Crystalline forms of sulfamide derivatives and their preparation methods

Abstract

The present disclosure relates to crystalline forms of sulfamide derivatives and methods for preparing same. Specifically, the present disclosure provides a novel crystalline form of the compound represented by Formula 1 and methods for preparing same. [Formula 1] TIFF2026505853000024.tif34168

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2023101075697, filed on February 10, 2023. The above Chinese patent application is incorporated herein by reference in its entirety.

[0002] The present disclosure belongs to the field of pharmaceutical technology and relates to crystalline forms of sulfamide derivatives and methods for preparing same. [Background technology]

[0003] Lysine acetyltransferases (KATs) are a class of enzymes that can catalyze the transfer of an acetyl group from acetyl-coenzyme A to the lysine ε-amino group of protein substrates. Lysine acetylation can affect protein function, thereby exerting important regulatory roles in chromosome structure, gene transcription regulation, DNA binding ability, enzyme activity and stability, protein interactions, and subcellular localization. KATs are divided into several subfamilies, of which MYST (MOZ, YBF2 / SAS3, SAS2, TIP60) is the largest, and includes KAT5 (TIP60), KAT6A (MOZ, MYST3), KAT6B (MORF, MYST4), KAT7 (HBO, MYST2), and KAT8 (MOF, MYST1). KAT6A / B, as the main member of the MYST family, plays a crucial role in development, stem cell maintenance in the hematopoiesis and immune systems, and tumor formation, progression, and drug resistance.

[0004] Patent applications that have disclosed inhibitors of KAT6 include WO2016198507A1, WO2019243491A1, WO2019043139A1, WO2019108824A1, WO2020216701A1, WO2020002587A1, WO2020254946A1, and WO2020254989A1, among others.

[0005] PCT / CN2022 / 111395 provides a KAT6 inhibitor, whose chemical name is N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzopyran[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfamide and has the structure shown in Formula 1. [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2016198507A1 [Patent Document 2] WO2019243491A1 [Patent Document 3] WO2019043139A1 [Patent Document 4] WO2019108824A1 [Patent Document 5] WO2020216701A1 [Patent Document 6] WO2020002587A1 [Patent Document 7] WO2020254946A1 [Patent Document 8] WO2020254989A1 Summary of the Invention [Problem to be solved by the invention]

[0007] The crystalline structure of a pharmaceutical active ingredient tends to affect the chemical stability of the drug, and depending on the crystallization and storage conditions, the crystalline structure of the compound may change, sometimes resulting in the formation of other crystalline forms. Generally, amorphous drug products do not have a regular crystalline structure and tend to have other defects, such as poor product stability, fine precipitated crystals, difficulty in filtration, prone to caking, poor flowability, etc. Drug crystalline polymorphs have different requirements for product storage, manufacturing, and scale-up. Therefore, it is necessary to study the crystalline form of the compound in detail and improve various properties of the compound. [Means for solving the problem]

[0008] (Summary of the Invention) The present disclosure provides a novel crystalline form of the compound of formula 1 that has good stability and can be more easily applied in clinical practice. [ka]

[0009] The A-type crystal of the compound represented by formula 1 provided by the present disclosure has characteristic peaks at 11.288, 16.624, 18.251, 19.639, 22.547, and 26.085 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles.

[0010] In some embodiments, the A-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 11.288, 16.624, 18.251, 19.639, 21.140, 22.547, 23.439, 26.085, 26.497, and 27.050.

[0011] In some embodiments, the A-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 11.288, 16.624, 17.312, 18.251, 19.639, 20.086, 21.140, 22.547, 23.439, 24.234, 26.085, 26.497, and 27.050.

[0012] In some embodiments, the A-type crystal of the compound of formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

[0013] The present disclosure further provides a method for preparing crystalline Form A of the compound of Formula 1, the method comprising: Method 1, which comprises adding a compound represented by formula 1 to a solvent (I), forming a slurry, and crystallizing the resultant mixture, wherein the solvent (I) is selected from one or more of an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a nitrile solvent, water, and dimethyl sulfoxide; the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, benzyl alcohol, 1,2-propanediol, and isoamyl alcohol; the ketone solvent is selected from acetone and methyl isobutyl ketone; the ester solvent is selected from ethyl acetate and isopropyl acetate; the ether solvent is selected from methyl tert-butyl ether, propylene glycol methyl ether, isopropyl ether, and tetrahydrofuran; the hydrocarbon solvent is selected from nitromethane, n-heptane, cyclohexane, toluene, and p-xylene; and the nitrile solvent is selected from acetonitrile; and Method 2, which comprises dissolving the compound of formula 1 in a solvent (II) by heating, and stirring at room temperature or at a lowered temperature to crystallize the compound, and the solvent (II) is selected from one or more of acetonitrile, nitromethane, benzyl alcohol, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile / methanol, and 1,2-dichloroethane; a third method, in which the compound of formula 1 is dissolved in a solvent (III), and a solvent (IV) is added and stirred to crystallize, wherein the solvent (III) is selected from dimethyl sulfoxide or dichloromethane, and the solvent (IV) is selected from one or more of water, methanol, ethanol, isopropanol, isopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, and toluene.

[0014] The present disclosure further provides a B-type crystal of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 7.100, 11.249, 18.241, 22.580, and 26.107.

[0015] In some embodiments, the B-type crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 6.454, 7.100, 11.249, 18.241, 19.637, 20.092, 20.407, 22.580, 26.107, and 26.550.

[0016] In some embodiments, the B-type crystals of the compound of Formula 1 have a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.454, 7.100, 10.448, 11.249, 16.595, 18.241, 19.637, 20.092, 20.407, 22.580, 23.470, 26.107, and 26.550.

[0017] In some embodiments, the B-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

[0018] The present disclosure further provides a method for preparing type B crystals, the method comprising: The method includes dissolving the compound of formula 1 in a solvent (V), adding a solvent (VI) and stirring to crystallize, wherein the solvent (V) is selected from dimethyl sulfoxide and the solvent (VI) is selected from methyl tert-butyl ether.

[0019] The present disclosure further provides crystalline Form C of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 6.484, 7.056, 7.907, 11.060, 14.223, and 20.342.

[0020] In some embodiments, the C-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 6.484, 7.056, 7.907, 11.060, 14.223, 15.973, 20.342, 21.460, 23.090, and 26.398.

[0021] In some embodiments, the C-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.484, 7.056, 7.907, 11.060, 12.702, 14.223, 15.973, 17.526, 20.342, 21.460, 23.090, 26.398, and 27.500.

