A crystalline form of a pharmaceutically acceptable salt of a pyrazolo-heteroaryl derivative

Abstract

The present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of a pyrazolo-heteroaryl derivative. In particular, the present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I). The novel crystalline forms of the present disclosure have good physicochemical properties.

Description

[0001] This application claims priority to Chinese patent application 2022114519333, filed on 2022 / 11 / 21. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure relates to the crystalline form of a pharmaceutically acceptable salt of a pyrazolone aryl derivative, and more particularly to the crystalline form of a pharmaceutically acceptable salt of a compound represented by formula (I). Background Technology

[0003] Both normal and tumor cells experience thousands of DNA damage events daily. This makes DNA damage repair crucial for maintaining genome stability and cell survival. Compared to normal cells, tumor cells endure greater replication stress, carry more endogenous DNA damage, and frequently exhibit the absence of one or more DNA damage repair pathways. This makes tumor cell survival even more dependent on the successful completion of DNA damage repair.

[0004] Homologous recombination repair is the primary mechanism for repairing DNA double-strand breaks. It uses the homologous sequence of an undamaged sister chromatid as a template to replicate the damaged DNA sequence, precisely repairing the DNA. This repair primarily occurs during the G2 and S phases of the cell cycle. ATR, a key enzyme in the homologous recombination repair pathway and belonging to the PIKK family, is activated when the ATR / ATRIP complex binds to damaged DNA covered by replication protein A (RPA). ATR then phosphorylates downstream proteins such as Chk1 and SMARCAL, regulating various checkpoints in the cell cycle, causing cell cycle arrest, ensuring the stability of damaged DNA, and increasing dNTP concentration, thus promoting DNA damage repair. The repair of DNA damage occurring in the S phase of the cell cycle is mainly accomplished by the ATR pathway, indicating that ATR is crucial for ensuring cell proliferation. Analysis of clinical tumor samples shows elevated ATR expression levels in various tumor tissues, including gastric cancer, liver cancer, colorectal cancer, ovarian cancer, and pancreatic cancer. Furthermore, high ATR levels are often associated with lower survival rates in patients with ovarian and pancreatic cancer. Therefore, ATR is an important target for cancer therapy.

[0005] WO2021098811A discloses a series of novel ATR inhibitors, among which the compound shown in formula (I) exhibits good ATR inhibitory activity, and its structure is shown below:

[0006]

[0007] The crystal structure of pharmaceutical active ingredients and their intermediates often affects their chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of compounds, sometimes even resulting in other crystal forms. Generally, amorphous products lack regular crystal structures and often have other defects, such as poor product stability, fine crystals, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, it is essential to improve the various properties of these products, and we need to conduct in-depth research to find new crystal forms with high purity and good chemical stability. Summary of the Invention

[0008] This disclosure provides a methanesulfonate crystal form γ of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.9, 16.4, 18.0, 20.7, and 21.6.

[0009]

[0010] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form γ has characteristic peaks at 2θ angles of 8.9, 12.7, 16.4, 18.0, 18.5, 19.7, 20.7, 21.6, 26.4 and 27.1.

[0011] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form γ has characteristic peaks at 2θ angles of 8.4, 8.9, 9.6, 11.4, 11.8, 12.7, 16.4, 18.0, 18.5, 19.7, 20.7, 21.6, 22.4, 23.1, 23.8, 24.7, 25.6, 26.4, 27.1, 27.8, 30.3, 31.9, 36.5, and 38.4.

[0012] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form γ is as follows: Figure 3 As shown.

[0013] In some embodiments, the molar ratio of the compound of formula (I) in the methanesulfonate crystal form γ to methanesulfonic acid is 3:1 to 1:3, preferably 1:1 or 1:2, more preferably 1:1.

[0014] This disclosure further provides a method for preparing the methanesulfonate crystal form γ of the compound shown in formula (I), the method comprising: mixing the compound shown in formula (I) with solvent I and methanesulfonic acid, wherein solvent I is selected from one or more of acetone, 2-butanone, methyl isobutyl ketone, isopropyl ether, propylene glycol monomethyl ether, acetonitrile, methyl tert-butyl ether, isopropyl acetate, ethyl acetate, and n-heptane, and then slurrying to precipitate crystals.

[0015] The crystal forms obtained in this disclosure were subjected to structural determination and crystal form study by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0016] The crystallization method of the crystal form disclosed herein is conventional, such as volatilization, cooling crystallization, or crystallization at room temperature.

[0017] The starting material used in the crystal form preparation method disclosed herein can be any form of the compound shown in formula (I), including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0018] This disclosure further provides a pharmaceutical composition comprising the mesylate crystal form γ of the compound shown in formula (I), and one or more pharmaceutically acceptable carriers or excipients.

[0019] This disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing the methanesulfonate crystal form γ of the compound shown in formula (I) with one or more pharmaceutically acceptable carriers or excipients.

