Crystal forms and uses of acid addition salts of ATR inhibitors

Abstract

This application discloses a crystal form of an acid addition salt of an ATR inhibitor, its preparation method, and its uses. The crystal form of the acid addition salt includes at least one of the hydrogen sulfate and methanesulfonate crystal forms of the compound shown in formula (I). The crystal form of the acid addition salt of this application has advantages such as strong preparation stability, high solubility, and low hygroscopicity, making it more suitable for formulation preparation. (I)

Description

Technical Field

[0001] This application belongs to the field of biopharmaceutical technology, specifically relating to the crystal form of an acid addition salt of an ATR inhibitor, its preparation method, and its uses. Background Technology

[0002] ATR, or ataxia-telangiectasia and Rad3-associated kinase, is a core key kinase in the DNA damage response (DDR). It is responsible for sensing replication stress and initiating DNA repair. Inhibition of ATR interferes with downstream signal transduction, leading to apoptosis. It can also induce apoptosis by phosphorylating p53, a tumor suppressor factor. Currently, ATR inhibitors are a hot topic in anti-tumor drug development. Potential indications for ATR inhibitors include solid tumors and some hematologic malignancies with DNA damage repair (DDR) deficiencies, particularly refractory tumors resistant to platinum-based, PARP-inhibited, and immunotherapies.

[0003] Compound (I) is a novel ATR inhibitor, classified as a Class 1.1 innovative drug. Currently, its solid-state information, such as its crystal form, is not publicly available. Drugs with the same compound structure may exhibit polymorphism, and the physicochemical properties of different crystal forms may differ significantly, such as appearance, density, hardness, melting point, solubility, stability, dissolution rate, and bioavailability. This phenomenon is particularly evident in oral solid dosage forms. It is essential to find a stable crystal form suitable for industrial production and formulation. However, the existence of polymorphisms in a compound, as well as the number and properties of polymorphs, are unpredictable.

[0004] (I) Summary of the Invention This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides a crystal form of an acid addition salt of an ATR inhibitor.

[0005] This application is based on the following discoveries of the inventors: Through experiments, the inventors discovered a series of free base crystal forms and found a stable free base crystal form with good stability and low hygroscopicity, but its solubility was low. In order to further find a solid form with more suitable solubility, the inventors conducted salt form screening and obtained a variety of salts, including hydrochloride. The solubility, stability, hygroscopicity and crystallinity of the salts were evaluated, and it was found that their stability was not ideal. The inventors further explored the acid salts and unexpectedly found that the solubility of hydrogen sulfate crystal form A and methanesulfonate crystal form A was significantly improved compared with the free base, and the stability was good with low hygroscopicity, which is suitable for formulation development.

[0006] In a first aspect of this application, a pharmaceutically acceptable acid addition salt of a compound represented by formula (I) is provided, said acid addition salt comprising at least one of a hydrogen sulfate and a methanesulfonate; (I).

[0007] According to embodiments of this application, the above-mentioned acid addition salt may further include at least one of the following technical features: In an optional embodiment of this application, the acid addition salt is the hydrogen sulfate salt of the compound shown in formula (I), and the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(0.5~3).

[0008] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(1.0~1.5).

[0009] In an optional embodiment of this application, the acid addition salt is a methanesulfonate of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to methanesulfonic acid is 1:(0.5~3).

[0010] In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to methanesulfonic acid is 1:(1.0~1.5).

[0011] In a second aspect of this application, this application provides a pharmaceutically acceptable crystal form of an acid addition salt of a compound represented by formula (I), the crystal form of which includes at least one of the hydrogen sulfate crystal form and the methanesulfonate crystal form of the compound represented by formula (I); (I).

[0012] According to embodiments of this application, the crystal form of the above-mentioned acid addition salt may further include at least one of the following technical features: In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the diffraction peaks of its X-ray powder diffraction pattern at the 2θ angle include: 4.8±0.2°, 14.2±0.2°, 18.9±0.2° and 23.7±0.2°.

[0013] In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the diffraction peaks of its X-ray powder diffraction pattern at the 2θ angle include: 4.8±0.2°, 14.2±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.8±0.2° and 28.3±0.2°.

[0014] In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the diffraction peaks at the 2θ angle in its X-ray powder diffraction pattern include: 4.8±0.2°, 14.2±0.2°, 15.0±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.8±0.2°, 25.9±0.2°, 26.5±0.2°, 28.3±0.2°, and 28.5±0.2°.

[0015] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), and the DSC diagram of the bisulfate crystal form contains an endothermic peak at 230.3℃±3℃.

[0016] In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the TGA of the hydrogen sulfate crystal form has a weight loss of about 0.1% ± 0.5% between 30℃ ± 3℃ and 150℃ ± 3℃.

[0017] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0018] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 2 The DSC diagram is shown.

[0019] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 3 The TGA diagram is shown.

[0020] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the diffraction peaks of its X-ray powder diffraction pattern at the 2θ angle include: 5.5±0.2°, 9.0±0.2°, 18.0±0.2° and 18.1±0.2°.

[0021] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the diffraction peaks of its X-ray powder diffraction pattern at the 2θ angle include: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2° and 18.1±0.2°.

[0022] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the diffraction peaks at the 2θ angle in its X-ray powder diffraction pattern include: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2°, 18.1±0.2°, 21.6±0.2°, 21.7±0.2°, 22.0±0.2°, 22.2±0.2°, 24.4±0.2°, 27.5±0.2°, and 36.9±0.2°.

[0023] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the DSC diagram of the methanesulfonate crystal form contains an endothermic peak at 177.9℃±3℃.

[0024] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the TGA of the methanesulfonate crystal form has a weight loss of about 0.1% ± 0.5% between 30℃ ± 3℃ and 150℃ ± 3℃.

[0025] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 4 The X-ray powder diffraction pattern shown.

[0026] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 5 The DSC diagram is shown.

[0027] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 6 The TGA diagram is shown.

[0028] In a third aspect of this application, a method is provided for preparing a pharmaceutically acceptable crystalline form of an acid addition salt of the compound represented by formula (I) as described in the second aspect. According to an embodiment of this application, the preparation method comprises: reacting the compound represented by formula (I) with an acid to crystallize and obtain the crystalline form of the acid addition salt; the acid comprising at least one of hydrogen sulfate and methanesulfonic acid; (I).

[0029] According to embodiments of this application, the above preparation method may further include at least one of the following technical features: In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to the acid is 1:(0.5~3).

[0030] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to the acid is 1:(1.0~1.5).

[0031] In one alternative embodiment of this application, the solvent in the crystallization reaction is selected from acetone.

[0032] In one optional embodiment of this application, the temperature of the crystallization reaction is 0°C to 5°C.

[0033] In one optional embodiment of this application, the crystallization reaction takes 1 h to 2 h.

