Crystal form of heterocyclic deuterated compound as PARP inhibitor, and preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of chemical medicine, and disclosed are a crystal form of a heterocyclic deuterated compound as a PARP inhibitor, and a preparation method therefor and a use thereof. The present invention provides multiple crystal forms of a compound of formula (1), and a preparation method therefor and a use thereof. The present invention provides support for dosage form research by studying crystal forms I, II, III, and IV of the compound, thereby effectively preventing / treating PARP-related diseases and meeting different clinical medication needs.

Description

Crystalline forms of a PARP inhibitor and heterocyclic deuterated compound, and methods of making and using the same TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine technology, and specifically relates to a plurality of crystalline forms of a deuterated small-molecule compound with PARP inhibitory activity, a preparation method thereof, and use thereof in the preparation of a drug for treating related diseases. BACKGROUND

[0002] During the growth of a cell, its DNA is continuously damaged by internal and external factors. Among DNA damage, the most serious damage types are single-strand breaks and double-strand breaks, of which single-strand breaks are more common. If these breaks are not repaired in time and accurately, they will lead to genomic instability, and further cause canceration, or even directly cause cell death. For single-strand breaks in DNA, its repair mainly depends on PARP enzymes. For double-strand breaks, there are two repair methods for double-strand DNA, one is non-homologous end joining, and the other is homologous recombination repair. Homologous recombination repair is a high-fidelity, error-free repair method, and is also the main way of double-strand DNA repair. Homologous recombination repair involves many proteins, of which the most well-known is the BRCA protein. Two studies in 2005 (Farmer H, McCabe N, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature, 2005, 434(7035): 917-921. Bryant, H., Schultz, N., Thomas, H. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymerase. Nature 434, 913-917 (2005)) showed that tumor cells lacking BRCA1 or BRCA2 are selectively inhibited by PARP inhibitors. Based on this research result, scholars proposed the concept of synthetic lethality: the absence of either BRCA or PARP is not lethal, but the simultaneous inactivation of both leads to cell death. Based on the synthetic lethality theory, PARP inhibitors (PARPi) are developed for selective targeting of BRCA1 / 2 mutant cancer cells.

[0003] PARP inhibitors have shown excellent clinical efficacy in homologous recombination-deficient cancer patients, however, hematologic toxicities (anemia, neutropenia and thrombocytopenia) and other toxicities limit the use of these drugs, either as monotherapy or in combination therapy. Related studies show (Harris P A, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. [J]. Journal of Medicinal Chemistry, 2008, 51(15): 4632.) that these adverse effects can be derived from the inhibition of PARP2 by marketed PARP inhibitors, which is not necessary for the therapeutic effect. A highly selective PARP1 inhibitor can reduce hematologic toxicity, increase the therapeutic safety window, and increase the potential for combination with other chemotherapy or targeted drugs. Therefore, there is an unmet clinical need for an effective and safe PARP inhibitor, especially a PARP inhibitor selective for PARP1.

[0004] When used to treat humans, it is important that a crystalline form of a therapeutic agent, like 1'-((7-(ethyl-d5)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1 ',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, retains its polymorphic stability and chemical stability, solubility, and other physicochemical properties over time and among different manufacturing batches of the agent. If these physicochemical properties change over time and among batches, the administration of a therapeutically effective dose is problematic and can result in toxic side effects or ineffective treatment, especially when a particular polymorph decomposes into a less active, inactive, or toxic compound prior to use. Therefore, it is important to select a crystalline form of an agent that is stable, reproducibly manufactured, and possesses physicochemical properties that facilitate its use as a therapeutic agent. SUMMARY

[0005] The present application studies a crystal form of a compound 1'-((7-(ethyl-d5)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide shown in formula 1 and a preparation method thereof, and its use in pharmaceutical compositions and in medicine, providing various crystal forms of the compound with the advantages of high selectivity, good activity, low toxicity and the like, and the crystal forms have the excellent characteristics of high purity, good solubility, stable physical and chemical properties, high temperature resistance, high humidity resistance, strong light resistance, low hygroscopicity and the like.

[0006] The present application first provides a crystal form I of a crystal form of the compound of formula 1:

[0007] The X-ray powder diffraction pattern of the crystal form I has the characteristic diffraction peaks with excellent stability and repeatability at the following 2θ positions: 7.59°±0.2°, 15.87°±0.2°, 19.70°±0.2°, 23.88°±0.2°.

[0008] In some specific embodiments, the X-ray powder diffraction pattern of the crystal form I has the characteristic diffraction peaks with less stability and repeatability at the following 2θ positions: 5.79°±0.2°, 7.59°±0.2°, 9.22°±0.2°, 9.84°±0.2°, 15.87°±0.2°, 16.60°±0.2°, 17.75°±0.2°, 19.07±0.2°, 19.70°±0.2°, 20.98°±0.2°, 22.60°±0.2°, 23.17°±0.2°, 23.88°±0.2°, 24.19°±0.2°, 29.70°±0.2°.

[0009] In some more specific embodiments, the XRPD pattern resolution data of the crystal form I are as follows:

[0010] The present application also provides a crystal form II of a crystal form of the compound of formula 1:

[0011] The X-ray powder diffraction pattern of the crystal form II has the characteristic diffraction peaks with excellent stability and repeatability at the following 2θ positions: 8.88°±0.2°, 17.17°±0.2°, 20.25°±0.2°, 22.62°±0.2°, 26.21°±0.2°, 26.66°±0.2°.

[0012] In certain embodiments, the X-ray powder diffraction pattern of said crystalline Form II has characteristic peaks with lesser stability and reproducibility at the following 2Θ positions: 8.88°±0.2°, 9.32°±0.2°, 11.24°±0.2°, 17.17°±0.2°, 18.08°±0.2°, 18.62°±0.2°, 20.25°±0.2°, 22.62°±0.2°, 24.71°±0.2°, 25.60°±0.2°, 26.21°±0.2°, 26.66°±0.2°, 28.10°±0.2°.

[0013] In certain more specific embodiments, the XRPD pattern of said crystalline Form II is resolved as follows:

[0014] The present application also provides a crystalline form of the compound of Formula 1, crystalline Form III:

[0015] The X-ray powder diffraction pattern of said crystalline Form III has characteristic peaks with excellent stability and reproducibility at the following 2Θ positions: 4.75°±0.2°, 9.48°±0.2°, 18.79°±0.2°, 21.60°±0.2°, 23.97°±0.2°.

[0016] In certain embodiments, the X-ray powder diffraction pattern of said crystalline Form III has characteristic peaks with lesser stability and reproducibility at the following 2Θ positions: 4.75°±0.2°, 9.48°±0.2°, 16.84°±0.2°, 18.10°±0.2°, 18.79°±0.2°, 19.84°±0.2°, 20.32°±0.2°, 21.60°±0.2°, 22.45°±0.2°, 23.97°±0.2°, 26.85°±0.2°.

[0017] In certain more specific embodiments, the XRPD pattern of said crystalline Form III is resolved as follows:

[0018] The present application also provides a crystalline form of the compound of Formula 1, crystalline Form IV:

[0019] The X-ray powder diffraction pattern of said crystalline Form IV has characteristic peaks with excellent stability and reproducibility at the following 2Θ positions: 8.24°±0.2°, 20.65°±0.2°, 22.34°±0.2°, 25.70°±0.2°.

[0020] In certain embodiments, the Form IV has an X-ray powder diffraction pattern with less stability and reproducibility of the characteristic peaks at the following 2-theta positions: 8.24°±0.2°, 9.81°±0.2°, 11.13°±0.2°, 12.36°±0.2°, 19.36°±0.2°, 19.57°±0.2°, 20.65°±0.2°, 22.34°±0.2°, 25.70°±0.2°, 27.47°±0.2°.

[0021] In certain more specific embodiments, the Form IV has an XRPD pattern with the following resolved data:

[0022] The crystalline forms of the present application can be prepared by the following methods:

[0023] 1. Suspension milling experiment: the sample is prepared into a suspension in different solvent systems, and stirred at different temperatures.

[0024] 2. Volatilization experiment: the clear solution of the sample in different solvent systems is volatilized to dryness.

[0025] 3. Cooling crystallization experiment: a certain amount of sample is dissolved in the corresponding solvent at high temperature, and then directly stirred at room temperature or low temperature for crystallization.

[0026] 4. Solvent-out crystallization experiment: the sample is dissolved in a good solvent, an anti-solvent (a poor solvent) is added, and the solid is immediately filtered after short stirring.

[0027] 5. Gas-liquid diffusion experiment: the sample is dissolved in a good solvent, and then placed in an environment containing a poor solvent for gas-liquid diffusion.

[0028] 6. Gas-solid diffusion experiment: the sample is placed in an environment containing a poor solvent for gas-solid diffusion.

[0029] 7. Grinding crystallization experiment: the sample is subjected to auxiliary grinding crystallization in different solvent systems or directly by dry method.

[0030] More specifically, the present application also provides a preparation method of the Form I, Form II, Form III and Form IV.

