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WO2025108423A1 - Crystal form of selective parp-1 inhibitor, preparation method therefor and use thereof - Google Patents

Crystal form of selective parp-1 inhibitor, preparation method therefor and use thereof Download PDF

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Publication number
WO2025108423A1
WO2025108423A1 PCT/CN2024/133824 CN2024133824W WO2025108423A1 WO 2025108423 A1 WO2025108423 A1 WO 2025108423A1 CN 2024133824 W CN2024133824 W CN 2024133824W WO 2025108423 A1 WO2025108423 A1 WO 2025108423A1
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Prior art keywords
formula
compound
ray powder
powder diffraction
diffraction pattern
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French (fr)
Chinese (zh)
Inventor
吕康乐
盛晓霞
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Hangzhou Solipharma Co Ltd
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Hangzhou Solipharma Co Ltd
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Publication of WO2025108423A1 publication Critical patent/WO2025108423A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to the field of pharmaceutical chemistry. Specifically, the present disclosure relates to a crystalline form of a selective PARP-1 inhibitor and a preparation method and use thereof.
  • PARP-1 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, having a structure represented by the following formula (I) (hereinafter referred to as the compound of formula (I)):
  • 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 with deleterious germline and/or somatic BRCA mutations, which are present in a significant portion of breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.
  • 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) has a PAR assay IC 50 of 0.02 ⁇ M disclosed in WO2014064149A1, and 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.
  • the compound of formula (I) Due to its high brain permeability, it has the potential to target 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.
  • PARP-1-mediated related diseases such as cancer, cardiovascular disease, nervous system damage, and inflammation.
  • crystal form of the compound there is no public report on the crystal form of the compound. Therefore, it is necessary to screen the polymorphs of the compound of formula (I) and select the crystal form with excellent properties for the development of formulation products of the compound of formula (I).
  • 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, avoiding crystal transformation of the drug during the development process and storage, simple and reliable preparation method, and great development value.
  • 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 preparations or water-based environments, excellent grinding stability and compressibility, extremely low hygroscopicity under 0% RH-80% RH conditions, no crystal transformation in a high humidity environment, and excellent solubility in water.
  • 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.
  • 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.
  • 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),
  • the X-ray powder diffraction (XRPD) pattern of FB-2 of the compound of formula (I) expressed in 2 ⁇ angle has characteristic peaks at one, two or three of 7.9° ⁇ 0.2°, 19.3° ⁇ 0.2° and 22.1° ⁇ 0.2°.
  • 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°2 ⁇ .
  • 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°2 ⁇ , 1 or 2 or 3 thereof; 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°2 ⁇ .
  • 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°2 ⁇ , 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°2 ⁇ .
  • 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°2 ⁇ .
  • the X-ray powder diffraction pattern of FB-2 of the compound of formula (I) has a characteristic peak at 22.1° ⁇ 0.2°2 ⁇ .
  • 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°2 ⁇ .
  • 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°, 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°
  • the compound FB-2 of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 5 .
  • the FB-2 of the compound of formula (I) is substantially pure.
  • the FB-2 of the compound of formula (I) has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.
  • the Fourier infrared spectrum (FT-IR) of FB-2 of the compound of formula (I) has a band at at least one of 3194.28cm -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 .
  • the compound FB-2 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 2 .
  • FB-2 of the compound of formula (I) is an anhydrate.
  • the compound FB-2 of formula (I) has a TGA pattern substantially as shown in FIG. 4 .
  • the compound FB-2 of formula (I) has a DSC spectrum substantially as shown in FIG. 3 .
  • 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.
  • the volume ratio of ethyl acetate to methyl tert-butyl ether is 2:3.
  • the stirring time is ⁇ 1 h
  • the stirring temperature is 4°C-80°C.
  • the stirring time is 3 days, and the stirring temperature is room temperature.
  • the drying temperature is 30°C-80°C, more preferably 40°C.
  • the crystalline form FB-2 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:
  • the FB-2 of the compound of formula (I) described in the present disclosure maintains the same crystal form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability.
  • the crystal form of FB-2 remains unchanged before and after the DVS test, and has good humidity stability.
  • the solubility of the crystalline form FB-2 provided in the present disclosure can meet the requirements for pharmaceutical use.
  • 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.
  • the crystal form FB-2 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.
  • 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 shown in formula (I).
  • FB-3 a crystalline form FB-3 (hereinafter referred to as FB-3) of a compound having a structure as shown in formula (I).
  • the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) expressed in 2 ⁇ angles has characteristic peaks at one, two or three of 4.7 ⁇ 0.2°, 9.5° ⁇ 0.2° and 18.1° ⁇ 0.2°.
  • 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°.
  • the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 1, 2 or 3 of 11.9° ⁇ 0.2°, 20.1° ⁇ 0.2° and 21.9° ⁇ 0.2°2 ⁇ ; 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°2 ⁇ .
  • the X-ray powder diffraction pattern of FB-3 of the compound of formula (I) has characteristic peaks at 1, 2 or 3 of 13.0° ⁇ 0.2°, 17.5° ⁇ 0.2° and 23.4° ⁇ 0.2°2 ⁇ ; 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°2 ⁇ .
  • 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°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has a characteristic peak at 4.7° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has a characteristic peak at 9.5° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has characteristic peaks at 4.7° ⁇ 0.2° and 18.1° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has characteristic peaks at 9.5° ⁇ 0.2° and 18.1° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has characteristic peaks at 4.7° ⁇ 0.2° and 9.5° ⁇ 0.2°2 ⁇ .
  • 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.
  • the compound FB-3 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).
  • the FB-3 of the compound of formula (I) is substantially pure.
  • the purity is greater than 90%; preferably, the purity is greater than 95%; more preferably, the purity is greater than 99%.
  • the Fourier infrared spectrum of the compound FB-3 of formula (I) has a band at at least one of 3225.55cm -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 .
  • the compound FB-3 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 7 .
  • FB-3 of the compound of formula (I) is a tunnel hydrate or anhydrate.
  • FB-3 of the compound of formula (I) is an anhydrate.
  • the compound FB-3 of formula (I) has a TGA spectrum substantially as shown in FIG. 9 .
  • the compound of formula (I) FB-3 has a DSC spectrum substantially as shown in FIG. 8 .
  • 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:
  • the volatilization temperature in method 1) is room temperature.
  • a small amount of FB-3 seed crystals can be added to the suspension and stirred together.
  • the stirring time is ⁇ 1 h
  • the stirring temperature is 4°C-80°C.
  • the stirring time is 1 day, 2 days or 3 days, and the stirring temperature is room temperature.
  • the drying temperature is 30°C-80°C, more preferably 40°C.
  • the crystalline form FB-3 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:
  • the crystalline form FB-3 of the compound of formula (I) disclosed in the present invention remains unchanged in crystalline form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability, which is conducive to drug storage.
  • the crystalline form FB-3 can maintain its crystal form unchanged in pure water or water-containing environment and has good stability in water, which makes the crystalline form FB-3 particularly suitable for the preparation process of water-containing preparations, such as wet granulation, and also makes it easier for preparations prepared using the crystalline form FB-3 to maintain crystal stability in an environment with high humidity.
  • the crystal form of FB-3 remains unchanged after grinding and has good mechanical stability.
  • the raw materials often need to be ground and crushed during the preparation process.
  • Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of the raw materials during the preparation process.
  • the crystalline form FB-3 is the most thermodynamically stable crystalline form in water and n-heptane.
  • the mixed solids of the crystalline forms FB-2, FB-3 and FB-4 were stirred in water and n-heptane respectively, and all transformed into the crystalline form FB-3.
  • the solubility of the crystalline form FB-3 provided in the present disclosure can meet the requirements for pharmaceutical use.
  • the crystal form FB-3 provided in the present disclosure has good compressibility, which is beneficial to improve the problems such as cracking in the tableting process and improve production efficiency.
  • the purity of the crystal form FB-3 provided by the present disclosure is as high as 99.9% or more, which is conducive to industrial production.
  • the crystal form FB-3 has a strong impurity removal ability, and a high-purity raw material can be obtained through the crystallization process of the preparation method disclosed in the present disclosure, and the problem of solvent residue is not likely to occur, which is suitable for medicinal use.
  • the crystal form FB-3 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.
  • 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 shown in formula (I).
  • FB-4 crystalline form FB-4
  • the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) expressed in 2 ⁇ angles has characteristic peaks at one, two or three of 5.9° ⁇ 0.2°, 16.5° ⁇ 0.2° and 21.7° ⁇ 0.2°.
  • 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°2 ⁇ .
  • 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°2 ⁇ .
  • 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°2 ⁇ , 1 or 2 or 3.
  • 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°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-4 of the formula (I) further has characteristic peaks at at least one of 17.2° ⁇ 0.2°, 20.7° ⁇ 0.2° and 24.7° ⁇ 0.2°2 ⁇ .
  • 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°2 ⁇ , 1 or 2 or 3.
  • 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°2 ⁇ .
  • 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°2 ⁇ .
  • the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has a characteristic peak at 5.9° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of the compound FB-4 of the formula (I) has a characteristic peak at 16.5° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 5.9° ⁇ 0.2° and 21.7° ⁇ 0.2°2 ⁇ .
  • the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 16.5° ⁇ 0.2° and 21.7° ⁇ 0.2° 2 ⁇ .
  • the compound FB-4 of formula (I) has an XRPD pattern substantially as shown in FIG. 12 .
  • the Fourier infrared spectrum of the compound FB-4 of formula (I) has a band at at least one of 3230.3cm -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 .
  • the compound FB-4 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 15 .
  • the FB-4 of the compound of formula (I) is substantially pure.
  • the FB-4 of the compound of formula (I) has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.
  • FB-4 of the compound of formula (I) is an anhydrate.
  • the compound FB-4 of formula (I) has a TGA pattern substantially as shown in FIG. 13 .
  • the compound FB-4 of formula (I) has a DSC spectrum substantially as shown in FIG. 14 .
  • FB-4 of the compound of formula (I) is a stable crystalline form under high temperature conditions.
  • 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:
  • the solid is a solid form other than FB-4 of the compound of formula (I);
  • the stirring time is ⁇ 1h
  • the stirring temperature is 4°C-80°C.
  • the solvent 4 is selected from a mixture of ethanol and water or a mixture of acetone and water;
  • the dissolving is carried out under high temperature conditions
  • the stirring time is ⁇ 1 h
  • the stirring temperature is 4°C-80°C.
  • the crystalline form FB-4 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:
  • the crystal form FB-4 disclosed in the present invention remains unchanged in crystal form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability.
  • 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.
  • the solubility of the crystalline form FB-4 provided in the present disclosure can meet the requirements for pharmaceutical use.
  • 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.
  • the crystal form FB-4 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.
  • the present disclosure relates to pharmaceutically acceptable solid state forms of compounds of formula (I).
  • the present disclosure relates to crystalline compounds of formula (I).
  • the present disclosure relates to the crystalline anhydrate of the compound of formula (I).
  • the present disclosure relates to crystalline tunnel hydrates of the compound of formula (I).
  • the present disclosure relates to the amorphous free base of the compound of formula (I).
  • the present disclosure relates to the anhydrate crystalline form FB-2 of the compound of formula (I).
  • the present disclosure relates to the anhydrate crystalline form FB-3 of the compound of formula (I).
  • the present disclosure relates to the anhydrate crystalline form FB-4 of the compound of formula (I).
  • Another aspect of the present disclosure is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of formula (I) FB-2, FB-3 and FB-4 described in the present disclosure, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is selected according to the mode and route of administration.
  • 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.
  • 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 methyl cellulose.
  • 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.
  • lubricants such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methylparaben and propylparaben
  • preservatives such as methylparaben and propylparaben
  • sweeteners such as stearate, and mineral oil
  • flavoring agents such as talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition may also include one or more pH adjusters or buffers, for example: an acid, such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid; or a base, such as any one or a combination of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris(hydroxymethyl)aminomethane; 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.
  • an acid such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, male
  • 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.
  • Another aspect of the present disclosure is to provide a preparation prepared from the above-mentioned pharmaceutical composition, wherein the preparation form is selected from oral preparations and parenteral preparations.
  • 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.
  • the preparation is in the form of an oral preparation; preferably, the preparation is in the form of a capsule.
  • Another aspect of the present disclosure is to provide the use of one or more of the 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.
  • the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.
  • 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 tumor of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma, Ewing's sarcoma and rhab
  • the cancer is glioma.
  • the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.
  • the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.
  • the inflammation is selected from colitis, arthritis and uveitis.
  • 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 FB-2, FB-3 and FB-4 of the compound of formula (I) described in the present disclosure or their pharmaceutical compositions or preparations.
  • the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.
  • 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 the pharmaceutical composition or preparation thereof.
  • 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 tumor of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma, Ewing's sarcoma and rhab
  • the cancer is glioma.
  • the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.
  • the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.
  • the inflammation is selected from colitis, arthritis and uveitis.
  • 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.
  • the other drug is temozolomide.
  • terapéuticaally effective amount 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.
  • treat refers to reversing, alleviating the development of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as defined immediately above. The term “treatment” also includes adjuvant therapy and neoadjuvant therapy of a subject.
  • room temperature refers to a temperature of 10 to 30°C.
  • the "separation” can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the reduced pressure filtration is generally carried out at room temperature with a pressure less than atmospheric pressure.
  • drying can be accomplished by conventional techniques in the art, such as room temperature drying, forced air drying or reduced pressure drying, and can also be carried out under reduced pressure or without reduced pressure.
  • the drying apparatus and method are not limited, and can be a fume hood, forced air oven, spray dryer, fluidized bed drying or vacuum oven; and can also be carried out under reduced pressure or without reduced pressure.
  • the “relative intensity (I%)” is expressed as a specific value in a specific XRPD spectrum. Based on the anisotropic properties of crystals and the principle of X-ray powder diffraction, the relative intensity value of the diffraction peak of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be accepted by technicians in this field.
  • ratios involved in the present disclosure are mass-to-volume ratios between liquid and solid, and volume ratios between liquids.
  • FIG1 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I);
  • FIG2 is an FT-IR spectrum of the crystalline form FB-2 of the compound of formula (I);
  • FIG3 is a DSC spectrum of the crystalline form FB-2 of the compound of formula (I);
  • FIG4 is a TGA spectrum of the crystalline form FB-2 of the compound of formula (I);
  • FIG5 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I) in Example 2;
  • FIG6 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I);
  • FIG7 is an FT-IR spectrum of the crystalline form FB-3 of the compound of formula (I);
  • FIG8 is a DSC spectrum of the crystalline form FB-3 of the compound of formula (I);
  • FIG9 is a TGA spectrum of the crystalline form FB-3 of the compound of formula (I);
  • FIG10 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I) in Example 4.
  • FIG11(A) is a full XRPD spectrum of the crystalline form FB-3 of the compound of formula (I) in Example 5;
  • FIG11(B) is an enlarged view of the XRPD spectrum of the crystalline form FB-3 of the compound of formula (I) in Example 5;
  • FIG12 is an XRPD pattern of the crystalline form FB-4 of the compound of formula (I);
  • FIG13 is a TGA spectrum of the crystalline form FB-4 of the compound of formula (I);
  • FIG15 is an FT-IR spectrum of the crystalline form FB-4 of the compound of formula (I);
  • FIG16 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;
  • FIG17 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;
  • FIG18 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;
  • FIG19 is an XRPD of the crystalline form FB-3 of the compound of formula (I) before and after grinding;
  • FIG20 is a DVS spectrum of the crystalline form FB-2 of the compound of formula (I);
  • FIG21 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after DVS testing;
  • FIG22 is a DVS spectrum of the crystalline form FB-3 of the compound of formula (I);
  • FIG23 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after DVS testing;
  • FIG24 is a DVS spectrum of the crystalline form FB-4 of the compound of formula (I);
  • FIG25 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after DVS testing;
  • FIG26 is an XRPD stack of Form FB-3 of the compound of formula (I) before and after tableting;
  • FIG27 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after solubility testing in water;
  • FIG28 is an XRPD overlay of the crystalline form FB-3 of the compound of formula (I) before and after solubility testing in water;
  • FIG29 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after solubility testing in water;
  • FIG30 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.
  • HPLC determination method chromatograph model: Ultimate3000, chromatographic column: C18 5 ⁇ m 4.6*250mm, column temperature: 30°C, flow rate: 1.1mL/min, detection wavelength: 254nm, diluent: acetonitrile, running time: 30min, mobile phase A: acetonitrile + 0.1% trifluoroacetic acid solution; mobile phase B: water + 0.1% trifluoroacetic acid solution.
  • the XRPD data are shown in the following table:
  • the FB-2 prepared in this example is an anhydrous substance.
  • the XRPD data are shown in the following table:
  • the FB-3 prepared in this example is an anhydrous substance.
  • Figure 11(A) 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).
  • the XRPD data are shown in the following table:
  • 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.
  • the FB-4 prepared in this example is an anhydrous substance.
  • the crystalline forms FB-2, FB-3 and FB-4 disclosed in the present invention were respectively taken, and their hygroscopicity was tested by a dynamic moisture sorption (DVS) instrument.
  • the crystalline forms were tested by XRPD before and after the DVS test. The results are shown in Figures 20-25.
  • a certain amount of crystal form FB-3 sample was weighed, placed in an infrared tablet press, kept at a pressure of 2 MPa for 2 min, and the crystal form before and after tableting was detected. The results are shown in FIG26 .