[0034] In a fourth aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the acid addition salt described in the first aspect, the crystalline form of the acid addition salt described in the second aspect, or the crystalline form of the acid addition salt prepared according to the preparation method described in the third aspect.

[0035] According to embodiments of this application, the pharmaceutical composition further includes pharmaceutically acceptable excipients, carriers, and mediators.

[0036] In a fifth aspect of this application, the use of the acid addition salt described in the first aspect, the crystal form of the acid addition salt described in the second aspect, the crystal form of the acid addition salt prepared according to the preparation method described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of an ATR inhibitor or a medicament for the prevention and / or treatment of ATR-related diseases is provided.

[0037] According to embodiments of this application, the ATR-related diseases are selected from cancer, age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, diabetic macular edema, progressive ossifying fibrous dysplasia, inflammation, angiogenesis-related diseases, and bacterial infections.

[0038] Beneficial effects: 1) The acid addition salts and their crystal forms of this application have good physicochemical stability; the hydrogen sulfate crystal form A and the methanesulfonate crystal form A can maintain physical and chemical stability under high temperature of 60℃, high humidity of 92.5%RH and light conditions, and the crystal form remains unchanged after being placed under accelerated conditions of 40℃ / 75%RH for 3 months, and the related substances do not change significantly, indicating good physicochemical stability; especially compared with other crystal forms, their physical and chemical stability is significantly better; 2) The acid addition salts and their crystal forms of this application have low hygroscopicity, making them suitable for pharmaceutical manufacturing; 3) The acid addition salts of this application and their crystal forms (especially the hydrogen sulfate crystal form A) showed good exposure levels in animal pharmacokinetic studies, meeting the requirements for in vivo drug exposure. 4) The preparation method of this application is relatively simple, the solvent is relatively green and environmentally friendly, and the yield is relatively high, making it suitable for industrial scale-up production.

[0039] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0040] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is the XRPD image of hydrogen sulfate crystal form A in Example 1 of this application; Figure 2 This is the DSC diagram of hydrogen sulfate crystal form A in Example 1 of this application; Figure 3 This is a TGA image of hydrogen sulfate crystal form A in Example 1 of this application; Figure 4 This is the XRPD image of methanesulfonate crystal form A in Example 2 of this application; Figure 5 This is the DSC diagram of methanesulfonate crystal form A in Example 1 of this application; Figure 6 This is a TGA image of methanesulfonate crystal form A in Example 1 of this application; Figure 7 This is the XRPD image of hydrochloride crystal form A in Example 3 of this application; Figure 8 This is the XRPD image of phosphate crystal form A in Example 3 of this application; Figure 9 This is the XRPD image of p-toluenesulfonate crystal form A in Example 3 of this application; Figure 10 This is the XRPD image of hydrobromide crystal form A in Example 3 of this application; Figure 11 This is the XRPD image of benzenesulfonate crystal form A in Example 3 of this application; Figure 12 This is the XRPD image of citrate crystal form A in Example 3 of this application; Figure 13 This is the XRPD image of fumarate crystal form B in Example 3 of this application; Figure 14 This is the XRPD image of L-tartrate crystal form A in Example 3 of this application; Figure 15 This is the XRPD image of salicylate crystal form A in Example 3 of this application; Figure 16 This is the XRPD image of oxalate crystal form A in Example 3 of this application; Figure 17 This is the XRPD image of maleate crystal form A in Example 3 of this application; Figure 18 This is the XRPD image of L-camphor sulfonate crystal form A in Example 3 of this application; Figure 19 This is the XRPD image of benzoate crystal form A in Example 3 of this application; Figure 20 This is the XRPD image of cinnamate crystal form A in Example 3 of this application; Figure 21 This is the XRPD image of L-malate crystal form A in Example 3 of this application; Figure 22 The XRPD diagram of the free alkali crystal form of compound (I) in Example 2 of this application is shown. Detailed Implementation

[0041] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0042] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0043] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0044] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0045] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0046] In this document, the term "acid addition salt of the compound represented by formula (I)" refers to the salt formed by the reaction of the compound represented by formula (I) (free base) with various suitable organic or inorganic acids, including but not limited to the hydrogen sulfate, methanesulfonate, hydrochloride, phosphate, hydrobromide, p-toluenesulfonate, fumarate, tartrate, benzenesulfonate, etc., described in this application. In this document, the term "crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure. A crystalline form can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template; crystallization on polymers, for example, in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0047] In this document, the term "solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this application include, but are not limited to, water, acetic acid, ethyl acetate, acetone, acetonitrile, methanol, toluene, isopropanol, tetrahydrofuran, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, mixtures thereof, etc.

[0048] In this document, the term "antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents may include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they may be the same liquid as the solvent but at a different temperature, or they may be a different liquid from the solvent.

[0049] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0050] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra mainly depend on the structure of the crystal form, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of this application has XRPD spectra with certain peak positions, which are basically as shown in the XRPD spectra provided in the accompanying drawings. Meanwhile, the measurement of 2θ in XRPD spectra can have experimental errors; the measurement of 2θ in XRPD spectra may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute.

[0051] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak in the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the DSC chart of the crystal form described in this application has characteristic peak positions, which are essentially as shown in the DSC chart provided in the accompanying drawings. However, DSC spectra can have experimental errors; the peak positions and peak values ​​of DSC spectra may differ slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in DSC cannot be considered absolute. Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance as a function of temperature under programmed control. It is suitable for examining the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown in the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and different samples. In the context of this application, 2θ values ​​in X-ray powder diffraction patterns are in degrees (°).

[0052] In this document, the term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in its figure.

[0053] In the context of this application, when the words “approximately” or “about” are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, to those skilled in the art, the terms “approximately” or “about” mean within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / –1%, N+ / –2%, N+ / –3%, N+ / –5%, N+ / –7%, N+ / –8%, or N+ / –10% is explicitly disclosed, where “+ / –” means addition or subtraction.

[0054] Unless otherwise indicated, the structural formulas described in this application include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compound of this application, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), are within the scope of this application.

[0055] This application discloses the crystal form of an acid addition salt of an ATR inhibitor, its preparation method, and its uses, which will be described in detail below.

[0056] Pharmaceutically acceptable acid addition salts of the compounds represented by formula (I) In a first aspect of this application, a pharmaceutically acceptable acid addition salt of a compound represented by formula (I) is provided, said acid addition salt comprising at least one of a hydrogen sulfate and a methanesulfonate; (I).

[0057] The acid addition salt of this application has the advantages of strong preparation stability, high solubility and low hygroscopicity, which is more conducive to the preparation of formulations; and it shows good exposure in animal pharmacokinetic studies, meeting the requirements for drug exposure in vivo.

