Crystalline forms of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione and processes for their preparation

Abstract

The present invention provides crystalline forms of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione and processes for their preparation.

Description

Technical Field

[0001] This invention relates to the crystalline form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione and its preparation. Background Technology

[0002] Poly(ADP-ribose) polymerase (PARP) catalyzes the addition of poly(ADP-ribose) to target protein molecules from NAD+, and is an important component of the DNA repair process. This process is crucial for maintaining the integrity and stability of DNA and chromosomes, and is an important guarantee for the survival of mammalian cells. The vast majority of intracellular ADP-ribose polymerization activity is catalyzed by PARP-1, although PARP-2 and other subtypes also have this function. Mice with PARP-1 knockout lack single-strand DNA damage repair function (Krishnakumar R and Kraus WL, Mol Cell, 2010, 39(1):8-24). Meanwhile, cancer cells with DNA repair deficiencies, such as BRCA1 (breast cancer 1) or BRCA2 (breast cancer 2) deficient cancer cells, are particularly sensitive to PARP inhibitors. Currently, several PARP inhibitors, including Olaparib, have been approved for the treatment of BRCA-mutated ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer. This shows that PARP inhibitors can be used as anticancer drugs to effectively treat a variety of cancers.

[0003] The use of PARP inhibitors to treat cancer is primarily based on two mechanisms. First, due to their rapid growth, cancer cells replicate DNA far more rapidly than normal cells. Therefore, drugs that cause DNA damage selectively kill cancer cells. However, due to the presence of DNA repair enzymes such as PARP, these drugs cannot be fully effective. Therefore, when PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapy drugs, their inhibition of DNA repair can produce a synergistic effect, greatly enhancing the efficacy of DNA-damaging chemotherapy drugs such as temozolomide (TMZ). Second, for cancer cells with DNA repair defects, such as triple-negative breast cancer cells lacking BRCA1 or BRCA2, PARP inhibitors can act independently as anticancer drugs, directly killing these cells (synthetic lethality).

[0004] WO2012130166A1 and WO2017167251 disclose methods for preparing 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione.

[0005] Alternative or improved synthetic methods are still needed, especially for large-scale, environmentally friendly production. Furthermore, a physically stable form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione suitable for production processes is desired. Summary of the Invention

[0006] The present invention provides the crystalline form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione.

[0007] In one or more embodiments, the present invention provides crystalline forms I, II, III, V, VI, IX, X, XI, VIII, XII and “VIII” of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione, or mixtures of two or more of these crystalline forms, such as mixtures of I and II, mixtures of I and XI, mixtures of II and IX, etc.

[0008] The present invention also provides the use of crystalline forms I, II, III, V, VI, IX, X, XI, VIII, XII or “VIII” of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione, or mixtures of two or more of these crystalline forms, such as mixtures of I and II, I and XI, and II and IX, in the preparation of medicaments for the treatment or prevention of clinical conditions caused by abnormal PARP activity, particularly the cancers described herein.

[0009] The present invention also provides a method for preparing 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione crystal form VIII, as well as methods for preparing other crystal forms I, II, III, V, VI, IX, X, XI, XII and "VIII".

[0010] The present invention also provides a method for preparing a drug, the method comprising the step of mixing crystal form VIII of the present invention with a pharmaceutically acceptable carrier or excipient. Preferably, the method further comprises the step of tableting or granulating the resulting mixture. Attached Figure Description

[0011] Figure 1 The XRPD plot of crystal form VIII is shown.

[0012] Figure 2 Showing the DSC plot of crystal form VIII.

[0013] Figure 3 TGA showing crystal form VIII.

[0014] Figure 4 DVS for crystal form VIII is displayed.

[0015] Figure 5 The XRPD plot of crystal form I is shown.

[0016] Figure 6 Showing the DSC diagram of crystal form I.

[0017] Figure 7 TGA showing crystal form I.

[0018] Figure 8 The XRPD plot of crystal form II is shown.

[0019] Figure 9 Showing the DSC diagram of crystal form II.

[0020] Figure 10 TGA showing crystal form II.

[0021] Figure 11 Displaying the DVS of crystal form II.

[0022] Figure 12 The XRPD plot of crystal form III is shown.

[0023] Figure 13 Showing the DSC diagram of crystal form III.

[0024] Figure 14 TGA showing crystal form III.

[0025] Figure 15 The XRPD plot of crystal form V is shown.

[0026] Figure 16 Showing the DSC diagram of crystal form V.

[0027] Figure 17 TGA showing crystal form V.

[0028] Figure 18 Displaying the DVS of crystal form V.

[0029] Figure 19 The XRPD plot of crystal form VI is shown.

[0030] Figure 20 Showing the DSC diagram of crystal form VI.

[0031] Figure 21 TGA showing crystal form VI.

[0032] Figure 22 Displaying the DVS of crystal form VI.

[0033] Figure 23 The XRPD plot of crystal form IX is shown.

[0034] Figure 24 Showing the DSC plot of crystal form IX.

[0035] Figure 25 TGA displaying crystal form IX.

[0036] Figure 26 The XRPD plot of crystal form X is shown.

[0037] Figure 27 Showing the DSC diagram of crystal form X.

[0038] Figure 28 TGA showing crystal form X.

[0039] Figure 29 The XRPD plot of crystal form XI is shown.

[0040] Figure 30 Showing the DSC plot of crystal form XI.

[0041] Figure 31 TGA displaying crystal form XI.

[0042] Figure 32 The XRPD diagram of crystal form "VIII" is shown.

[0043] Figure 33 This diagram shows the relationship between all crystal forms.

[0044] Figure 34 This shows the asymmetric unit of the single crystal structure of compound IA, crystal form VIII.

[0045] Figure 35 A schematic diagram of the hydrate crystal structure model showing the projection of crystal form VIII along the a-axis. Detailed Implementation

[0046] I. General Description

[0047] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details. The following description of several embodiments is given under the understanding that this disclosure is to be considered as examples of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments shown. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0048] II. Definition

[0049] Unless the context otherwise requires, throughout the specification and claims, the word “comprising” and its variations are interpreted in an open, inclusive sense, meaning “including but not limited to”; at the same time, “comprising” and its variations such as “including” also include “mainly composed of” and “composed of”.

[0050] Throughout this specification, the reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0051] Embodiments of "compound of formula I" throughout the specification include crystalline, salt, eutectic, and solvate forms of the formulas and / or compounds disclosed herein.

[0052] The invention disclosed herein is also intended to include all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. These radiolabeled compounds can be used to help determine or measure the effectiveness of compounds, for example, by characterizing the site or mode of action, or binding affinity to pharmacologically important sites of action. Certain isotope-labeled compounds of formula I, such as those incorporating a radioisotope, can be used for drug and / or substrate tissue distribution studies. Given their ease of incorporation and readily available detection methods, radioisotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Particularly suitable for this purpose.

[0053] Using heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to increased metabolic stability. For example, the in vivo half-life may increase or the dosage requirement may decrease. Therefore, in some cases, heavier isotopes may be preferred.

[0054] Using positron emission isotopes (e.g.) 11 C 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled Formula I compounds can generally be achieved using conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0055] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the FDA or NMPA or other relevant agencies as acceptable for use in humans or livestock.

[0056] "Pharmaceutical composition" refers to the compounds of the present invention and formulations of agents commonly accepted in the art for delivering bioactive compounds to mammals (e.g., humans). Such agents include all pharmaceutically acceptable excipients for this purpose.

[0057] "Effective amount" or "therapeutic effective amount" means an amount of the compound according to the invention that, when administered to a patient in need, is sufficient to achieve the treatment of a disease state, symptom, or disorder for which the compound is effective. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or patient sought by the researcher or clinician. The amount of the compound according to the invention constituting a therapeutic effective amount will vary depending on factors such as: the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or symptom being treated, the drugs used in combination with or in conjunction with the compound of the invention, and the patient's age, weight, general health, sex, and diet. Such a therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge, the prior art, and this disclosure.

[0058] Unless otherwise stated, the term “treatment” as used herein means reversing, alleviating, inhibiting the progression of, or preventing the impairment or condition to which the term applies, or one or more symptoms of such impairment or condition.

[0059] "Prevention" refers to any treatment that prevents the development of clinical symptoms of a disease or condition.

[0060] The terms "subject" or "patient" refer to an animal, such as a mammal (including a human), that has been or will be a subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), and / or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "A person in need (or patient)" means a person who may have or is suspected of having a disease or condition that would benefit from certain treatments; for example, treatment with the compounds disclosed herein according to this application.

[0061] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This invention includes tautomerisms of any of the compounds described.

[0062] References to the value or parameter “about” herein include (and describe) embodiments of that value or parameter itself. For example, a description of “about X” includes a description of “X”. Furthermore, the singular forms “a” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, a reference to “the compound” includes a variety of such compounds, and a reference to “the assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0063] "Pharmaceutically acceptable" or "physiologically acceptable" means a compound, salt, composition, dosage form, or other substance that can be used to prepare a pharmaceutical composition suitable for veterinary or human use.

[0064] "Unit dose form" is a physically discrete unit suitable for use as a subject (e.g., human subject and other mammals) at a unit dose, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, along with suitable pharmaceutical excipients.

