disease in a mammal, the method comprising administering to the mammal a pharmaceutical composition containing a compound of formula (I). In some embodiments, this document describes a method for treating an inflammatory airway disease in a mammal, the method comprising administering to the mammal a therapeutic amount of a pharmaceutical composition containing a compound of formula (I). In some embodiments, the inflammatory airway disease is COPD. In some embodiments, the inflammatory airway disease is bronchiectasis. In some embodiments, the inflammatory airway disease is noncystic fibrotic bronchiectasis (NCFBE). In some embodiments, the compound of formula (I) is administered orally in the form of a solid pharmaceutical composition containing a crystalline form of the compound of formula (I), wherein the crystalline form of the compound of formula (I) is A crystal form.

[0205] In some embodiments, this document describes a method for treating COPD in a human body, the method comprising orally administering a pharmaceutical composition containing a compound of formula (I) to a person in need. In some embodiments, this document describes a method for treating COPD in a human body, the method comprising orally administering a therapeutic amount of a pharmaceutical composition containing a crystalline form of a compound of formula (I) to a person in need. In some embodiments, this document describes a method for treating COPD in a human body, the method comprising orally administering a therapeutic amount of a pharmaceutical composition containing a crystalline form of a compound of formula (I) in a solid form to a person in need.

[0206] In some embodiments, this document describes a method for treating bronchiectasis in a human body, the method comprising orally administering to a person in need a pharmaceutical composition containing a compound of formula (I). In some embodiments, this document describes a method for treating bronchiectasis in a human body, the method comprising orally administering to a person in need a therapeutic amount of a crystalline pharmaceutical composition containing a compound of formula (I). In some embodiments, this document describes a method for treating bronchiectasis in a human body, the method comprising orally administering to a person in need a therapeutic amount of a crystalline solid form pharmaceutical composition containing a compound of formula (I).

[0207] In some embodiments, this document describes a method for treating noncystic fibrotic bronchiectasis (NCFBE) in a human, the method comprising orally administering a pharmaceutical composition containing a compound of formula (I) to a person in need. In some embodiments, this document describes a method for treating NCFBE in a human, the method comprising orally administering a therapeutic amount of a pharmaceutical composition in the crystalline form of a compound of formula (I) to a person in need. In some embodiments, this document describes a method for treating NCFBE in a human, the method comprising orally administering a therapeutic amount of a pharmaceutical composition in the crystalline solid form of a compound of formula (I) to a person in need.

[0208] In some embodiments, the pharmaceutical composition is a solid form pharmaceutical composition. In some embodiments, the solid form pharmaceutical composition is in the form of tablets, pills, or capsules. In some embodiments, the solid form pharmaceutical composition is in the form of tablets. In some embodiments, the solid form pharmaceutical composition is in the form of pills. In some embodiments, the solid form pharmaceutical composition is in the form of capsules. In some embodiments, the solid form pharmaceutical composition comprises crystal form A of a compound of formula (I). In some embodiments, the solid form pharmaceutical composition comprises a crystal form of a compound of formula (I), wherein the crystal form of formula (I) is crystal form A, and wherein crystal form A substantially does not contain other crystal forms of compound (I). In some embodiments, the solid form pharmaceutical composition comprises a crystal form of a compound of formula (I), wherein the crystal form of formula (I) is crystal form A, and wherein crystal form A substantially does not contain crystal forms B, C, D, and E of compound (I).

[0209] In some implementations, treating COPD in humans with a compound of formula (I) includes reducing the annual incidence of lung exacerbations, slowing the decline in lung function, prolonging the time until the first exacerbation, reducing the frequency of severe exacerbations, or a combination thereof, compared to COPD patients who have not been treated with a compound of formula (I).

[0210] In some implementations, treating COPD includes reducing the level of NSP activity in the plasma of the person suffering from COPD.

[0211] In some implementations, treating NCFBE in humans with a compound of formula (I) includes reducing the annual incidence of lung exacerbations, slowing the decline in lung function, prolonging the time until the first exacerbation, reducing the frequency of severe exacerbations, or a combination thereof, compared with NCFBE patients who have not been treated with a compound of formula (I).

[0212] In some implementations, treating NCFBE involves reducing the level of NSP activity in the plasma of the person suffering from NCFBE.

[0213] Further embodiments of any of the above embodiments include a single-dose effective amount of the compound of formula (I), including further embodiments in which (i) the compound of formula (I) is administered once daily; or (ii) the compound of formula (I) is administered to the mammal multiple times over a day.