[0022] In some embodiments, the C-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

[0023] The present disclosure further provides a method for preparing a C-type crystal, the method comprising: Method 1, which comprises dissolving the compound of formula 1 in a solvent (VII), adding a solvent (VIII) to precipitate and crystallize the compound, wherein the solvent (VII) is selected from dichloromethane or tetrahydrofuran, and the solvent (VIII) is selected from one or more of tetrahydrofuran and n-hexane; Method 2: dissolving the compound of formula 1 in solvent (IX) and stirring to crystallize, wherein the solvent (IX) is selected from chloroform.

[0024] The present disclosure further provides crystalline Form D of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 6.504, 7.051, 7.896, 11.086, 15.876, and 20.238.

[0025] In some embodiments, the D-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.504, 7.051, 7.896, 11.086, 13.560, 14.194, 15.876, 17.504, 18.599, 20.238, 22.244, and 23.963.

[0026] In some embodiments, the D-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.504, 7.051, 7.896, 11.086, 13.560, 14.194, 15.876, 17.504, 18.599, 20.238, 20.633, 22.244, 23.963, and 26.487.

[0027] In some embodiments, the D-form crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0028] The present disclosure further provides a method for preparing a D-type crystal, the method comprising: The compound of formula 1 is dissolved in a solvent (X), and the resulting solution is stirred to crystallize, and the solvent (X) is selected from N,N-dimethylformamide.

[0029] The present disclosure further provides crystalline Form E of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 6.490, 7.069, 10.968, 14.194, 16.199, and 20.486.

[0030] In some embodiments, the E-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.490, 7.069, 8.034, 10.968, 14.194, 16.199, 18.656, 20.486, 21.539, and 22.949.

[0031] In some embodiments, the E-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.490, 7.069, 8.034, 10.968, 14.194, 16.199, 18.656, 20.486, 21.539, 22.360, 22.949, 23.979, 24.676, and 26.411.

[0032] In some embodiments, the E-form crystal of the compound of formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0033] The present disclosure further provides a method for preparing Form E crystals, the method comprising: The compound represented by formula 1 is dissolved in a solvent (XI), and the resulting solution is stirred to crystallize, and the solvent (XI) is selected from 1,2-dichloroethane.

[0034] The present disclosure further provides crystalline form F of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 7.327, 9.387, 13.968, 15.793, 20.198, and 21.813.

[0035] In some embodiments, the F-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 7.327, 8.690, 9.387, 9.653, 12.583, 13.968, 15.793, 17.270, 20.198, 20.810, 21.813, 22.186, and 25.444.

[0036] In some embodiments, the F-type crystal of the compound of Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, with characteristic peaks at 7.327, 8.690, 8.970, 9.387, 9.653, 12.583, 13.968, 15.793, 16.429, 17.270, 17.975, 20.198, 20.810, 21.813, 22.186, 23.410, 24.438, 25.444, and 27.356.

[0037] In some embodiments, the F-type crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0038] The present disclosure further provides a method for preparing crystalline form F, the method comprising dissolving a compound of Formula 1 in a solvent (XII) and stirring to crystallize, wherein the solvent (XII) is selected from ethyl acetate.

[0039] In some embodiments, the G-form crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 6.614, 7.192, 8.164, 11.113, 16.302, and 20.560.

[0040] In some embodiments, the G-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 6.614, 7.192, 8.164, 11.113, 11.377, 12.978, 14.360, 16.302, 20.560, 21.639, 22.588, 23.042, 24.186, and 26.521.

[0041] In some embodiments, the G-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, with characteristic peaks at 6.614, 7.192, 8.164, 11.113, 11.377, 12.266, 12.978, 13.738, 14.360, 16.302, 18.807, 20.560, 21.639, 22.588, 23.042, 24.186, 26.080, and 26.521.

[0042] In some embodiments, the G-type crystal of the compound of Formula 1 is represented by a diffraction angle 2θ angle. The resulting powder X-ray diffraction pattern is shown in FIG.

[0043] The present disclosure further provides a method for preparing Type G crystals, the method comprising dissolving a compound represented by Formula 1 in a solvent (XIII) and evaporating the solvent to crystallize, wherein the solvent (XIII) is selected from dichloromethane.

[0044] The present disclosure further provides crystalline Form H of the compound of Formula 1, which has a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 5.271, 10.587, 13.230, 16.017, 21.498, 22.753, and 26.938.

[0045] In some embodiments, the H-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.271, 10.587, 11.892, 13.230, 16.017, 16.625, 19.110, 21.498, 22.753, 24.080, 26.938, and 27.536.

[0046] In some embodiments, the H-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, with characteristic peaks at 5.271, 10.587, 11.892, 13.230, 16.017, 16.625, 19.110, 21.498, 22.753, 24.080, 25.459, 26.175, 26.938, 27.536, 31.694, and 38.116.

[0047] In some embodiments, the H-form crystal of the compound of Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0048] The present disclosure further provides a method for preparing Form H crystals, the method comprising: a) mixing a compound of formula 1 with an aqueous sodium hydroxide solution; b) stirring at 37°C to precipitate a solid; c) discarding the supernatant, adding a hydrochloric acid-water solution, suspending at 37°C to form a slurry, centrifuging, and then vacuum drying to obtain a solid.

[0049] In some embodiments, the Form I crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 5.963, 11.883, 13.953, 19.518, 20.305, and 22.086.

[0050] In some embodiments, the Form I crystal of the compound of Formula 1 has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.963, 9.438, 10.303, 11.883, 13.953, 17.945, 18.356, 19.518, 19.807, 20.305, 22.086, 25.009, and 29.576.

[0051] In some embodiments, the Form I crystal of the compound of Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 5.963, 9.438, 10.303, 11.156, 11.883, 13.446, 13.953, 17.945, 18.356, 19.518, 19.807, 20.305, 21.559, 22.086, 25.009, 29.576, and 30.192.

[0052] In some embodiments, the Form I crystal of the compound represented by Formula 1 has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0053] The present disclosure further provides a method for preparing Form I crystals, the method comprising dissolving a compound of Formula 1 in a solvent (XIV) and evaporating the solvent to crystallize, wherein the solvent (XIV) is selected from dichloromethane.

[0054] The present disclosure further provides a pharmaceutical composition comprising the above-mentioned Type A crystals, Type B crystals, Type C crystals, Type D crystals, Type E crystals, Type F crystals, Type G crystals, Type H crystals or Type I crystals, and optionally a pharmaceutical additive selected from a pharmaceutically acceptable excipient.

[0055] The present disclosure further provides a pharmaceutical composition prepared from the above-mentioned Type A crystals, Type B crystals, Type C crystals, Type D crystals, Type E crystals, Type F crystals, Type G crystals, Type H crystals or Type I crystals, and optionally a pharmaceutically acceptable excipient.

