Crystal form of pyridopyrimidine derivative, preparation method therefor and use thereof

Abstract

Provided are a crystal form of a pyridopyrimidine derivative, a preparation method therefor, a pharmaceutical composition thereof and the use thereof. Specifically disclosed are a crystal form of a compound of formula (I), a preparation method therefor, a pharmaceutical composition thereof and the use thereof.

Description

Crystal form, preparation method and application of pyridopyrimidine derivatives

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the benefits and priority of Chinese invention patent application No. CN202410040440.3 filed with the State Intellectual Property Office of China on January 10, 2024, and Chinese invention patent application No. CN202510018660.0 filed with the State Intellectual Property Office of China on January 6, 2025, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present disclosure provides a crystal form, a preparation method and applications of a pyridopyrimidine derivative, and specifically discloses the crystal form, preparation method and applications of a compound of formula (I). Background Art

[0004] Cancers caused by mutations in NRAS, HRAS, and KRAS in the RAS family account for nearly a quarter of all human cancers, making it one of the most common gene mutations associated with cancer. It covers almost all types of cancer and causes 1 million deaths worldwide each year. Among them, KRAS is the most common oncogene (85% of all RAS mutations), present in 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mostly non-small cell lung cancers). Depending on the specific mutations present, G12C, G12D, and G12R are the most common KRAS mutations in patients. In addition, there are G12A, G12S, G12V, etc.

[0005] The KRAS protein is a small GTPase with GTP hydrolysis activity, involved in a variety of signaling pathways related to cell survival and growth. When bound to GTP (guanosine triphosphate), KRAS is in an active state, activating a series of downstream pathways. However, after GTP is hydrolyzed to GDP (guanosine diphosphate), KRAS becomes inactive. Normally, upon activation, KRAS is immediately inactivated by its own hydrolases. However, oncogenic KRAS mutations exhibit impaired GTPase activity, predisposing it to remain in the GTP-bound state. This leads to persistent KRAS activation, which in turn activates downstream pathways such as the RAF / MEK / ERK and PI3K / Akt pathways, promoting cell proliferation, differentiation, tumor formation, and tumor progression. KRAS G12D mutations account for 20%-50% of all KRAS-mutant tumors, but no KRAS G12D drugs have been marketed. Research into small molecule oral inhibitors that can inhibit KRAS G12D holds great promise for the treatment of malignant tumors. Summary of the Invention

[0006] The present disclosure provides a crystalline form A of a compound of formula (I), characterized in that its Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 21.34°±0.2°, 24.74°±0.2°, 25.26°±0.2°,

[0007] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 19.18°±0.2°, 19.49°±0.2°, 21.34°±0.2°, 24.74°±0.2°, and 25.26°±0.2°.

[0008] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.15°, 19.18°±0.15°, 19.49°±0.15°, 21.34°±0.15°, 24.74°±0.15°, and 25.26°±0.15°.

[0009] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 9.46°±0.2°, 13.95°±0.2°, 19.18°±0.2°, 19.49°±0.2°, 21.34°±0.2°, 24.74°±0.2°, and 25.26°±0.2°.

[0010] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.15°, 9.46°±0.15°, 13.95°±0.15°, 19.18°±0.15°, 19.49°±0.15°, 21.34°±0.15°, 24.74°±0.15°, and 25.26°±0.15°.

[0011] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 9.46°±0.2°, 13.95°±0.2°, 15.28°±0.2°, 17.12°±0.2°, 19.18°±0.2°, 19.49°±0.2°, 21.34°±0.2°, 24.74°±0.2°, and 25.26°±0.2°.

[0012] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.15°, 9.46°±0.15°, 13.95°±0.15°, 15.28°±0.15°, 17.12°±0.15°, 19.18°±0.15°, 19.49°±0.15°, 21.34°±0.15°, 24.74°±0.15°, and 25.26°±0.15°.

[0013] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 9.46°±0.2°, 13.95°±0.2°, 15.28°±0.2°, 17.12°±0.2°, 19.18°±0.2°, 19.49°±0.2°, 20.82°±0.2°, 21.34°±0.2°, 24.74°±0.2°, 25.26°±0.2°, and 28.32°±0.2°.

[0014] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.15°, 9.46°±0.15°, 13.95°±0.15°, 15.28°±0.15°, 17.12°±0.15°, 19.18°±0.15°, 19.49°±0.15°, 20.82°±0.15°, 21.34°±0.15°, 24.74°±0.15°, 25.26°±0.15°, and 28.32°±0.15°.

[0015] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 9.46°±0.2°, 12.10°±0.2°, 13.95°±0.2°, 15.28°±0.2°, 16.39°±0.2°, 17.12°±0.2°, 19.18°±0.2°, 19.49°±0.2°, 20.82°±0.2°, 21.34°±0.2°, 22.22°±0.2°, 24.74°±0.2°, 25.26°±0.2°, 27.99°±0.2°, and 28.32°±0.2°.

[0016] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.15°, 9.46°±0.15°, 12.10°±0.15°, 13.95°±0.15°, 15.28°±0.15°, 16.39°±0.15°, 17.12°±0.15°, 19.18°±0.15°, 19.49°±0.15°, 20.82°±0.15°, 21.34°±0.15°, 22.22°±0.15°, 24.74°±0.15°, 25.26°±0.15°, 27.99°±0.15°, and 28.32°±0.15°.

