Crystal form of piperazine derivative and preparation method therefor

Abstract

The present invention relates to a crystal form of a piperazine derivative or a hydrate or solvate thereof, a preparation method therefor, a pharmaceutical composition thereof, and the use thereof in the preparation of PARP1 inhibitors.

Description

A crystal form of a piperazine derivative and its preparation method Technical Field

[0001] This invention relates to a piperazine derivative, or the crystal form of its hydrate or solvate, as well as its preparation method or pharmaceutical composition and its use in the preparation of PARP1 inhibitors. Background Technology

[0002] PARPs (poly(ADP-ribose) polymerases) are a class of poly(ADP-ribose) polymerases that catalyze the poly-ADP-ribosylation of various proteins. This process plays a crucial role in many cellular processes, including DNA damage repair, transcriptional regulation, chromatin remodeling, and remodeling. Currently, although several PARP1 / 2 inhibitors have been successfully marketed, they still commonly cause hematological and gastrointestinal side effects, whether used alone or in combination, limiting their clinical application. Therefore, developing safer and more effective PARP inhibitors remains a pressing clinical challenge. A series of studies have shown that, compared to PARP1 / 2 inhibitors, highly selective PARP1 inhibitors offer better efficacy and lower toxicity, potentially reducing the potential risks of current PARP drugs, broadening their clinical application, and improving patients' quality of life.

[0003] PCT / CN2022 / 120890 provides a selective PARP1 inhibitor, offering patients a new treatment option.

[0004] The crystal structure of the compound represented by formula (I), as a pharmaceutically active ingredient, often affects the chemical and physical stability of the drug. Different crystal forms, preparation methods, and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor flowability. Given the importance of the crystal form and stability of solid drugs in clinical treatment, in-depth research on the crystal form of the compound represented by formula (I) is of great significance for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0005] The purpose of this invention is to provide a piperazine derivative, or the crystal form of its hydrate or solvate, as well as a method for its preparation or a pharmaceutical composition thereof and its use in the preparation of PARP1 inhibitors.

[0006] The technical problem solved by this invention is achieved by the following technical solution:

[0007] In a first aspect, the present invention provides a crystal form of 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)pyridinecarboxynitrile (compound 1) or its hydrate or solvate, wherein compound 1 has the following chemical structure (i.e., formula (I)):

[0008] The crystal form of the present invention exhibits at least the following advantages: good solubility, high stability, easy handling, processing and purification, improved oral bioavailability of drugs, extended drug shelf life, and easy manufacturing of various dosage forms.

[0009] The crystal form of this invention exhibits pharmaceutical advantages over the amorphous form of compound 1. In particular, the crystal form enhances chemical and physical stability, which is more advantageous for preparing solid drug dosage forms containing pharmacologically active ingredients.

[0010] The crystalline form of the present invention is present in the form of about 5% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 10% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 15% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 20% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 25% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 30% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 35% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 40% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 45% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present in the form of about 50% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 55% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 60% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 65% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 70% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 75% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 80% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 85% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 90% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 95% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystalline form of the present invention is present at about 98% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, the crystal form of the present invention is present at about 99% to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, substantially all of the active pharmaceutical ingredient is the crystal form of the present invention, i.e., the active pharmaceutical ingredient is substantially a phase-pure crystal.

[0011] Unless otherwise specified, all compounds 1 of this invention are in their amorphous form.

[0012] In one or more embodiments of the present invention, the crystal form I of compound 1 is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 12.227°±0.3°, 16.082°±0.3°, 22.533°±0.3°, and 26.702°±0.3°.

[0013] In one or more embodiments of the present invention, the crystal form I is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 15.533°±0.3°, 16.962°±0.3°, 21.755°±0.3°, 25.007°±0.3°, and 25.357°±0.3°.

[0014] In one or more embodiments of the present invention, the crystal form I is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 12.473°±0.3°, 14.961°±0.3°, 17.454°±0.3°, 19.498°±0.3°, and 20.651°±0.3°.

[0015] In one or more embodiments of the present invention, the X-ray powder diffraction pattern of crystal form I is basically as shown in Figure 1.

[0016] In one or more embodiments of the present invention, the TGA curve of crystal form I is basically as shown in Figure 2.

[0017] In one or more embodiments of the present invention, the DSC curve of crystal form I is basically as shown in Figure 3.

[0018] In one or more embodiments of the present invention, the crystal form II of compound 1 is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.048°±0.3°, 8.156°±0.3°, 12.276°±0.3°, and 17.942°±0.3°.

[0019] In one or more embodiments of the present invention, the crystal form II is irradiated with Cu-Kα, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 16.409°±0.3° and 19.640°±0.3°.

[0020] In one or more embodiments of the present invention, the X-ray powder diffraction pattern of crystal form II is basically as shown in Figure 4.

[0021] In one or more embodiments of the present invention, the TGA curve of the crystal form II is basically as shown in Figure 5.

[0022] In one or more embodiments of the present invention, the DSC curve of crystal form II is substantially as shown in Figure 6.

[0023] In one or more embodiments of the present invention, the crystal form III of compound 1 is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.384°±0.3°, 18.114°±0.3°, and 26.175°±0.3°.