[0056] The present disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing the above-mentioned Type A crystals, Type B crystals, Type C crystals, Type D crystals, Type E crystals, Type F crystals, Type G crystals, Type H crystals, or Type I crystals with a pharmaceutically acceptable excipient.

[0057] The present disclosure further provides use of the above-mentioned Type A crystals, Type B crystals, Type C crystals, Type D crystals, Type E crystals, Type F crystals, Type G crystals, Type H crystals or Type I crystals, or the above-mentioned composition, in the preparation of a medicament for preventing and / or treating cancer.

[0058] The use according to the present disclosure, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial carcinoma, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, primary thrombocytosis, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, hematopoietic carcinoma, thyroid cancer ... The cancer is selected from tuboblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor, preferably the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

[0059] The term "2θ or 2θ angle" used in the present disclosure refers to the diffraction angle, where θ is the Bragg angle and is expressed in ° or degrees. The error range of 2θ for each characteristic peak is ±0.20 (including rounding to the nearest decimal place), and specifically includes -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, - 0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0060] The numerical values ​​in this disclosure, such as those relating to substance content, are measured and calculated data, and some degree of error is unavoidable. Generally, ±10% is within a reasonable error range. Depending on the context of use, there may be some variation in error, and the variation in error may not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0061] In the method for preparing the crystalline form of the present disclosure, the starting material used may be a compound in any form, and specific forms include, but are not limited to, amorphous, any crystalline form, hydrate, solvate, etc.

[0062] The drying temperature described in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and drying may be performed under normal pressure or reduced pressure.

[0063] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, crystallization by solvent evaporation, and crystallization induction by adding seed crystals. The cooling temperature is 65°C or lower, preferably selected from the range of -10°C to 60°C, and stirring may be performed during the crystallization process.

[0064] "Differential scanning calorimetry or DSC" as used herein refers to the measurement of temperature and heat flow differences between a sample and a reference during a heating or isothermal process of the sample to characterize all physical and chemical changes associated with thermal effects and obtain information on the phase transitions of the sample.

[0065] Based on the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guidelines for Hygroscopicity of Drugs 9103" in Part 4 of the 2015 edition of the "Chinese Pharmacopoeia," deliquescence: absorption of sufficient water to form a liquid; Highly hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15% but not less than 2%. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2% but not less than 0.2%; No or almost no moisture absorption: Weight increase due to moisture absorption is less than 0.2%.

[0066] "Excipients" as referred to in this disclosure include, but are not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifier that has already been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or domestic animals. [Brief explanation of the drawings]

[0067] [Figure 1] 1 is an XRPD pattern of the A-type crystal of Compound 1. [Figure 2] 1 is an XRPD pattern of type B crystals of Compound 1. [Figure 3] 1 is an XRPD pattern of the C-type crystal of Compound 1. [Figure 4] 1 is an XRPD pattern of the D-type crystal of Compound 1. [Figure 5] 1 is an XRPD pattern of E-form crystals of Compound 1. [Figure 6] 1 is an XRPD pattern of the F-type crystal of Compound 1. [Figure 7] 1 is an XRPD pattern of the G-type crystal of Compound 1. [Figure 8] 1 is an XRPD pattern of H-type crystals of Compound 1. [Figure 9] 1 is an XRPD pattern of the type I crystal of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0068] Hereinafter, the present disclosure will be described in more detail in combination with examples or experimental examples. However, the examples or experimental examples of the present disclosure are merely for explaining the technical solutions of the present disclosure and do not limit the substance or scope of the present disclosure.

[0069] Test conditions for the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The NMR data are shown in ppm. A Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer was used for the NMR measurements, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0070] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0071] High performance liquid chromatography (HPLC) analysis was performed using high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0072] For high-performance liquid preparative chromatography, preparative chromatographs Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 were used.

[0073] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the carrier.

[0074] XRPD is a powder X-ray diffraction (XRD) measurement using a BRUKER D8 X-ray diffractometer. The specific collected data were a Cu anode (40 kV, 40 mA), Cu-Kα1 radiation (λ = 1.54060 Å), Kα2 radiation (λ = 1.54439 Å), and Kβ radiation (λ = 1.39222 Å). Scanning method: θ / 2θ, scanning range (2θ range): 5° to 45°.

[0075] DSC stands for differential scanning calorimetry. The measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10°C / min. The specific temperature range referred to the corresponding pattern (mainly 25-350°C), and the nitrogen gas purge rate was 50mL / min.

[0076] TGA is thermogravimetric analysis: a METTLER TOLEDO TGA 2 thermogravimetric analyzer was used for detection, the heating rate was 10°C / min, the specific temperature range referred to the corresponding pattern (mainly 25-350°C), and the nitrogen gas purge rate was 50 mL / min.

[0077] DVS is dynamic moisture adsorption: The detection is performed using SMS DVS Advantage, with a humidity change at 25°C of 50%-95%-0%-95%-50%, in 10% steps (with the last step being 5%) (the specific humidity range is based on the corresponding pattern, and this is the most common method used). The criterion is a dm / dt of 0.002% or less.

[0078] Known starting materials of the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0079] In the examples, unless otherwise specified, all reactions can be carried out in an argon gas atmosphere or a nitrogen gas atmosphere.

[0080] The argon or nitrogen gas atmosphere refers to an argon or nitrogen gas balloon with a volume of about 1 L connected to the reaction flask.

[0081] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvents used in the reaction, the eluent system for column chromatography to purify the compounds, and the developing solvent system for thin layer chromatography comprised A: n-hexane / ethyl acetate system and B: dichloromethane / methanol system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds, and could be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0082] Example 1 Preparation of Compounds of Formula 1 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfamide 1 [ka] [ka]

[0083] Step 1 4-Bromo-2-((2,4-dimethoxybenzyl)oxy)-6-fluorobenzonitrile 1b 4-Bromo-2,6-difluorobenzonitrile 1a (22 g, 101 mmol, Shaoyuan) and 2,4-dimethoxybenzyl alcohol (18.5 g, 110 mmol, Bi De) were dissolved in N,N-dimethylformamide (200 mL) and cesium carbonate (49 g, 150 mmol, Shaoyuan) was added. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and suction filtered under reduced pressure. The filtrate was diluted with ethyl acetate (500 mL) and washed with saturated sodium chloride solution (30 mL × 5). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1b (36.9 g, 100% yield). This product was used directly in the next reaction without further purification.

