Crystal form of pharmaceutically acceptable salt of 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 crystalline forms of pharmaceutically acceptable salts of a compound of formula (I). The novel crystal form disclosed by the invention has good physicochemical properties. # imgabs0 #

Description

A crystalline form of a pharmaceutically acceptable salt of a pyrazoloheteroaryl derivative

[0001] This application claims priority to Chinese Patent Application No. 2022114519333, filed on November 21, 2022. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of a pyrazoloheteroaryl derivative, and specifically to a crystalline form of a pharmaceutically acceptable salt of a compound represented by formula (I). Background Art

[0003] Thousands of DNA damages occur daily in both normal and tumor cells. This makes DNA damage repair crucial for maintaining genomic stability and cell survival. Compared to normal cells, tumor cells experience greater replication stress, carry more endogenous DNA damage, and often exhibit deficiencies in one or more DNA damage repair pathways. This makes tumor cell survival even more dependent on the smooth functioning of DNA damage repair.

[0004] Homologous recombination repair is the primary mechanism for repairing double-strand breaks in DNA. Using the homologous sequence of the intact sister chromatid as a template, the damaged DNA sequence is replicated, resulting in precise DNA repair. This repair process primarily occurs during the G2 and S phases of the cell. ATR is a key enzyme in the homologous recombination repair pathway and belongs to the PIKK family. When the ATR / ATRIP complex binds to damaged DNA coated with replication protein A (RPA), ATR becomes activated and phosphorylates downstream proteins such as Chk1 and SMARCAL, regulating various cell cycle checkpoints, causing cell cycle arrest; ensuring the stability of damaged DNA; and increasing dNTP concentrations, thereby facilitating DNA damage repair. DNA damage repair occurring during the S phase of the cell cycle is primarily accomplished by the ATR pathway, demonstrating the importance of ATR for cell proliferation. Analysis of clinical tumor samples has shown elevated ATR expression in various tumor tissues, including gastric, liver, colorectal, ovarian, and pancreatic cancers. Furthermore, high ATR levels are associated with lower survival rates in patients with ovarian and pancreatic cancers. This suggests that ATR is an important target for cancer therapy.

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

[0006] The crystal structure of pharmaceutical active ingredients and their intermediates often affects their chemical stability. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms. Generally speaking, amorphous products lack a regular crystal structure and often exhibit other drawbacks, such as poor stability, fine crystallization, difficulty filtering, agglomeration, and poor flowability. Therefore, improving the properties of these products is essential, requiring in-depth research to identify new crystal forms with high purity and excellent chemical stability.

[0007] Summary of the Invention

[0008] The present disclosure provides a mesylate crystal form γ of a compound represented by formula (I), which has characteristic peaks at 2θ angles of 8.9, 16.4, 18.0, 20.7 and 21.6.

[0009] In certain embodiments, the X-ray powder diffraction pattern of the mesylate salt 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.

[0010] In certain embodiments, the mesylate salt form γ has an X-ray powder diffraction pattern having 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.

[0011] In certain embodiments, the X-ray powder diffraction pattern of the mesylate salt crystalline form γ is shown in FIG3 .

[0012] In certain embodiments, the molar ratio of the compound represented by formula (I) to methanesulfonic acid in the mesylate salt form γ is 3:1-1:3, preferably 1:1 or 1:2, and more preferably 1:1.

[0013] The present disclosure further provides a method for preparing a crystalline form γ of a methanesulfonate salt of a compound represented by formula (I), the method comprising: mixing a compound represented by formula (I) with a solvent I and methanesulfonic acid, wherein the 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 slurrying and crystallizing.

[0014] The structure and crystal form of the crystal obtained in the present invention were determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0015] The crystallization method of the crystal form disclosed herein is conventional, such as evaporation crystallization, cooling crystallization or crystallization at room temperature.

[0016] The starting material used in the method for preparing the crystal form disclosed herein can be any form of the compound represented by formula (I), including but not limited to: amorphous form, any crystal form, hydrate, solvate, etc.

[0017] The present disclosure further provides a pharmaceutical composition comprising the mesylate crystal form γ of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers or excipients.

