WO2024083183A1 - Salt and crystal form of phosphonyl derivative and use thereof in medicine - Google Patents

Abstract

Provided in the present invention are a pharmaceutically acceptable salt of a compound as represented by formula (I) or a stereoisomer thereof, a solvate and/or a crystal form thereof, a preparation method therefor, a pharmaceutical composition thereof, and the use thereof in medicine.

Description

A salt and crystal form of a phosphono derivative and its use in medicine Technical Field

The present invention relates to the field of medicine, and in particular to a salt and a crystal form of a compound represented by formula (I) and a preparation method thereof, as well as a pharmaceutical composition and application thereof in medicine.

Background technique

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that can act as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis and angiogenesis (Nat. Rev. Cancer, 2007, 7, 169-181; Expert Opin. Ther. Targets, 2012, 16, 15-31.). Overexpression, mutation or amplification of the EGFR gene in the human body leads to abnormal increase in EGFR activity, which can lead to the occurrence of many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.). PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be used to treat various diseases. This technology has also received widespread attention in recent years (ACS Chem. Biol. 2017, 12, 892-898; Drug Discovery Today Technol. 2019, 31, 15-27.).

PCT/CN2022/090243 describes a compound represented by formula (I), which is a Protacs small molecule with good EGFR inhibition and degradation activity.

Summary of the invention

The purpose of the present invention is to provide a pharmaceutically acceptable salt of a compound represented by formula (I), a crystal form thereof, and a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing drugs for EGFR-related diseases such as cancer diseases.

The advantages of the compound represented by formula (I) or the pharmaceutically acceptable salt of its stereoisomer and its solvate and the crystalline or amorphous form of the compound represented by formula (I) include but are not limited to easy processing and crystallization, convenient handling, easy purification, easy industrialization, good fluidity, easy micronization, high solubility, good pharmacokinetic properties and good stability, and are suitable for preparing pharmaceutical preparations.

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt of its stereoisomer and a solvate thereof.

In some embodiments, the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalene disulfonate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentisate, salicylate, oxalate, or glutarate;

In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate;

In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate, maleate, 2-naphthalenesulfonate, oxalate;

In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of mesylate;

In some embodiments, the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:0.5 to 1:3.5;

In some embodiments, the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:1, 1:2, 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2, 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from maleate, and the molar ratio of the compound represented by formula (I): maleic acid is 1:2 or 1:1;

In some embodiments, the pharmaceutically acceptable salt is selected from 2-naphthalenesulfonate, and the molar ratio of the compound represented by formula (I): 2-naphthalenesulfonic acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from oxalates, and the molar ratio of the compound represented by formula (I): oxalic acid is 1:1;

In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonate, and the molar ratio of the compound represented by formula (I): benzenesulfonic acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from L-malate, and the molar ratio of the compound represented by formula (I): L-malic acid is 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from phosphates, and the molar ratio of the compound represented by formula (I): phosphoric acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from sulfates, and the molar ratio of the compound represented by formula (I): sulfuric acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from p-toluenesulfonate, and the molar ratio of the compound represented by formula (I): p-toluenesulfonic acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride, and the molar ratio of the compound represented by formula (I): hydrochloric acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from maleate salts, and the molar ratio of the compound represented by formula (I): maleic acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from hydrobromide, and the molar ratio of the compound represented by formula (I): hydrobromic acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from a methanesulfonate salt, and the molar ratio of the compound represented by formula (I): methanesulfonic acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from citrate, and the molar ratio of the compound represented by formula (I): citric acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from mandelate, and the molar ratio of the compound represented by formula (I): mandelic acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from succinate, and the molar ratio of the compound represented by formula (I): succinic acid is 1:1, 1:2 or 1:3;

In some embodiments, the pharmaceutically acceptable salt is selected from fumarate, and the molar ratio of the compound represented by formula (I): fumaric acid is 1:0.5, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from hippurate, and the molar ratio of the compound represented by formula (I): hippuric acid is 1:1;

In some embodiments, the pharmaceutically acceptable salt is selected from salicylates, and the molar ratio of the compound represented by formula (I): salicylic acid is 1:1;

In some embodiments, the pharmaceutically acceptable salt is selected from 1,5-dinaphthylidenesulfonate, and the molar ratio of the compound represented by formula (I): 1,5-dinaphthylidenesulfonic acid is 1:1, 1:2;

In some embodiments, the pharmaceutically acceptable salt is selected from nicotinate, and the molar ratio of the compound represented by formula (I): nicotinic acid is 1:3;

In some embodiments, the pharmaceutically acceptable salts described above are amorphous.

The present invention relates to a maleate crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 14.83°±0.2°, 16.53°±0.2°, 20.34°±0.2°, 22.87°±0.2°, and 23.92°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 6.75°±0.2°, 8.80°±0.2°, 14.83°±0.2°, 16.53°±0.2°, 20.34°±0.2°, 22.87°±0.2°, and 23.92°±0.2°. 2.87°±0.2°, 23.92°±0.2°; in some embodiments, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 6.75°±0.2°, 8.80°±0.2°, 10.97°±0.2°, 14.83°±0.2°, 16.53°±0.2°, 16.97°±0.2°, 18.68°±0.2°, 20.34°±0.2°, 21.08°±0.2°, 22.87°±0.2°, 23.92°±0.2°, 24.61°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 1.

The present invention relates to a dimaleate crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 4.18°±0.2°, 8.24°±0.2°, 18.40°±0.2°, 20.48°±0.2°, 21.96°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 4.18°±0.2°, 8.24°±0.2°, 18.40°±0.2°, 18.80°±0.2°, 20.48°±0.2°, 21.96°±0.2°, 23.66°±0.2°, 24.34°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.18°±0.2°, 8.24°±0.2°, 12.30±0.2°, 13.21°±0.2°, 16.34°±0.2°, 16.57°±0.2°, 18.40°±0.2°, 18.80°±0.2°, 20.00°±0.2°, 20.48°±0.2°, 20.81°±0.2°, 21.96°±0.2°, 23.66°±0.2°, 24.34°±0.2°, 25.73°±0.2°, and 27.98°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 6.