[0020] This disclosure further provides the use of the mesylate crystal form γ of the compound of formula (I) described herein or the pharmaceutical composition thereof in the preparation of a medicament for inhibiting ATR kinase.

[0021] This disclosure further provides the use of the methanesulfonate crystal form γ of the compound of formula (I) described herein or the pharmaceutical composition in the preparation of a medicament for treating hyperproliferative diseases.

[0022] This disclosure further provides the use of the methanesulfonate crystal form γ of the compound of formula (I) described herein or the pharmaceutical composition in the preparation of a medicament for treating tumor diseases.

[0023] The tumors described in this disclosure are selected from melanoma, brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumors, bladder cancer, and gallbladder cancer.

[0024] In the specification and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this disclosure, definitions and explanations of some related terms are provided below. Furthermore, in the event of any discrepancy between the definitions and explanations of terms provided herein and their commonly understood meanings by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0025] The "pulping" described in this disclosure refers to a purification method that utilizes the characteristic that substances have poor solubility in solvents, but impurities have good solubility in solvents. Pulping purification can remove color, change crystal form, or remove a small amount of impurities.

[0026] The “X-ray powder diffraction pattern or XRPD” described in this disclosure refers to the X-ray powder diffraction pattern obtained when X-rays are incident on an atomic surface of a crystal or part of a crystal sample with a lattice spacing of d at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) with a grazing angle θ.

[0027] The “X-ray powder diffraction pattern or XRPD” described in this disclosure is a pattern obtained by using Cu-Kα radiation in an X-ray powder diffractometer.

[0028] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0029] The “2θ or 2θ angle” mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. The error range of 2θ is ±0.3 or ±0.2 or ±0.1.

[0030] The "interplanar spacing or interplanar spacing (d-value)" described in this disclosure refers to the use of three non-parallel unit vectors a, b, and c to connect adjacent lattice points in a space lattice. These vectors divide the lattice into juxtaposed parallelepiped units, known as the interplanar spacing. The space lattice is divided according to these defined parallelepiped unit lines, resulting in a linear grid called a space lattice or crystal lattice. Lattices and crystal lattices respectively use geometric points and lines to reflect the periodicity of a crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is d / d. Or E.

[0031] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0032] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0033] The term "solvent" or "solvent compound" refers to a pharmaceutically usable solvate formed by the present disclosure of a drug with one or more solvent molecules, non-limiting examples of which include water, ethanol, methyl tert-butyl methyl ether, acetone, n-heptane, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0034] The term "carrier" is used in the context of the drugs disclosed herein, referring to a system that can alter the way a drug enters the body and its distribution within the body, control the rate of drug release, and deliver the drug to the target organ. Drug carrier release and targeting systems can reduce drug degradation and loss, decrease side effects, and improve bioavailability. For example, high-molecular-weight surfactants, due to their unique amphiphilic structure, can self-assemble to form various forms of aggregates, preferably such as micelles, microemulsions, gels, liquid crystals, and vesicles. These aggregates have the ability to encapsulate drug molecules while also exhibiting good membrane permeability, making them excellent drug carriers. Attached Figure Description

[0035] Figure 1 The image shows the XRPD pattern of the methanesulfonate crystal form α of the compound shown in formula (I).

[0036] Figure 2 The image shows the XRPD pattern of the methanesulfonate crystal form β of the compound shown in formula (I).

[0037] Figure 3 The XRPD spectrum of the methanesulfonate crystal form γ of the compound shown in formula (I) is shown.

[0038] Figure 4 The DSC spectrum is shown for the methanesulfonate crystal form α of the compound shown in formula (I).

[0039] Figure 5 The DSC spectrum is shown for the methanesulfonate crystal form β of the compound shown in formula (I).

[0040] Figure 6 The DSC spectrum is shown for the methanesulfonate crystal form γ of the compound shown in formula (I).

[0041] Figure 7 The XRPD pattern of the hydrochloride crystal form a of the compound shown in formula (I) is shown.

[0042] Figure 8 The image shows the XRPD pattern of the sulfate crystal form α of the compound shown in formula (I).

[0043] Figure 9 The image shows the XRPD pattern of p-toluenesulfonate crystal form a of the compound shown in formula (I).

[0044] Figure 10 The XRPD spectrum of the oxalate crystal form a of the compound shown in formula (I) is shown.

[0045] Figure 11 XRPD images of the methanesulfonate γ-crystal form of the compound shown in formula (I) before and after grinding.

[0046] Figure 12 XRPD images of the methanesulfonate α-crystal form of the compound shown in formula (I) before and after grinding.