[0024] In one or more embodiments of the present invention, the crystal form III is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 10.616°±0.3°, 13.240°±0.3°, and 22.026°±0.3°.

[0025] In one or more embodiments of the present invention, the X-ray powder diffraction pattern of crystal form III is basically as shown in Figure 7.

[0026] In one or more embodiments of the present invention, the TGA curve of crystal form III is substantially as shown in Figure 8.

[0027] In one or more embodiments of the present invention, the DSC curve of crystal form III is substantially as shown in Figure 9.

[0028] In one or more embodiments of the present invention, the crystal form IV of compound 1 is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 12.156°±0.3°, 21.724°±0.3°, 15.484°±0.3°, and 22.482±0.3°.

[0029] In one or more embodiments of the present invention, the crystal form IV is irradiated with Cu-Kα, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 26.658°±0.3°, 25.329°±0.3°, 24.955°±0.3°, and 12.391±0.3°.

[0030] In one or more embodiments of the present invention, the X-ray powder diffraction pattern of crystal form IV is basically as shown in Figure 12.

[0031] In one or more embodiments of the present invention, the TGA curve of the crystal form IV is substantially as shown in Figure 13.

[0032] In one or more embodiments of the present invention, the DSC curve of the crystal form IV is substantially as shown in Figure 14.

[0033] In one or more embodiments of the present invention, the crystal form V of compound 1 is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.175°±0.3°, 12.422°±0.3°, and 8.293°±0.3°.

[0034] In one or more embodiments of the present invention, the crystal form V is subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 18.089°±0.3°, 16.571°±0.3°, and 19.804°±0.3°.

[0035] In one or more embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form V is basically as shown in Figure 15.

[0036] In one or more embodiments of the present invention, the TGA curve of the crystal form V is substantially as shown in Figure 16.

[0037] In one or more embodiments of the present invention, the DSC curve of the crystal form V is substantially as shown in Figure 17.

[0038] This invention also relates to a method for preparing crystal form I, wherein the preparation method is selected from:

[0039] Compound 1 is added to solvent A-1, and then to solvent A-2 to obtain crystal form I; or

[0040] Compound 1 was added to solvent B and slurryed to obtain crystal form I;

[0041] The solvent A-1 is selected from any one or any mixture of several of the following solvents in any proportion: trifluoroethanol, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, ethanol, n-propanol, acetone and water.

[0042] Solvent A-2 is selected from any one or any mixture of several of the following solvents in any proportion: methanol, isopropyl acetate, acetonitrile, ethanol, n-propanol, acetone, and water.

[0043] Solvent B is selected from any one or any mixture of several of the following solvents in any proportion: ethanol, isopropanol, ethyl acetate, toluene, isopropyl acetate, n-heptane, acetonitrile, n-propanol, acetone, and water.

[0044] In one or more embodiments of the present invention, the preparation method is selected from: adding compound 1 to solvent A-1, then adding solvent A-2, and filtering to obtain crystal form I;

[0045] The solvent A-1 is selected from any one or any mixture of several of the following solvents in any proportion: trifluoroethanol, dimethyl sulfoxide, and N-methylpyrrolidone.

[0046] Solvent A-2 is selected from any one or any mixture of several of the following solvents in any proportion: methanol, isopropyl acetate, acetone, and water.

[0047] In one or more embodiments of the present invention, the preparation method is selected from: adding compound 1 to solvent B, pulping at 10 to 60°C for 5 to 10 days, and filtering to obtain crystal form I;

[0048] Solvent B is selected from any one or any mixture of several of the following solvents in any proportion: ethanol, isopropanol, ethyl acetate, toluene, isopropyl acetate, and n-heptane.

[0049] This invention also relates to a method for preparing crystal form II, wherein the preparation method is selected from:

[0050] Compound 1 is added to solvent C-1, and then solvent C-2 is added to induce crystallization or diffusion crystallization to obtain crystal form II;

[0051] Compound 1 is added to solvent C-1 and placed in a solvent C-2 atmosphere to crystallize or diffuse crystallize, yielding crystal form II; or

[0052] Compound 1 was added to solvent D-1, heated to 40 to 60°C, then added to solvent D-2, and cooled to crystallize, yielding crystal form II;

[0053] The solvent C-1 is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion;

[0054] The solvent C-2 is selected from any one or any mixture of several of isopropyl ether and acetonitrile in any proportion;

[0055] The solvent D-1 is selected from any one or any mixture of several of 1,4-dioxane, methanol, and acetonitrile in any proportion.

[0056] The solvent D-2 is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion.

[0057] This invention also relates to a method for preparing crystal form III, wherein the preparation method is selected from:

[0058] Compound 1 was added to solvent E and filtered to obtain crystal form III;

[0059] The solvent E is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion.

[0060] This invention also relates to a method for preparing crystal form IV, comprising the following steps:

[0061] The compound shown in formula (I) was added to solvent F, heated to 70 to 75°C to dissolve, filtered, and the temperature was controlled at 60 to 65°C. Water was added dropwise to the filtrate, stirred, filtered, and then dried under vacuum at 45 to 55°C to obtain crystal form IV.

[0062] The solvent F is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion.

