Salt forms of tetrasubstituted olefinic compounds, crystals thereof and methods for their production

Abstract

The present application relates to the salt form of tetra-substituted olefin compounds, the crystallization of the compounds and the salts and the preparation method thereof, in particular to the crystallization of the compound of formula (I), the salt thereof, the crystallization of the salt thereof and the preparation method thereof.

Description

[0001] This application is a divisional application of the invention patent application entitled "Salt form, crystallization and preparation method of tetrasubstituted olefin compounds", filed on December 30, 2021, with application number CN202180085964.9.

[0002] Citation of relevant applications This application claims the benefit and priority of Chinese Patent Application No. 202011613790.2, filed with the State Intellectual Property Office of the People's Republic of China on December 30, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the crystallization of a class of tetrasubstituted olefin compounds, their salts, the crystallization of their salts, and methods for their preparation. Background Technology

[0004] According to WHO statistics, breast cancer has become the second most common cancer worldwide and the most common cancer among women. After years of research, the role of the estrogen-estrogen receptor signaling pathway in breast cancer development has been established; and the estrogen receptor (ER) has become the most important biomarker for breast cancer. Using estrogen receptor expression as a distinguishing indicator, breast cancer can be classified into estrogen receptor-positive breast cancer and estrogen receptor-negative breast cancer; among them, estrogen receptor-positive breast cancer accounts for more than 70% of all breast cancer patients.

[0005] Endocrine therapy (ET), targeting the estrogen-estrogen receptor signaling pathway within breast cancer cells, has become the preferred treatment for estrogen receptor-positive breast cancer due to its minimal hazard and significant efficacy. First-line endocrine therapy primarily involves aromatase inhibitors (AIs). Although letrozole, an aromatase inhibitor, has shown good efficacy in treating estrogen receptor-positive breast cancer, resistance to these inhibitors has become increasingly prominent with the use of both classes of drugs. Numerous studies have shown that estrogen receptors can mutate in response to aromatase inhibitors, primarily the Y537X mutation. This mutation allows the mutated estrogen receptor to maintain its activated conformation even in the absence of estrogen, enabling it to continue its receptor function and promote breast cancer cell proliferation. Fulvestrant, the only marketed selective estrogen receptor downregulator, has shown good efficacy in treating hormone therapy-resistant breast cancer. However, fulvestrant presents several challenges in treating AI-resistant ER-mutant breast cancer. First, due to its poor pharmacokinetic properties, fulvestrant exhibits zero oral bioavailability; simultaneously, fulvestrant has a high blood clearance rate. For both reasons, this drug can only be administered via intramuscular injection. However, due to its strong lipophilic structure, intramuscularly administered fulvestrant also presents serious problems with tissue distribution; only about 50% of breast cancer patients using fulvestrant show a clinical response. Similarly, due to its poor pharmacokinetic properties, fulvestrant at currently approved doses cannot achieve complete degradation of the ER, especially mutated ER, in tissue concentrations, thus making it less than ideal for treating AI-resistant ER-mutated breast cancer. Therefore, developing drugs with better pharmacokinetic properties targeting ER-mutated breast cancer remains an unmet medical need. Summary of the Invention

[0006] On the one hand, this application provides crystallization of the compound of formula (I), .

[0007] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallized compound of formula (I) using Cu Kα radiation shows diffraction peaks at 17.60±0.20°, 19.98±0.20° and 23.41±0.20°, represented by 2θ values.

[0008] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallized compound of formula (I) using Cu Kα radiation shows diffraction peaks at 13.14±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20°, and 24.22±0.20°, represented by 2θ values.

[0009] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallized compound of formula (I) using Cu Kα radiation shows diffraction peaks at 13.14±0.20°, 14.68±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.32±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20°, 24.22±0.20°, 26.46±0.20°, and 28.84±0.20°, represented by 2θ values.

[0010] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallized compound of formula (I) using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 8.56±0.20°, 10.13±0.20°, 12.16±0.20°, 13.14±0.20°, 13.54±0.20°, 14.68±0.20°, 15.68±0.20°, 1 6.38±0.20°, 16.62±0.20°, 17.24±0.20°, 17.60±0.20°, 18.86±0.20°, 19.22±0.20°, 19.46±0.20°, 19.98±0.20°, 20.89±0.20°, 21.32±0.20°, 21.78±0.20°, 22.38±0.20°, 22.70 ±0.20°, 23.08±0.20°, 23.41±0.20°, 23.70±0.20°, 24.01±0.20°, 24.22±0.20°, 24.62±0.20°, 24.89±0.20°, 25.26±0.20°, 25.92±0.20°, 26.46±0.20°, 26.92±0.20°, 27.32±0. 20°, 28.18±0.20°, 28.54±0.20°, 28.84±0.20°, 29.42±0.20°, 30.24±0.20°, 30.70±0.20°, 30.94±0.20°, 31.34±0.20°, 31.64±0.20°, 32.71±0.20°, 33.22±0.20° and 34.84±0.20°.

[0011] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallization of the compound of formula (I) using Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 diffraction peaks selected from the following: 13.14±0.20°, 14.68±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.32±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20°, 24.22±0.20°, 26.46±0.20°, and 28.84±0.20°.

[0012] In some embodiments of this application, the X-ray powder diffraction pattern of the crystallization of the compound of formula (I) using Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 13.14±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20° and 24.22±0.20°.

[0013] In some embodiments of this application, the X-ray powder diffraction patterns of the crystals of the compound of formula (I) under Cu Kα radiation are expressed as 2θ values ​​at approximately 8.56°, 10.13°, 12.16°, 13.14°, 13.54°, 14.68°, 15.68°, 16.38°, 16.62°, 17.24°, 17.60°, 18.86°, 19.22°, 19.46°, 19.98°, 20.89°, 21.32°, 21.78°, 22.38°, 22.70°, and 23.0°. Diffraction peaks are observed at 8°, 23.41°, 23.70°, 24.01°, 24.22°, 24.62°, 24.89°, 25.26°, 25.92°, 26.46°, 26.92°, 27.32°, 28.18°, 28.54°, 28.84°, 29.42°, 30.24°, 30.70°, 30.94°, 31.34°, 31.64°, 32.71°, 33.22°, and 34.84°.

[0014] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the crystallized compound of formula (I) using Cu Kα radiation are shown in Table 1 below: Table 1. Peak positions and relative intensities of X-ray powder diffraction patterns of the crystals of compound (I).

[0015] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of the crystals of the compound of formula (I) using Cu Kα radiation are as follows: Figure 1 As shown.

[0016] In some embodiments of this application, the differential scanning calorimetry (DSC) curve of the crystallization of the compound of formula (I) has an endothermic peak at 144.92 ± 3 °C.

[0017] In some embodiments of this application, the DSC spectrum of the crystallization of the compound of formula (I) is as follows: Figure 2 As shown.

[0018] In some embodiments of this application, the thermogravimetric analysis (TGA) curve of the crystallization of the compound of formula (I) shows a weight loss of 0.108% at 200.00±3°C.

[0019] In some embodiments of this application, the TGA spectra of the crystals of the compound of formula (I) are as follows: Figure 3 As shown.

[0020] On the other hand, this application provides a method for preparing crystals of the compound of formula (I), comprising the step of precipitating the crystals of the compound of formula (I) in ethyl acetate solvent.

[0021] In some embodiments of this application, this application provides a method for preparing crystals of the compound of formula (I), comprising: adding ethyl acetate to the compound of formula (I), heating and stirring until dissolved, cooling and stirring, precipitating crystals, filtering and drying under reduced pressure to obtain crystals of the compound of formula (I).

[0022] On the other hand, this application also provides type I crystals of the hydrochloride salt of compound (I).

[0023] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 5.97±0.20°, 7.58±0.20° and 17.63±0.20°, represented by 2θ values.

[0024] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 5.97±0.20°, 7.58±0.20°, 16.49±0.20°, 17.63±0.20°, 20.25±0.20°, 22.84±0.20°, 23.99±0.20°, and 24.62±0.20°, expressed as 2θ values.

[0025] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystallization of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 11.08±0.20°, 11.38±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49 ±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.99±0.20° and 24.62±0.20°.

[0026] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystallization of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 9.83±0.20°, 11.08±0.20°, 11.38±0.20°, 12.69±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.79±0.20°, 23.99±0.20° and 24.62±0.20°.

[0027] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 16.49±0.20°, 17.63±0.20°, 20.25±0.20°, 22.84±0.20°, 23.99±0.20° and 24.62±0.20°.

[0028] In some embodiments of this application, the type I crystallization of the hydrochloride salt of the compound of formula (I) is achieved using Cu. In the X-ray powder diffraction pattern of Kα radiation, diffraction peaks, represented by 2θ values, are observed at 5.97±0.20°, 7.58±0.20°, 11.08±0.20°, 11.38±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.99±0.20°, and 24.62±0.20°.

[0029] In some embodiments of this application, the X-ray powder diffraction patterns of type I crystals of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation are expressed as 2θ values ​​at 5.97±0.20°, 7.58±0.20°, 9.83±0.20°, 11.08±0.20°, 11.38±0.20°, 12.69±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49±0.20°, and 17.63±0.20°. Diffraction peaks are observed at 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.79±0.20°, 23.99±0.20°, and 24.62±0.20°.

[0030] In some embodiments of this application, the type I crystallization of the hydrochloride salt of the compound of formula (I) is achieved using Cu. In the X-ray powder diffraction pattern of Kα radiation, diffraction peaks, represented by 2θ values, are observed at approximately 5.97°, 7.58°, 11.08°, 11.38°, 14.14°, 15.30°, 16.49°, 17.63°, 18.44°, 19.72°, 20.25°, 20.66°, 21.39°, 21.88°, 22.23°, 22.84°, 23.99°, 24.62°, 25.15°, 25.74°, 26.19°, 27.03°, 27.43°, 27.88°, 28.52°, 29.08°, 30.08°, 30.47°, 31.51°, and 31.94°.

