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

Abstract

The present disclosure relates to the field of pharmaceutical chemistry. Specifically, the present invention relates to a crystal form of a selective PARP-1 inhibitor hydrochloride, i.e., a crystal form of a hydrochloride of compound A having a structure of 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide, a preparation method therefor, and a use thereof. The crystal form of the hydrochloride of compound A 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, high melting point, good fluidity, good mechanical stress stability, good machinability such as good compressibility, good crystal morphology, good compression resistance, stable storage, avoiding crystal transformation of a drug during development and storage, simple and reliable preparation method, and great development value.

Description

A selective PARP-1 inhibitor hydrochloride 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 202410038609.1 filed with the State Intellectual Property Office of the People's Republic of China on January 10, 2024, and incorporates its 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 hydrochloride, a preparation method thereof, and uses thereof. Background Art

[0004] A selective poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor, chemically named 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide (hereinafter referred to as Compound A), has the following structure:

[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. Compound A is compound 11 in international application WO2014064149A1, which can be used to treat cancer, cardiovascular disease, nervous system damage, and inflammation. Compound A is used in the PAR assay IC disclosed in WO2014064149A1. 50It is 0.02μM and is a highly active and selective PARP-1 inhibitor. Compound A does not induce DNA capture and has higher tolerance in terms of hematopoietic system effects. Due to its high brain permeability, it has the potential to fight primary brain tumors and central nervous system metastases. Animal experiments have confirmed that compound A has good in vivo efficacy and low toxicity. Compound A 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 forms of this compound and its salts. Therefore, it is necessary to screen the polymorphs of compound A and its salts and select crystal forms with excellent properties for the development of formulation products of compound A. Summary of the Invention

[0006] The present disclosure provides a crystalline form of a selective PARP-1 inhibitor hydrochloride, which has at least one of the following excellent properties: good stability, high purity, good solubility, good dissolution, high bioavailability, low hygroscopicity, high melting point, 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 monohydrochloride salt form A33-3 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 mechanical stability and compressibility, extremely low hygroscopicity under 10% RH-80% RH conditions, no crystal transformation in high humidity environments, excellent solubility in water, etc.

[0008] In particular, the crystalline form A33-1 provided by the present disclosure has at least one of the following excellent properties, such as excellent stability under long-term and high temperature conditions, excellent mechanical stability and compressibility, extremely low hygroscopicity under 0% RH-80% RH conditions, improved solubility in water, good purity and crystallinity, etc.

[0009] One aspect of the present disclosure is to provide a crystalline form A33-1 of the monohydrochloride salt of Compound A (hereinafter referred to as Form A33-1), wherein Compound A is 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide, and its structural formula is shown in Formula (I):

[0010] Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystalline form A33-1 expressed in 2θ angles has characteristic peaks at one, two or three of 12.4°±0.2°, 16.0°±0.2° and 20.7°±0.2°.

[0011] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has characteristic peaks at 12.4°±0.2°, 16.0°±0.2° and 20.7°±0.2°2θ.

[0012] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 further has characteristic peaks at at least one of 10.7±0.2°, 16.3°±0.2° and 16.6°±0.2°2θ; preferably, the X-ray powder diffraction pattern of the crystalline form A33-1 further has characteristic peaks at 10.7±0.2°, 16.3°±0.2° and 16.6°±0.2°2θ.

[0013] In a preferred embodiment of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 further has characteristic peaks at at least one of 6.2°±0.2°, 24.7°±0.2°, and 25.0°±0.2° 2θ. Preferably, the X-ray powder diffraction pattern of the crystalline form A33-1 further has characteristic peaks at 6.2°±0.2°, 24.7°±0.2°, and 25.0°±0.2° 2θ.

[0014] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 12.4°±0.2°, 16.0°±0.2°, 20.7°±0.2°, 10.7±0.2°, 16.3°±0.2°, 16.6°±0.2°, 6.2°±0.2°, 24.7°±0.2°, and 25.0°±0.2°2θ.

[0015] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has a characteristic peak at 10.7°±0.2°2θ.

[0016] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has a characteristic peak at 6.2°±0.2°2θ.

[0017] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has characteristic peaks at 6.2°±0.2° and 10.7°±0.2°2θ.

[0018] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has characteristic peaks at 10.7°±0.2° and 16.0°±0.2°2θ.

[0019] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-1 has characteristic peaks at 10.7°±0.2° and 20.7°±0.2°2θ.

[0020] Without limitation, in a specific embodiment, the crystalline form A33-1 has an X-ray powder diffraction pattern substantially as shown in FIG1 or FIG5 .

[0021] In the preferred technical solution of the present disclosure, the Fourier infrared spectrum (IR) of the crystal form A33-1 is at 3220.4 cm -1 ±5cm - 1 、2502.7cm -1 ±5cm -1 、1668.0cm -1 ±5cm -1 、1387.0cm -1 ±5cm -1 、817.5cm -1 ±5cm -1 and 724.8cm - 1 ±5cm -1 There is at least one characteristic peak.

[0022] Without limitation, in a specific embodiment, the crystalline form A33-1 has a Fourier transform infrared spectrum substantially as shown in FIG4 .

[0023] In the preferred technical solution of the present disclosure, the crystal form A33-1 is substantially pure.