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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

一种选择性PARP-1抑制剂的晶型及其制备方法和用途A selective PARP-1 inhibitor crystal form and its preparation method and use

相关申请的引用Citation of Related Applications

本申请要求于2023年11月24日向中华人民共和国国家知识产权局提交的申请号为202311585745.4的发明专利申请、于2024年1月5日向中华人民共和国国家知识产权局提交的申请号为202410021396.1的发明专利申请的全部权益，并通过引用的方式将其全部内容并入本申请。This application claims all rights and interests of 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.

技术领域Technical Field

本公开涉及药物化学领域。具体而言，本公开涉及一种选择性PARP-1抑制剂的晶型及其制备方法和用途。The present disclosure relates to the field of pharmaceutical chemistry. Specifically, the present disclosure relates to a crystalline form of a selective PARP-1 inhibitor and a preparation method and use thereof.

背景技术Background Art

一种选择性聚腺苷二磷酸核糖聚合酶(poly(ADP-ribose)polymerase 1，简称PARP-1)抑制剂，化学名称为：2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid amide，结构如下式(I)所示的化合物(以下简称式(I)化合物)： 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, having a structure represented by the following formula (I) (hereinafter referred to as the compound of formula (I)):

PARP是一种参与DNA修复调控的酶。PARP抑制已被证明是一种成功的治疗策略，用于治疗携带有害的生殖系和/或体细胞BRCA突变的患者，这种突变在相当一部分乳腺癌、卵巢癌、前列腺癌和胰腺癌中存在。式(I)化合物为国际申请WO2014064149A1中的化合物11，其可以用于治疗癌症、心血管疾病、神经系统损伤和炎症。式(I)化合物在WO2014064149A1中公开的PAR assay IC50是0.02μM，为具有高活性何高选择性的PARP-1抑制剂。式(I)化合物不会诱导DNA捕获，在造血系统效应方面具有更高的耐受性。由于其高的脑透过性，它具有对抗原发性脑肿瘤和中枢神经系统转移的潜力。动物试验证实式(I)化合物具有良好的in vivo有效性和低毒性。式(I)化合物在临床上用于治疗PARP-1介导的相关疾病，例如癌症、心血管疾病、神经系统损伤和炎症。目前尚未公开关于该化合物晶型的相关报道，因此，有必要对式(I)化合物进行多晶型筛选，选择具有优良性质的晶型以用于式(I)化合物的制剂产品开发。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 with deleterious germline and/or somatic BRCA mutations, which are present in a significant portion of breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. 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) has a PAR assay IC 50 of 0.02 μM disclosed in WO2014064149A1, and 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 permeability, it has the potential to target 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. Currently, there is no public report on the crystal form of the compound. Therefore, it is necessary to screen the polymorphs of the compound of formula (I) and select the crystal form with excellent properties for the development of formulation products of the compound of formula (I).

发明内容Summary of the invention

本公开提供一种选择性PARP-1抑制剂的晶型，其至少具有以下一种优良的特性：稳定性良好，纯度高，溶解度好，溶出好，生物利用度高，引湿性低，流动性好，机械应力稳定性好、可加工性好例如可压性好，晶体形貌好，抗压性好，能稳定储存，避免药物在开发过程和储存中发生转晶，制备方法简单可靠，具有较大的开发价值。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, avoiding crystal transformation of the drug during the development process and storage, simple and reliable preparation method, and great development value.