[0031] In some embodiments of this application, the X-ray powder diffraction patterns of type I crystals of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation are expressed as 2θ values ​​at approximately 5.97°, 7.58°, 9.83°, 11.08°, 11.38°, 12.69°, 14.14°, 15.30°, 16.49°, 17.63°, 18.44°, 19.72°, 20.25°, 20.66°, 21.39°, and 21. Diffraction peaks are observed at 0.88°, 22.23°, 22.84°, 23.79°, 23.99°, 24.62°, 25.15°, 25.74°, 26.19°, 27.03°, 27.43°, 27.88°, 28.52°, 29.08°, 30.08°, 30.47°, 31.51°, and 31.94°.

[0032] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the type I crystals of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation are represented by the following Table 2: Table 2 shows the peak positions and relative intensities of the X-ray powder diffraction patterns of the type I crystals of the hydrochloride salts of compound (I).

[0033] In some embodiments of this application, the X-ray powder diffraction (XRPD) pattern of type I crystals of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation is shown below. Figure 4 As shown.

[0034] In some embodiments of this application, the differential scanning calorimetry (DSC) plot of the type I crystal of the hydrochloride salt of the compound of formula (I) has an endothermic peak at 204.5 ± 3 °C.

[0035] In some embodiments of this application, the DSC spectrum of type I crystals of the hydrochloride salt of the compound of formula (I) is as follows: Figure 5 As shown.

[0036] In some embodiments of this application, the thermogravimetric analysis (TGA) curve of the type I crystallization of the hydrochloride salt of the compound of formula (I) shows a weight loss of 2.28% at 150.0 ± 3 °C.

[0037] In some embodiments of this application, the TGA spectra of type I crystals of the hydrochloride salt of the compound of formula (I) are as follows: Figure 5 As shown.

[0038] On the other hand, this application provides a method for preparing type I crystals of the hydrochloride salt of the compound of formula (I), comprising the step of precipitating the crystals of the hydrochloride salt of the compound of formula (I) in a mixed solvent of ethyl acetate and water.

[0039] In some embodiments of this application, type I crystals of the hydrochloride salt of compound (I) of this application are prepared by a method comprising: (1) The compound of formula (I) is reacted with hydrochloric acid in the presence of ethyl acetate and water to obtain the hydrochloride salt of the compound of formula (I); (2) Crystallization.

[0040] In some embodiments of this application, in the type I crystallization of the hydrochloride salt of the compound of formula (I), the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1, or the hydrochloride salt of the compound of formula (I) is the compound of formula (II): .

[0041] In some embodiments of this application, a method for preparing type I crystals of the compound of formula (II) is provided, comprising: mixing the crystals of the compound of formula (I) with ethyl acetate and heating until the solution becomes clear, then adding an ethyl acetate solution of hydrochloric acid and stirring, cooling to crystallize, and then filtering and drying under reduced pressure to obtain type I crystals of the compound of formula (II).

[0042] On the other hand, this application also provides type II crystals of the hydrochloride salt of compound (I).

[0043] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 9.84±0.20°, 16.76±0.20°, and 20.09±0.20°, represented by 2θ values.

[0044] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 9.84±0.20°, 16.31±0.20°, 16.76±0.20°, 20.09±0.20°, 22.61±0.20°, 23.65±0.20°, 24.55±0.20°, and 25.32±0.20°, represented by 2θ values.

[0045] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystals of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 9.84 ±0.20°, 10.59 ±0.20°, 12.39 ±0.20°, 12.61 ±0.20°, 13.99 ±0.20°, 16.31 ±0.20°, 16.76 ±0.20°, 18.31 ±0.20°, 18.72 ±0.20°, 19.06 ±0.20°, 19.55 ±0.20°, 19.72 ±0.20°, 20.09 ±0.20°, 20.77 ±0.20°, 21.22 ±0.20°, 22.61 ±0.20°, 23.04 ±0.20°, 23.41 ±0.20°, 23.65 ±0.20°, 24.55 ±0.20°, 25.32 ±0.20°, 26.49 ±0.20°, 26.90 ±0.20°, 27.71 ±0.20°, 28.27 ±0.20°, 28.47 ±0.20°, 29.22 ±0.20°, 29.61 ±0.20°, 30.22 ±0.20°, 31.11 ±0.20°, 31.47 ±0.20°, 34.18 ±0.20°.

[0046] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystal of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 9.84±0.20°, 16.31±0.20°, 16.76±0.20°, 20.09±0.20°, 22.61±0.20°, 23.65±0.20°, 24.55±0.20°, 25.32±0.20°.

[0047] In some embodiments of this application, the X-ray powder diffraction patterns of type II crystals of the hydrochloride salt of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values ​​at approximately 9.84°, 10.59°, 12.39°, 12.61°, 13.99°, 16.31°, 16.76°, 18.31°, 18.72°, 19.06°, 19.55°, 19.72°, 20.09°, 20.77°, 21.22°, 2 Diffraction peaks are observed at 2.61°, 23.04°, 23.41°, 23.65°, 24.55°, 25.11°, 25.32°, 26.49°, 26.90°, 27.71°, 28.27°, 28.47°, 29.22°, 29.61°, 30.22°, 31.11°, 31.47°, and 34.18°.

[0048] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the type II crystals of the hydrochloride of the compound of formula (I) under CuKα radiation are represented by the following Table 10: Table 10 shows the X-ray powder diffraction patterns of type II crystals of the hydrochloride salts of compound (I), including peak positions and relative intensities.

[0049] In some embodiments of this application, the X-ray powder diffraction (XRPD) pattern of the type II crystals of the hydrochloride of the compound of formula (I) using Cu Kα radiation is shown below. Figure 17 As shown.

[0050] In some embodiments of this application, the differential scanning calorimetry (DSC) plots of type II crystals of the hydrochloride salt of the compound of formula (I) have endothermic peaks at 101.4±3℃, 113.3±3℃ and 195.9±3℃.

[0051] In some embodiments of this application, the DSC spectrum of the type II crystals of the hydrochloride salt of the compound of formula (I) is as follows: Figure 18 As shown.

[0052] In some embodiments of this application, the thermogravimetric analysis (TGA) curves of type II crystals of the hydrochloride salt of the compound of formula (I) show a weight loss of 5.48% at 55.0±3℃ and a weight loss of 9.67% at 90.0±3℃.

[0053] In some embodiments of this application, the TGA spectra of the type II crystals of the hydrochloride salt of the compound of formula (I) are as follows: Figure 18 As shown.

[0054] On the other hand, this application provides a method for preparing the crystallization of the hydrochloride salt of the compound of formula (I), comprising the step of precipitating the type II crystal of the compound of formula (II) in a mixed solvent of ethyl acetate and water.

[0055] In some embodiments of this application, type II crystals of the hydrochloride salt of compound (I) of this application are prepared by a method comprising: (1) The type I crystallization of the hydrochloride salt of compound (I) is reacted in the presence of ethyl acetate and water; (2) Crystallization.

[0056] In some embodiments of this application, in the type II crystallization of the hydrochloride salt of the compound of formula (I), the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1, or the hydrochloride salt of the compound of formula (I) is the compound of formula (II): .

[0057] In some embodiments of this application, a method for preparing type II crystals of the compound of formula (II) is provided, comprising: mixing type I crystals of the compound of formula (II) with ethyl acetate and water and heating and stirring until the solution becomes clear, cooling to crystallize, and then filtering and drying under reduced pressure to obtain type II crystals of the compound of formula (II).

[0058] On the other hand, this application provides the fumarate of compound (I).

[0059] In some embodiments of this application, the fumarate of the compound of formula (I) is in crystalline form.

[0060] On the other hand, this application provides crystallization of the fumarate of compound (I).

[0061] In some embodiments of this application, the X-ray powder diffraction patterns of the fumarate crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at 5.12±0.20°, 14.99±0.20° and 19.17±0.20°, represented by 2θ values.

[0062] In some embodiments of this application, the X-ray powder diffraction patterns of the fumarate crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at 5.12±0.20°, 9.20±0.20°, 14.99±0.20°, 18.08±0.20°, 19.17±0.20°, 21.39±0.20°, 22.57±0.20°, and 25.15±0.20°, represented by 2θ values.

[0063] In some embodiments of this application, the X-ray powder diffraction pattern of the fumarate crystals of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8 or more diffraction peaks selected from the following: 5.12±0.20°, 9.20±0.20°, 12.03±0.20°, 14.99±0.20°, 15.31±0.20°, 16.75±0.20°, 17.62±0.20°, 18.08±0.20°, 18.83±0.20°, 19.17±0.20°, 20.80°. ±0.20°, 21.39±0.20°, 22.21±0.20°, 22.57±0.20°, 23.09±0.20°, 23.50±0.20°, 24.42±0.20°, 25.15±0.20°, 25.78±0.20°, 27.14±0.20°, 28.25±0.20°, 29.54±0.20°, 30.50±0.20°, 31.09±0.20° and 32.16±0.20°.

[0064] In some embodiments of this application, the X-ray powder diffraction pattern of the fumarate crystals of the compound of formula (I) under Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.12±0.20°, 9.20±0.20°, 14.99±0.20°, 18.08±0.20°, 19.17±0.20°, 21.39±0.20°, 22.57±0.20° and 25.15±0.20°.

[0065] In some embodiments of this application, the X-ray powder diffraction patterns of the fumarate crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at approximately 5.12°, 9.20°, 12.03°, 14.99°, 15.31°, 16.75°, 17.62°, 18.08°, 18.83°, 19.17°, 20.80°, 21.39°, 22.21°, 22.57°, 23.09°, 23.50°, 24.42°, 25.15°, 25.78°, 27.14°, 28.25°, 29.54°, 30.50°, 31.09°, and 32.16°.