[0214] Further embodiments of any of the above-described embodiments include multiple doses of an effective amount of the compound of formula (I), further comprising the following embodiments: (i) administering the compound of formula (I) continuously or intermittently, as in a single dose; (ii) the interval between multiple doses is every 6 hours; (iii) administering the compound to the mammal every 8 hours; (iv) administering the compound to the mammal every 12 hours; (v) administering the compound to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday during which administration of the compound is temporarily suspended or the dosage of the compound is temporarily reduced; administration of the compound is resumed after the drug holiday ends. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0215] In certain circumstances, it is suitable to administer the compound of formula (I) in combination with one or more other therapeutic agents. The main advantages of this invention include:

[0216] 1. This invention provides a new crystal form of the compound of formula (I), its preparation method and application.

[0217] 2. The A crystal form of the present invention is easy to prepare, has better crystallinity than other crystal forms, a single melting point peak, is amorphous, has a short crystallization cycle and high yield, good physical and chemical stability, high purity, and low hygroscopicity, and has high industrial application value and economic value, with broad prospects for drug development.

[0218] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0219] All solvents used in this invention are commercially available and can be used without further purification.

[0220] The solvent used in this invention is commercially available.

[0221] The following abbreviations are used in this invention: DCM represents dichloromethane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; H2O represents water; NMM represents N-methylmorpholine; TFAA represents trifluoroacetic anhydride; MTBE represents methyl tert-butyl ether; Exo Up represents the upward exothermic peak in the DSC spectrum.

[0222] Compounds are named according to conventional naming principles in the field or using Software naming conventions; commercially available compounds should use supplier catalog names. Instruments and analytical methods.

[0223] Although the following diffractometer was used, other types of diffractometers can also be used. Furthermore, other wavelengths can be used and converted to Cu Kα wavelengths. In some implementations, Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD) can be used to characterize the crystal form.

[0224] The X-ray powder diffractometer (XRPD) method of this invention has the following instrument parameters, which are shown in Table 6. Table 6: XRPD Test Parameters

[0225] The second method of X-ray powder diffractometer (XRPD) in this invention uses X-ray diffraction patterns acquired by a Bruker D2 Phaser instrument. Instrument parameters are shown in Table 7. Table 7: XRPD Test Parameters

[0226] The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) methods for the crystal form of this invention have the following test parameters, which are shown in Table 8. Table 8: TGA and DSC Test Parameters

[0227] Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) methods of the present invention are described in Table 9. Table 9: TGA and DSC Test Parameters

[0228] The dynamic moisture adsorption (DVS) method for the crystal form of this invention was used to collect data on a DVS Intrinsic Plus instrument from SMS (Surface Measurement Systems) in the UK. The relative humidity at 25°C was corrected for the deliquescence points of lithium chloride (LiCl), magnesium nitrate [Mg(NO3)2], and potassium chloride (KCl). The test parameters are shown in Table 10. Table 10: DVS Test Parameters Example 1: Preparation of compound (I) and crystal form A

[0229] Synthesis route: first step

[0230] Compound 1 (149 g, 276.13 mmol) was dissolved in DCM (1500 mL), and NMM (111.72 g, 1.10 mol) was added at 0 °C, followed by dropwise addition of TFAA (115.99 g, 552.26 mmol). After the addition was complete, the reaction mixture was heated to 25 °C and stirred for 12 hours. Water (1000 mL) was added to the reaction mixture while stirring, and the mixture was allowed to stand to separate dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution (1000 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2. Step 2

[0231] Compound 2 (139 g, 266.50 mmol) was dissolved in formic acid (1000 mL), and H₂O (100 mL) was added with stirring. The reaction was stirred at 25 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (1 L). Dichloromethane (2 L) was added and stirred for 5 minutes. The pH was adjusted to 8 with 25% ammonia, and the mixture was stirred for 10 minutes until clear. The dichloromethane phase was separated. The organic phase was concentrated under reduced pressure to remove the remaining solvent, and isopropanol (1000 mL) was added and concentrated under reduced pressure to dryness. The solid was stirred with isopropanol (1500 mL) at 50 °C for 2 hours, then slowly returned to 25 °C and stirred for 1 hour. The mixture was filtered to obtain compound (I).

[0232] The compound of formula (I) obtained above was stirred in a mixed solvent of isopropanol (1500 mL) and water (100 mL) at 50 °C for 2 hours, then slowly cooled to 25 °C and stirred for 1 hour. After filtration, the filter cake was dried under vacuum (40 °C) to obtain a white solid product, which is the A crystal form of compound (I). The ee value was measured by SFC (column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: A phase is supercritical CO2, B phase is an ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%). For compound (I): ee% = 100%, RT = 2.091 min. HPLC (Column: Ultimate LP-C18, 150 × 4.6 mm, 5 μm; Mobile phase: Phase A - aqueous solution containing 0.04% trifluoroacetic acid, Phase B - acetonitrile solution containing 0.02% trifluoroacetic acid; Gradient: Phase B 10%-80%, elution time 10 min, 80% hold for 5 min; Flow rate: 1.5 mL / min; Column temperature: 50℃; Wavelength: UV 220 nm) purity was 98.8%, RT = 7.913. MS-ESI calculated value [M+H] + 422, measured value 422.