[0058] According to embodiments of this application, the above-mentioned acid addition salt may further include at least one of the following technical features: In an optional embodiment of this application, the acid addition salt is the hydrogen sulfate salt of the compound shown in formula (I), and the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(0.5~3).

[0059] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(0.5~1.5).

[0060] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(1.0~1.5).

[0061] In one optional embodiment of this application, the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0062] In an optional embodiment of this application, the acid addition salt is a methanesulfonate of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to methanesulfonic acid is 1:(0.5~3).

[0063] In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to methanesulfonic acid is 1:(0.5~1.5).

[0064] In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to methanesulfonic acid is 1:(1.0~1.5).

[0065] In one optional embodiment of this application, the molar ratio of the compound shown in formula (I) to methanesulfonic acid is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0066] The pharmaceutically acceptable crystalline form of the acid addition salt of the compound represented by formula (I) In a second aspect of this application, this application provides a pharmaceutically acceptable crystal form of an acid addition salt of a compound represented by formula (I), the crystal form of which includes at least one of the hydrogen sulfate crystal form and the methanesulfonate crystal form of the compound represented by formula (I); (I).

[0067] The crystal form of the acid addition salt of this application has the advantages of strong preparation stability, high solubility and low hygroscopicity, which is more conducive to the preparation of formulations; and it shows good exposure in animal pharmacokinetic studies, meeting the requirements for drug exposure in vivo.

[0068] Furthermore, this application evaluated the solubility, stability, hygroscopicity, and crystallinity of 17 salts, and found that the solubility of the crystal forms of the above-mentioned acid addition salts (such as hydrogen sulfate crystal form A and methanesulfonate crystal form A) was significantly improved compared with the free base, and they had good stability and low hygroscopicity, making them suitable for formulation development; in addition, they showed good exposure levels in animal pharmacokinetic studies, which were significantly improved compared with the free base, meeting the requirements for drug exposure levels in vivo.

[0069] According to embodiments of this application, the crystal form of the above-mentioned acid addition salt may further include at least one of the following technical features: In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 4.8±0.2°, 14.2±0.2°, 18.9±0.2°, and 23.7±0.2°. An exemplary reference is made to the hydrogen sulfate crystal form A of the compound shown in formula (I).

[0070] In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 4.8±0.2°, 14.2±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.8±0.2°, and 28.3±0.2°. An exemplary reference is made to the hydrogen sulfate crystal form A of the compound shown in formula (I).

[0071] In an optional embodiment of this application, the crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 4.8±0.2°, 14.2±0.2°, 15.0±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.8±0.2°, 25.9±0.2°, 26.5±0.2°, 28.3±0.2°, and 28.5±0.2°. An exemplary reference is made to the hydrogen sulfate crystal form A of the compound shown in formula (I).

[0072] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), and the DSC spectrum of the bisulfate crystal form contains an endothermic peak at 230.3℃ ± 3℃. An exemplary reference is made to the bisulfate crystal form A of the compound shown in formula (I).

[0073] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), wherein the TGA of the bisulfate crystal form exhibits a weight loss of approximately 0.1% ± 0.5% between 30°C ± 3°C and 150°C ± 3°C. An exemplary reference is made to bisulfate crystal form A of the compound shown in formula (I).

[0074] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0075] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 2 The DSC diagram is shown.

[0076] In an optional embodiment of this application, the crystal form of the acid addition salt is the bisulfate crystal form of the compound shown in formula (I), the bisulfate crystal form having substantially the following characteristics: Figure 3 The TGA diagram is shown.

[0077] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 5.5±0.2°, 9.0±0.2°, 18.0±0.2°, and 18.1±0.2°. An exemplary reference is made to the methanesulfonate crystal form A of the compound shown in formula (I).

[0078] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2°, and 18.1±0.2°. The methanesulfonate crystal form A of the compound shown in formula (I) is exemplarily referenced.

[0079] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ including: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2°, 18.1±0.2°, 21.6±0.2°, 21.7±0.2°, 22.0±0.2°, 22.2±0.2°, 24.4±0.2°, 27.5±0.2°, and 36.9±0.2°. The methanesulfonate crystal form A of the compound shown in formula (I) is exemplarily referenced.

[0080] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the DSC spectrum of the methanesulfonate crystal form contains an endothermic peak at 177.9 °C ± 3 °C. An exemplary reference is made to methanesulfonate crystal form A of the compound shown in formula (I).

[0081] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), wherein the TGA impurities of the methanesulfonate crystal form exhibit a weight loss of approximately 0.1% ± 0.5% between 30°C ± 3°C and 150°C ± 3°C. An exemplary reference is made to methanesulfonate crystal form A of the compound shown in formula (I).

[0082] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 2 The X-ray powder diffraction pattern shown.

[0083] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 5 The DSC diagram is shown.

[0084] In an optional embodiment of this application, the crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), the methanesulfonate crystal form having substantially the following characteristics: Figure 6 The TGA diagram is shown.

[0085] Preparation method In a third aspect of this application, a method is provided for preparing a pharmaceutically acceptable crystalline form of an acid addition salt of the compound represented by formula (I) as described in the second aspect. According to an embodiment of this application, the preparation method comprises: reacting the compound represented by formula (I) with an acid to crystallize and obtain the crystalline form of the acid addition salt; the acid comprising at least one of hydrogen sulfate and methanesulfonic acid; (I).

[0086] The preparation method described in this application is relatively simple, uses relatively green and environmentally friendly solvents, and has a high yield, making it suitable for industrial-scale production.

[0087] According to embodiments of this application, the above preparation method may further include at least one of the following technical features: In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to the acid is 1:(0.5~3).

[0088] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to the acid is 1:(0.5~1.5).

[0089] In an optional embodiment of this application, the molar ratio of the compound shown in formula (I) to the acid is 1:(1.0~1.5).

[0090] In an optional embodiment of this application, the molar ratio of the compound represented by formula (I) to the acid is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0091] In one alternative embodiment of this application, the solvent in the crystallization reaction is selected from acetone.

[0092] In one optional embodiment of this application, the temperature of the crystallization reaction is 0°C to 5°C.

[0093] In one optional embodiment of this application, the crystallization reaction takes 1 h to 2 h.

[0094] Pharmaceutical Composition In a fourth aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the acid addition salt described in the first aspect, the crystalline form of the acid addition salt described in the second aspect, or the crystalline form of the acid addition salt prepared according to the preparation method described in the third aspect.

[0095] According to embodiments of this application, the above-described pharmaceutical composition may further include at least one of the following technical features: In an optional embodiment of this application, the pharmaceutical composition further includes pharmaceutically acceptable excipients, carriers, and mediators.

[0096] In one optional embodiment of this application, pharmaceutically acceptable excipients refer to pharmaceutical excipients that are conventional in the pharmaceutical field, such as absorption enhancers, isotonic agents, stabilizers, regulators, etc.