[0066] In some embodiments of this application, the peak positions and relative intensities of the fumarate crystals of the compound of formula (I) under Cu Kα radiation are shown in Table 3 below: Table 3 shows the peak positions and relative intensities of the X-ray powder diffraction patterns of the fumarate crystals of compound (I).

[0067] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of the fumarate crystals of the compound of formula (I) using Cu Kα radiation are shown below. Figure 7 As shown.

[0068] In some embodiments of this application, the differential scanning calorimetry (DSC) plot of the fumarate crystals of the compound of formula (I) using Cu Kα radiation has an endothermic peak at 164.5 ± 3 °C.

[0069] In some embodiments of this application, the DSC spectrum of the fumarate crystals of the compound of formula (I) is as follows: Figure 8 As shown.

[0070] In some embodiments of this application, the thermogravimetric analysis (TGA) curve of the fumarate crystal of the compound of formula (I) shows a weight loss of 0.85% at 140.0 ± 3 °C.

[0071] In some embodiments of this application, the TGA spectra of the fumarate crystals of the compound of formula (I) are as follows: Figure 8 As shown.

[0072] On the other hand, this application provides a method for preparing the crystallization of the fumarate of the compound of formula (I), comprising the step of precipitating the crystallization of the fumarate of the compound of formula (I) in an acetone solvent.

[0073] In some embodiments of this application, the fumarate of compound (I) of this application is prepared by a method comprising: (1) The compound of formula (I) is reacted with fumaric acid in the presence of acetone to obtain the fumarate of the compound of formula (I); (2) Crystallization.

[0074] In some embodiments of this application, in the fumarate of compound (I) or the crystallization of the fumarate of compound (I), the molar ratio of compound (I) to fumaric acid is 1:1, or the fumarate of compound (I) is a compound of formula (III): .

[0075] In some embodiments of this application, a method for preparing crystals of the compound of formula (III) is provided, comprising: mixing the crystals of the compound of formula (I) with acetone and heating until the solution becomes clear, then adding fumaric acid and stirring, cooling to crystallize, and then filtering and drying under reduced pressure to obtain crystals of the compound of formula (III).

[0076] On the other hand, this application also provides maleate salts of compounds of formula (I).

[0077] In some embodiments of this application, the maleate salt of the compound of formula (I) is in crystalline form.

[0078] On the other hand, this application also provides crystals of the maleate salt of compound (I).

[0079] In some embodiments of this application, the X-ray powder diffraction pattern of the maleate crystal of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 4.55±0.20°, 18.12±0.20° and 21.18±0.20°, represented by 2θ values.

[0080] In some embodiments of this application, the X-ray powder diffraction patterns of the maleate crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at 4.55±0.20°, 12.85±0.20°, 16.19±0.20°, 16.68±0.20°, 18.12±0.20°, 21.18±0.20°, 22.71±0.20°, and 27.31±0.20°, represented by 2θ values.

[0081] In some embodiments of this application, the X-ray powder diffraction pattern of the maleate crystal of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8 or more diffraction peaks selected from the following: 4.55±0.20°, 9.06±0.20°, 10.63±0.20°, 11.00±0.20°, 12.85±0.20°, 13.75±0.20°, 15.96±0.20°, 16.19±0.20°, 16.68±0.20°, 16.99±0.20°, 17.51±0.20°. 18.12±0.20°, 20.12±0.20°, 20.75±0.20°, 21.18±0.20°, 22.71±0.20°, 23.04±0.20°, 24.13±0.20°, 24.55±0.20°, 25.32±0.20°, 25.95±0.20°, 27.31±0.20°, 28.38±0.20°, 28.97±0.20°, 29.62±0.20° and 34.09±0.20°.

[0082] In some embodiments of this application, the X-ray powder diffraction pattern of the maleate crystal of the compound of formula (I) under Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 4.55±0.20°, 12.85±0.20°, 16.19±0.20°, 16.68±0.20°, 18.12±0.20°, 21.18±0.20°, 22.71±0.20° and 27.31±0.20°.

[0083] In some embodiments of this application, the X-ray powder diffraction patterns of the maleate crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at approximately 4.55°, 9.06°, 10.63°, 11.00°, 12.85°, 13.75°, 15.96°, 16.19°, 16.68°, 16.99°, 17.51°, 18.12°, 20.12°, 20.75°, 21.18°, 22.71°, 23.04°, 24.13°, 24.55°, 25.32°, 25.95°, 27.31°, 28.38°, 28.97°, 29.62°, and 34.09°, expressed as 2θ values.

[0084] In some embodiments of this application, the peak positions and relative intensities of the maleate crystals of the compound of formula (I) under Cu Kα radiation X-ray powder diffraction patterns are represented by the following Table 4: Table 4 shows the peak positions and relative intensities of the X-ray powder diffraction patterns of the maleate crystals of compound (I).

[0085] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of the maleate crystals of the compound of formula (I) using Cu Kα radiation are as follows: Figure 9 As shown.

[0086] In some embodiments of this application, the differential scanning calorimetry (DSC) plot of the maleate crystal of the compound of formula (I) has an endothermic peak at 160.3 ± 3 °C.

[0087] In some embodiments of this application, the DSC spectrum of the maleate crystals of the compound of formula (I) is as follows: Figure 10 As shown.

[0088] In some embodiments of this application, the thermogravimetric analysis (TGA) curve of the maleate crystal of the compound of formula (I) shows a weight loss of 1.67% at 140.0 ± 3 °C.

[0089] In some embodiments of this application, the TGA spectra of the maleate crystals of the compound of formula (I) are as follows: Figure 10 As shown.

[0090] On the other hand, this application provides a method for preparing the crystallization of the maleate of the compound of formula (I), comprising the step of precipitating the crystallization of the maleate of the compound of formula (I) in ethyl acetate solvent.

[0091] In some embodiments of this application, the maleate salt of compound (I) is prepared by a method comprising: (1) The compound of formula (I) is reacted with maleic acid in the presence of ethyl acetate to obtain the maleate salt of compound (I); (2) Crystallization.

[0092] In some embodiments of this application, in the maleate salt of compound (I) or the crystallization of the maleate salt of compound (I), the molar ratio of compound (I) to maleic acid is 1:1, or the maleate salt of compound (I) is compound (IV): .

[0093] In some embodiments of this application, a method for preparing crystals of the compound of formula (IV) is provided, comprising: mixing the crystals of the compound of formula (I) with ethyl acetate and heating until the solution becomes clear, then adding maleic acid and stirring, cooling to crystallize, and then filtering and drying under reduced pressure to obtain crystals of the compound of formula (IV).

[0094] On the other hand, this application also provides methanesulfonate salts of compounds of formula (I).

[0095] In some embodiments of this application, the methanesulfonate salt of the compound of formula (I) is in crystalline form.

[0096] On the other hand, this application also provides type I crystals of the methanesulfonate of compound (I).

[0097] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystal of the methanesulfonate of the compound of formula (I) using Cu Kα radiation shows diffraction peaks at 5.47±0.20°, 6.25±0.20° and 16.11±0.20°, represented by 2θ values.

[0098] In some embodiments of this application, the X-ray powder diffraction patterns of the type I crystals of the methanesulfonate of the compound of formula (I) under Cu Kα radiation show diffraction peaks at 5.47±0.20°, 6.25±0.20°, 16.11±0.20°, 16.64±0.20°, 18.11±0.20°, 19.73±0.20°, 24.22±0.20°, and 25.12±0.20°, represented by 2θ values.

[0099] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystals of the methanesulfonate of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8 or more diffraction peaks selected from the following: 5.47±0.20°, 6.00±0.20°, 6.25±0.20°, 8.29±0.20°, 9.62±0.20°, 10.88±0.20°, 12.02±0.20°, 12.46±0.20°, 13.81±0.20°, 16.11±0.20°, 16.39±0.20°, 16.64±0.20°, 18 ... 0.20°, 18.72±0.20°, 19.73±0.20°, 20.21±0.20°, 21.08±0.20°, 21.41±0.20°, 22.80±0.20°, 23.45±0.20°, 24.22±0.20°, 24.55±0.20°, 25.12±0.20°, 25.64±0.20°, 26.00±0.20°, 26.99±0.20°, 29.06±0.20°, 29.88±0.20° and 31.18±0.20°.

[0100] In some embodiments of this application, the X-ray powder diffraction pattern of the type I crystal of the methanesulfonate of the compound of formula (I) using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.47±0.20°, 6.25±0.20°, 16.11±0.20°, 16.64±0.20°, 18.11±0.20°, 19.73±0.20°, 24.22±0.20° and 25.12±0.20°.

[0101] In some embodiments of this application, the X-ray powder diffraction patterns of the type I crystals of the methanesulfonate of the compound of formula (I) under Cu Kα radiation show diffraction peaks at approximately 5.47°, 6.00°, 6.25°, 8.29°, 9.62°, 10.88°, 12.02°, 12.46°, 13.81°, 16.11°, 16.39°, 16.64°, 18.11°, 18.72°, 19.73°, 20.21°, 21.08°, 21.41°, 22.80°, 23.45°, 24.22°, 24.55°, 25.12°, 25.64°, 26.00°, 26.99°, 29.06°, 29.88°, and 31.18°, expressed as 2θ values.

[0102] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the type I crystals of the methanesulfonate of formula (I) under Cu Kα radiation are shown in Table 5 below: Table 5. Peak positions and relative intensities of diffraction peaks for type I crystals of the methanesulfonate of compound (I).

[0103] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of type I crystals of the methanesulfonate of the compound of formula (I) using Cu Kα radiation are shown below. Figure 11 As shown.

[0104] On the other hand, this application provides a method for preparing type I crystals of the methanesulfonate of the compound of formula (I), comprising the step of precipitating type I crystals of the methanesulfonate of the compound of formula (I) in ethyl acetate solvent.