[0084] Step 2 4-Bromo-2-fluoro-6-hydroxybenzonitrile 1c Compound 1b (36.9 g, 100.7 mmol) was dissolved in dichloromethane (250 mL) and cooled to 0° C. Trifluoroacetic acid (39 g, 342 mmol, Adamas) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1c (9.7 g, yield: 44.5%).

[0085] Step 3 2-(Allyloxy)-4-bromo-6-fluorobenzonitrile 1d Compound 1c (10.7 g, 49.5 mmol) was dissolved in N,N-dimethylformamide (120 mL). The reaction mixture was cooled to 0 °C, and cesium carbonate (24 g, 73.7 mmol, Bi De) and allyl bromide (11.2 g, 92.6 mmol, Adams) were added. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was suction filtered under reduced pressure, and the filtrate was diluted with ethyl acetate (400 mL) and washed with saturated sodium chloride solution (30 mL x 3). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 1d (11.7 g, 92% yield). 1 H NMR (500 MHz, CDCl3) δ 7.02(dt, 1H), 6.95(t, 1H), 6.04(m, 1H), 5.57-5.47(m, 1H), 5.41(dt, 1H), 4.75-4.64(m, 2H).

[0086] Step 4 3-Allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile 1e Compound 1d (3.35 g, 13.1 mmol) was dissolved in 1,2-dichlorobenzene (80 mL), and the mixture was purged with nitrogen gas three times. The reaction mixture was stirred at 180° C. for 13 hours. The reaction mixture was cooled to room temperature, and the resulting residue was purified by silica gel column chromatography (loaded by the wet method) using eluent system A to give the title product 1e (2.77 g, yield: 82.7%). 1 H NMR (500 MHz, CDCl3) δ 7.07(dd, 1H), 6.45(s, 1H), 5.90(dddd, 1H), 5.24-5.10(m, 2H), 3.68-3.55(m, 2H).

[0087] Step 5 4-Bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile 1f Compound 1e (4.8 g, 18.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and borane tetrahydrofuran solution (1.0 M, 22 mL, 22 mmol, Adamas) was added dropwise at 0 °C. The reaction mixture was stirred in an ice bath for 2 h. 3 M aqueous sodium hydroxide solution (13 mL, 39 mmol) and 30% aqueous hydrogen peroxide solution (3.0 mL) were added sequentially in an ice bath, and the mixture was stirred for 10 min after the addition was complete. The reaction mixture was adjusted to pH 2 with 2 M hydrochloric acid and extracted with ethyl acetate (100 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1f (3.5 g, yield: 68.1%). MS m / z (ESI): 275.8 [M+1]. 1 H NMR (500 MHz, CDCl3) δ 7.04(d, 1H), 3.71(t, 2H), 3.00-2.98(m, 2H), 2.01-1.96(m, 2H).

[0088] Step 6 5-Bromo-7-fluorochroman-8-carbonitrile 1g Compound 1f (3.8 g, 13.9 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL). The reaction mixture was cooled to 0°C, and triphenylphosphine (4.4 g, 16.8 mmol, Sinopharm) and diisopropyl azodicarboxylate (3.4 g, 16.8 mmol, Shaoyuan) were added. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 1g (3.0 g, yield: 84.5%). 1 H NMR (500 MHz, CDCl3) δ 7.03(d, 1H), 4.33(t, 2H), 2.77-2.74(m, 2H), 2.12-2.08(m, 2H). MS m / z(ESI):257.8[M+1].

[0089] Step 7 Methyl 8-cyano-7-fluorochroman-5-carboxylate 1h Compound 1g (2.6 g, 10.2 mmol) was dissolved in 40 mL of a mixed solvent of methanol and N,N-dimethylformamide (V:V = 1:3) and sequentially added with 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (800 mg, 1.09 mmol, Adamas) and triethylamine (3.0 g, 2.93 mmol, China Pharmaceuticals). The mixture was purged with carbon monoxide three times and stirred at 10 bar and 90°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride solution (50 mL x 3). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 1h (2.1 g, yield: 87.9%). 1 H NMR (500 MHz, CDCl3) δ 7.26(d, 1H), 4.38-4.36(m, 2H), 3.93(s, 3H), 3.10-3.07(m, 2H), 2.08-2.03(m, 2H). MS m / z(ESI):235.9[M+1].

[0090] Step 8 7-Fluoro-5-(hydroxymethyl)chroman-8-carbonitrile 1i Compound 1h (2.1 g, 8.93 mmol) was dissolved in dry tetrahydrofuran (40 mL) and purged with nitrogen gas three times. The reaction mixture was cooled to 0 °C and lithium borohydride (2 M, 18 mmol, 9.0 mL, Adamas) was added. The reaction mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (100 mL), and washed with saturated sodium chloride solution (50 mL × 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 1i (1.84 g, yield: 99.5%). MS m / z (ESI): 207.9 [M+1].

[0091] Step 9 5-((1H-pyrazol-1-yl)methyl)-7-fluorochroman-8-carbonitrile 1k Compound 1i (1.8 g, 8.69 mmol) and 1-(methylsulfonyl)-1H-pyrazole 1j (1.5 g, 10.3 mmol, prepared according to the method described in WO2020254946A1, page 63, Intermediate 13 in Scheme 8) were dissolved in acetonitrile (30 mL), and cesium carbonate (4.2 g, 12.9 mmol, Shaoyuan) was added. The mixture was allowed to react at 70 °C for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 1k (1.9 g, 85.0% yield). MS m / z (ESI): 258.0 [M+1].

[0092] Step 10 5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-amine 1l Compound 1k (1.9 g, 7.39 mmol) and acetohydroxamic acid (1.7 g, 22.2 mmol, Adams) were dissolved in N,N-dimethylformamide (30 mL) and water (4.0 mL), and potassium carbonate (6.2 g, 44.9 mmol, China Pharmaceuticals) was added. The reaction mixture was stirred at 70 °C for 24 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was filtered. The filter cake was collected and dried to give the title product 1l (1.65 g, 82.7% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.78(d, 1H), 7.52(d, 1H), 6.34(s, 1H), 6.32(t, 1H), 5.85(s, 2H), 5.39(s, 2H), 4.25-4.23(m, 2H), 2.68(t, 2H), 2.03-1.98(m, 2H). MS m / z(ESI):271.0[M+1].

