Crystalline forms and preparation methods of KRAS G12D inhibitors

Abstract

The present disclosure relates to crystalline forms of KRAS G12D inhibitors and methods for preparing the same. Specifically, the present disclosure provides crystals of types A, B, C, D, E, F, G, H, I, J, K, L, M, N, and O of the compound of formula (I) and methods for preparing the same. [Case 1] JPEG2026500533000031.jpg53168

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022116420036, filed on December 20, 2022. The above Chinese patent application is incorporated herein by reference in its entirety.

[0002] (Technical field) The present disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a KRAS G12D inhibitor and a method for preparing the same. [Background technology]

[0003] RAS is one of the oncogenic genes with the highest mutation rates in tumors, with approximately 30% of human malignancies associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, of which KRAS mutations are the most common, accounting for approximately 85% of cases. KRAS mutations are common in solid tumors, and are frequently present in the three most lethal human cancers: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among KRAS gene mutations, 97% involve mutations at the 12th or 13th amino acid residue, with G12D being the most critical mutation. Data analysis of Western populations showed that the G12D mutation accounts for 36%, 12%, and 4% of pancreatic, colorectal, and non-small cell lung cancer patients, respectively.

[0004] After activation, KRAS regulates various functions such as cell proliferation, survival, migration, and metabolism through many downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. After the KRAS gene is mutated, the protein remains persistently activated, which continuously activates downstream signaling pathways and promotes tumor development.

[0005] The KRAS protein has long been considered an undruggable drug target because it lacks a traditional small molecule binding site on its surface and is highly resistant to inhibition due to its ultra-high affinity for guanylate. However, due to the importance and ubiquity of aberrant KRAS activation in cancer progression, KRAS has been and remains a highly sought-after target for drug development. Currently, there is a lack of KRAS inhibitors effective against other mutations other than KRAS G12C inhibitors, meaning that most patients with KRAS mutations remain without a therapeutic option. Because G12D is a widely overexpressed mutation in various tumors, the development of inhibitors targeting it is of great clinical significance.

[0006] Patent application PCT / CN2022 / 100016 provides a new KRAS G12D inhibitor (Formula I) with relatively good pharmacological activity. To meet the needs of drug development, its crystalline form needs to be studied. The crystalline form prepared in this disclosure has good physicochemical stability and can meet the needs of drug development and storage.

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] PCT / CN2022 / 100016 Summary of the Invention [Problem to be solved by the invention]

[0009] The present disclosure provides crystalline forms of the compound of formula (I) and methods for their preparation. [ka] [Means for solving the problem]

[0010] The present disclosure provides crystalline form A of the compound of formula (I), which has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 9.2, 13.1, 14.5, 16.6, 17.7, and 21.5.

[0011] In some embodiments, the powder X-ray diffraction pattern of Form A crystals of the compound of Formula (I) has characteristic peaks at 2θ angles of 6.6, 9.2, 10.1, 10.7, 13.1, 14.5, 15.1, 16.6, 17.7, 19.6, 20.9, 21.5, 22.2, 24.0, 24.5, 24.9, 25.9, 27.2, 28.6, and 30.2.

[0012] In some embodiments, the compound represented by formula (I) is a type A crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0013] In some embodiments, the A-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0014] The present disclosure further provides a method for preparing type A crystals of compound of formula (I), which comprises mixing the compound of formula (I) with an appropriate amount of a solvent, and lowering the temperature to cause crystallization, wherein the solvent is one or more selected from methanol and water / methanol.

[0015] The present disclosure further provides crystalline form B of the compound of formula (I), which has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 8.8, 12.7, 14.6, 14.9, 16.2, 18.0, and 21.4.

[0016] In some embodiments, the powder X-ray diffraction pattern of the Type B crystal of the compound of Formula (I) has characteristic peaks at 2θ angles of 7.3, 8.8, 10.1, 10.6, 12.7, 14.6, 14.9, 16.2, 16.6, 17.3, 18.0, 19.2, 20.0, 21.4, 22.2, 24.4, 25.0, 25.7, 28.7, and 29.4.

[0017] In some embodiments, the compound represented by formula (I) is a B-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0018] In some embodiments, the B-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0019] The present disclosure further provides a method for preparing type B crystals of compound of formula (I), which comprises mixing the compound of formula (I) with an appropriate amount of a solvent and lowering the temperature to cause crystallization, wherein the solvent is one or more selected from ethanol, isopropanol, n-propanol, ethyl acetate / ethanol, and ethyl acetate / n-heptane.

[0020] The present disclosure further provides crystalline Form C of the compound of formula (I), which has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 5.7, 7.6, 11.1, 11.4, 17.9, and 19.3.

[0021] In some embodiments, the powder X-ray diffraction pattern of the C-type crystal of the compound of Formula (I) has characteristic peaks at 2θ angles of 5.7, 6.4, 6.9, 7.6, 11.1, 11.4, 12.7, 13.9, 15.9, 17.2, 17.9, 19.3, 23.9, 24.4, 25.7, and 26.4.

[0022] In some embodiments, the compound represented by formula (I) is a C-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0023] In some embodiments, the C-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0024] The present disclosure further provides a method for preparing Type C crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with a suitable amount of a solvent and allowing it to crystallize, wherein the solvent is acetonitrile.

[0025] The present disclosure further provides crystalline form D of the compound of formula (I), whose powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.8, 6.7, and 8.2.

[0026] In some embodiments, the compound represented by formula (I) is a D-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0027] In some embodiments, the D-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0028] The present disclosure further provides a method for preparing type D crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with an appropriate amount of solvent I, adding solvent II, and stirring to cause crystallization, wherein solvent I is one or more selected from ethanol, acetonitrile / methanol, and solvent II is one or more selected from isopropyl acetate and methyl tert-butyl ether.

[0029] The present disclosure further provides crystalline Form E of the compound of Formula (I), which has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 6.7, 7.9, 9.4, 11.8, 12.3, 13.5, 14.0, 16.2, 17.5, 18.1, 20.3, 21.5, 23.6, and 24.9.

[0030] In some embodiments, the compound represented by formula (I) is crystalline form E, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0031] In some embodiments, the E-form crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0032] The present disclosure further provides a method for preparing Form E crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with a suitable amount of a solvent and evaporating to crystallize, wherein the solvent is ethyl acetate.

[0033] The present disclosure further provides Form F crystals of the compound of Formula (I), which have an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 5.7, 7.8, 10.4, 11.3, 12.4, 13.7, 15.6, 16.0, 17.1, 18.0, 19.0, 19.7, 23.3, 24.2, 25.0, 25.8, and 26.9.

[0034] In some embodiments, the compound represented by formula (I) is crystalline form F, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0035] In some embodiments, the F-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0036] The present disclosure further provides a method for preparing Type F crystals of the compound of Formula (I), which comprises mixing the compound of Formula (I) with a suitable amount of a solvent and allowing it to crystallize, wherein the solvent is methyl tert-butyl ether.