[0105] In some embodiments of this application, type I crystals of the methanesulfonate of compound (I) of this application are prepared by a method comprising: (1) The compound of formula (I) is reacted with methanesulfonic acid in the presence of ethyl acetate to obtain the methanesulfonate of the compound of formula (I); (2) Crystallization.

[0106] On the other hand, this application also provides type II crystals of the methanesulfonate of compound (I).

[0107] In some embodiments of this application, the X-ray powder diffraction patterns of the type II crystals of the methanesulfonate of the compound of formula (I) using CuKα radiation show diffraction peaks at 6.17±0.20°, 8.76±0.20°, and 23.03±0.20°, represented by 2θ values.

[0108] In some embodiments of this application, the X-ray powder diffraction patterns of the type II crystals of the methanesulfonate of the compound of formula (I) using CuKα radiation show diffraction peaks at 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 16.12±0.20°, 17.18±0.20°, 19.23±0.20°, 20.19±0.20°, and 23.03±0.20°, represented by 2θ values.

[0109] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystals of the methanesulfonate of formula (I) under CuKα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8 or more diffraction peaks selected from the following: 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 12.37±0.20°, 14.53±0.20°, 15.4... 6±0.20°, 16.12±0.20°, 17.18±0.20°, 17.40±0.20°, 18.30±0.20°, 18.78±0.20°, 19.23±0.20°, 19.71±0.20°, 20.19±0.20°, 20.74±0.20°, 21.05±0.20°, 22.19±0.20° and 23.03±0.20°.

[0110] In some embodiments of this application, the X-ray powder diffraction pattern of the type II crystals of the methanesulfonate of the compound of formula (I) using CuKα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 16.12±0.20°, 17.18±0.20°, 19.23±0.20°, 20.19±0.20° and 23.03±0.20°.

[0111] In some embodiments of this application, the X-ray powder diffraction patterns of the type II crystals of the methanesulfonate of the compound of formula (I) under CuKα radiation show diffraction peaks at approximately 6.17°, 8.76°, 12.16°, 12.37°, 14.53°, 15.46°, 16.12°, 17.18°, 17.40°, 18.30°, 18.78°, 19.23°, 19.71°, 20.19°, 20.74°, 21.05°, 22.19°, and 23.03°, represented by 2θ values.

[0112] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the type II crystals of the methanesulfonate of formula (I) under CuKα radiation are represented by the following Table 6: Table 6. Peak positions and relative intensities of diffraction peaks for type II crystals of methanesulfonate of compound (I).

[0113] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of type II crystals of the methanesulfonate of formula (I) are obtained using CuKα radiation, as shown below. Figure 12 As shown.

[0114] On the other hand, this application provides a method for preparing type II crystals of the methanesulfonate of the compound of formula (I), comprising the step of precipitating type II crystals of the methanesulfonate of the compound of formula (I) in acetone solvent.

[0115] In some embodiments of this application, type II crystals of the methanesulfonate of compound (I) of this application are prepared by a method comprising: (1) The compound of formula (I) is reacted with methanesulfonic acid in the presence of acetone to obtain the methanesulfonate of the compound of formula (I); (2) Crystallization.

[0116] In some embodiments of this application, in the methanesulfonate of compound (I), the type I crystal of methanesulfonate of compound (I), or the type II crystal of methanesulfonate of compound (I), the molar ratio of compound (I) to methanesulfonic acid is 1:2, or the methanesulfonate of compound (I) is a compound of formula (V): .

[0117] In some embodiments of this application, a method for preparing type I crystals of the compound of formula (V) is provided, comprising: mixing the crystals of the compound of formula (I) with ethyl acetate and heating until the solution becomes clear, then adding methanesulfonic acid and stirring, cooling to crystallize, and then filtering and drying under reduced pressure to obtain type I crystals of the compound of formula (V).

[0118] In some embodiments of this application, a method for preparing type II crystals of the compound of formula (V) is provided, comprising: mixing the crystals of the compound of formula (I) with acetone and heating until the solution becomes clear, then adding methanesulfonic acid and stirring, cooling to crystallize, and then filtering and drying under reduced pressure to obtain type II crystals of the compound of formula (V).

[0119] On the other hand, this application also provides hydrobromide salts of compounds of formula (I).

[0120] In some embodiments of this application, the hydrobromide of the compound of formula (I) is in crystalline form.

[0121] On the other hand, this application also provides crystallization of the hydrobromide of compound (I).

[0122] In some embodiments of this application, the crystallization of the hydrobromide of the compound of formula (I) is shown by X-ray powder diffraction using Cu Kα radiation, with diffraction peaks at 7.59±0.20°, 17.62±0.20° and 23.84±0.20°, represented by 2θ values.

[0123] In some embodiments of this application, the X-ray powder diffraction patterns of the hydrobromide crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 16.49±0.20°, 17.62±0.20°, 23.84±0.20°, 24.54±0.20°, and 30.30±0.20°, expressed as 2θ values.

[0124] In some embodiments of this application, the X-ray powder diffraction pattern of the hydrobromide crystals of the compound of formula (I) under Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8 or more diffraction peaks selected from the following: 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 9.76±0.20°, 11.11±0.20°, 12.78±0.20°, 16.49±0.20°, 17.62±0.20°, 18.44±0.20°, 19.57±0.20°, 20.69±0.20°, 21.16±0.20°, 22.16±0.20°, 22.77±0.20°, 23.84±0.20°, 24.31±0.20°, 24.54±0.20°, 25.15±0.20°, 26.07±0.20°, 27.31±0.20°, 27.83±0.20°, 28.91±0.20°, 30.30±0.20° and 31.74±0.20°.

[0125] In some embodiments of this application, the X-ray powder diffraction pattern of the hydrobromide crystal of the compound of formula (I) under Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 16.49±0.20°, 17.62±0.20°, 23.84±0.20°, 24.54±0.20° and 30.30±0.20°.

[0126] In some embodiments of this application, the X-ray powder diffraction patterns of the hydrobromide crystals of the compound of formula (I) under Cu Kα radiation show diffraction peaks at approximately 3.12°, 5.96°, 7.59°, 9.76°, 11.11°, 12.78°, 16.49°, 17.62°, 18.44°, 19.57°, 20.69°, 21.16°, 22.16°, 22.77°, 23.84°, 24.31°, 24.54°, 25.15°, 26.07°, 27.31°, 27.83°, 28.91°, 30.30°, and 31.74°, expressed as 2θ values.

[0127] In some embodiments of this application, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction patterns of the hydrobromide crystals of the compound of formula (I) under Cu Kα radiation are shown in Table 7 below: Table 7. Peak positions and relative intensities of diffraction peaks for the crystallization of hydrobromide of compound (I).

[0128] In some embodiments of this application, the X-ray powder diffraction (XRPD) patterns of the hydrobromide crystals of the compound of formula (I) using Cu Kα radiation are shown below. Figure 13 As shown.

[0129] On the other hand, this application provides a method for preparing the crystallization of the hydrobromide of the compound of formula (I), comprising the step of precipitating the crystallization of the hydrobromide of the compound of formula (I) in a mixed solvent of acetone and water.

[0130] In some embodiments of this application, the hydrobromide of compound (I) of this application is prepared by a method comprising: (1) The compound of formula (I) is reacted with hydrobromic acid in the presence of acetone and water to obtain the hydrobromide salt of the compound of formula (I); (2) Crystallization.

[0131] In some embodiments of this application, in the hydrobromide of compound (I) or the crystallization of hydrobromide of compound (I), the molar ratio of compound (I) to hydrobromic acid is 1:1, or the hydrobromide of compound (I) is compound (VI): .

[0132] In some embodiments of this application, a method for preparing type I crystals of the compound of formula (VI) is provided, comprising: mixing the crystals of the compound of formula (I) with acetone and heating until the solution becomes clear, then adding hydrobromic acid and stirring, cooling to precipitate crystals, and then filtering and drying under reduced pressure to obtain type I crystals of the compound of formula (VI).

[0133] On the other hand, this application provides a method for preparing the crystallization of the salt of the compound of formula (I), comprising: (1) The crystallization of the compound of formula (I) is mixed with a solvent selected from acetone or ethyl acetate and heated until the solution becomes clear; (2) Add an acid for salt formation to the above solution and stir, cool and crystallize, then filter and dry under reduced pressure to obtain the crystals of the salt of the compound of formula (I).

[0134] Alternatively, this application provides another method for preparing crystals of the salt of the compound of formula (I), comprising: mixing the crystals of a salt of one type of compound of formula (I) with ethyl acetate and water and heating and stirring until the solution becomes clear, cooling to crystallize, and then filtering and drying under reduced pressure to obtain crystals of another type of compound of formula (I).

[0135] On another aspect, this application provides a crystalline composition comprising crystals of the compound of formula (I), type I or type II crystals of the hydrochloride salt of the compound of formula (I), crystals of the fumarate salt of the compound of formula (I), crystals of the maleate salt of the compound of formula (I), type I crystals of the methanesulfonate salt of the compound of formula (I), type II crystals of the methanesulfonate salt of the compound of formula (I), and crystals of the hydrobromide salt of the compound of formula (I), wherein the crystals account for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0136] On another front, this application provides a pharmaceutical composition comprising a therapeutically or preventively effective amount of crystals of the compound of formula (I) of this application, a hydrochloride salt of the compound of formula (I) or a type I or type II crystal thereof, a fumarate salt of the compound of formula (I) or a crystal thereof, a maleate salt of the compound of formula (I) or a crystal thereof, a methanesulfonate salt of the compound of formula (I) or a type I or type II crystal thereof, a hydrobromide salt of the compound of formula (I) or a crystal thereof, or a combination of the above crystalline compositions. The pharmaceutical composition of this application may or may not contain pharmaceutically acceptable excipients. Furthermore, the pharmaceutical composition of this application may further comprise one or more other therapeutic agents.