[0018] The present disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing the mesylate crystal form γ of the compound represented by formula (I) with one or more pharmaceutically acceptable carriers or excipients.

[0019] The present disclosure further provides use of the mesylate crystal form γ of the compound represented by formula (I) or the pharmaceutical composition described in the present disclosure in the preparation of a drug for inhibiting ATR kinase.

[0020] The present disclosure further provides use of the mesylate crystal form γ of the compound represented by formula (I) or the pharmaceutical composition described in the present disclosure in the preparation of a drug for treating a hyperproliferative disease.

[0021] The present disclosure further provides use of the mesylate crystal form γ of the compound represented by formula (I) or the pharmaceutical composition described in the present disclosure in the preparation of a drug for treating tumor diseases.

[0022] The tumor described in the present disclosure is selected from melanoma, brain tumor, 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 tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.

[0023] In the specification and claims of the application, unless otherwise indicated, the scientific and technical terms used herein have the meaning commonly understood by those skilled in the art. However, in order to better understand the disclosure, the definition and explanation of some related terms are provided below. In addition, when the definition and explanation of the term provided in the application are inconsistent with the meaning commonly understood by those skilled in the art, the definition and explanation of the term provided in the application shall prevail.

[0024] The "beating" mentioned in the present disclosure refers to a purification method that utilizes the property that a substance has poor solubility in a solvent but impurities have good solubility in a solvent. Beating purification can remove color, change the crystal form or remove a small amount of impurities.

[0025] The "X-ray powder diffraction pattern or XRPD" described in the present disclosure refers to the Bragg formula 2d sinθ=nλ (wherein λ is the wavelength of the X-ray, the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1), when the X-ray is incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) on an atomic plane with a lattice plane spacing d of a crystal or a partial crystal sample, the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0026] The "X-ray powder diffraction pattern or XRPD" referred to in the present disclosure is a pattern obtained by using Cu-Kα radiation in an X-ray powder diffractometer.

[0027] The "differential scanning calorimetry or DSC" mentioned in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0028] The “2θ or 2θ angle” mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.3 or ±0.2 or ±0.1.

[0029] The "interplanar spacing or interplanar spacing (d value)" mentioned in the present disclosure refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, which are called space grids or lattices. The lattice and lattice respectively use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Or angstrom.

[0030] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0031] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0032] The term "solvate" or "solvate compound" refers to a pharmaceutically acceptable solvate formed between a drug of the present disclosure and one or more solvent molecules. Non-limiting examples of solvent molecules include water, ethanol, methyl tert-butyl methyl ether, acetone, n-heptane, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0033] The term "carrier" as used in the context of the present invention refers to a system that can alter the way a drug enters the human body and its distribution within the body, control the rate of drug release, and deliver the drug to a targeted organ. Drug carrier release and targeting systems can reduce drug degradation and loss, reduce side effects, and improve bioavailability. For example, polymeric surfactants that can be used as carriers can self-assemble to form various forms of aggregates due to their unique amphiphilic structure, preferably micelles, microemulsions, gels, liquid crystals, vesicles, and the like. These aggregates have the ability to encapsulate drug molecules while also having good membrane permeability, making them excellent drug carriers. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 is an XRPD pattern of the mesylate salt form α of the compound represented by formula (I).

[0035] FIG2 is an XRPD pattern of the mesylate salt form β of the compound represented by formula (I).

[0036] FIG3 is an XRPD pattern of the mesylate salt form γ of the compound represented by formula (I).

[0037] FIG4 is a DSC spectrum of the mesylate crystal form α of the compound represented by formula (I).

[0038] FIG5 is a DSC spectrum of the mesylate crystalline form β of the compound represented by formula (I).

[0039] FIG6 is a DSC spectrum of the mesylate crystal form γ of the compound represented by formula (I).

[0040] FIG7 is an XRPD pattern of the hydrochloride salt form a of the compound represented by formula (I).

[0041] FIG8 is an XRPD pattern of the sulfate crystal form α of the compound represented by formula (I).

[0042] FIG9 is an XRPD pattern of the p-toluenesulfonate crystalline form a of the compound represented by formula (I).

[0043] FIG10 is an XRPD pattern of oxalate salt form a of the compound represented by formula (I).