[0031] The present application provides a preparation method of the Form I of the compound of Formula 1, which comprises the following steps:

[0032] Method 1: the compound of Formula 1 is mixed with solvent A, suspended and stirred, filtered, and dried to obtain the Form I; the solvent A is methanol, ethanol or isopropanol; the mass-volume ratio of the compound of Formula 1 to solvent A is 40-60 mg: 0.5-10 ml;

[0033] Or, method 2: the compound of formula 1 is mixed with solvent B, stirred to dissolve at 40-60°C, and then cooled to 4- room temperature quickly (using a medium at room temperature or 4°C to cool directly) or slowly (gradient cooling) to 4- room temperature, and then crystallized by cooling, filtered, and dried to obtain the crystal form I; the solvent B is methanol; the mass-volume ratio of the compound of formula 1 and the solvent B is 4-6 mg: 0.2-5 ml;

[0034] Or, method 3: the compound of formula 1 is mixed with a good solvent C, stirred to dissolve, and then prepared into a solution of 5-15 mg / ml, and then added with a poor solvent D to crystallize, filtered, and dried to obtain the crystal form I; the good solvent C is N,N-dimethylformamide; the poor solvent D is water; the volume ratio of the good solvent C and the poor solvent D is 1:3-10;

[0035] Or, method 4: the compound of formula 1 is mixed with a good solvent E, stirred to dissolve, and then prepared into a solution of 20-30 mg / ml, and then added dropwise into a poor solvent F to crystallize, filtered, and dried to obtain the crystal form I; the good solvent E is N-methyl pyrrolidone; the poor solvent F is ethanol, acetone or acetonitrile; the volume ratio of the good solvent E and the poor solvent F is 1:5-15;

[0036] Or, method 5: the compound of formula 1 is mixed with a solvent G to grind and crystallize, filtered, and dried to obtain the crystal form I; the solvent G is methanol, isopropanol, acetone, tetrahydrofuran, acetonitrile or dichloromethane; the concentration of the mixture of the compound of formula 1 and the solvent G is 100-500 mg / ml.

[0037] Any one of the above methods 1-5 can be used to prepare the crystal form I, which is verified by XRD, DSC and TGA.

[0038] In the above method 1 for preparing the crystal form I of the compound of formula 1, the mass-volume ratio of the compound of formula 1 and the solvent A is 40-60 mg: 1 ml.

[0039] Preferably, in the above method 1 for preparing the crystal form I of the compound of formula 1, the mass-volume ratio of the compound of formula 1 and the solvent A is 50 mg: 1 ml.

[0040] In the above method 1 for preparing the crystal form I of the compound of formula 1, the temperature of the suspension stirring is room temperature-50°C.

[0041] In the above method 1 for preparing the crystal form I of the compound of formula 1, the time of the suspension stirring is 3-5 days.

[0042] In the above method 2 for preparing the crystal form I of the compound of formula 1, the mass-volume ratio of the compound of formula 1 and the solvent B is 4-6 mg: 1 ml.

[0043] Preferably, in the preparation method 2 of the compound of formula 1 crystalline form I, the mass-volume ratio of the compound of formula 1 and the solvent B is 5 mg: 1 ml.

[0044] Preferably, in the preparation method 3 of the compound of formula 1 crystalline form I, the compound of formula 1 is prepared into a solution of 8-12 mg / ml.

[0045] Preferably, in the preparation method 3 of the compound of formula 1 crystalline form I, the compound of formula 1 is prepared into a solution of 10 mg / ml.

[0046] Preferably, in the preparation method 3 of the compound of formula 1 crystalline form I, the volume ratio of the good solvent C and the poor solvent D is 1:6.

[0047] Preferably, in the preparation method 3 of the compound of formula 1 crystalline form I, the volume ratio of the good solvent C and the poor solvent D is 1:6.

[0048] Preferably, in the preparation method 4 of the compound of formula 1 crystalline form I, the compound of formula 1 is prepared into a solution of 25 mg / ml.

[0049] Preferably, in the preparation method 4 of the compound of formula 1 crystalline form I, the volume ratio of the good solvent E and the poor solvent F is 1:10.

[0050] Preferably, in the preparation method 4 of the compound of formula 1 crystalline form I, the volume ratio of the good solvent E and the poor solvent F is 1:10.

[0051] Preferably, in the preparation method 5 of the compound of formula 1 crystalline form I, the concentration of the compound of formula 1 and the solvent G is 250 mg / ml.

[0052] Preferably, in the preparation method 5 of the compound of formula 1 crystalline form I, the concentration of the compound of formula 1 and the solvent G is 250 mg / ml.

[0053] Preferably, in the preparation method 5 of the compound of formula 1 crystalline form I, the time of the grinding and crystallization is 1-3 minutes.

[0054] The present application also provides a preparation method of the compound of formula 1 crystalline form II, which comprises the following steps:

[0055] Method a: mixing the compound of formula 1 and solvent H, dissolving and clarifying, placing the dissolved solution in the environment of a container containing solvent I, and performing gas-liquid diffusion crystallization to obtain the crystal form II; the solvent H is N,N-dimethylformamide; the solvent I is acetonitrile, methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, water or 1,4-dioxane; the mass-volume ratio of the compound of formula 1, solvent H and solvent I is 30 mg: 1-5 ml: 2-10 ml;

[0056] Or, method b: mixing the compound of formula 1 and solvent J, stirring and suspending, filtering, and drying to obtain the crystal form II; the solvent J is acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, dimethyl sulfoxide, water, N,N-dimethylformamide, 1,4-dioxane or N-methyl pyrrolidone; the mass-volume ratio of the compound of formula 1 and solvent J is 40-60 mg: 0.5-5 ml;

[0057] Or, method c: mixing the compound of formula 1 and solvent K, stirring and dissolving at 40-60°C, and rapidly cooling or slowly cooling to 4°C- room temperature to crystallize, filtering, and drying to obtain the crystal form II; the solvent K is N,N-dimethylformamide; the mass-volume ratio of the compound of formula 1 and solvent K is 4-6 mg: 0.2-1 ml;

[0058] Or, method d: mixing the compound of formula 1 and good solvent L, stirring and dissolving to prepare a 5-15 mg / ml solution, adding poor solvent M to crystallize, filtering, and drying to obtain the crystal form II; the good solvent L is N,N-dimethylformamide; the poor solvent M is ethyl acetate or acetonitrile; the volume ratio of the good solvent L and poor solvent M ethyl acetate is 1:3-10; the volume ratio of the good solvent L and poor solvent M acetonitrile is 1:1-5;

[0059] Or, method e: mixing the compound of formula 1 and good solvent N, stirring and dissolving to prepare a 5-15 mg / ml solution, adding the dissolved solution dropwise into poor solvent O to crystallize, filtering, and drying to obtain the crystal form II; the good solvent N is N,N-dimethylformamide; the poor solvent O is ethyl acetate or acetonitrile; the volume ratio of the good solvent N and poor solvent O is 1:3-10;

[0060] Or, method f: mixing the compound of formula 1 and good solvent P, stirring and dissolving to prepare a 20-30 mg / ml solution, adding poor solvent Q to crystallize, filtering, and drying to obtain the crystal form II; the good solvent P is N-methyl pyrrolidone; the poor solvent Q is acetone or methyl tert-butyl ether; the volume ratio of the good solvent P and poor solvent Q is 1:5-15;

[0061] Or, method g: the compound of formula 1 is mixed with a good solvent R, stirred and dissolved to prepare a 20-30 mg / ml solution, the dissolved solution is added dropwise into a poor solvent S to crystallize, filtered, and dried to obtain the crystal form II; the good solvent R is N-methyl pyrrolidone; the poor solvent S is methyl tert-butyl ether; the volume ratio of the good solvent R and the poor solvent S is 1:5-15;

[0062] Or, method h: the compound of formula 1 is mixed with a solvent T, dissolved and clarified, and the dissolved solution is placed in a container environment with a solvent U to perform gas-liquid diffusion crystallization to obtain the crystal form II; the solvent T is dimethyl sulfoxide; the solvent U is acetonitrile or water; the mass-volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg: 1-5 ml: 2-10 ml;

[0063] Or, method i: the compound of formula 1 is mixed with a solvent V, dissolved and clarified, and the dissolved solution is placed in a container environment with a solvent W to perform gas-liquid diffusion crystallization to obtain the crystal form II; the solvent V is N-methyl pyrrolidone; the solvent W is methanol, ethanol, acetone, ethyl acetate, acetonitrile or methyl tert-butyl ether; the mass-volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg: 0.5-1.5 ml: 2-10 ml;

[0064] Or, method j: the compound of formula 1 is placed in a container environment with a solvent X to perform gas-solid diffusion crystallization to obtain the crystal form II; the solvent X is N-methyl pyrrolidone; the mass-volume ratio of the compound of formula 1 and the solvent X is 40-60 mg: 1-10 ml;

[0065] Or, method k: the compound of formula 1 is mixed with a solvent Y to perform grinding crystallization, filtered, and dried to obtain the crystal form II; the solvent Y is N,N-dimethylformamide; the concentration of the mixture of the compound of formula 1 and the solvent Y is 100-500 mg / ml.