[0137] In another aspect, this application provides a method for treating or preventing estrogen receptor-related conditions, the method comprising administering to an individual in need a therapeutic or preventative amount of crystals of the compound of formula (I), hydrochloride of the compound of formula (I) or its type I or type II crystals, fumarate of the compound of formula (I) or its crystals, maleate of the compound of formula (I) or its crystals, methanesulfonate of the compound of formula (I) or its type I or type II crystals, hydrobromide of the compound of formula (I) or its crystals, or the above-mentioned crystalline compositions, or the above-mentioned pharmaceutical compositions.

[0138] In another aspect, this application provides the use of crystals of the compound of formula (I), hydrochloride of the compound of formula (I) or its type I or type II crystals, fumarate of the compound of formula (I) or its crystals, maleate of the compound of formula (I) or its crystals, methanesulfonate of the compound of formula (I) or its type I or type II crystals, hydrobromide of the compound of formula (I) or its crystals, or the above-mentioned crystalline compositions, or the above-mentioned pharmaceutical compositions in the preparation of a medicament for treating or preventing estrogen receptor-related diseases.

[0139] On another aspect, this application provides the use of crystals of the compound of formula (I), hydrochloride of the compound of formula (I) or its type I or type II crystals, fumarate of the compound of formula (I) or its crystals, maleate of the compound of formula (I) or its crystals, methanesulfonate of the compound of formula (I) or its type I or type II crystals, hydrobromide of the compound of formula (I) or its crystals, or the above-mentioned crystalline compositions, or the above-mentioned pharmaceutical compositions in the treatment or prevention of estrogen receptor-related diseases.

[0140] On another aspect, this application provides crystals of the compound of formula (I), hydrochloride of the compound of formula (I) or its type I or type II crystals, fumarate of the compound of formula (I) or its crystals, maleate of the compound of formula (I) or its crystals, methanesulfonate of the compound of formula (I) or its type I or type II crystals, hydrobromide of the compound of formula (I) or its crystals, or the above-mentioned crystalline compositions, or the above-mentioned pharmaceutical compositions, for the treatment or prevention of conditions related to estrogen receptors.

[0141] In some embodiments of this application, the estrogen receptor-related condition is breast cancer.

[0142] In some embodiments of this application, the estrogen receptor-related condition is estrogen receptor-positive breast cancer.

[0143] Technical effect The compounds and their salts described in this application are simple to prepare by crystallization, exhibiting good solubility, physical stability, and chemical stability. They also possess good oral exposure and pharmacokinetic properties, making them suitable for pharmaceutical use. The crystals of these compounds and their salts exhibit good chemical stability under acidic, alkaline, and oxidizing conditions, facilitating storage and reducing the risk of drug instability caused by excipients in formulations, thus aiding in formulation screening. The crystals of these compounds and their salts exhibit low hygroscopicity. For example, DVS spectroscopy shows that the hygroscopicity of both type I and type II crystals of the hydrochloride salt of formula (I) is lower than that of the amorphous form of the hydrochloride salt of formula (I), with type I crystals of the hydrochloride salt of formula (I) showing particularly superior performance. The crystals of this application exhibit excellent properties in terms of pharmacokinetics, bioavailability, hygroscopicity, flowability, stability, solubility, purity, and quality uniformity.

[0144] Definitions and Explanations Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0145] For any given crystal form, the relative intensity of diffraction peaks can change due to preferred orientations caused by factors such as crystal morphology, as is well known in the field of crystallography. Where preferred orientations have an effect, peak intensities change, but the positions of the diffraction peaks of the crystal form cannot be altered. Furthermore, for any given crystal form, the positions of the peaks may be subject to slight measurement errors, which is also well known in the field of crystallography. For example, peak positions can shift due to temperature changes during sample analysis, sample movement, or instrument calibration; the measurement error of the 2θ value is sometimes approximately ±0.2 degrees. Therefore, it is understood by those skilled in the art that this error should be taken into account when determining each crystal structure.

[0146] DSC determines the transition temperature when crystals absorb or release heat due to changes in their crystalline structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within ±3°C in continuous analysis; when we say a compound has a given DSC peak or melting point, we mean that the DSC peak or melting point is ±3°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0147] The term "pharmaceuticalally acceptable excipients" refers to inert substances that are administered together with the active ingredient and that facilitate the administration of the active ingredient, including but not limited to any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the National Medical Products Administration for use in humans or animals (e.g., livestock).

[0148] The term "crystalline composition" refers to a mixture of one or more crystals of the compounds of formula (I), (II), (III), (IV), (V), or (VI) of this application with other crystal forms or amorphous substances or other impurities of the compound. For example, a crystalline composition of the compound of formula (I) refers to a mixture containing, in addition to crystals of the compound of formula (I) of this application, other crystal forms or amorphous substances or other impurities of the compound of formula (I).

[0149] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application, their salts, or crystals thereof, with optional pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0150] The therapeutic dose of the compound may be determined based on factors such as the specific therapeutic purpose, the method of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound in the pharmaceutical composition may not be fixed and may depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0151] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes: (i) Suppress the disease or disease state, that is, curb its development; (ii) To alleviate a disease or disease state, that is, to bring the disease or disease state to an end.

[0152] The term “prevention” means administering the compound or formulation described in this application to prevent one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0153] The therapeutically effective dose of the crystal form described in this application is from about 0.0001 to 20 mg / kg body weight / day, for example from 0.001 to 10 mg / kg body weight / day.

[0154] The term "therapeutic or preventive effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0155] Unless otherwise required by this application, throughout the specification and subsequent claims, the word “comprise” and its English variations such as “comprises” and “comprising” and their equivalents shall be interpreted in an open-ended, non-exclusive sense, meaning “including but not limited to”.

[0156] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0157] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this specification and appended claims includes the plural object unless expressly stated otherwise. In other words, throughout this document, unless the context clearly specifies otherwise, the singular term encompasses the plural referent, and vice versa. Thus, a reaction involving “catalyst,” for example, includes one catalyst, or two or more catalysts. It should also be understood that the term “or” is generally used to mean “and / or” unless expressly stated otherwise.

[0158] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe this application, the term "about" indicates an existing error value, such as a variation within ±5%, for example ±1%, or ±0.1% of a particular value.

[0159] The intermediate compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0160] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0161] The present application will be described in detail below through embodiments, which are not intended to limit the present application in any way.

[0162] All solvents used in this application are commercially available and can be used without further purification.

[0163] The solvents used in this application are commercially available.

[0164] This application uses the following abbreviations: 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 Microwatts per square centimeter; h: hour; Kg: kilogram; nM: nanomolar; RRT: relative retention time; rpm: rotational speed.

[0165] The compounds in this application are named in accordance with conventional naming principles in the art or using ChemDraw® software, and commercially available compounds are named according to the supplier catalog.

[0166] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0167] Instruments and Analytical Methods 1.1 X-ray powder diffractometer (XRPD) method of this application Instrument Model: PANalytical X'Pert³ X-ray Diffractometer Test method: Approximately 10 mg of sample was used for XRPD detection.

[0168] X-ray type: Cu, Kα, Kα1 (Å): 1.540598; Kα2 (Å): 1.544426, Kα2 / Kα1 intensity ratio: 0.50, voltage: 45 kV, current: 40 mA, divergence slit: 1 / 16 degree, scanning mode: continuous, scanning range: from 3.0 to 40.0 degrees.

[0169] 1.2 Differential Scanning Calorimeter (DSC) Method of this Application Instrument Model: TA Instruments Discovery DSC 2500 and Q200 Differential Scanning Calorimeter Test method: Place 1-5 mg of sample in a covered aluminum crucible and heat the sample from room temperature to 350°C at a heating rate of 10°C / min under the protection of dry N2 at a rate of 50 mL / min. At the same time, TA software records the heat change of the sample during the heating process.

[0170] 1.3 Thermogravimetric Analysis (TGA) Method of this Application Instrument models: TA Instruments Q5000 and Discovery TGA 5500 thermogravimetric analyzers Test method: Take 2-5 mg of sample and place it in a platinum crucible. Use segmented high-resolution detection method to raise the sample from room temperature to 350℃ at a heating rate of 10℃ / min under the protection of dry N2 at 50 mL / min. At the same time, TA software records the weight change of the sample during the heating process.

[0171] 1.4 Dynamic Vapor Sorption (DVS) Method of this Application Instrument Model: DVS Intrinsic instrument from SMS (Surface Measurement Systems) DVS test parameters: Temperature: 25℃, Sample volume: 10-30 mg, Protective gas and flow rate: N2, 200 mL / min, dm / dt: 0.002% / min, Minimum dm / dt equilibration time: 10 min, Maximum equilibration time: 180 min, RH range: 0%RH-95%RH-0%RH, RH gradient: 10% (90%RH-0%RH-90%RH), 5% (95%RH-90%RH and 90%RH-95%RH).

[0172] 1.5 Chloride ion content analysis method of this application Instrument model: SHIMADZU LC-20AD sp instrument Software type: Lab Solution Version 5.92 Column and mobile phase: SHIMADZU Shim-pack IC-A3 4.6mm 15cm 5μm; 8.0 mmol / L p-hydroxybenzoic acid + 3.2 mmol / L Bis-Tris buffer Mobile phase rate: 1.5 ml / min, column temperature: 40 degrees Celsius Test method: External standard single-point method. Accurately weigh the test sample and reference standard to prepare aqueous solutions. Accurately measure a certain amount of each and inject them into the solution. Record the chromatogram. Measure the peak area (or peak height) of the analyte in the reference solution and test sample solution. Calculate the content according to the following formula: Content (c) x )= c R ×A x / A R In the above formula, c R : Concentration of reference standard; A x Peak area of ​​the test sample; A R : Peak area of ​​the reference sample; Attached Figure Description Figure 1 The image shows the XRPD spectrum of the crystallized compound of formula (Ⅰ).