特别地，本公开提供的晶型FB-3具有以下至少一种优良的特性，例如在长期和加速条件下优良的物理和化学稳定性，良好的湿度稳定性，在水基制剂或水基环境中改良的物理稳定性，优异的研磨稳定性和可压性，在0％RH-80％RH条件下极低的引湿性，在高湿环境不转晶，在水中优良的溶解度。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 preparations or water-based environments, excellent grinding stability and compressibility, extremely low hygroscopicity under 0% RH-80% RH conditions, no crystal transformation in a high humidity environment, and excellent solubility in water.

特别地，本公开提供的晶型FB-2具有以下至少一种优良的特性，例如在长期和加速条件下优良的稳定性，良好的湿度稳定性，在水中改良的溶解度，良好的纯度和结晶度。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.

特别地，本公开提供的晶型FB-4具有以下至少一种优良的特性，例如在长期和加速条件下优良的物理和化学稳定性，在高温条件下改良的物理稳定性，良好的纯度和结晶度。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.

本公开的一个方面，在于提供一种结构如式(I)所示化合物的晶型FB-2(以下简称FB-2)，
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),

使用Cu-Kα辐射，所述式(I)化合物的FB-2以2θ角度表示的X-射线粉末衍射(XRPD)图谱在7.9°±0.2°、19.3°±0.2°和22.1°±0.2°中的1处或2处或3处有特征峰。Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) 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°.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在7.9°±0.2°、19.3°±0.2°和22.1°±0.2°2θ处有特征峰。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) has characteristic peaks at 7.9°±0.2°, 19.3°±0.2° and 22.1°±0.2°2θ.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱进一步在14.8±0.2°、17.5°±0.2°和21.3°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在14.8±0.2°、17.5°±0.2°和21.3°±0.2°2θ处有特征峰。In the preferred technical scheme 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 thereof; 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.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱进一步在13.4°±0.2°、24.5°±0.2°和29.7°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在13.4°±0.2°、24.5°±0.2°和29.7°±0.2°2θ处有特征峰。In the preferred technical scheme 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.

另一方面，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在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°和29.7°±0.2°2θ中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。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.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在22.1°±0.2°2θ处有特征峰。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.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在7.9°±0.2°和22.1°±0.2°2θ处有特征峰。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.

非限制性地，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在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°、25.1°±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°和39.3°±0.2°2θ处有特征峰。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°, 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.

非限制性地，在一个具体的实施例中，所述式(I)化合物的FB-2具有基本如图1或图5所示的X-射线粉末衍射图谱。Without limitation, in a specific embodiment, the compound FB-2 of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 5 .

本公开优选技术方案中，所述式(I)化合物的FB-2基本是纯的。In the preferred technical solution of the present disclosure, the FB-2 of the compound of formula (I) is substantially pure.

优选地，所述式(I)化合物的FB-2具有大于90％的纯度；优选为具有大于95％的纯度；更优选为具有大于99％的纯度。Preferably, the FB-2 of the compound of formula (I) has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.

本公开优选技术方案中，所述式(I)化合物的FB-2的傅里叶红外图谱(FT-IR)在3194.28cm-1±5cm-1、2932.13cm-1±5cm-1、2848.39cm-1±5cm-1、1664.03cm-1±5cm-1、1389.40cm- 1±5cm-1和742.75cm-1±5cm-1中的至少一处有谱带。In the preferred technical scheme of the present disclosure, the Fourier infrared spectrum (FT-IR) of FB-2 of the compound of formula (I) has a band at at least one of 3194.28cm -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 .

非限制性地，所述式(I)化合物的FB-2具有基本如图2所示的傅里叶红外图谱。Without limitation, the compound FB-2 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 2 .

非限制性地，所述式(I)化合物的FB-2为无水物。Without limitation, FB-2 of the compound of formula (I) is an anhydrate.

非限制性地，所述式(I)化合物的FB-2具有基本如图4所示的TGA图谱。Without limitation, the compound FB-2 of formula (I) has a TGA pattern substantially as shown in FIG. 4 .

非限制性地，所述式(I)化合物的FB-2具有基本如图3所示的DSC图谱。Without limitation, the compound FB-2 of formula (I) has a DSC spectrum substantially as shown in FIG. 3 .

本公开的另一方面，提供了一种式(I)化合物的晶型FB-2的制备方法，所述制备方法包括将式(I)化合物在溶剂1中形成混悬液，搅拌，分离固体，干燥，得到式(I)化合物的FB-2；其中所述溶剂1为乙酸乙酯和甲基叔丁基醚的混合溶剂。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.

在一些实施例中，所述乙酸乙酯和甲基叔丁基醚的体积比为2:3。In some embodiments, the volume ratio of ethyl acetate to methyl tert-butyl ether is 2:3.

优选地，所述搅拌时间≥1h，所述搅拌温度为4℃-80℃。Preferably, the stirring time is ≥1 h, and the stirring temperature is 4°C-80°C.

在一些具体实施例中，所述搅拌时间为3天，所述搅拌温度为室温。In some specific embodiments, the stirring time is 3 days, and the stirring temperature is room temperature.

优选地，所述干燥温度为30℃-80℃，更优选为40℃。Preferably, the drying temperature is 30°C-80°C, more preferably 40°C.

本公开所述式(I)化合物的晶型FB-2具有以下有益效果：The crystalline form FB-2 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

1)稳定性好。本公开所述的式(I)化合物的FB-2在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置60天晶型保持不变，且化学纯度保持不变，具有良好的物理和化学稳定性。1) Good stability. The FB-2 of the compound of formula (I) described in the present disclosure maintains the same crystal form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability.

同时，晶型FB-2在DVS测试前后晶型保持不变，具有良好的湿度稳定性。At the same time, the crystal form of FB-2 remains unchanged before and after the DVS test, and has good humidity stability.

2)溶解度好。本公开提供的晶型FB-2的溶解度可以满足药用需求。2) Good solubility. The solubility of the crystalline form FB-2 provided in the present disclosure can meet the requirements for pharmaceutical use.

3)纯度高。本公开提供的晶型FB-2的纯度高达99.9％以上，利于工业化生产。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.

4)结晶度好。本公开的提供的晶型FB-2结晶度好，适合药用。4) Good crystallinity. The crystal form FB-2 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

5)制备方法简单，重复性高，产业化前景高。5) The preparation method is simple, highly reproducible and has great industrial prospects.

本公开的另一方面，在于提供一种结构如式(I)所示化合物的晶型FB-3(以下简称FB-3)，使用Cu-Kα辐射，所述式(I)化合物的FB-3以2θ角度表示的X-射线粉末衍射图谱在4.7±0.2°、9.5°±0.2°和18.1°±0.2°中的1处或2处或3处有特征峰。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 shown in 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°.

本公开优选的技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在4.7±0.2°、9.5°±0.2°和18.1°±0.2°处有特征峰。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°.

本公开优选的技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在11.9°±0.2°、20.1°±0.2°和21.9°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在11.9°±0.2°、20.1°±0.2°和21.9°±0.2°2θ处有特征峰。In the preferred technical scheme 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 1, 2 or 3 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.

本公开优选的技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在13.0°±0.2°、17.5°±0.2°和23.4°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在13.0°±0.2°、17.5°±0.2°和23.4°±0.2°2θ处有特征峰。In the preferred technical scheme 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 1, 2 or 3 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.

另一方面，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在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°和23.4°±0.2°2θ中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。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.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在4.7°±0.2°2θ处有特征峰。Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has a characteristic peak at 4.7°±0.2°2θ.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在9.5°±0.2°2θ处有特征峰。Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has a characteristic peak at 9.5°±0.2°2θ.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在4.7°±0.2°和18.1°±0.2°2θ处有特征峰。Furthermore, 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° and 18.1°±0.2°2θ.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在9.5°±0.2°和18.1°±0.2°2θ处有特征峰。Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-3 of the formula (I) has characteristic peaks at 9.5°±0.2° and 18.1°±0.2°2θ.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在4.7°±0.2°和9.5°±0.2°2θ处有特征峰。Furthermore, 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° and 9.5°±0.2°2θ.

非限制性地，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在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°、31.5°±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°和39.7°±0.2°2θ处有特征峰。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.

非限制性地，所述式(I)化合物的FB-3其具有基本如图6或图10或图11(A)或图11(B)所示的X-射线粉末衍射图谱。Without limitation, the compound FB-3 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).

本公开优选技术方案中，所述式(I)化合物的FB-3基本是纯的。In the preferred technical solution of the present disclosure, the FB-3 of the compound of formula (I) is substantially pure.

优选地，具有大于90％的纯度；优选为具有大于95％的纯度；更优选为具有大于99％的纯度。Preferably, the purity is greater than 90%; preferably, the purity is greater than 95%; more preferably, the purity is greater than 99%.

本公开优选技术方案中，所述式(I)化合物的FB-3的傅里叶红外图谱在3225.55cm-1±5cm-1、3067.03cm-1±5cm-1、2958.00cm-1±5cm-1、1620.43cm-1±5cm-1、1593.18cm-1±5cm-1和735.01cm-1±5cm-1中的至少一处有谱带。In the preferred technical scheme of the present disclosure, the Fourier infrared spectrum of the compound FB-3 of formula (I) has a band at at least one of 3225.55cm -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 .

非限制性地，所述式(I)化合物的FB-3具有基本如图7所示的傅里叶红外图谱。Without limitation, the compound FB-3 of formula (I) has a Fourier transform infrared spectrum substantially as shown in FIG. 7 .

本公开优选技术方案中，所述式(I)化合物的FB-3为隧道水合物或无水物。In the preferred technical solution of the present disclosure, FB-3 of the compound of formula (I) is a tunnel hydrate or anhydrate.

非限制性地，所述式(I)化合物的FB-3为无水物。Without limitation, FB-3 of the compound of formula (I) is an anhydrate.

非限制性地，所述式(I)化合物的FB-3具有基本如图9所示的TGA图谱。Without limitation, the compound FB-3 of formula (I) has a TGA spectrum substantially as shown in FIG. 9 .

非限制性地，所述式(I)化合物的FB-3具有基本如图8所示的DSC图谱。Without limitation, the compound of formula (I) FB-3 has a DSC spectrum substantially as shown in FIG. 8 .