[0066] Any one of the above methods a-k can be used to prepare the crystal form II, which is verified by XRD, DSC and TGA.

[0067] In the above method for preparing the crystal form II of the compound of formula 1, in method a, the mass-volume ratio of the compound of formula 1, the solvent H and the solvent I is 30 mg: 2-4 ml: 3-5 ml.

[0068] Preferably, in the above method for preparing the crystal form II of the compound of formula 1, in method a, the mass-volume ratio of the compound of formula 1, the solvent H and the solvent I is 30 mg: 3 ml: 4 ml.

[0069] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0070] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0071] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0072] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0073] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0074] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method b, the mass-volume ratio of the compound of formula 1 to solvent J is 50 mg: 0.5-1 ml.

[0075] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, a 10 mg / ml solution is prepared.

[0076] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, a 10 mg / ml solution is prepared.

[0077] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:6.

[0078] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:6.

[0079] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:6.

[0080] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:6.

[0081] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method d, a 10 mg / ml solution is prepared.

[0082] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method e, a 10 mg / ml solution is prepared.

[0083] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method e, the volume ratio of the good solvent N and the poor solvent O is 1:6.

[0084] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method e, the volume ratio of the good solvent N and the poor solvent O is 1:6.

[0085] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method f, a 25 mg / ml solution is prepared.

[0086] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method f, the volume ratio of the good solvent P and the poor solvent Q is 1:10.

[0087] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method f, the volume ratio of the good solvent P and the poor solvent Q is 1:10.

[0088] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method g, a 25 mg / ml solution is prepared.

[0089] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method g, the volume ratio of the good solvent R and the poor solvent S is 1:10.

[0090] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method g, the volume ratio of the good solvent R and the poor solvent S is 1:10.

[0091] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method h, the mass volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg: 1-3 ml: 3-5 ml.

[0092] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method h, the mass volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg: 2 ml: 4 ml.

[0093] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method i, the mass volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg: 0.8-1.2 ml: 3-5 ml.

[0094] Preferably, in the preparation method of the compound of formula 1 crystalline form II, method i, the mass volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg: 1 ml: 4 ml.

[0095] The preparation method of the compound of formula 1 in the form of crystal II, wherein the mass / volume ratio of the compound of formula 1 to the solvent XX in the method j is 40-60 mg:4 ml.

[0096] Preferably, the preparation method of the compound of formula 1 in the form of crystal II, wherein the mass / volume ratio of the compound of formula 1 to the solvent XX in the method j is 50 mg:4 ml.

[0097] The preparation method of the compound of formula 1 in the form of crystal II, wherein the concentration of the compound of formula 1 mixed with the solvent Y in the method k is 200-300 mg / ml.

[0098] Preferably, the preparation method of the compound of formula 1 in the form of crystal II, wherein the concentration of the compound of formula 1 mixed with the solvent Y in the method k is 250 mg / ml.

[0099] The preparation method of the compound of formula 1 in the form of crystal II, wherein the grinding and crystallization time in the method k is 1-3 minutes.

[0100] The present application also provides a preparation method of the compound of formula 1 in the form of crystal III, which comprises the following steps: mixing the compound of formula 1 with dichloromethane in a mass / volume ratio of 40-60 mg:0.2-5 ml, stirring and suspending, filtering, and drying to obtain the crystal III.

[0101] The preparation method of the compound of formula 1 in the form of crystal III, wherein the mass / volume ratio of the compound of formula 1 to dichloromethane is 40-60 mg:1 ml.

[0102] Preferably, the preparation method of the compound of formula 1 in the form of crystal III, wherein the mass / volume ratio of the compound of formula 1 to dichloromethane is 50 mg:1 ml.

[0103] The preparation method of the compound of formula 1 in the form of crystal III, wherein the stirring and suspending temperature is room temperature-50°C.

[0104] The preparation method of the compound of formula 1 in the form of crystal III, wherein the stirring and suspending time is 3-5 days.

[0105] The present application also provides a preparation method of the compound of formula 1 in the form of crystal IV, which comprises the following steps: heating and recrystallizing the compound of formula 1 at 190-210°C to obtain the crystal IV.

[0106] The present application also provides a pharmaceutical composition containing a therapeutically effective amount of any one or a combination of two or more of the above-mentioned crystal I, crystal II, crystal III, and crystal IV, and a pharmaceutically acceptable carrier and / or excipient.

[0107] The pharmaceutical composition can be in the form of a unit formulation (unit formulation is also referred to as "formulation specification"). Preferably, in the above pharmaceutical composition, the therapeutically effective amount is 1-600 mg in terms of the free base of the compound of formula 1.

[0108] More preferably, in the above pharmaceutical composition, the therapeutically effective amount is 1-400 mg in terms of the free base of the compound of formula 1.

[0109] Most preferably, in the above pharmaceutical composition, the therapeutically effective amount is 1-200 mg in terms of the free base of the compound of formula 1.

[0110] The present application also provides the use of any one or a combination of two or more of the above crystal form I, crystal form II, crystal form III, crystal form IV, and pharmaceutical composition in the preparation of a PARP inhibitor.

[0111] Preferably, in the above use, the PARP inhibitor is a PARP1 inhibitor.

[0112] The present application also provides the use of any one or a combination of two or more of the above crystal form I, crystal form II, crystal form III, crystal form IV, and pharmaceutical composition in the preparation of a drug for treating and / or preventing a PARP-mediated related disease.

[0113] Preferably, in the above use, the PARP-mediated related disease is a tumor.

[0114] More preferably, in the above use, the tumor is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, glioblastoma, or lung cancer.

[0115] In the above use for preparing a drug for treating and / or preventing a PARP-mediated related disease, the therapeutically effective amount of the main drug is 1-600 mg in terms of the free base of the compound of formula 1.

[0116] Preferably, the therapeutically effective amount of the main drug is 1-400 mg in terms of the free base of the compound of formula 1.

[0117] More preferably, the therapeutically effective amount of the main drug is 1-200 mg in terms of the free base of the compound of formula 1.

[0118] An "effective amount" or "therapeutically effective amount" as described herein refers to a sufficient amount of a crystalline form disclosed herein being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a crystalline form disclosed herein that is needed to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount, calculated as the free base, include but are not limited to 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 2-500 mg, 2-400 mg, 2-300 mg, 2-200 mg, 2-150 mg, 2-125 mg, 2-100 mg, 2-90 mg, 2-80 mg, 2-70 mg, 2-60 mg, 2-50 mg, 2-40 mg, 2-30 mg, 2-20 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg.

[0119] In some embodiments, the pharmaceutical compositions or formulations of the present application contain a therapeutically effective amount of a crystalline form of the present application as described above.

[0120] The present application relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the crystalline form of the present application and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit formulation (the amount of the main drug in the unit formulation is also referred to as "formulation specification"). In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg of the crystalline form of the present application, calculated as the free base.

[0121] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of the present application, preferably 1-600 mg calculated as the free base, and a pharmaceutically acceptable carrier and / or excipient, the disease preferably a tumor.

[0122] A method for treating a disease in a mammal, the method comprising administering to the subject a crystalline form of the present invention, in a daily dose of 1-600 mg / day, in free base terms, as a single dose or in divided doses, in some embodiments, the daily dose includes, but is not limited to, 1-600 mg / day, 2-600 mg / day, 5-600 mg / day, 10-600 mg / day, 20-600 mg / day, 25-600 mg / day, 50-600 mg / day, 75-600 mg / day, 100-600 mg / day, 1-500 mg / day, 2-500 mg / day, 5-500 mg / day, 10-500 mg / day, 20-500 mg / day, 25-500 mg / day, 50-500 mg / day, 75-500 mg / day, 100-500 mg / day, 1-400 mg / day, 2-400 mg / day, 5-400 mg / day, 10-400 mg / day, 20-400 mg / day, 25-400 mg / day, 50-400 mg / day, 75-400 mg / day, 100-400 mg / day, 1-300 mg / day, 2-300 mg / day, 5-300 mg / day, 10-300 mg / day, 20-300 mg / day, 25-300 mg / day, 50-300 mg / day, 75-300 mg / day, 100-300 mg / day, 1-200 mg / day, 2-200 mg / day, 5-200 mg / day, 10-200 mg / day, 20-200 mg / day, 25-200 mg / day, 50-200 mg / day, 75-200 mg / day, 100-200 mg / day, in some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day.

[0123] The present invention relates to a kit which can comprise a crystalline form in single or multiple dose form, the kit comprising a crystalline form of the present invention, in an amount as described above for the pharmaceutical composition. The amount of the crystalline form of the present invention in the present invention is in each case calculated as free base.