The present invention relates to a 2-naphthalenesulfonate salt crystal form 1 of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 5.82°±0.2°, 17.52°±0.2°, 20.13°±0.2°, 21.16°±0.2°, and 26.80°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 5.82°±0.2°, 12.58°±0.2°, 14.92°±0.2°, 17.52°±0.2°, 20.13°±0.2°, 21.16°±0.2°, 22.95°±0.2°, 26.80 °±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.82°±0.2°, 7.10°±0.2°, 8.78°±0.2°, 11.59°±0.2°, 12.58°±0.2°, 14.92°±0.2°, 17.03°±0.2°, 17.52°±0.2°, 18.80°±0.2°, 20.13°±0.2°, 21.16°±0.2°, 21.72°±0.2°, 22.22°±0.2°, 22.95°±0.2°, 26.80°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 11.

The present invention relates to an oxalate crystal form 1 of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 19.69°±0.2°, 20.07°±0.2°, 23.75°±0.2°, 24.45°±0.2°, 26.82°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 13.79°±0.2°, 17.86°±0.2°, 19.69°±0.2°, 20.07°±0.2°, 23.75°±0.2°, 24.45°±0.2°, 24.82°±0.2°, 26.82°±0.2°, 27.07° ±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.91°±0.2°, 7.63°±0.2°, 13.52°±0.2°, 13.79°±0.2°, 17.86°±0.2°, 18.87°±0.2°, 19.69°±0.2°, 20.07°±0.2°, 20.71°±0.2°, 23.75°±0.2°, 24.45°±0.2°, 24.82°±0.2°, 26.82°±0.2°, 27.07°±0.2°, 29.44°±0.2°, 31.28°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 16.

The present invention relates to an amorphous dimethanesulfonate of a compound represented by formula (I), and its X-ray powder diffraction pattern is shown in FIG36 .

The present invention relates to a crystalline form 1 of a compound represented by formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.03°±0.2°, 15.35°±0.2°, 19.43°±0.2°, 19.88°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 2°, 5.03°±0.2°, 8.03°±0.2°, 13.25°±0.2°, 14.57°±0.2°, 14.88°±0.2°, 15.35°±0.2°, 19.43°±0.2°, 19.88°±0.2°, 23.83±0.2°, 24.71°±0.2°, 26.44°±0.2°, 29.93°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.03°±0.2°, 8.03°±0.2°, 8.99°±0.2°, 48°±0.2°; in some embodiments, Cu-Kα radiation is used, and the X-ray powder diffraction pattern thereof is shown in FIG48.

The present invention relates to a method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the method comprises: a step of forming a salt using the compound represented by formula (I) and an acid; in some embodiments, the solvent used is selected from one or more of _C1-6 halogenated alkane solvents, _C2-6 ester solvents, _C2-6 ether solvents, _C1-6 alcohol solvents or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.

The present invention relates to a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) above, and a pharmaceutically acceptable carrier or excipient.

The present invention relates to the use of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) or the pharmaceutical composition described above in the preparation of a drug for treating diseases (preferably cancer) related to the inhibition or degradation of EGFR.

The present invention relates to the use of a crystalline or amorphous pharmaceutically acceptable salt of any one of the compounds represented by formula (I) or the pharmaceutical composition described above in the preparation of a drug for treating diseases (preferably cancer) related to the inhibition or degradation of EGFR.

In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").

"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts (calculated as the free base) include, but are not limited to, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg g, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg g, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 1-100mg, 2-100mg, 5-100mg, 10-100mg, 15-100mg, 20-100mg, 25-100mg, 30-100mg, 40-100mg, 50-100mg, 60-100mg, 70-100mg, 75-100mg, 80-100mg, 90-100mg.

In some embodiments, examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg.

A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt or cocrystal of the compound of the present invention, preferably 1-800 mg, wherein the disease is preferably a disease related to the inhibition or degradation of EGFR (preferably cancer).

A method for treating a disease in a mammal, the method comprising administering a pharmaceutically acceptable salt or co-crystal of a compound of the present invention to a subject at a daily dose of 1-1000 mg/day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50- 400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day.

The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a pharmaceutically acceptable salt or co-crystal of the compound of the present invention, and the amount of the pharmaceutically acceptable salt or co-crystal of the compound of the present invention is the same as that in the above-mentioned pharmaceutical composition.

The crystal form of the compound shown in formula (I) of the present invention has excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, and high humidity resistance. For example, the crystal form of the present invention can significantly reduce the filtration time, shorten the production cycle, and save costs during the preparation process. The crystal form of the present invention also has good light stability, thermal stability, and wet stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not need to be specially packaged to prevent the influence of light, temperature, and humidity, thereby reducing costs. The crystal form will not be degraded due to the influence of light, high temperature, and high humidity, thereby improving the safety of the preparation and the effectiveness after long-term storage. Patients taking the crystal form will not worry about the photosensitivity reaction of the preparation due to exposure to sunlight.

The crystalline form of the compound represented by formula (I) of the present invention degrades very little or less when stored or transported at ambient temperature, has good thermal stability, can be stably maintained for a long time, and is suitable for standard preparation production processes.

The crystal form of the compound represented by formula (I) described in the present invention is suitable and convenient for mass preparation. The preparation prepared using the aforementioned crystal form can reduce irritation and improve absorption, so that the problem of metabolic rate can be solved, toxicity can be significantly reduced, safety can be improved, and the quality and efficacy of the preparation can be effectively guaranteed.

It can be understood that the expressions such as “preferably, ..., further having a characteristic diffraction peak at the following 2θ position” or “more preferably, ..., further having a characteristic diffraction peak at the following 2θ position” described in the present invention mean that on the basis of having a characteristic diffraction peak at the aforementioned 2θ position, there is further a characteristic diffraction peak at the “following 2θ position”.

It is understood that the numerical values described and protected by the present invention are approximate values. The variation in the numerical values may be due to the calibration of the equipment, equipment error, purity of the crystal, crystal size, sample size and other factors.

The crystalline structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to, X-ray powder diffraction (XRD), ion chromatography (IC), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

It is to be understood that the crystal forms of the present invention are not limited to characteristic spectra that are completely identical to the characteristic spectra described in the accompanying drawings disclosed in the present invention, such as XRD, DSC, TGA, and any crystal forms having characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings fall within the scope of the present invention.