[0233] XRPD, DSC, and TGA of compound A (Formula I) were tested using the corresponding method one. The XRPD, DSC, and TGA results are shown in Figures 1, 2, and 3, respectively, and the DVS results are shown in Figure 16. The DSC characterization results showed an endothermic peak, and the TGA results showed no weight loss before 100°C, indicating that compound A (Formula I) is an amorphous form. Example 2: Preparation of compound B (Formula I)

[0234] 40.71 mg of compound (I) was weighed into a glass bottle and 1 mL of ethyl acetate was added. The sample was stirred at 50 °C for 3 days and then filtered. The resulting solid was purged with nitrogen for 4 hours to obtain crystal form B of compound (I). The XRPD, DSC, and TGA of crystal form B of compound (I) were tested using the corresponding method II. The XRPD, DSC, and TGA test results are shown in Figures 4, 5, and 6, respectively. Example 3: Preparation of crystal form C of compound (I)

[0235] 90.58 mg of compound (I) was weighed into a glass bottle, and 2 mL of ethanol was added. The mixture was stirred at 50 °C to obtain a clear solution, which was then filtered. The filtrate was cooled from 50 °C to 25 °C (at a rate of 0.2 °C / min) and stirred for 16 h without any solid precipitation. Then, the mixture was cooled to -10 °C and stirred for 20 h, after which solid precipitated. The solid was filtered, and the obtained solid was purged with nitrogen for 4 h to obtain the C-crystal form of compound (I). The XRPD, DSC, and TGA results of the C-crystal form of compound (I) were tested using the corresponding Method II, and the results are shown in Figures 7, 8, and 9, respectively. The TGA results showed a weight loss of 6.495% between 25 and 100 °C. 1 ¹H NMR results showed 6.9% ethanol (0.7 mol) residue. Heating the C crystal form of compound (I) to 85 °C and 120 °C did not change the crystal form. Therefore, it is inferred that the C crystal form of compound (I) is the solvate (0.7 mol ethanol). Example 4: Preparation of the D crystal form of compound (I)

[0236] 30.92 mg of compound (I) was weighed into a glass bottle, 1 mL of methanol was added, and after dissolving, the solution was filtered. The solution was then allowed to evaporate slowly at room temperature (15-22 °C) to obtain the D crystal form of compound (I). The XRPD, DSC, and TGA results of the D crystal form of compound (I) were tested using the corresponding Method II. The results are shown in Figures 10, 11, and 12, respectively. The DSC results showed two endothermic peaks, and the TGA results showed a weight loss of 2.273% between 23 and 120 °C. 1 ¹H NMR results showed no solvent residue. Heating the D crystal form to 115°C transformed it into the A crystal form. Therefore, it is inferred that the D crystal form of compound (I) is a hydrate (0.5 mol). Example 5: Preparation of the E crystal form of compound (I)

[0237] Compound (I) (405.10 mg) was weighed into a glass bottle, and 12.5 mL of ethanol was added. The mixture was stirred at 70–80 °C to obtain a clear solution, which was then filtered. The filtered solution was cooled from 25 °C to -10 °C (at a rate of 0.2 °C / min), and then stirred at -10 °C for 24 h. A sample was taken for XRPD measurement, and the result showed that it was the C crystal form of compound (I). After stirring at -10 °C for another 24 h, the mixture was filtered again. The filter cake was vacuum dried at 50 °C for 20 h to obtain the E crystal form of compound (I). The XRPD of the E crystal form of compound (I) was tested using the corresponding Method II, and the DSC and TGA tests were also performed using the corresponding Method II. The XRPD, DSC, and TGA results are shown in Figures 13, 14, and 15, respectively. Heating the E crystal form of compound (I) to 80 °C did not change its crystal form, but heating it to 120 °C transformed it into the A crystal form of compound (I). DSC characterization results showed one endothermic peak and one exothermic peak, while TGA results showed a weight loss of 0.293% at 30-100℃. 1 ¹H NMR results showed no solvent residue, suggesting that the E crystal form of compound (I) is an anhydrous. Example 6: Hygroscopicity study of crystal form A of compound (I)

[0238] Experimental materials: SMSDVS intrinsic plus dynamic water vapor adsorption instrument (UK)

[0239] Experimental method: Take 30-50 mg of crystal form A of compound (I) and place it in a DVS sample tray for testing.