[0017] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 9.46°±0.2°, 12.10°±0.2°, 12.78°±0.2°, 13.06°±0.2°, 13.95°±0.2°, 15.28°±0.2°, 16.39°±0.2°, 17.12°±0.2°, 18.56°±0.2°, 18.86°±0.2°, 19.18°±0.2°. °, 19.49°±0.2°, 19.84°±0.2°, 20.82°±0.2°, 21.34°±0.2°, 22.22±0.2°, 22.96°±0.2°, 23.58°±0.2°, 24.11°±0.2°, 24.74°±0.2°, 25.26°±0.2°, 27.99°±0.2°, 28.32°±0.2°, 29.00°±0.2°, and 30.21°±0.2°.

[0018] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.29°±0.2°, 8.09°±0.2°, 9.46°±0.2°, 9.75°±0.2°, 11.06°±0.2°, 12.10°±0.2°, 12.78°±0.2°, 13.06°±0.2°, 13.95°±0.2°, 14.87°±0.2°, 15.28°±0.2°, 16.39°±0.2°, 17. .12°±0.2°、17.54°±0.2°、18.56°±0.2°、18.86°±0.2°、19.18°±0.2°、19.49°±0.2°、19.84°±0.2°、20.82°±0.2°、21.34°±0.2°、22.22°±0.2°、22.96°±0.2°、23.58°±0.2°、24.11°±0.2°、24.74°±0.2°、25.26 ° ± 0.2°, 25.73° ± 0.2°, 26.11° ± 0.2°, 26.50° ± 0.2°, 26.64° ± 0.2°, 27.54° ± 0.2°, 27.99° ± 0.2°, 28.32° ± 0.2°, 28.78° ± 0.2°, 29.00° ± 0.2°, 30.21° ± 0.2°, 30.50° ± 0.2°, 31.03° ± 0.2°, 31.99° ± 0.2°, 33.33° ± 0.2° .2°, 33.69°±0.2°, 34.01°±0.2°, 34.39°±0.2°, 34.81°±0.2°, 35.48°±0.2°, 35.82°±0.2°, 36.37°±0.2°, 36.63°±0.2°, 37.34°±0.2°, 37.78°±0.2°, 38.39°±0.2°, 38.71°±0.2°, 39.14°±0.2°, and 39.57°±0.2°.

[0019] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°±0.2°, 21.34°±0.2°, 24.74°±0.2°, 25.26°±0.2°, and / or 7.29°±0.2°, and / or 9.46°±0.2°, and / or 9.75°±0.2°, and / or 11.06°±0.2°, and / or 12.10°±0.2°, and / or 12.78°±0.2°, and / or 13.06°±0.2°, and / or 13.95°±0.2°, and / or 14.87°±0.2°, and / or 15. and / or 15.28°±0.2°, and / or 16.39°±0.2°, and / or 17.12°±0.2°, and / or 17.54°±0.2°, and / or 18.56°±0.2°, and / or 18.86°±0.2°, and / or 19.18°±0.2°, and / or 19.49°±0.2°, and / or 19.84°±0.2°, and / or 20.82°±0.2°, and / or 22.22°±0.2°, and / or 22.96°±0.2°, and / or 23.58°±0.2°, and / or 24.11°±0.2°, and and / or 25.73°±0.2°, and / or 26.11°±0.2°, and / or 26.50°±0.2°, and / or 26.64°±0.2°, and / or 27.54°±0.2°, and / or 27.99°±0.2°, and / or 28.32°±0.2°, and / or 28.78°±0.2°, and / or 29.00°±0.2°, and / or 30.21°±0.2°, and / or 30.50°±0.2°, and / or 31.03°±0.2°, and / or 31.99°±0.2°, and / or 33.33°±0.2°, and / or 33.69°±0.2°, and / or 34.01°±0.2°, and / or 34.39°±0.2°, and / or 34.81°±0.2°, and / or 35.48°±0.2°, and / or 35.82°±0.2°, and / or 36.37°±0.2°, and / or 36.63°±0.2°, and / or 37.34°±0.2°, and / or 37.78°±0.2°, and / or 38.39°±0.2°, and / or 38.71°±0.2°, and / or 39.14°±0.2°, and / or 39.57°±0.2°.

[0020] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09°, 9.46°, 12.10°, 13.95°, 15.28°, 16.39°, 17.12°, 19.18°, 19.49°, 20.82°, 21.34°, 22.22°, 24.74°, 25.26°, 27.99°, and 28.32°.

[0021] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the above-mentioned A crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.29°, 8.09°, 9.46°, 9.75°, 11.06°, 12.10°, 12.78°, 13.06°, 13.95°, 14.87°, 15.28°, 16.39°, 17.12°, 17.54°, 18.56°, 18.86°, 19.18°, 19.49°, 19.84°, 20.82°, 21.34°, 22.22°, 22.96°, 23.58°, 24.11°, 24.74°. °, 25.26°, 25.73°, 26.11°, 26.50°, 26.64°, 27.54°, 27.99°, 28.32°, 28.78°, 29.00°, 30.21°, 30.50°, 31.03°, 31.99°, 33.33°, 33.69°, 34.01°, 34.39°, 34.81°, 35.48°, 35.82°, 36.37°, 36.63°, 37.34°, 37.78°, 38.39°, 38.71°, 39.14°, 39.57°.

[0022] In some embodiments of the present disclosure, the XRPD pattern of the above-mentioned Form A is basically as shown in Figure 1.

[0023] In some embodiments of the present disclosure, the XRPD diffraction peak data of the above-mentioned Form A are shown in Table 1.

[0024] Table 1 XRPD diffraction peak data of the crystal form A of compound of formula (I)

[0025] In some embodiments of the present disclosure, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A has an onset value of an exothermic peak at 199.55±3.00°C.

[0026] In some embodiments of the present disclosure, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A has an exothermic peak at 204.65±3.00°C.

[0027] In some embodiments of the present disclosure, the DSC spectrum of the above-mentioned crystal form A is basically as shown in Figure 2.