[0065] When referring to, for example, XRPD plots, DSC thermograms, DVS plots, or TGA plots, the term “substantially as shown” includes plots, thermograms, or figures that are not necessarily the same as those described herein, but which, when considered by a person of ordinary skill in the art, fall within the limits of experimental error or bias.

[0066] In some embodiments, with respect to a particular crystalline form of the compound, the terms "substantially pure" or "substantially free" mean that the composition containing that crystalline form contains less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other crystalline forms and / or impurities. In some embodiments, "substantially pure" or "substantially free" means free from substances other than other substances (including other crystalline forms and / or impurities). For example, impurities may include byproducts or residual reagents from chemical reactions, contaminants, degradation products, other crystalline forms, water, and solvents.

[0067] In this invention, the permissible error for the angular position (2θ) of the characteristic powder X-ray diffraction peak positions of a crystal form is ±0.2°. This error is used when comparing two powder X-ray diffraction patterns. If a diffraction peak in one pattern is designated as a certain angular position range (2θ) within ±0.2° of the measured peak position, and a diffraction peak in another pattern is designated as another angular position range (2θ) within ±0.2° of the measured peak position, and if these peak ranges overlap, then the two peaks are considered to have the same angular position (2θ). For example, if a diffraction peak in one pattern is measured at 5.20°, the permissible error for comparison allows the peak to be designated in the range of 5.00°–5.40°. If a control peak in another diffraction pattern is measured at 5.35°, the permissible error for comparison allows the peak to be designated in the range of 5.15°–5.55°. Because there is overlap between the two peak position ranges, the two peaks being compared are considered to have the same angular position (2θ). In some implementations, the tolerance for the angular position (2θ) is ±0.1°.

[0068] III. Crystalline Form

[0069] This invention provides a crystalline form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione. The crystalline form of this invention possesses properties suitable for medical or pharmaceutical use, including but not limited to bioavailability, stability, purity, and / or manufacturability.

[0070] Specifically, the present invention provides crystalline forms I, II, III, V, VI, VIII, IX, X, XI, XII and “VIII” of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione, or mixtures of two or more of these crystalline forms, such as mixtures of crystalline form I and crystalline form II, mixtures of crystalline form I and crystalline form XI, mixtures of crystalline form II and crystalline form IX, etc.

[0071] Crystal form VIII

[0072] The X-ray powder diffraction (XRPD) pattern of the crystalline form of the compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione of the present invention contains diffraction peaks (characteristic peaks) at 2θ = 6.7° ± 0.2°, 11.0° ± 0.2°, 22.2° ± 0.2°, and 25.7° ± 0.2°. Preferably, the XRPD pattern of the crystalline form also contains a diffraction peak at 2θ = 27.0° ± 0.2°. Optionally, the XRPD pattern of the crystal form further includes diffraction peaks at any one, two, three or more, or all of the following positions: (a) 10.5°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 23.3°±0.2°, and 29.7°±0.2°; or (b) diffraction peaks at any one, two, three or more, or all of the following positions: 11.7°±0.2°, 16.1°±0.2°, 17.2°±0.2°, and 30.0°±0.2°.

[0073] In some embodiments, the compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione has crystal form VIII, whose XRPD pattern contains diffraction peaks at 2θ = 6.7°±0.2°, 10.5°±0.2°, 11.0°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 22.2°±0.2°, 23.3°±0.2°, 25.7°±0.2°, 27.0°±0.2°, and 29.7°±0.2°. Preferably, crystal form VIII is a dihydrate. More preferably, the KF value of crystal form VIII is 6% to 10%, more preferably 6.6% to 9%. Preferably, crystal form VIII has substantially the following characteristics: Figure 1 The XRPD pattern is shown. In some embodiments, the crystal form VIII of the present invention has essentially the following characteristics. Figure 2The DSC diagram is shown. In some embodiments, the crystal form VIII of the present invention has essentially the following... Figure 3 The TGA diagram is shown. In some embodiments, the crystal form VIII of the present invention has essentially the following... Figure 4 The DVS diagram shown.

[0074] In a preferred embodiment, the crystal form VIII of the present invention has at least one, any two, any three, any four, or all five of the following (a) to (e):

[0075] (a) having essentially as Figure 1 The XRPD map shown;

[0076] (b) having essentially as Figure 2 The DSC diagram shown;

[0077] (c) Having essentially as Figure 3 The TGA diagram shown;

[0078] (d) having essentially as Figure 4 The DVS diagram shown; and

[0079] (e) having essentially as Figure 34 The diagram shows an asymmetric unit.

[0080] Crystal form VIII is dehydrated under low humidity (30% RH) to obtain crystal form "VIII". The XRPD pattern of crystal form "VIII" contains diffraction peaks at 2θ = 6.8°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 22.1°±0.2°, 25.8°±0.2°, 27.2°±0.2°, and 30.0°±0.2°. Preferably, crystal form "VIII" has substantially the following characteristics: Figure 32 The XRPD map shown.

[0081] Under lower humidity conditions, such as <30%RH or 0%RH, crystal form VIII is dehydrated to obtain crystal form XII.

[0082] Under specific humidity conditions, crystal form "VIII" and crystal form XII will gradually transform into crystal form VIII.

[0083] Crystal form I

[0084] The XRPD pattern of crystal form I provided by this invention includes diffraction peaks (characteristic peaks) at 2θ = 5.2°±0.2°, 6.6°±0.2°, 13.3°±0.2°, and 19.9°±0.2°. Preferably, crystal form I has essentially the following characteristics. Figure 5 The XRPD map shown.

[0085] Crystal form I of the present invention may have substantially the following characteristics: Figure 6 The DSC thermogram shown.

[0086] Crystal form I of the present invention may have substantially the following characteristics: Figure 7 The TGA diagram shown.

[0087] In some embodiments, the crystal form I of the present invention has at least one, any two, or all three of the following (a) to (c):

[0088] (a) having essentially as Figure 5 The XRPD map shown;

[0089] (b) having essentially as Figure 6 The DSC diagram shown; and

[0090] (c) Having essentially as Figure 7 The TGA diagram shown.

[0091] Crystal form II

[0092] The XRPD pattern of crystal form II provided by this invention includes diffraction peaks at 2θ = 10.6° ± 0.2°, 11.0° ± 0.2°, 15.5° ± 0.2°, and 16.8° ± 0.2°. Preferably, the XRPD pattern of crystal form II also includes a diffraction peak at 2θ = 20.8° ± 0.2°. Preferably, crystal form II has essentially the following characteristics: Figure 8 The XRPD map shown.

[0093] Crystal form II of the present invention may have substantially the following characteristics: Figure 9 The DSC thermogram shown.

[0094] Crystal form II of the present invention may have substantially the following characteristics: Figure 10 The TGA diagram shown.

[0095] Crystal form II of the present invention may have substantially the following characteristics: Figure 11 The DVS diagram shown.

[0096] In some embodiments, the crystal form II of the present invention has at least one, any two, any three, or all four of the following (a) to (d):

[0097] (a) having essentially as Figure 8 The XRPD map shown;

[0098] (b) having essentially as Figure 9 The DSC diagram shown;

[0099] (c) Having essentially as Figure 10The TGA diagram shown; and

[0100] (d) having essentially as Figure 11 The DVS diagram shown.

[0101] Crystal form III

[0102] The XRPD pattern of crystal form III provided by this invention includes diffraction peaks (characteristic peaks) at 2θ = 12.5°±0.2°, 13.5°±0.2°, 16.7°±0.2°, and 17.6°±0.2°. Preferably, the XRPD pattern of crystal form III also includes diffraction peaks at any one, any two, or all three of the following locations: 2θ = 8.4°±0.2°, 11.2°±0.2°, and 15.8°±0.2°. Preferably, crystal form III has essentially the following characteristics: Figure 12 The XRPD map shown.

[0103] Crystal form III of the present invention may have substantially the following characteristics: Figure 13 The DSC thermogram shown.

[0104] Crystal form III of the present invention may have substantially the following characteristics: Figure 14 The TGA diagram shown.

[0105] In some embodiments, the crystal form III of the present invention has at least one, any two, or all three of the following (a) to (c):

[0106] (a) having essentially as Figure 12 The XRPD map shown;

[0107] (b) having essentially as Figure 13 The DSC diagram shown; and

[0108] (c) Having essentially as Figure 14 The TGA diagram shown.

[0109] Crystal form V

[0110] The XRPD pattern of crystal form V provided by this invention includes diffraction peaks at 2θ = 7.0°±0.2°, 13.9°±0.2°, 15.8°±0.2°, and 24.9°±0.2°. Preferably, crystal form V has essentially the following characteristics: Figure 15 The XRPD map shown.

[0111] The crystal form V of the present invention can have essentially the following characteristics: Figure 16 The DSC thermogram shown.

[0112] The crystal form V of the present invention can have essentially the following characteristics: Figure 17 The TGA diagram shown.

[0113] The crystal form V of the present invention can have essentially the following characteristics: Figure 18 The DVS diagram shown.

[0114] In some embodiments, the crystal form V of the present invention has at least one, any two, any three, or all four of the following (a) to (d):

[0115] (a) having essentially as Figure 15 The XRPD map shown;

[0116] (b) having essentially as Figure 16 The DSC diagram shown;

[0117] (c) Having essentially as Figure 17 The TGA diagram shown; and

[0118] (d) having essentially as Figure 18 The DVS diagram shown.