本公开的另一方面，在于提供一种式(I)化合物的晶型FB-3的制备方法，所述制备方法选自以下方法中的任一种：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:

1)将式(I)化合物在溶剂2中溶清，挥发，得到式(I)化合物的FB-3；其中所述溶剂3为乙腈；或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)将式(I)化合物在溶剂3中形成混悬液，搅拌，分离固体，干燥，得到式(I)化合物的FB-3；其中所述溶剂3为异丙醚；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;

优选地，方法1)中所述挥发温度为室温。Preferably, the volatilization temperature in method 1) is room temperature.

优选地，方法2)中混悬液中可加入少量FB-3晶种一起搅拌。Preferably, in method 2), a small amount of FB-3 seed crystals can be added to the suspension and stirred together.

优选地，方法2)中所述搅拌时间≥1h，所述搅拌温度为4℃-80℃。Preferably, in method 2), the stirring time is ≥ 1 h, and the stirring temperature is 4°C-80°C.

在一些具体实施例中，所述搅拌时间为1天或2天或3天，所述搅拌温度为室温。In some specific embodiments, the stirring time is 1 day, 2 days or 3 days, and the stirring temperature is room temperature.

优选地，所述干燥温度为30℃-80℃，更优选为40℃。Preferably, the drying temperature is 30°C-80°C, more preferably 40°C.

本公开所述式(I)化合物的晶型FB-3具有以下有益效果：The crystalline form FB-3 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

1)稳定性好。本公开的式(I)化合物的晶型FB-3在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置60天晶型保持不变，且化学纯度保持不变，具有良好的物理和化学稳定性，有利于药物储存。1) Good stability. The crystalline form FB-3 of the compound of formula (I) disclosed in the present invention remains unchanged in crystalline form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability, which is conducive to drug storage.

同时，晶型FB-3可在纯水或者含水环境中保持晶型不变，具有良好的水中稳定性，这使得晶型FB-3特别适合有水的制剂制备过程，例如湿法制粒，也使得采用晶型FB-3制备的制剂更易在湿度较大的环境下保持晶型稳定。At the same time, the crystalline form FB-3 can maintain its crystal form unchanged in pure water or water-containing environment and has good stability in water, which makes the crystalline form FB-3 particularly suitable for the preparation process of water-containing preparations, such as wet granulation, and also makes it easier for preparations prepared using the crystalline form FB-3 to maintain crystal stability in an environment with high humidity.

同时，晶型FB-3研磨后晶型保持不变，具有良好的机械稳定性，制剂加工过程中常需要研磨粉碎原料药，良好的机械稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。At the same time, the crystal form of FB-3 remains unchanged after grinding and has good mechanical stability. The raw materials often need to be ground and crushed during the preparation process. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of the raw materials during the preparation process.

同时，晶型FB-3在水中和正庚烷中为热力学最稳晶型。晶型FB-2、晶型FB-3和晶型FB-4的混合固体分别在水中和正庚烷中搅拌，均转变为晶型FB-3。At the same time, the crystalline form FB-3 is the most thermodynamically stable crystalline form in water and n-heptane. The mixed solids of the crystalline forms FB-2, FB-3 and FB-4 were stirred in water and n-heptane respectively, and all transformed into the crystalline form FB-3.

2)溶解度好。本公开提供的晶型FB-3的溶解度可以满足药用需求。2) Good solubility. The solubility of the crystalline form FB-3 provided in the present disclosure can meet the requirements for pharmaceutical use.

3)可压性好。本公开提供的晶型FB-3可压性好。有利于改善压片工艺中出现的裂片等问题，提升生产效率。3) Good compressibility. The crystal form FB-3 provided in the present disclosure has good compressibility, which is beneficial to improve the problems such as cracking in the tableting process and improve production efficiency.

4)纯度高。本公开提供的晶型FB-3的纯度高达99.9％以上，利于工业化生产。晶型FB-3具有较强的杂质排除能力，且可通过本公开的制备方法结晶工艺得到纯度高的原料药，并且不易出现溶剂残留的问题，适合药用。4) High purity. The purity of the crystal form FB-3 provided by the present disclosure is as high as 99.9% or more, which is conducive to industrial production. The crystal form FB-3 has a strong impurity removal ability, and a high-purity raw material can be obtained through the crystallization process of the preparation method disclosed in the present disclosure, and the problem of solvent residue is not likely to occur, which is suitable for medicinal use.

5)结晶度好。本公开的提供的晶型FB-3结晶度好，适合药用。5) Good crystallinity. The crystal form FB-3 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

6)制备方法简单，重复性高，产业化前景高。6) The preparation method is simple, highly reproducible and has high industrialization prospects.

本公开的一个方面，在于提供一种结构如式(I)所示化合物的晶型FB-4(以下简称FB-4)，使用Cu-Kα辐射，所述式(I)化合物的FB-4以2θ角度表示的X-射线粉末衍射图谱在5.9°±0.2°、16.5°±0.2°和21.7°±0.2°中的1处或2处或3处有特征峰。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 shown in 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°.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在5.9°±0.2°、16.5°±0.2°和21.7°±0.2°2θ处有特征峰。In the preferred technical solution of the present invention, 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.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在11.6±0.2°、13.1°±0.2°和26.8°±0.2°2θ中的至少一处有特征峰。In the preferred technical solution of the present invention, 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.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在11.6±0.2°、13.1°±0.2°和26.8°±0.2°2θ中的1处或2处或3处有特征峰。优选地，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在11.6±0.2°、13.1°±0.2°和26.8°±0.2°2θ处有特征峰。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 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.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在17.2°±0.2°、20.7°±0.2°和24.7°±0.2°2θ中的至少一处有特征峰。In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-4 of the 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.

本公开优选技术方案中，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在17.2°±0.2°、20.7°±0.2°和24.7°±0.2°2θ中的1处或2处或3处有特征峰。优选地，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在17.2°±0.2°、20.7°±0.2°和24.7°±0.2°2θ处有特征峰。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 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.

另一方面，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在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°和24.7°±0.2°2θ中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。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.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在5.9°±0.2°2θ处有特征峰。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.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在16.5°±0.2°2θ处有特征峰。Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the compound FB-4 of the formula (I) has a characteristic peak at 16.5°±0.2°2θ.

进一步地，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在5.9°±0.2°和21.7°±0.2°2θ处有特征峰。Further, 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° and 21.7°±0.2°2θ.

非限制性地，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在16.5°±0.2°和21.7°±0.2°2θ处有特征峰。Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of FB-4 of the compound of formula (I) has characteristic peaks at 16.5°±0.2° and 21.7°±0.2° 2θ.

非限制性地，在一个具体的实施例中，所述式(I)化合物的FB-4具有基本如图12所示的XRPD图谱。Without limitation, in a specific embodiment, the compound FB-4 of formula (I) has an XRPD pattern substantially as shown in FIG. 12 .

本公开优选技术方案中，所述式(I)化合物的FB-4的傅里叶红外图谱在3230.3cm-1±5cm-1、2920.6cm-1±5cm-1、1662.4cm-1±5cm-1、1596.1cm-1±5cm-1、1389.9cm-1±5cm-1和738.4cm-1±5cm-1中的至少一处有谱带。In the preferred technical scheme of the present disclosure, the Fourier infrared spectrum of the compound FB-4 of formula (I) has a band at at least one of 3230.3cm -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 .

非限制性地，在一个具体的实施例中，所述式(I)化合物的FB-4具有基本如图15所述的傅里叶红外图谱。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 .

本公开优选技术方案中，所述式(I)化合物的FB-4基本是纯的。In the preferred technical solution of the present disclosure, the FB-4 of the compound of formula (I) is substantially pure.

优选地，所述式(I)化合物的FB-4具有大于90％的纯度；优选为具有大于95％的纯度；更优选为具有大于99％的纯度。Preferably, the FB-4 of the compound of formula (I) has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%.

非限制性地，所述式(I)化合物的FB-4为无水物。Without limitation, FB-4 of the compound of formula (I) is an anhydrate.

非限制性地，所述式(I)化合物的FB-4具有基本如图13所示的TGA图谱。Without limitation, the compound FB-4 of formula (I) has a TGA pattern substantially as shown in FIG. 13 .

非限制性地，所述式(I)化合物的FB-4具有基本如图14所示的DSC图谱。Without limitation, the compound FB-4 of formula (I) has a DSC spectrum substantially as shown in FIG. 14 .

本公开优选技术方案中，所述式(I)化合物的FB-4为高温条件下稳定的晶型。In the preferred technical solution of the present disclosure, FB-4 of the compound of formula (I) is a stable crystalline form under high temperature conditions.

本公开的另一方面，提供了一种式(I)化合物的晶型FB-4的制备方法，所述制备方法选自以下方法中的任一种：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:

1)将式(I)化合物在水中形成混悬液，搅拌，分离固体，加热固体至170℃以上，再降至室温，得到FB-4；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;

优选地，所述固体为式(I)化合物的FB-4以外的其他固体形式；Preferably, the solid is a solid form other than FB-4 of the compound of formula (I);

优选地，所述搅拌时间≥1h，所述搅拌温度为4℃-80℃。Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C.

2)将式(I)化合物在溶剂4中溶清，加入FB-4晶种，搅拌，离心，干燥，得到FB-4；2) dissolving the compound of formula (I) in solvent 4, adding FB-4 seed crystals, stirring, centrifuging, and drying to obtain FB-4;

优选地，所述溶剂4选自乙醇和水的混合或丙酮和水的混和；Preferably, the solvent 4 is selected from a mixture of ethanol and water or a mixture of acetone and water;

优选地，所述溶清在高温条件下进行；Preferably, the dissolving is carried out under high temperature conditions;

优选地，所述搅拌时间≥1h，所述搅拌温度为4℃-80℃。Preferably, the stirring time is ≥1 h, and the stirring temperature is 4°C-80°C.

本公开所述式(I)化合物的晶型FB-4具有以下有益效果：The crystalline form FB-4 of the compound of formula (I) disclosed in the present invention has the following beneficial effects:

1)稳定性好。本公开所述的晶型FB-4在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置60天晶型保持不变，且化学纯度保持不变，具有良好的物理和化学稳定性。1) Good stability. The crystal form FB-4 disclosed in the present invention remains unchanged in crystal form and chemical purity after being placed under long-term (25°C/60% RH/open) and accelerated (40°C/75% RH/open) conditions for 60 days, and has good physical and chemical stability.

2)熔点高。本公开所述的晶型FB-4熔点高，接近240℃，具有良好的高温晶型稳定性。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.

