Crystal form of selective PARP-1 inhibitor, preparation method therefor and use thereof

Abstract

The present disclosure relates to the field of pharmaceutical chemistry, and specifically relates to a crystal form of a selective PARP-1 inhibitor, i.e. a crystal form of a compound represented by formula (I), a preparation method therefor and the use thereof. The crystal form of the compound represented by formula (I) provided by the present disclosure has at least one of the following excellent characteristics: good stability, high purity, good solubility, good dissolution, high bioavailability, low hygroscopicity, good fluidity, good mechanical stress stability, good processability, such as good compressibility, good crystal morphology, good pressure resistance, capability of stable storage, capability of avoiding crystal transformation of a drug during development and storage processes, a simple and reliable preparation method and high development value.

Description

A selective PARP-1 inhibitor crystal form and its preparation method and use

[0001] Citation of Related Applications

[0002] This application claims all rights and interests in the invention patent application with application number 202311585745.4 filed with the State Intellectual Property Office of the People's Republic of China on November 24, 2023, and the invention patent application with application number 202410021396.1 filed with the State Intellectual Property Office of the People's Republic of China on January 5, 2024, and incorporates their entire contents into this application by reference. Technical Field

[0003] The present disclosure relates to the field of medicinal chemistry. Specifically, the present disclosure relates to a crystalline form of a selective PARP-1 inhibitor, a preparation method thereof, and uses thereof. Background Art

[0004] A selective poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor, chemically named 2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide, has a structure represented by the following formula (I) (hereinafter referred to as the compound of formula (I)):

[0005] PARP is an enzyme involved in the regulation of DNA repair. PARP inhibition has been shown to be a successful therapeutic strategy for treating patients carrying harmful germline and / or somatic BRCA mutations, which are present in a significant proportion of breast, ovarian, prostate and pancreatic cancers. The compound of formula (I) is compound 11 in international application WO2014064149A1, which can be used to treat cancer, cardiovascular disease, nervous system damage and inflammation. The compound of formula (I) is the PAR assay IC disclosed in WO2014064149A1. 50It is 0.02 μM, which is a highly active and selective PARP-1 inhibitor. The compound of formula (I) does not induce DNA capture and has higher tolerance in terms of hematopoietic system effects. Due to its high brain penetrance, it has the potential to fight against primary brain tumors and central nervous system metastases. Animal experiments have confirmed that the compound of formula (I) has good in vivo efficacy and low toxicity. The compound of formula (I) is clinically used to treat PARP-1-mediated related diseases, such as cancer, cardiovascular disease, nervous system damage and inflammation. There are currently no public reports on the crystal form of this compound. Therefore, it is necessary to screen the polymorphs of the compound of formula (I) and select a crystal form with excellent properties for the development of formulation products of the compound of formula (I). Summary of the Invention

[0006] The present disclosure provides a crystalline form of a selective PARP-1 inhibitor, which has at least one of the following excellent properties: good stability, high purity, good solubility, good dissolution, high bioavailability, low hygroscopicity, good fluidity, good mechanical stress stability, good processability such as good compressibility, good crystal morphology, good compression resistance, stable storage, avoidance of drug crystal transformation during development and storage, simple and reliable preparation method, and great development value.

[0007] In particular, the crystalline form FB-3 provided by the present disclosure has at least one of the following excellent properties, such as excellent physical and chemical stability under long-term and accelerated conditions, good humidity stability, improved physical stability in water-based formulations or water-based environments, excellent grinding stability and compressibility, extremely low hygroscopicity under 0% RH-80% RH conditions, no crystal transformation in high humidity environments, and excellent solubility in water.

[0008] In particular, the crystalline form FB-2 provided by the present disclosure has at least one of the following excellent properties, such as excellent stability under long-term and accelerated conditions, good humidity stability, improved solubility in water, good purity and crystallinity.

[0009] In particular, the crystalline form FB-4 provided by the present disclosure has at least one of the following excellent properties, such as excellent physical and chemical stability under long-term and accelerated conditions, improved physical stability under high temperature conditions, good purity and crystallinity.

[0010] One aspect of the present disclosure is to provide a crystalline form FB-2 (hereinafter referred to as FB-2) of a compound having a structure as shown in formula (I).

[0011] Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of FB-2 of the compound of formula (I) expressed in 2θ angles has characteristic peaks at one, two or three of 7.9°±0.2°, 19.3°±0.2° and 22.1°±0.2°.

[0012] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 7.9°±0.2°, 19.3°±0.2° and 22.1°±0.2°2θ.

[0013] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) further has characteristic peaks at 14.8±0.2°, 17.5°±0.2° and 21.3°±0.2°2θ, 1 or 2 or 3 of the following: preferably, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 14.8±0.2°, 17.5°±0.2° and 21.3°±0.2°2θ.

[0014] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) further has characteristic peaks at 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ, 1 or 2 or 3 of the following: preferably, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ.

[0015] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 7.9°±0.2°, 19.3°±0.2°, 22.1°±0.2°, 14.8±0.2°, 17.5°±0.2°, 21.3°±0.2°, 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ.

[0016] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has a characteristic peak at 22.1°±0.2°2θ.

[0017] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 7.9°±0.2° and 22.1°±0.2°2θ.

[0018] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) is 6.6°±0.2°, 7.9°±0.2°, 9.8°±0.2°, 12.0°±0.2°, 13.4°±0.2°, 14.5°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 20.3°±0.2°, 21.3°±0.2°, 22.1°±0.2°, 23.6°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25 There are characteristic peaks at 0.2°, 25.1°±0.2°, 25.4°±0.2°, 25.9°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 28.9°±0.2°, 29.2°±0.2°, 29.7°±0.2°, 30.2°±0.2°, 31.0°±0.2°, 31.9°±0.2°, 32.6°±0.2°, 33.2°±0.2°, 33.9°±0.2°, 35.4°±0.2°, 35.7°±0.2°, 36.7°±0.2°, 37.4°±0.2° and 39.3°±0.2°2θ.