[0093] Step 11 N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-chromeno[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfamide 1 Compound 1l (200 mg, 0.740 mmol) and compound 1m (300 mg, 1.27 mmol) were dissolved in pyridine (5.0 mL) and purged with nitrogen gas three times. The reaction mixture was reacted at 120 °C in a microwave oven for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (Xtimate phenyl-hexyl Prep C18 5 μm, 30 × 150 mm, mobile phase: A - aqueous phase (0.1% ammonia water): B - acetonitrile = 5% to 45% (20 min), flow rate: 30 mL / min) to obtain the title product 1 (40 mg, yield: 11.5%). 1 H NMR (500 MHz, DMSO-d6) δ 9.40(s, 1H), 7.79(d, 1H), 7.52(d, 1H), 7.48(t, 1H), 6.77(d, 2H), 6.43(s, 1H), 6. 32(t, 1H), 5.42(s, 2H), 4.25(t, 2H), 3.78(s, 6H), 2.70(t, 2H), 2.04-1.99(m, 2H). MS m / z(ESI):470.8[M+1].

[0094] Test Example 1: Detection of Enzyme Activity of Compound KAT6 of Formula 1 (AlphaScreen Method) 1. Experimental materials 1.KAT6A (Chempartner customized) 2. Ovalbumin (Sigma-Aldrich, A5378-5G) 3.2 M Tris-HCl solution, pH 7.8, sterilized (Seiko B548140-0500) 4.5M NaCl solution (Seiko, B548121-0100) 5.EDTA (0.5M), pH8.0, RNase-free (Thermofisher, AM9260G) 6.Tween-20 (raw material, A100777-0500) 7.DTT, 1M (Invitrogen, P2325) 8. Acetyl coenzyme A (Ac-CoA, CAYMAN, Cat. No. 16160) 9. Recombinant Histone H3.1 biotinylated (Human) (Active Motif 31696) 10. 384-well plate, light gray (Perkin Elmer, Cat. No. 6005350) 11. Anacardic acid (MCE, Cat. No. HY-N2020) 12. AlphaScreen Streptavidin Donor beads, 5 mg (PerkinElmer, 6760002) 13. AlphaScreen Protein A Acceptor beads, 5 mg (PerkinElmer, 6760137M) 14. Acetylated-Lysine Antibody (#9441) (CST 9441S) 15. PHERA star plate reader (BMG labtech) 2. Experimental Method 1. Reagent Preparation a. 1x detection buffer: 100mM Tris-HCl, pH 7.8, 15mM NaCl, 1mM EDTA, 0.01% Tween-20, 1mM DTT, 0.01% m / v ovalbumin. b. KAT enzyme solution: final concentration 1.25 nM prepared in 1× detection buffer. c. Mixed substrate of Ac-CoA and H3: A mixed substrate of Ac-CoA at a final concentration of 1000 nM and H3 at a final concentration of 55 nM prepared in 1× detection buffer. d. Compounds: initial concentration 100 μM, 3-fold dilutions, 10 concentration gradient. All concentration compounds were diluted 83-fold with 1× detection buffer and ready for use. e. Detection reagent: AlphaScreen Protein A acceptor beads at a final concentration of 8 ng / μL, AlphaScreen Streptavidin Donor beads at 8 ng / μL, acetylated lysine antibody diluted 1:1500, and 100 μM anacardic acid prepared in 1× detection buffer. 2. Experimental Procedure 3 μL of the prepared enzyme solution was added to each well of a 384-well plate, and 3 μL of 1x detection buffer was added to wells in columns 23 and 24 (Min). 3 μL of compound solution was added to each well, 3 μL of buffer was added to each well in Min, and 3 μL of DMSO solution was added to each well in columns 1 and 2 (Max) as a control. The plates were centrifuged, mixed evenly, shaken for 2 minutes, and incubated at room temperature for 15 minutes. 6 μL of Ac-CoA and H3 mixed substrate was added to each well, centrifuged, mixed evenly, shaken for 2 minutes, and incubated at room temperature for 20 minutes. 6 μL of detection reagent was added to each well, centrifuged, mixed evenly, shaken for 2 minutes, and incubated at room temperature in the dark for 120 minutes. The plate was read using a plate reader, and the counts obtained by AlphaScreen were recorded. The compound IC values ​​were plotted using Graphpad software. 50 The value was calculated and the result was IC 50 =0.3nM Conclusion: The compound of formula 1 has excellent inhibitory activity against KAT6A.

[0095] Test Example 2 Anti-ZR-75-1 proliferation test of the compound of formula 1 1. Reagents and equipment 1. ZR-75-1 (ATCC CRL1500) 2.1640 Medium (Gibco, 22400-089) 3. 0.25% Trypsin-EDTA (1x) (Gibco, 25200-072) 4. Penicillin-streptomycin (Gibco, 15140-122) 5.DPBS(1×)(Gibco, 14190-144) 6. FBS (Gibco, 10091148) 7. 96-well clear black bottom detection plate (Corning, 3603) 8. 96-well non-treated round bottom formulation plate (JET BIOFIL, TCP-002-096) 9.CellTiter-Glo buffer (Promega, G756B) 10.CellTiter-Glo substrate (Promega, G755B) 11. Automated cell counter (Countstar, IC1000) 12. Constant temperature incubator (Thermo, I160) 13.PHERAstar FS(BMG labtech, PHERAstar FS) 2. Experimental Method 1. Seeding cells onto plates (Day 0) a. Observe the cells under a microscope to ensure that the cell confluence is approximately 90%. b) The supernatant was removed, the cells were rinsed once with DPBS, and the DPBS was discarded. An appropriate amount of trypsin was added to digest the cells, and the cells were left to stand at 37°C for 5 minutes. c. The digestion was stopped by adding an equal volume of 1640 medium containing 10% FBS, and the cell suspension was collected and centrifuged at 300 g for 3 minutes. The cells were then suspended in an appropriate amount of fresh medium. d. The resuspended cell suspension was taken and counted. e. The cell suspension was diluted with 1640 medium containing 10% FBS to 5 x 104 / mL, 50 μL / well. ZR-75-1 was at 2500 cells / well. f. The cell culture plate was placed in an incubator at 37°C with 5% carbon dioxide and cultured overnight. 2. Medication intake (Day 1) a. Each compound was diluted in DMSO to nine concentration points (initial concentration 100 μM, 3-fold dilution, different compounds were diluted to the highest concentration IC 50 For example, in a 96-well round-bottom formulation plate, 3 μL of compound was diluted in a gradient into 6 μL of DMSO. b. Each concentration point of each compound was diluted 500-fold into the corresponding volume of 1640 medium. c. 50 μL of the diluted compound solution was added to 50 μL / well of cell supernatant in turn in each cell plate. d. The drug-added cell plate was placed in an incubator at 37°C with 5% carbon dioxide and cultured. 3. Re-digestion, plating, and drug addition (Day 7) a. Six days after drug addition, the drug-containing culture medium was removed, and 150 μL / well of DPBS was added to rinse once, and the DPBS was immediately aspirated off. b. Cells were digested by adding 50 μL of trypsin, incubated at 37° C. for 3 minutes, and digestion was stopped by adding 150 μL / well of 1640 medium containing 10% FBS. c. The cells were mixed evenly by pipetting using a multichannel pipette and replated in a 1:8 ratio by aspirating 25 μL of the cell suspension and placing it in a new 96-well plate (previously adding 25 μL of 1640 medium containing 10% FBS to the new plate). Compound preparation and drug addition were performed at 50 μL / well according to steps a. to c. in d.2. e. The drug-loaded cell plates were placed in an incubator at 37°C with 5% carbon dioxide and cultured. 4.CTG detection (day 14) a. Before use, the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate were allowed to equilibrate to room temperature, and then the two were thoroughly mixed to homogenize to prepare 100 mL of CellTiter-Glo reagent (alternatively, the premixed CellTiter-Glo reagent was removed from -20°C and allowed to equilibrate to room temperature). b. Plates awaiting detection were removed from the incubator, equilibrated to room temperature, and 50 μL of CellTiter-Glo reagent was added to each well. c. The cells were thoroughly lysed by mixing uniformly with shaking for 2 minutes. d. The mixture was left at room temperature for 28 minutes, and after the signal stabilized, it was detected using a PHERAstar FS.