[0119] Crystal form VI

[0120] The XRPD pattern of crystal form VI provided by the present invention includes diffraction peaks at 2θ = 12.8°±0.2°, 13.3°±0.2°, 14.0°±0.2°, and 17.3°±0.2°. Preferably, the XRPD pattern of crystal form VI also includes diffraction peaks at any one, any two, any three, or all four of the following locations: 2θ = 4.7°±0.2°, 8.6°±0.2°, 16.9°±0.2°, and 17.9°±0.2°. More preferably, the XRPD pattern of crystal form VI also includes a diffraction peak at 2θ = 8.4°±0.2°. Preferably, crystal form VI has substantially the following characteristics: Figure 19 The XRPD map shown.

[0121] Crystal form VI of the present invention may have substantially the following characteristics: Figure 20 The DSC thermogram shown.

[0122] Crystal form VI of the present invention may have substantially the following characteristics: Figure 21 The TGA diagram shown.

[0123] Crystal form VI of the present invention may have substantially the following characteristics: Figure 22 The DVS diagram shown.

[0124] In some embodiments, the crystal form VI of the present invention has at least one, any two, any three, or all four of the following (a) to (d):

[0125] (a) having essentially as Figure 19 The XRPD map shown;

[0126] (b) having essentially as Figure 20 The DSC diagram shown;

[0127] (c) Having essentially as Figure 21 The TGA diagram shown; and

[0128] (d) having essentially as Figure 22 The DVS diagram shown.

[0129] Crystal form IX

[0130] The XRPD pattern of crystal form IX provided by this invention includes diffraction peaks (characteristic peaks) at 2θ = 14.5°±0.2°, 20.0°±0.2°, 21.6°±0.2°, and 26.7°±0.2°. Preferably, the XRPD pattern of crystal form IX also includes diffraction peaks at any one, any two, any three, or all four of the following positions: 2θ = 12.1°±0.2°, 12.4°±0.2°, 14.9°±0.2°, and 21.1°±0.2°. Preferably, the XRPD pattern of crystal form IX also includes diffraction peaks at any one, any two, any three, any four, or all five of the following positions: 15.3°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 21.9°±0.2°, and 31.9°±0.2°. Preferably, the crystal form IX has a substantially similar shape to... Figure 23 The XRPD map shown.

[0131] The crystal form IX of the present invention can have essentially the following characteristics: Figure 24 The DSC thermogram shown.

[0132] The crystal form IX of the present invention can have essentially the following characteristics: Figure 25 The TGA diagram shown.

[0133] In some embodiments, the crystal form IX of the present invention has at least one, any two, or all three of the following (a) to (c):

[0134] (a) having essentially as Figure 23 The XRPD map shown;

[0135] (b) having essentially as Figure 24 The DSC diagram shown; and

[0136] (c) Having essentially as Figure 25 The TGA diagram shown.

[0137] Crystal form X

[0138] The XRPD pattern of crystal form X provided by this invention includes diffraction peaks (characteristic peaks) at 2θ = 7.5° ± 0.2°, 9.8° ± 0.2°, 11.3° ± 0.2°, and 14.8° ± 0.2°. Preferably, the XRPD pattern of crystal form X also includes a diffraction peak at 2θ = 17.6° ± 0.2°. Preferably, crystal form X has essentially the following characteristics: Figure 26 The XRPD map shown.

[0139] The crystal form X of the present invention may have substantially the following characteristics: Figure 27 The DSC thermogram shown.

[0140] The crystal form X of the present invention may have substantially the following characteristics: Figure 28 The TGA diagram shown.

[0141] In some embodiments, the crystal form X of the present invention has at least one, any two, or all three of the following (a) to (c):

[0142] (a) having essentially as Figure 26 The XRPD map shown;

[0143] (b) having essentially as Figure 27 The DSC diagram shown; and

[0144] (c) Having essentially as Figure 28 The TGA diagram shown.

[0145] Crystal form XI

[0146] The XRPD pattern of crystal form XI provided by this invention contains diffraction peaks (characteristic peaks) at 2θ = 6.8°±0.2°, 9.2°±0.2°, 11.0°±0.2°, and 17.2°±0.2°. Preferably, the crystal form XI has essentially the following characteristics. Figure 29 The XRPD map shown.

[0147] The crystal form XI of the present invention can have essentially the following characteristics: Figure 30 The DSC diagram shown.

[0148] The crystal form XI of the present invention can have essentially the following characteristics: Figure 31 The TGA diagram shown.

[0149] In some embodiments, the crystal form XI of the present invention has at least one, any two, or all three of the following (a) to (c):

[0150] (a) having essentially as Figure 29 The XRPD map shown;

[0151] (b) having essentially as Figure 30 The DSC diagram shown; and

[0152] (c) Having essentially as Figure 31 The TGA diagram shown.

[0153] Figure 33 The crystal form relationship of the compound of Formula I of the present invention is shown, with the initial crystal form being crystal form VIII. Crystal form "VIII" is a transient crystal form formed by dehydration of crystal form VIII under low humidity (approximately 30% RH) without sufficient moisture balance. After a long period of moisture balance, it will further transform into crystal form XII. Crystal form XII is a hydrated crystal form or an amorphous crystal form formed by dehydration of crystal form VIII under even lower humidity (0–30% RH). Under specific humidity conditions, crystal forms "VIII" and XII will gradually transform back into crystal form VIII.

[0154] Crystal form VIII transforms into crystal form II when slurried in a solvent containing water (except for the DMSO aqueous system). Crystal form I is obtained by evaporation in a commonly used organic solvent, and further slurrying in ethanol at 25°C yields crystal form III. Crystal form VIII can be crystallized in ethanol under different methods and conditions to yield crystal forms V, VI, IX, and X, respectively, and heated and cooled in methanol to yield crystal form XI.

[0155] Physical characterization results show that crystal forms III, V, VI and IX are amorphous, crystal forms I, II, VIII, "VIII", X and XI are hydrated crystal forms, and crystal form XII is an amorphous form of crystal form VIII after dehydration, which is stable only at low humidity.

[0156] The results of the competition showed that crystal form V was the dominant amorphous crystal form, crystal form II was the dominant hydrated crystal form except in the DMSO aqueous system, and crystal form VIII was the dominant hydrated crystal form in the DMSO aqueous system.

[0157] Physical stability results showed that the dominant crystal forms V and II did not change in crystal form after two weeks of accelerated and long-term exposure. Stability studies indicated that crystal form VIII was stable under long-term conditions.

[0158] IV. Hydrates

[0159] This invention specifically includes a hydrate of the compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione. Preferably, each molecule of this compound binds 1 to 2 water molecules. More preferably, the compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione provided by this invention is a dihydrate, that is, each molecule of this compound binds 2 water molecules.

[0160] Preferably, the KF value of the hydrate of the present invention is 6% to 10%, more preferably 6.6% to 9%.

[0161] Preferably, the hydrate of the present invention has the crystal form of the aforementioned crystal forms I, II, VIII, "VIII", X and XI, preferably crystal form VIII or crystal form "VIII", and more preferably crystal form VIII.

[0162] The hydrates of the present invention can be stably stored under conditions of relative humidity of 10% or higher, preferably 30% or higher, and more preferably 40% or higher. Generally, under conditions of relative humidity below 40% and not 0%, each molecule of the compound of the present invention binds to fewer than 2 water molecules; under conditions of relative humidity of 40% or higher, each molecule of the compound of the present invention binds to 2 water molecules and can exist stably.

[0163] V. Preparation Method

[0164] This invention provides a method for preparing compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione (Formula I), the method comprising:

[0165] (1) Prepare compound III from compound IV and compound V:

[0166]

[0167] (2) Hydrolyze compound III to obtain compound II:

[0168]

[0169] (3) Compound of Formula II is condensed with compound of Formula A to prepare compound of Formula I:

[0170]

[0171] Preferably, in step (1), the compound of formula III is prepared as follows:

[0172] (a) Reacting a compound of formula IV with hexamethyldisilazane in an organic solvent (such as toluene) under acidic conditions (e.g., in the presence of sulfuric acid) to prepare an organic solvent solution (such as a toluene solution) containing the following formula IV-TMS.

[0173]

[0174] (b) In the presence of an organic solvent (such as sulfolane), the compound of formula V and the organic solvent solution containing the compound of formula IV-TMS obtained in step (a) are mixed and reacted to give the compound of formula III.

[0175] Preferably, the reaction temperature of the compound of formula IV with hexamethyldisilazane is 105–120°C, more preferably 112–120°C; the reaction time is 10–20 hours. More preferably, the compound of formula IV is dissolved in a suitable organic solvent (e.g., toluene), hexamethyldisilazane is added, followed by the dropwise addition of sulfuric acid. The mixture is stirred at, for example, about 105–120°C (preferably 112–120°C) for a suitable time (e.g., about 10–20 hours) until the solid is completely dissolved. The reaction solution is cooled to a suitable temperature (e.g., about 55–65°C) and then concentrated to obtain an organic solvent (e.g., toluene) solution containing the compound of formula IV-TMS. Preferably, the volume of the organic solvent used to dissolve the compound of formula IV is 5 to 6.5 times that of the compound of formula IV, such as about 6 times; the molar ratio of the compound of formula IV to hexamethyldisilazane can be from 1:1.5 to 1:3, such as about 1:2.5; and the molar ratio of the compound of formula IV to sulfuric acid can be from 12:1 to 8:1, such as about 10:1.