[0097] In one alternative embodiment of this application, a pharmaceutically acceptable carrier refers to a drug carrier conventional in the pharmaceutical field.

[0098] In one alternative embodiment of this application, pharmaceutically acceptable mediators refer to pharmaceutical mediators conventional in the pharmaceutical field, such as solutions (e.g., water).

[0099] In one alternative embodiment of this application, examples of suitable pharmaceutically acceptable carriers, excipients, and mediators are well known in the art. Pharmaceutical compositions comprising such carriers, excipients, and mediators can be formulated using known conventional methods.

[0100] In an optional embodiment of this application, the pharmaceutical composition of this application may also contain other active ingredients for treatment.

[0101] The pharmaceutical composition of this application can be administered via various routes (e.g., orally or intravenously). Preferably, the pharmaceutical composition of this application is in solution form. Clinical dosing regimens are determined by the attending physician and clinical factors. As is known in the medical field, the dosage for any given patient depends on many factors, including patient size, body surface area, age, the drug to be administered, sex, time and route of administration, general health, and other concurrently administered medications. The pharmaceutical composition of this application can be administered topically or systemically. Preferably, it can be administered intravenously or subcutaneously. The pharmaceutical composition of this application can also be administered directly to the target site, for example, by targeted delivery to internal or external target sites.

[0102] use In a fifth aspect of this application, the use of the acid addition salt described in the first aspect, the crystal form of the acid addition salt described in the second aspect, the crystal form of the acid addition salt prepared according to the preparation method described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of an ATR inhibitor or a medicament for the prevention and / or treatment of ATR-related diseases is provided.

[0103] In one aspect, this application proposes the use of the acid addition salt described in the first aspect, the crystal form of the acid addition salt described in the second aspect, the crystal form of the acid addition salt prepared according to the preparation method described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of an ATR inhibitor or a medicament for the prevention and / or treatment of ATR-related diseases.

[0104] On the other hand, this application proposes the use of the acid addition salt described in the first aspect, the crystal form of the acid addition salt described in the second aspect, the crystal form of the acid addition salt prepared according to the preparation method described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the prevention and / or treatment of ATR-related diseases.

[0105] In another aspect, this application provides the acid addition salt described in the first aspect, the crystal form of the acid addition salt described in the second aspect, the crystal form of the acid addition salt prepared according to the preparation method described in the third aspect, or the pharmaceutical composition described in the fourth aspect, for the prevention and / or treatment of ATR-related diseases.

[0106] In one optional embodiment of this application, the ATR-related diseases are selected from cancer, age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, diabetic macular edema, progressive ossifying fibrous dysplasia, inflammation, angiogenesis-related diseases, and bacterial infections.

[0107] Treatment methods for ATR-related diseases In a sixth aspect of this application, a method for preventing and / or treating ATR-related diseases is provided. According to embodiments of this application, the method comprises administering to a subject a pharmaceutically acceptable dose of the acid addition salt of the first aspect, the crystalline form of the acid addition salt of the second aspect, the crystalline form of the acid addition salt prepared according to the preparation method of the third aspect, or the pharmaceutical composition of the fourth aspect.

[0108] In one alternative embodiment of this application, the pharmaceutically acceptable dose may be selected from the effective dose (or effective amount).

[0109] The effective amount of the crystal form or pharmaceutical composition described in this application may vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0110] The crystal form or pharmaceutical composition of this application may be incorporated into suitable pharmaceuticals, which may be prepared in various forms, such as liquids. Various routes of administration of the crystal form, pharmaceutical composition, or pharmaceutical composition of this application are contemplated, including intravenous, intramuscular, and subcutaneous injection, but this application is not limited to these exemplified routes of administration.

[0111] In one optional embodiment of this application, the ATR-related diseases are selected from cancer, age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, diabetic macular edema, progressive ossifying fibrous dysplasia, inflammation, angiogenesis-related diseases, and bacterial infections.

[0112] In one optional embodiment of this application, the cancer is brain cancer, breast cancer, central nervous system cancer, colorectal cancer, glioblastoma, melanoma, leukemia, liver cancer, lung cancer, lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, or kidney cancer.

[0113] In one optional embodiment of this application, the cancer is ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomeningeal disease, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma or malignant fibrous histiocytoma, brain tumor, breast cancer, prostate cancer, bronchoma, Burkitt lymphoma, spinal cord tumor, carcinoid tumor, tumor of unknown primary origin, atypical teratoid / rhabdoid tumor of the central nervous system, leptomeningeal disease, embryonal tumor of the central nervous system, central nervous system... Systemic lymphoma, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelodysplastic syndrome, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family tumors, extracranial germ cell tumors, gonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gliomas, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip or oral cancer, lung cancer, non-Hodgkin's lymphoma, primary central nervous system cancer. Lymphoma, Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma), medulloblastoma, medullary epithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary lesions, multiple endocrine neoplasia syndrome, oral cancer, multiple myeloma / plasma cell vegetations, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative vegetations, multiple myeloma, myeloproliferative disorders, nasal cavity or paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma or malignant fibrous histiocytoma of bone, pancreatic cancer, papillomatosis, paranasal sinus or nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, intermediately differentiated pineal parenchymal tumors, pineal blastoma or supratentorial primitive extraneuron Germ cell tumors, pituitary adenomas, pleural pulmonary blastomas, prostate cancer, rectal cancer, pelvic or ureteral cancer, respiratory tract cancers involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, high-grade prostate cancer, intermediate-grade prostate cancer, low-grade prostate cancer, castration-resistant prostate cancer, salivary gland cancer, sarcoma, Thessalj syndrome, skin cancer such as skin cancer, eye cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck carcinoma with occult primary lesions, supratentorial primitive neuroectodermal tumors, T-cell lymphomas, testicular cancer, pharyngeal cancer, thymoma or thymic carcinoma, thyroid cancer, transitional cell carcinoma of the kidney, pelvis or ureter, cancers of unknown primary site, rare childhood cancers, urethral cancer, Wilms' tumor, or cancers in women.Such as breast cancer, cervical cancer, endometrial cancer, gestational trophoblastic tumor, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, low-grade malignant potential ovarian tumor, pregnancy-related cancers, uterine sarcoma, vaginal cancer, or vulvar cancer.

[0114] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0115] General Experiment 1. A table of solvent names in Chinese and English Table A1: Comparison of Chinese and English Names of Solvents Used in the Experiment

[0116] 2. Instrument Information and Methods X-ray powder diffraction (XRPD): XRPD patterns were acquired on an X-ray powder diffraction analyzer manufactured by Panaco.

[0117] Table A2: XRPD Test Parameters

[0118] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): The DSC and TGA plots were acquired using a TA Q200 differential scanning calorimeter and a METTLER TGA2 thermogravimetric analyzer, respectively.