It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern with a characteristic peak position, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ± 3 ° C.

Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The same meaning. If there is a contradiction, the definition provided in the present application shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred values with any lower range limit or preferred values, regardless of whether the range is specifically disclosed. Unless otherwise specified, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "optional" or "optionally" used herein means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.

When used with a numerical variable, the terms "about" and "approximately" used herein generally refer to the numerical value of the variable and all numerical values of the variable within experimental error (e.g., within a 95% confidence interval for the mean value) or within ±10% of the specified numerical value, or a wider range.

Unless otherwise specified, percentages, parts, etc. herein are all by weight.

"Amorphous" as used herein refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystal diffraction analysis, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As described below, the XRPD pattern produced by an amorphous solid has no obvious diffraction characteristic peaks.

As used herein, "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, in contrast to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

The "seed crystals" mentioned in the present invention refer to the formation of crystal nuclei by adding insoluble additives in the crystallization method, which accelerates or promotes the growth of enantiomer crystals with the same crystal form or stereo configuration.

The "pharmaceutical composition" described in the present invention refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients.

The "carrier" mentioned in the present invention refers to a carrier or diluent that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound.

The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further enhance the administration of a compound.

The "IC ₅₀ " in the present invention refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

The "ether solvent" described in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, ethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.

The "alcohol solvent" described in the present invention refers to a group derived from one or more "hydroxyl groups" replacing one or more hydrogen atoms on a "C _1-6 alkyl group", wherein the "hydroxyl group" and "C _1-6 alkyl group" are as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.

The "ester solvent" described in the present invention refers to a combination of a low-level organic acid containing 1 to 4 carbon atoms and a low-level alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.

The "ketone solvent" described in the present invention refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. Depending on the different hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples include but are not limited to: acetone, acetophenone, 4-methyl-2-pentanone.

The "nitrile solvent" described in the present invention refers to a group derived from one or more "cyano" replacing one or more hydrogen atoms on a "C _1-6 alkyl". The "cyano" and "C _1-6 alkyl" are as defined above, and specific examples include but are not limited to: acetonitrile or propionitrile.

The "halogenated hydrocarbon solvent" described in the present invention refers to a group derived from one or more "halogen atoms" replacing one or more hydrogen atoms on a "C _1-6 alkyl group", wherein the "halogen atom" and "C _1-6 alkyl group" are as defined above, and specific examples include but are not limited to: dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.

The "crystal of the present invention", "crystal form of the present invention", "polymorph of the present invention" and the like described in the present invention can be used interchangeably.

The "room temperature" mentioned in the present invention generally refers to 4-30°C, preferably refers to 20±5°C.

The drying temperature of the present invention is generally 20 to 100° C., preferably 25 to 70° C., and can be either normal pressure drying or reduced pressure drying (vacuum drying). Preferably, the drying is carried out under reduced pressure.

The "X-ray powder diffraction pattern (XRPD pattern)" of the present invention refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. An XRPD pattern is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).

The "2θ or 2θ angle" described in the present invention refers to the diffraction angle, θ is the Bragg angle, which is based on the peak position expressed in degrees (°) set in the X-ray diffraction experiment, and is usually the horizontal coordinate unit in the diffraction spectrum. If the incident beam forms an angle θ with a certain lattice plane and the reflection is diffracted, the experimental setting needs to record the reflected beam at an angle of 2θ. It should be understood that the specific 2θ value of a specific crystal form mentioned in this article is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of 2θ is ±0.3, which can be ±0.3, ±0.2 or ±0.1.

"Substantially the same" as used herein means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will show some variation, typically up to 0.1 to 0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to instrumental differences as well as degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one skilled in the art, and should be considered as only qualitative measurements.

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

According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Drug Hygroscopicity Guidance" in Part IV of the 2020 edition of the Chinese Pharmacopoeia,

Deliquesce: Absorbs enough water to form a liquid;

Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

No or almost no hygroscopicity: moisture gain is less than 0.2%.

The crystal form disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:

1. The volatilization experiment is to evaporate the clear solution of the sample at different temperatures until the solvent is dry.

2. The slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids) at a certain temperature in different solvent systems.

3. The anti-solvent test is to dissolve the sample in a good solvent, add an anti-solvent, stir the precipitated solid for a short time and then filter it immediately.

4. The cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.

5. The polymer template experiment is to add different types of polymer materials to the sample clear solution and leave it open at room temperature to evaporate until the solvent is dry.

6. The thermal method experiment is to treat the sample under certain thermal method crystallization conditions and cool it to room temperature.

7. The water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an X-ray powder diffraction pattern of maleate salt form 1 of the compound represented by formula (I).

FIG2 is a thermogravimetric analysis spectrum of the maleate salt form 1 of the compound represented by formula (I).

FIG3 is a differential scanning calorimetry curve of maleate salt form 1 of the compound represented by formula (I).

FIG4 is an isothermal adsorption curve of maleate salt form 1 of the compound represented by formula (I).

FIG5 is a DVS spectrum of the maleate salt form 1 of the compound represented by formula (I).

FIG6 is an X-ray powder diffraction pattern of the dimaleate crystalline form 1 of the compound represented by formula (I).

FIG. 7 is a thermogravimetric analysis spectrum of the dimaleate crystal form 1 of the compound represented by formula (I).

FIG8 is a differential scanning calorimetry curve of the dimaleate crystal form 1 of the compound represented by formula (I).

FIG9 is an isothermal adsorption curve of the dimaleate crystal form 1 of the compound represented by formula (I).

FIG10 is a DVS spectrum of the dimaleate crystal form 1 of the compound represented by formula (I).

FIG11 is an X-ray powder diffraction pattern of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).

FIG12 is a thermogravimetric analysis spectrum of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).

FIG13 is a differential scanning calorimetry curve of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).

FIG14 is an isothermal adsorption curve of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).

FIG15 is a DVS spectrum of 2-naphthalenesulfonic acid form 1 of the compound represented by formula (I).

FIG16 is an X-ray powder diffraction pattern of oxalate crystal form 1 of the compound represented by formula (I).

FIG. 17 is a thermogravimetric analysis spectrum of the oxalate salt form 1 of the compound represented by formula (I).