3)溶解度好。本公开提供的晶型FB-4的溶解度可以满足药用需求。3) Good solubility. The solubility of the crystalline form FB-4 provided in the present disclosure can meet the requirements for pharmaceutical use.

4)纯度高。本公开提供的晶型FB-4的纯度高达99.9％以上，利于工业化生产。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.

5)结晶度好。本公开的提供的晶型FB-4得结晶度好，适合药用。5) Good crystallinity. The crystal form FB-4 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

6)制备方法简单，重复性高，产业化前景高。6) The preparation method is simple, highly reproducible and has high industrialization prospects.

另一方面，本公开涉及式(I)化合物药学上可接受的固态形式。In another aspect, the present disclosure relates to pharmaceutically acceptable solid state forms of compounds of formula (I).

优选地，本公开涉及结晶的式(I)化合物。Preferably, the present disclosure relates to crystalline compounds of formula (I).

优选地，本公开涉及式(I)化合物的结晶无水物。Preferably, the present disclosure relates to the crystalline anhydrate of the compound of formula (I).

优选地，本公开涉及式(I)化合物的结晶隧道水合物。Preferably, the present disclosure relates to crystalline tunnel hydrates of the compound of formula (I).

优选地，本公开涉及式(I)化合物的无定型游离碱。Preferably, the present disclosure relates to the amorphous free base of the compound of formula (I).

优选地，本公开涉及涉及式(I)化合物的无水物晶型FB-2。Preferably, the present disclosure relates to the anhydrate crystalline form FB-2 of the compound of formula (I).

优选地，本公开涉及涉及式(I)化合物的无水物晶型FB-3。Preferably, the present disclosure relates to the anhydrate crystalline form FB-3 of the compound of formula (I).

优选地，本公开涉及涉及式(I)化合物的无水物晶型FB-4。Preferably, the present disclosure relates to the anhydrate crystalline form FB-4 of the compound of formula (I).

本公开的另一方面，在于提供一种药物组合物，所述药物组合物包含治疗有效量的一种或多种的本公开所述的式(I)化合物的FB-2、FB-3和FB-4，以及至少一种药学上可接受的载体。Another aspect of the present disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of formula (I) FB-2, FB-3 and FB-4 described in the present disclosure, and at least one pharmaceutically acceptable carrier.

其中，所述药学上可接受的载体为是根据施用方式和途径来选择。The pharmaceutically acceptable carrier is selected according to the mode and route of administration.

上述药物组合物还可包含一种或多种式(I)化合物的其他晶型，以及至少一种药学上可接受的载体。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.

非限制性地，合适的载体可以是乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。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 methyl cellulose.

非限制性地，所述药物组合物中还可以包含润滑剂，例如滑石、硬脂酸镁和矿物油；润湿剂；乳化剂和悬浮剂；防腐剂，例如羟基苯甲酸甲酯和羟基苯甲酸丙酯；甜味剂；和调味剂。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.

非限制性地，所述药物组合物还可以包含一种或多种pH调整剂或缓冲剂，举例来说：酸，例如乙酸、硼酸、柠檬酸、富马酸、马来酸、酒石酸、苹果酸、乳酸、磷酸、盐酸的任一种或其组合；或者碱，例如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠、三羟甲基氨基甲烷的任一种或其组合物；或者缓冲剂，例如柠檬酸盐/葡萄糖、碳酸氢钠、氯化铵和类似物；用作碱的此类缓冲剂可具有除钠以外的平衡离子，例如钾、镁、钙、铵和其它平衡离子；以及其他将组分的pH维持在可接受范围内所需的量，包含此类酸、碱和缓冲剂的溶液或固体。Without limitation, the pharmaceutical composition may also include one or more pH adjusters or buffers, for example: an acid, such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid; or a base, such as any one or a combination of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris(hydroxymethyl)aminomethane; 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.

非限制性地，所述药物组合物的给药途径包括口服、舌下、经颊、透皮、皮内、肌内、肠胃外、静脉内、动脉内、颅内、皮下、眶内、脑室内、脊柱内、腹膜内、鼻内、吸入和局部施用。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.

本公开的另一方面，还在于提供一种上述药物组合物制备成的制剂，所述制剂形式选自口服制剂和肠胃外制剂。Another aspect of the present disclosure is to provide a preparation prepared from the above-mentioned pharmaceutical composition, wherein the preparation form is selected from oral preparations and parenteral preparations.

本公开优选技术方案中，所述制剂形式为胶囊剂、片剂、混悬剂、散剂、缓释制剂、速释制剂、丸剂、栓剂、颗粒剂、细粒剂/锭剂、药囊剂、扁囊剂、酊剂、酏剂、乳剂、乳膏剂、气雾剂、凝胶剂、溶液剂和糖浆剂。In the preferred technical scheme of the present invention, 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.

本公开优选技术方案中，所述制剂形式为口服制剂；优选地，所述制剂形式为胶囊剂。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.

本公开的另一方面，在于提供一种或多种的本公开所述的式(I)化合物的FB-2、FB-3和FB-4或其所述的药物组合物或制剂在制备用于治疗由PARP-1介导的疾病的药物中的用途。Another aspect of the present disclosure is to provide the use of one or more of the 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.

优选地，所述由PARP-1介导的疾病选自癌症、心血管疾病、神经系统损伤和炎症。Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

优选地，所述癌症选自膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌，包括小细胞肺癌、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌，包括鳞状细胞癌；淋巴系的造血系统癌(hematopoietic tumor)，包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、何杰金淋巴瘤、非何杰金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤；髓系的造血系统癌，包括急性和慢性髓性白血病、骨髓增生异常综合征和前髓细胞性白血病；间质起源的肿瘤，包括纤维肉瘤、尤因肉瘤和横纹肌肉瘤；中枢和周围神经系统肿瘤，包括星形细胞瘤、神经细胞瘤、神经胶质瘤和许旺细胞瘤；和其它肿瘤，包括黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化黄瘤(keratoxanthoma)、甲状腺毛囊癌和卡波西肉瘤。优选地，所述癌症，例如乳腺癌、卵巢癌、神经胶质瘤，为BRCA突变型。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 tumor of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma, Ewing's sarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors, including astrocytoma, neurocytoma, glioma and Schwannoma; and other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma and Kaposi's sarcoma. Preferably, the cancer, such as breast cancer, ovarian cancer, glioma, is a BRCA mutant.

优选地，所述癌症为神经胶质瘤。Preferably, the cancer is glioma.

优选地，所述心血管疾病选自心肌再灌注损伤、心肌病和糖尿病性心血管功能障碍。Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

优选地，所述神经系统损伤选自中风、脑损伤和神经变性障碍。Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

优选地，所述炎症选自结肠炎、关节炎和葡萄膜炎。Preferably, the inflammation is selected from colitis, arthritis and uveitis.

本公开的另一方面，在于提供一种用于治疗由PARP-1介导的疾病的方法，其包括向患者施加一种或多种的本公开所述的式(I)化合物的FB-2、FB-3和FB-4或其所述的药物组合物或制剂。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 FB-2, FB-3 and FB-4 of the compound of formula (I) described in the present disclosure or their pharmaceutical compositions or preparations.

优选地，所述由PARP-1介导的疾病选自癌症、心血管疾病、神经系统损伤和炎症。Preferably, the disease mediated by PARP-1 is selected from cancer, cardiovascular disease, nervous system damage and inflammation.

本公开的另一方面，在于提供一种用于治疗癌症的方法，其包括向患者施加一种或多种的本公开所述的式(I)化合物的晶型FB-2、FB-3和FB-4或其所述的药物组合物或制剂。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 the pharmaceutical composition or preparation thereof.

优选地，所述癌症选自膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌，包括小细胞肺癌、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌，包括鳞状细胞癌；淋巴系的造血系统癌(hematopoietic tumor)，包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、何杰金淋巴瘤、非何杰金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤；髓系的造血系统癌，包括急性和慢性髓性白血病、骨髓增生异常综合征和前髓细胞性白血病；间质起源的肿瘤，包括纤维肉瘤、尤因肉瘤和横纹肌肉瘤；中枢和周围神经系统肿瘤，包括星形细胞瘤、神经细胞瘤、神经胶质瘤和许旺细胞瘤；和其它肿瘤，包括黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化黄瘤(keratoxanthoma)、甲状腺毛囊癌和卡波西肉瘤。优选地，所述癌症，优选地，所述癌症，例如乳腺癌、卵巢癌、神经胶质瘤，为BRCA突变型。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 tumor of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic cancers of the myeloid lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma, Ewing's sarcoma and rhabdomyosarcoma; central and peripheral nervous system tumors, including astrocytoma, neurocytoma, glioma and Schwannoma; and other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicle carcinoma and Kaposi's sarcoma. Preferably, the cancer, preferably, the cancer, such as breast cancer, ovarian cancer, glioma, is a BRCA mutant.

优选地，所述癌症为神经胶质瘤。Preferably, the cancer is glioma.

优选地，所述心血管疾病选自心肌再灌注损伤、心肌病和糖尿病性心血管功能障碍。Preferably, the cardiovascular disease is selected from the group consisting of myocardial reperfusion injury, cardiomyopathy and diabetic cardiovascular dysfunction.

优选地，所述神经系统损伤选自中风、脑损伤和神经变性障碍。Preferably, the nervous system injury is selected from the group consisting of stroke, brain injury and neurodegenerative disorders.

优选地，所述炎症选自结肠炎、关节炎和葡萄膜炎。Preferably, the inflammation is selected from colitis, arthritis and uveitis.

本公开的另一方面，在于提供一种或多种的本公开所述的式(I)化合物的FB-2、FB-3和FB-4或其所述的药物组合物或制剂与其他药物的联合应用。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.

优选地，所述其他药物为替莫唑胺。Preferably, the other drug is temozolomide.

如本文所用，除非另外指明，否则单数形式“一(a/an)”及“该(the)”包括复数个体及物。As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

当由本领域技术人员考虑时，术语“约”意指具有落入可接受的平均值误差标准内的值。The term "about" means having a value within an acceptable standard of error of the mean when considered by one of ordinary skill in the art.

如本文所用的术语“治疗有效量”系指将在一定程度上减轻所治疗的病症的一或多种症状的所给药的化合物的量。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.