[0037] The present disclosure further provides crystalline form G of the compound of formula (I), which has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 7.7, 10.9, 12.8, 15.4, 20.5, and 22.0.

[0038] In some embodiments, the compound represented by formula (I) is a G-form crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0039] In some embodiments, the G-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0040] The present disclosure further provides a method for preparing Form G crystals of compound of Formula (I), which comprises mixing the compound of Formula (I) with an appropriate amount of a solvent, stirring at room temperature for 2 days, and allowing the compound to crystallize, wherein the solvent is dichloromethane.

[0041] The present disclosure further provides crystalline Form H of the compound of Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 7.5, 8.6, 9.4, 12.3, 14.0, 15.9, 17.4, 18.4, 19.4, 20.5, 21.6, 22.9, 24.8, 26.6, and 27.2.

[0042] In some embodiments, the compound represented by formula (I) is crystalline form H, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0043] In some embodiments, the H-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0044] The present disclosure further provides a method for preparing Form H crystals of the compound of Formula (I), which comprises heating Form E crystals of the compound of Formula (I).

[0045] The present disclosure further provides Form I crystals of the compound of formula (I), which have characteristic peaks in their powder X-ray diffraction pattern at 2θ angles of 6.9, 15.3, 16.6, and 20.1.

[0046] In some embodiments, the Form I crystal of the compound of Formula (I) has a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 5.6, 6.9, 8.3, 9.6, 11.4, 13.9, 15.3, 16.6, 18.4, 20.1, 20.6, 21.1, 22.1, 23.1, 24.5, 26.0, and 33.0.

[0047] In some embodiments, the compound represented by formula (I) has a type I crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0048] In some embodiments, the Type I crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0049] The present disclosure further provides a method for preparing Form I crystals of the compound of Formula (I), which comprises mixing the compound of Formula (I) with a suitable amount of a solvent and stirring at room temperature to cause crystallization, wherein the solvent is one or more selected from methanol, ethanol, n-propanol, water / methanol, water / ethanol, water / isopropanol, acetonitrile / methanol, acetone, water / acetone, 2-butanone, acetonitrile, ethyl acetate, isopropyl acetate, n-heptane, tetrahydrofuran / ethanol, ethyl acetate / ethanol, ethyl acetate / n-heptane, isopropyl ether, and methyl tert-butyl ether.

[0050] The present disclosure further provides Form J crystals of the compound of formula (I), which have characteristic peaks in their powder X-ray diffraction pattern at 2θ angles of 7.2, 7.7, 8.5, 9.8, 10.6, and 14.9.

[0051] In some embodiments, the powder X-ray diffraction pattern of Form J crystals of the compound of Formula (I) has characteristic peaks at 2θ angles of 7.2, 7.7, 8.5, 9.8, 10.6, 12.2, 13.5, 14.9, 15.7, 17.1, 17.9, 19.1, 20.0, 20.5, 21.6, 23.3, 24.3, 25.1, 25.7, and 28.3.

[0052] In some embodiments, the compound represented by formula (I) has a J-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0053] In some embodiments, the J-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0054] The present disclosure further provides a method for preparing Type J crystals of the compound of Formula (I), which comprises mixing the compound of Formula (I) with an appropriate amount of a solvent and stirring at room temperature overnight to cause crystallization, wherein the solvent is dichloromethane.

[0055] The present disclosure further provides a crystalline form K of the compound of Formula (I), whose powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.3, 6.7, 10.7, 12.3, 13.5, 14.8, 18.1, 20.6, 21.3, and 27.3.

[0056] In some embodiments, the compound represented by formula (I) is a K-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0057] In some embodiments, the K-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0058] The present disclosure further provides a method for preparing type K crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with a suitable amount of a solvent and allowing it to crystallize, wherein the solvent is tetrahydrofuran.

[0059] The present disclosure further provides Form L crystals of the compound of Formula (I), which have a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 6.8, 8.4, 9.5, 12.3, 14.0, 16.8, 18.3, 20.3, 21.7, 22.7, and 24.8.

[0060] In some embodiments, the compound represented by formula (I) is a form L crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0061] In some embodiments, the L-form crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0062] The present disclosure further provides a method for preparing Form L crystals of compound of formula (I), which comprises mixing the compound of formula (I) with an appropriate amount of a solvent and allowing it to crystallize, wherein the solvent is ethyl acetate.

[0063] The present disclosure further provides a type M crystal of the compound of Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 6.7, 7.8, 9.5, 11.9, 12.3, 13.0, 13.6, 14.3, 14.9, 15.8, 16.8, 17.7, 18.3, 19.1, 20.4, 21.7, 22.4, 23.9, 24.9, 26.7, 27.4, and 27.9.

[0064] In some embodiments, the compound represented by formula (I) is an M-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0065] In some embodiments, the M-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0066] The present disclosure further provides a method for preparing Type M crystals of the compound of Formula (I), which comprises mixing the compound of Formula (I) with a suitable amount of a solvent and allowing it to crystallize, wherein the solvent is isopropyl acetate.

[0067] The present disclosure further provides Form N crystals of the compound of Formula (I), which have a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 6.6, 7.7, 8.2, 9.1, 10.1, 11.3, 11.8, 12.6, 14.0, 15.4, 17.8, 19.0, 19.9, 21.7, 23.1, 24.0, and 25.6.

[0068] In some embodiments, the compound represented by formula (I) has an N-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0069] In some embodiments, the N-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0070] The present disclosure further provides a method for preparing N-type crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with a suitable amount of a solvent and allowing it to crystallize, wherein the solvent is acetone.

[0071] The present disclosure further provides Form O crystals of the compound of Formula (I), which have a powder X-ray diffraction pattern with characteristic peaks at 2θ angles of 7.0, 7.5, 8.9, 9.7, 10.5, 12.0, 12.8, 13.2, 14.0, 14.4, 15.1, 17.5, 18.1, 18.8, 19.6, 20.6, 21.2, 22.3, 24.2, 25.0, 25.9, 27.7, and 28.3.

[0072] In some embodiments, the compound represented by formula (I) is an O-type crystal, and the powder X-ray diffraction pattern thereof is as shown in FIG.

[0073] In some embodiments, the O-type crystal of the compound represented by formula (I) has a 2θ angle error range of ±0.2.

[0074] The present disclosure further provides a method for preparing type O crystals of the compound of formula (I), which comprises mixing the compound of formula (I) with a suitable amount of a solvent and stirring at room temperature to cause crystallization, wherein the solvent is isopropanol.

[0075] The structure of the crystalline form obtained in this disclosure is determined and studied by powder X-ray diffraction pattern (XRPD) and differential scanning calorimetry (DSC).

[0076] The crystallization methods for the crystalline forms in this disclosure are conventional, such as, for example, crystallization by evaporation, crystallization by cooling, or crystallization at room temperature.

[0077] The starting material used in the method for preparing the salt or crystalline form according to the present disclosure may be a compound of formula (I) in any form, including, but not limited to, amorphous, any crystalline form, hydrate, solvate, etc.