[0028] In some embodiments of the present disclosure, the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form A shows a weight loss of 4.502% at 220.00±3.00°C.

[0029] In some embodiments of the present disclosure, the TGA spectrum of the above-mentioned crystal form A is basically as shown in Figure 3.

[0030] The present disclosure also provides a pharmaceutical composition comprising the crystal form A of the compound of formula (I).

[0031] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0032] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the crystal form A of the compound of formula (I) and a pharmaceutically acceptable excipient.

[0033] The present disclosure also provides a method for treating KRAS G12D mutated solid tumors, comprising administering a therapeutically effective amount of the above-mentioned crystalline form A of the compound of formula (I) or a pharmaceutical composition thereof to an individual in need thereof (eg, a mammal, preferably a human).

[0034] The present disclosure also provides the crystal form A of the compound of formula (I) or a pharmaceutical composition thereof for use in treating solid tumors with KRAS G12D mutation.

[0035] The present disclosure also provides use of the above-mentioned crystal form A of the compound of formula (I) or a pharmaceutical composition thereof in the treatment of solid tumors with KRAS G12D mutation.

[0036] The present disclosure also provides use of the crystal form A of the compound of formula (I) in the preparation of a drug for treating solid tumors with KRAS G12D mutation.

[0037] In some embodiments of the present disclosure, the solid tumor with the KRAS G12D mutation is selected from colon cancer and pancreatic cancer.

[0038] Technical Effects

[0039] The crystalline form of the disclosed compound has good stability and good hygroscopicity, has good cell proliferation inhibitory activity against KRAS G12D mutant tumor cells, effectively inhibits p-ERK, has good PK properties, and has a significant tumor inhibitory effect.

[0040] Definition and Description

[0041] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0042] The intermediate compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0043] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0044] Unless otherwise noted, the positions or relative intensities of peaks in powder X-ray diffraction spectra may vary due to factors such as the instrument, method, and conditions. For any particular crystalline form, the positions of the peaks may vary, and the 2θ values ​​may have errors of ±0.2°, ±0.15°, and ±0.1°. Therefore, these errors should be taken into account when determining each crystalline form, and values ​​within this tolerance are within the scope of this application.

[0045] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter. For example, Use straight solid key and straight dashed bond Indicates the relative configuration of the stereocenter, representing mixture; represent mixture.

[0046] The present disclosure will be described in detail below through examples, which are not intended to limit the present disclosure in any way.

[0047] The structures of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. If the disclosure relates to the absolute configuration of a compound, such absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data on a cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0048] In this disclosure, the term "therapeutically effective amount" means an amount of a drug or pharmaceutical agent that (i) treats a specific disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder. The amount of Form A of the compound of Formula (I) of the present disclosure, or a pharmaceutical composition thereof, that constitutes a "therapeutically effective amount" varies depending on the drug or pharmaceutical agent, the disease state and its severity, the route of administration, and the age of the individual to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0049] The term "treating" means administering a drug or agent to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0050] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0051] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0052] In the present disclosure, the term "subject" includes humans and animals, for example, mammals (such as primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).

[0053] The term "pharmaceutically acceptable excipient" refers to excipients that are non-irritating to organisms and do not impair the biological activity and properties of the active substance. Conventional pharmaceutical excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, carriers, diluents, isotonicity regulators, pH regulators, and the like. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.

[0054] Typical routes of administration of Form A of the compound of formula (I) or its pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0055] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0056] In some embodiments, the pharmaceutical composition can be in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active substance with pharmaceutically acceptable excipients well known in the art. These excipients enable the disclosed Form A of the compound of formula (I) or its pharmaceutical composition to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

[0057] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0058] The pharmaceutical composition of the present disclosure contains a therapeutically effective amount of the crystalline form A of the compound of formula (I) selected from 0.001 mg / kg body weight to 1000 mg / kg body weight, for example 0.01 mg / kg body weight to 500 mg / kg body weight, in the form of single or divided doses.

[0059] Those skilled in the art recognize that the measured data of XRPD peak positions and / or intensities for a given crystalline form of the same compound will vary within a range of error. The 2θ values ​​in this disclosure encompass an appropriate range of error, which is typically represented by "±". For example, a 2θ value represented in this disclosure as a specific angle value of ±0.20° represents that the specific angle value has an error range of ±0.20°, i.e., 8.09°±0.2° represents a 2θ range of 7.89° to 8.29°. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operator bias, etc., those skilled in the art recognize that an appropriate error range for XRPD diffraction angles may be ±0.20°, ±0.15°, ±0.10°, ±0.05° or less, and that some variability in peak intensity is allowed. The terms "substantially the same" or "substantially as shown" when used to describe an XRPD pattern refer to a pattern that includes diffraction peaks that have at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the diffraction angles within a standard deviation of ±0.2° 2θ.

[0060] As those skilled in the art recognize that the measured data of the DSC spectra for a given crystalline form of the same compound will vary within an error tolerance. The starting value of the peak and the single peak value (expressed in degrees Celsius) are allowed an appropriate error range. Typically, the error range is represented by "±". For the same crystal form of the same compound, in consecutive analyses, the thermal transition temperature and melting point errors are typically within ± 3.00 ° C. For example, a peak value of "204.65 ± 3.00 ° C" is represented as being within the range of 207.65 ° C to 201.65 ° C. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operator bias, etc., those skilled in the art recognize that the appropriate error range for the single peak value may be ± 3.0 ° C, ± 2.0 ° C or less.