[0063] This invention also relates to a method for preparing crystal form V, wherein the preparation method is selected from:

[0064] The compound shown in formula (I) was added to solvent G, heated to 70 to 75 °C to dissolve, and then the solution was added to water, stirred, filtered, and dried under vacuum at 45 to 55 °C to obtain crystal form V.

[0065] The solvent G is selected from any one or any mixture of several of trifluoroethanol and N,N-dimethylformamide in any proportion.

[0066] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound 1 or its hydrate, a solvate crystal form (including crystal form I, crystal form II, crystal form III, crystal form IV, and crystal form V), and a pharmaceutically acceptable carrier or excipient.

[0067] The present invention also relates to the crystal form of the above-described compound 1 or its hydrate or solvate, or the use of the above-described pharmaceutical composition as a medicine (i.e., for therapeutic purposes).

[0068] The present invention also relates to the crystal form of the above-mentioned compound 1 or its hydrate, solvate, or the use of the above-mentioned pharmaceutical composition in the preparation of PARP1 inhibitors.

[0069] The present invention also relates to the crystal form of the above-mentioned compound 1 or its hydrate or solvate, or the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment and prevention of cancer.

[0070] The present invention also relates to a method for treating and preventing cancer, comprising administering to a patient in need a therapeutically effective amount of the above-mentioned compound 1 or its hydrate, solvate crystal form, or the above-mentioned pharmaceutical composition. Attached Figure Description

[0071] Figure 1 is the X-ray powder diffraction pattern of crystal form I.

[0072] Figure 2 is the TGA diagram of crystal form I.

[0073] Figure 3 is the DSC diagram of crystal form I.

[0074] Figure 4 is the X-ray powder diffraction pattern of crystal form II.

[0075] Figure 5 is the TGA diagram of crystal form II.

[0076] Figure 6 is the DSC diagram of crystal form II.

[0077] Figure 7 is the X-ray powder diffraction pattern of crystal form III.

[0078] Figure 8 is the TGA diagram of crystal form III.

[0079] Figure 9 is the DSC diagram of crystal form III.

[0080] Figure 10 shows the DVS diagram of crystal form I.

[0081] Figure 11 shows the XRPD images of crystal form I before and after the DVS test.

[0082] Figure 12 shows the X-ray powder diffraction pattern of crystal form IV.

[0083] Figure 13 shows the TGA diagram of crystal form IV.

[0084] Figure 14 shows the DSC diagram of crystal form IV.

[0085] Figure 15 shows the X-ray powder diffraction pattern of crystal form V.

[0086] Figure 16 shows the TGA diagram of crystal form V.

[0087] Figure 17 shows the DSC diagram of crystal form V.

[0088] Figure 18 shows the XRPD plot of the stability study of crystal form I.

[0089] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0090] "Effective dose" refers to the amount of a compound that causes physiological or medical translation in an tissue, system, or subject. This amount is sought, including the amount of a compound, when administered to a subject, sufficient to prevent the occurrence of one or more symptoms of the treated disease or condition or to alleviate them to some extent.

[0091] "IC50" refers to the half-maximum inhibition concentration, which is the concentration at which half of the maximum inhibition effect is achieved. The crystal structure of this invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to X-ray powder diffraction (XRD).

[0092] The X-ray powder diffraction pattern disclosed in this invention, and those substantially the same, also fall within the scope of this invention.

[0093] It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by DSC plots with characteristic peak positions, possessing substantially the same properties as the DSC plots provided in the accompanying drawings of the present invention, with an error tolerance of ±3°C.

[0094] It is understood that the numerical values ​​described and protected in this invention are approximate. Variations within these values ​​may be attributed to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

[0095] It is understood that the crystal forms of the present invention are not limited to those with the same characteristic spectra as those described in the accompanying drawings, such as XRD. Any crystal form having a characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings falls within the scope of the present invention.

[0096] Various modifications and alterations to this invention will be apparent to those skilled in the art upon consideration of the description and embodiments thereof without departing from the scope and spirit of the invention.

[0097] Unless otherwise stated, the English abbreviations used in the specification and claims have the following meanings. Detailed Implementation

[0098] This specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the following embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles; such improvements and modifications also fall within the scope of protection of the claims. The beneficial effects of the invention are illustrated below through specific examples.

[0099] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0100] Unless otherwise specified, the experimental conditions for crystallization are generally room temperature (20-30℃, 30-70% RH), and the solvent ratio refers to the volume ratio.

[0101] Compound 1

[0102] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)pyridinecarboxylonitrile (Compound 1)

[0103] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile

[0104] first step

[0105] 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c)

[0106] tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

[0107] 5-Bromobenzonitrile compound 1a (909 mg, 5.00 mmol) and tert-butylpiperazine-1-carboxylic acid ester compound 1b (838 mg, 4.5 mmol) were dissolved in toluene (15 mL). Palladium acetate (112 mg, 0.5 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (311 mg, 0.5 mmol) were added. After purging the reaction flask with nitrogen, it was placed in an oil bath at 120 °C and reacted. After 16 h, water (20 mL) was added to quench the reaction, and ethyl acetate (3 × 30 mL) was added for extraction. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to give compound 1c (yellow solid, 1.32 g, yield 92%).

[0108] LCMS m / s = 289.16 [M+1].