[0024] Preferably, the crystalline form A33-1 has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.

[0025] Without limitation, the crystalline form A33-1 is an anhydrate.

[0026] Without limitation, the crystalline form A33-1 has a TGA pattern substantially as shown in FIG2 or FIG6 .

[0027] Without limitation, the crystalline form A33-1 has a DSC spectrum substantially as shown in FIG3 or FIG7 .

[0028] Another aspect of the present disclosure provides a method for preparing crystalline form A33-1, comprising:

[0029] Compound A was dissolved in solvent 1, hydrochloric acid was added dropwise to the solution, stirred, solid was precipitated, centrifuged and dried to obtain crystal form A33-1.

[0030] Wherein, the solvent 1 is a solvent that does not contain water.

[0031] Furthermore, the solvent 1 is ethanol or acetonitrile;

[0032] Preferably, the dissolving is carried out under high temperature conditions;

[0033] Preferably, the stirring time is ≥5 min, and the stirring temperature is 4°C-80°C;

[0034] In some embodiments, the drying temperature is 40°C;

[0035] Preferably, the molar ratio of compound A to hydrochloric acid is about 1:0.8-1:1.2;

[0036] In some embodiments, the hydrochloric acid is concentrated hydrochloric acid.

[0037] The crystalline form A33-1 of the monohydrochloride salt of Compound A disclosed herein has the following beneficial effects:

[0038] 1) Good stability. The crystal form A33-1 described in the present disclosure maintained its crystal form and chemical purity substantially unchanged after 30 days of storage under long-term (25°C / 60% RH / uncovered) and high-temperature (60°C / <30% RH / uncovered) conditions. This demonstrates that crystal form A33-1 maintains good physicochemical stability under both long-term and high-temperature conditions, facilitating drug storage.

[0039] At the same time, the crystal form A33-1 remains unchanged before and after grinding and has good mechanical stability. During the preparation process, it is often necessary to grind and crush the raw materials. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of the raw materials during the preparation process.

[0040] 2) Good solubility. The crystalline form A33-1 disclosed herein has extremely high solubility in water (≥25 mg / mL), which is at least 250 times higher than the solubility of the free solid form over 24 hours.

[0041] 3) Low hygroscopicity: The crystalline form A33-1 provided herein has a weight gain of only 0.5 w / w% upon moisture absorption between 0% and 80% RH. This low hygroscopicity facilitates accurate quantitative determination during formulation preparation and subsequent transportation and storage.

[0042] 4) Good compressibility. The crystal form A33-1 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during tableting and improve production efficiency.

[0043] 5) High purity. The purity of the crystal form A33-1 provided in the present disclosure is as high as 99.9% or more, which is conducive to industrial production.

[0044] 6) Good crystallinity. The crystal form A33-1 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0045] 7) Good thermal stability. Decomposition temperature is higher than 200℃.

[0046] Another aspect of the present disclosure is to provide a crystalline form A33-3 of the monohydrochloride salt of Compound A (hereinafter referred to as Form A33-3), wherein Compound A is 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide, and its structural formula is shown in Formula (I):

[0047] Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystalline form A33-3 expressed in 2θ angles has characteristic peaks at one, two or three of 7.7°±0.2°, 20.8°±0.2° and 21.8°±0.2°.

[0048] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 has characteristic peaks at 7.7°±0.2°, 20.8°±0.2° and 21.8°±0.2°2θ.

[0049] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at at least one of 12.7°±0.2°, 13.7°±0.2° and 19.3°±0.2°2θ; preferably, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at 12.7°±0.2°, 13.7°±0.2° and 19.3°±0.2°2θ.

[0050] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at at least one of 15.4°±0.2°, 24.5°±0.2° and 25.3°±0.2°2θ; preferably, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at 15.4°±0.2°, 24.5°±0.2° and 25.3°±0.2°2θ.

[0051] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 7.7°±0.2°, 20.8°±0.2°, 21.8°±0.2°, 12.7°±0.2°, 13.7°±0.2°, 19.3°±0.2°, 15.4°±0.2°, 24.5°±0.2°, and 25.3°±0.2°2θ.

[0052] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 has a characteristic peak at 7.7°±0.2°2θ.

[0053] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 has characteristic peaks at 7.7°±0.2° and 20.8°±0.2°2θ.

[0054] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 has characteristic peaks at 7.7°±0.2° and 21.8°±0.2°2θ.

[0055] Without limitation, in a specific embodiment, the crystalline form A33-3 has an X-ray powder diffraction pattern substantially as shown in FIG8 .

[0056] In the preferred technical solution of the present disclosure, the Fourier infrared spectrum (IR) of the crystal form A33-3 is at 3490.0 cm -1 ±5cm -1 、3393.9cm -1 ±5cm -1 、2927.2cm -1 ±5cm -1 、1596.7cm -1 ±5cm -1 、1449.8cm -1 ±5cm -1 、696.1cm -1 ±5cm -1 .

[0057] Without limitation, in a specific embodiment, the crystalline form A33-3 has a Fourier transform infrared spectrum substantially as shown in FIG11 .

[0058] In the preferred technical solution of the present disclosure, the crystal form A33-3 is substantially pure.