[0061] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0062] This disclosure uses the following abbreviations:

[0063] ACN stands for acetonitrile; DMSO stands for dimethyl sulfoxide; MTBE stands for methyl tert-butyl ether; N2: nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; ℃: degree Celsius; μm: micrometer; mm: millimeter; μL: microliter; mol / L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; μw / cm 2 : microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole; 1M represents 1 moL / L; rpm: rotational speed; XRPD stands for X-ray powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for proton nuclear magnetic resonance.

[0064] The compounds disclosed herein are named according to the conventional nomenclature in the art or using Software nomenclature, commercially available compounds use supplier catalog names, and all solvents used in this disclosure are commercially available.

[0065] Instruments and analytical methods

[0066] The present invention discloses an X-ray powder diffractometer (XRPD) method

[0067] Instrument model: Bruker D2 PHASER X-ray powder diffractometer

[0068] Test method: Approximately 10-20 mg of sample was used for XRPD detection.

[0069] The detailed XRPD parameters are as follows:

[0070] Radiation source: Cu, kα,

[0071] Light tube voltage: 30kV, light tube current: 10mA

[0072] Divergence slit: 1mm

[0073] Detector slit: 0.075mm

[0074] Anti-scatter slit: 3mm

[0075] Scanning range: 3-40 degrees

[0076] Step diameter: 0.02deg

[0077] Step length: 0.3 seconds

[0078] Single crystal X-ray diffraction detection and analysis of the present invention

[0079] Instrument model: Bruker D8 VENTURE

[0080] Cryogenic equipment model: Oxford Cryostream 800

[0081] Test parameters:

[0082] Cu target: Power: 2.5kW,

[0083] Distance from sample to detector: d = 45 mm

[0084] Voltage: 50kV

[0085] Current: 50mA

[0086] Diffraction experiment temperature T = 173K

[0087] The present invention discloses a differential scanning calorimeter (DSC) method

[0088] Instrument model: Discovery 2500 differential scanning calorimeter

[0089] Test Method: A precisely weighed sample (2-3 mg) was placed in a DSC aluminum crucible, sealed, and positioned at the sensor sample end (S). A blank reference crucible was prepared similarly and positioned at the sensor reference end (R). The sample was heated from 30°C (room temperature) to 400°C at a rate of 10°C / min under 50 mL / min N₂ conditions.

[0090] Thermogravimetric analysis (TGA) method disclosed herein

[0091] Instrument model: Discovery 5500 Thermogravimetric Analyzer

[0092] Test method: Place an empty crucible on the sensor and reset to zero. Using the built-in balance, weigh 5.581 mg of sample into the crucible and test. Heat the sample from 30°C to 400°C at a rate of 10°C / min under 25 mL / min N2.

[0093] The present invention discloses a dynamic vapor sorption analysis (DVS) method

[0094] Instrument model: SMSDVS Advantage dynamic vapor adsorption instrument

[0095] Test conditions: Take a sample (10-30 mg) and place it in the DVS sample tray for testing.

[0096] The detailed DVS parameters are as follows:

[0097] Temperature: 25℃

[0098] Balance: dm / dt = 0.005% / min (minimum: 10 min, maximum: 180 min)

[0099] Gas: N2

[0100] RH (%) test steps: 10% (90%-0%-90%); 5% (95%-90%, 90%-95%)

[0101] RH (%) test step range: 0%-95%-0%

[0102] The moisture absorption evaluation is classified as follows:

[0103] Table 2. Hygroscopicity evaluation classification

[0104] Note: ΔW% indicates the weight gain of the test sample due to moisture absorption at 25±1℃ and 80±2% RH. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1: XRPD spectrum of the crystal form A of the compound of formula (I) using Cu-Kα radiation.

[0106] Figure 2: DSC spectrum of crystalline form A of compound of formula (I).

[0107] Figure 3: TGA spectrum of crystalline form A of compound of formula (I).

[0108] Figure 4: DVS spectrum of the crystalline form A of compound of formula (I).

[0109] Figure 5: Ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I). DETAILED DESCRIPTION

[0110] The present disclosure is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0111] Example 1: Synthesis of compound of formula (I)

[0112] Step 1: Preparation of intermediate 2-2

[0113] Intermediate 2-1 (50 g, 418.09 mmol) was dissolved in dichloromethane (500 mL), and triethylamine (84.61 g, 836.17 mmol) was added, followed by di-tert-butyl dicarbonate (100.37 g, 459.90 mmol). The mixture was allowed to react at 25°C for 16 hours. 100 mL of water was added to the reaction solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain intermediate 2-2. MS: m / z = 206.1 [M+Na] + .

[0114] Step 2: Preparation of intermediate 2-3

[0115] Intermediate 2-2 was dissolved in anhydrous tetrahydrofuran (25 g, 136.43 mmol) (350 mL). 3,7-Dipropyl-3,7-diazabicyclo[3.3.1]nonane (37.31 g, 177.36 mmol) was added and cooled to -65°C. Sec-butyllithium (1.3 M, 157.42 mL) was slowly added dropwise. After reacting for 1 hour, methyl chloroformate (15.73 g, 166.44 mmol) was added dropwise. The mixture was allowed to react at -65°C for 2 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride (20 mL) and extracted with ethyl acetate (300 mL x 2). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 50 / 1 to 25 / 1) to obtain Intermediate 2-3. MS: m / z = 186.0 [M-tBu+H] + .