[0109] Step 2

[0110] 6-(piperazin-1-yl)pyridinecarboxynitrile (compound 1d)

[0111] 6-(piperazin-1-yl)picolinonitrile

[0112] A 1,4-dioxane solution (4 M, 15 mL) of hydrochloric acid was added to compound 1c (1.32 g, 4.60 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filter cake was collected to give compound 1d (yellow solid, 1.0 g, yield 91%).

[0113] LCMS m / s = 189.10 [M+1].

[0114] Step 3

[0115] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthid-3-yl)methyl)piperazin-1-yl)pyridinecarboxylonitrile (Compound 1)

[0116] 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinonitrile

[0117] Compound 1d (46 mg, 0.24 mmol) and compound 1e (65.5 mg, 0.24 mmol) were dissolved in acetonitrile (3 mL), and N,N-diisopropylethylamine (155 mg, 1.20 mmol) was added. After the reaction system was purged with nitrogen, it was placed in an oil bath at 70 °C for 3 h. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (MeOH:DCM = 1:60 to 1:15) to obtain compound 1 (white solid, 47 mg, yield 51%).

[0118] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.42(d,J=3.0Hz,1H),8.40(d,J=1.9Hz,1H),7.79–7.72(m,2H),7.61( s,1H),7.36(dd,J=8.9,3.0Hz,1H),3.64(s,2H),3.43-3.40(m,4H),2.58–2.51(m,6H),1.18(t,J=7.4Hz,3H).

[0119] LCMS m / s = 375.16 [M+1].

[0120] Example 1

[0121] Preparation method of crystal form I (Form 1) of compound 1

[0122] 499.1 mg of compound 1 was weighed and dissolved in 7.5 mL of trifluoroethanol. After filtration, the clear solution was added dropwise to 90 mL of acetone to induce crystallization. After stirring for 24 h, the solution was centrifuged and dried under vacuum at 40 °C overnight to obtain 320 mg of white solid, which is crystal form I (Form 1, also known as "Form A").

[0123] Example 2

[0124] Preparation method of crystal form I (Form 1) of compound 1

[0125] Weigh 20.0 mg of compound 1 and dissolve it in 0.3 mL of trifluoroethanol. Add 3.0 mL of acetone, methanol or water to the reaction solution and filter to obtain crystal form I (Form 1).

[0126] Example 3

[0127] Preparation method of crystal form I (Form 1) of compound 1

[0128] Weigh 20.0 mg of compound 1 and dissolve it in 2 mL of dimethyl sulfoxide. Add the reaction solution to 14.0 mL of water and filter to obtain crystal form I (Form 1).

[0129] Example 4

[0130] Preparation method of crystal form I (Form 1) of compound 1

[0131] Weigh 20.0 mg of compound 1 and dissolve it in 0.9 mL of N-methylpyrrolidone. Add the reaction solution to 8.1 mL of isopropyl acetate and filter to obtain crystal form I (Form 1).

[0132] Example 5

[0133] Preparation method of crystal form I (Form 1) of compound 1

[0134] Weigh 20.0 mg of compound 1 and dissolve it in 10 mL of ethanol, ethyl acetate, toluene, water, isopropyl acetate, or n-heptane. Slurry the solution at room temperature for 7 days, filter, and obtain crystal form I (Form 1).

[0135] Example 6

[0136] Preparation method of crystal form I (Form 1) of compound 1

[0137] Weigh 20.0 mg of compound 1 and dissolve it in 10 mL of ethanol, isopropanol, ethyl acetate, toluene, water, isopropyl acetate, or n-heptane. Slurry the solution at 50 °C for 7 days, filter, and obtain crystal form I (Form 1).

[0138] Example 7

[0139] Preparation method of crystal form I (Form 1) of compound 1

[0140] Weigh 20.0 mg of compound 1 and dissolve it in 0.9 mL of trifluoroethanol. Add 0.8 mL of acetone and allow it to crystallize at room temperature for 0.5 hours. Filter to obtain crystal form I (Form 1).

[0141] Test Example 1

[0142] X-ray powder diffraction analysis:

[0143] The crystal form I of compound 1 was determined using an X-ray diffractometer (Bruker D8 Advance (Bruker, GER)). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk.

[0144] Table 1. X-ray powder diffraction data for crystal form I.

[0145] The X-ray powder diffraction pattern of crystal form I of compound 1 is shown in Figure 1.

[0146] TGA and DSC analysis:

[0147] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on crystal form I of compound 1. TGA and DSC data were collected using a TGA analyzer (TA Discovery 55 (TA, US)) and a DSC analyzer (TA Discovery 250 (TA, US)), respectively. Table 2 lists the TGA and DSC test parameters. The test results are shown in Figures 2 and 3, respectively. The TGA / DSC results show that there was no weight loss when heated to 150℃, a 1.0% weight loss between 150-260℃, and possible decomposition above 340℃. The DSC results show an endothermic peak at approximately 247℃ for Form 1.

[0148] Table 2 TGA and DSC Test Parameters

[0149] DVS Analysis:

[0150] Dynamic moisture adsorption-desorption (DVS) analysis was performed on crystal form I of compound 1 using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations ranging from 0% to 95% to 0%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes, or each gradient maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the sample to confirm whether the solid morphology had changed.