[0059] Preferably, the crystalline form A33-3 has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.

[0060] Without limitation, the crystalline form A33-3 is a hydrate.

[0061] In some specific embodiments, the crystalline form A33-3 is a dihydrate.

[0062] Without limitation, the crystalline form A33-3 has a TGA pattern substantially as shown in FIG9 .

[0063] Without limitation, the crystalline form A33-3 has a DSC spectrum substantially as shown in FIG10 .

[0064] Another aspect of the present disclosure provides a method for preparing the crystalline form A33-3, wherein the method is selected from any one of the following methods:

[0065] 1) dissolving the monohydrochloride solid of Compound A in solvent 2, stirring, precipitating the solid, and removing the solvent to obtain Form A33-3, wherein the solvent 2 is an aqueous solvent or water.

[0066] Preferably, the solvent 2 is a mixed solvent of an organic solvent and water;

[0067] Preferably, the organic solvent is a nitrile or an alcohol;

[0068] In some embodiments, the organic solvent is acetonitrile;

[0069] In some embodiments, the organic solvent is ethanol;

[0070] Preferably, the method of removing the solvent is filtration and drying;

[0071] Furthermore, the drying temperature is not higher than room temperature;

[0072] In some embodiments, the drying temperature is room temperature;

[0073] Preferably, the stirring time is ≥5 min;

[0074] Preferably, the mass volume ratio of the monohydrochloride salt of compound A to solvent 2 is 30:1-200:1;

[0075] Preferably, the ratio of the organic solvent to water is 1:1-30:1.

[0076] 2) Compound A was dissolved in solvent 3, hydrochloric acid was added dropwise to the solution, stirred, solid was precipitated, centrifuged, and dried to obtain Form A33-3.

[0077] Preferably, the solvent 3 is a mixed solvent of an organic solvent and water;

[0078] Preferably, the organic solvent is a nitrile or an alcohol;

[0079] In some embodiments, the organic solvent is acetonitrile;

[0080] In some embodiments, the organic solvent is ethanol;

[0081] Preferably, the dissolving is carried out under high temperature conditions;

[0082] In some embodiments, the dissolution temperature is 80°C;

[0083] Preferably, the stirring time is ≥5 min, and the stirring temperature is 4°C-80°C;

[0084] Preferably, the drying temperature is not higher than room temperature;

[0085] In some embodiments, the drying is vacuum drying at room temperature;

[0086] Preferably, the molar ratio of compound A to hydrochloric acid is about 1:0.8-1:1.2;

[0087] In some embodiments, the hydrochloric acid is concentrated hydrochloric acid.

[0088] The crystalline form A33-3 of the monohydrochloride salt of Compound A disclosed herein has the following beneficial effects:

[0089] 1) Good stability. The crystal form A33-3 described in the present disclosure maintained its crystalline form and chemical purity substantially unchanged after 15 days of storage under long-term (25°C / 60% RH / unopen) and accelerated (40°C / 75% RH / unopen) conditions. This indicates that crystal form A33-3 maintains good physicochemical stability under both long-term and accelerated conditions, which is beneficial for drug storage.

[0090] At the same time, the crystal form A33-3 remains unchanged before and 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.

[0091] Meanwhile, Form A33-3 is the most thermodynamically stable form in aqueous solvents or water. A mixed solid of Form A33-1 and Form A33-3 is stirred in a water-saturated ethyl acetate solvent and converted to Form A33-3.

[0092] 2) Good solubility. The crystalline form A33-3 disclosed herein has extremely high solubility in water (≥25 mg / mL), which is at least 250 times higher than the solubility of the free solid form over 24 hours.

[0093] 3) Low hygroscopicity. The crystalline form A33-3 provided herein has a moisture weight gain of only 0.2 w / w% at 10-80% RH, and the crystalline form remains unchanged before and after DVS testing. This low hygroscopicity facilitates accurate quantitative determination during formulation preparation and subsequent transportation and storage.

[0094] 5) High purity. The purity of the crystal form A33-3 provided in the present disclosure is as high as 99.9% or more, which is conducive to industrial production.

[0095] 6) Good crystallinity. The crystal form A33-3 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0096] In another aspect of the present disclosure, a crystalline form A33-4 of the monohydrochloride salt of Compound A (hereinafter referred to as crystalline form A33-4) is provided, wherein the crystalline form A33-4 has an X-ray powder diffraction pattern substantially as shown in FIG12 .

[0097] In some embodiments, the crystalline form A33-4 may be a hydrate.

[0098] Another aspect of the present disclosure provides a method for preparing the crystal form A33-4, comprising heating the crystal form A33-3 to 55° C. on a hot plate and maintaining the temperature for 10 minutes to obtain the crystal form A33-4.

[0099] In another aspect of the present disclosure, a crystalline form A33-2 of the monohydrochloride salt of Compound A (hereinafter referred to as crystalline form A33-2) is provided, wherein the crystalline form A33-2 has an X-ray powder diffraction pattern substantially as shown in FIG13 .

[0100] In some embodiments, the crystalline form A33-2 is a mixed crystal of crystalline form A33-3 and crystalline form A33-4.

[0101] Another aspect of the present disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the crystalline form A33-1, crystalline form A33-2, crystalline form A33-3 and crystalline form A33-4 described in the present disclosure, and at least one pharmaceutically acceptable carrier.