[0124] "Strength" refers to the amount of drug substance present in each unit of a preparation. The crystalline forms described herein are present in about 5% to about 100% by weight of the drug substance; in certain embodiments, about 10% to about 100% by weight of the drug substance; in certain embodiments, about 15% to about 100% by weight of the drug substance; in certain embodiments, about 20% to about 100% by weight of the drug substance; in certain embodiments, about 25% to about 100% by weight of the drug substance; in certain embodiments, about 30% to about 100% by weight of the drug substance; in certain embodiments, about 35% to about 100% by weight of the drug substance; in certain embodiments, about 40% to about 100% by weight of the drug substance; in certain embodiments, about 45% to about 100% by weight of the drug substance; in certain embodiments, about 50% to about 100% by weight of the drug substance; in certain embodiments, about 55% to about 100% by weight of the drug substance; in certain embodiments, about 60% to about 100% by weight of the drug substance; in certain embodiments, about 65% to about 100% by weight of the drug substance; in certain embodiments, about 70% to about 100% by weight of the drug substance; in certain embodiments, about 75% to about 100% by weight of the drug substance; in certain embodiments, about 80% to about 100% by weight of the drug substance; in certain embodiments, about 85% to about 100% by weight of the drug substance; in certain embodiments, about 90% to about 100% by weight of the drug substance; in certain embodiments, about 95% to about 100% by weight of the drug substance; in certain embodiments, about 98% to about 100% by weight of the drug substance; in certain embodiments, about 99% to about 100% by weight of the drug substance; in certain embodiments, substantially all of the drug substance is substantially pure crystalline, i.e., about 100% by weight of the drug substance.

[0125] The good solvent and the poor solvent described herein are relative terms, in a pair of solvents, the one with higher solubility is the good solvent, and the one with lower solubility is the poor solvent.

[0126] The X-ray powder diffraction or DSC pattern, TGA pattern disclosed herein, and those substantially identical thereto, are also within the scope of the present application.

[0127] Unless otherwise stated, the terms used in the specification and claims are intended to have the following meanings.

[0128] As used herein, "crystal of the present application", "crystalline form of the present application", "crystalline form of the present application", and the like are used interchangeably.

[0129] As used herein, "room temperature" refers to 20 ± 5 °C.

[0130] The crystal form structures of the present application can be analyzed using a variety of analytical techniques known to one of ordinary skill in the art, including, but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and / or Thermogravimelric Analysis (TGA), also known as Thermogravimetry (TG).

[0131] The X-ray powder diffraction pattern test parameters for each of the crystal forms of the present application use Cu-Ka radiation.

[0132] As used herein, "2Θ or 2Θ angle" refers to the peak position in degrees (°) set in an X-ray diffraction experiment and is typically the unit of the abscissa in a diffraction pattern. If a reflection is diffracted when the incident beam makes an angle of Θ with a crystal plane, the experimental setup requires that the reflected beam be recorded at a 2Θ angle. It should be understood that a particular 2Θ value mentioned herein for a particular crystal form is intended to represent the 2Θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein, and that the error range for the 2Θ can be ± 0.3, ± 0.2, or ± 0.1.

[0133] It is understood that the numerical values described and claimed herein are approximations. Variations in the numerical values within the stated ranges are permitted due to the nature of the devices, equipment, and other factors.

[0134] It is understood that the crystal forms of the present application are not limited to having exactly the same characteristic patterns described in the figures disclosed herein, such as XRD, DSC, TGA, and that any crystal form having substantially the same or essentially the same characteristic patterns as those described in the figures disclosed herein fall within the scope of the present application.

[0135] It is understood that, as is well known in the art of differential scanning calorimetry (DSC), the height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present application have DSC patterns with characteristic peak positions having substantially the same properties as the DSC patterns provided in the figures disclosed herein, with a tolerance of ± 5 °C, and typically ± 3 °C.

[0136] "Carriers" refer to a system that does not cause significant irritation to an organism, does not eliminate the biological activity and characteristics of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ, non-limiting examples of which include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0137] "Excipient" refers to a substance, not itself a therapeutic agent, used as a diluent, adjuvant, binder, and / or vehicle, added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutical excipients can serve various functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners, as known to those skilled in the art. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium methylcellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and crosscarmellose (e.g., crosscarmellose sodium); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, soybean oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0138] Advantages of the present application:

[0139] The present application provides support for dosage form research by studying the I, II, III and IV crystal forms of the compound, thereby more effectively preventing / treating PARP-related diseases and meeting different clinical medication needs. BRIEF DESCRIPTION OF DRAWINGS

[0140] Figure 1 is an X-ray powder diffraction pattern of crystal form I of compound 1.

[0141] Figure 2 is a differential scanning calorimetry curve and thermogravimetric analysis curve superimposed pattern of crystal form I of compound 1.

[0142] Figure 3 is an X-ray powder diffraction pattern of crystal form II of compound 1.

[0143] Figure 4 is a differential scanning calorimetry curve and thermogravimetric analysis curve superimposed pattern of crystal form II of compound 1.

[0144] Figure 5 is an X-ray powder diffraction pattern of crystalline Form III of compound 1.

[0145] Figure 6 is an overlay of differential scanning calorimetry and thermogravimetric analysis curves of crystalline Form III of compound 1.

[0146] Figure 7 is an X-ray powder diffraction pattern of crystalline Form IV of compound 1. DETAILED DESCRIPTION

[0147] The technical solutions of the present application are described in detail below in combination with the accompanying drawings and examples, but the protection scope of the present application includes but is not limited to this.

[0148] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a nuclear magnetic instrument (Bruker Avance II 400 and JMTC-400 / 54 / JJ / YH), and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0149] The MS is measured by (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC is measured by using Waters ALLIANCE E2695 liquid chromatograph and C18, 4.6x250mm, 5μm chromatographic column.

[0150] The XRD is measured by using X-ray powder diffractometer Rigaku SmartLab SE for analysis. According to Appendix IX of the People's Republic of China (2010 Edition Part II) F X-ray powder diffraction method test.

[0151] The TGA and DSC graphs are collected on Netzsch STA 449F3 differential scanning calorimeter, and the test parameters are as follows:

[0152] Detection conditions: nitrogen, 50 mL / min; scanning program: 30-400℃, temperature rising rate: 10℃ / min; detection sample mass: about 3mg (alumina sample pan); detection basis: JY / T 014-1996 General thermal analysis method.

[0153] The known starting materials of the present application can be synthesized by or according to the methods known in the art, or can be purchased from Titan Kogyo, Anjieji Chemical, Jiangsu Aikang, Luyan Reagent, Bid Pharmaceutical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0154] In the examples, the solution refers to an aqueous solution unless otherwise specified.

[0155] Unless otherwise specified, room temperature is 20-30°C.

[0156] The following detailed description of the implementation process and the beneficial effects of the present application is intended to help the reader better understand the essence and characteristics of the present application, and is not intended to limit the scope of the case.

[0157] DMAC: N,N-dimethylacetamide; NMP: N-methylpyrrolidone; MTBE: methyl tert-butyl ether; DCM: dichloromethane.

[0158] Example 1: Preparation of compound 1

[0159] First step: In a 7ml dioxane, 3ml anhydrous ethanol and 4ml water mixed solvent, compound int-1a (1g, 4.6mmol), int-1b (1.7g, 5.5mmol), Pd(dppf)Cl2 (0.3g, 0.46mmol) and potassium carbonate (1.6g, 11.5mmol) were added, then replaced with nitrogen three times, and reacted at 90°C under nitrogen protection for 2h. After TLC detection of complete reaction, the reaction was reduced to room temperature, 30ml dichloromethane and 20ml water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with dichloromethane, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound int-1c (1g, white solid).

[0160] Second step: In a 100ml reaction bottle, int-1c (1g, 3mmol), aqueous methylamine solution (5g, 161.3mmol) and anhydrous methanol (20ml) were added, and stirred at room temperature overnight. After TLC monitoring of complete reaction, the reaction was concentrated under reduced pressure to obtain compound int-1d (0.8g, white solid).

[0161] Third step: Compound int-1d (0.5g, 1.5mmol) was added to 10ml anhydrous methanol, followed by the addition of 10ml 4mol / L hydrochloric acid dioxane solution, and stirred at room temperature for 0.5-1h. After TLC monitoring of complete reaction, the reaction was concentrated under reduced pressure to obtain compound int-1 (0.5g, white solid).

[0162] Fourth step: Weigh 60% sodium hydride (16 g, 406 mmol), add DME (200 mL), replace nitrogen three times, cool to 0 °C, and then drop compound 1a (76 g, 338 mmol). The reaction is raised to room temperature for 2 hours, deuterated bromoethane (50 g, 439 mmol) is added dropwise, and the reaction is raised to 60 °C for 3 hours. After monitoring the progress of the reaction by HPLC, the reaction solution is slowly poured into ice water to quench, extracted with ethyl acetate three times, and then the organic phase is combined, dried with anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude compound 1c (83 g, colorless liquid) is obtained.