[0176] Preferably, a solution of an organic solvent containing the directly obtained, unpurified compound of formula IV-TMS is reacted with a compound of formula V. Preferably, in step (b), a sulfolane solution of the compound of formula V is mixed with a solution of an organic solvent (such as toluene) containing the compound of IV-TMS, and the reaction is carried out. Mixing can be performed at 35–45°C, such as around 40°C. After mixing, the temperature is raised to the reaction temperature, and the reaction is carried out. The reaction temperature can be 95–105°C, and the reaction time (stirring time) can be 10–30 hours. In a preferred embodiment, process control is performed by sampling and analysis using HPLC, wherein the IPC is limited to IV / (IV+III+II) ≤ 10.0%. If IV / (IV+III+II) > 10.0%, stirring continues until the limit value is reached. After the reaction is complete, an alcohol (such as methanol) is slowly added, and crystallization is precipitated by stirring at 55–65°C. Then, process water is slowly added, and stirring continues at 20°C, followed by centrifugation. The filter cake is washed with a methanol-water solution (2-3 times its weight), and then dried under reduced pressure for 10-30 hours to obtain compound III. In a preferred embodiment, the process control for reduced pressure drying is as follows: IPC is limited to KF ≤ 2.0%, and methanol residue ≤ 1.0%. If the limits are not met, reduced pressure drying continues until the limits are reached. Preferably, the molar ratio of compound V to compound IV can be 1:1 to 2:1, such as about 1.5:1.

[0177] In step (2), preferably, the compound of formula III is added to a mixture of an aqueous solution of an inorganic base (e.g., KOH or NaOH) and an organic solvent (e.g., methanol or ethanol). Typically, the molar ratio of the inorganic base to the compound of formula III is 1.5:1 to 3.0:1, for example, about 2.3 to 2.5; the weight of the organic solvent is about 0.8 to 1.3 times the weight of the compound of formula III; and the weight of water in the aqueous solution of the inorganic base is about 2.8 to 3.5 times the weight of the compound of formula III. The resulting mixture can be stirred at a suitable temperature (e.g., about 30 to 50°C, preferably 30 to 40°C) for a suitable time, for example, about 1 to 6 hours, preferably 2 to 5 hours. Preferably, sampling is performed by HPLC analysis for process control, wherein the IPC limit is: III / (II+III) ≤ 0.8%; if III / (II+III) > 0.8%, the reaction time is appropriately extended until the limit value is reached.

[0178] After the reaction is complete, add appropriate amounts of water (2.5 to 4 times the weight of III) and methanol (2 to 3 times the weight of III). Adjust the pH of the reaction solution to 1.5 to 3 at the same temperature (e.g., by adding an inorganic acid dropwise). Then stir and slowly cool to 20 to 30°C. The inorganic acid can be hydrochloric acid, and its concentration can be determined according to the actual situation, as long as the pH of the reaction solution can be adjusted to the above range. After stirring, filter and wash the filter cake, for example, by washing with methanol and water (V:V, 1:1) and then with methanol sequentially. Dry under reduced pressure to obtain II. Preferably, the process control of reduced pressure drying is as follows: IPC limit: KF ≤ 0.5%. If the limit requirement is not met, continue reduced pressure drying until the limit value is reached.

[0179] Preferably, in step (3), the compound of formula II is first dissolved in a suitable organic solvent (e.g., ethyl acetate). The temperature of the reaction vessel is controlled at 15–25°C, and the organic solvent solution of the compound of formula II is added to the reaction vessel. Then, the temperature of the reaction vessel is adjusted to 20±2°C, and a suitable condensing agent (e.g., HATU, TBTU, HBTU, and T3P, etc.) and a suitable organic base (e.g., NMM and DIPEA, etc.) are added. The reaction solution is then heated to 35–45°C, and the organic solvent solution (e.g., ethyl acetate) of compound A is added, and the mixture is stirred for 15–25 hours. The compound of formula II can be dissolved in about 10–20 times (by weight), such as about 16 times the amount of organic solvent (e.g., ethyl acetate). The molar ratio of the condensing agent to the compound of formula II can be 1:1 to 1:2.5, such as about 1:1.8; the molar ratio of the organic base to the compound of formula II can be 1:2 to 1:4, such as about 1:3. The molar ratio of compound A to compound II can be from 2:1 to 0.8:1, for example, about 1.2:1. Typically, when preparing an organic solvent solution of compound A, the weight of the organic solvent can be 2 to 4 times that of compound A. Preferably, the reaction process is controlled by HPLC, wherein the IPC is limited to: II / (II+I) ≤ 1.0%. If II / (II+I) > 1.0%, stirring continues. If the reaction still does not reach the limit value after stirring, a 50% ethyl acetate solution of propylphosphonic anhydride is added and stirring continues until the limit value is reached. After the reaction is complete, purified water (0.1 to 0.5 times the weight of compound A) is added to the reaction product, and the mixture is stirred for 1 to 3 hours. The mixture is filtered, and the filter cake is washed with ethyl acetate. The wet product is returned to the reactor, and dimethyl sulfoxide (15 to 25 times the weight of compound A) is added and stirred for 1 to 3 hours. Then, purified water (1 to 5 times the weight of compound A) and seed crystals of compound I are added, and stirring continues. The filter cake is washed with purified water (3 to 6 times the weight of compound A) and dried under vacuum at 50 to 60°C for 50 to 70 hours, or 60 to 70 hours, to obtain the compound shown in Formula I. During vacuum drying, samples are taken for testing to control the process. The IPC is limited to KF ≤ 0.5%. If the limit is not met, drying continues until the limit is reached.In some embodiments, compound II is dissolved in ethyl acetate, and the reactor temperature is controlled at 15–25°C. The ethyl acetate solution of compound II is added to the reactor, and the reactor temperature is adjusted to 20 ± 2°C. An ethyl acetate solution of propylphosphonic anhydride (a condensing agent) and diisopropylethylamine (an organic base) are added. The reaction mixture is heated to 35–45°C, and an ethyl acetate solution of compound A is added. The mixture is stirred for 15–25 hours. After the reaction is complete, pure water is added to the reaction product, and the mixture is stirred for 1–3 hours. The mixture is filtered, and the filter cake is washed with ethyl acetate. The wet product is returned to the reactor, and dimethyl sulfoxide is added and stirred for 1–3 hours. Then, pure water and crystals of crystal form VIII are added, and the mixture is stirred for another 4–6 hours. The filter cake is washed with pure water, and the mixture is dried under vacuum at 50–60°C for 60–70 hours to obtain compound I. The amounts or proportions of each substance in the reaction system are described above.

[0180] In a preferred embodiment, after obtaining compound I by vacuum drying at 50–60°C for 50–70 hours, a crystallization step is further included; preferably, the crystallization is carried out in a three-in-one reactor under a nitrogen atmosphere. Specifically, the crystallization step includes: opening the nitrogen valve in the three-in-one reactor and purging with nitrogen for 18–22 hours, thereby obtaining crystal form VIII.

[0181] In a preferred embodiment, crystallization in a three-in-one reactor may include the following steps. Specifically, Compound I and dimethyl sulfoxide (DMSO) are mixed in a first reactor and stirred at 55–65°C until clear. The amount of DMSO used can be 7–10 times, such as about 8 times, the weight of Compound I. Pure water and DMSO are added to a second reactor, and then the temperature of the second reactor is adjusted to 50 ± 3°C before adding crystal form VIII seed crystals. The amount of pure water used can be 12–20 times the weight of Compound I, the amount of DMSO used can be 6–10 times the weight of Compound I, and the amount of seed crystals used can be 0.003–0.007 times the weight of Compound I. The solution in the first reactor is slowly transferred to the second reactor and stirred until the resulting crystal form is consistent with the standard crystal form. Then, the mixture is filtered, and the filter cake is washed with pure water until the residual DMSO is ≤2000 ppm. The filter cake is dried under vacuum in the reactor until KF ≤ 8.0%, and then humidified with nitrogen until KF is between 6.6% and 9.0% and XRPD is consistent with the standard, thereby obtaining crystal form VIII.

[0182] In some embodiments, products produced by any of the above preparation methods are within the scope of this application. Preferably, the product contains crystal form VIII and has a KF value of 6%-10%, more preferably 6.6%-9%.

[0183] VI. Methods and Applications

[0184] The compounds of the present invention are PARP inhibitors. Therefore, the various crystal forms and hydrates of the compounds of the present invention can be used to prepare drugs for treating or preventing clinical conditions caused by abnormal PARP activity.

[0185] In this article, clinical symptoms caused by abnormal PARP activity refer to diseases or symptoms whose pathogenesis and development can be treated or prevented by inhibiting PARP activity.

[0186] In this article, clinical conditions caused by abnormal PARP activity include cancer and other diseases that respond to PARP activity inhibition, such as excessive cell death, including central nervous system diseases such as stroke and neurodegenerative diseases.