[0240] Hygroscopicity assessment reference: Guidelines for Hygroscopicity Testing of Drugs, Chinese Pharmacopoeia 2015 Edition, Part IV. The classification of hygroscopicity evaluation is shown in Table 11 below: Table 11 Description of Hygroscopicity Characteristics and Definition of Hygroscopic Weight Gain. Note: ΔW% represents the moisture gain of the test sample at 25±1℃ and 80±2% RH.

[0241] Experimental results: The DVS spectrum of crystal form A of compound (I) is shown in Figure 16. The DVS results show that the sample has a 0.431% weight gain due to hygroscopicity under the conditions of 25℃ / 80%RH, indicating that the sample is slightly hygroscopic. XRPD test results show that the crystal form of the sample did not change before and after the DVS test.

[0242] Experimental conclusion: Compound A of formula (I) exhibits slight hygroscopicity at 25±1℃ and 80±2% RH, and the crystal form remains unchanged before and after the DVS test. Example 7: Competitive pulping experiment

[0243] Saturated solutions of the A crystal form of compound (I) in ethanol, n-heptane, isopropanol, and MTBE were prepared at 25°C and 50°C, respectively.

[0244] 10 mg each of crystal form A and crystal form E of compound (I) were weighed and added to the same saturated solution at the corresponding temperature. Samples were taken and XRPD was measured after 1 day and 4 days of stirring, respectively. The experimental results are shown in Table 12. Table 12 Results of competitive pulping experiment

[0245] Experimental conclusions: The competitive pulping experiment results showed that all obtained compounds were in crystal form A of formula (I). Crystal form A was more stable than crystal form E, further indicating that crystal form A is the stable crystal form. Bioactivity evaluation

[0246] The bioactivity of compound (I) was previously disclosed in PCT / CN2022 / 074088 (see Bioactivity of Compound 8, which shows that the compound exhibits potent inhibitory activity against DPP1 enzyme and good inhibitory activity against DPP1 in U937 cells, good pharmacokinetic properties in CD-1 mice and SD mice, high distribution in bone marrow of CD-1 mice and SD mice, and can significantly inhibit the activity of neutrophil elastase in rats in vivo).

[0247] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A crystalline form of a compound of Formula (I) wherein, The crystal form is Form A, Form B, Form C, Form D, or Form E. Among them, the X-ray powder diffraction pattern of crystal type A measured by Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200° and 20.673±0.200°; The X-ray powder diffraction pattern of the B crystal form, measured using Cu(Kα) radiation, shows diffraction peaks at the following 2θ angles: 8.954±0.200°, 13.530±0.200°, 15.480±0.200°, and 18.122±0.200°. The X-ray powder diffraction pattern of the C crystal form measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 8.069±0.200°, 11.606±0.200°, 13.120±0.200° and 19.812±0.200°; The X-ray powder diffraction pattern of the D crystal form measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 9.105±0.200°, 15.206±0.200°, and 16.904±0.200°; The X-ray powder diffraction pattern of the E crystal form, measured using Cu(Kα) radiation, shows diffraction peaks at the following 2θ angles: 9.331±0.200°, 12.051±0.200°, and 15.214±0.200°.

2. The morphic form of claim 1, characterized by, The crystal form is A crystal form.

3. The crystal form according to claim 2, wherein its X-ray powder diffraction pattern measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 20.673±0.200° and 24.134±0.200°.

4. The crystal form according to claim 2, wherein its X-ray powder diffraction pattern measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 20.673±0.200°, 24.134±0.200°.

5. The crystal form according to claim 2, wherein its X-ray powder diffraction pattern measured using Cu(Kα) radiation has diffraction peaks at the following 2θ angles: 10.267±0.200°, 11.716±0.200°, 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, 17.550±0.200°, 18.110±0.200°, 19.863±0.200°, 20.673±0.200°, 23.025±0.200°, 23.513±0.200°, and 24.134±0.200°.

6. The crystal form according to claim 1, wherein crystal form A has one or more features selected from the group consisting of: The basic XRPD map is shown in Figure 1; Its DSC spectrum is basically shown in Figure 2; and / or Its TGA spectrum is basically shown in Figure 3.

7. The crystal form according to claim 1, wherein crystal form A has one or more features selected from the group consisting of: Its differential scanning calorimetry curve has an endothermic peak at 141.01±3℃; and / or Its thermogravimetric analysis curve shows a weight loss of 0.040% at 150.0±3℃.