[0163] Fifth step: In a reaction bottle, add 60% sodium hydride (13 g, 322 mmol), add 200 ml of tetrahydrofuran, and then replace nitrogen three times. Cool to 0 °C, slowly drop compound 1c (83 g, 322 mmol), stir for 10 minutes at 0 °C, stir for 10 minutes at room temperature, and then stir for 5 minutes at 40 °C. Cool the reaction to -78 °C. Slowly drop compound 1d (48 g, 215 mmol) dissolved in 200 ml of tetrahydrofuran, and stir for 1 hour at -78 °C. After monitoring the completion of the reaction by TLC, the reaction solution is slowly added to ice saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate three times, and then the organic phase is combined, dried with anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude compound 1e (41 g, yellow-green liquid) is purified by column chromatography. +

[0164] Sixth step: Compound 1e (1.0 g, 3.0 mmol) is added to 10 ml of anhydrous ethanol, then Pd / C (0.1 g, 10%) is added, and then hydrogen is replaced three times. Stir at room temperature overnight. After monitoring the completion of the reaction by LC-MS, filter the reaction solution, rinse the filter residue with a large amount of ethanol, combine the filtrate, and rotary evaporate to concentrate. Add 4 mol / L hydrochloric acid in 1,4-dioxane solution (12 ml), stir at room temperature for 30 minutes, add ether to precipitate a large amount of solid, filter, and dry to obtain compound 1f (0.51 g, white solid); LC-MS: ESI [M+H] +

[0165] Seventh step: In a 50 ml reaction bottle, add compound 1f (0.51 g, 2.0 mmol) and 15 mL of 1,4-dioxane, then add DDQ (0.50 g, 2.2 mmol), and reflux for overnight. After monitoring the completion of the reaction by LC-MS, rotary evaporate the reaction solution, add saturated aqueous sodium bicarbonate solution, stir for 1 hour, filter, rinse the filter residue with water, wash with a small amount of ether, and dry to obtain compound 1g (0.3 g, yellow solid). LC-MS: ESI [M+H] + ​​= 252.3.

[0166] Eighth step: In a reaction flask, compound 1g (0.3 g, 1.2 mmol) was added with 15 ml of tetrahydrofuran, cooled to 0 °C, then added with 2.5 mol / L lithium aluminum hydride tetrahydrofuran solution (1.44 ml, 3.6 mmol), reacted at 0 °C for 2 hours. After TLC monitoring, the reaction was quenched by adding 1 ml of water, dried with a large amount of anhydrous sodium sulfate, filtered, the filter residue was washed with a large amount of dichloromethane, and the filtrate was combined and concentrated by rotary evaporation. After drying, compound 1h (0.2 g, yellow solid) was obtained. LC-MS: ESI [M+H] + = 210.3.

[0167] Ninth step: In a 25 ml reaction flask, compound 1h (0.2 g, 0.96 mmol) was added with 10 ml of dichloromethane and 0.1 ml of N,N-dimethylformamide, cooled to 0 °C, and added dropwise with dichloro sulfoxide (0.35 g, 2.9 mmol), reacted at 0 °C for 1 hour. After TLC monitoring, the reaction solution was concentrated by rotary evaporation, and the obtained crude product was purified by column chromatography to obtain compound 1i (0.2 g, gray solid). LC-MS: ESI [M+H] + = 228.7.

[0168] Tenth step: Compound 1i (0.2 g, 0.88 mmol), int-1 (0.25 g, 0.88 mmol), N,N-diisopropyl ethylamine (0.45 g, 3.52 mmol) and potassium iodide (15 mg, 0.09 mmol) were added to 10 ml of anhydrous acetonitrile, and the reaction was stirred at 85 °C for 2 hours. After TLC monitoring, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain compound 1 (160 mg, white solid) LC-MS: ESI [M+H] + = 409.5; 1H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 4.9 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J = 8.2, 2.3 Hz, 1H), 7.66 (s, 1H), 6.23 (s, 1H), 3.78 (s, 2H), 3.27 (d, J = 3.1 Hz, 2H), 3.04 (d, J = 5.1 Hz, 3H), 2.79 (t, J = 5.6 Hz, 2H), 2.60 (d, J = 1.4 Hz, 2H).

[0169] Example 2: Preparation of crystal form I

[0170] Method 1: Take compound of formula 1 50 mg, add 1 ml of methanol or ethanol or isopropanol, stir suspension at room temperature or 50 °C for 3 days or 5 days, filter, dry, all get crystal form I.

[0171] Method 2: Take compound of formula 1 5 mg, add 1 ml of methanol, stir to dissolve at 50 °C, fast cooling (use medium at room temperature or 4 °C to cool directly) or slow cooling (gradient cooling) to room temperature or 4 °C, cooling crystallization, filter, dry, all get crystal form I.

[0172] Method 3: Take compound of formula 1, add good solvent N,N-dimethylformamide to stir to dissolve, prepare 10 mg / ml solution, add poor solvent water (V 良 / V 不良 = 1:6) to crystallize, filter, dry to get crystal form I.

[0173] Method 4: Take compound of formula 1, add good solvent N-methyl pyrrolidone to stir to dissolve, prepare 25 mg / ml solution, drop the solution into poor solvent ethanol (V 良 / V 不良 = 1:10) or acetone (V 良 / V 不良 = 1:10) or acetonitrile (V 良 / V 不良 = 1:10) to crystallize, filter, dry, all get crystal form I.

[0174] Method 5: Take compound of formula 1 50 mg, add 0.2 ml of methanol or isopropanol or acetone or tetrahydrofuran or acetonitrile or dichloromethane to grind and crystallize for 1 minute or 3 minutes, filter, dry, all get crystal form I.

[0175] The X-ray powder diffraction pattern (XRD), differential scanning calorimetry curve and thermogravimetric analysis curve of crystal form I of compound 1 (Method 1) are shown in Figures 1 and 2. The specific peak values are shown in Table 1:

[0176] Table 1 Peak values of crystal form I

[0177] Example 3: Preparation of crystal form II

[0178] Method a: Take compound of formula 1 30 mg, add 3 ml of N,N-dimethylformamide to dissolve and clarify, place the solution in a container containing 4 ml of acetonitrile or methanol or ethanol or acetone or ethyl acetate or tetrahydrofuran or methyl tert-butyl ether or dichloromethane or water or 1,4-dioxane to perform gas-liquid diffusion crystallization, all get crystal form II.

[0179] Method b: Take compound of formula 1 50 mg, add 1 ml of acetone or butanone or ethyl acetate or isopropyl acetate or methyl acetate or tetrahydrofuran or 2-methyltetrahydrofuran or acetonitrile or methyl tert-butyl ether or toluene or dimethyl sulfoxide or water or N,N-dimethylformamide or 1,4-dioxane or 0.5 ml of N-methylpyrrolidone, stir to suspend at room temperature or 50°C for 3 days or 5 days, filter, dry, all get crystal form II.

[0180] Method c: Take compound of formula 1 5 mg, add 0.5 ml of N,N-dimethylformamide, stir to dissolve at 50°C, fast cooling (use medium at room temperature or 4°C to cool directly) or slow cooling (gradient cooling) to room temperature or 4°C, cooling crystallization, filter, dry, all get crystal form II.

[0181] Method d: Take compound of formula 1, add good solvent N,N-dimethylformamide to stir to dissolve, prepare 10 mg / ml solution, add poor solvent ethyl acetate (V 良 / V 不良 =1:6) or acetonitrile (V 良 / V 不良 =1:2) to crystallize, filter, dry, all get crystal form II.

[0182] Method e: Take compound of formula 1, add good solvent N,N-dimethylformamide to stir to dissolve, prepare 10 mg / ml solution, drop the dissolved solution into poor solvent ethyl acetate (V 良 / V 不良 =1:6) or acetonitrile (V 良 / V 不良 =1:6) to crystallize, filter, dry, all get crystal form II.

[0183] Method f: Take compound of formula 1, add good solvent N-methylpyrrolidone to stir to dissolve, prepare 25 mg / ml solution, add poor solvent acetone (V 良 / V 不良 =1:10) or methyl tert-butyl ether (V 良 / V 不良 =1:10) to crystallize, filter, dry, all get crystal form II.

[0184] Method g: Take compound of formula 1, add good solvent N-methylpyrrolidone to stir to dissolve, prepare 25 mg / ml solution, drop the dissolved solution into poor solvent methyl tert-butyl ether (V 良 / V 不良 =1:10) to crystallize, filter, dry to get crystal form II.

[0185] Method h: Take compound 1 of formula 1 30 mg, add 2 ml dimethyl sulfoxide to dissolve and clarify, and place the dissolved solution in a container environment with 4 ml of acetonitrile or water to perform gas-liquid diffusion crystallization, and both obtain crystal form II.

[0186] Method i: Take compound 1 of formula 1 25 mg, add 1 ml N-methyl pyrrolidone to dissolve and clarify, and place the dissolved solution in a container environment with 4 ml of methanol or ethanol or acetone or ethyl acetate or acetonitrile or methyl tert-butyl ether to perform gas-liquid diffusion crystallization, and both obtain crystal form II.

[0187] Method j: Take compound 1 of formula 1 50 mg, and place the solid sample in a container environment with 4 ml of N-methyl pyrrolidone to perform gas-solid diffusion crystallization, and obtain crystal form II.

[0188] Method k: Take compound 1 of formula 1 50 mg, add 0.2 ml N,N-dimethylformamide to perform grinding crystallization for 1 minute or 3 minutes, filter, and dry, and both obtain crystal form II.