[0119] Table A3: TGA and DSC Test Parameters

[0120] Liquid NMR: Liquid NMR spectra were acquired on a Bruker 400M NMR spectrometer, DMSO- d 6 is used as a solvent.

[0121] Table A4: Parameters for Proton NMR Spectroscopy in Liquid Crystal NMR Spectroscopy

[0122] Dynamic moisture adsorption (DVS) Dynamic moisture adsorption (DVS) curves were acquired on the DVSIntrinsic device of SMS (Surface Measurement Systems). The DVS test parameters are listed in Table A5.

[0123] Table A5 DVS Test Parameters

[0124] High performance liquid chromatography The stability test in the experiment was conducted using a Waters liquid chromatograph, and the conditions are shown in Table A6.

[0125] Table A6 High Performance Liquid Chromatography Test Conditions (Stability)

[0126] Preparation Example 1: Preparation of Compound (I)

[0127] Step 1: Synthesize INT01 Step 1: Synthesize INT01 Add n-BuOH (320 mL) to the reaction flask, then add 20 g of RM2 (acetate with a free base of 1.0 eq, actually 1.2 eq) at 25 °C, NaOEt (2.0 eq), and RM1 (1.1 eq) sequentially. After the addition is complete, heat the system to 100 °C and stir for 20 h. Take a sample and monitor the reaction by HPLC. After the reaction is complete, cool the system to 25 °C, add water (160 mL) to quench the reaction, and add AcOH (2.0 eq) to adjust the pH of the system to 6-7. A large amount of solid precipitates from the system. Filter under reduced pressure, wash the filter cake with n-BuOH (40 mL), then wash the filter cake with H2O (40 mL), and dry under reduced pressure at 50 °C for 24 h to obtain product INT01.

[0128] Step 2: Synthesize INT02 Add 100 mL of CH3CN to the reaction flask, add 10 g of INT01, and slowly add 2.0 eq of POCl3 dropwise at 25 °C. After the addition is complete, raise the temperature of the system to 80 °C and stir the reaction for 18 h. Take a sample and monitor the reaction with HPLC until the reaction is complete. Then concentrate under reduced pressure to a thick consistency. Add 100 mL of DCM to dissolve it, cool to 0 °C, and add saturated Na2CO3 aqueous solution dropwise to adjust the pH to about 7. Then add 100 mL of water dropwise at 0 °C to precipitate crystals, filter, wash the filter cake with water (50 mL), and vacuum dry to obtain a dry product. Dissolve it again with 100 mL of DCM, concentrate the crude product, and pass it through a column to obtain the product INT02.

[0129] Step 3: Synthesize compound (I) Add 50 mL of DMSO and 5 g of INT02 to the reaction flask, and then add 1.2 eq of RM3 and 1.0 eq of DIEA dropwise at 25 °C. After the addition is complete, heat the system to 80 °C and stir for 18 h. Monitor the reaction with HPLC until completion, then cool the reaction system to 25 °C and add 125 mL of H2O to induce crystallization. Filter under reduced pressure, wash the filter cake with water (25 mL), and dry under reduced pressure at 40 °C to obtain a white product (I). Perform NMR, mass spectrometry, and HPLC tests; the NMR results were consistent with expectations; the HPLC results showed a purity of 99.34%, and the mass spectrometry showed a purity of 363 [M+H]. + .

[0130] Preparation Example 2: Preparation of the free base of compound (I) 100 mg of compound (I) was added to dichloromethane (3 mL), stirred at 40 °C to dissolve, then n-heptane (2 mL) was added, and the mixture was slowly cooled to 0 °C to crystallize, yielding a white solid powder, which is the free base of compound (I).

[0131] X-ray powder diffraction (XRPD) analysis identified the following characteristic peaks (expressed in terms of angle 2θ) using Cu-Kα radiation: 7.0±0.2°, 9.4±0.2°, 9.8±0.2°, 10.9±0.2°, 17.6±0.2°, 18.3±0.2°, and 18.6±0.2°. The spectrum is consistent with... Figure 22 Basically the same.

[0132] Example 1: Preparation of the hydrogen sulfate crystal form A of compound (I) 1) Preparation of hydrogen sulfate crystal form A 1.08 g of the free base of formula (I) (prepared according to the method of Preparation Example 2) was added to acetone (20 mL) and stirred at 50 °C until dissolved. Sulfuric acid was weighed at a molar ratio of free base to acid of 1:1.2 and diluted with 10 mL of acetone. The solution gradually turned yellow and a pale yellow solid precipitated. The solution was cooled to 0 °C and stirred for 2 h. After filtration, the solution was dried at 50 °C for 22 h to obtain 1.23 g of solid. The yield was 89%, the HPLC purity was 99.73%, and the XRPD was determined to be hydrogen sulfate crystal form A.

[0133] 2) Identification of hydrogen sulfate crystal form A X-ray powder diffraction (XRPD) analysis identified the following characteristic peaks (expressed in terms of angle 2θ) using Cu-Kα radiation: 4.8±0.2°, 14.1±0.2°, 15.0±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.8±0.2°, and 28.3±0.2°. The spectrum is consistent with... Figure 1 They are basically the same, and their diffraction peak data are detailed in the table below:

[0134] Differential scanning calorimetry (DSC) analysis using a TA Q200 identified an endothermic peak at a scan rate of 10℃ / min, with an initial peak temperature of 227.6℃ and an error tolerance of ±3℃. The spectral characteristics are consistent with... Figure 2 Basically the same.

[0135] Thermogravimetric analysis (TGA) confirmed that at a heating rate of 10℃ / min, the weight loss between 30 and 150℃ was approximately 0.1%, and its chromatogram was consistent with... Figure 3 Basically the same.

[0136] Example 2: Preparation of methanesulfonate crystal form A of compound (I) 1) Preparation of methanesulfonate crystal form A 1.08 g of the free base of compound (I) (prepared according to the method of Preparation Example 2) was added to acetone (20 mL) and stirred at 50 °C until dissolved. Methanesulfonic acid was weighed at a molar ratio of free base to acid of 1:1.2 and diluted with 10 mL of acetone. The solution was slowly added dropwise, and the solution gradually turned yellow. The temperature was lowered to 0 °C and 1% seed crystals were added to induce crystallization. The mixture was stirred for 2 h, filtered, and dried at 50 °C for 22 h to obtain 1.0 g of solid. The yield was 73%, the HPLC purity was 99.43%, and the XRPD was measured to be methanesulfonate crystal form A.