[0116] Step 3: Preparation of Intermediate 2-4

[0117] Intermediate 2-3 (12 g, 49.73 mmol) was dissolved in tetrahydrofuran (120 mL), and 3-chloro-2-chloromethylpropene (24.87 g, 198.94 mmol) was added. The mixture was cooled to -40°C, and lithium bis(trimethylsilyl)amide (1 M, 99.47 mL) was slowly added dropwise. The temperature was gradually raised to 20°C and the reaction was allowed to react for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain Intermediate 2-4, a mixture of relative configurations. TLC (petroleum ether:acetone = 5:1) was performed twice. The Rf value of 2-4 was 0.5, and the Rf value of its isomer was 0.55. The retention time of 2-4 on LCMS (column: Agilent Poroshell 120EC-C18 2.7 μm 3.0*30 mm, mobile phase: A: water (0.037% formic acid) - B: acetonitrile (0.0187% formic acid); gradient: B: 5%-95%) was 0.776 min, and the retention time of its isomer was 0.801 min. MS: m / z = 274.0 [M-tBu+H] + .

[0118] Step 4: Preparation of Intermediate 2-5

[0119] Intermediate 2-4 (3.6 g, 10.92 mmol) was dissolved in hydrogen chloride / ethyl acetate (4 M, 27.29 mL) and reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride salt of intermediate 2-5. MS: m / z = 230.1 [M+H] + .

[0120] Step 5: Preparation of Intermediate 2-6

[0121] The hydrochloride salt of Intermediate 2-5 (2.9 g) was dissolved in methanol (100 mL) and potassium carbonate (4.52 g, 32.69 mmol) was added. The mixture was allowed to react at 20°C for 2 hours. Dichloromethane (80 mL) was added to the reaction solution, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain Intermediate 2-6. MS: m / z = 194.1 [M+H] + .

[0122] Step 6: Preparation of Intermediate 2-7

[0123] Intermediate 2-6 (1.6 g, 8.28 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium aluminum tetrahydride (628.51 mg, 16.56 mmol) was added. The mixture was allowed to react at 0°C for 2 hours. The reaction solution was diluted dropwise with ethyl acetate (10 mL), followed by water (0.63 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude intermediate 2-7. MS: m / z = 166.1 [M+H] + .

[0124] Step 7: Preparation of Intermediate 1-2

[0125] Intermediate 1-1 (25 g, 99.03 mmol) was dissolved in dichloromethane (200 mL) and cooled to -30°C. N,N-diisopropylethylamine (38.40 g, 297.08 mmol) and 1-1B (21.02 g, 99.03 mmol) were then added sequentially. The mixture was reacted at -30°C for 2 hours. The mixture was then concentrated under reduced pressure to obtain the crude intermediate 1-2. MS: m / z = 428.1 [M+1] + .

[0126] Step 8: Preparation of Intermediate 1-3A

[0127] Intermediate 1-2 (23 g) and intermediate 2-7 (9.76 g) were dissolved in anhydrous toluene (300 mL). Sodium tert-butoxide (13.93 g, 145.00 mmol) was slowly added at 0°C. The mixture was reacted at 0°C for 0.5 hour and then at 20°C for 0.5 hour. The reaction solution was diluted with 200 mL of ethyl acetate, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford crude product 1-3. The crude product 1-3 was purified by preparative SFC (column: DAICEL CHIRALCEL OD (250 mm x 50 mm, 10 μm); mobile phase: [A (supercritical carbon dioxide), B (ethanol containing 0.1% ammonia)]; B: 40%) to afford single isomer 1-3A and its isomers. The retention time of 1-3A under the conditions of SFC analysis (chromatographic column: Cellulose 2 100mm*4.6mm, 3μm) mobile phase: [A (supercritical carbon dioxide), B (methanol (0.05% diethylamine))]; B: 40%) was 4.964min, and the ee value was 95.7%. 1H NMR(400MHz,CD3OD)δ8.76(s,1H),4.98-4.87(m,2H),4.51–4.48(m,3H),4.34-4.29(m,1H),4.27(br s,2H),4.23-4.18(m,1H),3.61–3.58(m,3H),3.12(d,J=9.5Hz,1H),2.78(br d,J=16.8Hz,1H),2.71(dd,J=4.0,9.6Hz,1H),2.45(br d,J=16.8Hz,1H),1.83–1.72(m,2H),1.75-1.62(m,3H),1.55–1.51(m,1H),1.42(s,9H),0.60(q,J=4.2Hz,1H),0.47-0.42(m,1H). MS: m / z=557.2[M+1] + The retention time of its isomer under the same conditions was 8.382 min and the ee value was 96.5%.

[0128] Step 9: Synthesis of Intermediate 1-4

[0129] Intermediate 1-3A (11.3 g, 20.29 mmol) was added to water (60 mL) and anhydrous dioxane (240 mL). Then, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.48 g, 2.03 mmol), Intermediate 1-4A (15.38 g, 24.34 mmol), and cesium carbonate (13.22 g, 40.57 mmol) were added. The mixture was reacted at 87°C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (mobile phase: dichloromethane:methanol = 50:1 to 20:1) to obtain Intermediate 1-4. MS(ESI)m / z:862.4[M+H2O-Ph2CO+1] + .

[0130] Step 10: Synthesis of Intermediate 1-5

[0131] Intermediate 1-4 (8.4 g, 8.18 mmol) was added to ethyl acetate (30 mL) and water (10 mL), followed by the addition of hydrochloric acid / ethyl acetate (4 M, 62.37 mL) and allowed to react at 20°C for 2 hours. Water (30 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL x 2). The aqueous phases were combined and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The product was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 1-5. MS (ESI) m / z: 762.3 [M+1] + .