[0102] The pharmaceutically acceptable carrier is selected according to the mode and route of administration.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] Another aspect of the present disclosure is to provide the use of one or more of the crystalline forms A33-1, A33-2, A33-3 and A33-4 described in the present disclosure, or the pharmaceutical compositions or preparations described therein, in the preparation of drugs for treating diseases mediated by PARP-1.

[0111] Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

[0112] 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; The present invention relates to a group of hematopoietic cancers, including leukemias, acute lymphoblastic leukemias, acute lymphoblastic leukemias, B-cell lymphomas, T-cell lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, hairy cell lymphomas, and Burkitt's lymphomas; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; tumors of mesenchymal origin, including fibrosarcomas, Ewing's sarcomas, and rhabdomyosarcomas; tumors of the central and peripheral nervous system, including astrocytomas, neurocytomas, gliomas such as glioblastomas, and schwannomas; and other tumors, including melanomas, seminoma, teratomas, osteosarcomas, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma, and Kaposi's sarcoma.

[0113] Preferably, the cancer, such as breast cancer, ovarian cancer, glioma, is BRCA mutant.

[0114] Preferably, the cancer is glioma.

[0115] Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

[0116] Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

[0117] Preferably, the inflammatory disease is selected from the group consisting of colitis, arthritis and uveitis.

[0118] 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 of the crystalline form A33-1, crystalline form A33-2, crystalline form A33-3 and crystalline form A33-4 described in the present disclosure, or the pharmaceutical compositions or preparations thereof.

[0119] Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

[0120] 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; The present invention relates to a group of hematopoietic cancers, including leukemias, acute lymphoblastic leukemias, acute lymphoblastic leukemias, B-cell lymphomas, T-cell lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, hairy cell lymphomas, and Burkitt's lymphomas; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; tumors of mesenchymal origin, including fibrosarcomas, Ewing's sarcomas, and rhabdomyosarcomas; tumors of the central and peripheral nervous system, including astrocytomas, neurocytomas, gliomas such as glioblastomas, and schwannomas; and other tumors, including melanomas, seminoma, teratomas, osteosarcomas, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma, and Kaposi's sarcoma.

[0121] Preferably, the cancer, such as breast cancer, ovarian cancer, glioma, is BRCA mutant.

[0122] Preferably, the cancer is glioma.

[0123] Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

[0124] Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

[0125] Preferably, the inflammatory disease is selected from the group consisting of colitis, arthritis and uveitis.

[0126] Another aspect of the present disclosure is to provide one or more of the crystalline forms A33-1, A33-2, A33-3 and A33-4 described in the present disclosure or their pharmaceutical compositions or preparations in combination with other drugs.

[0127] Preferably, the other drug is temozolomide.

[0128] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] Unless otherwise specified, the "room temperature" described in this disclosure refers to a temperature of 10 to 30°C.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] The "concentrated hydrochloric acid" mentioned above refers to various commercially available hydrogen chloride solutions, generally referring to aqueous hydrogen chloride solutions with a concentration of 36%-38% (w / w).

[0137] 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

[0138] FIG1 is an XRPD pattern of Form A33-1 of the monohydrochloride salt in Example 1;

[0139] FIG2 is a TGA spectrum of the monohydrochloride crystalline form A33-1 in Example 1;

[0140] FIG3 is a DSC spectrum of Form A33-1 of the monohydrochloride salt in Example 1;

[0141] FIG4 is an IR spectrum of Form A33-1 of the monohydrochloride salt in Example 1;

[0142] FIG5 is an XRPD pattern of Form A33-1 of the monohydrochloride salt in Example 2;

[0143] FIG6 is a TGA spectrum of Form A33-1 of the monohydrochloride salt in Example 2;

[0144] FIG7 is a DSC spectrum of Form A33-1 of the monohydrochloride salt in Example 2;

[0145] FIG8 is an XRPD pattern of Form A33-3 of the monohydrochloride salt in Example 4;

[0146] FIG9 is a TGA spectrum of Form A33-3 of the monohydrochloride salt in Example 4;

[0147] FIG10 is a DSC spectrum of Form A33-3 of the monohydrochloride salt in Example 4;

[0148] FIG11 is an IR spectrum of Form A33-3 of the monohydrochloride salt in Example 4;

[0149] FIG12 is an XRPD pattern of Form A33-4 of the monohydrochloride salt in Example 7;

[0150] FIG13 is an XRPD pattern of Form A33-2 of the monohydrochloride salt in Example 8;

[0151] FIG14 is an XRPD pattern of the free form FB-2 in Example 9;

[0152] FIG15 is an XRPD pattern of the free form FB-3 in Example 9;

[0153] FIG16 is an XRPD pattern of the free form FB-4 in Example 9;

[0154] FIG17 is an XRPD stack of Form A33-1 of the monohydrochloride salt in Experimental Example 1 before and after long-term storage at high temperature;

[0155] FIG18 is an XRPD stack of Form A33-3 of the monohydrochloride salt in Experimental Example 1 before and after long-term and accelerated storage;

[0156] FIG19 is an XRPD stack of Form A33-1 of the monohydrochloride salt in Experimental Example 2 before and after the grinding test;