[0187] Cancers caused by abnormal PARP activity include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, and colon cancer. Cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0188] Therefore, the present invention provides the use of the hydrates of the present invention and the crystal forms I, II, III, V, VI, VIII, IX, X, XI, XII and “VIII” or mixtures of two or more of these crystal forms in the preparation of medicaments for the treatment or prevention of clinical conditions caused by abnormal PARP activity, particularly cancers as described herein.

[0189] In a particularly preferred embodiment, the present invention provides the use of the dihydrate of the present invention in the preparation of medicaments for treating or preventing clinical conditions caused by abnormal PARP activity, particularly cancers as described herein.

[0190] In a particularly preferred embodiment, the present invention provides the use of the crystal form VIII described herein as a drug substance in the preparation of a medicament for the treatment or prevention of clinical conditions caused by abnormal PARP activity, particularly the cancers described herein.

[0191] Also provided are the hydrates of the present invention and mixtures of crystal forms I, II, III, V, VI, VIII, IX, X, XI, XII and “VIII” or two or more of these crystal forms, especially dihydrates, and crystal form VIII, crystal form “VIII” or crystal form XII and any mixture thereof, for the preparation of medicaments for the treatment or prevention of clinical conditions caused by abnormal PARP activity, such as cancer, especially cancer as described herein.

[0192] A method for preparing a drug is also provided, comprising the step of mixing the crystal form or mixture of crystal forms described in this invention, particularly crystal form VIII, with a pharmaceutically acceptable carrier or excipient. Preferably, the method further comprises a granulation or tableting step. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, those disclosed in WO2016155655; preferably, the drug is an amorphous solid dispersion as described in WO2016155655. The entire contents of this document are incorporated herein by reference.

[0193] The examples illustrated below further illustrate the embodiments described herein and should not be construed as limiting the scope of the embodiments described herein. Compounds, starting materials, and reagents useful in the processes described herein, such as compounds of formula V, may be commercially available or prepared using methods known to those skilled in the art.

[0194] Example I: Preparation of Compound I

[0195] Example 1

[0196] Preparation of methyl 2-fluoro-5-((5-fluoro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoate (III)

[0197]

[0198] Preparation of IV-TMS: The reactor was dehydrated using toluene. IV (31.9 kg, 177.1 mol), toluene (254 kg, 5.9 V), hexamethyldisilazane (71.4 kg, 442.4 mol), and sulfuric acid (1.7 kg, 17.3 mol) were added to the reactor and refluxed at 112–120 °C for 16 hours. The mixture was then concentrated under reduced pressure at a controlled temperature below 65 °C to obtain an IV-TMS toluene solution.

[0199] Preparation III: At 40°C, 264 kg of sulfolane solution of V was added to the IV-TMS toluene solution. The solution was concentrated under reduced pressure while maintaining the temperature. The temperature was then raised to 95–105°C and stirred for 20 hours. After cooling, samples were analyzed by HPLC for process control (IPC limit: IV / (IV+III+II) ≤ 10.0%; if IV / (IV+III+II) > 10.0%, stirring continued until the limit was reached). Methanol was slowly added, and crystallization was achieved by stirring at 55–65°C. Process water was then slowly added at a controlled rate, and stirring continued at 20°C. The mixture was centrifuged. The filter cake was washed with a methanol-water solution (2.4 times by weight), dried under reduced pressure for 20 hours, and analyzed for process control (IPC limit: KF ≤ 2.0%, methanol residue ≤ 1.0%; if the limits were not met, drying under reduced pressure continued until the limit was reached). 52.3 kg of III was obtained with an HPLC purity of 99.5% and a yield of 55%.

[0200] HPLC (std): 9.32 min; 1 H NMR (400MHz, DMSO-d6): δ11.72(s,1H), 7.87(d,J=6.8Hz,1H), 7.64(dd,J=6,7Hz,2H), 7.32(t,J=8.8Hz,1H), 7.00-7.09(m,2H), 5.33(s,2H).

[0201] Example 2

[0202] Preparation of 2-fluoro-5-((5-fluoro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoic acid II

[0203]

[0204] Under nitrogen protection, the reactor was heated to 15–25°C. NaOH (12.7 kg, 317.5 mol) was added to water (142 kg, 3.0X), and the mixture was stirred for 20–40 minutes. Then, methanol (48.0 kg, 1.0X) and 5-fluoro-1-(4-fluoro-3-methoxycarbonylbenzyl)quinazolin-2,4(1H,3H)-dione (III, 47.0 kg, 135.7 mol) were added. The mixture was heated to 30–40°C and stirred for 2–4 hours. Samples were taken for process control via HPLC analysis (IPC limit: III / (II+III) ≤ 0.8%; if III / (II+III) > 0.8%, the reaction time should be appropriately extended until the limit is reached).

[0205] After the reaction was complete, methanol (113 kg, 2.4X) and water (141 kg, 3.0X) were added, and the temperature was controlled at 30–40 °C. 2N hydrochloric acid aqueous solution (162 kg, 3.5X) was slowly added dropwise to adjust the pH to 1.5–3.0. The mixture was stirred and slowly cooled to 20–30 °C. The mixture was filtered, and the filter cake was washed sequentially with methanol-water (V:V, 1:1) and methanol, followed by vacuum drying. Samples were analyzed for process control (IPC limit: KF ≤ 0.5%; if the limit is not met, vacuum drying continues until the limit is reached). Product II (44.4 kg, HPLC purity 100%, yield 98%) was obtained.

[0206] HPLC (std): 9.97 min; 1 H NMR (400MHz, DMSO-d6): δ13.34(brs,1H), 11.73(s,1H), 7.84(d,J=2Hz,1H), 7.66-7. 61(m,1H), 7.82-7.63(m,2H), 7.27(t,J=10.4Hz,1H), 7.10-7.03(m,2H), 5.32(s,2H).

[0207] Example 3

[0208] 5-Fluoro-1-(4-Fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione dihydrate

[0209] Preparation of (IA)

[0210]

[0211] Synthesis: Compound 2-(piperazin-1-yl)pyrimidine (A, 23.15 kg, 141.0 mol) was dissolved in ethyl acetate (121 kg, 3.0X) and stirred at 15–25 °C to prepare an ethyl acetate solution of A for later use. The reaction vessel was kept at 15–25 °C, and 5-fluoro-1-(4-fluoro-3-carboxylic acid benzyl)quinazolin-2,4(1H,3H)-dione (II, 40.0 kg, 120.4 mol), ethyl acetate (638 kg, 16.0X), and the temperature was adjusted to 20 °C. Then, a 50% ethyl acetate solution of propyl phosphoric anhydride (139.2 kg, 218.7 mol) and diisopropylethylamine (48.1 kg, 372.2 mol) were added. The reaction mixture was heated to 35–45 °C, and the prepared ethyl acetate solution of A was slowly added. Stirring continued for 18–22 hours. Cool down, take a sample and perform HPLC analysis (IPC: II / (II+I)≤1.0%; if II / (II+I)>1.0%, and the reaction still does not reach the limit value after stirring, add 50% propylphosphonic anhydride ethyl acetate solution and continue until the limit value is reached).

[0212] After the reaction was complete, purified water (12 kg, 0.30X) was added, and the mixture was stirred for 1–3 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate. The wet product was returned to the reactor, and dimethyl sulfoxide (840 kg, 21.0X) was added and stirred for 1–3 hours. Then, purified water (92 kg, 2.3X) and VIII seed crystals were added, and stirring continued. The filter cake was washed with purified water (5.0X). The wet product was dried under vacuum at 50–60 °C for 64 hours. Samples were taken for testing (IPC limit: KF ≤ 0.5%; if the limit is not met, drying should continue until the limit is reached). 46.3 kg of the product 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione (I, yield: 74%) was obtained as an off-white solid.

[0213] HPLC (std): 23.05 min; 1 H NMR (400MHz, DMSO-d6): δ11.68(brs,1H), 8..39(d,J=4.8Hz,2H), 7.42(t,J=15.6Hz,1H), 7.32-7.27(m,3H), 7.0 4(t,J=9.2Hz,2H), 6.68(t,J=4.8Hz,1H), 5.32(s,2H), 3.82-3.81(m,2H), 3.70-3.64(m,4H), 3.24-3.22(m,2H).

[0214] Crystallization: In reactor R1, dimethyl sulfoxide (338 kg, 8.0X the weight of compound I, hereinafter the same) was added to 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione (I, 42.0 kg, 87.8 mol), and stirred at 55–65 °C until clear. In reactor R2, purified water (672 kg, 16.0X) and dimethyl sulfoxide (372 kg, 8.9X) were added. The internal temperature of R2 was adjusted to 50 °C, and then seed crystals VIII (0.21 kg, 0.005X) were added. The solution in R1 was slowly transferred to R2 and stirred. Samples were taken for process control by XRPD analysis (IPC, consistent with the crystal form of the standard; otherwise, stirring was continued until the requirements were met). The mixture was filtered, and the filter cake was washed with pure water. Samples were taken for process control via GC analysis (IPC, dimethyl sulfoxide residue ≤2000ppm; otherwise, continue rinsing with pure water until the requirements are met). The filter cake was dried under vacuum in a three-in-one reactor, and samples were taken for process control via KF analysis (IPC, KF ≤8.0%; otherwise, continue drying until the requirements are met). The nitrogen valve was opened, and nitrogen was purged to humidify the atmosphere. Samples were taken for process control (IPC, KF 6.6–9.0%, XRPD consistent with the standard; otherwise, continue purging with humidified nitrogen until the requirements are met). 42.8 kg of the target compound 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione dihydrate (IA, yield: 94%) was obtained as an off-white powder.