[0132] Step 11: Synthesis of compound of formula (I)

[0133] Intermediate 1-5 (6.2 g) was added to acetonitrile (70 mL), followed by tetramethylammonium fluoride (2.29 g, 13.83 mmol), and the mixture was allowed to react at 60°C for 1 hour. The reaction mixture was diluted with 100 mL of ethyl acetate, washed with 30 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane (10% ammonia in methanol): methanol = 20:1 to 10:1) to obtain the compound of formula (I). MS (ESI) m / z: 606.3 [M+1] + , 1 H NMR (400MHz, CD3OD) δ=9.01(s,1H),7.76(dd,J=5.6,9.2Hz,1H),7.28-7.19(m,2H),7.15(d,J=2.3Hz,1H),5.08(br s,1H),5.01(br s,1H),4.70-4.54(m,3H),4.43(dd,J=7.3,10.0Hz,1H),4.32(dd,J=6.3,10.3 Hz,1H),3.78-3.65(m,5H),3.39-3.34(m,1H),3.23(d,J=9.5Hz,1H),2.93(br d,J=17.3Hz,1H),2.82(dd,J=4.0,9.3Hz,1H),2.56(br d,J=17.1Hz,1H),1.91-1.76(m,5H),1.64(td,J=3.6,6.9Hz,1H),0.72(q,J=4.0Hz,1H),0.61-0.53(m,1H).

[0134] Example 2-1: Preparation of Crystalline Form A of Compound (I)

[0135] The compound of formula (I) (37 g) was added to 250 mL of methyl tert-butyl ether, suspended and stirred at 45°C for 4 hours, and then stirred at 20°C for 16 hours. The mixture was filtered, and the filter cake was rinsed with 30 mL of methyl tert-butyl ether. The filter cake was dried under reduced pressure to obtain a solid, crystalline Form A of the compound of formula (I). Its XRPD spectrum is shown in Figure 1 , its DSC spectrum is shown in Figure 2 , and its TGA spectrum is shown in Figure 3 .

[0136] Example 2-2: Preparation of Crystalline Form A of Compound of Formula (I)

[0137] Compound (I) (34 g) was added to 60 mL of ethanol and heated at 45°C to dissolve. 40 mL of methyl tert-butyl ether was slowly added, and seed crystals of Form A were added for induction. The mixture was stirred at 45°C for 2 hours. 200 mL of methyl tert-butyl ether was then slowly added. The mixture was stirred at 45°C for 1 hour, then cooled to 20°C and stirred for 16 hours. The mixture was filtered, and the filter cake was rinsed with 20 mL of n-heptane. The filter cake was dried to obtain Form A of Compound (I). Its XRPD pattern was substantially consistent with Figure 1 , its DSC pattern was substantially consistent with Figure 2 , and its TGA pattern was substantially consistent with Figure 3 .

[0138] Example 2-3: Preparation of a crystalline form of the compound of formula (I)

[0139] 10 mg of the compound of formula (I) was added to 2 mL of ethanol and stirred. If the sample did not dissolve, 0.5 mL of methanol was added dropwise and stirred until the sample was completely dissolved, yielding a yellow clear solution. The sample solution was placed in a 4 mL semi-sealed sample vial and allowed to evaporate slowly at room temperature. After one week, colorless blocky crystals were obtained.

[0140] Example 3: Study on the Hygroscopicity of Crystal Form A of Compound (I)

[0141] Experimental Materials:

[0142] SMS DVS Intrinsic Dynamic Vapor Sorption Analyzer

[0143] Experimental methods:

[0144] 10-30 mg of the crystalline form A of the compound of formula (I) was placed in a DVS sample tray for testing.

[0145] Experimental results:

[0146] The DVS spectrum of the crystal form A of the compound of formula (I) is shown in FIG4 . When the humidity rises to 80%, ΔW=1.606%.

[0147] Experimental conclusion:

[0148] The weight gain of the crystal form A of the compound of formula (I) at 25° C. and 80% RH was 1.606%, indicating that the sample was slightly hygroscopic.

[0149] Example 4: Single crystal X-ray diffraction analysis of the compound of formula (I)

[0150] The colorless block crystals obtained in Example 2-3 were taken and the diffraction intensity data were collected using a single crystal X-ray diffractometer. The basic structural information of the compound is: Molecular formula C 35 H 33 F2N7O, monoclinic system, space group P21. Unit cell parameters α=γ=90°, β=95.763(3)°, volume The absolute configuration parameter Flack value is 0.16 (17). The absolute configuration of the compound of formula (I) can be determined from the single crystal data. A three-dimensional structure ellipsoid diagram of a single crystal of the compound of formula (I) is shown in Figure 5. The crystal structure data and parameters of the compound of formula (I) are shown in Tables 3, 4, 5, 6, 7 and 8.

[0151] Table 3 Crystal data of single crystal of compound of formula (I)

[0152] Table 4 Atomic coordinates of the crystal of compound of formula (I) (×10 4 ) and the equivalent isotropic shift parameter

[0153] Table 5 Bond lengths of crystals of compound of formula (I)

[0154] Table 6 Bond angles of single crystals of compound of formula (I) (Angle / °)

[0155] Table 7 Twist angle of single crystal of compound of formula (I) (Angle / °)

[0156] Table 8 Hydrogen atom coordinates of single crystal of compound of formula (I) (×10 4 ) and isotropic shift parameters

[0157] Example 5: Solid Stability Test of Crystalline Form A of Compound (I)

[0158] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 9001), in order to evaluate the solid stability of the crystal form A of compound of formula (I), the crystal form A was subjected to high temperature (60°C, open), high humidity (25°C / 92.5% relative humidity, open), light (open, at 5000±500 lux (visible light) and 90μw / cm 2 (UV) irradiation for 10 days, the total illumination received is not less than 1.2×10 6 Lux·hr, near-ultraviolet energy not less than 200w·hr / m 2 , and the light-shielded control group samples were placed at the same time and wrapped in tin foil. 1.5 g of each sample was placed. After the placement, XRPD tests were performed on all stability samples. The results are shown in Table 9.