[0096] [Table 1]

[0097] Conclusion: The compound of formula 1 has excellent inhibitory effect on the proliferation of ZR-75-1.

[0098] Example 2 Preparation of Type A Crystals of the Compound of Formula 1 10 mg of the compound of Formula 1 was added to 1 mL of solvent and stirred at a temperature ramp rate of ±0.75°C / min from 60°C to 5°C to form a slurry. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain a solid. The product was defined as Type A crystals by powder X-ray diffraction analysis, and the solvent used was as shown in Table 2 below. The XRPD pattern is shown in Figure 1, and the characteristic peak positions are shown in Table 3. The DSC pattern showed an endothermic peak at 240.55°C. The TGA pattern showed essentially no weight loss between 30°C and 267°C.

[0099] [Table 2]

[0100] [Table 3]

[0101] Example 3: Preparation of Form A Crystals of the Compound of Formula 1 10 mg of the compound represented by formula 1 was added to 1 mL of solvent, clarified by stirring at 60°C, cooled and stirred to crystallize, centrifuged, and then vacuum-dried to obtain a solid. When detected by powder X-ray diffraction, the product was type A crystal.

[0102] [Table 4]

[0103] Example 4: Preparation of Form A Crystals of the Compound of Formula 1 10 mg of the compound represented by formula 1 was dissolved in 0.2 mL of dimethyl sulfoxide, and 1 mL of solvent was added to precipitate it. The precipitate was centrifuged and then vacuum-dried to obtain a solid. The crystal form of the obtained solid was confirmed by powder X-ray diffraction measurement, and the results are shown in Table 5 below.

[0104] [Table 5]

[0105] Example 5: Preparation of Form A Crystals of the Compound of Formula 1 10 mg of the compound of formula 1 was dissolved in 0.2 mL of dimethyl sulfoxide, and 1 mL of acetone was added. No precipitation occurred after the solution was cooled to 5°C and stirred to crystallize. The solution was centrifuged and then vacuum-dried to obtain a solid. When detected by powder X-ray diffraction, the product was Type A crystals.

[0106] Example 6: Preparation of Form A Crystals of the Compound of Formula 1 10 mg of the compound represented by formula 1 was dissolved in 0.3 mL of dichloromethane, and 1 mL of solvent was added to precipitate it. The precipitate was centrifuged and then vacuum dried to obtain a solid. The crystal form of the obtained solid was confirmed by powder X-ray diffraction measurement, and the results are shown in Table 6 below.

[0107] [Table 6]

[0108] Example 7: Preparation of B-type crystals of the compound of formula 1 10 mg of the compound represented by Formula 1 was dissolved in 0.2 mL of dimethyl sulfoxide, 1 mL of methyl tert-butyl ether was added, and the mixture was stirred at room temperature to form a slurry. The precipitate was then centrifuged and vacuum dried to obtain a solid. Powder X-ray diffraction analysis revealed that the product was defined as type B crystals. The XRPD pattern is shown in Figure 2, and the characteristic peak positions are shown in Table 7. The DSC pattern showed endothermic peaks at 79.87 °C and 240.13 °C. The TGA pattern showed a weight loss of 2.43% between 30 °C and 130 °C.

[0109] [Table 7]

[0110] Example 8: Preparation of C-type crystals of the compound of formula 1 10 mg of the compound represented by Formula 1 was dissolved in 0.3 mL of dichloromethane, 1 mL of tetrahydrofuran was added, the temperature was lowered to 5°C, and the mixture was stirred to crystallize. The crystals were centrifuged and then dried under vacuum to obtain a solid. Powder X-ray diffraction analysis identified the product as type C crystals, and the XRPD pattern is shown in Figure 3, with the characteristic peak positions shown in Table 8. The DSC pattern showed endothermic peaks at 99.14°C and 240.84°C. The TGA pattern showed a weight loss of 10.28% between 30°C and 130°C.

[0111] [Table 8]

[0112] Example 9: Preparation of C-type crystals of the compound of formula 1 10 mg of the compound of formula 1 was added to 0.3 mL of chloroform, clarified by stirring at 60°C, cooled and stirred to crystallize, centrifuged, and vacuum-dried to obtain a solid. When detected by powder X-ray diffraction, the product was type C crystals.

[0113] Example 10: Preparation of D-type crystals of the compound of formula 1 10 mg of the compound represented by Formula 1 was added to 0.25 mL of N,N-dimethylformamide and clarified by stirring at 60°C. The temperature was lowered and the crystallization was continued by stirring. The crystals were centrifuged and then dried under vacuum to obtain a solid. Powder X-ray diffraction analysis identified the product as type D crystals. The XRPD pattern is shown in Figure 4, and the characteristic peak positions are shown in Table 9. The DSC pattern showed endothermic peaks at 104.54°C and 240.90°C. The TGA pattern showed a weight loss of 11.10% between 30 and 200°C.

[0114] [Table 9]

[0115] Example 11: Preparation of E-form crystals of the compound of formula 1 10 mg of the compound represented by Formula 1 was added to 0.6 mL of 1,2-dichloroethane and clarified by stirring at 60°C. The temperature was lowered and the crystallization was continued by stirring. The crystals were centrifuged and then dried under vacuum to obtain a solid. Powder X-ray diffraction analysis revealed that the product was defined as E-type crystals. The XRPD pattern is shown in Figure 5, and the characteristic peak positions are shown in Table 10. The DSC pattern showed endothermic peaks at 113.17°C and 241.21°C. The TGA pattern showed a weight loss of 11.13% between 30 and 130°C.