[0019] Without limitation, in a specific embodiment, the compound FB-2 of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG1 or FIG5 .

[0020] In the preferred technical solution of the present disclosure, the FB-2 of the compound of formula (I) is substantially pure.

[0021] Preferably, the FB-2 of the compound of formula (I) has a purity greater than 90%; preferably, a purity greater than 95%; more preferably, a purity greater than 99%.

[0022] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum (FT-IR) of the compound of formula (I) FB-2 is at 3194.28 cm -1 ±5cm -1 、2932.13cm -1 ±5cm -1 、2848.39cm -1 ±5cm -1 、1664.03cm -1 ±5cm -1 、1389.40cm - 1 ±5cm -1and 742.75cm -1 ±5cm -1 There is a band in at least one of the two.

[0023] Without limitation, the compound FB-2 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG2 .

[0024] Without limitation, FB-2 of the compound of formula (I) is an anhydrate.

[0025] Without limitation, the compound FB-2 of formula (I) has a TGA pattern substantially as shown in FIG4 .

[0026] Without limitation, the compound FB-2 of formula (I) has a DSC spectrum substantially as shown in FIG3 .

[0027] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-2 of the compound of formula (I), the preparation method comprising forming a suspension of the compound of formula (I) in solvent 1, stirring, separating the solid, and drying to obtain FB-2 of the compound of formula (I); wherein the solvent 1 is a mixed solvent of ethyl acetate and methyl tert-butyl ether.

[0028] In some embodiments, the volume ratio of ethyl acetate to methyl tert-butyl ether is 2:3.

[0029] Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C.

[0030] In some specific embodiments, the stirring time is 3 days, and the stirring temperature is room temperature.

[0031] Preferably, the drying temperature is 30°C-80°C, more preferably 40°C.

[0032] The crystalline form FB-2 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

[0033] 1) Good stability. FB-2 of the compound of formula (I) described in the present disclosure maintains its crystalline form and chemical purity after 60 days of storage under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions, demonstrating excellent physical and chemical stability.

[0034] At the same time, the crystal form FB-2 remains unchanged before and after the DVS test, and has good humidity stability.

[0035] 2) Good solubility: The solubility of the crystalline form FB-2 provided in the present disclosure can meet pharmaceutical requirements.

[0036] 3) High purity: The purity of the crystal form FB-2 provided in the present disclosure is as high as 99.9% or more, which is conducive to industrial production.

[0037] 4) Good crystallinity: The crystal form FB-2 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0038] 5) The preparation method is simple, highly reproducible, and has great industrialization prospects.

[0039] Another aspect of the present disclosure is to provide a crystalline form FB-3 (hereinafter referred to as FB-3) of a compound having a structure as represented by formula (I). Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) expressed in 2θ angles has characteristic peaks at one, two, or three of 4.7±0.2°, 9.5°±0.2°, and 18.1°±0.2°.

[0040] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 4.7±0.2°, 9.5°±0.2° and 18.1°±0.2°.

[0041] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at one, two or three of 11.9°±0.2°, 20.1°±0.2° and 21.9°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 11.9°±0.2°, 20.1°±0.2° and 21.9°±0.2°2θ.

[0042] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at one, two or three of 13.0°±0.2°, 17.5°±0.2° and 23.4°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 13.0°±0.2°, 17.5°±0.2° and 23.4°±0.2°2θ.

[0043] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 4.7±0.2°, 9.5±0.2°, 18.1±0.2°, 11.9±0.2°, 20.1±0.2°, 21.9±0.2°, 13.0±0.2°, 17.5±0.2°, and 23.4±0.2°2θ.

[0044] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of formula (I) has a characteristic peak at 4.7°±0.2°2θ.

[0045] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of formula (I) has a characteristic peak at 9.5°±0.2°2θ.

[0046] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of formula (I) has characteristic peaks at 4.7°±0.2° and 18.1°±0.2°2θ.

[0047] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of formula (I) has characteristic peaks at 9.5°±0.2° and 18.1°±0.2°2θ.

[0048] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of formula (I) has characteristic peaks at 4.7°±0.2° and 9.5°±0.2°2θ.

[0049] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) is 4.7°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 11.2°±0.2°, 11.9°±0.2°, 13.0°±0.2°, 14.3°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 23.1°±0.2°, 23.4°±0.2°, 24.0°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 26.3°±0.2°, 26.6°±0.2°, 27.0°±0.2°, 28.3°±0.2°, 28.5°±0.2°, 29.2°±0.2°, 30.3°±0.2°, 31.0°±0.2°, 31. There are characteristic peaks at 5°±0.2°, 32.1°±0.2°, 32.9°±0.2°, 34.0°±0.2°, 34.5°±0.2°, 36.8°±0.2°, 37.2°±0.2°, 37.9°±0.2°, 38.6°±0.2°, 39.4°±0.2° and 39.7°±0.2°2θ.

[0050] Without limitation, the compound FB-3 of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG6 or FIG10 or FIG11(A) or FIG11(B).

[0051] In the preferred technical solution of the present disclosure, the FB-3 of the compound of formula (I) is substantially pure.

[0052] Preferably, the purity is greater than 90%; more preferably, the purity is greater than 95%; and more preferably, the purity is greater than 99%.

[0053] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of FB-3 of the compound of formula (I) is at 3225.55 cm -1 ±5cm -1 、3067.03cm -1 ±5cm -1 、2958.00cm -1 ±5cm -1 、1620.43cm -1 ±5cm -1 、1593.18cm -1 ±5cm -1 and 735.01cm -1 ±5cm-1 There is a band in at least one of the two.

[0054] Without limitation, the compound FB-3 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 7 .