[0159] Table 9 Solid stability test results of compound A of formula (I)

[0160] Conclusion: The crystal form of compound A of formula (I) did not undergo significant changes under all stability conditions (high temperature, high humidity, and light), and has good chemical stability.

[0161] Biological test data

[0162] Experimental Example 1: Inhibitory effect of crystal form A of compound of formula (I) on the proliferation of GP2D cell line

[0163] 1. Experimental Materials

[0164] Table 10. Cell and culture medium preparation

[0165] Table 11. Main reagents

[0166] 2. Experimental Methods

[0167] Experimental cell culture medium: Add fetal bovine serum with a final concentration of 10% and 1% penicillin / streptomycin solution to DMEM cell culture medium and store at 4°C until use.

[0168] GP2D cells that have reached 80% cell confluence were digested with trypsin, resuspended and counted by centrifugation, and cell suspension was prepared with culture medium. 180 μL / well cell suspension (1000 cells / well) was added to each well of a 96-well plate, and the plate was cultured in a cell culture incubator containing 5% CO2 at 37°C overnight.

[0169] The test compound was diluted to 200 μM in DMSO and then to 10 μM in complete culture medium. Nine dilutions were performed in a 5x descending order, starting at 10 μM. After overnight cell culture, the diluted mixture was transferred to the corresponding cell plates. The final compound concentration was 1 μM, and the mixture was diluted in a 5x descending order for nine concentrations. The cells were mixed and incubated at 37°C in a cell culture incubator with 5% CO2 for 5 days.

[0170] After incubation for the indicated time, remove the 96-well cell culture plate, discard 50 μL of supernatant, and add 80 μL of 3D-CellTiter Glo. Incubate at room temperature with shaking for 30 minutes. Read the plate on an Envision reader using the *US LUM-US LUM 96 (cps) program.

[0171] The signal values ​​of each group were normalized by subtracting the signal value of the cell-free control well. The data were used to calculate the cell viability after compound treatment according to the following formula: % inhibition rate = (1-(RFU compound-AVER(RFU negative control) / (AVER(RFU positive control)-AVER(RFU negative control))) × 100%. Positive control: cells treated with 0.5% DMSO; negative control: cells without cells and complete medium only. The IC values ​​of the compounds were calculated using Prism 8.3.0. 50 Value,IC 50 The value is calculated as log(inhibitor) vs.response(three parameters): Y=Bottom+(Top-Bottom) / (1+10^((X-LogIC 50 ))).

[0172] 3. Experimental Results

[0173] IC of compounds for cell proliferation inhibition 50 As shown in the following table.

[0174] Table 12 Inhibitory effect of compounds on GP2D cell proliferation

[0175] Experimental conclusion: Crystal form A of compound of formula (I) has a significant proliferation inhibitory effect on GP2D cells with KRAS G12D mutation.

[0176] Experimental Example 2: Inhibitory effect of the compound of formula (I) on the proliferation of PANC04.03 cell line

[0177] 1. Experimental purpose:

[0178] This experiment aims to verify the inhibitory effect of the disclosed compounds on the proliferation of KRAS G12D mutated PANC04.03 human pancreatic cancer cells.

[0179] 2. Experimental Materials

[0180] The cell line PANC04.03 and RPMI-1640 culture medium were purchased from GIBCO, FBS was purchased from Hyclone, and human insulin was purchased from Yeasen. 96-well plates were purchased from Ultra Low Cluster, 3D Cell Viability Assay (3D cell viability chemiluminescence detection reagent) reagent was purchased from Promega, and 2104 EnVision plate reader was purchased from PerkinElmer.

[0181] 3. Experimental methods:

[0182] PANC04.03 cells were cultured in RPMI-1640 with 15% FBS and 5 μg / ml human insulin at 37°C and 5% CO₂ in an incubator. Cells were passaged regularly, and cells in the logarithmic growth phase were harvested for plating. PANC04.03 cells were seeded in 96-well U-bottom cell culture plates, with 135 μL of cell suspension per well containing 2,000 PANC04.03 cells. The plates were incubated overnight at 37°C, 5% CO₂, and 100% relative humidity. Test compounds were diluted five-fold using a pipette to the eighth concentration, from 200 μM to 2.56 nM, in duplicate. 78 μL of culture medium was added to the middle plate, and 2 μL of the serially diluted compound was transferred to each well of the corresponding position. After mixing, 20 μL of the compound was transferred to each well of the cell plate. The concentration of the compound transferred to the cell plate ranged from 1 μM to 0.0128 nM. The cell plates were incubated in a CO2 incubator for 7 days. After the incubation period, 100 μL of cell viability chemiluminescent detection reagent was added to each well of the cell plates. The cells were incubated at room temperature for 10 minutes to allow the luminescent signal to stabilize. The cells were then read using a multi-label analyzer.

[0183] 4. Data Analysis

[0184] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained in "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism).

[0185] 5. Experimental results

[0186] The results are shown in Table 13.

[0187] Table 13 IC values ​​of compounds against PANC04.03 cell proliferation 50 value

[0188] Experimental conclusion: The compound of formula (I) has significant anti-proliferative activity against PANC04.03 cells with KRAS G12D mutation.

[0189] Experimental Example 3. In vivo pharmacokinetic experiment

[0190] 1. Experimental purpose:

[0191] The purpose of this experiment is to investigate the pharmacokinetic characteristics of the disclosed compounds in CD-1 mice after oral and intravenous administration.