[0151] The results showed that at 95% RH, the adsorption weight gain was approximately 0.72%, at 80% RH, the adsorption weight gain was approximately 0.31%, the desorption weight gain was approximately 0.45%, and at 0% RH, the desorption weight gain was 0.23%, indicating that Form 1 is slightly hygroscopic (see Figure 10). XRPD results showed that the sample did not undergo a change in crystal form after the DVS test (see Figure 11, where Form A is Form 1).

[0152] Example 8

[0153] Preparation of Form II (Form 2) of Compound 1

[0154] Take solid compound 1 (about 60.1 mg), add trifluoroethanol (1.2 mL) to dissolve it at 25±5 °C, add isopropyl ether (0.4 mL) to crystallize for 30 min, centrifuge, and dry under vacuum at room temperature to obtain crystal form II (Form 2).

[0155] Example 9

[0156] Preparation of Form II (Form 2) of Compound 1

[0157] At room temperature, compound 1 (approximately 99.9 mg) and N-methylpyrrolidone (4.5 mL) were dissolved, and the mixture was allowed to diffuse and crystallize in an acetonitrile atmosphere. After filtration, crystal form II (Form 2) was obtained.

[0158] Example 10

[0159] Preparation of Form II (Form 2) of Compound 1

[0160] At room temperature, take about 20 mg of compound 1 and add 1,4-dioxane (1.0 mL) to form a suspension. Heat to 50 °C and add trifluoroethanol (2.6 mL) until dissolved. Quickly transfer the solution to room temperature and let it stand at room temperature for 2 hours. If no sufficient solid precipitates, cool the solution at 4 °C. If no sufficient solid still precipitates, cool the solution further at -15 °C to induce crystallization. Filter to obtain crystal form II (Form 2).

[0161] Example 11

[0162] Preparation of Form II (Form 2) of Compound 1

[0163] At room temperature, compound 1 (approximately 19.9 mg) was mixed with methanol (0.5 mL) to form a suspension. The mixture was heated to 50 °C, and N-methylpyrrolidone (1.2 mL) was added until dissolved. The solution was rapidly transferred to room temperature and allowed to stand for 2 hours. If no sufficient solid precipitated, the solution was cooled to 4 °C. If no sufficient solid precipitated, the solution was further cooled to -15 °C to induce crystallization. The crystals were filtered to obtain crystal form II (Form 2).

[0164] Example 12

[0165] Preparation of Form II (Form 2) of Compound 1

[0166] At room temperature, compound 1 (approximately 19.3 mg) was mixed with acetonitrile (0.5 mL) to form a suspension. The mixture was heated to 50 °C, and N-methylpyrrolidone (10 mL) was added until dissolved. The solution was rapidly transferred to room temperature and allowed to stand for 2 hours. If no sufficient solid precipitated, the solution was cooled to 4 °C. If no sufficient solid precipitated, the solution was further cooled to -15 °C to induce crystallization. The crystals were filtered to obtain crystal form II (Form 2).

[0167] Test Example 2

[0168] X-ray powder diffraction analysis:

[0169] Crystal form II of compound 1 was measured using an X-ray diffractometer (Bruker D8 Advance (Bruker, GER)). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk. Powder diffraction patterns were obtained, and the data were analyzed. The X-ray powder diffraction data of crystal form II are shown in Table 3.

[0170] Table 3 X-ray powder diffraction data for crystal form II

[0171] The X-ray powder diffraction pattern of crystal form II of compound 1 is shown in Figure 4.

[0172] TGA and DSC analysis:

[0173] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on crystal form II (Form 2) of compound 1. TGA and DSC data were collected using a TGA analyzer (TA Discovery 55 (TA, US)) and a DSC analyzer (TA Discovery 250 (TA, US)), respectively. Table 4 lists the TGA and DSC test parameters. The test results are shown in Figures 5 and 6, respectively. The TGA results show that Form 2 does not lose weight when heated to 90℃, loses 1.2% weight between 90-260℃, and may decompose above 340℃. The DSC results show that Form 2 has an exothermic peak around 230℃ and an endothermic peak around 246℃. The thermal transformation experiment shows that the crystal form of Form 2 remains unchanged after heating to 180℃, but transforms into Form 1 (Form A) after further heating to 232℃. In conclusion, Form 2 is likely an amorphous form.

[0174] Table 4 TGA and DSC Test Parameters

[0175] Example 13

[0176] Preparation of Form III of Compound 1

[0177] Weigh 20.4 mg of compound 1 and dissolve it completely in 3.0 mL of trifluoroethanol. Filter the solution and rotary evaporate it to remove all solvents to obtain an off-white solid. Dry the solid under vacuum overnight at room temperature to obtain crystal form III (Form 3).

[0178] Test Example 3

[0179] X-ray powder diffraction analysis:

[0180] Crystal form III of compound 1 was measured using an X-ray diffractometer (Bruker D8 Advance (Bruker, GER)). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk. Powder diffraction patterns were obtained, and the data were analyzed. The X-ray powder diffraction data for crystal form III are shown in Table 5.