[0055] In the preferred technical solution of the present disclosure, FB-3 of the compound of formula (I) is a tunnel hydrate or anhydrate.

[0056] Without limitation, FB-3 of the compound of formula (I) is an anhydrate.

[0057] Without limitation, the compound FB-3 of formula (I) has a TGA pattern substantially as shown in FIG9 .

[0058] Without limitation, the compound of formula (I) FB-3 has a DSC spectrum substantially as shown in FIG8 .

[0059] Another aspect of the present disclosure is to provide a method for preparing the crystalline form FB-3 of the compound of formula (I), wherein the preparation method is selected from any one of the following methods:

[0060] 1) dissolving the compound of formula (I) in solvent 2 and volatilizing to obtain FB-3 of the compound of formula (I); wherein the solvent 3 is acetonitrile; or

[0061] 2) forming a suspension of the compound of formula (I) in solvent 3, stirring, separating the solid, and drying to obtain FB-3 of the compound of formula (I); wherein the solvent 3 is isopropyl ether;

[0062] Preferably, the volatilization temperature in method 1) is room temperature.

[0063] Preferably, a small amount of FB-3 seed crystals can be added to the suspension in method 2) and stirred together.

[0064] Preferably, in method 2), the stirring time is ≥ 1 h, and the stirring temperature is 4° C.-80° C.

[0065] In some specific embodiments, the stirring time is 1 day, 2 days, or 3 days, and the stirring temperature is room temperature.

[0066] Preferably, the drying temperature is 30°C-80°C, more preferably 40°C.

[0067] The crystalline form FB-3 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

[0068] 1) Good stability. The crystalline form FB-3 of the compound of formula (I) disclosed herein maintains its crystalline form and chemical purity after 60 days of storage under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions. This demonstrates excellent physical and chemical stability, facilitating drug storage.

[0069] At the same time, crystalline form FB-3 can maintain its crystal form unchanged in pure water or aqueous environments and has good stability in water. This makes crystalline form FB-3 particularly suitable for aqueous preparation processes, such as wet granulation, and also makes it easier for preparations prepared using crystalline form FB-3 to maintain crystal stability in environments with high humidity.

[0070] At the same time, the crystal form FB-3 remains unchanged after grinding and has good mechanical stability. Grinding and crushing of raw materials is often required during the preparation processing. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of raw materials during the preparation processing.

[0071] Meanwhile, Form FB-3 is the most thermodynamically stable form in water and n-heptane. A solid mixture of Forms FB-2, FB-3, and FB-4 transformed into Form FB-3 when stirred in water and n-heptane, respectively.

[0072] 2) Good solubility. The solubility of the crystalline form FB-3 provided in the present disclosure can meet the requirements for pharmaceutical use.

[0073] 3) Good compressibility. The crystalline form FB-3 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during tableting and improve production efficiency.

[0074] 4) High purity. The crystalline form FB-3 provided herein has a purity exceeding 99.9%, making it suitable for industrial production. Crystalline form FB-3 has a strong impurity removal capability, and the disclosed preparation method and crystallization process can yield a high-purity API, which is less susceptible to residual solvents and is therefore suitable for pharmaceutical use.

[0075] 5) Good crystallinity. The crystal form FB-3 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0076] 6) The preparation method is simple, highly reproducible, and has great industrialization prospects.

[0077] One aspect of the present disclosure is to provide a crystalline form FB-4 (hereinafter referred to as FB-4) of a compound having a structure as represented by formula (I). Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) expressed in 2θ angles has characteristic peaks at one, two, or three of 5.9°±0.2°, 16.5°±0.2°, and 21.7°±0.2°.

[0078] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 5.9°±0.2°, 16.5°±0.2° and 21.7°±0.2°2θ.

[0079] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at at least one of 11.6±0.2°, 13.1°±0.2° and 26.8°±0.2°2θ.

[0080] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at one, two, or three of 11.6±0.2°, 13.1°±0.2°, and 26.8°±0.2° 2θ. Preferably, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 11.6±0.2°, 13.1°±0.2°, and 26.8°±0.2° 2θ.

[0081] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at at least one of 17.2°±0.2°, 20.7°±0.2° and 24.7°±0.2°2θ.

[0082] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at one, two, or three of 17.2°±0.2°, 20.7°±0.2°, and 24.7°±0.2° 2θ. Preferably, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 17.2°±0.2°, 20.7°±0.2°, and 24.7°±0.2° 2θ.

[0083] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 5.9°±0.2°, 16.5°±0.2°, 21.7°±0.2°, 11.6±0.2°, 13.1°±0.2°, 26.8°±0.2°, 17.2°±0.2°, 20.7°±0.2° and 24.7°±0.2°2θ.

[0084] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has a characteristic peak at 5.9°±0.2°2θ.

[0085] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has a characteristic peak at 16.5°±0.2°2θ.

[0086] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-4 of formula (I) has characteristic peaks at 5.9°±0.2° and 21.7°±0.2°2θ.

[0087] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound of formula (I) FB-4 has characteristic peaks at 16.5°±0.2° and 21.7°±0.2° 2θ.

[0088] Without limitation, in a specific embodiment, the compound of formula (I) FB-4 has an XRPD pattern substantially as shown in FIG12 .

[0089] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of FB-4 of the compound of formula (I) is at 3230.3 cm -1 ±5cm -1 、2920.6cm -1 ±5cm -1 、1662.4cm -1 ±5cm -1 、1596.1cm -1 ±5cm -1 、1389.9cm -1 ±5cm -1 and 738.4cm -1 ±5cm -1 There is a band in at least one of the two.

[0090] Without limitation, in a specific embodiment, the compound FB-4 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 15 .

[0091] In the preferred technical solution of the present disclosure, the FB-4 of the compound of formula (I) is substantially pure.