除非另外指明，否则本文所用的术语“治疗”是指逆转、减轻该术语所应用的病症或病状或此类病症或病状的一或多种症状的发展，或预防该病症或病状或该病症或病状的一或多种症状。除非另外指明，否则本文所用的术语“治疗(treatment)”系指如紧接上文所定义的“治疗(treating)”的治疗行为。术语“治疗”亦包括对受试者的辅助治疗及新辅助治疗。Unless otherwise indicated, the term "treat" as used herein refers to reversing, alleviating the development of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. Unless otherwise indicated, the term "treatment" as used herein refers to the act of treating as defined immediately above. The term "treatment" also includes adjuvant therapy and neoadjuvant therapy of a subject.

除非特殊注明，本公开所述的“室温”是指10～30℃的温度。Unless otherwise specified, the "room temperature" described in the present disclosure refers to a temperature of 10 to 30°C.

所述“分离”可以采用本领域的常规方法，例如离心或过滤。其中减压过滤，一般是在室温下以小于大气压的压力进行抽滤。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.

所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥，亦可以在减压或不减压下进行。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；亦可以在减压或不减压下进行。The "drying" can be accomplished by conventional techniques in the art, such as room temperature drying, forced air drying or reduced pressure drying, and can also be carried out under reduced pressure or without reduced pressure. The drying apparatus and method are not limited, and can be a fume hood, forced air oven, spray dryer, fluidized bed drying or vacuum oven; and can also be carried out under reduced pressure or without reduced pressure.

所述的“相对强度(I％)”，在具体的XRPD图谱中表现为具体数值。基于晶体的各向异性特性以及X-射线粉末衍射的原理，同一个晶型的衍射峰的相对强度数值随样品的择优取向现象会有波动，该波动不影响同一晶型的判断的常识应该被本领域的技术人员所接受。The "relative intensity (I%)" is expressed as a specific value in a specific XRPD spectrum. Based on the anisotropic properties of crystals and the principle of X-ray powder diffraction, the relative intensity value of the diffraction peak of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be accepted by technicians in this field.

如无特殊说明，本公开涉及的比例，液体与固体之间，为质量体积比，液体与液体之间，为体积比。Unless otherwise specified, the ratios involved in the present disclosure are mass-to-volume ratios between liquid and solid, and volume ratios between liquids.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为式(I)化合物的晶型FB-2的XRPD图谱；FIG1 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I);

图2为式(I)化合物的晶型FB-2的FT-IR图谱；FIG2 is an FT-IR spectrum of the crystalline form FB-2 of the compound of formula (I);

图3为式(I)化合物的晶型FB-2的DSC图谱；FIG3 is a DSC spectrum of the crystalline form FB-2 of the compound of formula (I);

图4为式(I)化合物的晶型FB-2的TGA图谱；FIG4 is a TGA spectrum of the crystalline form FB-2 of the compound of formula (I);

图5为实施例2中式(I)化合物的晶型FB-2的XRPD图谱；FIG5 is an XRPD pattern of the crystalline form FB-2 of the compound of formula (I) in Example 2;

图6为式(I)化合物的晶型FB-3的XRPD图谱；FIG6 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I);

图7为式(I)化合物的晶型FB-3的FT-IR图谱；FIG7 is an FT-IR spectrum of the crystalline form FB-3 of the compound of formula (I);

图8为式(I)化合物的晶型FB-3的DSC图谱；FIG8 is a DSC spectrum of the crystalline form FB-3 of the compound of formula (I);

图9为式(I)化合物的晶型FB-3的TGA图谱；FIG9 is a TGA spectrum of the crystalline form FB-3 of the compound of formula (I);

图10为实施例4中式(I)化合物的晶型FB-3的XRPD图谱；FIG10 is an XRPD pattern of the crystalline form FB-3 of the compound of formula (I) in Example 4;

图11(A)为实施例5中式(I)化合物的晶型FB-3的XRPD图谱全图；FIG11(A) is a full XRPD spectrum of the crystalline form FB-3 of the compound of formula (I) in Example 5;

图11(B)为实施例5中式(I)化合物的晶型FB-3的XRPD图谱放大图；FIG11(B) is an enlarged view of the XRPD spectrum of the crystalline form FB-3 of the compound of formula (I) in Example 5;

图12为式(I)化合物的晶型FB-4的XRPD图谱；FIG12 is an XRPD pattern of the crystalline form FB-4 of the compound of formula (I);

图13为式(I)化合物的晶型FB-4的TGA图谱；FIG13 is a TGA spectrum of the crystalline form FB-4 of the compound of formula (I);

图14为式(I)化合物的晶型FB-4的DSC图谱；FIG14 is a DSC spectrum of the crystalline form FB-4 of the compound of formula (I);

图15为式(I)化合物的晶型FB-4的FT-IR图谱；FIG15 is an FT-IR spectrum of the crystalline form FB-4 of the compound of formula (I);

图16为式(I)化合物的晶型FB-2在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置前后的XRPD叠图；FIG16 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;

图17为式(I)化合物的晶型FB-3在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置前后的XRPD叠图；FIG17 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;

图18为式(I)化合物的晶型FB-4在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置前后的XRPD叠图；FIG18 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after being placed under long-term (25° C./60% RH/open) and accelerated (40° C./75% RH/open) conditions;

图19为式(I)化合物的晶型FB-3研磨前后的XRPD；FIG19 is an XRPD of the crystalline form FB-3 of the compound of formula (I) before and after grinding;

图20为式(I)化合物的晶型FB-2的DVS图谱；FIG20 is a DVS spectrum of the crystalline form FB-2 of the compound of formula (I);

图21为式(I)化合物的晶型FB-2在DVS测试前后的XRPD叠图；FIG21 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after DVS testing;

图22为式(I)化合物的晶型FB-3的DVS图谱；FIG22 is a DVS spectrum of the crystalline form FB-3 of the compound of formula (I);

图23为式(I)化合物的晶型FB-3在DVS测试前后的XRPD叠图；FIG23 is an XRPD overlay of Form FB-3 of the compound of formula (I) before and after DVS testing;

图24为式(I)化合物的晶型FB-4的DVS图谱；FIG24 is a DVS spectrum of the crystalline form FB-4 of the compound of formula (I);

图25为式(I)化合物的晶型FB-4在DVS测试前后的XRPD叠图；FIG25 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after DVS testing;

图26为式(I)化合物的晶型FB-3在压片前后的XRPD叠图；FIG26 is an XRPD stack of Form FB-3 of the compound of formula (I) before and after tableting;

图27为式(I)化合物的晶型FB-2在水中测试溶解度前后的XRPD叠图；FIG27 is an XRPD overlay of Form FB-2 of the compound of formula (I) before and after solubility testing in water;

图28为式(I)化合物的晶型FB-3在水中测试溶解度前后的XRPD叠图；FIG28 is an XRPD overlay of the crystalline form FB-3 of the compound of formula (I) before and after solubility testing in water;

图29为式(I)化合物的晶型FB-4在水中测试溶解度前后的XRPD叠图；FIG29 is an XRPD overlay of Form FB-4 of the compound of formula (I) before and after solubility testing in water;

图30为式(I)化合物晶型FB-2、FB-3和FB-4的混合物在水和正庚烷中竞争前后的XRPD叠图。FIG30 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.

具体实施方式DETAILED DESCRIPTION

通过下述实施例将有助于进一步理解本公开，但是不用于限制本公开的内容。The following examples will help to further understand the present disclosure, but are not intended to limit the contents of the present disclosure.

检测仪器及方法：
Testing instruments and methods:

HPLC测定方法：色谱仪型号：Ultimate3000，色谱柱：C18 5μm 4.6*250mm，柱温：30℃，流速:1.1mL/min，检测波长：254nm，稀释剂：乙腈，运行时间：30min，流动相A：乙腈+0.1％三氟乙酸溶液；流动相B：水+0.1％三氟乙酸溶液。HPLC determination method: chromatograph model: Ultimate3000, chromatographic column: C18 5μm 4.6*250mm, column temperature: 30℃, flow rate: 1.1mL/min, detection wavelength: 254nm, diluent: acetonitrile, running time: 30min, mobile phase A: acetonitrile + 0.1% trifluoroacetic acid solution; mobile phase B: water + 0.1% trifluoroacetic acid solution.

本公开中，起始物料式(I)所示化合物可通过市售获得，也可通过现有技术制备得到，如WO2014064149A1中提到的方法制备得到。In the present disclosure, the compound represented by the starting material formula (I) can be obtained commercially, or prepared by existing techniques, such as the method mentioned in WO2014064149A1.

实施例1：式(I)化合物的晶型FB-2的制备Example 1: Preparation of Crystalline Form FB-2 of the Compound of Formula (I)

取式(I)化合物约20mg，加入0.4mL乙酸乙酯和0.6mL甲基叔丁基醚得到混悬液，将悬浮液在室温条件下搅拌3天，分离出固体，40℃真空干燥过夜，得到FB-2。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, the suspension was stirred at room temperature for 3 days, the solid was separated, and vacuum dried at 40° C. overnight to obtain FB-2.

测定其XRPD数据，如下表所示：
The XRPD data are shown in the following table:

其XRPD图谱如图1所示。Its XRPD pattern is shown in Figure 1.

其傅里叶红外图谱如图2所示。Its Fourier transform infrared spectrum is shown in Figure 2.

其DSC图谱如图3所示。Its DSC spectrum is shown in Figure 3.

其TGA图谱如图4所示，显示在120℃之前有约0.8％的失重。Its TGA spectrum is shown in FIG4 , which shows that there is a weight loss of about 0.8% before 120° C.

本实施例制备得到的FB-2为无水物。The FB-2 prepared in this example is an anhydrous substance.

实施例2：式(I)化合物的晶型FB-2的制备Example 2: Preparation of Crystalline Form FB-2 of the Compound of Formula (I)

取式(I)化合物约200mg，加0.8mL乙酸乙酯和1.2mL甲基叔丁基醚得到混悬液，将悬浮液在室温条件下搅拌5天，分离出固体，40℃真空干燥过夜，得到FB-2。About 200 mg of the compound of formula (I) was taken, 0.8 mL of ethyl acetate and 1.2 mL of methyl tert-butyl ether were added to obtain a suspension, the suspension was stirred at room temperature for 5 days, the solid was separated, and vacuum dried at 40° C. overnight to obtain FB-2.

经检测，其XRPD图谱如图5所示。After testing, its XRPD spectrum is shown in Figure 5.