[0189] The X-ray powder diffraction pattern (XRD), differential scanning calorimetry curve, and thermogravimetric analysis curve superimposed pattern of crystal form II of compound 1 (Method 2) are shown in FIGS. 3 and 4. The specific peak values are shown in Table 2:

[0190] Table 2 Peak values of crystal form II

[0191] Example 4: Preparation of crystal form III

[0192] Take compound 1 of formula 1 50 mg, add 1 ml dichloromethane, and perform suspension stirring at room temperature or 50°C for 3 days or 5 days, filter, and dry, and both obtain crystal form III. The X-ray powder diffraction pattern (XRD), differential scanning calorimetry curve, and thermogravimetric analysis curve superimposed pattern of crystal form III of compound 1 are shown in FIGS. 5 and 6. The specific peak values are shown in Table 3:

[0193] Table 3 Peak values of crystal form III

[0194] Example 5: Preparation of crystal form IV

[0195] Take compound 1 of formula 1 50 mg, and heat to recrystallize at 200°C to obtain crystal form IV. The X-ray powder diffraction pattern (XRD) of crystal form IV of compound 1 is shown in FIG. 7. The specific peak values are shown in Table 4:

[0196] Table 4 Peak values of crystal form IV

[0197] Example 6: Stability test of crystal form II

[0198] A sample of Compound of Formula 1 Form II was placed under light (cool white light, 5000 Lux ± 500 Lux, closed), 60 °C (closed) and 25 °C / 90% RH (open) for 5 days (5D) and 10 days (10D) respectively. The solid samples were tested by XRPD and HPLC purity after storage to analyze the stability of crystal form and chemical stability. The results showed that the crystal form and purity of Form II did not change significantly under the conditions of light, high humidity and high temperature for 10 days, and the physical and chemical properties remained stable. The specific experimental results are shown in Table 5.

[0199] HPLC purity test conditions: detection instrument: Waters ALLIANCE E2695; column: C18, 4.6x250 mm, 5 μm; column temperature: 27 °C; mobile phase: A: 0.05% trifluoroacetic acid aqueous solution; B: acetonitrile; detection wavelength: 257 nm; gradient (T / B%): 0 / 5%, 12 / 95%, 15 / 95%, 18 / 5%, 20 / 5%; flow rate: 1.0 mL / min; injection volume: 5 μL; diluent: acetonitrile: water (1 / 1, v / v).

[0200] Table 5 Chemical stability of Form II under different conditions

[0201] Biological activity test

[0202] 1. PARP enzyme inhibition activity determination

[0203] The detection of PARP enzyme activity is carried out by the method of ELISA. First, the substrate coating and blocking are carried out: 5x histone mixture is diluted 5 times with PBS, 25 μL of the histone mixture is added to each well of the detection plate, and incubated at 4°C overnight; the detection plate is washed with 100 μL of PBST buffer three times (5 min / time), 25 μL of blocking buffer is added and incubated for 90 min; the detection plate is washed with 100 μL of PBST buffer three times (5 min / time). Then, the enzyme activity detection of PARP is carried out, 100 nL of compound 1 is added to each well of the reaction plate, centrifuged at 1000 rpm for 1 min; 5 μL of PARP enzyme is added to each well, centrifuged at 1000 rpm for 1 min; then 5 μL of the substrate mixture is added to each well, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 1 h. Finally, the experimental signal detection is carried out: the detection plate is washed with 100 μL of PBST buffer three times (5 min / time); 25 μL of St-HRP diluted with blocking solution (dilution ratio is 1:2000) is added to each well, and incubated at 25°C for 30 min; the detection plate is washed with 100 μL of PBST buffer three times (5 min / time); 25 μL of ELISA ECL Sub A and ELISA ECL Sub B mixture (mixed in equal volume) is added to each well. The Luminescence signal value is read by using the BMG enzyme label instrument. The IC 50 value of the compound is calculated by the non-linear fitting formula in the GraphPad software, and the inhibition rate is calculated according to the following formula: inhibition rate (%) Inh = (signal 化合物 -signal 阴性对照 ) / (signal 阳性对照 -signal 阴 性对照 )*100%. Negative control: DMSO (highest signal value). Positive control: the highest concentration test value of the positive control compound (lowest signal value).

[0204] Table 6 PARP enzyme inhibition activity determination experimental materials

[0205] The test results are as shown in the following table 7:

[0206] Table 7 PARP enzyme test results

[0207] Conclusion: The compound 1 of the present application selectively inhibits the PARP1 enzyme activity.

[0208] 2, Evaluation of compound 1 on PARP1 / 2 DNA capture

[0209] PARP "capture" (PARP DNA trapping) test experiment, using TR-FRET method to measure the DNA complex formation of PARP enzyme. After adding the inhibitor containing 1% DMSO using Echo, 2 μL of PARP1 (ICE, S2202T-H27H) enzyme and PARP1 (ICE, S2203-H31G) enzyme solution with a final concentration of 2 nM was added, centrifuged at 1000 rpm for 1 minute. 2 μL of biotin-labeled PARP-DNA (GenScript) solution with a final concentration of 2 nM was added, centrifuged at 1000 rpm for 1 minute, and then reacted at 25°C for 60 minutes; 1 μL of NAD+ (SIGMA, N6522) reagent with a final concentration of 12 μM was added, and finally a mixed solution containing 0.67 nM Streptavidin-Tb (Cisbio, 61SATLB) and 53.33 nM MAb Anti-6HIS-d2 (Cisbio, 61HISDLB) was added, centrifuged at 1000 rpm for 1 minute, and then reacted at 25°C for 60 minutes. Then the ratio 665 / 620 signal value was read using the BMG instrument, and the data was non-linearly fitted to the S-shaped dose-response curve using GraphPad Prism 8 software to determine the EC 50 Value. Compound Ola parib was purchased from Shanghai MedChemExpress Company.

[0210] Table 8 PARP1 / 2 DNA capture test results of compound 1

[0211] Conclusion: The compound 1 of the present application can selectively induce PARP1 to capture DNA, and has high selectivity for PARP2 to capture DNA.

[0212] 3. Cell anti-proliferative activity test:

[0213] BRCA mutant cell MDA-MB-436 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL of penicillin, 100 μg / mL of streptomycin, and placed in a 37℃ 5% saturated CO2 incubator for culture. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10 min, and plated at 1200 cells per well in a 96-well plate. After 24 h, different final concentrations of PARPi (0, 0.01, 0.1, 1, 10, 100, 1000 nM) were added, and the culture was continued for 72 h. The cells were treated with a liquid exchange (the same final concentration of PARPi was added again), and the culture was continued for 96 h. The 96-well plate was removed, the OD value at 450 nm was detected by CCK8 method, and the cell inhibition rate was calculated: inhibition rate % = 1- (average OD value of the drug group-average OD value of the blank group) / (average OD value of the control group-average OD value of the blank group) * 100%.

[0214] BRCA wild-type cell DLD-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U / mL of penicillin, 100 μg / mL of streptomycin, and placed in a 37℃ 5% saturated CO2 incubator for culture. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10 min, and plated at 1000 cells per well in a 96-well plate. After 24 h, different final concentrations of PARPi (0, 1, 10 μM) were added, and the culture was continued for 72 h. The cells were treated with a liquid exchange (the same final concentration of PARPi was added again), and the culture was continued for 96 h. The 96-well plate was removed, the OD value at 450 nm was detected by CCK8 method, and the cell inhibition rate was calculated: inhibition rate % = 1- (average OD value of the drug group-average OD value of the blank group) / (average OD value of the control group-average OD value of the blank group) * 100%. The test results are as shown in Table 9:

[0215] Table 9 Test results of cell anti-proliferation activity

[0216] Conclusion: The compound 1 and its crystal form of the present application have significant inhibition on BRCA mutant MDA-MB-436 cells, and have no obvious inhibition on BRCA wild-type DLD-1 cells, indicating that the compound 1 and its crystal form of the present application specifically inhibit homologous recombination-deficient tumor cells.

[0217] 4. Pharmacokinetic evaluation of compound 1 crystal form in Balb / c mice

[0218] Purpose of the experiment: To understand the pharmacokinetics of compound 1 crystal form.

[0219] Guidelines for nonclinical pharmacokinetic studies of chemical drugs, 2014.

[0220] Experimental scheme: through intravenous administration (1 mg·kg -1 ) and gavage administration (1 mg·kg -1 ) of Balb / c mice, the pharmacokinetics of the compound 1 crystal form was investigated.

[0221] Sample preparation: about 0.2 mg of compound 1 crystal form was weighed, dissolved in 10 μL of DMSO, and then 10 μL of sodium chloride solution for injection was added to prepare a 0.1 mg·mL -1 compound 1 crystal form solution for administration.

[0222] Sample collection: 6 Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 were administered intravenously (IV) at 1 mg·kg -1 , 3 were administered orally (PO) at 1 mg·kg -1 , and about 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected and stored at -40℃ for testing. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and the pharmacokinetic parameters such as peak time (Cmax), area under the curve (AUC(0-t)), half-life (T 1 / 2 ), clearance (CL), tissue distribution (V dss ), and bioavailability (F) were calculated.

[0223] Table 10 Pharmacokinetic test results of compound 1 crystal form in Balb / c mice

[0224] Conclusion: The compound 1 crystal form of the present application has good pharmacokinetic properties in Balb / c mice.