[0092] Preferably, the FB-4 of the compound of formula (I) has a purity greater than 90%; preferably, a purity greater than 95%; more preferably, a purity greater than 99%.

[0093] Without limitation, FB-4 of the compound of formula (I) is an anhydrate.

[0094] Without limitation, the compound of formula (I) FB-4 has a TGA pattern substantially as shown in FIG13 .

[0095] Without limitation, the compound of formula (I) FB-4 has a DSC spectrum substantially as shown in FIG14 .

[0096] In the preferred technical solution of the present disclosure, FB-4 of the compound of formula (I) is a stable crystal form under high temperature conditions.

[0097] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-4 of the compound of formula (I), wherein the preparation method is selected from any one of the following methods:

[0098] 1) Suspending the compound of formula (I) in water, stirring, separating the solid, heating the solid to above 170° C., and then cooling to room temperature to obtain FB-4;

[0099] Preferably, the solid is a solid form other than FB-4 of the compound of formula (I);

[0100] Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C.

[0101] 2) dissolving the compound of formula (I) in solvent 4, adding FB-4 seed crystals, stirring, centrifuging, and drying to obtain FB-4;

[0102] Preferably, the solvent 4 is selected from a mixture of ethanol and water or a mixture of acetone and water;

[0103] Preferably, the dissolving is carried out under high temperature conditions;

[0104] Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C.

[0105] The crystalline form FB-4 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

[0106] 1) Good stability. The crystalline form FB-4 described in the present disclosure maintains its crystalline form and chemical purity after 60 days of storage under long-term (25°C / 60% RH / open) and accelerated (40°C / 75% RH / open) conditions, demonstrating excellent physical and chemical stability.

[0107] 2) High melting point. The crystal form FB-4 disclosed in the present invention has a high melting point, close to 240°C, and has good high-temperature crystal stability.

[0108] 3) Good solubility. The solubility of the crystalline form FB-4 provided in the present disclosure can meet the requirements for pharmaceutical use.

[0109] 4) High purity: The purity of the crystal form FB-4 provided in the present disclosure is as high as 99.9% or more, which is conducive to industrial production.

[0110] 5) Good crystallinity: The crystal form FB-4 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0111] 6) The preparation method is simple, highly reproducible, and has great industrialization prospects.

[0112] In another aspect, the present disclosure relates to pharmaceutically acceptable solid state forms of compounds of formula (I).

[0113] Preferably, the present disclosure relates to crystalline compounds of formula (I).

[0114] Preferably, the present disclosure relates to the crystalline anhydrate of the compound of formula (I).

[0115] Preferably, the present disclosure relates to crystalline tunnel hydrates of the compound of formula (I).

[0116] Preferably, the present disclosure relates to the amorphous free base of the compound of formula (I).

[0117] Preferably, the present disclosure relates to the anhydrate crystalline form FB-2 of the compound of formula (I).

[0118] Preferably, the present disclosure relates to the anhydrate crystalline form FB-3 of the compound of formula (I).

[0119] Preferably, the present disclosure relates to the anhydrate crystalline form FB-4 of the compound of formula (I).

[0120] Another aspect of the present disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) FB-2, FB-3 and FB-4 of the present disclosure, and at least one pharmaceutically acceptable carrier.

[0121] The pharmaceutically acceptable carrier is selected according to the mode and route of administration.

[0122] The above pharmaceutical composition may further comprise one or more other crystalline forms of the compound of formula (I), and at least one pharmaceutically acceptable carrier.

[0123] Suitable carriers may be, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose.

[0124] Without limitation, the pharmaceutical composition may also include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0125] Without limitation, the pharmaceutical composition may further comprise one or more pH adjusters or buffers, for example: an acid, such as any one of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid, or a combination thereof; or a base, such as any one of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris(hydroxymethyl)aminomethane, or a combination thereof; or a buffer, such as citrate / dextrose, sodium bicarbonate, ammonium chloride, and the like; such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, and other counterions; and other amounts required to maintain the pH of the components within an acceptable range, comprising solutions or solids of such acids, bases, and buffers.

[0126] Without limitation, routes of administration of the pharmaceutical composition include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intracerebroventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.

[0127] Another aspect of the present disclosure is to provide a preparation prepared from the above-mentioned pharmaceutical composition, wherein the preparation is in the form selected from oral preparations and parenteral preparations.

[0128] In the preferred technical solution of the present disclosure, the preparation form is capsule, tablet, suspension, powder, sustained-release preparation, immediate-release preparation, pill, suppository, granule, granule / tablet, sachet, cachet, tincture, elixir, emulsion, cream, aerosol, gel, solution and syrup.

[0129] In the preferred technical solution of the present disclosure, the preparation is in the form of an oral preparation; preferably, the preparation is in the form of a capsule.

[0130] Another aspect of the present disclosure is to provide the use of one or more compounds of formula (I) FB-2, FB-3 and FB-4 or their pharmaceutical compositions or preparations in the preparation of drugs for treating diseases mediated by PARP-1.

[0131] Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

[0132] Preferably, the cancer is selected from bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic cancer of the lymphoid lineage; Tumors of the central and peripheral nervous system include astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including melanomas, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma, and Kaposi's sarcoma. Preferably, the cancer, such as breast cancer, ovarian cancer, or glioma, is a BRCA mutant.

[0133] Preferably, the cancer is glioma.

[0134] Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

[0135] Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

[0136] Preferably, the inflammatory disease is selected from the group consisting of colitis, arthritis and uveitis.

[0137] Another aspect of the present disclosure is to provide a method for treating diseases mediated by PARP-1, which comprises administering to a patient one or more FB-2, FB-3 and FB-4 of the compound of formula (I) described in the present disclosure or their pharmaceutical compositions or formulations.

[0138] Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

[0139] Another aspect of the present disclosure is to provide a method for treating cancer, comprising administering to a patient one or more of the crystalline forms FB-2, FB-3 and FB-4 of the compound of formula (I) described in the present disclosure or their pharmaceutical compositions or formulations.