实施例3：式(I)化合物的晶型FB-3的制备Example 3: Preparation of the crystalline form FB-3 of the compound of formula (I)

取式(I)化合物约20mg，加入1.2mL异丙醚得到混悬液，将混悬液置于室温条件下搅拌3天，分离出固体，40℃真空干燥过夜，得到FB-3。About 20 mg of the compound of formula (I) was taken, 1.2 mL of isopropyl ether was added to obtain a suspension, the suspension was stirred at room temperature for 3 days, the solid was separated, and vacuum dried at 40° C. overnight to obtain FB-3.

测定其XRPD数据，如下表所示：

The XRPD data are shown in the following table:

其XRPD图谱如图6所示。Its XRPD pattern is shown in Figure 6.

其傅里叶红外图谱如图7所示。Its Fourier transform infrared spectrum is shown in Figure 7.

其DSC图谱如图8所示。Its DSC spectrum is shown in Figure 8.

其TGA图谱如图9所示。Its TGA spectrum is shown in Figure 9.

本实施例制备得到的FB-3为无水物。The FB-3 prepared in this example is an anhydrous substance.

实施例4：式(I)化合物的晶型FB-3的制备Example 4: Preparation of Crystalline Form FB-3 of the Compound of Formula (I)

取式(I)化合物约200mg，加2mL异丙醚得到混悬液，加入少量FB-3晶种，置于室温条件下搅拌1天，离心，40℃真空干燥过夜即得。Take about 200 mg of the compound of formula (I), add 2 mL of isopropyl ether to obtain a suspension, add a small amount of FB-3 seed crystals, stir at room temperature for 1 day, centrifuge, and dry in vacuum at 40°C overnight to obtain the suspension.

经检测，其XRPD图谱如图10所示。After testing, its XRPD spectrum is shown in Figure 10.

实施例5：式(I)化合物的晶型FB-3的制备Example 5: Preparation of Crystalline Form FB-3 of the Compound of Formula (I)

取式(I)化合物约5mg，加入2mL乙腈溶清，室温挥发至干得到FB-3。Take about 5 mg of the compound of formula (I), add 2 mL of acetonitrile to dissolve, and evaporate to dryness at room temperature to obtain FB-3.

经检测，其XRPD图谱如11(A)和11(B)所示，其中图11(B)为图11(A)的局部放大图。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).

实施例6：式(I)化合物的晶型FB-4的制备Example 6: Preparation of Crystalline Form FB-4 of the Compound of Formula (I)

取式(I)化合物约20mg，加入1.0mL水得到混悬液，室温搅拌3天，分离出固体，固体加热到170℃，保持5min，降至室温，得到FB-4。Take about 20 mg of the compound of formula (I), add 1.0 mL of water to obtain a suspension, stir at room temperature for 3 days, separate the solid, heat the solid to 170°C, maintain for 5 min, and cool to room temperature to obtain FB-4.

测定其XRPD数据，如下表所示：
The XRPD data are shown in the following table:

其XRPD图谱如图12所示。Its XRPD pattern is shown in Figure 12.

其TGA图谱如图13所示，显示在150℃之前有约0.4％的失重。Its TGA spectrum is shown in FIG13 , which shows that there is a weight loss of about 0.4% before 150° C.

其DSC图谱如图14所示，显示加热至239℃附近开始出现吸热峰，为FB-4的的熔点。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.

其FT-IR图谱如图15所示。Its FT-IR spectrum is shown in Figure 15.

本实施例制备得到的FB-4为无水物。The FB-4 prepared in this example is an anhydrous substance.

实施例7：式(I)化合物的晶型FB-4的制备Example 7: Preparation of Crystalline Form FB-4 of the Compound of Formula (I)

取式(I)化合物约100mg，加入5.0mL乙醇及1.0mL水升温至60℃溶清，室温下加入5mg FB-4晶种，搅拌2h，离心，40℃真空干燥过夜，得到FB-4。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.

实施例8：物理和化学稳定性研究Example 8: Physical and Chemical Stability Studies

分别取本公开的晶型FB-2、FB-3和FB-4样品适量，放置在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下，定期采用HPLC和XRPD测定纯度和晶型。结果如表1和图16-18所示。Appropriate amounts of the crystal forms FB-2, FB-3 and FB-4 of the present disclosure were taken and placed under long-term (25°C/60%RH/open) and accelerated (40°C/75%RH/open) conditions, and the purity and crystal form were determined regularly by HPLC and XRPD. The results are shown in Table 1 and Figures 16-18.

表1
Table 1

结果表明，晶型FB-2、FB-3和FB-4在长期(25℃/60％RH/敞口)和加速(40℃/75％RH/敞口)条件下放置,至少60天晶型保持不变，且放置前后化学纯度基本保持不变，可见晶型FB-2、FB-3和FB-4在长期和加速条件下具有良好的物理稳定性和化学稳定性。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 remains basically unchanged before and after placement. 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.

实施例9：研磨稳定性研究Example 9: Grinding stability study

取本公开的晶型FB-3样品适量，置于研钵中，手动研磨，测试研磨前后样品的XRPD。研磨前后XRPD图谱如图19所示。Take an appropriate amount of the crystal form FB-3 sample disclosed in the present invention, put it in a mortar, grind it manually, and test the XRPD of the sample before and after grinding. The XRPD spectra before and after grinding are shown in Figure 19.

结果表明，晶型FB-3在研磨前后晶型保持不变，具有良好的研磨稳定性。The results showed that the crystal form of FB-3 remained unchanged before and after grinding, and had good grinding stability.

实施例10：引湿性研究Example 10: Hygroscopicity Study

分别取本公开的晶型FB-2、FB-3和FB-4，采用动态水分吸附(DVS)仪测试其引湿性，并在DVS测试前后，用XRPD测试晶型，结果如图20-25所示。The crystalline forms FB-2, FB-3 and FB-4 disclosed in the present invention were respectively taken, and their hygroscopicity was tested by a dynamic moisture sorption (DVS) instrument. The crystalline forms were tested by XRPD before and after the DVS test. The results are shown in Figures 20-25.

结果表明，晶型FB-2、FB-3和FB-4在0-80％的引湿增重分别为2.1w/w％、0.1w/w％和1.9w/w％，DVS测试前后，晶型均保持不变。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.

实施例11：粉末可压性研究Example 11: Powder compressibility study

称取一定量的晶型FB-3样品，置于红外压片机下，在2Mpa压力下保持2min，并检测压片前后的晶型。结果如图26所示。A certain amount of crystal form FB-3 sample was weighed, placed in an infrared tablet press, kept at a pressure of 2 MPa for 2 min, and the crystal form before and after tableting was detected. The results are shown in FIG26 .

结果表明，晶型FB-3在压片前后晶型保持不变。The results showed that the crystal form of FB-3 remained unchanged before and after tableting.

实施例12：溶解度研究Example 12: Solubility Study

分别称取晶型FB-2、FB-3和FB-4约40mg，加入5mL水，室温下搅拌，定时取样检测溶解度和晶型。结果如表2和图27-29所示。About 40 mg of the crystal forms FB-2, FB-3 and FB-4 were weighed respectively, 5 mL of water was added, and the mixture was stirred at room temperature. Samples were taken at regular intervals to detect the solubility and crystal form. The results are shown in Table 2 and Figures 27-29.

表2
Table 2

结果表明：晶型FB-2、FB-3和FB-4室温条件下在水中24小时均具有较高的溶解度，其中晶型FB-3未发生转变，晶型FB-2和FB-4在24小时检测时，晶型发生了转变，均开始出现晶型FB-3。The results showed that the crystal forms FB-2, FB-3 and FB-4 had high solubility in water at room temperature for 24 hours, among which the crystal form FB-3 did not change. The crystal forms FB-2 and FB-4 changed when tested after 24 hours, and the crystal form FB-3 began to appear.

实施例13：晶型转化研究Example 13: Crystal form conversion study

取适量本公开的晶型FB-2、FB-3和FB-4样品，混合均匀，取样进行XRPD表征；在混合样品中加入1mL相应溶剂形成悬浊液，室温下搅拌，取样进行XRPD表征。结果如表3和图30所示。Take appropriate amounts of the crystal forms FB-2, FB-3 and FB-4 samples disclosed herein, mix them evenly, and take samples for XRPD characterization; add 1 mL of the corresponding solvent to the mixed sample to form a suspension, stir at room temperature, and take samples for XRPD characterization. The results are shown in Table 3 and Figure 30.

表3
Table 3

结果表明，晶型FB-2、FB-3和FB-4的混合样品分别在水和正庚烷中搅拌6天，均转成了晶型FB-3。The results showed that the mixed samples of crystalline forms FB-2, FB-3 and FB-4 were stirred in water and n-heptane for 6 days, respectively, and all turned into crystalline form FB-3.

以上所述，仅为本公开的具体实施方式，但本公开的保护范围并不局限于此，任何熟悉本领域的技术人员在本公开所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本公开的保护范围之内。因此，本公开的保护范围应该以权利要求书所限定的保护范围为准。The above is only a specific implementation of the present disclosure, but the protection scope of the present disclosure is not limited thereto. Any changes or substitutions that can be thought of by any person skilled in the art within the technical scope disclosed in the present disclosure without creative work should be included in the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure should be based on the protection scope defined in the claims.