[0225] 5. Pharmacokinetic evaluation of compound 1 crystal form in SD rats

[0226] Experimental purpose: to understand the pharmacokinetics of compound 1 crystal form.

[0227] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0228] Experimental scheme: through oral and intravenous administration of SD rats, the pharmacokinetics of compound 1 crystal form was investigated.

[0229] Experimental procedure: Compound 1 crystal form was weighed, a small amount of DMSO was added, and then sodium chloride injection was added to prepare a solution for administration. 6 SD rats, male, were administered orally, and about 0.1 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h after administration. Centrifugation was performed at 3500 rpm for 15 min, and the supernatant plasma was collected. 5 μL of plasma was taken into an EP tube, 100 μL of acetonitrile containing 20 ng·ml -1 The internal standard SAHA was precipitated with acetonitrile, vortexed for 30 s, centrifuged at 13000 rpm for 15 min, and the supernatant was taken into a sample bottle for testing. The standard curve range was 10-10000 ng·ml -1 The pharmacokinetic evaluation results are as follows in Table 11:

[0230] Table 11 Pharmacokinetic test results of compound 1 crystal form in SD rats

[0231] Conclusion: The compound 1 crystal form of the present application has good pharmacokinetic properties in SD rats, including good oral bioavailability, exposure, half-life and clearance rate, etc.

Claims

1. A crystalline form of the compound of formula 1 characterized by: The X-ray powder diffraction pattern of the crystal form I has the following characteristic diffraction peaks with excellent stability and reproducibility: 7.59°±0.2°, 15.87°±0.2°, 19.70°±0.2°, 23.88°±0.2°.

2. The crystalline form I of the compound of formula 1 according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystal form I has the following characteristic diffraction peaks with less stability and reproducibility: 5.79°±0.2°, 7.59°±0.2°, 9.22°±0.2°, 9.84°±0.2°, 15.87°±0.2°, 16.60°±0.2°, 17.75°±0.2°, 19.07±0.2°, 19.70°±0.2°, 20.98°±0.2°, 22.60°±0.2°, 23.17°±0.2°, 23.88°±0.2°, 24.19°±0.2°, 29.70°±0.2°; Preferably, the XRPD pattern of said Form I is as shown in the following table:

3. Form II of the compound of formula 1, characterized by: The X-ray powder diffraction pattern of the crystal form II has the following characteristic diffraction peaks with excellent stability and reproducibility: 8.88°±0.2°, 17.17°±0.2°, 20.25°±0.2°, 22.62°±0.2°, 26.21°±0.2°, 26.66°±0.2°.

4. The crystalline form of the compound of formula 1 according to claim 3, characterized in that: The X-ray powder diffraction pattern of the crystal form II has the following characteristic diffraction peaks with less stability and reproducibility: 8.88°±0.2°, 9.32°±0.2°, 11.24°±0.2°, 17.17°±0.2°, 18.08°±0.2°, 18.62°±0.2°, 20.25°±0.2°, 22.62°±0.2°, 24.71°±0.2°, 25.60°±0.2°, 26.21°±0.2°, 26.66°±0.2°, 28.10°±0.2°; Preferably, the XRPD pattern of said Form II is resolved as shown below:

5. A crystalline form III of the compound of formula 1 characterized by: The X-ray powder diffraction pattern of the crystal form III has the following characteristic diffraction peaks with excellent stability and reproducibility: 4.75°±0.2°, 9.48°±0.2°, 18.79°±0.2°, 21.60°±0.2°, 23.97°±0.2°.

6. The compound of Formula 1 according to claim 5, characterized in that: The X-ray powder diffraction pattern of the crystal form III has the following characteristic diffraction peaks with less stability and reproducibility: 4.75°±0.2°, 9.48°±0.2°, 16.84°±0.2°, 18.10°±0.2°, 18.79°±0.2°, 19.84°±0.2°, 20.32°±0.2°, 21.60°±0.2°, 22.45°±0.2°, 23.97°±0.2°, 26.85°±0.2°; Preferably, the XRPD pattern of said Form III is resolved as shown below:

7. A crystalline form IV of the compound of formula 1 characterized by: The X-ray powder diffraction pattern of the crystal form IV has the following characteristic diffraction peaks with excellent stability and reproducibility: 8.24°±0.2°, 20.65°±0.2°, 22.34°±0.2°, 25.70°±0.2°.

8. The compound of Formula 1 according to claim 7, characterized in that: The X-ray powder diffraction pattern of the crystal form IV has the following characteristic diffraction peaks with stability and repeatability in the following 2θ positions: 8.24°±0.2°, 9.81°±0.2°, 11.13°±0.2°, 12.36°±0.2°, 19.36°±0.2°, 19.57°±0.2°, 20.65°±0.2°, 22.34°±0.2°, 25.70°±0.2°, 27.47°±0.2°; Preferably, the Form IV has the XRPD pattern as shown in Table 1 below:

9. A process for preparing the crystalline form I of the compound of formula 1 according to claim 1 or 2, characterized in that: comprising the following steps: Method 1: mixing the compound of formula 1 with solvent A, stirring to suspend, filtering, drying to obtain the crystal form I; the solvent A is methanol, ethanol or isopropanol; the mass-volume ratio of the compound of formula 1 to solvent A is 40-60 mg: 0.5-10 ml; or, Method 2: mixing the compound of formula 1 with solvent B, stirring to dissolve at 40-60°C, quickly cooling or slowly cooling to 4°C- room temperature, cooling to crystallize, filtering, drying to obtain the crystal form I; the solvent B is methanol; the mass-volume ratio of the compound of formula 1 to solvent B is 4-6 mg: 0.2-5 ml; or, Method 3: mixing the compound of formula 1 with good solvent C, stirring to dissolve, preparing a 5-15 mg / ml solution, adding poor solvent D to crystallize, filtering, drying to obtain the crystal form I; the good solvent C is N,N-dimethylformamide; the poor solvent D is water; the volume ratio of the good solvent C to poor solvent D is 1:3-10; or, Method 4: mixing the compound of formula 1 with good solvent E, stirring to dissolve, preparing a 20-30 mg / ml solution, adding the dissolved solution to poor solvent F to crystallize, filtering, drying to obtain the crystal form I; the good solvent E is N-methyl pyrrolidone; the poor solvent F is ethanol, acetone or acetonitrile; the volume ratio of the good solvent E to poor solvent F is 1:5-15; or, Method 5: mixing the compound of formula 1 with solvent G to grind and crystallize, filtering, drying to obtain the crystal form I; the solvent G is methanol, isopropanol, acetone, tetrahydrofuran, acetonitrile or dichloromethane; the concentration of the mixture of the compound of formula 1 and solvent G is 100-500 mg / ml.

10. A process for preparing the crystalline form I of the compound of formula 1 according to claim 9, characterized by: At least one of the following is met: In Method 1, the mass-volume ratio of the compound of formula 1 to solvent A is 40-60 mg: 1 ml; preferably, in Method 1, the mass-volume ratio of the compound of formula 1 to solvent A is 50 mg: 1 ml; In Method 1, the temperature of the stirring to suspend is room temperature-50°C; In Method 1, the time of the stirring to suspend is 3-5 days; In Method 2, the mass-volume ratio of the compound of formula 1 to solvent B is 4-6 mg: 1 ml; preferably, in Method 2, the mass-volume ratio of the compound of formula 1 to solvent B is 5 mg: 1 ml; In Method 3, a 8-12 mg / ml solution is prepared; preferably, in Method 3, a 10 mg / ml solution is prepared; In Method 3, the volume ratio of the good solvent C to poor solvent D is 1:5-7; preferably, in Method 3, the volume ratio of the good solvent C to poor solvent D is 1:6; In Method 3, the volume ratio of the good solvent C to poor solvent D is 1:5-7; preferably, in Method 3, the volume ratio of the good solvent C to poor solvent D is 1:6; In method 4, the compound of formula 1 is prepared into a 25 mg / ml solution; In method 4, the volume ratio of the good solvent E to the poor solvent F is 1:8-12; preferably, in method 4, the volume ratio of the good solvent E to the poor solvent F is 1:10; In method 5, the concentration of the compound of formula 1 mixed with the solvent G is 200-300 mg / ml; preferably, in method 5, the concentration of the compound of formula 1 mixed with the solvent G is 250 mg / ml; In method 5, the time for the grinding crystallization is 1-3 minutes.