[0140] Preferably, the cancer is selected from bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic cancer of the lymphoid lineage; Tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including melanomas, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma, and Kaposi's sarcoma. Preferably, the cancer, such as breast cancer, ovarian cancer, or glioma, is a BRCA mutant.

[0141] Preferably, the cancer is glioma.

[0142] Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

[0143] Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

[0144] Preferably, the inflammatory disease is selected from the group consisting of colitis, arthritis and uveitis.

[0145] Another aspect of the present disclosure is to provide one or more compounds of formula (I) FB-2, FB-3 and FB-4 described in the present disclosure or their pharmaceutical compositions or preparations in combination with other drugs.

[0146] Preferably, the other drug is temozolomide.

[0147] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0148] The term "about" means having a value that falls within an acceptable standard of error of the mean when considered by one skilled in the art.

[0149] The term "therapeutically effective amount" as used herein refers to that amount of the administered compound which will relieve to some extent one or more of the symptoms of the condition being treated.

[0150] As used herein, unless otherwise indicated, the term "treat" refers to reversing, alleviating the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject.

[0151] Unless otherwise specified, the "room temperature" described in this disclosure refers to a temperature of 10 to 30°C.

[0152] The "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration. Among them, the reduced pressure filtration is generally carried out at room temperature with a pressure less than atmospheric pressure.

[0153] The drying process can be accomplished using conventional techniques in the art, such as room temperature drying, forced air drying, or reduced pressure drying, and can be performed under reduced pressure or without reduced pressure. The drying apparatus and method are not limited and can include a fume hood, forced air oven, spray dryer, fluidized bed dryer, or vacuum oven; and can be performed under reduced pressure or without reduced pressure.

[0154] The "relative intensity (I%)" is expressed as a specific value in a specific XRPD pattern. Due to the anisotropic properties of crystals and the principles of X-ray powder diffraction, the relative intensity values ​​of diffraction peaks within the same crystal form may fluctuate due to the preferred orientation of the sample. It is common knowledge among those skilled in the art that such fluctuations do not affect the determination of the same crystal form.

[0155] Unless otherwise specified, the ratios involved in the present disclosure are mass-to-volume ratios between liquids and solids, and volume ratios between liquids. BRIEF DESCRIPTION OF THE DRAWINGS

[0156] FIG1 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I);

[0157] FIG2 is an FT-IR spectrum of the crystalline form FB-2 of the compound of formula (I);

[0158] FIG3 is a DSC spectrum of the crystalline form FB-2 of the compound of formula (I);

[0159] FIG4 is a TGA spectrum of the crystalline form FB-2 of the compound of formula (I);

[0160] FIG5 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I) in Example 2;

[0161] FIG6 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I);

[0162] FIG7 is an FT-IR spectrum of the crystalline form FB-3 of the compound of formula (I);

[0163] FIG8 is a DSC spectrum of the crystalline form FB-3 of the compound of formula (I);

[0164] FIG9 is a TGA spectrum of the crystalline form FB-3 of the compound of formula (I);

[0165] FIG10 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I) in Example 4;

[0166] FIG11(A) is a full XRPD pattern of the crystalline form FB-3 of the compound of formula (I) in Example 5;

[0167] FIG11(B) is an enlarged XRPD pattern of Form FB-3 of the compound of formula (I) in Example 5;

[0168] FIG12 is an XRPD pattern of the crystalline form FB-4 of the compound of formula (I);

[0169] FIG13 is a TGA spectrum of the crystalline form FB-4 of the compound of formula (I);

[0170] FIG14 is a DSC spectrum of the crystalline form FB-4 of the compound of formula (I);

[0171] Figure 15 is an FT-IR spectrum of the crystalline form FB-4 of the compound of formula (I);

[0172] FIG16 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after long-term (25° C. / 60% RH / unopen) and accelerated (40° C. / 75% RH / unopen) storage conditions;

[0173] FIG17 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after long-term (25° C. / 60% RH / unopen) and accelerated (40° C. / 75% RH / unopen) storage conditions;

[0174] FIG18 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after long-term (25° C. / 60% RH / unopen) and accelerated (40° C. / 75% RH / unopen) storage conditions;

[0175] FIG19 is an XRPD diagram of Form FB-3 of the compound of formula (I) before and after grinding;

[0176] Figure 20 is a DVS spectrum of the crystalline form FB-2 of the compound of formula (I);

[0177] FIG21 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after DVS testing;

[0178] Figure 22 is a DVS spectrum of the crystalline form FB-3 of the compound of formula (I);

[0179] FIG23 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after DVS testing;

[0180] FIG24 is a DVS spectrum of the crystalline form FB-4 of the compound of formula (I);

[0181] FIG25 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after DVS testing;

[0182] FIG26 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after tableting;

[0183] FIG27 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after solubility testing in water;

[0184] FIG28 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after solubility testing in water;

[0185] FIG29 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after solubility testing in water;

[0186] Figure 30 is an XRPD overlay of a mixture of crystalline forms FB-2, FB-3 and FB-4 of the compound of formula (I) before and after competition in water and n-heptane. DETAILED DESCRIPTION

[0187] The following examples will help to further understand the present disclosure, but are not intended to limit the contents of the present disclosure.

[0188] Testing instruments and methods:

[0189] HPLC determination method: chromatograph model: Ultimate3000, chromatographic column: C18 5μm 4.6*250mm, column temperature: 30°C, flow rate: 1.1mL / min, detection wavelength: 254nm, diluent: acetonitrile, run time: 30min, mobile phase A: acetonitrile + 0.1% trifluoroacetic acid solution; mobile phase B: water + 0.1% trifluoroacetic acid solution.