[0157] FIG20 is an XRPD stack of Form A33-3 of the monohydrochloride salt in Experimental Example 2 before and after the grinding test;

[0158] FIG21 is a DVS spectrum of Form A33-1 of the monohydrochloride salt in Experimental Example 3;

[0159] FIG22 is a DVS spectrum of Form A33-3 of the monohydrochloride salt in Experimental Example 3;

[0160] FIG23 is an XRPD stack of Form A33-3 of the monohydrochloride salt in Experimental Example 3 before and after DVS testing;

[0161] FIG24 is a PSD spectrum of Form A33-1 of the monohydrochloride salt in Experimental Example 4;

[0162] Figure 25 is a PSD spectrum of Form A33-3 of the monohydrochloride salt in Experimental Example 4;

[0163] Figure 26 is an XRPD overlay of the monohydrochloride Form A33-1 and Form A33-3 before and after the crystal transformation study in Experimental Example 6.

[0164] Figure 27 is an XRPD overlay of the monohydrochloride salt form A33-1 before and after tableting in Experimental Example 7.

[0165] Figure 28 is an XRPD overlay of the monohydrochloride salt form A33-3 in Experimental Example 7 before and after tableting. DETAILED DESCRIPTION

[0166] The following examples will help to further understand the present disclosure, but are not intended to limit the contents of the present disclosure.

[0167] Testing instruments and methods:

[0168] In the present disclosure, the starting material compound A can be obtained commercially or prepared by existing techniques, such as the method mentioned in WO2014064149A1.

[0169] Example 1: Preparation of Compound A Monohydrochloride Form A33-1

[0170] About 30 mg of compound A was taken, 2 mL of ethanol was added and dissolved at 80°C, then the mixture was brought to room temperature, and 7.3 μL of concentrated hydrochloric acid was added dropwise while hot. After stirring for 5 minutes, solid began to precipitate. Stirring was continued for 2 days, and the mixture was centrifuged and dried in vacuo at 40°C overnight to obtain Form A33-1.

[0171] The XRPD data are shown in the following table:

[0172] Ion chromatography (IC) analysis showed that the molar ratio of compound A to hydrochloric acid in the crystalline form A33-1 prepared in this example was 1:1.

[0173] Its XRPD pattern is shown in Figure 1.

[0174] The TGA spectrum thereof is shown in FIG2 , which shows that the weight loss is less than 1.0% before 150° C.

[0175] Its DSC spectrum is shown in Figure 3.

[0176] Its IR spectrum is shown in Figure 4.

[0177] The A33-1 prepared in this example is an anhydrous form.

[0178] Example 2: Preparation of Compound A Monohydrochloride Form A33-1

[0179] Take about 500 mg of compound A, add 36 ml of ethanol, dissolve in a 75°C water bath, transfer to room temperature, add 123 μl of concentrated hydrochloric acid while hot, stir overnight, precipitate solid, filter, and vacuum dry at 50°C overnight to obtain Form A33-1.

[0180] Its XRPD pattern is shown in Figure 5.

[0181] The TGA spectrum thereof is shown in FIG6 , which shows that there is a weight loss of less than 1.0% before 150° C., specifically, a weight loss of about 0.5%.

[0182] Its DSC spectrum is shown in Figure 7.

[0183] Example 3: Preparation of Compound A Monohydrochloride Form A33-1

[0184] About 30 mg of compound A was taken, 5 mL of acetonitrile was added, and the mixture was heated to 80°C to dissolve. The mixture was then cooled to room temperature, and 7.3 μL of concentrated hydrochloric acid was added dropwise while the mixture was hot. After stirring for 5 minutes, a solid began to precipitate. The mixture was centrifuged and dried in vacuo at 40°C overnight to obtain Form A33-1.

[0185] Example 4: Preparation of Compound A Monohydrochloride Form A33-3

[0186] About 300 mg of Form A33-1 was taken, 2 ml of acetonitrile and 0.5 mL of water were added, stirred for 20 min, filtered, and dried at room temperature to obtain Form A33-3.

[0187] Its XRPD pattern is shown in Figure 8.

[0188] The TGA spectrum thereof is shown in FIG9 , which shows that there is a weight loss of about 8.5% before 150° C.

[0189] Its DSC spectrum is shown in Figure 10.

[0190] Its IR spectrum is shown in Figure 11.

[0191] The A33-3 prepared in this example is a hydrate containing approximately 2 water molecules.

[0192] Example 5: Preparation of Compound A Monohydrochloride Form A33-3

[0193] About 300 mg of Form A33-1 was taken, 4 ml of ethanol and 0.5 mL of water were added, stirred for 20 min, filtered, and dried at room temperature to obtain Form A33-3.

[0194] Example 6: Preparation of Compound A Monohydrochloride Form A33-3

[0195] Take about 30 mg of compound A, add 5 mL of acetonitrile and 0.5 ml of water to dissolve at 80°C, then transfer to room temperature, add 7.3 μL of concentrated hydrochloric acid dropwise while hot, stir for 5 minutes, solid precipitates, continue stirring for 2 days, centrifuge, and dry in vacuo at room temperature to obtain Form A33-3.