FIG18 is a differential scanning calorimetry curve of the oxalate crystal form 1 of the compound represented by formula (I).

FIG19 is an X-ray powder diffraction pattern of the amorphous benzenesulfonate salt of the compound represented by formula (I).

FIG. 20 is an X-ray powder diffraction pattern of the amorphous triphenylsulfonate salt of the compound represented by formula (I).

FIG21 is an X-ray powder diffraction pattern of the amorphous di-L-malate salt of the compound represented by formula (I).

FIG. 22 is an X-ray powder diffraction pattern of the amorphous phosphate of the compound represented by formula (I).

FIG. 23 is an X-ray powder diffraction pattern of the amorphous diphosphate of the compound represented by formula (I).

FIG. 24 is an X-ray powder diffraction pattern of the amorphous sulfate salt of the compound represented by formula (I).

FIG25 is an X-ray powder diffraction pattern of the amorphous disulfate salt of the compound represented by formula (I).

FIG26 is an X-ray powder diffraction pattern of the amorphous trisulfate salt of the compound represented by formula (I).

FIG. 27 is an X-ray powder diffraction pattern of the amorphous di-p-toluenesulfonate salt of the compound represented by formula (I).

FIG28 is an X-ray powder diffraction pattern of the amorphous hydrochloride salt of the compound represented by formula (I).

FIG29 is an X-ray powder diffraction pattern of the amorphous dihydrochloride salt of the compound represented by formula (I).

FIG30 is an X-ray powder diffraction pattern of the amorphous trihydrochloride salt of the compound represented by formula (I).

FIG31 is an X-ray powder diffraction pattern of the amorphous di-2-naphthalenesulfonate salt of the compound represented by formula (I).

FIG32 is an X-ray powder diffraction pattern of the amorphous hydrobromide salt of the compound represented by formula (I).

FIG33 is an X-ray powder diffraction pattern of the amorphous dihydrobromide salt of the compound represented by formula (I).

FIG34 is an X-ray powder diffraction pattern of the amorphous trihydrobromide salt of the compound represented by formula (I).

FIG35 is an X-ray powder diffraction pattern of the amorphous methanesulfonate salt of the compound represented by formula (I).

FIG36 is an X-ray powder diffraction pattern of the amorphous dimesylate salt of the compound represented by formula (I).

FIG37 is an X-ray powder diffraction pattern of the amorphous trimesylate salt of the compound represented by formula (I).

FIG38 is an X-ray powder diffraction pattern of the amorphous mandelate salt of the compound represented by formula (I).

FIG39 is an X-ray powder diffraction pattern of the amorphous bimandelate salt of the compound represented by formula (I).

FIG40 is an X-ray powder diffraction pattern of the amorphous succinate salt of the compound represented by formula (I).

FIG41 is an X-ray powder diffraction pattern of the amorphous salicylate of the compound represented by formula (I).

FIG42 is an X-ray powder diffraction pattern of amorphous 1,5-naphthalene disulfonate of the compound represented by formula (I).

FIG43 is an X-ray powder diffraction pattern of amorphous di-1,5-naphthalene disulfonate of the compound represented by formula (I).

FIG44 is an X-ray powder diffraction pattern of the amorphous hemi-fumarate salt of the compound represented by formula (I).

Figure 45 is an X-ray powder diffraction pattern of the amorphous difumarate salt of the compound represented by formula (I).

FIG46 is an X-ray powder diffraction pattern of the amorphous trinicotinate salt of the compound represented by formula (I).

FIG47 is an X-ray powder diffraction pattern of the amorphous hippurate salt of the compound represented by formula (I).

Figure 48 is an X-ray powder diffraction pattern of Form 1 of the compound represented by formula (I).

FIG49 is a thermogravimetric analysis spectrum of Form 1 of the compound represented by formula (I).

Figure 50 is a differential scanning calorimetry curve of Form 1 of the compound represented by formula (I).

Detailed ways

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS was used for determination (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Eclipse Plus C18, 150×4.6mm).

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

The following describes in detail the implementation process of the present invention and the beneficial effects produced by the specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention, and is not intended to limit the scope of implementation of the present invention.

Example 1: Preparation of Compound 1

Step 1: Preparation of 1C

1A (16 g, 56.45 mmol) and 1B (14.8 g, 59.27 mmol) were dissolved in DMSO (200 mL), potassium carbonate (23.5 g, 0.17 mol) was added, and the mixture was stirred at 120°C for 4 hours. The reaction solution was cooled to room temperature, 300 mL of water was added, and a yellow solid was precipitated. The solid was filtered and the filter cake was washed with water 3 times. The filter cake was redissolved in dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane/methanol (V/V) = 50/1-15/1) to obtain 1C (22 g, yield: 76%).

Step 4: Preparation of 1E

1C (400 g, 0.78 mol) and 1D (158 g, 1.24 mol) were dissolved in a mixed solvent of 1,4-dioxane (1.6 L) and water (0.4 L), potassium carbonate (216 g, 1.56 mol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (38 g, 0.047 mol) were added, and nitrogen was replaced three times. The reaction was stirred at 90°C overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure and then 500 mL of ethyl acetate was added to dilute the reaction solution. The reaction solution was washed with water three times and saturated sodium chloride once. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 1E. A PE/EA＝3/1 mixed solution (1600 mL) was added and slurried for 30 minutes. The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain 1E (377 g, yield: 94%).

LCMS m/z＝515.3[M+H] ⁺

Step 5: Preparation of 1F

1E (377 g, 0.73 mol) was dissolved in methanol (600 mL), and hydrogen chloride-dioxane solution (4 mol/L, 2.5 L) was added. The reaction was stirred at room temperature for 60 min, and the crude product was concentrated under reduced pressure. 2.5 L of water and 500 mL of concentrated hydrochloric acid were added to the crude product, and the product was extracted with ethyl acetate (1.5 L*2). The pH of the aqueous phase was adjusted to 13 with sodium hydroxide solution, and the product was extracted with dichloromethane (1.5 L*2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a PE/MTBE mixed solution (v/v=1/1, 1.2 L) for slurrying, filtered, and the filter cake was concentrated under reduced pressure to obtain 1F (256 g, yield: 85%).