[0137] 2) Identification of methanesulfonate crystal form A X-ray powder diffraction (XRPD) analysis identified the following characteristic peaks (expressed in terms of angle 2θ) using Cu-Kα radiation: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 18.0±0.2°, 21.6±0.2°, 22.0±0.2°, and 27.5±0.2°. The spectral pattern is consistent with... Figure 4 They are basically the same, and their diffraction peak data are detailed in the table below:

[0138] Differential scanning calorimetry (DSC) analysis using a TA Q200 identified an endothermic peak at a scan rate of 10℃ / min (initial peak temperature was 173.8℃), with an error tolerance of ±3℃. The spectral characteristics were consistent with... Figure 5 Basically the same.

[0139] Thermogravimetric analysis (TGA) confirmed that at a heating rate of 10℃ / min, the weight loss between 30 and 150℃ was approximately 0.1%, and its chromatogram was consistent with... Figure 6Basically the same.

[0140] Example 3: Preparation of other salts of compound (I) 1) Preparation of other salts Take an appropriate amount of the free base of compound (I) (prepared according to the method of Preparation Example 2), add an appropriate amount of acetone, stir at 50°C until dissolved, weigh out various acids according to the molar ratio of free base to acid = 1:1.2, and slowly add them dropwise to form salt crystals, as detailed in the table below:

[0141] 2) Identification of other salts X-ray powder diffraction (XRPD) analysis identified that, using Cu-Kα radiation, each of the other types exhibited the following characteristic peaks, denoted by the angle 2θ. Hydrochloride crystal forms A: 4.5±0.2°, 9.0±0.2°, 9.4±0.2°, 11.5±0.2°, 18.1±0.2°, 18.5±0.2°, 23.7±0.2°, 25.8±0.2°, and 27.0±0.2°, whose spectra are similar to... Figure 7 Basically the same.

[0142] Phosphate crystal forms A: 4.7±0.2°, 9.2±0.2°, 13.7±0.2°, 17.4±0.2°, 19.7±0.2°, 21.1±0.2°, 24.1±0.2°, 25.7±0.2°, and 28.2±0.2°, whose spectra are similar to... Figure 8 Basically the same.

[0143] p-Toluenesulfonate crystal forms A: 7.4±0.2°, 8.9±0.2°, 10.4±0.2°, 11.0±0.2°, 12.0±0.2°, 12.4±0.2°, 13.8±0.2°, 14.7±0.2°, 15.1±0.2°, 17.1±0.2°, 18.3±0.2°, 18.7±0.2°, 19.5±0.2°, 20.4±0.2°, 20.8±0.2°, 22.4±0.2°, 22.8±0.2°, 24.5±0.2°, 25.0±0.2°, 26.0±0.2°, 27.9±0.2°, and 29.9±0.2°. Their spectra are similar to... Figure 9 Basically the same.

[0144] Hydrobromide crystal forms A: 4.9±0.2°, 9.6±0.2°, 9.9±0.2°, 13.0±0.2°, 14.6±0.2°, 16.9±0.2°, 17.4±0.2°, 17.7±0.2°, 18.3±0.2°, 19.3±0.2°, 19.8±0.2°, 21.3±0.2°, 22.1±0.2°, 23.1±0.2°, 24.4±0.2°, 25.5±0.2°, 25.8±0.2°, 27.1±0.2°, 27.7±0.2°, 28.4±0.2°, and 29.8±0.2°. Their spectra are similar to... Figure 10 Basically the same.

[0145] Benzenesulfonate crystal form A: 8.3±0.2°, 8.9±0.2°, 10.8±0.2°, 11.0±0.2°, 11.6±0.2°, 12.3±0.2°, 14.0±0.2°, 14.5±0.2°, 16.4±0.2°, 17.8±0.2°, 18.5±0.2°, 19.0±0.2°, 19.6±0.2°, 19.9±0.2°, 20.5±0.2°, 20.8±0.2°, 23.0±0.2°, 23.4±0.2°, 23.9±0.2°, 24.4±0.2°, 24.8±0.2°, 26.1±0.2° 26.6±0.2° and 28.2±0.2°, their spectra are similar to Figure 11 Basically the same.

[0146] Citrate crystal forms A: 4.0±0.2°, 8.9±0.2°, 9.5±0.2°, 11.8±0.2°, 14.7±0.2°, 17.4±0.2°, 17.8±0.2°, 19.1±0.2°, and 20.0±0.2°, whose spectra are similar to... Figure 12 Basically the same.

[0147] Fumarate crystal forms B: 9.6±0.2°, 10.4±0.2°, 12.7±0.2°, 17.1±0.2°, 17.9±0.2°, and 21.7±0.2°, whose spectra are similar to... Figure 13 Basically the same.

[0148] L-tartrate crystal forms A: 5.6±0.2°, 8.9±0.2°, 10.0±0.2°, 10.2±0.2°, 11.8±0.2°, 15.2±0.2°, 16.7±0.2°, 17.4±0.2°, 17.8, 18.5, 19.7, 20.3, 21.2, 22.2, 23.1, 24.5, 25.4, 27.9, 28.6, 29.8, 30.5, 33.2, 35.3, and 38.1±0.2°, whose spectra are similar to... Figure 14 Basically the same.

[0149] Salicylate crystal forms A: 5.2±0.2°, 8.7±0.2°, 9.8±0.2°, 10.4±0.2°, 13.0±0.2°, 17.4±0.2°, 18.3±0.2°, 22.5±0.2°, and 26.3±0.2°, whose spectra are similar to... Figure 15 Basically the same.

[0150] Oxalate crystal forms A: 6.0±0.2°, 9.5±0.2°, 10.2±0.2°, 12.1±0.2°, 14.6±0.2°, 16.1±0.2°, 18.1±0.2°, 19.3±0.2°, 20.6±0.2°, 24.2±0.2°, and 26.4±0.2°, whose spectra are similar to... Figure 16 Basically the same.

[0151] Maleate crystal forms A: 8.8±0.2°, 10.2±0.2°, 16.6±0.2°, 16.8±0.2°, 18.6±0.2°, 19.3±0.2°, 20.6±0.2°, 23.2±0.2°, 25.0±0.2°, 25.6±0.2°, 36.2±0.2°, and 26.1±0.2°, whose spectra are similar to... Figure 17 Basically the same.

[0152] L-camphor sulfonate crystal forms A: 7.9±0.2°, 10.6±0.2°, 12.6±0.2°, 15.2±0.2°, 16.6±0.2°, 17.6±0.2°, 18.7±0.2°, 20.2±0.2°, 21.3±0.2°, 22.0±0.2°, 23.7±0.2°, and 25.3±0.2°, whose spectra are similar to... Figure 18 Basically the same.

[0153] Benzoate crystal forms A: 5.2±0.2°, 8.1±0.2°, 8.3±0.2°, 9.7±0.2°, 10.0±0.2°, 16.8±0.2°, and 18.1±0.2°, whose spectra are similar to... Figure 19 Basically the same.