[0215] HPLC (std): 23.05 min; 1 H NMR (400MHz, DMSO-d6): δ11.68(brs,1H), 8..39(d,J=4.8Hz,2H), 7.42(t,J=15.6Hz,1H), 7.32-7.27(m,3H), 7.0 4(t,J=9.2Hz,2H), 6.68(t,J=4.8Hz,1H), 5.32(s,2H), 3.82-3.81(m,2H), 3.70-3.64(m,4H), 3.24-3.22(m,2H).

[0216] Example II: Crystal form study of compound I

[0217] 1. Instrument parameters and test methods

[0218] 1) X-ray powder diffractometer (XRPD, manufacturer: Bruker, model D8 advance)

[0219] Approximately 10 mg of the compound was weighed and evenly spread on a single-crystal silicon sample holder, and the sample was tested using XRPD. The specific XRPD method used is as follows:

[0220] Optical tube: Cu:K-Alpha

[0221] Generator: Voltage: 40kV; Current: 40mA;

[0222] Scan range: 3-40 degrees;

[0223] Sample rotation speed: 15 rpm;

[0224] Scan rate: 10 deg / min.

[0225] 2) Differential thermal scanner (DSC, manufacturer TA, model Q2000)

[0226] Approximately 1 mg of the compound was weighed into a perforated aluminum dish, and the sample was tested using DSC. The specific DSC method used in the experiment was as follows: heating from room temperature to 300°C at a rate of 10°C / min.

[0227] 3) Thermogravimetric analyzer (TGA, manufacturer TA, model Q5000IR)

[0228] Approximately 5 mg of the compound was weighed into a crucible and the sample was tested using TGA. The specific TGA method used in the experiment was as follows: heating from room temperature to 300°C at a rate of 10°C / min.

[0229] 4) Dynamic Vapor Adsorption Analyzer (DVS, manufacturer: SMS, model: Advantage-1)

[0230] Approximately 10 mg of sample was transferred to the DVS sample pan, and the weight change was recorded at 25°C with variations in ambient humidity. After DVS testing, the sample also needed to be analyzed by XRPD to determine if the crystal form had changed. The following parameters were used:

[0231] Equilibrium dm / dt: 0.01% / min (time: 10 min maximum 180 min);

[0232] Drying: 0% RH, 120 min;

[0233] RH (%) measurement gradient: 10%;

[0234] RH (%) measurement gradient range: 0%~90%~0%.

[0235] Hygroscopicity evaluation criteria

[0236] Hygroscopic classification Moisture absorption and weight gain* deliquescence Absorbs sufficient water to form a liquid Extremely hygroscopic The weight gain due to moisture absorption should not be less than 15%. Hygroscopic The weight gain due to moisture absorption is less than 15% but not less than 2%. Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2%. None or almost none hygroscopic The weight gain due to moisture absorption is less than 0.2%.

[0237] *: Moisture absorption weight gain at 25℃ / 80% RH (Chinese Pharmacopoeia 9103 Guidelines for Hygroscopicity Testing of Drugs)

[0238] 5) High Performance Liquid Chromatography (HPLC) Conditions

[0239]

[0240] 2. Crystal form screening and results

[0241] Example 4: Compound of Formula IA, Crystal Form VIII

[0242] The compound of formula IA obtained in Example 3 was characterized by XRPD, DSC, TGA and DVS, and its crystal form was VIII.

[0243] Figure 1 The XRPD plot of crystal form VIII is shown; Figure 2 The DSC diagram of crystal form VIII is shown; Figure 3 TGA of crystal form VIII is shown; Figure 4 The DVS of crystal form VIII is shown.

[0244] Example 5: Crystal form I of compound of formula I

[0245] Additionally, approximately 20 mg of compound IA (crystal form VIII) was weighed into a 4 mL transparent glass bottle, and a certain amount of the solvent listed in the table below was added to obtain a slightly supersaturated solution. The suspension was filtered, and the resulting filtrate was left open in a fume hood to evaporate slowly. The bottle was covered with aluminum foil and perforated to prevent contamination. After complete evaporation, the resulting solid was vacuum-dried overnight at 40°C, and its crystal form change was determined by XRPD. The results showed that crystal form I was obtained.

[0246] solvent Crystal form (dried sample) Acetonitrile I acetone I Tetrahydrofuran I dichloromethane I chloroform I 1,4-Dioxane I

[0247] In addition, at 50°C, 200 mg of compound IA (crystal form VIII) was first saturated in 5 mL of dimethylformamide. After filtering with a needle filter, 1 mL was transferred to a 40 mL transparent glass bottle, and seed crystals of crystal form I (tetrahydrofuran volatilization) were added to obtain a slightly suspended solution. The solution was stirred, and 10 mL of cyclohexane was slowly added dropwise. After stirring at room temperature for 1 hour, the solid and liquid were separated by centrifugation. The obtained solid was vacuum dried overnight at 40°C, and its crystal form change was determined by XRPD. The XRPD results showed that crystal form I was obtained. From the thermal analysis results, crystal form I is very likely a hydrate, with a crystal form transition temperature of 155°C and a final melting point of about 280°C.

[0248] Figure 5 The XRPD plot of crystal form I is shown; Figure 6 The DSC diagram of crystal form I is shown; Figure 7 The TGA of crystal form I is shown.

[0249] Example 6: Compound I crystal form II

[0250] Approximately 200 mg of compound IA (crystal form VIII) was weighed into a 40 mL transparent glass bottle, and then 10 mL of acetone:water (9:1, v / v) was added. The resulting suspension was magnetically stirred at 50 °C, and portions of the solid were collected at different time points. After being vacuum dried overnight at 40 °C, the crystal form change was determined by XRPD.

[0251] Based on the XRPD results, crystal form II was obtained using the above method, and the crystals are needle-shaped. Thermal analysis indicates that it may also be a hydrate, exhibiting an endothermic peak at 220℃, which may be the crystal form transition temperature, with a final melting point of around 280℃. XRPD and DVS results show that, due to the extremely similar crystal structures of crystal form II and crystal form VIII, the adsorption and desorption processes are also basically the same, indicating that they are hygroscopic.

[0252] Figure 8 The XRPD plot of crystal form II is shown; Figure 9 The DSC diagram of crystal form II is shown; Figure 10 TGA of crystal form II is shown; Figure 11 The DVS of crystal form II is shown.

[0253] Example 7: Crystal form III of compound of formula I

[0254] Approximately 10 mg of compound I (crystal form I) was transferred to a 1.5 mL HPLC vial, and then 1.5 mL of ethanol was added. The resulting suspension was shaken at 25 °C, and portions of the solid were collected at different time points. After being vacuum dried overnight at 40 °C, the crystal form change was determined by XRPD.

[0255] The results showed that the thermal analysis indicated that crystal form III was amorphous and had a melting point of approximately 280°C.

[0256] Figure 12 The XRPD plot of crystal form III is shown; Figure 13 The DSC diagram of crystal form III is shown; Figure 14 TGA of crystal form III is shown.

[0257] Example 8: Crystal form V of compound of formula I

[0258] Approximately 200 mg of compound IA (crystal form VIII) was weighed into a 40 mL transparent glass bottle, and then 10 mL of methanol was added. The resulting suspension was magnetically stirred at 50 °C, and portions of the solid were collected at different time points. After being vacuum dried overnight at 40 °C, the crystal form change was determined by XRPD.

[0259] XRPD results showed that at 50℃, crystal form VIII, after being pulped in methanol for 1 day, yielded crystal form VI, and after 5 days of pulping, yielded crystal form V. This suggests that at 50℃, crystal form VI will always transform into crystal form V, but the transformation rate varies in different solvents. Thermal analysis showed that crystal form V is amorphous, with a melting point of approximately 270℃. DVS results indicated a 0.8% weight gain upon water absorption at 0%–80% RH, indicating slight hygroscopicity; the crystal form remained unchanged before and after the test.

[0260] Figure 15 The XRPD plot of crystal form V is shown; Figure 16 The DSC diagram of crystal form V is shown; Figure 17 TGA of crystal form V is shown; Figure 18 The DVS of crystal form V is shown.

[0261] Example 9: Crystal form VI of compound of formula I

[0262] Approximately 200 mg of compound IA (crystal form VIII) was weighed into a 40 mL transparent glass bottle, and then 10 mL of ethanol was added. The resulting suspension was shaken at 50 °C for 5 days, followed by magnetic stirring for 1 day. Samples of the solid were collected at different time points, vacuum dried overnight at 40 °C, and the crystal form change was determined by XRPD.

[0263] DSC and TGA analyses indicate that crystal form VI is amorphous and has a melting point of 280℃. DVS results show that it gains 0.5% weight upon water absorption at 0%–80% RH, indicating slight hygroscopicity, and the crystal form remained unchanged before and after the test.