[0190] In the present disclosure, the compound represented by formula (I) as the starting material can be obtained commercially or prepared by existing techniques, such as the method mentioned in WO2014064149A1.

[0191] Example 1: Preparation of Crystalline Form FB-2 of the Compound of Formula (I)

[0192] About 20 mg of the compound of formula (I) was taken, 0.4 mL of ethyl acetate and 0.6 mL of methyl tert-butyl ether were added to obtain a suspension, and the suspension was stirred at room temperature for 3 days. The solid was separated and dried in vacuo at 40°C overnight to obtain FB-2.

[0193] The XRPD data are shown in the following table:

[0194] Its XRPD pattern is shown in Figure 1.

[0195] Its Fourier transform infrared spectrum is shown in Figure 2.

[0196] Its DSC spectrum is shown in Figure 3.

[0197] The TGA spectrum thereof is shown in FIG4 , which shows that there is a weight loss of about 0.8% before 120° C.

[0198] The FB-2 prepared in this example is an anhydrous form.

[0199] Example 2: Preparation of Crystalline Form FB-2 of the Compound of Formula (I)

[0200] About 200 mg of the compound of formula (I) was added with 0.8 mL of ethyl acetate and 1.2 mL of methyl tert-butyl ether to obtain a suspension. The suspension was stirred at room temperature for 5 days, and the solid was separated and dried under vacuum at 40° C. overnight to obtain FB-2.

[0201] After testing, its XRPD pattern is shown in Figure 5.

[0202] Example 3: Preparation of Crystalline Form FB-3 of the Compound of Formula (I)

[0203] About 20 mg of the compound of formula (I) was added to 1.2 mL of isopropyl ether to obtain a suspension. The suspension was stirred at room temperature for 3 days, and the solid was separated and dried in vacuo at 40° C. overnight to obtain FB-3.

[0204] The XRPD data are shown in the following table:

[0205] Its XRPD pattern is shown in Figure 6.

[0206] Its Fourier transform infrared spectrum is shown in Figure 7.

[0207] Its DSC spectrum is shown in Figure 8.

[0208] Its TGA spectrum is shown in Figure 9.

[0209] The FB-3 prepared in this example is an anhydrous form.

[0210] Example 4: Preparation of Crystalline Form FB-3 of the Compound of Formula (I)

[0211] About 200 mg of the compound of formula (I) was added to 2 mL of isopropyl ether to obtain a suspension, to which a small amount of FB-3 seed crystals was added. The suspension was stirred at room temperature for 1 day, centrifuged, and dried in vacuo at 40°C overnight.

[0212] After testing, its XRPD pattern is shown in Figure 10.

[0213] Example 5: Preparation of Crystalline Form FB-3 of the Compound of Formula (I)

[0214] About 5 mg of the compound of formula (I) was taken, added into 2 mL of acetonitrile to dissolve, and evaporated to dryness at room temperature to obtain FB-3.

[0215] After testing, its XRPD spectrum is shown in Figures 11(A) and 11(B), wherein Figure 11(B) is a partial enlarged view of Figure 11(A).

[0216] Example 6: Preparation of Crystalline Form FB-4 of the Compound of Formula (I)

[0217] About 20 mg of the compound of formula (I) was added to 1.0 mL of water to obtain a suspension, which was stirred at room temperature for 3 days. A solid was separated, and the solid was heated to 170° C. for 5 min and then cooled to room temperature to obtain FB-4.

[0218] The XRPD data are shown in the following table:

[0219] Its XRPD pattern is shown in Figure 12.

[0220] The TGA spectrum thereof is shown in FIG13 , which shows that there is a weight loss of about 0.4% before 150° C.

[0221] The DSC spectrum thereof is shown in FIG14 , which shows that an endothermic peak begins to appear when heated to around 239° C., which is the melting point of FB-4.

[0222] Its FT-IR spectrum is shown in Figure 15.

[0223] The FB-4 prepared in this example is an anhydrous form.

[0224] Example 7: Preparation of Crystalline Form FB-4 of the Compound of Formula (I)

[0225] Take about 100 mg of the compound of formula (I), add 5.0 mL of ethanol and 1.0 mL of water, heat to 60°C to dissolve, add 5 mg of FB-4 seeds at room temperature, stir for 2 h, centrifuge, and dry in vacuum at 40°C overnight to obtain FB-4.

[0226] Example 8: Physical and chemical stability studies

[0227] Appropriate samples of the disclosed Forms FB-2, FB-3, and FB-4 were taken and placed under long-term (25°C / 60% RH / unexposed) and accelerated (40°C / 75% RH / unexposed) conditions. Purity and crystal form were determined periodically using HPLC and XRPD. The results are shown in Table 1 and Figures 16-18.

[0228] Table 1

[0229] The results show that the crystal forms FB-2, FB-3 and FB-4 remain unchanged for at least 60 days under long-term (25°C / 60% RH / open) and accelerated (40°C / 75% RH / open) conditions, and the chemical purity before and after placement remains basically unchanged. It can be seen that the crystal forms FB-2, FB-3 and FB-4 have good physical and chemical stability under long-term and accelerated conditions.

[0230] Example 9: Grinding stability study

[0231] An appropriate amount of the disclosed crystal form FB-3 sample was taken, placed in a mortar, and manually ground. The XRPD patterns of the sample before and after grinding were measured. The XRPD patterns before and after grinding are shown in FIG19 .

[0232] The results showed that the crystal form of FB-3 remained unchanged before and after grinding, and had good grinding stability.

[0233] Example 10: Hygroscopicity Study

[0234] The hygroscopicity of the crystal forms FB-2, FB-3 and FB-4 disclosed herein was tested using a dynamic moisture sorption (DVS) instrument. The crystal forms were tested using XRPD before and after the DVS test. The results are shown in Figures 20-25.