[0078] The present disclosure further provides a pharmaceutical composition comprising the following components: (a) a crystalline form of the compound of Formula (I); and (b) optionally, a pharmaceutically acceptable carrier, diluent, or excipient.

[0079] The present disclosure further provides a method for preparing a pharmaceutical composition, the method comprising mixing (a) a crystalline form of the compound of Formula (I), and (b) optionally, a pharmaceutically acceptable carrier, diluent, or excipient.

[0080] The present disclosure further provides the use of a crystalline form of the compound of formula (I) or the composition in the preparation of a medicament for inhibiting KRAS G12D.

[0081] The present disclosure further provides the use of a crystalline form of the compound of formula (I) or said composition in the preparation of a medicament for treating and / or preventing a disease or condition, wherein said disease or condition is cancer.

[0082] In some embodiments, the disease or condition is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0083] In some embodiments, the disease or condition is selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0084] In the specification and claims of this application, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. However, in order to facilitate a better understanding of this disclosure, the following provides definitions and interpretations of some relevant terms. However, if the definitions and interpretations of terms provided herein are inconsistent with the meanings that are commonly understood by those skilled in the art, the definitions and interpretations of terms provided herein shall prevail.

[0085] The term "X-ray powder diffraction pattern or XRPD" as used herein means that, based on the Bragg equation, 2d sin θ=nλ (where λ is the wavelength of the X-ray, the diffraction order n is any positive integer, and generally the first-order diffraction peak is taken, where n=1), when an X-ray is incident on a crystal at a sweep angle θ (the complement of the incident angle, also called the Bragg angle), or on a certain atomic plane having an interplanar distance of d in some crystal samples, the Bragg equation can be satisfied, and thus the X-ray powder diffraction pattern of this group can be measured.

[0086] "X-ray powder diffraction pattern or XRPD" as referred to in this disclosure is a pattern obtained by using Cu-Kα radiation in an X-ray powder diffractometer.

[0087] "Differential scanning calorimetry or DSC" as used in this disclosure refers to the measurement of temperature and heat flow differences between a sample and a reference during ramping or isothermal heating of the sample to characterize all physical and chemical changes associated with thermal effects and obtain phase transition information of the sample.

[0088] "Thermogravimetric analysis or TGA" as used in this disclosure means the continuous measurement of the change in mass of a sample with temperature or time under a programmed temperature.

[0089] "2θ or 2θ angle" as used in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and is expressed in ° or degrees, with an error range of ±0.3, ±0.2, or ±0.1 for 2θ.

[0090] The "lattice spacing or lattice spacing (d value)" in this disclosure refers to selecting three unit vectors a, b, and c that are not parallel to each other in a space lattice and connect two adjacent lattice points, and dividing the lattice into parallel parallelepiped units using them, which are called lattice spacing. The space lattice is divided according to the connecting lines of the determined parallelepiped units, resulting in a set of linear lattices called a space lattice or a crystal lattice. The lattice and the crystal lattice reflect the periodicity of the crystal structure with geometric points and lines, respectively, and different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes), and the unit is Å or angstroms. [Brief explanation of the drawings]

[0091] [Figure 1] 1 is an XRPD pattern of type A crystals of the compound of formula (I). [Figure 2] 1 is an XRPD pattern of type B crystals of the compound of formula (I). [Figure 3] 1 is an XRPD pattern of the C-type crystal of the compound represented by formula (I). [Figure 4] 1 is an XRPD pattern of type D crystal of the compound represented by formula (I). [Figure 5] 1 is an XRPD pattern of type E crystals of the compound of formula (I). [Figure 6] 1 is an XRPD pattern of type F crystals of the compound represented by formula (I). [Figure 7] 1 is an XRPD pattern of the G-type crystal of the compound represented by formula (I). [Figure 8] 1 is an XRPD pattern of H-type crystals of the compound of formula (I). [Figure 9] 1 is an XRPD pattern of type I crystal of the compound represented by formula (I). [Figure 10] 1 is an XRPD pattern of type J crystal of the compound represented by formula (I). [Figure 11] 1 is an XRPD pattern of the K-type crystal of the compound represented by formula (I). [Figure 12]1 is an XRPD pattern of crystalline form L of the compound represented by formula (I). [Figure 13] 1 is an XRPD pattern of M-type crystals of the compound represented by formula (I). [Figure 14] 1 is an XRPD pattern of N-type crystals of the compound represented by formula (I). [Figure 15] 1 is an XRPD pattern of O-type crystals of the compound represented by formula (I). [Figure 16] 1 is an XRPD pattern of an amorphous compound represented by formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0092] Hereinafter, the present disclosure will be described in more detail in combination with examples. However, the examples of the present disclosure are only for illustrating the technical solutions of the present disclosure and do not limit the substance and scope of the present disclosure.

[0093] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The values ​​are shown in units of ppm. NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer, with the measurement solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0094] For MS measurements, a liquid chromatograph mass spectrometer Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS) was used.

[0095] Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS Model Number: Waters ACQuity Qda Detector / Waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model Number: THERMO Q Exactive) High-performance liquid chromatography (HPLC) analysis was performed using high-pressure liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0096] For chiral HPLC analysis, a high performance liquid chromatograph, Agilent 1260 DAD, was used.

[0097] For high-performance liquid preparative chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0098] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0099] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0100] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography. The silica gel plate specifications used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for isolating and purifying the product by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0101] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the carrier.

[0102] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0103] 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.

[0104] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0105] 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.

[0106] The hydrogen gas atmosphere refers to a hydrogen gas balloon with a volume of approximately 1 L connected to the reaction flask.

[0107] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen gas generator or an HC2-SS hydrogenation apparatus were used.

[0108] The hydrogenation reaction was usually carried out by repeating the procedure of evacuating and filling with hydrogen gas three times.

[0109] A CEM Discover-S 908860 microwave reactor was used for the microwave reactions.

[0110] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0111] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0112] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin layer chromatography comprised A: dichloromethane / methanol system and B: n-hexane / ethyl acetate. The volume ratio of the solvents may be adjusted according to the polarity of the compound, and may also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0113] Where the compounds in the Examples contain two or more chiral centers, the relative stereochemistry of those compounds has been identified by NMR studies and / or X-ray diffraction. In such cases, the prefix "rel" is used and the compounds are identified by R / S nomenclature, where R / S does not denote absolute stereochemistry but provides only relative stereochemical information. For example, [ka] teeth, [ka] and [ka] This refers to a 1:1 mixture of , i.e., a racemate.

[0114] XRPD is a powder X-ray diffraction method. Measurements were performed using a BRUKER D8 X-ray diffractometer with 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): 3 to 45°.

[0115] DSC stands for differential scanning calorimetry. A METTLER TOLEDO DSC 3+ differential scanning calorimeter was used for the measurement. The heating rate was 10°C / min. The specific temperature range referred to the corresponding pattern (mainly 25-300°C or 25-350°C). The nitrogen gas purge rate was 50mL / min.