[0154] Cinnamate crystal form A: 5.5±0.2°, 5.7±0.2°, 7.9±0.2°, 8.7±0.2°, 9.1±0.2°, 9.9±0.2°, 11.1±0.2°, 11.9±0.2°, 15.8±0.2°, 16.9±0.2°, 17.0±0.2°, 17.4±0.2°, 18.4±0.2°, 18.7±0.2°, 19.6±0.2°, 19.9±0.2°, 21.7±0.2°, 21.9±0.2°, 23.1±0.2°, 24.3±0.2°, 25.1±0.2°, 27.1±0.2° 29.3±0.2° and 31.9±0.2°, their spectra are similar to Figure 20 Basically the same.

[0155] L-malate crystal forms A: 4.5±0.2°, 8.9±0.2°, 9.7±0.2°, 10.9±0.2°, 12.3±0.2°, 13.1±0.2°, 15.7±0.2°, 15.9±0.2°, 17.5, 18.5, 19.6, 20.5, 22.0, 23.4, 24.8, 25.7, 26.7, 27.9, 32.9, 35.2, and 37.5±0.2°, whose spectra are similar to... Figure 21 Basically the same.

[0156] Example 4: Salt formation ratio test The hydrochloride and hydrogen sulfate salts of the compound of formula (I) prepared according to the above examples were sent for anion content analysis. The test results showed that both the hydrochloride and hydrogen sulfate salts formed salts with free bases in a 1:1 ratio. The ion chromatography characterization results of the hydrochloride and hydrogen sulfate salts of formula (I) are shown in the table below:

[0157] Example 5: Solubility Test Experiment The solubility of the free base (prepared according to the method of Preparation Example 2) and the acid addition salt of the compound of formula (I) prepared according to the above examples (hereinafter referred to as the salt form) was tested in pure water at 37°C and simulated gastric juice for different equilibration times. The results are shown in Tables 1 and 2.

[0158] The results showed that, compared with free alkali, the solubility of hydrogen sulfate crystal form A and methanesulfonate crystal form A was significantly improved in different solutions; although hydrochloride crystal form A and hydrobromide crystal form A also had good solubility in simulated gastric juice, their crystal forms were unstable and underwent significant degradation under the influencing factors of stability; only hydrogen sulfate crystal form A and methanesulfonate crystal form A were more suitable solids.

[0159] Table 1: Solubility results of free alkali and its salt form in pure water

[0160] Table 2: Solubility results of free base and salt forms in simulated gastric fluid

[0161] Example 6: Stability Test of Influencing Factors In accordance with the guidelines for drug formulation stability testing, experiments were conducted on influencing factors such as high temperature test, high humidity test, and strong light irradiation test to investigate the effects on the stability of their crystal forms, including hydrogen sulfate crystal form A, methanesulfonate crystal form A, and hydrochloride crystal form A.

[0162] 1) High humidity test Take an appropriate amount of sample, spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. Then, take the above sample at 5, 10, 15 and 30 days respectively, and test its crystal form by X-ray powder diffraction (XRPD). The results are shown in Table 3.

[0163] The results showed that the crystal forms of both hydrogen sulfate (crystal form A) and methanesulfonate (crystal form A) remained unchanged after 30 days at 25℃ and RH 92.5±5%, with no significant decrease in purity, demonstrating good physical and chemical stability. However, the hydrochloride salt exhibited crystal instability, showing crystal transformation after 5 days of high humidity.

[0164] Table 3: Results of High Humidity Test

[0165] 2) High temperature test Take an appropriate amount of sample, spread it evenly in a weighing bottle, place it in a drying oven at 60℃, and then take the above sample (the salt form of compound (I) prepared according to the above example) at 5, 10, 15 and 30 days respectively, and test its crystal form by X-ray powder diffraction (XRPD). The results are shown in Table 4.

[0166] The results showed that both hydrogen sulfate (crystal form A) and methanesulfonate (crystal form A) maintained their crystal forms after 30 days at 60℃, indicating good physical and chemical stability. However, the hydrochloride salt exhibited unstable crystal forms, and some free alkali appeared after 5 days at high temperature.

[0167] Table 4: High Temperature Test Results

[0168] 3) Light test Take an appropriate amount of sample (the salt form of compound (I) prepared according to the above example), spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber (25℃, RH60%±5%) with visible light 4500 Lux±500 Lux (VIS) and ultraviolet light 1.7 W*h / m2 (UV). Then, take the above sample at 5, 10, 15 and 30 days respectively, and test its crystal form by X-ray powder diffraction (XRPD). The results are shown in Table 5.

[0169] The results showed that both hydrogen sulfate (form A) and methanesulfonate (form A) maintained their crystal forms for 30 days under constant temperature and humidity conditions (25℃, RH 60%±5%) with visible light (4500 Lux±500 Lux) and ultraviolet light (1.7 W*h / m2), exhibiting good physical and chemical stability. However, the hydrochloride salt showed instability, with some free alkali appearing after 5 days at high temperature.

[0170] Table 5: Results of the Illumination Test

[0171] Example 7: Accelerated Stability Test Experimental procedure: The salt form of the compound of formula (I) prepared according to the above examples was placed under accelerated stability (40±2℃, RH=75±5%) for 1, 2 and 3 months and then the XRPD was measured. The results are shown in Tables 6 and 7.

[0172] The results showed that the hydrogen sulfate crystal form A and the methanesulfonate crystal form A maintained their crystal form and purity unchanged after being placed under accelerated stabilization conditions for 3 months, demonstrating excellent physical and chemical stability.

[0173] Table 6: Accelerated stability test of hydrogen sulfate crystal form A

[0174] Table 7: Accelerated stability test of methanesulfonate crystal form A

[0175] Example 8: Hygroscopicity Test Appropriate amounts of the salt form and free alkali (prepared according to the method of Preparation Example 2) prepared in the above examples were subjected to hygroscopicity tests at 25°C / 80% relative humidity. The results are shown in Table 8.

[0176] The results showed that the free alkali crystal form increased in weight by 0.14% at 80% relative humidity, while the hydrogen sulfate crystal form A and the methanesulfonate crystal form A increased in weight even less due to moisture absorption at 80% relative humidity. This indicates that the hydrogen sulfate crystal form A and the methanesulfonate crystal form A have lower hygroscopicity.

[0177] Table 8: Hygroscopicity Results

[0178] Example 9: Thermal Stability Test Appropriate amounts of the salt form and free alkali prepared in the above examples (prepared according to the method of preparation example 2) were tested for high-temperature thermal stability at 60°C. The results are shown in Table 9.

[0179] The results showed that the purity of the free alkali crystal form decreased at high temperatures, from 99.45% at day 0 to 96.89% at day 30; while the purity of the hydrogen sulfate crystal form A and the methanesulfonate crystal form A remained unchanged, showing better stability.