Step 6: Preparation of 1G

1F (120 g, 0.29 mol) was dissolved in DMSO (600 mL), and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (80 g, 0.29 mmol) and diisopropylethylamine (112 g, 0.87 mmol) were added in sequence, and the mixture was reacted at 100°C overnight. 2.0 L of water was added, and the solid was precipitated and filtered. The filter cake was dissolved and extracted with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (V/V) = 100/1-10/1) to obtain 1G (186 g, yield: 96%).

Step 7: Preparation of 1H

1G (130 g, 0.19 mmol) was dissolved in a mixture of THF (1.3 L) and water (400 mL), and ammonium chloride (51 g, 0.95 mmol) and zinc powder (62 g, 0.95 mmol) were added. The temperature was slowly raised to 40-60 °C for reaction for 1-2 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with 1 L of DCM. The organic phases were combined, and the organic phases were washed with 0.5 L of ammonia water and 0.5 L of saturated brine in sequence. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 1H as a yellow solid.

LCMS m/z＝641.3[M+H] ⁺

Step 8: Preparation of Compound 1

1H (80 g, 126 mmol) and 1M (51 g, 126 mmol) were dissolved in DMF (500 mL), p-toluenesulfonic acid monohydrate (48 g, 252 mmol) was added, and the mixture was reacted at 100°C overnight. After cooling to room temperature, 800 mL of saturated sodium bicarbonate aqueous solution was slowly added, and the mixture was filtered, and the filter cake was dissolved and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol (V/V) = 100/1-100/4). 64 g of compound 1 (64 g, yield: 50%) was obtained by column chromatography.

LCMS m/z=502.7[(M+2H)/2] ⁺ .

¹ H NMR (400 MHz, D ₂ O/CF ₃ COOD (v/v＝1:1))δ8.23(s,1H),7.96-7.75(m,5H),7.46(s,1H),7.35( s, 1H), 7.31-7.15 (m, 2H), 6.91 (d, 1H), 5.12 (dd, 1H), 4.22-4.07 (m, 5H), 4.03 (s, 3H), 3.93-3.70 (m, 6H) ,3.62-3.48(m,2H),3.39-3.18(m,4H),2.95-2.85(m,2H),2.82-2.67(m,1H),2.63-2.44(m,1H),2.37-2.16( m, 3H), 2.12-1.88 (m, 9H), 1.19-1.08 (m, 2H), 0.73-0.65 (m, 2H).

Example 2: Preparation of Maleate Salt Form 1 of Compound 1

Take about 100 mg of compound 1, add 2.0 ml of tetrahydrofuran, add 0.2 ml of tetrahydrofuran solution mixed with 13 mg of maleic acid, stir overnight at room temperature, centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain maleate crystal form 1 of compound 1, whose XRD, DSC, TGA, isothermal adsorption curve and DVS are shown in Figures 1-5 respectively.

Example 3: Preparation of dimaleic acid crystal form 1 of compound 1

Take about 100 mg of compound 1, add 2.0 ml of tetrahydrofuran, add 0.4 ml of tetrahydrofuran solution mixed with 26 mg of maleic acid, and precipitate. Stir at room temperature for 2 days, centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain dimaleate crystal form 1 of compound 1, whose XRD, DSC, TGA, isothermal adsorption curve and DVS are shown in Figures 6-10 respectively.

Through the peak shift analysis of 1H NMR (400MHz, DMSO-d ₆ ), the chemical shift 5.12 (dd, J=12.9, 5.4Hz, 1H) of compound 1 is the -CH peak at position 38, and the peak at 6.15 (s, 4H) is the -CH peak of maleic acid. The ratio is 1:4. Therefore, it can be analyzed that the ratio of compound 1 to maleic acid is 1:2.

Example 4: Preparation of 2-naphthalenesulfonate salt form 1 of compound 1

Take about 100 mg of compound 1, add 2.0 ml of chloroform, and add 0.2 ml of ethanol solution mixed with 23 mg of 2-naphthalenesulfonic acid. Stir at room temperature for 2 days, centrifuge, and vacuum dry the obtained solid overnight at room temperature to obtain 2-naphthalenesulfonate salt form 1 of compound 1, whose XRD, DSC, TGA, isothermal adsorption curves and DVS are shown in Figures 11-15 respectively.

Through the peak shift analysis of 1H NMR (400MHz, DMSO-d ₆ ), the chemical shift 5.12 (dd, J＝12.9,5.4Hz,1H) of compound 1 is the -CH peak at position 38, and the peaks of 8.31-8.14 (m,4H) are the peaks of 2-naphthalenesulfonic acid, and the ratio is 1:4. Therefore, it can be analyzed that the ratio of compound 1 to 2-naphthalenesulfonic acid is 1:1.

Example 5: Preparation of Oxalate Form 1 of Compound 1

Take about 50 mg of compound 1, add 2.0 ml of dichloromethane, add 0.2 ml of ethanol solution mixed with 15 mg of oxalic acid, mix well at room temperature, stir overnight at 4°C, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain oxalate crystal form 1 of compound 1, whose XRD, DSC, and TGA are shown in Figures 16-18 respectively.

Ion chromatography (IC) test results showed that the salt ratio was 1:1.

Example 6: Preparation of amorphous benzenesulfonate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.1 ml of methanol solution mixed with 10 mg of benzenesulfonic acid. Stir overnight at room temperature, add 2.0 ml of n-heptane and 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain amorphous benzenesulfonate of compound 1. Its XRD is shown in Figure 19.

Example 7: Preparation of amorphous triphenylsulfonate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of tetrahydrofuran, add 0.3 ml of tetrahydrofuran solution mixed with 29 mg of benzenesulfonic acid, stir at room temperature overnight, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain tribenzenesulfonate of compound 1, whose XRD is shown in Figure 20.

Example 8: Preparation of amorphous di-L-malate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, and add 0.2 ml of methanol solution mixed with 15 mg of L-malic acid. Stir overnight at room temperature, add 2.0 mL of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain the amorphous di-L-malate of compound 1. Its XRD is shown in Figure 21.

Example 9: Preparation of amorphous phosphate of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.1 ml of ethanol solution mixed with 6 mg of phosphoric acid, and precipitate solid. Stir overnight at room temperature, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain amorphous phosphate of compound 1, whose XRD is shown in Figure 22.