[0116] [Table 10]

[0117] Example 12: Preparation of F-type crystals of the compound of formula 1

[0118] The compound of Formula 1 (11 g, 23.4 mmol) was dispersed in 55 mL of ethyl acetate, stirred at room temperature for 1 hour, filtered to collect the solid, and dried under vacuum at 40°C for 6 hours to obtain a solid. Powder X-ray diffraction analysis identified the product as type F crystals. The XRPD pattern is shown in Figure 6, and the characteristic peak positions are shown in Table 11. The DSC pattern showed endothermic peaks at 111.60°C, 115.04°C, and 241.06°C. The TGA pattern showed a weight loss of 9.12% between 40°C and 180°C.

[0119] [Table 11]

[0120] Example 13: Preparation of G-type crystals of the compound of formula 1 The compound of Formula 1 (216 mg, 0.46 mmol) was dispersed in 10 mL of dichloromethane, stirred at room temperature to clarify, concentrated under reduced pressure, and the solid was retained and dried under vacuum at room temperature for 2 hours to obtain a solid. Powder X-ray diffraction analysis identified the product as type G crystals. The characteristic peak positions are shown in Table 12, and the powder X-ray diffraction pattern is shown in Figure 7. The DSC pattern showed endothermic peaks at 87.44°C and 239.07°C, and exothermic peaks at 113.64°C and 294.50°C. The TGA pattern showed a weight loss of 2.51% from 40°C to 150°C and a weight loss of 6.48% from 150°C to 280°C.

[0121] [Table 12]

[0122] Example 14: Preparation of H-type crystals of the compound of formula 1 100 mg of the compound of Formula 1 was added to 2 mL of 2 M sodium hydroxide solution, and 3 mL of purified water was added to dissolve the mixture. The mixture was stirred at 37 °C for 1 hour to precipitate a solid. The mixture was centrifuged and the supernatant was discarded. 5 mL of 0.1 M hydrochloric acid solution was added, and the mixture was suspended at 37 °C to form a slurry. The mixture was centrifuged and then vacuum dried to obtain a solid. Powder X-ray diffraction analysis revealed that the product was defined as H-type crystals. The XRPD pattern is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 13. The DSC pattern showed an endothermic peak at 240.45 °C. The TGA pattern showed a weight loss of 0.20% between 30 and 233 °C.

[0123] [Table 13]

[0124] Example 15: Preparation of Form I Crystals of the Compound of Formula 1 The compound of Formula 1 (14 mg, 0.03 mmol) was dissolved in 0.5 mL of dichloromethane, filtered, and the filtrate was collected. After standing at room temperature for 120 hours, a solid precipitated. Powder X-ray diffraction analysis identified the product as Type I crystals. The characteristic peak positions are shown in Table 14, and the powder X-ray diffraction pattern is shown in Figure 9. The DSC pattern showed endothermic peaks at 77.76°C and 241.38°C, and the exothermic peak at 113.29°C. The TGA pattern showed a weight loss of 7.58% between 40°C and 200°C.

[0125] [Table 14]

[0126] Example 16: Hygroscopicity study of crystalline forms Surface Measurement Systems intrinsic DVS was used to measure humidity in the range of 0% to 95% at 25°C with a 10% step size. The criteria were that the mass change dM / dT for each gradient was less than 0.002%, TMAX was 360 min, and two cycles were performed.

[0127] [Table 15]

[0128] Example 17: Stability study of crystal form influencing factors The free samples were opened and spread out, and the stability of the samples was examined under the conditions of light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). The sampling examination period was 30 days.

[0129] [Table 16]

[0130] The experimental results of the influencing factors show that the A-type crystal has good physical and chemical stability under high temperature, high humidity and light irradiation.

[0131] Example 18: Long-term / accelerated stability of crystalline forms The free samples were sealed in aluminum foil bags and left at 25°C / 60% RH and 40°C / 75% RH, respectively, to examine their stability. The results are shown below.

[0132] [Table 17]

[0133] As is clear from the experimental results, the A-type crystals have good physical and chemical stability after being left under long-term accelerated conditions for 9 months.

Claims

1. A type A crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, has characteristic peaks at 11.288, 16.624, 18.251, 19.639, 22.547 and 26.085, preferably at 11.288, 16.624, 18.251, 19.639, 21.140, 22.547, 23.439, 26.085, 26.497 and 27.050, and more preferably at 11.288, 16.624, 17.312, 18.251, 19.639, 20.086, 21.140, 22.547, 23.439, 24.234, 26.085, 26.497 and 27.

050. A type crystal. 【Chemistry 1】

2. The powder X-ray diffraction pattern expressed as a diffraction angle 2θ angle is as shown in FIG. The A-type crystal according to claim 1.

3. 3. A method for preparing the A-type crystals of claim 1 or 2, the method comprising: In a first method, a compound represented by formula 1 is added to a solvent (I), and the resulting mixture is slurried and crystallized, the solvent (I) being selected from one or more of an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a nitrile solvent, water, and dimethyl sulfoxide; the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, benzyl alcohol, 1,2-propanediol, and isoamyl alcohol; the ketone solvent is selected from acetone and methyl isobutyl ketone; the ester solvent is selected from ethyl acetate and isopropyl acetate, the ether solvent is selected from methyl tert-butyl ether, propylene glycol methyl ether, isopropyl ether, and tetrahydrofuran; the hydrocarbon solvent is selected from nitromethane, n-heptane, cyclohexane, toluene, and p-xylene; Method 1, wherein the nitrile solvent is selected from acetonitrile; a second method, comprising dissolving the compound of formula 1 in a solvent (II) by heating, followed by stirring at room temperature or at a lowered temperature to crystallize the compound, wherein the solvent (II) is selected from one or more of acetonitrile, acetone, nitromethane, benzyl alcohol, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile / methanol, and 1,2-dichloroethane; a method 3, in which the compound of formula 1 is dissolved in a solvent (III), a solvent (IV) is added, and the mixture is stirred to crystallize, the solvent (III) being selected from dimethyl sulfoxide and dichloromethane, and the solvent (IV) being selected from one or more of water, methanol, ethanol, isopropanol, isopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, and toluene; method.