Claims (35)

一种结构如式(I)所示化合物的晶型FB-2，
A crystalline form FB-2 of a compound having a structure as shown in formula (I),
使用Cu-Kα辐射，所述式(I)化合物的FB-2以2θ角度表示的X-射线粉末衍射图谱在7.9°±0.2°、19.3°±0.2°和22.1°±0.2°中的1处或2处或3处有特征峰。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°. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在7.9°±0.2°、19.3°±0.2°和22.1°±0.2°2θ处有特征峰。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. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱进一步在14.8±0.2°、17.5°±0.2°和21.3°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在14.8±0.2°、17.5°±0.2°和21.3°±0.2°2θ处有特征峰。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 14.8±0.2°, 17.5°±0.2° and 21.3°±0.2°2θ, 1 or 2 or 3; 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. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-2的X-射线粉末衍射图谱进一步在13.4°±0.2°、24.5°±0.2°和29.7°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-2的X-射线粉末衍射图谱在13.4°±0.2°、24.5°±0.2°和29.7°±0.2°2θ处有特征峰。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 13.4°±0.2°, 24.5°±0.2° and 29.7°±0.2°2θ, 1 or 2 or 3; 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. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，所述式(I)化合物的FB-2具有基本如图1或图5所示的X-射线粉末衍射图谱。The FB-2 of the compound of formula (I) according to claim 1, characterized in that the FB-2 of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 1 or Figure 5. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，所述式(I)化合物的FB-2基本是纯的。优选地，所述式(I)化合物的FB-2具有大于99％的纯度。The 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%. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，所述式(I)化合物的FB-2的傅里叶红外图谱在3194.28cm-1±5cm-1、2932.13cm-1±5cm-1、2848.39cm-1±5cm-1、1664.03cm-1±5cm-1、1389.40cm-1±5cm-1和742.75cm-1±5cm-1中的至少一处有谱带。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) has a band at at least one of 3194.28cm -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 . 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，所述式(I)化合物的FB-2具有基本如图2所示的傅里叶红外图谱。The FB-2 of the compound of formula (I) according to claim 1, characterized in that the FB-2 of the compound of formula (I) has a Fourier transform infrared spectrum substantially as shown in Figure 2. 根据权利要求1所述的式(I)化合物的FB-2，其特征在于，所述式(I)化合物的FB-2为无水物。The 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. 根据权利要求1-9任一项所述式(I)化合物的晶型FB-2的制备方法，所述制备方法包括将式(I)化合物在溶剂1中形成混悬液，搅拌，分离固体，干燥，得到式(I)化合物的FB-2；其中所述溶剂1为乙酸乙酯和甲基叔丁基醚的混合溶剂。According to any one of claims 1 to 9, the preparation method comprises 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. 一种结构如式(I)所示化合物的晶型FB-3，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-3以2θ角度表示的X-射线粉末衍射图谱在4.7±0.2°、9.5°±0.2°和18.1°±0.2°中的1处或2处或3处有特征峰。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 angles has characteristic peaks at one, two or three of 4.7±0.2°, 9.5°±0.2° and 18.1°±0.2°. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在4.7±0.2°、9.5°±0.2°和18.1°±0.2°处有特征峰。The 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 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°. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在11.9°±0.2°、20.1°±0.2°和21.9°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在11.9°±0.2°、20.1°±0.2°和21.9°±0.2°2θ处有特征峰。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 11.9°±0.2°, 20.1°±0.2° and 21.9°±0.2°2θ, 2 or 3; 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. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在13.0°±0.2°、17.5°±0.2°和23.4°±0.2°2θ中的1处或2处或3处有特征峰；优选地，所述式(I)化合物的FB-3的X-射线粉末衍射图谱在13.0°±0.2°、17.5°±0.2°和23.4°±0.2°2θ处有特征峰。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 1, 2 or 3 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. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，所述式(I)化合物的FB-3其具有基本如图6或图10或图11(A)或图11(B)所示的X-射线粉末衍射图谱。The 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 Figure 6 or Figure 10 or Figure 11 (A) or Figure 11 (B). 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，所述式(I)化合物的FB-3基本是纯的。优选地，所述式(I)化合物的FB-3具有大于99％的纯度。The 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%. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，所述式(I)化合物的FB-3的傅里叶红外图谱在3225.55cm-1±5cm-1、3067.03cm-1±5cm-1、2958.00cm-1±5cm-1、1620.43cm-1±5cm-1、1593.18cm-1±5cm-1和735.01cm-1±5cm-1中的至少一处有谱带。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) has a band at least one of 3225.55cm -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 . 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，所述式(I)化合物的FB-3具有基本如图7所示的傅里叶红外图谱。The 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 a Fourier transform infrared spectrum substantially as shown in Figure 7. 根据权利要求11所述的式(I)化合物的FB-3，其特征在于，所述式(I)化合物的FB-3为无水物。The 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. 根据权利要求11-19任一项所述的式(I)化合物的FB-3的制备方法，所述制备方法选自以下方法中的任一种：The method for preparing FB-3 of the compound of formula (I) according to any one of claims 11 to 19, wherein the preparation method is selected from any one of the following methods: 1)将式(I)化合物在溶剂2中溶清，挥发，得到式(I)化合物的FB-3；其中所述溶剂3为乙腈；或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)将式(I)化合物在溶剂3中形成混悬液，搅拌，分离固体，干燥，得到式(I)化合物的FB-3；其中所述溶剂3为异丙醚；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; 优选地，方法2)中混悬液中可加入少量FB-3晶种一起搅拌。Preferably, in method 2), a small amount of FB-3 seed crystals can be added to the suspension and stirred together. 一种结构如式(I)所示化合物的晶型FB-4，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-4以2θ角度表示的X-射线粉末衍射图谱在5.9°±0.2°、16.5°±0.2°和21.7°±0.2°中的1处或2处或3处有特征峰。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 angles has characteristic peaks at one, two or three of 5.9°±0.2°, 16.5°±0.2° and 21.7°±0.2°. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)所示化合物的FB-4的X-射线粉末衍射图谱在5.9°±0.2°、16.5°±0.2°和21.7°±0.2°2θ处有特征峰。FB-4 of the compound of formula (I) according to claim 21, characterized in that the X-ray powder diffraction pattern of FB-4 of the compound represented by formula (I) has characteristic peaks at 5.9°±0.2°, 16.5°±0.2° and 21.7°±0.2°2θ. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在11.6±0.2°、13.1°±0.2°和26.8°±0.2°2θ中的1处或2处或3处有特征峰。优选地，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在11.6±0.2°、13.1°±0.2°和26.8°±0.2°2θ处有特征峰。The 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 the 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 the 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. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，使用Cu-Kα辐射，所述式(I)化合物的FB-4的X-射线粉末衍射图谱进一步在17.2°±0.2°、20.7°±0.2°和24.7°±0.2°2θ中的1处或2处或3处有特征峰。优选地，所述式(I)化合物的FB-4的X-射线粉末衍射图谱在17.2°±0.2°、20.7°±0.2°和24.7°±0.2°2θ处有特征峰。The 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 the 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, 2 or 3. Preferably, the X-ray powder diffraction pattern of the 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. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)化合物的FB-4具有基本如图12所示的XRPD图谱。FB-4 of the compound of formula (I) according to claim 21, characterized in that the FB-4 of the compound of formula (I) has an XRPD pattern substantially as shown in Figure 12. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)化合物的FB-4的傅里叶红外图谱在3230.3cm-1±5cm-1、2920.6cm-1±5cm-1、1662.4cm-1±5cm-1、1596.1cm-1±5cm-1、1389.9cm-1±5cm-1和738.4cm-1±5cm-1中的至少一处有谱带。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) has a band at least one of 3230.3cm -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 . 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)化合物的FB-4具有基本如图15所述的傅里叶红外图谱。The FB-4 of the compound of formula (I) according to claim 21 is characterized in that the FB-4 of the compound of formula (I) has a Fourier transform infrared spectrum substantially as shown in Figure 15. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)化合物的FB-4基本是纯的。优选地，所述式(I)化合物的FB-4具有大于99％的纯度。The 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%. 根据权利要求21所述的式(I)化合物的FB-4，其特征在于，所述式(I)化合物的FB-4为无水物。FB-4 of the compound of formula (I) according to claim 21, characterized in that FB-4 of the compound of formula (I) is an anhydrate. 根据权利要求21-29任一项所述的式(I)化合物的晶型FB-4的制备方法，所述制备方法选自以下方法中的任一种：The 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 preparation method is selected from any one of the following methods: 1)将式(I)化合物在水中形成混悬液，搅拌，分离固体，加热固体至170℃以上，再降至室温，得到FB-4；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; 优选地，所述固体为式(I)化合物的FB-4以外的其他固体形式；Preferably, the solid is a solid form other than FB-4 of the compound of formula (I); 优选地，所述搅拌时间≥1h，所述搅拌温度为4℃-80℃。Preferably, the stirring time is ≥1h, and the stirring temperature is 4°C-80°C. 2)将式(I)化合物在溶剂4中溶清，加入FB-4晶种，搅拌，离心，干燥，得到FB-4；2) dissolving the compound of formula (I) in solvent 4, adding FB-4 seed crystals, stirring, centrifuging, and drying to obtain FB-4; 优选地，所述溶剂4选自乙醇和水的混合或丙酮和水的混和；Preferably, the solvent 4 is selected from a mixture of ethanol and water or a mixture of acetone and water; 优选地，所述溶清在高温条件下进行；Preferably, the dissolving is carried out under high temperature conditions; 一种药物组合物，所述药物组合物包含治疗有效量的一种或多种的权利要求1-9任一项所述的式(I)化合物的FB-2、权利要求11-19任一项所述的式(I)化合物的FB-3和权利要求21-29任一项所述的式(I)化合物的FB-4，以及至少一种药学上可接受的载体。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. 一种权利要求31所述的药物组合物制备成的制剂，所述制剂形式选自口服制剂和肠胃外制剂。优选地，所述制剂形式为口服制剂；更优选地，所述制剂形式为胶囊剂。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. 一种或多种的权利要求1-9任一项所述的式(I)化合物的FB-2、权利要求11-19任一项所述的式(I)化合物的FB-3和权利要求21-29任一项所述的式(I)化合物的FB-4或权利要求31所述的药物组合物或权利要求32所述的制剂在制备用于治疗由PARP-1介导的疾病的药物中的用途。优选地，所述由PARP-1介导的疾病选自癌症、心血管疾病、神经系统损伤和炎症。更优选地，所述癌症为神经胶质瘤。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. 一种用于治疗由PARP-1介导的疾病的方法，其包括向患者施加一种或多种的权利要求1-9任一项所述的式(I)化合物的FB-2、权利要求11-19任一项所述的式(I)化合物的FB-3和权利要求21-29任一项所述的式(I)化合物的FB-4或权利要求31所述的药物组合物或权利要求32所述的制剂。优选地，所述由PARP-1介导的疾病选自癌症、心血管疾病、神经系统损伤和炎症。更优选地，所述癌症为神经胶质瘤。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. 一种或多种的权利要求1-9任一项所述的式(I)化合物的FB-2、权利要求11-19任一项所述的式(I)化合物的FB-3和权利要求21-29任一项所述的式(I)化合物的FB-4或权利要求31所述的药物组合物或权利要求32所述的制剂与其他药物的联合应用。优选地，所述其他药物为替莫唑胺。One or more 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, in combination with other drugs. Preferably, the other drug is temozolomide.
PCT/CN2024/133824 2023-11-24 2024-11-22 Crystal form of selective parp-1 inhibitor, preparation method therefor and use thereof Pending WO2025108423A1 (en)

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