[0044] FIG11 is an XRPD pattern of the γ-form of the mesylate salt of the compound represented by formula (I) before and after grinding.

[0045] FIG12 is an XRPD pattern of the α-crystalline form of the mesylate salt of the compound represented by formula (I) before and after grinding.

[0046] FIG13 is an XRPD pattern of the oxalate salt form a of the compound represented by formula (I) before and after grinding. DETAILED DESCRIPTION

[0047] The present disclosure will be explained in more detail below with reference to 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 essence and scope of the present disclosure.

[0048] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of 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), and tetramethylsilane (TMS) was used as the internal standard.

[0049] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0050] Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS Model: Waters ACQuity Qda Detector / Waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0051] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1260DAD, Agilent HPLC 1260VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0052] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0053] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0054] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0055] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0056] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0057] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0058] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0059] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0060] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0061] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0062] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0063] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0064] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0065] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0066] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0067] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0068] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography 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 compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0069] THP is tetrahydropyranyl.

[0070] Test conditions of the instruments used in the test:

[0071] 1. Differential Scanning Calorimeter (DSC)

[0072] Instrument model: Mettler Toledo DSC 3+

[0073] Purge gas: nitrogen

[0074] Heating rate: 10.0℃ / min

[0075] Temperature range: 25-300℃

[0076] 2. X-ray Powder Diffraction (XRPD)

[0077] Instrument model: BRUKER D8 Discover X-ray powder diffractometer

[0078] Rays: Monochromatic Cu-Kα rays

[0079] Scanning mode: θ / 2θ, scanning range (2θ range): 3 to 50°

[0080] Voltage: 40kV, Current: 40mA

[0081] 3. Ion chromatography

[0082] Instrument model: American DIONEX INTEGRION HPIC ion chromatograph

[0083] Detection method: conductivity; separation column: Dionex IonPac TM -AS11-HC

[0084] Eluent: EGC-500-KOH

[0085] Flow rate: 1.4 ml / min

[0086] Example 1

[0087] 0.25 ml of a methyl tert-butyl ether solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 17.7 μL of a 1.5 mol / L methanesulfonic acid ethanol solution, slurried, and the solid separated by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as mesylate crystalline form α. Ion chromatography analysis revealed a methanesulfonate ion content of 20.0%. The XRPD spectrum is shown in Figure 1 , and the positions of the characteristic peaks are shown in Table 1 .

[0088] Table 1

[0089] Example 2

[0090] 0.25 ml of a methyl tert-butyl ether solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 35.4 μL of a 1.5 mol / L methanesulfonic acid ethanol solution, slurried, and the solid separated by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as the mesylate salt, Form β. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 2.

[0091] Table 2

[0092] Example 3

[0093] 1.0 ml of an acetone solution containing approximately 20 mg of the compound represented by formula (I) was mixed with 36 μl of a 1.5 mol / L ethyl methanesulfonic acid solution in ethyl acetate. 2 ml of n-heptane was added to precipitate a solid, which was then separated by centrifugation and dried in vacuo to obtain the product. X-ray powder diffraction analysis identified the product as mesylate crystalline form γ. Ion chromatography analysis revealed a mesylate ion content of 22.1%. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 3.

[0094] Table 3

[0095] Example 4

[0096] 1.0 ml of an isopropyl acetate solution containing approximately 20 mg of the compound represented by formula (I) was mixed with 0.5 mL of a 0.11 mol / L isopropyl methanesulfonate solution to precipitate a solid, which was separated by centrifugation and dried in vacuo to obtain the mesylate crystalline form γ of the compound represented by formula (I).

[0097] Example 5

[0098] 0.25 ml of a methyl tert-butyl ether solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 22.5 μL of a 1.2 mol / L hydrochloric acid-ethanol solution, slurried, and the solid separated by centrifugation. The product was then dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as hydrochloride Form a. The XRPD spectrum is shown in Figure 7 , and the positions of its characteristic peaks are shown in Table 4.