[0173] Figure 2 The image shows the DSC spectrum of the crystallized compound of formula (Ⅰ).

[0174] Figure 3 The TGA spectrum of the crystallized compound of formula (Ⅰ) is shown.

[0175] Figure 4 The XRPD spectrum is that of the type I crystal of compound (II).

[0176] Figure 5The DSC and TGA spectra of the type I crystal of compound (II) are shown.

[0177] Figure 6 The image shows the DVS spectrum of the type I crystal of compound (II).

[0178] Figure 7 The XRPD spectrum of the crystallized compound of formula (III) is shown.

[0179] Figure 8 The DSC and TGA spectra of the crystals of compound (III) are shown.

[0180] Figure 9 The XRPD spectrum of the crystallized compound of formula (IV) is shown.

[0181] Figure 10 The DSC and TGA spectra of the crystals of compound (IV) are shown.

[0182] Figure 11 The image shows the XRPD spectrum of the type I crystal of compound (V).

[0183] Figure 12 The XRPD spectrum is for type II crystallization of compound (V).

[0184] Figure 13 The XRPD spectrum of the crystallized compound of formula (VI) is shown.

[0185] Figure 14 The XRPD spectrum of the hydrochloride salt of compound (I) of Example 1 is shown.

[0186] Figure 15 The DSC and TGA spectra of the hydrochloride salt of compound (I) of Example 1 are shown.

[0187] Figure 16 The image shows the DVS spectrum of the hydrochloride salt of compound (I) of Example 1.

[0188] Figure 17 The XRPD spectrum is for the type II crystallization of compound (II).

[0189] Figure 18 The DSC and TGA spectra of the type II crystals of compound (II) are shown.

[0190] Figure 19 The image shows the DVS spectrum of the type II crystal of compound (II). Detailed Implementation

[0191] The present application is described in detail below through examples, but this does not imply any adverse limitation on the present application. The compounds of this application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of this application without departing from the spirit and scope of this application, and such changes and modifications do not depart from the protection scope of this application.

[0192] Example 1: Preparation of compound (I) and its hydrochloride salt Following the method disclosed in Example 3 of WO2020125640, the compound of formula (I) and a hydrochloride salt of the compound of formula (I) were obtained.

[0193] The monohydrochloride salt of compound (I) is amorphous, and its XRPD, DSC, TGA, and DVS spectra are shown below. Figure 14-16 Its DSC plot shows an endothermic peak at 80.0℃, and its TGA plot shows a weight loss of 3.94% at 120.0℃.

[0194] Example 2: Preparation of crystallization of compound (I) Weigh 53 g of compound (I) into a 1-liter transparent glass bottle, add 500 mL of ethyl acetate, heat to 100°C and stir for 20 minutes until the system is clear. Turn off the heat and allow it to cool naturally to 25°C, then continue stirring at 25°C for 11 hours and 40 minutes. Filter, and dry the filter cake under reduced pressure (45°C, ≤-0.1 MPa) to obtain crystals of compound (I). Its XRPD, DSC, and TGA spectra are shown below. Figure 1-3 . 1 H NMR (400 MHz, DMSO-d6) δ = 11.46 (s, 1H), 7.62 (d, J =2.4 Hz, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 - 7.27 (m,2H), 7.25 - 7.08 (m, 6H), 6.66 - 6.53 (m, 2H), 6.51 - 6.44 (m, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.29 (d, J= 4.8 Hz, 2H), 2.97 (s, 3H), 2.83 (s, 3H), 2.75 (t, J =5.2 Hz, 2H), 2.48 - 2.41 (m, 2H), 2.02 (br s, 1H), 0.89 (t, J = 7.6 Hz, 3H).

[0195] Example 3: Preparation of Type I crystallization of compound (II)

[0196] The crystals (57.5 g) of formula (I) prepared in Example 2 and 690 mL of ethyl acetate were added sequentially to a glass bottle and heated to 90°C until the system became clear. Then, 20 mL of ethyl acetate solution containing 9.5 mL of concentrated hydrochloric acid (36-38 wt%, 1.05 equivalent) was added, and the mixture was stirred at 90°C for 17 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with ethyl acetate (20 mL). The filter cake was dried under reduced pressure (50°C, ≤-0.1 MPa) to obtain type I crystals of compound (II). Its XRPD, DSC, TGA, and DVS spectra are shown in [Figure number missing]. Figure 4-6 Analysis revealed an average Cl ion content of 6.19%, with a salt formation coefficient of 1. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 11.55 (s, 1H), 9.31 (br s, 2H), 7.66 (d, J =2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.10-7.33 (m,8H), 6.81 (d, J = 15.2 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.54-6.61 (m, 1H), 4.37(t, J = 4.8 Hz, 2H), 3.76 (d, J = 6.4 Hz, 2H), 3.17-3.28 (m, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.41-2.48 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H).

[0197] Example 4: Preparation of crystallization of compound (III)

[0198] The crystals of compound (I) prepared in Example 2 (101.34 mg) were weighed and added to an 8 mL transparent glass bottle, followed by 1.4 mL of acetone. The mixture was heated to 53°C until dissolved. Fumaric acid (23.83 mg, 1.05 equivalent) was added to the mixture. The mixture was stirred at 53°C for 0.5 hours, then cooled to room temperature and stirred for 12 hours. The mixture was filtered, and the filter cake was dried under reduced pressure (45°C, ≤-0.1 MPa) to obtain the crystals of compound (III). Its XRPD, DSC, and TGA spectra are shown below. Figure 7-8 . 1 H NMR (400MHz, DMSO- d 6) δ ppm11.49 (br s, 1H), 7.59-7.66 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.10-7.33 (m, 8H), 6.49-6.63 (m, 5H), 4.21 (d, J =4.4 Hz, 2H), 3.45(s, 2H), 2.98 (s, 3H), 2.92 (s, 2H), 2.84 (s, 3H), 2.44 (m,2H), 0.89 (t, J = 7.4 Hz, 3H).

[0199] Example 5: Preparation of crystallization of compound (IV)

[0200] 100.45 mg of the crystals of compound (I) prepared in Example 2 were weighed and added to an 8 mL glass bottle. 1.2 mL of ethyl acetate was then added, and the mixture was heated to 80°C to dissolve. Maleic acid (1.05 equivalent, 23.84 mg) was then added. The mixture was stirred at 78°C for 1 hour, then the heating was turned off and allowed to cool naturally to room temperature. Stirring was continued at room temperature for 12 hours. The mixture was filtered, and the filter cake was dried under reduced pressure (45°C, ≤-0.1 MPa) to obtain the crystals of compound (IV). Its XRPD, DSC, and TGA spectra are shown below. Figure 9-10 . 1 HNMR (400 MHz, DMSO- d 6) δ ppm 11.50 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.49 (d,J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11-7.33 (m, 8H), 6.77 (d, J = 14.8 Hz,1H), 6.50-6.67 (m, 2H), 6.02 (s, 2H), 4.33 (t, J = 4.8 Hz, 2H), 3.77 (d, J = 6.4Hz, 2H), 3.25 (t, J = 4.8 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3 H), 2.42-2.48 (m,2H), 0.89 ppm (t, J = 7.4 Hz, 3H).

[0201] Example 6: Preparation of Type I crystallization of compound (V)

[0202] 100.25 mg of the crystals of compound (I) prepared in Example 2 were weighed and added to an 8 mL glass bottle. 1.4 mL of ethyl acetate was then added, and the mixture was heated to 80°C to dissolve. Methanesulfonic acid (1.05 equivalent, 14.5 μL) was then added. The mixture was stirred at 78°C for 1 hour, then the heating was turned off, and the mixture was allowed to cool naturally to room temperature. Stirring was continued at room temperature for 12 hours. The mixture was filtered, and the filter cake was dried under reduced pressure (45°C, ≤-0.1 MPa) to obtain type I crystals of compound (V). Its XRPD spectrum is shown in [Figure number missing]. Figure 11 . 1 H NMR (400MHz, DMSO- d 6) δ ppm 11.51 (s, 1H), 8.87 (br s, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.27-7.35 (m, 2H), 7.16-7.27(m, 5H), 7.07-7.16 (m, 1H), 6.79 (d, J = 15.2 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.54 (m, 1H), 4.35 (t, J= 4.8 Hz, 2H), 3.79 (q, J = 5.6 Hz, 2H), 3.26 (br s,2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.41-2.47 (m, 2H), 2.36 (s, 6H), 0.89 ppm(t, J = 7.4 Hz, 3H).

[0203] Example 7: Preparation of type II crystallization of compound (V) 100.39 mg of the crystals of compound (I) prepared in Example 2 were weighed and added to an 8 mL glass bottle. 1.4 mL of acetone was added, and the mixture was heated to 53°C to dissolve. Then, methanesulfonic acid (1.05 equivalents, 14.5 μL) was added. The mixture was stirred at 53°C for 0.5 hours, then the heating was turned off, and the mixture was allowed to cool naturally to room temperature. Stirring was continued at room temperature for 12 hours. The mixture was filtered, and the filter cake was dried under reduced pressure (50°C) to obtain type II crystals of compound (V). Its XRPD spectrum is shown in [Figure number missing]. Figure 12 . 1 H NMR (400 MHz, DMSO- d 6)δ ppm11.52 (s, 1H), 8.88 (br s, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.27-7.35 (m, 2H), 7.16-7.27 (m, 5H), 7.08-7.16 (m, 1H), 6.79 (d, J = 15.2 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.54 (m, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 (q, J = 5.6 Hz, 2H), 3.26 (br s, 2H), 3.02 (s,3H), 2.86 (s, 3H), 2.42-2.48 (m, 2H), 2.37 (s, 6H), 0.89 (t, J = 7.4 Hz, 3H).