Example 10: Preparation of the amorphous diphosphate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 13 mg of phosphoric acid, and precipitate solid. Stir overnight at room temperature, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain the amorphous diphosphate of compound 1, whose XRD is shown in Figure 23.

Example 11: Preparation of the Sulfate Amorphous Form of Compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.1 ml of methanol solution mixed with 5.5 mg of sulfuric acid. Stir overnight at room temperature, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain the amorphous sulfate of compound 1. Its XRD is shown in Figure 24.

Example 12: Preparation of the disulfate amorphous form of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.2 ml of methanol solution mixed with 11 mg of sulfuric acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the amorphous disulfate of compound 1, whose XRD is shown in Figure 25.

Example 13: Preparation of the trisulfate amorphous form of compound 1

Take about 50 mg of compound 1, add 1.0 ml of tetrahydrofuran, add 0.3 ml of tetrahydrofuran solution mixed with 16.5 mg of sulfuric acid, stir at room temperature overnight, precipitate solid, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain the trisulfate amorphous form of compound 1, whose XRD is shown in Figure 26.

Example 14: Preparation of amorphous di-p-toluenesulfonate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.2 ml of methanol solution mixed with 19 mg of p-toluenesulfonic acid, stir at room temperature overnight, add 2.0 mL of methyl tert-butyl ether, precipitate solid, stir for 6 hours, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain amorphous di-p-toluenesulfonate of compound 1, whose XRD is shown in Figure 27.

Example 15: Preparation of amorphous hydrochloride of compound 1

Take about 50 mg of the compound represented by formula (I), add 1.0 ml of dichloromethane, add 0.1 ml of methanol solution mixed with 6 mg of hydrochloric acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, precipitate solid, stir for 6 hours, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the amorphous hydrochloride of compound 1, whose XRD is shown in Figure 28.

Example 16: Preparation of amorphous dihydrochloride salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.2 ml of methanol solution mixed with 11 mg of hydrochloric acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the amorphous dihydrochloride of compound 1, whose XRD is shown in Figure 29.

Example 17: Preparation of amorphous trihydrochloride salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of tetrahydrofuran, add 0.3 ml of tetrahydrofuran solution mixed with 17 mg of hydrochloric acid, and precipitate solid. Stir overnight at room temperature, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain the trihydrochloride amorphous form of compound 1, whose XRD is shown in Figure 30.

Example 18: Preparation of amorphous di-2-naphthalenesulfonate of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, and add 0.2 ml of ethanol solution mixed with 23 mg of 2-naphthalenesulfonic acid. Stir overnight at room temperature, add 2.0 mL of n-heptane, stir for 6 hours, precipitate solid, centrifuge, and vacuum dry the solid at room temperature overnight to obtain the amorphous di-2-naphthalenesulfonate of compound 1, whose XRD is shown in Figure 31.

Example 19: Preparation of the Amorphous Hydrobromide Salt of Compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.1 ml of methanol solution mixed with 11 mg of hydrobromic acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the amorphous hydrobromide salt of compound 1, whose XRD is shown in Figure 32.

Example 20: Preparation of amorphous dihydrobromide salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.2 ml of methanol solution mixed with 22 mg of hydrobromic acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the amorphous dihydrobromide salt of compound 1, whose XRD is shown in Figure 33.

Example 21: Preparation of amorphous trihydrobromide salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of tetrahydrofuran, add 0.3 ml of tetrahydrofuran solution mixed with 33 mg of hydrobromic acid, and precipitate solid. Stir overnight at room temperature, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain the amorphous trihydrobromide salt of compound 1, whose XRD is shown in Figure 34.

Example 22: Preparation of amorphous mesylate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.1 ml of methanol solution mixed with 5 mg of methanesulfonic acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain amorphous methanesulfonate of compound 1, whose XRD is shown in Figure 35.

Example 23: Preparation of the amorphous dimesylate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of dichloromethane, add 0.2 ml of methanol solution mixed with 11 mg of methanesulfonic acid, stir at room temperature overnight, add 2.0 ml of methyl tert-butyl ether, stir for 6 hours, precipitate solid, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the dimethanesulfonate amorphous form of compound 1, whose XRD is shown in Figure 36.

Through the peak shift analysis of 1H NMR (400MHz, DMSO-d6), the chemical shift 5.12 (dd, J=12.9, 5.4Hz, 1H) of compound 1 is the -CH peak at position 38, and the peak at 2.70 (s, 6H) is the peak of methanesulfonic acid, and the ratio is 1:6. Therefore, it can be analyzed that the ratio of compound 1 to methanesulfonic acid is 1:2.

Example 24: Preparation of the amorphous trimesylate salt of compound 1

About 50 mg of compound 1 was added to 1.0 ml of tetrahydrofuran, and 0.3 ml of tetrahydrofuran solution mixed with 16 mg of methanesulfonic acid was added to precipitate a solid. The mixture was stirred overnight at room temperature, centrifuged, and the obtained solid was dried in vacuum at room temperature overnight to obtain an amorphous trimesylate salt of compound 1, whose XRD is shown in FIG37 .

Example 25: Preparation of amorphous mandelate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 9 mg of mandelic acid, and stir the solution in After stirring at 4°C overnight, no solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. After centrifugation, the obtained solid was dried in vacuo at room temperature overnight to obtain the amorphous mandelate salt of compound 1, whose XRD is shown in FIG38 .

Example 26: Preparation of the Amorphous Dimandelate Salt of Compound 1

About 50 mg of compound 1 was taken, 1.0 ml of chloroform was added, 0.2 ml of ethanol solution mixed with 18 mg of mandelic acid was added, and the solution was stirred at 4°C overnight. No solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. Centrifugation was performed, and the obtained solid was vacuum dried at room temperature overnight to obtain the amorphous dimandelate salt of compound 1, whose XRD is shown in Figure 39.

Example 27: Preparation of amorphous succinate of compound 1

About 50 mg of compound 1 was taken, 1.0 ml of chloroform was added, 0.2 ml of ethanol solution mixed with 7 mg of succinic acid was added, and the solution was stirred at 4°C overnight. No solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. Centrifugation was performed, and the obtained solid was vacuum dried at room temperature overnight to obtain amorphous succinate of compound 1, whose XRD is shown in Figure 40.