[0196] Example 7: Preparation of Compound A Monohydrochloride Form A33-4

[0197] A small amount of Form A33-3 sample was placed on a copper plate, heated to 55°C on a hot plate, and maintained for 10 min to obtain Form A33-4.

[0198] Its XRPD pattern is shown in Figure 12.

[0199] The crystal form A33-4 prepared in this example is unstable and will transform into the crystal form A33-3 after being cooled to room temperature.

[0200] Example 8: Preparation of Compound A Monohydrochloride Form A33-2

[0201] The crystal form A33-4 obtained on the hot stage in Example 7 was placed at room temperature for 50 minutes to prepare the crystal form A33-2.

[0202] Its XRPD pattern is shown in Figure 13. It is a mixed crystal of crystal forms A33-3 and A33-4.

[0203] Example 9: Preparation of free solid form of Compound A

[0204] Preparation of free crystal form FB-2

[0205] Approximately 20 mg of compound A was added to 0.4 mL of ethyl acetate and 0.6 mL of methyl tert-butyl ether to obtain a suspension. The suspension was stirred at room temperature for 3 days. The solid was separated and dried under vacuum at 40°C overnight to obtain the free crystalline Form FB-2. Its XRPD pattern is shown in Figure 14.

[0206] Preparation of free crystal form FB-3

[0207] Approximately 20 mg of compound A was added to 1.2 mL of isopropyl ether to obtain a suspension. The suspension was stirred at room temperature for 3 days, and a solid was separated and dried under vacuum at 40°C overnight to obtain the free crystalline form FB-3. The XRPD pattern of the solid is shown in Figure 15.

[0208] Preparation of free crystal form FB-4

[0209] Approximately 20 mg of compound A was added to 1.0 mL of water to obtain a suspension. The suspension was stirred at room temperature for 3 days, and a solid was separated. The solid was heated to 170°C for 5 minutes and then cooled to room temperature to obtain the free-state crystalline Form FB-4. Its XRPD pattern is shown in Figure 16.

[0210] Test Example 1: Physical and Chemical Stability Studies

[0211] An appropriate amount of Form A33-1 sample was stored under long-term (25°C / 60% RH / uncovered) and high-temperature (60°C / <30% RH / uncovered) conditions. The chemical purity and crystalline form were determined periodically using HPLC and XRPD. The results are shown in Table 1 and Figure 17.

[0212] Table 1

[0213] The results show that the crystal form A33-1 can maintain its crystal form for at least 30 days under long-term (25°C / 60% RH / open) and high-temperature (25°C / 60% RH / open) conditions, and its chemical purity remains basically unchanged, showing good physical and chemical stability.

[0214] Appropriate samples of Form A33-3 of the present disclosure were placed under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions, and the chemical purity and crystalline form were determined periodically using HPLC and XRPD. The results are shown in Table 2 and Figure 18.

[0215] Table 2

[0216] The results show that the crystal form A33-3 can maintain its crystal form for at least 30 days under long-term (25°C / 60% RH / open) and accelerated (40°C / 75% RH / open) conditions, and the chemical purity remains basically unchanged, showing good physical and chemical stability.

[0217] Test Example 2: Mechanical stability study

[0218] Appropriate amounts of Form A33-1 and Form A33-3 samples of the present disclosure were taken, placed in a mortar, and manually ground. The XRPD patterns of the samples before and after grinding were measured. The XRPD patterns before and after grinding are shown in Figures 19-20.

[0219] The results showed that the crystal forms A33-1 and A33-3 remained unchanged before and after grinding and had good mechanical stability.

[0220] Test Example 3: Moisture absorption study

[0221] The crystalline forms A33-1 and A33-3 disclosed herein were respectively taken and their hygroscopicity was tested using a dynamic moisture sorption (DVS) instrument. The crystalline forms were tested using XRPD before and after the DVS test. The results are shown in Figures 21-23.

[0222] The results show that the moisture gain of crystal form A33-1 between 0-80% RH is 0.5 w / w%, and the moisture gain of crystal form A33-3 between 10% RH-80% RH is 0.2% w / w%. The crystal form of crystal form A33-3 remains unchanged before and after the DVS test.

[0223] Test Example 4: Particle Size Test Study

[0224] Samples of Form A33-1 and Form A33-3 were taken, mixed with an appropriate amount of n-heptane by ultrasonication, and then tested on a PSD instrument. The results are shown in Table 3 and Figures 24-25.

[0225] Table 3

[0226] The results showed that the particle sizes of Form A33-1 and Form A33-3 were uniform and normally distributed. This uniform particle size helps simplify the production process and improve product quality.

[0227] Test Example 5: Solubility Study

[0228] Approximately 40 mg of the free crystalline forms FB-2, FB-3, and FB-4, and the hydrochloride forms A33-1 and A33-3 were weighed, added to 5 mL of water, and stirred at room temperature. Samples were taken after 24 hours to test for purity and crystalline form. The results are shown in Table 4.

[0229] Table 4

[0230] The results showed that the crystalline forms A33-1 and A33-1 disclosed herein dissolved instantly in water, with solubility reaching 25,000 μg / mL, which was at least 250 times higher than the solubility of the free solid form over 24 hours.