[0204] Example 8: Preparation of crystallization of compound (VI)

[0205] Weigh approximately 1 gram of the crystals of compound (I) prepared in Example 2 into a glass bottle, add 14 mL of acetone, heat to 53°C to dissolve, then add hydrobromic acid (48% w aqueous solution, 1.05 equivalents, 225 μL), stir at 53°C for 0.5 hours, turn off the heat, allow to cool naturally to room temperature, continue stirring at room temperature for 12 hours, filter, and dry the filter cake under reduced pressure (50°C) to obtain the crystals of compound (VI). Its XRPD spectrum is shown in [Figure number missing]. Figure 13 . 1 H NMR (400 MHz, DMSO- d 6) δppm11.47-11.61 (m, 1H), 8.94-9.23 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.49 (d, J =7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.27-7.33 (m, 2H), 7.16-7.27 (m, 5H), 7.09-7.16 (m, 1H), 6.76-6.89 (m, 1H), 6.64 (d, J =8.4 Hz, 1H), 6.51-6.61 (m,1H), 4.37 (br s, 2H), 3.78 (d, J = 6.4 Hz, 2H), 3.19-3.29 (m, 2H), 3.02 (s,3H), 2.86 (s, 3H), 2.41-2.48 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).

[0206] Example 9: Preparation of type II crystallization of compound (II)

[0207] 1 g of type I crystals of compound (II) and 3 mL of ethyl acetate and 3 mL of water were added sequentially to a glass bottle. The mixture was heated to 60°C in an oil bath and stirred for 0.1 hours until it became clear. The oil bath was then replaced with a 20°C water bath and cooled to room temperature. The mixture was stirred at room temperature for 12 hours. The filtered cake was dried under reduced pressure (50°C, ≤-0.1 MPa) to obtain type II crystals of compound (II). The XRPD, DSC, TGA, and DVS spectra are shown below. Figures 17-19 . 1H NMR (400 MHz, DMSO-d6) δ = 11.58 (s, 1H), 9.49 (s, 2H), 7.67 (d, J = 2.4 Hz, 1H), 7.49 (d, J =8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.26 - 7.11 (m,6H), 6.83 (d, J = 15.2 Hz, 1H), 6.67 - 6.53 (m, 2H), 4.40 (t, J = 4.8 Hz, 2H), 3.76 (d, J = 6.4 Hz, 2H), 3.23 (t, J = 4.8 Hz, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 2.49 - 2.41 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H) Experimental Example 1: Study of Crystal Form Properties Take 1-2 mg of the sample to be tested in a semi-automatic filtration vial, add 450 μL of pure water or FeSSIF simulated solution (saturated intestinal simulated solution) to obtain a supersaturated suspension, and vortex the sample for at least 2 minutes. Place the vial on a shaker and shake for 24 hours at 37°C and 800 rpm. After centrifugation and filtration, the sample concentration is analyzed by HPLC-UV linear quantification.

[0208] FeSSIF (Salivated Intestinal Simulator): A buffered aqueous solution containing 0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, and 1.52% (w / v) potassium chloride, with a pH of 5.0 ± 0.05.

[0209] Table 8

[0210] Experimental Example 2: In vivo pharmacokinetic study of type I crystals of compound (II) Experimental objective: The purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after a single oral gavage and to examine its bioavailability.

[0211] Experimental procedure: Two female beagle dogs were given a single oral dose of 100 mg / kg of type I crystals of compound (II) one hour after feeding. Plasma samples were collected at 0.0833 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 12 and 24 hours after administration. The concentration of the test substance in the plasma samples was determined by LC-MS / MS. The experimental results are shown in Table 9.

[0212] Table 9. Evaluation results of in vivo PK properties

[0213] T 1 / 2 Half-life; AUC 0-last Area under the curve; C0: Initial concentration; C max Maximum concentration; T max Time to peak concentration.

[0214] Experiment Example 3: Forced Degradation Experiment Control group: Weigh 20 mg of sample, add an appropriate amount of diluent (acetonitrile:water = 1:1, v / v) to dissolve the sample, and then make up the volume to 100 mL with diluent (acetonitrile:water = 1:1, v / v); take an appropriate amount of the solution for testing.

[0215] Acid degradation: Weigh 20 mg of sample, add 1 mL of 1M HCl aqueous solution, and let stand at room temperature for 24 hours. Then neutralize with 1 mL of 1M NaOH aqueous solution. Dilute the solution to 100 mL with diluent (acetonitrile:water = 1:1, v / v); take an appropriate amount of this solution for testing.

[0216] Alkaline degradation: Weigh 20 mg of sample, add 1 mL of 1M NaOH aqueous solution, and let stand at room temperature for 24 hours. Then neutralize with 1 mL of 1M HCl aqueous solution. Dilute the solution to 100 mL with diluent (acetonitrile:water = 1:1, v / v); take an appropriate amount of this solution for testing.

[0217] Oxidative degradation: Weigh 20 mg of sample, add 1 mL of 3% hydrogen peroxide solution, and let stand at room temperature for 24 hours. Dilute the solution to 100 mL with diluent (acetonitrile:water = 1:1, v / v); take an appropriate amount of this solution for testing.

[0218] The experimental results are shown in Tables 10-11.

[0219] Table 10 shows the forced degradation results of type I crystals of compound (II).

[0220] Table 11 Forced degradation results of the monohydrochloride (amorphous) salt of compound (I)

[0221] Therefore, the crystals of this application exhibit good solubility, hygroscopicity, pharmacokinetic properties, bioavailability, and stability.

Claims

1. Crystallization of compound (I), salt of compound (I), or crystallization thereof, in, The salt of the compound of formula (I) is selected from fumarate, maleate, methanesulfonate, or hydrobromide, and the crystallization of the salt of the compound of formula (I) is selected from the crystallization of hydrochloride, fumarate, maleate, methanesulfonate, or hydrobromide. 。 2. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, For the crystallization of the compound of formula (I), the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 13.14±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20° and 24.22±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 17.60±0.20°, 19.98±0.20°, and 23.41±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 13.14±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20°, and 24.22±0.20°. Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 13.14±0.20°, 14.68±0.20°, 16.62±0.20°, 17.60±0.20°, 19.98±0.20°, 21.32±0.20°, 21.78±0.20°, 22.38±0.20°, 23.41±0.20°, 24.22±0.20°, 26.46±0.20°, and 28.84±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​are expressed as 8.56±0.20°, 10.13±0.20°, 12.16±0.20°, 13.14±0.20°, 13.54±0.20°, 14.68±0.20°, 15.68±0.20°, 16.38±0.20°, 16.62±0.20°, and 17.

24. ±0.20°, 17.60±0.20°, 18.86±0.20°, 19.22±0.20°, 19.46±0.20°, 19.98±0.20°, 20.89±0.20°, 21.32±0.20°, 21.78±0.20°, 22.38±0.20°, 22.70±0.20°, 23.08±0.2 0°, 23.41±0.20°, 23.70±0.20°, 24.01±0.20°, 24.22±0.20°, 24.62±0.20°, 24.89±0.20°, 25.26±0.20°, 25.92±0.20°, 26.46±0.20°, 26.92±0.20°, 27.32±0.20°, 2 Diffraction peaks are observed at 8.18±0.20°, 28.54±0.20°, 28.84±0.20°, 29.42±0.20°, 30.24±0.20°, 30.70±0.20°, 30.94±0.20°, 31.64±0.20°, 32.71±0.20°, 33.22±0.20°, and 34.84±0.20°. Alternatively, the X-ray powder diffraction pattern of the crystallized compound of formula (I) using Cu Kα radiation is shown in Figure 1. Alternatively, the differential scanning calorimetry curve of the crystallization of the compound of formula (I) has an endothermic peak at 144.92±3℃.

3. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, The salt of the compound of formula (I) is crystallized as a hydrochloride salt, and in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 16.49±0.20°, 17.63±0.20°, 20.25±0.20°, 22.84±0.20°, 23.99±0.20° and 24.62±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 11.08±0.20°, 11.38±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49 ±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.99±0.20° and 24.62±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ value indicates that it contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 5.97±0.20°, 7.58±0.20°, 9.83±0.20°, 11.08±0.20°, 11.38±0.20°, 12.69±0.20°, 14.14±0.20°, 15.30±0.20°. 16.49±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.79±0.20°, 23.99±0.20° and 24.62±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 5.97±0.20°, 7.58±0.20°, and 17.63±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks are indicated by 2θ values ​​at 5.97±0.20°, 7.58±0.20°, 16.49±0.20°, 17.63±0.20°, 20.25±0.20°, 22.84±0.20°, 23.99±0.20°, and 24.62±0.20°. Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks are indicated by 2θ values ​​at 5.97±0.20°, 7.58±0.20°, 11.08±0.20°, 11.38±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49±0.20°, 17.63±0.20°, 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.99±0.20°, and 24.62±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​are expressed as 5.97±0.20°, 7.58±0.20°, 9.83±0.20°, 11.08±0.20°, 11.38±0.20°, 12.69±0.20°, 14.14±0.20°, 15.30±0.20°, 16.49±0.20°, and 17.63±0.20°. Diffraction peaks are observed at 18.44±0.20°, 19.72±0.20°, 20.25±0.20°, 20.66±0.20°, 21.39±0.20°, 21.88±0.20°, 22.23±0.20°, 22.84±0.20°, 23.79±0.20°, 23.99±0.20°, and 24.62±0.20°. Alternatively, the X-ray powder diffraction pattern of the hydrochloride salt of the compound of formula (I) using Cu Kα radiation is shown in Figure 4. Alternatively, in the X-ray powder diffraction pattern using CuKα radiation, represented by 2θ values, there are 3, 4, 5, 6, 7, or 8 diffraction peaks selected from the following: 9.84±0.20°, 16.31±0.20°, 16.76±0.20°, 20.09±0.20°, 22.61±0.20°, 23.65±0.20°, 24.55±0.20°, and 25.32±0.20°; Alternatively, in the X-ray powder diffraction pattern using CuKα radiation, diffraction peaks at 9.84±0.20°, 16.76±0.20°, and 20.09±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using CuKα radiation, the 2θ values ​​indicate diffraction peaks at 9.84±0.20°, 16.31±0.20°, 16.76±0.20°, 20.09±0.20°, 22.61±0.20°, 23.65±0.20°, 24.55±0.20°, and 25.32±0.20°. Alternatively, in X-ray powder diffraction patterns using CuKα radiation, the 2θ values ​​are expressed as 9.84±0.20°, 10.59±0.20°, 12.39±0.20°, 12.61±0.20°, 13.99±0.20°, 16.31±0.20°, 16.76±0.20°, 18.31±0.20°, 18.72±0.20°, 19.06±0.20°, 19.55±0.20°, 19.72±0.20°, 20.09±0.20°, 20.77±0.20°, 21.22±0.20°, and 22.