Example 28: Preparation of amorphous salicylate of compound 1

About 50 mg of compound 1 was taken, 1.0 ml of chloroform was added, 0.2 ml of ethanol solution mixed with 8 mg of salicylic acid was added, and the solution was stirred at 4°C overnight. No solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. Centrifugation was performed, and the obtained solid was vacuum dried at room temperature overnight to obtain the amorphous succinate of compound 1, whose XRD and DSC are shown in Figure 41.

Example 29: Preparation of amorphous 1,5-naphthalene disulfonate salt of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 22 mg of 1,5-naphthalene disulfonic acid, stir the solution at 4°C overnight, and precipitate solid. Centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain the amorphous 1,5-naphthalene disulfonic acid salt of compound 1, whose XRD is shown in Figure 42.

Example 30: Preparation of amorphous di-1,5-naphthalene disulfonate of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 44 mg of 1,5-naphthalenedisulfonic acid, stir the solution at 4°C overnight, and precipitate solid. Centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain the amorphous di-1,5-naphthalenedisulfonate of compound 1, whose XRD is shown in Figure 43.

Example 31: Preparation of amorphous hemifumarate of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 7 mg of fumaric acid, stir the solution at 4°C overnight, and precipitate solid. Centrifuge, and vacuum dry the obtained solid at room temperature overnight to obtain amorphous hemifumarate of compound 1, whose XRD is shown in Figure 44.

Example 32: Preparation of amorphous difumarate of compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 14 mg of fumaric acid, stir the solution at 4°C overnight, precipitate solid, add about 4 mL of n-heptane to obtain a suspension, stir overnight at 4°C. Centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain amorphous difumarate of compound 1, whose XRD is shown in Figure 45.

Example 33: Preparation of the Amorphous Trinicotinate of Compound 1

About 50 mg of compound 1 was taken, 1.0 ml of chloroform was added, 0.2 ml of ethanol solution mixed with 8 mg of nicotinic acid was added, and the solution was stirred at 4°C overnight. No solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. Centrifugation was performed, and the obtained solid was vacuum dried at room temperature overnight to obtain an amorphous trinicotinate of compound 1, whose XRD is shown in Figure 46.

Example 34: Preparation of the Amorphous Hippurate Salt of Compound 1

Take about 50 mg of compound 1, add 1.0 ml of chloroform, add 0.2 ml of ethanol solution mixed with 11 mg of hippuric acid, and mix the solution. After stirring at 4°C overnight, no solid was precipitated, and about 4 mL of n-heptane was added to obtain a suspension, which was stirred at 4°C overnight. After centrifugation, the obtained solid was dried under vacuum at room temperature overnight to obtain the hippurate amorphous form of compound 1, whose XRD is shown in FIG47 .

Example 35: Preparation of Form 1 of Compound 1

About 50 mg of compound 1 was taken, 1.0 ml of tetrahydrofuran was added, the solution was stirred at room temperature overnight, centrifuged, and the obtained solid was dried under vacuum at room temperature overnight to obtain Form 1 of compound 1, whose XRD, TGA and DSC are shown in Figures 48-50.

X-ray powder diffractometer (XRD)/DSC/TGA/DVS/IC test

XRD/DSC/TGA/DVS test parameters are shown in Table 1.

Table 1 XRD/DSC/TGA/DVS test instruments and parameters

Ion Chromatography (IC)

Table 2: XRD peak list of maleate salt form 1 of compound 1

Table 3: XRD peak list of dimaleate salt form 1 of compound 1

Table 4: XRD peak list of 2-naphthalenesulfonate salt form 1 of compound 1

Table 5: XRD peak list of oxalate salt form 1 of compound 1

Table 6: XRD peak list of Form 1 of Compound 1

Table 7. Solubility of amorphous form of pharmaceutically acceptable salt of compound 1 in water (mg/mL)

Table 8. Crystalline Hygroscopicity of Pharmaceutically Acceptable Salts of Compound 1

Biological activity test

Test Example 1: Proliferation Inhibitory Activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) Cells

NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC, and the culture medium was RPMI1640 + 10% FBS and DMEM + 10% FBS, respectively, and cultured in a 37 ° C, 5% CO ₂ incubator. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and live cells were counted using an automatic cell analyzer (countstar). The cell suspension was adjusted with culture medium and plated on a 96-well cell culture plate, with 1000 NCI-H1975 (EGFR-L858R-T790M) cells per well and 3000 A431 cells per well. On the second day, the culture medium was aspirated, and 90 μL of fresh culture medium and 10 μL of different concentrations of compounds were added to each well, with a final DMSO concentration of 0.1% per well. The cells were cultured in an incubator at 37°C and 5% CO ₂ for 72 hours. After 72 hours of drug treatment, 50 μL of CTG solution (promega, G7572) pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with a microplate reader (PHERAstar FSX).

The cell viability was calculated using the formula V _sample /V _{vehicle control} x 100%. V _sample is the reading of the drug treatment group, V _{vehicle control is} The values are the average values of the solvent control group. Using origin9.2 software, nonlinear regression model was used to draw the S-shaped dose-survival rate curve and calculate the IC ₅₀ value.

Table 9 Results of proliferation inhibition activity on NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells

Conclusion: The compound has good proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) cells, but poor proliferation inhibitory activity against A431 (EGFR-WT) cells, and has good selectivity.

Test Example 2: Proliferation Inhibitory Activity on Cells NCI-H1975 EGFR-L858R-T790M-C797S

Cells NCI-H1975 EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO ₂ incubator in RPMI1640+10% FBS+100μg/mL hygromycin. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to an appropriate concentration with a medium without hygromycin and plated on a 96-well plate with a density of 1500 cells/well and a volume of 90μL. 10μL of compounds of different concentrations were added, and a solvent control group of cells plus DMSO was set up, and the concentration of DMSO was 0.1%. The cell culture plate was placed in a 37°C, 5% CO ₂ incubator for 72 hours. After the culture, according to the instructions of the CellTiter-Glo kit (Promega, G7572), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with an ELISA reader (Envision2104). The cell survival rate (Surviving cells%) data were processed using formula (2), and GraphPad Prism 5.0 software was used to draw an S-shaped dose-survival rate curve using a nonlinear regression model and calculate the IC ₅₀ value. Where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the reading of the control group.