[0231] Test Example 6: Crystal transformation study

[0232] Appropriate amounts of Form A33-1 and Form A33-3 samples of the present disclosure were mixed and then sampled for XRPD characterization. 1 mL of the corresponding solvent was added to the mixed sample to form a suspension. The suspension was stirred at room temperature, and both wet and dry samples were sampled for XRPD characterization. The results are shown in Table 5 and Figure 26.

[0233] Table 5

[0234] The results showed that a mixed sample of Form A33-1 and Form A33-3 converted into Form A33-3 in a water-saturated ethyl acetate solvent at room temperature, indicating that Form A33-3 is a stable form in an aqueous system.

[0235] Test Example 7: Compressibility Study

[0236] Appropriate samples of Form A33-1 and Form A33-3 of the present disclosure were placed in an infrared tablet press and held at 2 MPa for 2 minutes. XRPD analysis was performed before and after tableting. The XRPD patterns before and after tableting are shown in Figures 27-28. The results indicate that Form A33-1 and Form A33-3 remained unchanged, demonstrating good compressibility.

[0237] 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. Crystal form A33-1 of compound A monohydrochloride, wherein compound A is 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide, and its structural formula is shown as formula (I): It is characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-1 shows characteristic peaks at one or two or three of 12.4° ± 0.2°, 16.0° ± 0.2°, and 20.7° ± 0.2° in terms of 2θ angle.

2. The crystalline form A33-1 of the compound A monohydrochloride according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-1 has characteristic peaks at 12.4° ± 0.2°, 16.0° ± 0.2°, and 20.7° 2θ.

3. The crystalline form A33-1 of the compound A monohydrochloride according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-1 further has characteristic peaks at at least one of 10.7 ± 0.2°, 16.3° ± 0.2°, and 16.6° 2θ; preferably, the X-ray powder diffraction pattern of the crystal form A33-1 further has characteristic peaks at 10.7 ± 0.2°, 16.3° ± 0.2°, and 16.6° 2θ.

4. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-1 further has characteristic peaks at at least one of 6.2° ± 0.2°, 24.7° ± 0.2°, and 25.0° 2θ; preferably, the X-ray powder diffraction pattern of the crystal form A33-1 further has characteristic peaks at 6.2° ± 0.2°, 24.7° ± 0.2°, and 25.0° 2θ.

5. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 has an X-ray powder diffraction pattern substantially as shown in Figure 1 or Figure 5.

6. The crystalline form A33-1 of the compound A monohydrochloride according to claim 1, characterized in that, The Fourier transform infrared spectrum of the crystalline form A33-1 has characteristic peaks at least at one of 3220.4 cm -1 ±5 cm -1 , 2502.7 cm -1 ±5 cm -1 , 1668.0 cm -1 ±5 cm -1 , 1387.0 cm -1 ±5 cm -1 , 817.5 cm -1 ±5 cm -1 and 724.8 cm -1 ±5 cm -1 .

7. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 has a Fourier transform infrared spectrum substantially as shown in Figure 4.

8. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 is substantially pure.

9. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 is an anhydrate.

10. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 has a TGA pattern substantially as shown in Figure 2 or Figure 6.

11. The crystalline form A33-1 of compound A monohydrochloride according to claim 1, characterized in that, The crystal form A33-1 has a DSC pattern substantially as shown in Figure 3 or Figure 7.

12. The preparation method of the crystal form A33-1 according to any one of claims 1-11, the preparation method comprising: Dissolving compound A in solvent 1 until clear, dropping hydrochloric acid into the clear solution, stirring, precipitating a solid, centrifuging, and drying to obtain the crystal form A33-1. Wherein, the solvent 1 is a water-free solvent. Further, the solvent 1 is ethanol or acetonitrile; Preferably, the dissolving until clear is carried out under high temperature conditions; Preferably, the stirring time ≥ 5 min, and the stirring temperature is 4°C - 80°C; In some embodiments, the drying temperature is 40°C; Preferably, the molar ratio of the feed of compound A and hydrochloric acid is about 1:0.8 - 1:1.2; In some embodiments, the hydrochloric acid is concentrated hydrochloric acid.

13. Crystal form A33-3 of compound A monohydrochloride, wherein compound A is 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide, and its structural formula is shown as formula (I): It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-3 shows characteristic peaks at one or two or three of 7.7° ± 0.2°, 20.8° ± 0.2°, and 21.8° ± 0.2° in terms of 2θ angle.

14. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A33-3 has characteristic peaks at 7.7° ± 0.2°, 20.8° ± 0.2°, and 21.8° 2θ.

15. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at at least one of 12.7° ± 0.2°, 13.7° ± 0.2°, and 19.3° ± 0.2° 2θ; preferably, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at 12.7° ± 0.2°, 13.7° ± 0.2°, and 19.3° ± 0.2° 2θ.

16. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at at least one of 15.4° ± 0.2°, 24.5° ± 0.2°, and 25.3° ± 0.2° 2θ; preferably, the X-ray powder diffraction pattern of the crystalline form A33-3 further has characteristic peaks at 15.4° ± 0.2°, 24.5° ± 0.2°, and 25.3° ± 0.2° 2θ.

17. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 has an X-ray powder diffraction pattern substantially as shown in Figure 8.

18. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The Fourier transform infrared spectrum of the crystalline form A33-3 is at 3490.0 cm -1 ±5 cm -1 、3393.9 cm -1 ±5 cm -1 、2927.2 cm -1 ±5 cm -1 、1596.7 cm -1 ±5 cm -1 、1449.8 cm -1 ±5 cm -1 、696.1 cm -1 ±5 cm -1 .

19. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 has a Fourier transform infrared spectrum substantially as shown in Figure 11.

20. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 is substantially pure.

21. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 is a hydrate; preferably, the crystalline form A33-3 is a dihydrate.

22. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 has a TGA pattern substantially as shown in Figure 9.

23. The crystalline form A33-3 of compound A monohydrochloride according to claim 13, characterized in that, The crystalline form A33-3 has a DSC pattern substantially as shown in Figure 10.

24. A method for preparing the crystalline form A33-3 of the compound A monohydrochloride according to claims 13-23, wherein the preparation method is selected from any one of the following methods: 1) Dissolve the solid of the compound A monohydrochloride in solvent 2, stir, precipitate a solid, and obtain the crystalline form A33-3 after removing the solvent, wherein the solvent 2 is a water-containing solvent or water. Preferably, the solvent 2 is a mixed solvent of an organic solvent and water; Preferably, the organic solvent is nitrile or alcohol; In some embodiments, the organic solvent is acetonitrile; In some embodiments, the organic solvent is ethanol; Preferably, the way of removing the solvent is suction filtration and drying; Furthermore, the drying temperature is not higher than room temperature; In some embodiments, the drying temperature is room temperature; Preferably, the stirring time ≥ 5 min; Preferably, the mass-volume ratio of the compound A monohydrochloride to the solvent 2 is 30:1 - 200:1; Preferably, the ratio of the organic solvent to water is 1:1 - 30:

1. 2) Dissolve the compound A in solvent 3 until clear, add hydrochloric acid dropwise to the clear solution, stir, precipitate a solid, centrifuge, and dry to obtain the crystalline form A33-3. Preferably, the solvent 3 is a mixed solvent of an organic solvent and water; Preferably, the organic solvent is nitrile or alcohol; In some embodiments, the organic solvent is acetonitrile; In some embodiments, the organic solvent is ethanol; Preferably, the dissolution until clear is carried out under high temperature conditions; In some embodiments, the dissolution temperature is 80°C; Preferably, the stirring time ≥ 5 min, and the stirring temperature is 4°C - 80°C; Preferably, the drying temperature is not higher than room temperature; In some embodiments, the drying is carried out under vacuum at room temperature; Preferably, the molar ratio of the charged compound A to hydrochloric acid is about 1:0.8 - 1:1.2; In some embodiments, the hydrochloric acid is concentrated hydrochloric acid.

25. A crystal form A33 - 4 of compound A monohydrochloride, the crystal form A33 - 4 having an X - ray powder diffraction pattern substantially as shown in Figure 12.

26. A method for preparing the crystal form A33 - 4 of compound A monohydrochloride according to claim 25, the preparation method comprising heating the crystal form A33 - 3 on a hot stage to 55 °C and holding for 10 min to obtain the crystal form A33 - 4.

27. A crystal form A33 - 2 of compound A monohydrochloride, the crystal form A33 - 2 having an X - ray powder diffraction pattern substantially as shown in Figure 13.

28. A pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of one or more of the crystal form A33 - 1 according to any one of claims 1 - 11, the crystal form A33 - 2 according to claim 27, the crystal form A33 - 3 according to any one of claims 13 - 23, and the crystal form A33 - 4 according to claim 25, and at least one pharmaceutically acceptable carrier.

29. A preparation prepared from the pharmaceutical composition according to claim 28, the preparation form being selected from oral preparations and parenteral preparations. Preferably, the preparation form is an oral preparation; more preferably, the preparation form is a capsule.

30. Use of one or more of the crystal form A33 - 1 according to any one of claims 1 - 11, the crystal form A33 - 2 according to claim 27, the crystal form A33 - 3 according to any one of claims 13 - 23, and the crystal form A33 - 4 according to claim 25, or the composition according to claim 28, or the preparation according to claim 29 in the preparation of a drug for treating a PARP - 1 - mediated disease. Preferably, the PARP - 1 - mediated diseases are selected from cancer, cardiovascular diseases, nervous system injuries, and inflammation. Preferably, the cancer is glioma.

31. A method for treating a PARP - 1 - mediated disease, which comprises administering to a patient one or more of the crystal form A33 - 1 according to any one of claims 1 - 11, the crystal form A33 - 2 according to claim 27, the crystal form A33 - 3 according to any one of claims 13 - 23, and the crystal form A33 - 4 according to claim 25, or the composition according to claim 28, or the preparation according to claim 29. Preferably, the PARP - 1 - mediated diseases are selected from cancer, cardiovascular diseases, nervous system injuries, and inflammation. Preferably, the cancer is glioma.

32. The combined use of the crystal form A33 - 1 according to any one of claims 1 - 11, the crystal form A33 - 2 according to claim 27, the crystal form A33 - 3 according to any one of claims 13 - 23, and the crystal form A33 - 4 according to claim 25, or the pharmaceutical composition or preparation according to claim 28 with other drugs. Preferably, the other drug is temozolomide.

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