[0180] Table 9: High-Temperature Thermal Stability Test

[0181] Example 10: In vivo PK test in animals Experimental procedure: Using the hydrogen sulfate crystal form A and the free base (prepared according to the method of preparation example 2) obtained in the above examples as raw materials, tablets were prepared for in vivo PK test in animals (beagle dogs, dosage of 12.6 mg / kg).

[0182] Using bisulfate crystal form A and free base as active pharmaceutical ingredients (APIs), pure API tablets were prepared using a tableting machine for in vivo pharmacokinetic (PK) testing in animals (beagle dogs, dosage 12.6 mg / kg), as detailed below: Beagles, approximately 8 kg in weight, were fasted overnight. Four beagles (two males and two females) were administered the drug orally via gavage at a dose of 12.6 mg / kg. Blood samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, 6, 8, 24, and 30 hours post-administration. Whole blood samples were anticoagulated in EDTA-K2 tubes, centrifuged at 4 °C for 15 minutes, and plasma was separated. 20 μL of plasma from each time point was collected, mixed with 300 μL of acetonitrile solution containing the internal standard, vortexed, and centrifuged at 3220 rpm for 5 minutes at 4 °C. 60 μL of the supernatant was analyzed by LC-MS / MS. The results are shown in Table 10.

[0183] The results showed that the tablet drug of hydrogen sulfate crystal form A had good exposure levels in animals, which were significantly higher than the exposure levels of the free base in vivo.

[0184] Table 10: Beagle Animal Comparison Data

[0185] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0186] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A pharmaceutically acceptable acid addition salt of a compound of formula (I), said acid addition salt comprising at least one of a hydrogen sulfate and a methanesulfonate; (I)； Optionally, the acid addition salt is the hydrogen sulfate salt of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(0.5~3). Preferably, the molar ratio of the compound shown in formula (I) to hydrogen sulfate is 1:(1.0~1.5). Optionally, the acid addition salt is a methanesulfonate of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to methanesulfonic acid is 1:(0.5~3). Preferably, the molar ratio of the compound shown in formula (I) to methanesulfonic acid is 1:(1.0~1.5).

2. A pharmaceutically acceptable crystal form of an acid addition salt of a compound of formula (I), said acid addition salt comprising at least one of the hydrogen sulfate crystal form and the methanesulfonate crystal form of the compound of formula (I); (I)。 3. The crystal form of the acid addition salt according to claim 2, characterized in that, The acid addition salt satisfies one or more of the following conditions: 1) The crystal form of the acid addition salt is the hydrogen sulfate form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 4.8±0.2°, 14.2±0.2°, 18.9±0.2° and 23.7±0.2°; 2) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 5.5±0.2°, 9.0±0.2°, 18.0±0.2° and 18.1±0.2°.

4. The crystal form of the acid addition salt according to claim 2, characterized in that, The acid addition salt satisfies one or more of the following conditions: 1) The crystal form of the acid addition salt is the hydrogen sulfate form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 4.8±0.2°, 14.2±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.8±0.2° and 28.3±0.2°; 2) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2° and 18.1±0.2°.

5. The crystal form of the acid addition salt according to claim 2, characterized in that, The acid addition salt satisfies one or more of the following conditions: 1) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 4.8±0.2°, 14.2±0.2°, 15.0±0.2°, 18.9±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.8±0.2°, 25.9±0.2°, 26.5±0.2°, 28.3±0.2° and 28.5±0.2°; 2) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the DSC diagram of the hydrogen sulfate crystal form contains an endothermic peak at 230.3℃±3℃. 3) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the TGA of the hydrogen sulfate crystal form has a weight loss of about 0.1% ± 0.5% between 30℃ ± 3℃ and 150℃ ± 3℃. 4) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at an angle of 2θ, including: 5.5±0.2°, 9.0±0.2°, 13.1±0.2°, 14.3±0.2°, 15.3±0.2°, 15.4±0.2°, 18.0±0.2°, 18.1±0.2°, 21.6±0.2°, 21.7±0.2°, 22.0±0.2°, 22.2±0.2°, 24.4±0.2°, 27.5±0.2° and 36.9±0.2°; 5) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the DSC diagram of the methanesulfonate crystal form contains an endothermic peak at 177.9℃±3℃. 6) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the TGA of the methanesulfonate crystal form has a weight loss of about 0.1% ± 0.5% between 30℃ ± 3℃ and 150℃ ± 3℃.

6. The crystal form of the acid addition salt according to claim 2, characterized in that, The acid addition salt satisfies one or more of the following conditions: 1) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 1; 2) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the hydrogen sulfate crystal form has a DSC diagram that is substantially as shown in Figure 2; 3) The crystal form of the acid addition salt is the hydrogen sulfate crystal form of the compound shown in formula (I), and the hydrogen sulfate crystal form has a TGA diagram that is substantially as shown in Figure 3; 4) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the methanesulfonate crystal form has an X-ray powder diffraction pattern substantially as shown in Figure 4; 5) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), and the methanesulfonate crystal form has a DSC diagram substantially as shown in Figure 5; 6) The crystal form of the acid addition salt is the methanesulfonate crystal form of the compound shown in formula (I), which has a TGA diagram substantially as shown in Figure 6.

7. A method for preparing a pharmaceutically acceptable acid addition salt crystal form of the compound of formula (I) according to any one of claims 2 to 6, characterized in that, include: The compound shown in formula (I) is subjected to a crystallization reaction with an acid to obtain the crystal form of the acid addition salt; The acid includes at least one of hydrogen sulfate and methanesulfonic acid; (I)； Optionally, the molar ratio of the compound shown in formula (I) to the acid is 1:(0.5~3); Preferably, the molar ratio of the compound shown in formula (I) to the acid is 1:(1.0~1.5). Optionally, the solvent in the crystallization reaction is selected from acetone; Optionally, the temperature of the crystallization reaction is 0℃~5℃; Optionally, the crystallization reaction takes 1 h to 2 h.

8. A pharmaceutical composition, characterized in that, It includes the acid addition salt of claim 1, the crystal form of any one of claims 2 to 6 or the crystal form prepared according to the preparation method of claim 7, and optionally pharmaceutically acceptable doses of excipients, carriers, and mediators.

9. Use of the acid addition salt of claim 1, the crystal form of any one of claims 2 to 6, the crystal form prepared according to the preparation method of claim 7, or the pharmaceutical composition of claim 8 in the preparation of an ATR inhibitor or a medicament for the prevention and / or treatment of ATR-related diseases.

10. The use according to claim 9, characterized in that, The ATR-related diseases are selected from cancer, age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, diabetic macular edema, progressive ossifying fibrous dysplasia, inflammation, angiogenesis-related diseases, and bacterial infections.

Images