[0181] Table 5. X-ray powder diffraction data of compound 1, crystal form III

[0182] The X-ray powder diffraction pattern of crystal form III of compound 1 is shown in Figure 7.

[0183] TGA and DSC analysis:

[0184] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on crystal form III (Form 3) of compound 1. TGA and DSC data were collected using a TGA analyzer (TA Discovery 55 (TA, US)) and a DSC analyzer (TA Discovery 250 (TA, US)), respectively. Table 6 lists the TGA and DSC test parameters. The test results are shown in Figures 8 and 9, respectively. The TGA results show that Form 3 experiences a 3.5% weight loss when heated to 170℃, and decomposition may occur above 340℃. The DSC results show that Form 3 has a broad endothermic peak corresponding to the TGA weight loss in the 70-160℃ range, an exothermic peak around 191℃, an endothermic peak around 238℃, a possible exothermic peak around 240℃, and endothermic peaks around 246℃ and 253℃. The results of the thermal crystallization experiment showed that the crystal form of Form 3 transformed into Form 1 when heated to 220℃. After heating to 240℃, the XRPD results showed Form 1+ multi-peaks. The sample melted after the temperature was further increased to 247℃.

[0185] Table 6 TGA and DSC Test Parameters

[0186] Example 14

[0187] Preparation of Form IV (Form 4) of Compound 1

[0188] Weigh 1.00 g of compound 1 and dissolve it in 6.0 mL of trifluoroethanol. Heat the solution to 70–75 °C until it is completely dissolved. Filter the solution and control the temperature at 60–65 °C. Slowly add 3 mL of purified water to the filtrate and stir for 2 h. Filter the solution and dry it under vacuum at 50 °C to obtain 0.83 g of white solid, which is crystal form IV (Form 4).

[0189] Test Example 4

[0190] X-ray powder diffraction analysis:

[0191] Crystal form IV of compound 1 was measured using an X-ray diffractometer (Bruker D8 Advance (Bruker, GER)). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk. Powder diffraction patterns were obtained, and the data were analyzed. The X-ray powder diffraction data for crystal form IV are shown in Table 7.

[0192] Table 7 X-ray powder diffraction data for crystal form IV

[0193] The X-ray powder diffraction pattern of crystal form IV of compound 1 is shown in Figure 12.

[0194] TGA and DSC analysis:

[0195] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on crystal form IV (Form 4) of compound 1. TGA and DSC data were acquired using a TGA analyzer (TA Discovery 55 (TA, US)) and a DSC analyzer (TA Discovery 250 (TA, US)), respectively. Table 8 lists the TGA and DSC test parameters. The test results are shown in Figures 13 and 14, respectively. The TGA results show that Form 4 experiences a 0.943% weight loss when heated to 260℃, and decomposition may occur above 340℃. The DSC results show endothermic peaks in Form 4 at approximately 244℃ and 256℃.

[0196] Table 8 TGA and DSC Test Parameters

[0197] Example 15

[0198] Preparation of crystal form V (Form 5) of compound 1

[0199] Weigh 1.00 g of compound 1 and dissolve it in 20 mL of N,N-dimethylformamide. Heat the solution to 70-75 °C and pour it into 60 mL of purified water. Stir for 2 h, filter, and dry under vacuum at 50 °C to obtain 0.83 g of white solid, which is crystal form V (Form 5).

[0200] X-ray powder diffraction analysis:

[0201] The crystalline form V of compound 1 was measured using an X-ray diffractometer (Bruker D8 Advance (Bruker, GER)). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk. Powder diffraction patterns were obtained, and the data were analyzed. The X-ray powder diffraction data of crystalline form V are shown in Table 9.

[0202] Table 9 X-ray powder diffraction data for crystal form V

[0203] The X-ray powder diffraction pattern of crystal form V of compound 1 is shown in Figure 15.

[0204] TGA and DSC analysis:

[0205] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on crystal form V (Form 5) of compound 1. TGA and DSC data were collected using a TGA analyzer (TA Discovery 55 (TA, US)) and a differential scanning calorimeter (TA Discovery 250 (TA, US)), respectively. Table 10 lists the TGA and DSC test parameters. The test results are shown in Figures 16 and 17, respectively. The TGA results show that Form 5 experiences a 0.1404% weight loss during heating to 105℃, and decomposition may occur above 340℃. The DSC results show that Form 5 has broad endothermic peaks corresponding to the TGA weight loss in the ranges of 228–240℃ and 242–250℃.

[0206] Table 10 TGA and DSC Test Parameters

[0207] Test Example 4

[0208] In vivo pharmacokinetic studies

[0209] The results showed that all crystal forms of compound 1, including crystal form I, crystal form II, crystal form III, crystal form IV, and crystal form V, had good pharmacokinetic characteristics.

[0210] Test Example 5

[0211] Stability Study

[0212] Test type and conditions

[0213] 2.1 Influencing Factors Experiment

[0214] 2.1.1 High temperature test: 60℃, open placement

[0215] 2.1.2 High humidity test: 25℃ / 92.5% RH, open storage

[0216] 2.1.3 Light test: 25℃ / 4500Lux, placed in an open container.