61. Diffraction peaks are observed at ±0.20°, 23.04±0.20°, 23.41±0.20°, 23.65±0.20°, 24.55±0.20°, 25.11±0.20°, 25.32±0.20°, 26.49±0.20°, 26.90±0.20°, 27.71±0.20°, 28.27±0.20°, 28.47±0.20°, 29.22±0.20°, 29.61±0.20°, 30.22±0.20°, 31.11±0.20°, 31.47±0.20°, and 34.18±0.20°. Alternatively, the X-ray powder diffraction pattern of the hydrochloride salt of the compound of formula (I) using CuKα radiation is shown in Figure 17. Alternatively, the differential scanning calorimetry (DSC) curve of the crystallization of the hydrochloride salt of the compound of formula (I) has an endothermic peak at 204.5 ± 3 °C; or, the DSC curve of the crystallization of the hydrochloride salt of the compound of formula (I) has endothermic peaks at 101.4 ± 3 °C, 113.3 ± 3 °C and 195.9 ± 3 °C.

4. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, The salt of the compound of formula (I) is a fumarate crystal, and in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.12±0.20°, 9.20±0.20°, 14.99±0.20°, 18.08±0.20°, 19.17±0.20°, 21.39±0.20°, 22.57±0.20° and 25.15±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 5.12±0.20°, 14.99±0.20°, and 19.17±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 5.12±0.20°, 9.20±0.20°, 14.99±0.20°, 18.08±0.20°, 19.17±0.20°, 21.39±0.20°, 22.57±0.20°, and 25.15±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​are expressed as 5.12±0.20°, 9.20±0.20°, 12.03±0.20°, 14.99±0.20°, 15.31±0.20°, 16.75±0.20°, 17.62±0.20°, 18.08±0.20°, 18.83±0.20°, 19.17±0.20°, 20.80±0.20°, and 21.39±0.20°. Diffraction peaks are observed at 0°, 22.21±0.20°, 22.57±0.20°, 23.09±0.20°, 23.50±0.20°, 24.42±0.20°, 25.15±0.20°, 25.78±0.20°, 27.14±0.20°, 28.25±0.20°, 29.54±0.20°, 30.50±0.20°, 31.09±0.20°, and 32.16±0.20°. Alternatively, the X-ray powder diffraction pattern of the fumarate crystal of the compound of formula (I) using Cu Kα radiation is shown in Figure 7. Alternatively, the differential scanning calorimetry plot of the fumarate crystal of the compound of formula (I) has an endothermic peak at 164.5 ± 3 °C.

5. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, The salt of the compound of formula (I) is a maleate crystal, and in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 4.55±0.20°, 12.85±0.20°, 16.19±0.20°, 16.68±0.20°, 18.12±0.20°, 21.18±0.20°, 22.71±0.20° and 27.31±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 4.55±0.20°, 18.12±0.20°, and 21.18±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 4.55±0.20°, 12.85±0.20°, 16.19±0.20°, 16.68±0.20°, 18.12±0.20°, 21.18±0.20°, 22.71±0.20°, and 27.31±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​are expressed as 4.55±0.20°, 18.12±0.20°, 21.18±0.20°, 9.06±0.20°, 10.63±0.20°, 11.00±0.20°, 12.85±0.20°, 13.75±0.20°, 15.96±0.20°, 16.19±0.20°, 16.68±0.20°, 16.99±0.20°, and 17. Diffraction peaks are observed at 51±0.20°, 20.12±0.20°, 20.75±0.20°, 22.71±0.20°, 23.04±0.20°, 24.13±0.20°, 24.55±0.20°, 25.32±0.20°, 25.95±0.20°, 27.31±0.20°, 28.38±0.20°, 28.97±0.20°, 29.62±0.20°, and 34.09±0.20°. Alternatively, the X-ray powder diffraction pattern of the maleate crystal of the compound of formula (I) using Cu Kα radiation is shown in Figure 9. Alternatively, the differential scanning calorimetry plot of the maleate crystal of the compound of formula (I) has an endothermic peak at 160.3 ± 3 °C.

6. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, The salt of the compound of formula (I) is a crystallized methanesulfonate, and in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 5.47±0.20°, 6.25±0.20°, 16.11±0.20°, 16.64±0.20°, 18.11±0.20°, 19.73±0.20°, 24.22±0.20° and 25.12±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 5.47±0.20°, 6.25±0.20°, and 16.11±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 5.47±0.20°, 6.25±0.20°, 16.11±0.20°, 16.64±0.20°, 18.11±0.20°, 19.73±0.20°, 24.22±0.20°, and 25.12±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​can be expressed as 5.47±0.20°, 6.00±0.20°, 6.25±0.20°, 8.29±0.20°, 9.62±0.20°, 10.88±0.20°, 12.02±0.20°, 12.46±0.20°, 13.81±0.20°, 16.11±0.20°, 16.39±0.20°, 16.64±0.20°, 18.11±0.20°, and 18.72±0.20°. Diffraction peaks are observed at 19.73±0.20°, 20.21±0.20°, 21.08±0.20°, 21.41±0.20°, 22.80±0.20°, 23.45±0.20°, 24.22±0.20°, 24.55±0.20°, 25.12±0.20°, 25.64±0.20°, 26.00±0.20°, 26.99±0.20°, 29.06±0.20°, 29.88±0.20°, and 31.18±0.20°. Alternatively, the X-ray powder diffraction pattern of the crystallized methanesulfonate of the compound of formula (I) using Cu Kα radiation is shown in Figure 11. Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, there are 3, 4, 5, 6, 7, or 8 diffraction peaks selected from the following: 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 16.12±0.20°, 17.18±0.20°, 19.23±0.20°, 20.19±0.20°, and 23.03±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 6.17±0.20°, 8.76±0.20°, and 23.03±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 16.12±0.20°, 17.18±0.20°, 19.23±0.20°, 20.19±0.20°, and 23.03±0.20°. Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 6.17±0.20°, 8.76±0.20°, 12.16±0.20°, 12.37±0.20°, 14.53±0.20°, 15.46±0.20°, 16.12±0.20°, 17.18±0.20°, 17.40±0.20°, 18.30±0.20°, 18.78±0.20°, 19.23±0.20°, 19.71±0.20°, 20.19±0.20°, 20.74±0.20°, 21.05±0.20°, 22.19±0.20°, and 23.03±0.20°. Alternatively, the X-ray powder diffraction pattern of the methanesulfonate crystal of the compound of formula (I) using Cu Kα radiation is shown in Figure 12.

7. Crystallization of the compound of formula (I) according to claim 1, a salt of the compound of formula (I), or crystallization thereof, wherein, The salt of the compound of formula (I) is a crystal of hydrobromide, and in the X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, it contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 16.49±0.20°, 17.62±0.20°, 23.84±0.20°, 24.54±0.20° and 30.30±0.20°; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, diffraction peaks at 7.59±0.20°, 17.62±0.20°, and 23.84±0.20° are indicated by 2θ values; Alternatively, in the X-ray powder diffraction pattern using Cu Kα radiation, the 2θ values ​​indicate diffraction peaks at 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 16.49±0.20°, 17.62±0.20°, 23.84±0.20°, 24.54±0.20°, and 30.30±0.20°. Alternatively, in X-ray powder diffraction patterns using Cu Kα radiation, the 2θ values ​​are expressed as 3.12±0.20°, 5.96±0.20°, 7.59±0.20°, 9.76±0.20°, 11.11±0.20°, 12.78±0.20°, 16.49±0.20°, 17.62±0.20°, 18.44±0.20°, 19.57±0.20°, 20.69±0.20°, and 21.1°. Diffraction peaks are observed at 6±0.20°, 22.16±0.20°, 22.77±0.20°, 23.84±0.20°, 24.31±0.20°, 24.54±0.20°, 25.15±0.20°, 26.07±0.20°, 27.31±0.20°, 27.83±0.20°, 28.91±0.20°, 30.30±0.20°, and 31.74±0.20°. Alternatively, the X-ray powder diffraction pattern of the hydrobromide crystal of the compound of formula (I) using Cu Kα radiation is shown in Figure 13.

8. A crystalline composition comprising the crystals according to any one of claims 1-7, wherein the crystals comprise 50% or more by weight of the crystalline composition, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more.

9. A pharmaceutical composition comprising a therapeutically or preventively effective amount of crystals of the compound of formula (I) according to any one of claims 1-7, a salt of the compound of formula (I) or crystals thereof, or the crystalline composition according to claim 8.

10. A crystal of the compound of formula (I) according to any one of claims 1-7, a salt of the compound of formula (I) or crystals thereof, a crystalline composition according to claim 8 or a pharmaceutical composition according to claim 9, for the treatment or prevention of estrogen receptor-related conditions; preferably, the estrogen receptor-related condition is breast cancer; more preferably, the estrogen receptor-related condition is estrogen receptor-positive breast cancer.

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