Surviving cells%＝V _sample /V _{vehicle control} x100% (Formula 2)

Table 10 Proliferation inhibitory activity on cells NCI-H1975 EGFR-L858R-T790M-C797S

Conclusion: The compound has good proliferation inhibitory activity on NCI-H1975 EGFR-L858R-T790M-C797S cells.

Test Example 3: Pharmacokinetic Test in Rats

1.1 Experimental animals: Male SD rats, about 220 g, 6-8 weeks old, 3 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

1.2 Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

Dosing Information

Note: Intragastric administration solvent: 0.5% MC (MC: methylcellulose)

Before and after drug administration, 0.15 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 11 Pharmacokinetic parameters in rats

It can be seen from Table 11 that different salts of Compound 1 have good oral properties.

Test Example 4: Beagle dog pharmacokinetic test

Experimental animals: Male beagle dogs, about 8-11 kg, 3 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the gavage group were: 0, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 12 Pharmacokinetic parameters in dogs

It can be seen from Table 12 that different salts of Compound 1 have good oral properties.

Claims (18)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt of its stereoisomer and a solvate thereof,
   

   The pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonate, fumarate, hydrohalide (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline salt, ferulate salt, 2-hydroxyethanesulfonate salt, mandelate salt, nitrate salt, methanesulfonate salt, malonate salt, gentisate salt, salicylate salt, oxalate salt or glutarate salt; preferably selected from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelate salt, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate and oxalate salt; more preferably selected from methanesulfonate salt.
2. The pharmaceutically acceptable salt and solvate thereof according to claim 1, wherein the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:0.5 to 1:3.5;

   Preferably, the molar ratio of the compound represented by formula (I): the pharmaceutically acceptable salt is 1:1, 1:2, or 1:3.
3. A maleate crystalline form 1 of a compound represented by formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions: 14.83°±0.2°, 16.53°±0.2°, 20.34°±0.2°, 22.87°±0.2°, 23.92°±0.2°; preferably, further has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 6.75°±0.2°, 8.80°±0.2°; more preferably, further has characteristic diffraction peaks at the following 2θ positions: 10.97°±0.2°, 16.97°±0.2°, 18.68°±0.2°, 21.08°±0.2°, 24.61°±0.2°.
4. According to the crystalline form 1 of claim 3, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 1.
5. A dimaleate crystalline form 1 of a compound represented by formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions: 4.18°±0.2°, 8.24°±0.2°, 18.40°±0.2°, 20.48°±0.2°, 21.96°±0.2°; preferably, further has characteristic diffraction peaks at the following 2θ positions: 18.80°±0. 2°, 23.66°±0.2°, 24.34°±0.2°; more preferably, it further has characteristic diffraction peaks at the following 2θ positions: 12.30±0.2°, 13.21°±0.2°, 16.34°±0.2°, 16.57°±0.2°, 20.00°±0.2°, 20.81°±0.2°, 25.73°±0.2°, 27.98°±0.2°.
6. According to the crystalline form 1 of claim 5, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 6.
7. A 2-naphthalenesulfonate salt form 1 of a compound represented by formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 5.82°±0.2°, 17.52°±0.2°, 20.13°±0.2°, 21.16°±0.2°, 26.80°±0.2°; preferably, further having characteristic diffraction peaks at the following 2θ positions: 1 2.58°±0.2°, 14.92°±0.2°, 22.95°±0.2°; more preferably, further having characteristic diffraction peaks at the following 2θ positions: 7.10°±0.2°, 8.78°±0.2°, 11.59°±0.2°, 17.03°±0.2°, 18.80°±0.2°, 21.72°±0.2°, 22.22°±0.2°.
8. According to the crystalline form 1 of claim 7, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 11.
9. An oxalate crystalline form 1 of the compound represented by formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions: 19.69°±0.2°, 20.07°±0.2°, 23.75°±0.2°, 24.45°±0.2°, 26.82°±0.2°; more preferably, further has characteristic diffraction peaks at the following 2θ positions: 13.79 °±0.2°, 17.86°±0.2°, 24.82°±0.2°, 27.07°±0.2°; further, characteristic diffraction peaks are present at the following 2θ positions: 6.91°±0.2°, 7.63°±0.2°, 13.52°±0.2°, 18.87°±0.2°, 20.71°±0.2°, 29.44°±0.2°, 31.28°±0.2°.
10. According to the crystalline form 1 of claim 9, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 16.
11. The pharmaceutically acceptable salt of the compound represented by formula (I) according to claim 1, wherein the pharmaceutically acceptable salt is in the form of an amorphous solid.
12. An amorphous dimethanesulfonate of the compound represented by formula (I).
13. A crystalline form 1 of a compound represented by formula (I), using Cu-Kα radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 5.03°±0.2°, 15.35°±0.2°, 19.43°±0.2°, 19.88°±0.2°; preferably, further having characteristic diffraction peaks at the following 2θ positions: 8.03°±0.2°, 13.25°±0.2°, 14.57°±0 .2°, 14.88°±0.2°, 23.83±0.2°, 24.71°±0.2°, 26.44°±0.2°, 29.93°±0.2°; more preferably, it further has characteristic diffraction peaks at the following 2θ positions: 8.99°±0.2°, 20.17±0.2°, 22.32±0.2°, 22.55±0.2°, 26.17±0.2°, 29.49±0.2°.
14. According to the crystalline form 1 of claim 13, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 48.
15. A method for preparing a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the method comprises: a step of forming a salt with the compound represented by formula (I) and an acid.
16. The preparation method according to claim 15, wherein the solvent used is selected from one or more of C1-6 halogenated alkane solvents, C2-6 ester solvents, C2-6 ether solvents, C1-6 alcohol solvents or water, and preferably the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, ether, tetrahydrofuran and water.
17. A pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of the crystalline form or amorphous form according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier or excipient.
18. Use of the pharmaceutically acceptable salt and solvate thereof according to claim 1 or 2, the crystalline form or amorphous form according to any one of claims 3 to 14, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease associated with the inhibition or degradation of EGFR, wherein the disease is preferably selected from cancer.