[0116] TGA is thermogravimetric analysis, and a METTLER TOLEDO TGA 2 type thermogravimetric analyzer is used for detection. The heating rate is 10°C / min, the specific temperature range refers to the corresponding pattern (mainly 25-400°C), and the nitrogen gas purge rate is 50mL / min.

[0117] DVS is dynamic moisture adsorption. SMS DVS Advantage is used for detection. At 25°C, the humidity change is 50%-95%-0%-95%-50%, with 10% steps (the last step is 5%) (the specific humidity range is based on the corresponding pattern, and this is the most common usage method). The judgment criterion is that dm / dt is less than 0.002%.

[0118] Example 1 (±)-rel-(1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 1H [ka] [ka]

[0119] Step 1 (±)-5-Methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester 1b (±)-2-Pyrrolidone-5-methyl formate 1a (100 g, 698.61 mmol, Shanghai Bide) and dimethyl sulfate (110 g, 872.10 mmol) were mixed and reacted at 60°C for 16 hours. The reaction mixture was cooled to room temperature and added to a solution of triethylamine (100 g) and methyl tert-butyl ether (150 mL) in an ice bath. The mixture was extracted with methyl tert-butyl ether (300 mL x 6) and then concentrated under reduced pressure to give the crude product, title compound 1b (90 g, yield: 81.9%). The product was used directly in the next reaction without further purification. MS m / z(ESI): 158.1 [M+1].

[0120] Step 2 (±)-5-(2-Methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate methyl ester 1c The crude product, compound 1b (90 g, 572.64 mmol), and methyl nitroacetate (68.18 g, 572.63 mmol) were mixed, heated to 60°C, and reacted with stirring for 30 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate (300 mL) was added. After stirring for 0.5 hours, the mixture was filtered. The filter cake was dried to obtain the title compound 1c (70 g, yield: 50%). The product was used directly in the next reaction without purification. MS m / z(ESI):245.1[M+1].

[0121] Step 3 Methyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (mixture of diastereomers) 1d The crude product, compound 1c (14 g, 57.3 mmol), was dissolved in 600 mL of methanol, and 14 g of 10% wet palladium-carbon catalyst was added. The atmosphere was purged with hydrogen gas three times and the reaction was stirred for 48 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the crude product, title compound 1d (10 g, yield: 94.6%). This product was used directly in the next reaction without further purification. MS m / z(ESI): 185.2 [M+1].

[0122] Step 4 8-(tert-butyl) 2-methyl(±)-rel-(1R,2R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1e The crude product, compound 1d (10 g, 54.2 mmol), was dissolved in 300 mL of dichloromethane, and triethylamine (16 g, 158.12 mmol) and di-tert-butyl dicarbonate (11 g, 50.4 mmol, Shanghai Shaoyuan) were added in an ice bath. The mixture was stirred for 14 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1e (3.3 g, yield: 21.3%). MS m / z(ESI):285.2[M+1]. HPLC analysis: retention time 1.02 min, purity 98.5% (column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1 × 50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: 10% to 95% acetonitrile).

[0123] Step 5 8-(tert-butyl)2-methyl(±)-rel-(1R,2R,5S)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1f Compound 1e (400 mg, 1.4 mmol) was dissolved in 2 mL of tetrahydrofuran, and 3.5 mL of a 2 M solution of borane dimethyl sulfide complex in tetrahydrofuran was added. The mixture was stirred for 14 hours, quenched by adding methanol to the reaction mixture, and the mixture was allowed to react at 50°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1f (176 mg, yield: 46.2%). MS m / z(ESI):271.2[M+1].

[0124] Step 6 (±)-rel-(1R,2R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 1g Compound 1f (1 g, 3.69 μmol) was dissolved in 15 mL of tetrahydrofuran, and 4.4 mL of a 1 M solution of lithium aluminum hydride in tetrahydrofuran was added. The mixture was allowed to react at 0°C for 1 hour with stirring. 0.2 mL of water, 0.2 mL of a 15% aqueous sodium hydroxide solution, and 0.4 mL of water were added to the reaction mixture in that order, and then anhydrous sodium sulfate was added and the mixture was stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated to obtain the title compound 1g (430 mg, yield: 47.9%). The product was used directly in the next reaction without purification. MS m / z(ESI):243.1[M+1].

[0125] Step 7 (±)-rel-(1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 1H 1g (8.8g, 36.3mmol), tert-butyldimethylchlorosilane (16g, 106.1558mmol), and 4-dimethylaminopyridine (4g, 32.4739mmol) were dissolved in 200mL of dichloromethane, and triethylamine (15g, 148.23mmol, 21.4286mL) was added. The mixture was stirred for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1h (8g, yield: 61.7%). MS m / z(ESI): 357.1 [M+1].

[0126] Example 2 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p1 [ka] [ka]

[0127] Step 8 2,6-Dichloro-3-fluoropyridin-4-amine 1j Compound 4-amino-2,6-dichloropyridine 1i (5 g, 30.6 mmol, Shanghai Bide) was dissolved in 20 mL of N,N-dimethylformamide and 20 mL of acetonitrile, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (13 g, 36.8 mmol) was added. The mixture was reacted at 80°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1j (2.2 g, yield: 39.6%).

[0128] Step 9 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 1k Compound 1j (1.8 g, 9.94 mmol) was dissolved in tetrahydrofuran (50 mL), and 20 mL of a 2 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran was added in an ice bath. The mixture was stirred for 0.5 hours, and then di-tert-butyl dicarbonate (6.5 g, 29.7 mmol) was added and the mixture was stirred for 14 hours. The reaction mixture was quenched by adding a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to obtain title compound 1k (1 g, yield: 26.3%). The product was used directly in the next reaction without further purification. MS m / z(ESI): 381.1 [M+1].

[0129] Step 10 4-amino-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 1L Compound 1k (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), and 3 mL of 4 M hydrochloric acid in dioxane was added. The mixture was stirred for 2 hours, and the pH was adjusted to neutral with 4 M aqueous sodium hydroxide in an ice bath. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to obtain the crude product, title compound 1l (500 mg, yield: 67.8%). MS m / z(ESI):281.1[M+1].

[0130] Step 11 2,6-Dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido) tert-butyl nicotinate 1m The crude product, Compound 1l (500 mg, 1.77 mmol), was dissolved in tetrahydrofuran (10 mL), and trichloroacetyl isocyanate (670 mg, 3.55 mmol) was added. The mixture was stirred for 30 minutes, and the reaction mixture was concentrated under reduced pressure to give the crude product, title Compound 1m (835 mg, yield: 99.7%). The product was used in the next reaction without further purification. MS m / z(ESI): 467.9 [M+1].