[0217] 2.2 Accelerated Testing

[0218] Conditions: 40℃ / 75% RH, sealed storage

[0219] Experimental steps:

[0220] Take crystal form I (Form 1) powder of compound 1 and place it under the following conditions:

[0221] High temperature: in a 60℃ constant temperature drying oven;

[0222] High humidity: 25℃, 92.5% RH constant humidity chamber (achieved through saturated KNO3 solution);

[0223] Illumination: In the illumination test chamber, the illuminance is 4500 Lux and the temperature is 25℃.

[0224] Acceleration: Place in a 40℃ / 75% RH constant temperature and humidity chamber;

[0225] Samples were taken at 7 days and 15 days for XRPD characterization and HPLC testing, and the results are shown in Table 11 and Figure 18.

[0226] Table 11

[0227] XRPD results showed that crystal form I remained stable for 15 days under high temperature, high humidity, light, and accelerated conditions without any crystal form transformation. HPLC results showed that the chemical purity of crystal form I remained essentially unchanged after 15 days under high temperature, high humidity, and accelerated conditions.

[0228] The results showed that crystal form I of compound 1 has good physical and chemical stability, while crystal forms II, III, IV and V also have good physical and chemical stability.

[0229] Test Example 6

[0230] Using crystal form I (Form 1), crystal form II (Form 2), crystal form III (Form 3), crystal form IV (Form 4), and crystal form V (Form 5) as starting materials, competitive suspension experiments of anhydrous systems were conducted at 10℃, RT (room temperature), and 50℃, respectively. The results are shown in Table 12 below.

[0231] Table 12

[0232] The results showed that, within the temperature range of 10-50℃, the competitive suspension experiments in both solvent systems (DMSO / tetrahydrofuran / water, ethylene glycol methyl ether) yielded a final product dominated by crystal form I, indicating that crystal form I is thermodynamically very stable.