4. A B-type crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, has characteristic peaks at 7.100, 11.249, 18.241, 22.580 and 26.107, preferably at 6.454, 7.100, 11.249, 18.241, 19.637, 20.092, 20.407, 22.580, 26.107 and 26.550, and more preferably at 6.454, 7.100, 10.448, 11.249, 16.595, 18.241, 19.637, 20.092, 20.407, 22.580, 23.470, 26.107 and 26.

550. B type crystal.

5. The powder X-ray diffraction pattern expressed as a diffraction angle 2θ angle is as shown in FIG. The B-type crystal according to claim 4.

6. 6. A method for preparing the B-type crystals according to claim 4 or 5, the method comprising: a method for crystallizing a compound of formula 1 by dissolving the compound of formula 1 in a solvent (V), adding a solvent (VI) and stirring the mixture, wherein the solvent (V) is selected from dimethyl sulfoxide and the solvent (VI) is selected from methyl tert-butyl ether; method.

7. A C-type crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, has characteristic peaks at 6.484, 7.056, 7.907, 11.060, 14.223 and 20.342, preferably at 6.484, 7.056, 7.907, 11.060, 14.223, 15.973, 20.342, 21.460, 23.090 and 26.398, more preferably at 6.484, 7.056, 7.907, 11.060, 12.702, 14.223, 15.973, 17.526, 20.342, 21.460, 23.090, 26.398 and 27.

500. C type crystal.

8. The powder X-ray diffraction pattern represented by the diffraction angle 2θ angle is as shown in FIG. The C-type crystal according to claim 7.

9. 9. A method for preparing the C-type crystals according to claim 7 or 8, the method comprising: Method 1, which comprises dissolving the compound of formula 1 in solvent (VII), adding solvent (VIII) to precipitate and crystallize the compound, wherein the solvent (VII) is selected from dichloromethane or tetrahydrofuran, and the solvent (VIII) is selected from one or more of tetrahydrofuran and n-hexane; a method 2 in which the compound of formula 1 is dissolved in a solvent (IX) and stirred to crystallize, and the solvent (IX) is selected from chloroform; method.

10. The D-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle 2θ angle, which has characteristic peaks at 6.504, 7.051, 7.896, 11.086, 15.876 and 20.238, preferably 6.504, 7.051, 7.896, 11.086, 13.560, 14.194, 15.876, 17.504, 18.5 and more preferably, characterized by characteristic peaks at 6.504, 7.051, 7.896, 11.086, 13.560, 14.194, 15.876, 17.504, 18.599, 20.238, 20.633, 22.244, 23.963 and 26.

487. D type crystal.

11. The powder X-ray diffraction pattern expressed as a diffraction angle 2θ angle is as shown in FIG. The D-type crystal according to claim 10.

12. 12. A method for preparing the D-type crystals according to claim 10 or 11, the method comprising: The compound of formula 1 is dissolved in a solvent (X), and the solution is stirred to crystallize, and the solvent (X) is selected from N,N-dimethylformamide. method.

13. A type E crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, has characteristic peaks at 6.490, 7.069, 10.968, 14.194, 16.199 and 20.486, preferably at 6.490, 7.069, 8.034, 10.968, 14.194, 16.199, 18.656, 20.486, 21.539 and 22.949, more preferably at 6.490, 7.069, 8.034, 10.968, 14.194, 16.199, 18.656, 20.486, 21.539, 22.360, 22.949, 23.979, 24.676 and 26.

411. E type crystal.

14. The powder X-ray diffraction pattern represented by the diffraction angle 2θ angle is as shown in FIG. The E-type crystal according to claim 13.

15. 15. A method for preparing the E-type crystals according to claim 13 or 14, the method comprising: dissolving the compound of formula 1 in a solvent (XI) and stirring to crystallize, wherein the solvent (XI) is selected from 1,2-dichloroethane; method.

16. The F-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern expressed by diffraction angles 2θ angles, which has characteristic peaks at 7.327, 9.387, 13.968, 15.793, 20.198 and 21.813, and preferably at 7.327, 8.690, 9.387, 9.653, 12.583, 13.968, 15.793, 17.270, 20.198, 20.810, 21.813, 22. and more preferably characterized by characteristic peaks at 7.327, 8.690, 8.970, 9.387, 9.653, 12.583, 13.968, 15.793, 16.429, 17.270, 17.975, 20.198, 20.810, 21.813, 22.186, 23.410, 24.438, 25.444 and 27.

356. F type crystal.

17. The powder X-ray diffraction pattern represented by the diffraction angle 2θ angle is as shown in FIG. The F-type crystal according to claim 16.

18. 18. A method for preparing the F-type crystals according to claim 16 or 17, the method comprising: dissolving the compound of formula 1 in a solvent (XII) and stirring to crystallize, wherein the solvent (XII) is selected from ethyl acetate; method.

19. The H-type crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle 2θ angle having characteristic peaks at 5.271, 10.587, 13.230, 16.017, 21.498, 22.753 and 26.938, preferably 5.271, 10.587, 11.892, 13.230, 16.017, 16.625, 19.110, 21.498, 22.753, and 24.080, 26.938, and 27.536, and more preferably 5.271, 10.587, 11.892, 13.230, 16.017, 16.625, 19.110, 21.498, 22.753, 24.080, 25.459, 26.175, 26.938, 27.536, 31.694, and 38.

116. H type crystal.

20. The powder X-ray diffraction pattern represented by the diffraction angle 2θ angle is as shown in FIG. The H-type crystal according to claim 19.

21. 21. A method for preparing H-type crystals according to claim 19 or 20, the method comprising: Step a. Dissolving the compound of Formula 1 in aqueous sodium hydroxide and stirring; Step b. Adding an aqueous hydrochloric acid solution to the solid obtained in step a to form a slurry and crystallize it; method.

22. The error range of the 2θ angle is ±0.

20. The crystalline form according to any one of claims 1 to 2, 4 to 5, 7 to 8, 10 to 11, 13 to 14, 16 to 17, and 19 to 20.

23. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 2, 4 to 5, 7 to 8, 10 to 11, 13 to 14, 16 to 17, 19 to 20 and optionally a pharmaceutically acceptable excipient. Pharmaceutical compositions.

24. A method for preparing a pharmaceutical composition, comprising mixing the crystalline form according to any one of claims 1 to 2, 4 to 5, 7 to 8, 10 to 11, 13 to 14, 16 to 17, 19 to 20 and a pharmaceutically acceptable excipient; Preparation method.

25. Use of the crystalline form of any one of claims 1 to 2, 4 to 5, 7 to 8, 10 to 11, 13 to 14, 16 to 17, 19 to 20, or the composition of claim 23, in the preparation of a medicament for preventing and / or treating cancer, use.

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