[0235] The results showed that the moisture weight gains of the crystal forms FB-2, FB-3 and FB-4 from 0 to 80% were 2.1 w / w%, 0.1 w / w% and 1.9 w / w%, respectively. The crystal forms remained unchanged before and after the DVS test.

[0236] Example 11: Powder Compressibility Study

[0237] A certain amount of crystalline form FB-3 sample was weighed and placed in an infrared tablet press. The pressure was maintained at 2 MPa for 2 minutes, and the crystal form was tested before and after tableting. The results are shown in Figure 26.

[0238] The results showed that the crystal form of FB-3 remained unchanged before and after tableting.

[0239] Example 12: Solubility Study

[0240] Approximately 40 mg of each of Forms FB-2, FB-3, and FB-4 was weighed and added to 5 mL of water. The mixture was stirred at room temperature, and samples were taken periodically to test solubility and crystal form. The results are shown in Table 2 and Figures 27-29.

[0241] Table 2

[0242] The results showed that the crystal forms FB-2, FB-3 and FB-4 all had high solubility in water at room temperature for 24 hours, among which the crystal form FB-3 did not undergo transformation. The crystal forms FB-2 and FB-4 underwent transformation during the 24-hour test, and the crystal form FB-3 began to appear.

[0243] Example 13: Crystal form conversion study

[0244] Appropriate amounts of the disclosed Forms FB-2, FB-3, and FB-4 were mixed and sampled for XRPD characterization. 1 mL of the corresponding solvent was added to the mixed sample to form a suspension, which was stirred at room temperature and sampled for XRPD characterization. The results are shown in Table 3 and Figure 30.

[0245] Table 3

[0246] The results showed that the mixed samples of crystalline forms FB-2, FB-3 and FB-4 were transformed into crystalline form FB-3 after being stirred in water and n-heptane for 6 days, respectively.

[0247] The above description is merely a specific embodiment of the present disclosure, but the scope of protection of the present disclosure is not limited thereto. Any changes or substitutions that can be conceived by a person skilled in the art within the technical scope disclosed in the present disclosure without inventive effort should be included in the scope of protection of the present disclosure. Therefore, the scope of protection of the present disclosure should be based on the scope of protection defined in the claims.

Claims

1. A crystalline form FB-2 of a compound having a structure as shown in formula (I), Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) expressed in 2θ angle has characteristic peaks at one, two or three of 7.9°±0.2°, 19.3°±0.2° and 22.1°±0.2°.

2. FB-2 of the compound of formula (I) according to claim 1, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 7.9°±0.2°, 19.3°±0.2° and 22.1°±0.2° 2θ.

3. FB-2 of the compound of formula (I) according to claim 1, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) further has characteristic peaks at 1, 2 or 3 of 14.8±0.2°, 17.5°±0.2° and 21.3°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 14.8±0.2°, 17.5°±0.2° and 21.3°±0.2°2θ.

4. FB-2 of the compound of formula (I) according to claim 1, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) further has characteristic peaks at 1, 2 or 3 of 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has characteristic peaks at 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ.

5. FB-2 of the compound of formula (I) according to claim 1, characterized in that The compound FB-2 of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 5 .

6. FB-2 of the compound of formula (I) according to claim 1, characterized in that The FB-2 of the compound of formula (I) is substantially pure. Preferably, the FB-2 of the compound of formula (I) has a purity greater than 99%.

7. FB-2 of the compound of formula (I) according to claim 1, characterized in that The Fourier infrared spectrum of FB-2 of the compound of formula (I) is at 3194.28 cm -1 ±5cm -1 、2932.13cm -1 ±5cm -1 、2848.39cm -1 ±5cm -1 、1664.03cm -1 ±5cm -1 、1389.40cm -1 ±5cm -1 and 742.75cm -1 ±5cm -1 There is a band in at least one of the regions.

8. FB-2 of the compound of formula (I) according to claim 1, characterized in that The compound FB-2 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 2 .

9. FB-2 of the compound of formula (I) according to claim 1, characterized in that The FB-2 of the compound of formula (I) is an anhydrate.

10. A method for preparing the crystalline form FB-2 of the compound of formula (I) according to any one of claims 1 to 9, the method comprising forming a suspension of the compound of formula (I) in solvent 1, stirring, separating the solid, and drying to obtain FB-2 of the compound of formula (I); wherein the solvent 1 is a mixed solvent of ethyl acetate and methyl tert-butyl ether.

11. A crystalline form FB-3 of a compound having a structure as shown in formula (I), characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) expressed in 2θ angle has characteristic peaks at one, two or three of 4.7±0.2°, 9.5°±0.2° and 18.1°±0.2°.

12. FB-3 of the compound of formula (I) according to claim 11, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has characteristic peaks at 4.7±0.2°, 9.5°±0.2° and 18.1°±0.2°.

13. FB-3 of the compound of formula (I) according to claim 11, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at one, two or three of 11.9°±0.2°, 20.1°±0.2° and 21.9°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 11.9°±0.2°, 20.1°±0.2° and 21.9°±0.2°2θ.

14. FB-3 of the compound of formula (I) according to claim 11, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at one, two or three of 13.0°±0.2°, 17.5°±0.2° and 23.4°±0.2°2θ; preferably, the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 13.0°±0.2°, 17.5°±0.2° and 23.4°±0.2°2θ.

15. FB-3 of the compound of formula (I) according to claim 11, characterized in that The FB-3 of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 6 or FIG. 10 or FIG. 11(A) or FIG. 11(B).

16. FB-3 of the compound of formula (I) according to claim 11, characterized in that The FB-3 of the compound of formula (I) is substantially pure. Preferably, the FB-3 of the compound of formula (I) has a purity greater than 99%.