[0131] Step 12 5,7-Dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol 1n The crude product, Compound 1m (835 mg, 1.77 mmol), was dissolved in 7 M ammonia methanol solution (10 mL) and reacted with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added to the residue. After stirring for 0.5 hours, the mixture was filtered. The filter cake was dried to obtain the crude product, title Compound 1n (400 mg, yield: 89.9%). The product was used directly in the next reaction without purification. MS m / z(ESI):249.9[M+1].

[0132] Step 13 2,4,5,7-Tetrachloro-8-fluoro-pyrido[4,3-d]pyrimidine 1o The crude product, Compound 1n (300 mg, 1.19 mmol), was dissolved in phosphorus oxychloride (6 mL), and N,N-diisopropylethylamine (800 mg, 6.19 mmol) was added. The mixture was stirred at 110°C for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give the crude product, title Compound 1o (344 mg, yield: 97.7%). The product was used directly in the next reaction without further purification. MS m / z(ESI):285.8[M+1].

[0133] Step 14 (±)-rel-(1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 1p Compound 1o (1.0 g, 3.48 mmol) and N,N-diisopropylethylamine (0.9 g, 6.9 mmol) were dissolved in 15 mL of dichloromethane, and 1h (1.25 g, 3.5 mmol) was added at -78 ° C. The mixture was stirred for 1 hour at the same temperature, then the mixture was allowed to react for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the crude product, title compound 1p (1.56 g, yield: 73.7%). MS m / z(ESI): 606.2 [M+1].

[0134] Step 15 tert-Butyl (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1q-1 and Diastereomeric mixture of (1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1q-2 Compound 1p (1.4 g, 2.3 mmol) was dissolved in 1,4-dioxane (20 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (650 mg, 4.08 mmol, Pharmaceuticals), N,N-diisopropylethylamine (1.5 g, 11.6 mmol), and 4A molecular sieves (1.4 g) were added. The mixture was stirred at 105°C for 6 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to give the crude product, a diastereomeric mixture of the title compounds 1q-1 and 1q-2 (1.68 g, yield: 99.8%). The product was used directly in the next reaction without further purification. MS m / z(ESI):729.2[M+1].

[0135] Step 16 tert-Butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1r-1 and a diastereomeric mixture of (5aR,6R,9S)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1r-2 The crude product, a diastereomeric mixture of compounds 1q-1 and 1q-2 (1.68 g, 2.3 mmol), was added to tetrabutylammonium fluoride (2.59 g, 11.51 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified with eluent system B to give a diastereomeric mixture of the title compounds 1r-1 and 1r-2 (1.0 g, yield: 75.0%). MS m / z(ESI): 579.2 [M+1].

[0136] Step 17 tert-Butyl (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1s-1 and 1:1 mixture of diastereomers of tert-butyl (5aR,6R,9S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1s-2 A diastereomeric mixture of compounds 1r-1 and 1r-2 (300 mg, 518.1 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280 mg, 777.2 μmol, prepared by the method disclosed in intermediate 18 on page 104 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (120 mg, 103.8 μmol), and cesium carbonate (506 mg, 1.55 mmol) were dissolved in 6 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The mixture was reacted at 100°C for 6 hours under a nitrogen gas atmosphere, and the reaction mixture was concentrated under reduced pressure to obtain a crude product, a 1:1 mixture of diastereomers of the title compounds 1s-1 and 1s-2 (400 mg). The product was used directly in the next reaction without purification. MS m / z(ESI):777.2[M+1].

[0137] Step 18 5-ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p1 and 5-Ethyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p2 The crude product, a diastereomeric mixture of compounds 1s-1 and 1s-2 (160 mg, 205.9 μmol) was dissolved in ethyl acetate (5 mL), and 1 mL of a 4 M solution of hydrochloric acid in dioxane was added. The mixture was allowed to react at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient mixing ratio: 38% to 45% acetonitrile, flow rate: 30 mL / min) to give a 1:1 mixture of diastereomeric title compounds 1-p1 and 1-p2 (10 mg, yield: 7.2%). MS m / z(ESI): 633.2 [M+1]. 1 H NMR(500 MHz,CD3OD):δ 7.67(ddd, 1H),7.32-7.21(m, 2H),7.11-7.01(m, 1H),5.38-5.35(m, 2H),5.11-5.03(m, 1H),4.64-4.59(m, 1H),4.52-4.46(m, 1H),4.34-4.29(m, 1H),4.25(dd, 1H),4.18-4.12(m, 1H),3.74(br, 1H),3.65(br, 1H),3.26-3.23(m, 3H),3.05-3.01(m, 1H),2.61-1.81(m, 12H), 0.94-0.82(m, 3H).

[0138] The diastereomeric mixture of compounds 1-p1 and 1-p2 was separated using a Chimera column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25 × 250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (0.1% of 7 M NH3 in MeOH), gradient ratio: A:B: 40:60, flow rate: 30 mL / min) to give the title compounds 1-p1 (26 mg, yield: 43.3%) and 1-p2 (26 mg, yield: 43.3%).

[0139] Single configuration compound (relatively short retention time) 1-p2: (26 mg, yield: 43.3%).

[0140] MS m / z(ESI): 633.2 [M+1].

[0141] Chimera HPLC analysis: retention time 7.89 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250 × 4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min).

[0142] 1 H NMR (500 MHz, CD3OD): δ 7.67(ddd, 1H),7.32-7.21(m, 2H),7.11-7.01(m, 1H),5.38-5.27(m, 2H),5.11-5.03(m, 1H),4.64-4.59(m, 1H),4.52-4.44(m, 1H),4.33(d, 1H),4.24(dd, 1H),4.18-4.12(m, 1H),3.75(br, 1H),3.66(br, 1H),3.27-3.18(m, 3H),3.05-3.03(m, 1H),2.60-1.81(m, 12H),0.93-0.82(m, 3H).

[0143] Single configuration compound (relatively long retention time) 1-p1: (26 mg, yield: 43.3%).

[0144] MS m / z(ESI): 633.2 [M+1].

[0145] Chimera HPLC analysis: retention time 13.8 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250 × 4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min).

[0146] 1H NMR (500 MHz, CD3OD): δ 7.67(ddd, 1H),7.32-7.21(m, 2H),7.11-7.01(m, 1H),5.38-5.35(m, 2H),5.11-5.03(m, 1H),4.64-4.59(m, 1H),4.52-4.46(m, 1H),4.34-4.29(m, 1H),4.25(dd, 1H),4.18-4.12(m, 1H),3.74(br, 1H),3.65(br, 1H),3.26-3.23(m, 3H),3.05-3.01(m, 1H),2.61-1.81(m, 12H), 0.94-0.82(m, 3H).

[0147] Compound 1-p1, which is a compound represented by formula (I) in the present disclosure, was detected as amorphous by powder X-ray diffraction, and its powder X-ray diffraction pattern is shown in FIG.

[0148] Biological evaluation Test Example 1: Biological evaluation of AGS cell ERK phosphorylation inhibition experiment (HTRF method) 1. Purpose of the test This experiment was conducted to detect the inhibitory effect of compound 1-p1 on cellular ERK phosphorylation, and to evaluate the IC 50 The inhibitory effect of the compounds on the KRAS target was evaluated based on the magnitude of the .DELTA..times ...