[0264] Figure 19 The XRPD plot of crystal form VI is shown; Figure 20 The DSC diagram of crystal form VI is shown; Figure 21 The TGA of crystal form VI is shown; Figure 22 The DVS of crystal form VI is shown.

[0265] Example 10: Crystal form IX of compound of formula I

[0266] Approximately 10 mg of compound IA (crystal form VIII) was weighed into an 8 mL transparent glass bottle, covered with aluminum foil and punched with a hole. The bottle was then transferred to a 40 mL transparent glass bottle containing 4 mL of ethanol, and the bottle was capped with a gasket. One month later, the solid sample was removed, and its crystal form change was determined by XRPD. The results showed that crystal form IX, an anhydrous compound, was obtained in ethanol.

[0267] When ethyl acetate is used instead of ethanol, a mixture of crystal form I and crystal form II is obtained; when dichloromethane is used instead of ethanol, a mixture of crystal form I and crystal form XI is obtained.

[0268] Figure 23 The XRPD plot of crystal form IX is shown; Figure 24 The DSC plot of crystal form IX is shown; Figure 25 The TGA of crystal form IX is shown.

[0269] Example 11: Crystal form X of compound of formula I

[0270] At 60°C, 100 mg of compound IA (crystal form VIII) was first saturated in 5 mL of ethanol. After filtration through a syringe filter, the filtrate was transferred to a 40 mL clear glass bottle and then placed in a -20°C freezer overnight. The resulting solid was then vacuum dried overnight at 40°C, and its crystal form change was determined by XRPD.

[0271] The result was crystal form X, which exhibited similar thermodynamic properties to crystal form I and was also very likely a hydrate. It showed significant crystal transformation behavior around 170℃, with a final melting point of 280℃.

[0272] Figure 26 The XRPD plot of crystal form X is shown; Figure 27 The DSC diagram of crystal form X is shown; Figure 28 The TGA of crystal form X is shown.

[0273] Example 12: Crystal form XI of compound of formula I

[0274] At 60°C, 100 mg of compound IA (crystal form VIII) was first saturated in 5 mL of methanol. After filtration through a syringe filter, the filtrate was transferred to a 40 mL clear glass bottle and then placed in a -20°C freezer overnight. The resulting solid was then vacuum dried overnight at 40°C, and its crystal form change was determined by XRPD.

[0275] The results show that crystal form XI obtained by the above method exhibits similar thermodynamic behavior to crystal form I and is also very likely a hydrate. It shows significant crystal transformation behavior around 170℃, with a final melting point of 280℃.

[0276] When methanol was replaced with acetonitrile or acetone, a mixture of crystal form I and crystal form XI was obtained.

[0277] Figure 29 The XRPD plot of crystal form XI is shown; Figure 30 The DSC plot of crystal form XI is shown; Figure 31 The TGA of crystal form XI is shown.

[0278] Example 13: Crystal form "VIII" of Formula I compound

[0279] Crystal form "VIII" is the crystal form of crystal form VIII at 30% RH. It can be transformed into crystal form VIII under conditions such as heating to dehydrate and reabsorb water, 5℃, room temperature / 75% RH, and 40℃ / 75% RH.

[0280] XRPD diagram of crystal form "VIII" is shown below Figure 32 As shown.

[0281] Example III: Thermodynamic Stability Study of Different Crystal Forms and Competition among Organic Solvents

[0282] Example 14

[0283] Saturated with crystal form VIII in the following solvents at different temperatures, the solutions were filtered through a syringe filter, and the filtrates were transferred to 1.5 mL HPLC vials. 5 mg of crystal forms V and VI were weighed into the filtrates, and the resulting suspensions were shaken for a period of time in the following solvents at different temperatures. Solid-liquid separation was then performed using a centrifuge, and the resulting solids were vacuum-dried overnight at 40 °C. XRPD was used to determine the transformation between the different crystal forms.

[0284] Based on existing XRPD results, the dominant crystal form in anhydrous solvents is crystal form V, indicating that crystal form V is more stable than crystal form VI at 25°C, 50°C, and 80°C. In aqueous solvents, crystal forms V and VI transform into crystal form II.

[0285] Saturated with crystal form VIII in the following solvents at different temperatures, the solutions were filtered through a syringe filter, and the filtrates were transferred to 1.5 mL HPLC vials. 5 mg of crystal forms III, V, and IX were weighed into the filtrates, and the resulting suspensions were shaken for a period of time in the following solvents at different temperatures. Solid-liquid separation was then performed using a centrifuge, and the resulting solids were vacuum-dried overnight at 40 °C. XRPD was used to determine the transformation between the different crystal forms.

[0286] The results of the two rounds of competition showed that, in anhydrous solvents below 50°C, amorphous form V was the dominant crystal form, while the remaining amorphous forms III, VI, and IX were all anhydrous metastable crystal forms.

[0287]

[0288] Example 15: Water Activity Competition

[0289] Saturate crystal form VIII in the following water activity solutions, filter using a syringe filter, and transfer the filtrate to a 1.5 mL HPLC vial. Weigh 2 mg of crystal forms I, II, VIII, X, and XI into the filtrate, and shake the resulting suspensions at different temperatures in the following solvents for a period of time. Then, separate the solid and liquid phases using a centrifuge. After the solids are allowed to evaporate naturally at room temperature (washed with tert-butyl methyl ether in the dimethyl sulfoxide system), XRPD is used to determine the transformation between the different crystal forms.

[0290] Current results indicate that in water-activity solutions, the resulting hydrated crystal forms all transform into crystal form II after one day, while in DMSO systems they transform into crystal form VIII.

[0291] Crystal form II is the dominant crystalline form in water-active solutions, so amorphous form V was added to investigate their transformation relationship. The results showed that at low water activity (Aw < 0.3), crystal form II transforms into crystal form V. At high water activity (Aw > 0.3), crystal form V transforms into crystal form II. Furthermore, it was also largely determined that crystal form V is the dominant crystalline form in pure organic solvents.

[0292]

[0293] Example IV: Physical Stability Study

[0294] Approximately 10 mg of crystal form II, crystal form V, and crystal form VI were weighed into 1.5 mL liquid chromatography vials and placed in 25℃ / 60%RH and 40℃ / 75%RH conditions for a period of time, respectively. After being removed at different time points, the crystal form changes were determined by XRPD.

[0295] The results showed that no crystal form changes occurred in crystal forms II, V, and VI within 2 weeks under different conditions (see table below).

[0296]

[0297] The long-term stability of crystal form VIII under conditions of 25℃ / 60% RH was studied. The results showed that crystal form VIII was stable under long-term conditions for 24 months, with no change in crystal morphology and no significant change in water content.

[0298]

[0299] Example V: Humidity X-ray powder diffraction (RH-XRPD) of crystal form VIII

[0300] The aforementioned results indicate that crystal form VIII is highly likely to be a hydrate, but given its extremely hygroscopic nature, it is very likely to be a channel-type hydrate, making it difficult to detect its crystal form after dehydration. Therefore, RH-XRPD was used to further characterize IMP4297 crystal form VIII to confirm that it is a hydrated crystal form and to understand its crystal form transformation under different humidity conditions.

[0301] The specific XRPD parameters used in the experiment are as follows:

[0302] Optical tube: Cu:K-Alpha

[0303] Generator: Voltage: 40kV; Current: 40mA

[0304] Scan range: 3-40 degrees;

[0305] Scan rate: 10 deg / min.

[0306] Weigh approximately 100 mg of the compound and spread it evenly in a humidity-controlled sample cell. Place the sample cell into the humidity control unit and control the humidity atmosphere inside the chamber by changing the ratio of dry to wet compressed nitrogen gas. The specific humidity and equilibration time are listed in the table below.

[0307]

[0308] The results show that crystal form VIII is the dehydrated crystal form VIII (named crystal form XII) at 0% RH, while crystal form "VIII" refers to the crystal form of crystal form VIII at 30% RH. Under specific conditions, it gradually transforms into crystal form VIII, such as at 5℃ / 75% RH, room temperature / 75% RH, or 40℃ / 75% RH. During the adsorption process from 0% to 40% RH, crystal form XII gradually transforms into hydrated crystal form VIII, which is stable in an atmosphere with RH above 40%. The desorption process is slightly delayed, consistent with the DVS results, showing complete dehydration from 30% RH to 0% RH to form crystal form XII. The RH-XRPD results are consistent with the DVS results and inferences, and the crystal form transformation after dehydration is indeed confirmed, thus proving that crystal form VIII is indeed the hydrated crystal form. Based on previous DVS results, calculations show that crystal form VIII is bound to two water molecules and can exist stably above 40% RH. Below this humidity, there is a risk of dehydration and crystal transformation.

[0309] The specific calculation formula is as follows:

[0310]

[0311] Example VI: Elucidating Crystal Structure by Microcrystal Electron Diffraction

[0312] Since it is difficult to obtain suitable single crystals for structural analysis, microcrystalline electron diffraction, which can be applied to smaller single crystals, was chosen for single crystal analysis to further identify the hydrate structure and water of crystallization of compound IA crystal form VIII.

[0313] The testing methods and steps are as follows:

[0314] 1. Insert the sample rod into liquid nitrogen until the temperature of the sample rod stabilizes.