[0099] Table 4

[0100] Example 6

[0101] 0.25 ml of a methyl tert-butyl ether solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 14.7 μL of a 1.8 mol / L ethanolic sulfuric acid solution, slurried, and the solid separated by centrifugation. The product was then dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as sulfate salt crystalline form α. Ion chromatography analysis revealed a sulfate ion content of 17.9%. The XRPD spectrum is shown in Figure 8 , and the positions of the characteristic peaks are shown in Table 5.

[0102] Table 5

[0103] Example 7

[0104] 0.4 ml of an MTBE solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 30 μL of a 1 mol / L p-toluenesulfonic acid ethanol solution, slurried, and the solid separated by centrifugation. The product was then dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as p-toluenesulfonate Form a. Ion chromatography analysis revealed a p-toluenesulfonate ion content of 34.6%. The XRPD spectrum is shown in FIG9 , and the positions of the characteristic peaks are shown in Table 6.

[0105] Table 6

[0106] Example 8

[0107] 0.4 mL of a methyl tert-butyl ether solution containing approximately 10 mg of the compound represented by formula (I) was mixed with 30 μL of a 1 mol / L ethanolic oxalic acid solution, slurried, and the solid separated by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as oxalate Form a. Ion chromatography analysis revealed an oxalate ion content of 10.9%. The XRPD spectrum is shown in Figure 10 , and the positions of the characteristic peaks are shown in Table 7.

[0108] Table 7

[0109] Example 9

[0110] Methanesulfonate crystal forms α and γ, sulfate crystal form α, and p-toluenesulfonate crystal form a were sealed in aluminum foil bags and placed under -20°C, 4°C, 25°C / 60% RH, and 40°C / 75% RH conditions for stability testing. The results are as follows.

[0111] Table 8

[0112] Table 9

[0113] Long-term / accelerated stability experiments show that the physical stability of the mesylate salt forms α and γ is good. In terms of chemical stability, the mesylate salt form γ is stable. The mesylate salt form α degrades under 40°C / 75% RH conditions. The sulfate salt form α and the p-toluenesulfonate salt form a have poor stability under 40°C and 75% RH conditions.

[0114] Example 10

[0115] The properties of the γ-methanesulfonate crystal form and other salt forms are compared in Table 10. In terms of residual solubility, melting point, grinding stability, and hygroscopicity, the γ-methanesulfonate crystal form is superior to other crystal forms.

[0116] Table 10. Comparison of properties of the γ-methanesulfonate crystal form with other salt forms Note: NA means not tested.

[0117] A comparison revealed that the residual solvents in hydrochloride Form a, sulfate Form α, methanesulfonate Form α, and methanesulfonate Form β exceeded the limits for each type of solvent specified in the ICH Q3C-R8 Guideline; methanesulfonate Form α was severely hygroscopic; methanesulfonate Form γ had good grinding stability and did not undergo crystal transformation (Figure 11), while oxalate Form a underwent crystal transformation during grinding (Figure 13).

[0118] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may 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 crystalline form γ of a methanesulfonate salt of a compound represented by formula (I), having an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 8.9, 16.4, 18.0, 20.7 and 21.6, 2. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern of the mesylate salt crystalline 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, preferably having 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, more preferably the X-ray powder diffraction pattern of the mesylate salt crystalline form γ is shown in Figure 3.

3. The crystal form according to claim 1 or 2, wherein the error range of the 2θ angle is ±0.

2.

4. A method for preparing the mesylate crystalline form γ of the compound of formula (I) according to any one of claims 1 to 3, the method comprising: The compound represented by 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 the mixture is slurried for crystallization.

5. A pharmaceutical composition comprising the mesylate crystalline form γ of the compound of formula (I) according to any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers or excipients.

6. A method for preparing a pharmaceutical composition, comprising the step of mixing the mesylate crystalline form γ of the compound of formula (I) according to any one of claims 1 to 3 with one or more pharmaceutically acceptable carriers or excipients.

7. Use of the mesylate crystal form γ of the compound of formula (I) according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for inhibiting ATR kinase.

8. Use of the mesylate crystalline form γ of the compound of formula (I) according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating a hyperproliferative disease.

9. Use of the mesylate crystalline form γ of the compound of formula (I) according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating a tumor disease; preferably, the tumor is selected from melanoma, brain tumor, 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 tumor, bladder cancer and gallbladder cancer.

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