[0192] 2. Experimental methods:

[0193] The test compound was mixed with 10% dimethyl sulfoxide (DMSO) and 90% (10% hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solution), vortexed, and sonicated to prepare clear solutions at 0.6, 3.0, and 10.0 mg / mL, respectively. Male CD-1 mice aged 7 to 10 weeks were administered the candidate compound solution intravenously (iv) at a dose of 3 mg / kg (dosing concentration 0.6 mg / mL). The candidate compound solution was administered orally (po) at a dose of 30 mg / kg (dosing concentration 3.0 mg / mL) or 100 mg / kg (dosing concentration 10.0 mg / mL). Whole blood was collected at specific times and plasma was prepared. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA).

[0194] 3. Experimental results:

[0195] The results are shown in Table 14.

[0196] Table 14 PK properties of the compound of formula (I) in CD-1 mice

[0197] Experimental conclusion: The compound of formula (I) has good pharmacokinetic characteristics in mice.

Claims

1. The A crystal form of the compound of formula (I), characterized in that, Its X-ray powder diffraction pattern of Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09° ± 0.2°, 21.34° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°, 2. The A crystal form according to claim 1 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 8.09° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 21.34° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°.

3. The A crystal form according to claim 2 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 8.09° ± 0.2°, 9.46° ± 0.2°, 13.95° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 21.34° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°.

4. The A crystal form according to claim 3 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 8.09° ± 0.2°, 9.46° ± 0.2°, 13.95° ± 0.2°, 15.28° ± 0.2°, 17.12° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 21.34° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°.

5. The A crystal form according to claim 4 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 8.09° ± 0.2°, 9.46° ± 0.2°, 13.95° ± 0.2°, 15.28° ± 0.2°, 17.12° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 20.82° ± 0.2°, 21.34° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°, 28.32° ± 0.2°.

6. The A crystal form according to claim 5 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 8.09° ± 0.2°, 9.46° ± 0.2°, 12.10° ± 0.2°, 13.95° ± 0.2°, 15.28° ± 0.2°, 16.39° ± 0.2°, 17.12° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 20.82° ± 0.2°, 21.34° ± 0.2°, 22.22° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°, 27.99° ± 0.2°, 28.32° ± 0.2°.

7. The A crystal form according to claim 6, wherein the X-ray powder diffraction pattern with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 8.09° ± 0.2°, 9.46° ± 0.2°, 12.10° ± 0.2°, 12.78° ± 0.2°, 13.06° ± 0.2°, 13.95° ± 0.2°, 15.28° ± 0.2°, 16.39° ± 0.2°, 17.12° ± 0.2°, 18.56° ± 0.2°, 18.86° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 19.84° ± 0.2°, 20.82° ± 0.2°, 21.34° ± 0.2°, 22.22 ± 0.2°, 22.96° ± 0.2°, 23.58° ± 0.2°, 24.11° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°, 27.99° ± 0.2°, 28.32° ± 0.2°, 29.00° ± 0.2°, 30.21° ± 0.2°.

8. The A crystal form according to claim 7 has characteristic diffraction peaks in the X-ray powder diffraction pattern with Cu Kα radiation at the following 2θ angles: 7.29° ± 0.2°, 8.09° ± 0.2°, 9.46° ± 0.2°, 9.75° ± 0.2°, 11.06° ± 0.2°, 12.10° ± 0.2°, 12.78° ± 0.2°, 13.06° ± 0.2°, 13.95° ± 0.2°, 14.87° ± 0.2°, 15.28° ± 0.2°, 16.39° ± 0.2°, 17.12° ± 0.2°, 17.54° ± 0.2°, 18.56° ± 0.2°, 18.86° ± 0.2°, 19.18° ± 0.2°, 19.49° ± 0.2°, 19.84° ± 0.2°, 20.82° ± 0.2°, 21.34° ± 0.2°, 22.22° ± 0.2°, 22.96° ± 0.2°, 23.58° ± 0.2°, 24.11° ± 0.2°, 24.74° ± 0.2°, 25.26° ± 0.2°, 25.73° ± 0.2°, 26.11° ± 0.2°, 26.50° ± 0.2°, 26.64° ± 0.2°, 27.54° ± 0.2°, 27.99° ± 0.2°, 28.32° ± 0.2°, 28.78° ± 0.2°, 29.00° ± 0.2°, 30.21° ± 0.2°, 30.50° ± 0.2°, 31.03° ± 0.2°, 31.99° ± 0.2°, 33.33° ± 0.2°, 33.69° ± 0.2°, 34.01° ± 0.2°, 34.39° ± 0.2°, 34.81° ± 0.2°, 35.48° ± 0.2°, 35.82° ± 0.2°, 36.37° ± 0.2°, 36.63° ± 0.2°, 37.34° ± 0.2°, 37.78° ± 0.2°, 38.39° ± 0.2°, 38.71° ± 0.2°, 39.14° ± 0.2°, 39.57° ± 0.2°.

9. The A crystal form according to claim 8 has an XRPD pattern substantially as shown in Figure 1.

10. The A crystal form according to any one of claims 1-9 has an onset of an exothermic peak in the differential scanning calorimetry (DSC) curve at 199.55 ± 3.00 °C.

11. The A crystal form according to any one of claims 1-9 has a DSC pattern substantially as shown in Figure 2.

12. The A crystal form according to any one of claims 1-9 has a weight loss of 4.502% in the thermogravimetric analysis (TGA) curve at 220.00 ± 3.00 °C.

13. The A crystal form according to claim 12 has a TGA pattern substantially as shown in Figure 3.

14. A pharmaceutical composition comprising the A crystal form of the compound of formula (I) according to any one of claims 1-13; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

15. Use of the A crystal form of the compound of formula (I) according to any one of claims 1-13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating solid tumors with KRAS G12D mutation; Preferably, the solid tumors with KRAS G12D mutation are selected from colon cancer and pancreatic cancer.

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