[0315] 2. Take an appropriate amount of crystal form VIII sample and place it in a PE tube. Then, take a clean copper mesh and put it into the PE tube so that the crystal form VIII sample is adsorbed onto the copper mesh.

[0316] 3. Quickly immerse the sample-carrying copper mesh into the liquid nitrogen in the refrigeration workbench to lock in the moisture within the crystal sample.

[0317] 4. While keeping the sample-carrying copper mesh immersed in liquid nitrogen, load it into the cryo-sample rod, then insert the cryo-sample rod into the cryo-electron microscope tube to begin the formal sample measurement.

[0318] MicroED (microcrystalline electron diffraction) technology was used to collect, analyze, and refine the structure of the sample. A schematic diagram of the asymmetric unit cell of the single-crystal structure of compound IA, crystal form VIII, is shown below. Figure 34 As shown; a schematic diagram of the hydrate crystal structure model projected from the a-axis direction is shown below. Figure 35 As shown. The results indicate that the asymmetric unit of crystal form VIII of compound IA consists of one molecule of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione and two water molecules. The 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione molecules have cavities between each other, and the water molecules are bound together by hydrogen bonds.

[0319] The crystal structure analysis results confirmed the crystal form VIII structure of compound IA, showing that the ratio of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione to water was 1:2, which is a dicrystalline form.

Claims

The crystalline form of the dihydrate of 1,5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione, characterized in that, The crystalline form is crystal type VIII, and its XRPD pattern contains diffraction peaks at 2θ = 6.7°±0.2°, 10.5°±0.2°, 11.0°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 22.2°±0.2°, 23.3°±0.2°, 25.7°±0.2°, 27.0°±0.2°, and 29.7°±0.2°.

2. The crystalline form of the dihydrate of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione as described in claim 1, characterized in that, The KF value of crystal form VIII is 6% to 10%.

3. The crystalline form of the dihydrate of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione as described in claim 1, characterized in that, The KF value of crystal form VIII is 6.6% to 9%.

4. The crystalline form of the dihydrate of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione as described in claim 1, characterized in that, The crystal form VIII has at least one, any two, any three, any four, or all five of the following: (a) to (e) (a) It has an XRPD pattern that is essentially as shown in Figure 1; (b) Has a DSC diagram that is essentially as shown in Figure 2; (c) It has a TGA diagram that is essentially as shown in Figure 3; (d) Has a DVS diagram that is essentially as shown in Figure 4; and (e) It has a schematic diagram of asymmetric elements as shown in Figure 34.

5. The use of the crystalline form of the dihydrate of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione as a raw material in the preparation of a medicament for the treatment or prevention of clinical symptoms caused by abnormal PARP activity.

6. The application as described in claim 5, characterized in that, The clinical conditions described are cancers, selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer, and prostate cancer.

7. A method for preparing the crystalline form of the dihydrate of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazolin-2,4(1H,3H)-dione according to any one of claims 1-4, characterized in that, The method includes: (1) Prepare compound III from compound IV and compound V: ； (2) Hydrolyze compound III to obtain compound II: ； (3) Compound of formula II is condensed with compound of formula A to prepare compound of formula I: ； In step (3), compound II is dissolved in ethyl acetate, the temperature of the reactor is controlled at 15-25℃, the ethyl acetate solution of compound II is added to the reactor, the temperature of the reactor is adjusted to 20±2℃, a condensing agent and an organic base are added, the reaction solution is heated to 35-45℃, the ethyl acetate solution of compound A is added, and the mixture is stirred for 15-25 hours. After the reaction is completed, pure water is added to the reaction product, the mixture is stirred for 1-3 hours, filtered, the filter cake is washed with ethyl acetate, the wet product is returned to the reactor, dimethyl sulfoxide is added and stirred for 1-3 hours, then pure water and seed crystals of compound I are added, the mixture is stirred for 4-6 hours, the filter cake is washed with pure water, and the mixture is dried under vacuum at 50-60℃ for 50-70 hours. Then, the nitrogen valve is opened in the three-in-one reactor and nitrogen is blown for 18-22 hours to obtain crystal form VIII.

8. The method as described in claim 7, characterized in that, Step (1) includes: (a) Reacting compound IV with hexamethyldisilazane in an organic solvent under acidic conditions to prepare an organic solvent solution containing compound IV-TMS, wherein the molar ratio of compound IV to hexamethyldisilazane is 1:1.5 to 1:3, the weight of the organic solvent used to dissolve compound IV is 5 to 6.5 times that of compound IV, the reaction temperature is 105 to 120 °C, and the reaction time is 10 to 20 hours; IV-TMS (b) Mixing the compound of formula V and the organic solvent solution containing the compound of formula IV-TMS in the presence of an organic solvent to react them to obtain the compound of formula III.

9. The method as described in claim 8, characterized in that, In step (a), the compound represented by formula IV is dissolved in toluene, hexamethyldisilazine is added, followed by the dropwise addition of sulfuric acid. The resulting mixture is stirred at 112–120°C for 10–20 hours until the solid is completely dissolved. The reaction solution is then cooled to 55–65°C and concentrated to obtain a toluene solution containing the compound of formula IV-TMS, wherein the molar ratio of the compound of formula IV to sulfuric acid is 12:1 to 8:

1.

10. The method as described in claim 8, characterized in that, In step (b), an organic solvent solution containing the directly obtained, unpurified compound of formula IV-TMS is mixed with the compound of formula V and reacted.

11. The method as described in claim 10, characterized in that, A sulfolane solution of compound V is mixed with an organic solvent solution containing compound IV-TMS, and the mixture is reacted. The mixing is carried out at 35–45°C, the reaction temperature is 95–105°C, and the reaction time is 10–30 hours. After the reaction is completed, methanol is slowly added, and the mixture is stirred at 55–65°C to induce crystallization. Then, process water is slowly added, and the mixture is stirred at 20°C. After centrifugation, the filter cake is washed with a methanol-water solution and dried under reduced pressure for 10–30 hours to obtain compound III. The amount of compound V used in step (b) is calculated based on the amount of compound IV used in step (a).

12. The method as described in claim 11, characterized in that, The molar ratio of compound V to compound IV is 1:1 to 2:

1.

13. The method as described in claim 7, characterized in that, In step (2), compound III is added to a mixture of an inorganic alkaline aqueous solution and a C1-C4 monohydric alcohol. The resulting mixture is stirred at 30-50°C for 1-6 hours. After the reaction is complete, 2.5-4 times the weight of water and 2-3 times the weight of the mixture of formula III are added. The pH of the reaction solution is adjusted to 1.5-3 at the same temperature. Then the mixture is stirred and slowly cooled to 20-30°C. After stirring, the mixture is filtered, the filter cake is washed, and the mixture is dried under reduced pressure to obtain compound II.

14. The method as described in claim 13, characterized in that, The molar ratio of the inorganic base to the compound of formula III is 1.5:1 to 3.0:1, the weight of the organic solvent is 0.8 to 1.3 times the weight of the compound of formula III, and the weight of water in the aqueous solution of the inorganic base is 2.8 to 3.5 times the weight of the compound of formula III.

15. The method as described in claim 7, characterized in that, In step (3), the molar ratio of the condensing agent to the compound of formula II is 1:1 to 1:2.5, the molar ratio of the organic base to the compound of formula II is 1:2 to 1:4, and the molar ratio of the compound of formula A to the compound of formula II is 2:1 to 0.8:

1.

16. The method as described in claim 7, characterized in that, In step (3), after the reaction is complete, 0.1 to 0.5 times the weight of compound A in purified water is added to the reaction product, stirred for 1 to 3 hours, filtered, and the filter cake is washed with ethyl acetate; the wet product is returned to the reactor, 15 to 25 times the weight of compound A in dimethyl sulfoxide is added, stirred for 1 to 3 hours, then 1 to 5 times the weight of compound A in purified water and the seed crystals of compound I are added, and stirring is continued; the filter cake is washed with 3 to 6 times the weight of compound A in purified water, dried under vacuum at 50 to 60°C for 50 to 70 hours, and then the nitrogen valve is opened in the three-in-one reactor to purge with moist nitrogen for 18 to 22 hours to obtain crystal form VIII.

17. The method as described in claim 16, characterized in that, Compound I and dimethyl sulfoxide (DMSO) are mixed in a first reactor and stirred at 55–65°C until clear. The amount of DMSO is 7–10 times the weight of compound I. In a second reactor, pure water and DMSO are added. The temperature of the second reactor is then adjusted to 50 ± 3°C, and seed crystals are added. The amount of pure water is 12–20 times the weight of compound I, the amount of DMSO is 6–10 times the weight of compound I, and the amount of seed crystals is 0.003–0.007 times the weight of compound I. The solution in the first reactor is slowly transferred to the second reactor and stirred until the resulting crystal form is consistent with the standard crystal form. The mixture is then filtered, and the filter cake is washed with pure water until the residual DMSO is ≤2000 ppm. The filter cake is dried under vacuum in the reactor until KF ≤ 8.0%, and then humidified with nitrogen until KF is between 6.6% and 9.0% and XRPD is consistent with the standard, thus obtaining crystal form VIII.

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