[0047] Figure 13 XRPD images of the oxalate crystal form a of the compound shown in formula (I) before and after grinding. Detailed Implementation

[0048] The present disclosure will be explained in more detail below with reference to the embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0049] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0050] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0051] Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS Model: Waters ACQuity QdaDetector / Waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0052] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1260DAD, Agilent HPLC 1260VWD, and Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0053] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0054] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0055] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0056] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0057] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0058] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0059] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0060] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0061] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0062] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0063] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0064] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0065] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0066] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0067] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0068] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0069] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0070] THP stands for tetrahydropyranyl.

[0071] Test conditions for the instruments used in the experiment:

[0072] 1. Differential Scanning Calorimeter (DSC)

[0073] Instrument model: Mettler Toledo DSC 3+

[0074] Purge gas: Nitrogen

[0075] Heating rate: 10.0℃ / min

[0076] Temperature range: 25-300℃

[0077] 2. X-ray diffraction (XRPD)

[0078] Instrument Model: BRUKER D8 Discover X-ray Powder Diffractometer

[0079] Rays: Monochromatic Cu-Kα rays

[0080] Scanning mode: θ / 2θ, scanning range (2θ range): 3~50°

[0081] Voltage: 40kV, Current: 40mA

[0082] 3. Ion chromatography

[0083] Instrument Model: DIONEX INTEGRION HPIC Ion Chromatograph (USA)

[0084] Detection method: conductivity; Separation column: Dionex IonPac TM -AS11-HC

[0085] Rinse solution: EGC-500-KOH

[0086] Flow rate: 1.4 ml / min

[0087] Example 1

[0088] A 0.25 mL solution of methyl tert-butyl ether containing approximately 10 mg of the compound shown in formula (I) was mixed with 17.7 μL of a 1.5 mol / L methanesulfonic acid ethanol solution and slurried. The solid was separated by centrifugation and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as methanesulfonate crystal form α, and ion chromatography showed a methanesulfonate ion content of 20.0%. The XRPD spectrum is shown below. Figure 1 As shown in Table 1, the positions of its characteristic peaks are as follows.

[0089] Table 1

[0090]

[0091]

[0092] Example 2

[0093] A 0.25 mL solution of methyl tert-butyl ether containing approximately 10 mg of the compound shown in formula (I) was mixed with 35.4 μL of a 1.5 mol / L methanesulfonic acid ethanol solution and slurried. The solid was separated by centrifugation and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as methanesulfonate crystal form β, and the XRPD spectrum is shown below. Figure 2 As shown in Table 2, the positions of its characteristic peaks are as follows.

[0094] Table 2

[0095]

[0096] Example 3

[0097] A solution of acetone containing approximately 20 mg of the compound shown in formula (I) was mixed with 36 μl of 1.5 mol / L ethyl methanesulfonate solution. After adding 2 mL of n-heptane, a solid precipitated. The solid was separated by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as methanesulfonate crystal form γ. Ion chromatography showed that the methanesulfonate ion content was 22.1%. The XRPD spectrum is shown below. Figure 3 As shown in Table 3, the positions of its characteristic peaks are as follows.

[0098] Table 3

[0099]

[0100]

[0101] Example 4

[0102] 1.0 mL of a solution of isopropyl acetate containing about 20 mg of the compound shown in formula (I) was mixed with 0.5 mL of a 0.11 mol / L solution of isopropyl acetate methanesulfonate to precipitate a solid. The solid was separated by centrifugation and dried under vacuum to obtain the methanesulfonate crystal form γ of the compound shown in formula (I).

[0103] Example 5

[0104] A solution of methyl tert-butyl ether containing approximately 10 mg of the compound shown in formula (I) was mixed with 22.5 μL of 1.2 mol / L hydrochloric acid ethanol solution and slurried. The solid was separated by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as hydrochloride crystal form a, and the XRPD spectrum is shown below. Figure 7 As shown in Table 4, the positions of its characteristic peaks are as follows.

[0105] Table 4

[0106]

[0107]

[0108] Example 6

[0109] A solution of methyl tert-butyl ether containing approximately 10 mg of the compound shown in formula (I) was mixed with 14.7 μL of 1.8 mol / L sulfuric acid ethanol solution and slurried. The solid was separated by centrifugation and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as sulfate α-form, and ion chromatography showed a sulfate ion content of 17.9%. The XRPD spectrum is shown below. Figure 8 As shown in Table 5, the positions of its characteristic peaks are as follows.

[0110] Table 5

[0111]

[0112] Example 7

[0113] 0.4 mL of an MTBE solution containing approximately 10 mg of the compound shown in formula (I) was mixed with 30 μL of a 1 mol / L p-toluenesulfonic acid ethanol solution and slurried. The solid was separated by centrifugation and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form a, and ion chromatography analysis showed that its p-toluenesulfonate ion content was 34.6%. The XRPD spectrum is shown below. Figure 9 As shown in Table 6, the positions of its characteristic peaks are as follows.