[0233] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

A crystalline form of a compound of Formula (I): The crystalline form of claim 1, characterized in that, The crystal form I of the compound shown in formula (I) has characteristic diffraction peaks at the following 2θ positions when subjected to Cu-Kα radiation: 12.227°±0.3°, 16.082°±0.3°, 22.533°±0.3°, and 26.702°±0.3°. The crystalline form of claim 2, characterized in that, The crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 15.533°±0.3°, 16.962°±0.3°, 21.755°±0.3°, 25.007°±0.3°, and 25.357°±0.3°. The crystalline form of claim 3, characterized in that, The crystal form I, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 12.473°±0.3°, 14.961°±0.3°, 17.454°±0.3°, 19.498°±0.3°, and 20.651°±0.3°. The crystalline form according to any one of claims 2 to 4, characterized in that, The X-ray powder diffraction pattern of crystal form I is basically shown in Figure 1. The crystalline form according to any one of claims 2 to 5, characterized in that, The TGA curve of crystal form I is basically shown in Figure 2. The crystalline form according to any one of claims 2 to 5, characterized in that, The DSC curve of crystal form I is basically shown in Figure 3. The crystalline form of claim 1, characterized in that, The crystal form II of the compound shown in formula (I) has characteristic diffraction peaks at the following 2θ positions when subjected to Cu-Kα radiation: 4.048°±0.3°, 8.156°±0.3°, 12.276°±0.3°, and 17.942°±0.3°. The crystalline form of claim 8, characterized in that, The crystal form II, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 16.409°±0.3° and 19.640°±0.3°. The crystalline form according to any one of claims 8 to 9, characterized in that, The X-ray powder diffraction pattern of crystal form II is basically shown in Figure 4. The crystalline form according to any one of claims 8 to 10, characterized in that, The TGA curve of crystal form II is basically shown in Figure 5. The crystalline form according to any one of claims 8 to 10, characterized in that, The DSC curve of crystal form II is basically shown in Figure 6. The crystalline form of claim 1, characterized in that, The crystal form III of the compound shown in formula (I) exhibits characteristic diffraction peaks at the following 2θ positions when subjected to Cu-Kα radiation: 3.384°±0.3°, 18.114°±0.3°, and 26.175°±0.3°. The crystalline form of claim 13, characterized in that, The crystal form III, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 10.616°±0.3°, 13.240°±0.3°, and 22.026°±0.3°. The crystalline form according to any one of claims 13 to 14, characterized in that, The X-ray powder diffraction pattern of crystal form III is basically shown in Figure 7. The crystalline form according to any one of claims 13 to 15, characterized in that, The TGA curve of crystal form III is basically shown in Figure 8. The crystalline form according to any one of claims 13 to 15, characterized in that, The DSC curve of crystal form III is basically shown in Figure 9. The crystalline form of claim 1, characterized in that, The crystal form IV of the compound shown in formula (I) was irradiated with Cu-Kα, and its X-ray powder diffraction pattern had characteristic diffraction peaks at the following 2θ positions: 12.156°±0.3°, 21.724°±0.3°, 15.484°±0.3°, and 22.482±0.3°. The crystalline form of claim 18, characterized in that, The crystal form IV was subjected to Cu-Kα radiation, and its X-ray powder diffraction pattern also showed characteristic diffraction peaks at the following 2θ positions: 26.658°±0.3°, 25.329°±0.3°, 24.955°±0.3°, and 12.391±0.3°. The crystalline form according to any one of claims 18 to 19, characterized in that, The X-ray powder diffraction pattern of crystal form IV is basically shown in Figure 12. The crystalline form according to any one of claims 18 to 20, characterized in that, The TGA curve of the crystal form IV is basically shown in Figure 13. The crystalline form according to any one of claims 18 to 20, characterized in that, The DSC curve of crystal form IV is basically shown in Figure 14. The crystalline form of claim 1, characterized in that, The crystal form V of the compound shown in formula (I) exhibits characteristic diffraction peaks at the following 2θ positions when subjected to Cu-Kα radiation: 4.175°±0.3°, 12.422°±0.3°, and 8.293°±0.3°. The crystalline form of claim 23, characterized in that, The crystal form V, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 18.089°±0.3°, 16.571°±0.3°, and 19.804°±0.3°. The crystalline form of any one of claims 23-24, characterized in that, The X-ray powder diffraction pattern of crystal form V is basically shown in Figure 15. The crystalline form according to any one of claims 23 to 25, characterized in that, The TGA curve of crystal form V is basically shown in Figure 16. The crystalline form according to any one of claims 23 to 25, characterized in that, The DSC curve of crystal form V is basically shown in Figure 17. A process for preparing the crystalline Form I of any one of claims 2 to 7, characterized in that, The preparation method is selected from: The compound shown in formula (I) is added to solvent A-1, and then to solvent A-2 to obtain crystal form I; or The compound shown in formula (I) was added to solvent B and slurried to obtain crystal form I; The solvent A-1 is selected from any one or any mixture of several of the following solvents in any proportion: trifluoroethanol, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, ethanol, n-propanol, acetone and water. Solvent A-2 is selected from any one or any mixture of several of the following solvents in any proportion: methanol, isopropyl acetate, acetonitrile, ethanol, n-propanol, acetone, and water. Solvent B is selected from any one or any mixture of several of the following solvents in any proportion: ethanol, isopropanol, ethyl acetate, toluene, isopropyl acetate, n-heptane, acetonitrile, n-propanol, acetone, and water. The method of claim 28, wherein The preparation method is selected from: The compound shown in formula (I) was added to solvent A-1, then to solvent A-2, and filtered to obtain crystal form I; The solvent A-1 is selected from any one or any mixture of several of the following solvents in any proportion: trifluoroethanol, dimethyl sulfoxide, and N-methylpyrrolidone. Solvent A-2 is selected from any one or any mixture of several of the following solvents in any proportion: methanol, isopropyl acetate, acetone, and water. The method of claim 28, wherein The preparation method is selected from: The compound shown in formula (I) was added to solvent B and pulped at 10 to 60°C for 5 to 10 days, and then filtered to obtain crystal form I. Solvent B is selected from any one or any mixture of several of the following solvents in any proportion: ethanol, isopropanol, ethyl acetate, toluene, isopropyl acetate, and n-heptane. A process for preparing crystalline Form II according to any one of claims 8 to 12, characterized in that, The preparation method is selected from: The compound shown in formula (I) is added to solvent C-1, and then solvent C-2 is added to crystallize or diffuse crystallize to obtain crystal form II; The compound shown in formula (I) is added to solvent C-1 and placed in an atmosphere of solvent C-2 for crystallization or diffusion crystallization to obtain crystal form II; or The compound shown in formula (I) is added to solvent D-1, heated to 40 to 60 °C, then added to solvent D-2, and cooled to crystallize, yielding crystal form II; The solvent C-1 is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion; The solvent C-2 is selected from any one or any mixture of several of isopropyl ether and acetonitrile in any proportion; The solvent D-1 is selected from any one or any mixture of several of 1,4-dioxane, methanol, and acetonitrile in any proportion. The solvent D-2 is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion. A process for preparing the crystalline Form III of any one of claims 13 to 17, characterized in that, The preparation method is selected from: The compound shown in formula (I) was added to solvent E and filtered to obtain crystal form III; The solvent E is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion. A process for preparing the crystalline Form IV of any one of claims 18 to 22, characterized in that, The preparation method is selected from: The compound shown in formula (I) was added to solvent F, heated to 70 to 75°C to dissolve, filtered, and the temperature was controlled at 60 to 65°C. Water was added dropwise to the filtrate, stirred, filtered, and then dried under vacuum at 45 to 55°C to obtain crystal form IV. The solvent F is selected from any one or any mixture of several of trifluoroethanol and N-methylpyrrolidone in any proportion. A method of preparing the crystalline Form V of any one of claims 23 to 27, characterized in that, The preparation method is selected from: The compound shown in formula (I) was added to solvent G, heated to 70 to 75 °C to dissolve, and then the solution was added to water, stirred, filtered, and dried under vacuum at 45 to 55 °C to obtain crystal form V. The solvent G is selected from any one or any mixture of several of trifluoroethanol and N,N-dimethylformamide in any proportion. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form according to any one of claims 1 to 27, and a pharmaceutically acceptable carrier or excipient. Use of the crystal form according to any one of claims 1 to 27, or the pharmaceutical composition according to claim 35, in the preparation of a PARP1 inhibitor. Use of the crystal form according to any one of claims 1 to 27, or the pharmaceutical composition according to claim 35, in the preparation of a medicament for treating and preventing cancer.

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