[0149] 2. Experimental Method AGS cells (Nanjing Kebai, CBP60476) were cultured in complete RPMI 1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded into a 96-well plate at a density of 40,000 cells / well in complete medium, with 190 μL of cell suspension added to each well. The cells were then cultured overnight in a cell incubator at 37°C with 5% CO2.

[0150] The next day, 10 μL of the compound to be tested, prepared in complete medium and diluted 5-fold in nine concentration points, was added to each well. The final compound concentration was 10 μM, with a blank control containing 0.5% DMSO. The well plate was then incubated in a cell incubator at 37°C and 5% CO2 for 1 hour. After incubation, the 96-well cell culture plate was removed, the medium was aspirated, and each well was washed once with 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320). The PBS was then aspirated, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on a shaker and lysed for 40 minutes at room temperature. After dissolution, the solution was mixed uniformly by pipetting, and 16 μL of the solution was transferred from each well to two 96-well HTRF detection plates (Cisbio, 66PL96100). Then, 4 μL of premixed phospho-ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or premixed total ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to each plate. The microplates were sealed with plate sealing film, centrifuged for 1 minute in a microplate centrifuge, and incubated overnight in the dark at room temperature.

[0151] On the third day, fluorescence values ​​were read using an ENVISION multifunction plate reader (PerkinElmer, ENVISION) with excitation at 337 nm and emission at 665 nm and 620 nm.

[0152] 3. Data analysis and results The IC of the compound inhibitory activity was calculated by the compound concentration and the ratio of phosphorylated ERK to total ERK using the software Graphpad Prism. 50 The IC value of compound 1-p1 was calculated. 50 The concentration of α-glucan in the α-glucan-containing agonist was 0.4 nM, which had a relatively good inhibitory effect on ERK phosphorylation in AGS cells.

[0153] Test Example 2: Biological evaluation of GP2d and AGS cell 3D growth inhibition experiments 1. Purpose of the test The inhibitory effect of compound 1-p1 on the KRAS target was evaluated by testing the 3D growth inhibitory effect of compound 1-p1 on GP2d and AGS cells.

[0154] 2. Experimental Method GP2d cells (Nanjing Kebai, CBP60010) were cultured in complete medium, i.e., DMEM / high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded in complete medium into a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1,000 cells / well, with 90 μL of cell suspension per well. The cells were centrifuged at 2,000 rpm at room temperature for 5 minutes and then cultured overnight in a cell incubator at 37°C with 5% CO2.

[0155] AGS cells (Nanjing Kebai, CBP60476) were cultured in complete medium, i.e., RPMI 1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded in complete medium into a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1,000 cells / well, with 90 μL of cell suspension per well. The cells were centrifuged at 2,000 rpm at room temperature for 5 minutes and then placed in a 37°C, 5% CO2 cell incubator for overnight incubation.

[0156] The next day, 10 μL of compound prepared in complete medium and serially diluted to prepare the test compound was added to each well. The final compound concentration for GP2d cells was 1 μM, followed by 3-fold serial dilutions for nine concentration points. The final compound concentration for AGS cells was 10 μM, followed by 3-fold serial dilutions for nine concentration points. A blank control containing 0.5% DMSO was also included. The well plate was placed in a cell incubator at 37°C and 5% CO2 for 120 hours. On day 7, the 96-well cell culture plate was removed, and 50 μL of CellTiter-Glo® 3D Reagent (Promega, G9682) was added to each well. After shaking for 25 minutes at room temperature, the mixture was mixed thoroughly by pipetting. 50 μL of the mixture was then transferred to a white, opaque 96-well plate (PE, 6005290). The luminescence signal was read using a multifunction microplate reader (PerkinElmer, ENVISION).

[0157] 3. Data analysis and results The IC of the inhibitory activity of the compound was calculated using the software Graphpad Prism. 50 The IC value of AGS cells was calculated. 50 is 5.8 nM, and IC for GP2d cells 50 The inhibitory effect of compound 1-p1 on the 3D proliferation of AGS and GP2d cells was 0.9 nM.

[0158] Test Example 3: Detection of compound affinity for KRAS protein isoform G12D or WT by SPR method First, biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was diluted to 20 μg / mL in 1x HBS-P+ (Cat. #BR1006-71) buffer containing 100 mM MgCl2 and run through channel 2 of an SA (Cat. #BR1005-31) biosensor chip for 420 s, achieving a coupling level of approximately 5000–7000 RU. Compound samples were then injected for 120 s, followed by a 720 s dissociation period. The assay was performed in single-cycle kinetics mode. The reaction signal was detected in real time using a Biacore 8K instrument, and binding / dissociation curves were obtained. After the assay was completed, data analysis was performed using the Biacore 8K evaluation software, and affinity data was obtained by fitting the data to a 1:1 model. As a result, compound 1-p1 has a KD value of 0.03E-09 mol / L for KRAS G12D and a KD value of 1.54E-09 mol / L for WT, and compound 1-p1 has a relatively good affinity for KRAS protein isoform G12D or WT.

[0159] Example 3 Preparation of Form A Crystals of the Compound of Formula (I) 8 mg of the compound of formula (I) was weighed and dissolved in 0.04 mL of methanol, cooled to 5°C, stirred to crystallize, centrifuged, and the solid was dried under vacuum to obtain a product. The XRPD pattern was detected by powder X-ray diffraction, and the positions of its characteristic peaks are shown in Figure 1 and Table 1. This product was defined as type A crystal of the compound of formula (I). The DSC pattern showed endothermic peak values ​​of 74.81°C, 140.13°C, and 196.78°C.

[0160] [Table 1]

[0161] Example 4 Preparation of Type A Crystals of the Compound of Formula (I) 8 mg of the compound of formula (I) was weighed and dissolved in 0.04 mL of 10% water / methanol (v / v), cooled to 5°C, stirred to crystallize, centrifuged, and the solid was dried under vacuum to obtain a product, which was identified by powder X-ray diffraction as type A crystals of the compound of formula (I).

[0162] Example 5 Preparation of B-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was added to 0.04 mL of ethanol, stirred at room temperature to dissolve, cooled to 5°C, stirred to precipitate, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 2, with characteristic peak positions shown in Table 2. The product was defined as type B crystals of the compound of formula (I). The DSC pattern showed an endothermic peak at 226.81°C.

[0163] [Table 2]

[0164] Example 6 Preparation of B-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was added to 0.8 mL of ethyl acetate / n-heptane (v / v=1:1), stirred at room temperature for 2 days, centrifuged, and the solid was dried under vacuum to obtain a product, which was detected by powder X-ray diffraction to be type B crystals of the compound of formula (I).

[0165] Example 7 Preparation of C-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was dissolved in 0.8 mL of acetonitrile at 50°C, cooled to 5°C, stirred to crystallize, centrifuged, and the solid was dried under vacuum to obtain the product. The XRPD pattern was detected by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 3 and Table 3. The product was defined as type C crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 198.44°C.