17. FB-3 of the compound of formula (I) according to claim 11, characterized in that The Fourier infrared spectrum of FB-3 of the compound of formula (I) is at 3225.55 cm -1 ±5cm -1 、3067.03cm -1 ±5cm -1 、2958.00cm -1 ±5cm -1 、1620.43cm -1 ±5cm -1 、1593.18cm -1 ±5cm -1 and 735.01cm -1 ±5cm -1 There is a band in at least one of the regions.

18. FB-3 of the compound of formula (I) according to claim 11, characterized in that The compound FB-3 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 7 .

19. FB-3 of the compound of formula (I) according to claim 11, characterized in that The FB-3 of the compound of formula (I) is an anhydrate.

20. A method for preparing FB-3 of the compound of formula (I) according to any one of claims 11 to 19, wherein the method is selected from any one of the following methods: 1) dissolving the compound of formula (I) in solvent 2 and volatilizing to obtain FB-3 of the compound of formula (I); wherein the solvent 3 is acetonitrile; or 2) forming a suspension of the compound of formula (I) in solvent 3, stirring, separating the solid, and drying to obtain FB-3 of the compound of formula (I); wherein the solvent 3 is isopropyl ether; Preferably, in method 2), a small amount of FB-3 seed crystals can be added to the suspension and stirred together.

21. A crystalline form FB-4 of a compound having a structure as shown in formula (I), characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) expressed in 2θ angle has characteristic peaks at one, two or three of 5.9°±0.2°, 16.5°±0.2° and 21.7°±0.2°.

22. FB-4 of the compound of formula (I) according to claim 21, characterized in that The X-ray powder diffraction spectrum of the compound FB-4 represented by the formula (I) has characteristic peaks at 5.9°±0.2°, 16.5°±0.2° and 21.7°±0.2°2θ.

23. FB-4 of the compound of formula (I) according to claim 21, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at 11.6±0.2°, 13.1°±0.2° and 26.8°±0.2°2θ, 1 or 2 or 3. Preferably, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 11.6±0.2°, 13.1°±0.2° and 26.8°±0.2°2θ.

24. FB-4 of the compound of formula (I) according to claim 21, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) further has characteristic peaks at 17.2°±0.2°, 20.7°±0.2° and 24.7°±0.2°2θ, 1 or 2 or 3. Preferably, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 17.2°±0.2°, 20.7°±0.2° and 24.7°±0.2°2θ.

25. FB-4 of the compound of formula (I) according to claim 21, characterized in that FB-4 of the compound of formula (I) has an XRPD pattern substantially as shown in FIG. 12 .

26. FB-4 of the compound of formula (I) according to claim 21, characterized in that The Fourier infrared spectrum of FB-4 of the compound of formula (I) is at 3230.3 cm -1 ±5cm -1 、2920.6cm -1 ±5cm -1 、1662.4cm -1 ±5cm -1 、1596.1cm -1 ±5cm -1 、1389.9cm -1 ±5cm -1 and 738.4cm -1 ±5cm -1 There is a band in at least one of the regions.

27. FB-4 of the compound of formula (I) according to claim 21, characterized in that The compound FB-4 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 15 .

28. FB-4 of the compound of formula (I) according to claim 21, characterized in that The FB-4 of the compound of formula (I) is substantially pure. Preferably, the FB-4 of the compound of formula (I) has a purity greater than 99%.

29. FB-4 of the compound of formula (I) according to claim 21, characterized in that The FB-4 of the compound of formula (I) is an anhydrate.

30. A method for preparing the crystalline form FB-4 of the compound of formula (I) according to any one of claims 21 to 29, wherein the method is selected from any one of the following methods: 1) Forming a suspension of the compound of formula (I) in water, stirring, separating the solid, heating the solid to above 170° C., and then cooling to room temperature to obtain FB-4; Preferably, the solid is a solid form other than FB-4 of the compound of formula (I); Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C. 2) dissolving the compound of formula (I) in solvent 4, adding FB-4 seed crystals, stirring, centrifuging, and drying to obtain FB-4; Preferably, the solvent 4 is selected from a mixture of ethanol and water or a mixture of acetone and water; Preferably, the dissolving is carried out under high temperature conditions; 31. A pharmaceutical composition comprising a therapeutically effective amount of one or more of FB-2 of the compound of formula (I) according to any one of claims 1 to 9, FB-3 of the compound of formula (I) according to any one of claims 11 to 19, and FB-4 of the compound of formula (I) according to any one of claims 21 to 29, and at least one pharmaceutically acceptable carrier.

32. A preparation prepared from the pharmaceutical composition of claim 31, wherein the preparation is in the form of an oral preparation and a parenteral preparation. Preferably, the preparation is in the form of an oral preparation; more preferably, the preparation is in the form of a capsule.

33. Use of one or more of FB-2 of the compound of formula (I) according to any one of claims 1 to 9, FB-3 of the compound of formula (I) according to any one of claims 11 to 19, and FB-4 of the compound of formula (I) according to any one of claims 21 to 29, or the pharmaceutical composition according to claim 31, or the formulation according to claim 32 in the preparation of a medicament for treating a disease mediated by PARP-1. Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage, and inflammation. More preferably, the cancer is glioma.

34. A method for treating a disease mediated by PARP-1, comprising administering to a patient one or more of FB-2 of a compound of formula (I) according to any one of claims 1 to 9, FB-3 of a compound of formula (I) according to any one of claims 11 to 19, and FB-4 of a compound of formula (I) according to any one of claims 21 to 29, or a pharmaceutical composition according to claim 31, or a formulation according to claim 32. Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage, and inflammation. More preferably, the cancer is glioma.

35. A combination of one or more of FB-2 of the compound of formula (I) according to any one of claims 1 to 9, FB-3 of the compound of formula (I) according to any one of claims 11 to 19, and FB-4 of the compound of formula (I) according to any one of claims 21 to 29, or the pharmaceutical composition according to claim 31, or the preparation according to claim 32, with other drugs. Preferably, the other drug is temozolomide.

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