11. A process for preparing crystalline Form II of the compound of formula 1 according to claim 3 or 4, characterized in that: The method comprises the following steps: Method a: the compound of formula 1 is mixed with a solvent H, dissolved and clarified, and the solution is placed in an environment of a container containing a solvent I to perform gas-liquid diffusion crystallization to obtain the crystal form II; the solvent H is N,N-dimethylformamide; the solvent I is acetonitrile, methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, water or 1,4-dioxane; the mass-volume ratio of the compound of formula 1, the solvent H and the solvent I is 30 mg: 1-5 ml: 2-10 ml; Or, method b: the compound of formula 1 is mixed with a solvent J to be suspended and stirred, filtered and dried to obtain the crystal form II; the solvent J is acetone, butanone, ethyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, toluene, dimethyl sulfoxide, water, N,N-dimethylformamide, 1,4-dioxane or N-methyl pyrrolidone; the mass-volume ratio of the compound of formula 1 to the solvent J is 40-60 mg: 0.5-5 ml; Or, method c: the compound of formula 1 is mixed with a solvent K, stirred and dissolved at 40-60°C, quickly cooled or slowly cooled to 4°C-room temperature, cooled and crystallized, filtered and dried to obtain the crystal form II; the solvent K is N,N-dimethylformamide; the mass-volume ratio of the compound of formula 1 to the solvent K is 4-6 mg: 0.2-1 ml; Or, method d: the compound of formula 1 is mixed with a good solvent L, stirred and dissolved, prepared into a 5-15 mg / ml solution, and then a poor solvent M is added to perform crystallization, filtered and dried to obtain the crystal form II; the good solvent L is N,N-dimethylformamide; the poor solvent M is ethyl acetate or acetonitrile; the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:3-10; the volume ratio of the good solvent L to the poor solvent M acetonitrile is 1:1-5; Or, method e: the compound of formula 1 is mixed with a good solvent N, stirred and dissolved, prepared into a 5-15 mg / ml solution, and then the solution is added dropwise into a poor solvent O to perform crystallization, filtered and dried to obtain the crystal form II; the good solvent N is N,N-dimethylformamide; the poor solvent O is ethyl acetate or acetonitrile; the volume ratio of the good solvent N to the poor solvent O is 1:3-10. Or, method f: mixing the compound of formula 1 and good solvent P, stirring and dissolving, preparing 20-30 mg / ml solution, adding poor solvent Q to crystallize, filtering and drying to obtain crystal form II; the good solvent P is N-methyl pyrrolidone; the poor solvent Q is acetone or methyl tert-butyl ether; the volume ratio of the good solvent P and the poor solvent Q is 1:5-15; Or, method g: mixing the compound of formula 1 and good solvent R, stirring and dissolving, preparing 20-30 mg / ml solution, adding the solution dropwise into poor solvent S to crystallize, filtering and drying to obtain crystal form II; the good solvent R is N-methyl pyrrolidone; the poor solvent S is methyl tert-butyl ether; the volume ratio of the good solvent R and the poor solvent S is 1:5-15; Or, method h: mixing the compound of formula 1 and solvent T, dissolving and clarifying, placing the solution in a container with solvent U to perform gas-liquid diffusion crystallization to obtain crystal form II; the solvent T is dimethyl sulfoxide; the solvent U is acetonitrile or water; the mass volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg:1-5 ml:2-10 ml; Or, method i: mixing the compound of formula 1 and solvent V, dissolving and clarifying, placing the solution in a container with solvent W to perform gas-liquid diffusion crystallization to obtain crystal form II; the solvent V is N-methyl pyrrolidone; the solvent W is methanol, ethanol, acetone, ethyl acetate, acetonitrile or methyl tert-butyl ether; the mass volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg:0.5-1.5 ml:2-10 ml; Or, method j: placing the compound of formula 1 in a container with solvent X to perform gas-solid diffusion crystallization to obtain crystal form II; the solvent X is N-methyl pyrrolidone; the mass volume ratio of the compound of formula 1 and the solvent X is 40-60 mg:1-10 ml; Or, method k: mixing the compound of formula 1 and solvent Y to perform grinding crystallization, filtering and drying to obtain crystal form II; the solvent Y is N,N-dimethylformamide; the concentration of the mixture of the compound of formula 1 and the solvent Y is 100-500 mg / ml.

12. A process for preparing crystalline Form II of the compound of Formula 1 according to claim 11, characterized in that: At least one of the following is met: In method a, the mass volume ratio of the compound of formula 1, the solvent H and the solvent I is 30 mg:2-4 ml:3-5 ml; preferably, in method a, the mass volume ratio of the compound of formula 1, the solvent H and the solvent I is 30 mg:3 ml:4 ml; In method b, the mass volume ratio of the compound of formula 1 and the solvent J is 40-60 mg:0.5-1 ml; preferably, in method b, the mass volume ratio of the compound of formula 1 and the solvent J is 50 mg:0.5-1 ml; In method b, the temperature of the suspension stirring is room temperature-50°C; In method b, the time of the suspension stirring is 3-5 days; In method c, the mass volume ratio of the compound of formula 1 and the solvent K is 4-6 mg:0.5 ml; preferably, in method c, the mass volume ratio of the compound of formula 1 and the solvent K is 5 mg:0.5 ml; In method d, the compound of formula 1 is prepared into a solution of 8-12 mg / ml; preferably, in method d, the compound of formula 1 is prepared into a solution of 10 mg / ml; In method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:5-7; preferably, in method d, the volume ratio of the good solvent L to the poor solvent M ethyl acetate is 1:6; In method d, the volume ratio of the good solvent L to the poor solvent M acetonitrile is 1:1-3; preferably, in method d, the volume ratio of the good solvent L to the poor solvent M acetonitrile is 1:2; In method e, the compound of formula 1 is prepared into a solution of 8-12 mg / ml; preferably, in method e, the compound of formula 1 is prepared into a solution of 10 mg / ml; In method e, the volume ratio of the good solvent N to the poor solvent O is 1:5-7; preferably, in method e, the volume ratio of the good solvent N to the poor solvent O is 1:6; In method f, the compound of formula 1 is prepared into a solution of 25 mg / ml; In method f, the volume ratio of the good solvent P to the poor solvent Q is 1:8-12; preferably, in method f, the volume ratio of the good solvent P to the poor solvent Q is 1:10; In method g, the compound of formula 1 is prepared into a solution of 25 mg / ml; In method g, the volume ratio of the good solvent R to the poor solvent S is 1:8-12; preferably, in method g, the volume ratio of the good solvent R to the poor solvent S is 1:10; In method h, the mass volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg:1-3 ml:3-5 ml; preferably, in method h, the mass volume ratio of the compound of formula 1, the solvent T and the solvent U is 30 mg:2 ml:4 ml; In method i, the mass volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg:0.8-1.2 ml:3-5 ml; preferably, in method i, the mass volume ratio of the compound of formula 1, the solvent V and the solvent W is 25 mg:1 ml:4 ml; In method j, the mass volume ratio of the compound of formula 1 to the solvent X is 40-60 mg:4 ml; preferably, in method j, the mass volume ratio of the compound of formula 1 to the solvent X is 50 mg:4 ml; In method k, the concentration of the compound of formula 1 mixed with the solvent Y is 200-300 mg / ml; preferably, in method k, the concentration of the compound of formula 1 mixed with the solvent Y is 250 mg / ml; In method k, the time for the grinding crystallization is 1-3 minutes.

13. A process for preparing crystalline Form III of the compound of Formula 1 according to claim 5 or 6, characterized in that: The method comprises the following steps: The compound of formula 1 and dichloromethane are mixed in a mass volume ratio of 40-60 mg:0.2-5 ml, suspended and stirred, filtered, and dried to obtain crystal form III.

14. A process for preparing crystalline Form III of the compound of formula 1 according to claim 13, characterized in that: At least one of the following is satisfied: The mass volume ratio of the compound of formula 1 to dichloromethane is 40-60 mg:1 ml; preferably, the mass volume ratio of the compound of formula 1 to dichloromethane is 50 mg:1 ml; The temperature for the suspended stirring is room temperature-50°C; The time for the suspended stirring is 3-5 days.

15. A process for preparing the crystalline form IV of the compound of formula 1 according to claim 7 or 8, characterized in that: The method comprises the following steps: The compound of formula 1 is heated to recrystallize at 190-210°C to obtain crystal form IV.

16. A pharmaceutical composition, characterized by: The pharmaceutical composition contains a therapeutically effective amount of the crystalline form I of claim 1 or 2, the crystalline form II of claim 3 or 4, the crystalline form III of claim 5 or 6, the crystalline form IV of claim 7 or 8, and a pharmaceutically acceptable carrier and / or excipient; preferably, the therapeutically effective amount is 1-600 mg of the free base of the compound of formula 1; more preferably, 1-400 mg; most preferably, 1-200 mg.

17. Use of the crystalline form I of claim 1 or 2, the crystalline form II of claim 3 or 4, the crystalline form III of claim 5 or 6, the crystalline form IV of claim 7 or 8, or the pharmaceutical composition of claim 16, for the manufacture of a PARP inhibitor; preferably, a PARP1 inhibitor.

18. Use of the crystalline form I of claim 1 or 2, the crystalline form II of claim 3 or 4, the crystalline form III of claim 5 or 6, the crystalline form IV of claim 7 or 8, or the pharmaceutical composition of claim 16, for the manufacture of a medicament for the treatment and / or prevention of a PARP-mediated related disease; preferably, the PARP-mediated related disease is a tumor; more preferably, the tumor is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, glioblastoma, or lung cancer.

19. Use according to claim 18, characterized in that: The therapeutically effective amount of the main drug of the medicament is 1-600 mg of the free base of the compound of formula 1; preferably, 1-400 mg; more preferably, 1-200 mg.

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