8. A crystalline form of the compound of formula (I) ###0002### wherein, The crystalline form is Form A; The A-type crystal is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; and one or two of the following: Differential scanning calorimetry curve with an endothermic peak at 141.01±3℃; or The thermogravimetric analysis curve shows a weight loss of 0.040% at 150.0±3℃.

9. The crystal form according to claim 8, wherein the crystal form A is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200° and 20.673±0.200°; and a differential scanning calorimetry curve with an endothermic peak at 141.01±3 °C.

10. The crystal form according to claim 8, wherein the crystal form A is characterized by having an X-ray powder diffraction pattern measured using Cu(Kα) radiation with peaks at the following 2θ angles: 13.822±0.200°, 15.236±0.200°, 16.899±0.200°, and 20.673±0.200°; and a thermogravimetric analysis curve showing a weight loss of up to 0.040% at 150.0±3 °C.

11. A crystalline form of a compound of formula (I) ###0002### wherein, The crystalline form is Form A; The A-type is characterized by having an XRPD pattern as shown in Figure 1; and The basic DSC spectrum is shown in Figure 2; and / or The basic TGA spectrum is shown in Figure 3.

12. The crystal form according to claim 11, wherein the crystal form A is characterized by having an XRPD pattern substantially as shown in FIG1; and a DSC pattern substantially as shown in FIG2.

13. The crystal form according to claim 11, wherein the crystal form A is characterized by having an XRPD pattern substantially as shown in FIG1; and a TGA pattern substantially as shown in FIG3.

14. A pharmaceutical composition comprising: The crystal form according to any one of claims 1-13, and the pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein the solid form pharmaceutical composition is a tablet, pill, or capsule.

17. The use of the crystal form according to any one of claims 1-13 or the pharmaceutical composition according to any one of claims 14-16 in the preparation of a DPP1 inhibitor or a medicament for the prevention or treatment of DPP1-related diseases.

18. A process for preparing a crystalline form of the compound of formula (I) as claimed in claim 1, wherein the process comprises, Including the following steps: The compound of formula (I) was stirred in a mixed solvent of isopropanol and water until a solid precipitated, filtered, and dried at 20-45°C (preferably 30-40°C) to obtain crystal form A.

19. The use of the crystal form according to any one of claims 1-13 in the treatment of inflammatory diseases of the human airway.

20. The use of the pharmaceutical composition according to any one of claims 14-16 in the treatment of inflammatory diseases of the human airways.

21. The application according to claim 19 or 20, wherein the airway inflammatory disease is chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, acute respiratory distress syndrome, exercise-induced bronchoconstriction (EIB), chronic bronchitis, emphysema, α1-antitrypsin deficiency, pulmonary fibrosis with emphysema (CPFE), or asthma-COPD overlap syndrome (ACOS).

22. The application according to claim 21, wherein the asthma is allergic asthma, aspirin-induced asthma, cough-variant asthma, exercise-induced asthma, nocturnal asthma, steroid-resistant asthma, occupational asthma, eosinophilic asthma, neutrophilic asthma, or mixed eosinophilic and neutrophilic asthma.

23. The application according to claim 19 or 20, wherein the airway inflammatory disease is chronic obstructive pulmonary disease (COPD).

24. The application according to claim 19 or 20, wherein the airway inflammatory disease is bronchiectasis.

25. A method for treating an inflammatory disease of the airways in a person, the method comprising administering to a person in need a therapeutically effective amount of the crystal form according to any one of claims 1-13.

26. The method of claim 25, wherein the therapeutically effective amount of the crystal form is administered in the form of a solid pharmaceutical composition.

27. The method of claim 26, wherein the solid form pharmaceutical composition is a tablet, pill, or capsule.

28. The method according to any one of claims 25-27, wherein the airway inflammatory disease is chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, acute respiratory distress syndrome, exercise-induced bronchoconstriction (EIB), chronic bronchitis, emphysema, α1-antitrypsin deficiency, pulmonary fibrosis with emphysema (CPFE), or asthma-COPD overlap syndrome (ACOS).

29. The method of claim 28, wherein the asthma is allergic asthma, aspirin-induced asthma, cough-variant asthma, exercise-induced asthma, nocturnal asthma, steroid-resistant asthma, occupational asthma, eosinophilic asthma, neutrophilic asthma, or mixed eosinophilic and neutrophilic asthma.

30. The method according to any one of claims 25-27, wherein the airway inflammatory disease is chronic obstructive pulmonary disease (COPD).

31. The method according to any one of claims 25-27, wherein the airway inflammatory disease is bronchiectasis.

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