[0166] [Table 3]

[0167] Example 9 Preparation of D-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was added to 0.05 mL of ethanol and dissolved by stirring at room temperature. 0.3 mL of isopropyl acetate was added and stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 4, with characteristic peak positions shown in Table 4. The product was identified as type D crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 178.74 °C.

[0168] [Table 4]

[0169] Example 10 Preparation of E-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was dissolved in 0.6 mL of ethyl acetate, evaporated, and crystallized to obtain a product. The XRPD pattern was detected by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 5 and Table 5. The product was defined as E-form crystals of the compound of formula (I). The DSC pattern showed endothermic peaks at 44.15 °C, 167.45 °C, and 189.43 °C.

[0170] [Table 5]

[0171] Example 11 Preparation of F-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was added to 0.8 mL of methyl tert-butyl ether, stirred at room temperature for 2 days, centrifuged, and the solid was dried under vacuum to obtain a product. The XRPD pattern was detected by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 6 and Table 6. The product was identified as type F crystal of the compound of formula (I). The DSC pattern showed endothermic peaks at 198.57 °C and 208.23 °C.

[0172] [Table 6]

[0173] Example 12 Preparation of G-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was added to 0.8 mL of dichloromethane, stirred at room temperature for 2 days, centrifuged, and the solid was dried under vacuum to obtain the product. The XRPD pattern was determined by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 7 and Table 7. The product was identified as the G-type crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 177.46 °C.

[0174] [Table 7]

[0175] Example 13 Preparation of H-type crystals of the compound of formula (I) The E-type crystals of the compound of formula (I) (Example 10) were heated to 180°C to obtain a product. The XRPD pattern was detected by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 8 and Table 8, respectively. The product was defined as the H-type crystals of the compound of formula (I). The DSC pattern showed an endothermic peak value of 193.39°C.

[0176] [Table 8]

[0177] Example 14 Preparation of Form I Crystals of the Compound of Formula (I) 30 mg of the compound of formula (I) was dissolved in 0.3 mL of ethanol, stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 9, with characteristic peak positions shown in Table 9. This product was identified as type I crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 251.58 °C.

[0178] [Table 9]

[0179] Example 15 Preparation of Form I Crystals of the Compound of Formula (I) 8 mg of the compound of formula (I) was added to 0.8 mL of acetonitrile, stirred at room temperature for 2 days, filtered, and the solid was dried under vacuum to obtain a product, which was detected by powder X-ray diffraction to be Form I crystals of the compound of formula (I).

[0180] Example 16 Preparation of Form I Crystals of the Compound of Formula (I) 8 mg of the compound of formula (I) was dissolved in 0.04 mL of ethyl acetate, stirred overnight at room temperature, filtered, and the solid was dried under vacuum to obtain a product, which was detected by powder X-ray diffraction to be Form I crystals of the compound of formula (I).

[0181] Example 17 Preparation of J-type crystals of the compound of formula (I) 60 mg of the compound of formula (I) was added to 0.5 mL of dichloromethane, stirred overnight at room temperature, filtered, and the solid was dried under vacuum to obtain the product. The XRPD pattern was determined by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 10 and Table 10, respectively. This product was identified as type J crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 208.11 °C.

[0182] [Table 10]

[0183] Example 18 Preparation of K-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was dissolved in 0.04 mL of tetrahydrofuran, stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 11, with characteristic peak positions shown in Table 11. The product was identified as type K crystal of the compound of formula (I). The DSC pattern showed an endothermic peak at 208.48 °C.

[0184] [Table 11]

[0185] Example 19 Preparation of L-type crystals of the compound of formula (I) 60 mg of the compound of formula (I) was dissolved in 1 mL of ethyl acetate, stirred at room temperature to precipitate, filtered, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 12, with characteristic peak positions shown in Table 12. The product was identified as type L crystal of the compound of formula (I). The DSC pattern showed endothermic peak values ​​of 57.12 °C, 137.09 °C, and 193.02 °C.

[0186] [Table 12]

[0187] Example 20 Preparation of M-type crystals of the compound of formula (I) 60 mg of the compound of formula (I) was dispersed in 5 mL of isopropyl acetate, stirred at room temperature for 5 days, filtered, and the solid was dried under vacuum to obtain a product. The XRPD pattern was determined by powder X-ray diffraction, and the characteristic peak positions are shown in Figure 13 and Table 13, respectively. This product was identified as M-type crystals of the compound of formula (I). The DSC pattern showed endothermic peaks at 45.80 °C, 130.75 °C, and 193.53 °C.

[0188] [Table 13]

[0189] Example 21 Preparation of N-type crystals of the compound of formula (I) 60 mg of the compound of formula (I) was dissolved in 1 mL of acetone, stirred at room temperature to precipitate, filtered, and the solid was dried under vacuum to obtain a product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 14, with characteristic peak positions shown in Table 14. This product was identified as N-type crystals of the compound of formula (I). The DSC pattern showed endothermic peaks at 76.42 °C and 143.82 °C.

[0190] [Table 14]

[0191] Example 22 Preparation of O-type crystals of the compound of formula (I) 8 mg of the compound of formula (I) was dissolved in 0.12 mL of isopropanol, stirred at room temperature to precipitate, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction analysis revealed an XRPD pattern shown in Figure 15, with characteristic peak positions shown in Table 15. The product was identified as type O crystal of the compound of formula (I). The DSC pattern showed endothermic peaks at 120.14 ° C and 177.32 ° C.

[0192] [Table 15]

[0193] Example 23: Stability studies of crystalline forms The A, B, C, I, J, and K types of crystals of the compound of formula (I) were left flat in an open state, 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 period was 30 days, and the results are shown in Table 16.

[0194] [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4]

[0195] Conclusion: The influencing factor experiments showed that the A, B, C, I, J, and K types of crystals had good physical and chemical properties after being left under high temperature and humidity conditions for 30 days.

[0196] Example 24 Long-Term / Accelerated Stability The stability of the A, B, C, I, J, and K types of crystals of the compound of formula (I) was examined under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively, and the results are shown in Table 17.

[0197] [Table 17]

[0198] Conclusion: As evidenced by the long-term accelerated experiments, the A, B, C, I, J, and K crystals have good physical and chemical stability after storage for 3 or 6 months at 25°C / 60%RH and 40°C / 75%RH.

Claims

1. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 9.2, 13.1, 14.5, 16.6, 17.7, and 21.

5. A type crystal of the compound of formula (I).

2. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 6.6, 9.2, 10.1, 10.7, 13.1, 14.5, 15.1, 16.6, 17.7, 19.6, 20.9, 21.5, 22.2, 24.0, 24.5, 24.9, 25.9, 27.2, 28.6, and 30.

2. A type A crystal of the compound of formula (I) according to claim 1.

3. The powder X-ray diffraction pattern is shown in Figure 1. A type A crystal of the compound of formula (I) according to claim 1.

4. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 8.8, 12.7, 14.6, 14.9, 16.2, 18.0, and 21.

4. A B-type crystal of the compound of formula (I).

5. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 7.3, 8.8, 10.1, 10.6, 12.7, 14.6, 14.9, 16.2, 16.6, 17.3, 18.0, 19.2, 20.0, 21.4, 22.2, 24.4, 25.0, 25.7, 28.7, and 29.

4. A B-type crystal of the compound of formula (I) according to claim 4.

6. The powder X-ray diffraction pattern is shown in Figure 2. A B-type crystal of the compound of formula (I) according to claim 4.

7. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.7, 7.6, 11.1, 11.4, 17.9, and 19.

3. C-type crystals of the compound of formula (I).

8. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.7, 6.4, 6.9, 7.6, 11.1, 11.4, 12.7, 13.9, 15.9, 17.2, 17.9, 19.3, 23.9, 24.4, 25.7, and 26.

4. A C-type crystal of the compound of formula (I) according to claim 7.

9. The powder X-ray diffraction pattern is shown in Figure 3. A C-type crystal of the compound of formula (I) according to claim 7.

10. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 6.9, 15.3, 16.6, and 20.

1. Form I crystal of the compound represented by formula (I).

11. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.6, 6.9, 8.3, 9.6, 11.4, 13.9, 15.3, 16.6, 18.4, 20.1, 20.6, 21.1, 22.1, 23.1, 24.5, 26.0, and 33.

0. A type I crystal of the compound represented by formula (I) according to claim 10.

12. The powder X-ray diffraction pattern is shown in Figure 9. A type I crystal of the compound represented by formula (I) according to claim 10.

13. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 7.2, 7.7, 8.5, 9.8, 10.6, and 14.

9. Form J crystal of the compound of formula (I).

14. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 7.2, 7.7, 8.5, 9.8, 10.6, 12.2, 13.5, 14.9, 15.7, 17.1, 17.9, 19.1, 20.0, 20.5, 21.6, 23.3, 24.3, 25.1, 25.7, and 28.

3. A J-type crystal of the compound of formula (I) according to claim 13.

15. The powder X-ray diffraction pattern is shown in Figure 10. A J-type crystal of the compound of formula (I) according to claim 13.

16. The powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 5.3, 6.7, 10.7, 12.3, 13.5, 14.8, 18.1, 20.6, 21.3, and 27.

3. Form K crystal of the compound of formula (I).

17. The powder X-ray diffraction pattern is shown in Figure 11. A K-type crystal of the compound of formula (I) according to claim 16.

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

2. A crystalline form of the compound of formula (I) according to any one of claims 1 to 17.

19. A method for preparing the A-type crystal of the compound of formula (I) according to any one of claims 1 to 3 and 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent, and lowering the temperature to cause crystallization, wherein the solvent is one or more selected from methanol and water / methanol. method.

20. A method for preparing type B crystals of the compound of formula (I) according to any one of claims 4 to 6 and 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent and lowering the temperature to cause crystallization, wherein the solvent is one or more selected from ethanol, isopropanol, n-propanol, ethyl acetate / ethanol, and ethyl acetate / n-heptane. method.

21. A method for preparing the C-type crystals of the compound of formula (I) according to any one of claims 7 to 9 and 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent and crystallizing the compound, wherein the solvent is acetonitrile. method.

22. A method for preparing the type I crystal of the compound of formula (I) according to any one of claims 10 to 12 and 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent and stirring at room temperature to cause crystallization, wherein the solvent is one or more selected from methanol, ethanol, n-propanol, water / methanol, water / ethanol, water / isopropanol, acetonitrile / methanol, acetone, water / acetone, 2-butanone, acetonitrile, ethyl acetate, isopropyl acetate, n-heptane, tetrahydrofuran / ethanol, ethyl acetate / ethanol, ethyl acetate / n-heptane, isopropyl ether, and methyl tert-butyl ether. method.

23. A method for preparing the J-type crystal of the compound of formula (I) according to any one of claims 13 to 15 and 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent and crystallizing the compound, wherein the solvent is dichloromethane. method.

24. A method for preparing the K-type crystals of the compound of formula (I) according to any one of claims 16 to 18, comprising mixing the compound of formula (I) with an appropriate amount of a solvent and crystallizing the compound, wherein the solvent is tetrahydrofuran. method.

25. A pharmaceutical composition comprising the following components: (a) A-type crystal of the compound represented by formula (I) according to any one of claims 1 to 3 and 18, B-type crystal of the compound represented by formula (I) according to any one of claims 4 to 6 and 18, C-type crystal of the compound represented by formula (I) according to any one of claims 7 to 9 and 18, I-type crystal of the compound represented by formula (I) according to any one of claims 10 to 12 and 18, J-type crystal of the compound represented by formula (I) according to any one of claims 13 to 15 and 18, or K-type crystal of the compound represented by formula (I) according to any one of claims 16 to 18, (b) optionally a pharmaceutically acceptable carrier, diluent or excipient; and A pharmaceutical composition comprising:

26. 1. A method for preparing a pharmaceutical composition, comprising: (a) A-type crystal of the compound represented by formula (I) according to any one of claims 1 to 3 and 18, B-type crystal of the compound represented by formula (I) according to any one of claims 4 to 6 and 18, C-type crystal of the compound represented by formula (I) according to any one of claims 7 to 9 and 18, I-type crystal of the compound represented by formula (I) according to any one of claims 10 to 12 and 18, J-type crystal of the compound represented by formula (I) according to any one of claims 13 to 15 and 18, or K-type crystal of the compound represented by formula (I) according to any one of claims 16 to 18, (b) optionally mixing with a pharmaceutically acceptable carrier, diluent or excipient; Preparation method.

27. A type crystal of the compound represented by formula (I) according to any one of claims 1 to 3 and 18, a type B crystal of the compound represented by formula (I) according to any one of claims 4 to 6 and 18, a type C crystal of the compound represented by formula (I) according to any one of claims 7 to 9 and 18, a type I crystal of the compound represented by formula (I) according to any one of claims 10 to 12 and 18, a type J crystal of the compound represented by formula (I) according to any one of claims 13 to 15 and 18, a type K crystal of the compound represented by formula (I) according to any one of claims 16 to 18, or the composition according to claim 25, use.

28. Use of a type A crystal of the compound of formula (I) according to any one of claims 1 to 3 and 18, a type B crystal of the compound of formula (I) according to any one of claims 4 to 6 and 18, a type C crystal of the compound of formula (I) according to any one of claims 7 to 9 and 18, a type I crystal of the compound of formula (I) according to any one of claims 10 to 12 and 18, a type J crystal of the compound of formula (I) according to any one of claims 13 to 15 and 18, a type K crystal of the compound of formula (I) according to any one of claims 16 to 18, or the composition according to claim 25 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is cancer. use.

29. The disease or condition is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer; 29. The use according to claim 28.

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