[0114] Table 6

[0115]

[0116] Example 8

[0117] A solution of methyl tert-butyl ether containing approximately 10 mg of the compound shown in formula (I) was mixed with 30 μL of 1 mol / L oxalate ethanol solution and slurried. The solid was separated by centrifugation and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as oxalate crystal form a, and ion chromatography showed that its oxalate ion content was 10.9%. The XRPD spectrum is shown below. Figure 10 As shown in Table 7, the positions of its characteristic peaks are as follows.

[0118] Table 7

[0119]

[0120] Example 9

[0121] The methanesulfonate crystal form α, γ, sulfate crystal form α, and p-toluenesulfonate crystal form a were sealed in aluminum foil bags and their stability was investigated under conditions of -20℃, 4℃, 25℃ / 60%RH, and 40℃ / 75%RH, respectively. The results are as follows.

[0122] Table 8

[0123]

[0124] Table 9

[0125]

[0126] Long-term / accelerated stability tests showed that methanesulfonate crystal forms α and γ had good physical stability. In terms of chemical stability, methanesulfonate crystal form γ had good stability, while methanesulfonate crystal form α degraded under 40℃ / 75%RH conditions. Sulfate crystal form α and p-toluenesulfonate crystal form a had poor stability under 40℃ and 75%RH conditions.

[0127] Example 10

[0128] Table 10 compares the properties of the γ-form methanesulfonate with other salt forms. In terms of solubility, melting point, grinding stability, and hygroscopicity, the γ-form methanesulfonate is superior to the other forms.

[0129] Table 10. Comparison of properties of γ-crystal form of methanesulfonate with other salt forms

[0130]

[0131] Note: NA indicates untested.

[0132] Comparative analysis revealed that the residual solvents in hydrochloride crystal form α, sulfate crystal form α, methanesulfonate crystal form α, and methanesulfonate crystal form β exceeded the limits specified in the ICH Q3C-R8 Guideline for various solvents; methanesulfonate crystal form α exhibited severe hygroscopicity; and methanesulfonate crystal form γ showed good grinding stability and did not undergo crystal transformation. Figure 11 Oxalate crystal form a undergoes transformation during grinding. Figure 13 ).

[0133] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A methanesulfonate crystal form γ of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.9, 16.4, 18.0, 20.7 and 21.

6. 。 2. According to claim 1, the X-ray powder diffraction pattern of the methanesulfonate crystal form γ has characteristic peaks at 2θ angles of 8.9, 12.7, 16.4, 18.0, 18.5, 19.7, 20.7, 21.6, 26.4 and 27.

1.

3. The X-ray powder diffraction pattern of the methanesulfonate crystal form γ according to claim 1. Characteristic peaks are found at 2θ angles of 8.4, 8.9, 9.6, 11.4, 11.8, 12.7, 16.4, 18.0, 18.5, 19.7, 20.7, 21.6, 22.4, 23.1, 23.8, 24.7, 25.6, 26.4, 27.1, 27.8, 30.3, 31.9, 36.5, and 38.

4.

4. The crystal form according to claim 1, the X-ray powder diffraction pattern of the methanesulfonate crystal form γ is shown in Figure 3.

5. The crystal form according to any one of claims 1 to 4, wherein the error range of the 2θ angle is ±0.

2.

6. A method for preparing the methanesulfonate crystal form γ of the compound of formula (I) as described in any one of claims 1-5, the method comprising: The compound comprising formula (I), solvent I and methanesulfonic acid are mixed, wherein solvent I is selected from one or more of acetone, 2-butanone, methyl isobutyl ketone, isopropyl ether, propylene glycol monomethyl ether, acetonitrile, methyl tert-butyl ether, isopropyl acetate, ethyl acetate, and n-heptane, and then slurryed and crystallized.

7. A pharmaceutical composition comprising the methanesulfonate crystal form γ of the compound of formula (I) according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

8. A method for preparing a pharmaceutical composition, comprising the step of mixing the methanesulfonate crystal form γ of the compound of formula (I) according to any one of claims 1-5 with one or more pharmaceutically acceptable carriers or excipients.

9. Use of the methanesulfonate crystal form γ of the compound of formula (I) according to any one of claims 1-5 or the pharmaceutical composition of claim 7 in the preparation of a medicament for inhibiting ATR kinase.

10. Use of the methanesulfonate crystal form γ of the compound of formula (I) according to any one of claims 1-5 or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating hyperproliferative diseases.

11. Use of the methanesulfonate crystal form γ of the compound of formula (I) according to any one of claims 1-5 or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating tumor diseases.

12. The use according to claim 11, wherein the tumor is selected from brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, sarcoma, uterine cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumors, bladder cancer, and gallbladder cancer.

13. The use according to claim 11, wherein the tumor is selected from melanoma, neuroblastoma, glioma, bone cancer, and endometrial cancer.

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