Pharmaceutically acceptable salts of tetralin derivatives, crystalline forms and preparation methods

Abstract

The present invention relates to pharmaceutically acceptable salts, crystalline forms, and preparation methods of tetralin derivatives. Specifically, the present disclosure provides pharmaceutically acceptable salts, crystalline forms, and preparation methods for (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which have good stability and can be used in clinical treatment.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022111977804, filed on September 29, 2022. The entire text of the above Chinese patent application is incorporated herein by reference.

[0002] The present disclosure is in the pharmaceutical field and relates to pharmaceutically acceptable salts and crystalline forms of tetralin-based derivatives. [Background technology]

[0003] Protein proteolysis-targeting chimeras (PROTACs) are heterogeneous bifunctional small molecules. Their structure contains two distinct ligands: an E3 ubiquitin ligase ligand and a target protein-binding ligand, connected by a linker arm. PROTACs bring the target protein into close proximity with an intracellular E3 ubiquitin ligase, forming a target protein-PROTAC-E3 ternary complex. The E3 ubiquitin ligase then tags the target protein with a ubiquitin-protein tag, initiating a powerful cellular ubiquitin hydrolysis process that leads to specific degradation of the target protein via the ubiquitin-proteasome pathway. Compared with traditional small molecule inhibitors, PROTACs offer unique advantages: 1. PROTACs do not require long-term or strong binding to target proteins, and their target protein degradation process resembles a catalytic reaction. By periodically binding and degrading target proteins, they can reduce systemic drug exposure and minimize toxicity and side effects. 2. Because target proteins must be synthesized again after degradation to restore function, degrading them offers more effective and long-lasting antitumor effects than inhibiting their activity and does not lead to drug resistance due to target protein mutations. 3. PROTACs may be therapeutic targets currently considered undruggable, such as transcription factors, scaffolding proteins, and regulatory proteins.

[0004] The discovery of cerebellar protein (CRBN)-type E3 ligase ligands is relevant to research into the mechanism of action of thalidomide. In 2010, during research into thalidomide toxicity, it was discovered that the binding of thalidomide to CRBN in the body may be the cause of thalidomide's teratogenicity (Science, 2010, 327, 1345). Subsequent research has shown that thalidomide and its derivatives can be used as anti-inflammatory, anti-angiogenic, and anti-cancer drugs. Among them, lenalidomide and pomalidomide have significantly improved safety profiles and significantly reduced teratogenic effects. Further research has revealed that lenalidomide functions by degrading two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). This study revealed that the mechanism of action of thalidomide and its derivatives is to degrade target proteins by binding to the CRBN-type E3 ubiquitin ligase protein complex.

[0005] Based on this, CRBN ligands have been widely used to prepare protein degraders, and a series of PROTAC molecules based on CRBN ligands have been developed. PCT / CN2022 / 083597 discloses a novel tetralin-based derivative, of which Compound I has the chemical name (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which is indicated for use as an estrogen receptor degrader in the treatment of estrogen receptor-mediated or dependent diseases. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Science, 2010, 327, 1345 Summary of the Invention [Problem to be solved by the invention]

[0007] The crystalline structure of a pharmaceutical active ingredient tends to affect the chemical and physical stability of the drug, and depending on the crystallization and storage conditions, the crystalline structure of the compound may change, sometimes resulting in the formation of other crystalline forms. Generally, amorphous drug products do not have a regular crystalline structure and tend to have other defects, such as relatively poor product stability, relatively difficult filtration, prone to caking, and poor flowability. Therefore, studying the crystalline form of a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is of great significance for the development of pharmaceuticals suitable for industrial production and with good biological activity. [Means for solving the problem]

[0008] (Summary of the Invention) One aspect of the present disclosure provides Form A crystals of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0009] In some embodiments, the A-type crystal has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 14.2, 15.3, 16.1, 17.4, and 19.1.

[0010] In some other embodiments, the type A crystal has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 14.2, 15.3, 16.1, 17.4, 19.1, 20.0, 20.9, and 22.3.

[0011] In some other embodiments, the type A crystal has a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 5.0, 6.0, 14.2, 15.3, 16.1, 17.4, 19.1, 20.0, 20.9, 22.3, 24.8, and 26.9.

[0012] In some other embodiments, the powder X-ray diffraction pattern of the Type A crystals, expressed at diffraction angles 2θ, is as shown in FIG.

[0013] Another aspect of the present disclosure provides a pharmaceutically acceptable salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, wherein the pharmaceutically acceptable salt is selected from hydrochloride, maleate, fumarate, L-tartrate, succinate, D-malate, L-malate, sulfate, phosphate, and citrate.

[0014] In an alternative embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to the acid is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0015] In another embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to the acid is 2:1 to 1:2.

[0016] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to hydrogen chloride is 1:1 or 1:2.

[0017] In an alternative embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to maleic acid is 1:1.

[0018] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to fumaric acid is 1:1 or 1:2.

[0019] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to L-tartaric acid is 1:1 or 2:1.

[0020] In an alternative embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to succinic acid is 1:1.

[0021] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to D-malic acid is 2:1 or 1:1.

[0022] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to L-malic acid is 2:1 or 1:1.

[0023] In alternative embodiments, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to sulfuric acid is 1:1 or 1:2.

[0024] In an alternative embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to phosphoric acid is 1:1.

[0025] In an alternative embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to citric acid is 1:1.

[0026] The present disclosure also provides a method for producing a hydroxybenzoate of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione with an acid selected from the group consisting of hydrochloric acid, maleic acid, fumaric acid, L-tartaric acid, succinic acid, D-malic acid, L-malic acid, sulfuric acid, phosphoric acid, and the like. and citric acid.

[0027] Solvents used in forming the salts of the present disclosure are selected from, but are not limited to, acetonitrile, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, ethanol / ethyl acetate, methanol, ethanol / water, tetrahydrofuran / ethanol, dichloromethane / ethanol, methyl tert-butyl ether / ethanol.

[0028] Furthermore, in optional embodiments, the process for preparing the pharmaceutically acceptable salt also includes steps such as crystallization, filtering, washing, or drying.

[0029] Another embodiment of the present disclosure also provides Form I crystals of hydrochloride salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 13.8, 15.9, 19.0, 20.1, and 22.8.

[0030] In some other embodiments, the hydrochloride salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6, and 22.8.

[0031] In some other embodiments, the hydrochloride salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 10.8, 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6, 22.8, 25.2, and 26.5.

[0032] In some other embodiments, the hydrochloride salt crystalline form I has a powder X-ray diffraction pattern shown at diffraction angles 2θ as shown in FIG.

[0033] The present disclosure also provides Form II crystalline form of hydrochloride salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern shown at diffraction angles 2θ having characteristic peaks at 13.2, 17.1, 19.7, 20.6, 22.8, and 25.0.

[0034] In some embodiments, the hydrochloride salt crystalline Form II has a powder X-ray diffraction pattern expressed as a diffraction angle 2θ having characteristic peaks at 10.4, 13.2, 14.5, 15.1, 17.1, 19.7, 20.6, 22.8, 25.0, and 26.1.

[0035] In some embodiments, the hydrochloride salt crystalline Form II has a powder X-ray diffraction pattern expressed as diffraction angles 2θ having characteristic peaks at 5.6, 10.4, 13.2, 13.8, 14.5, 15.1, 17.1, 19.7, 20.6, 22.8, 23.3, 25.0, and 26.1.

[0036] In some other embodiments, the hydrochloride salt crystalline form I has a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0037] The present disclosure also provides Form I crystalline maleate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 5.6, 8.8, 9.4, 10.2, 10.7, and 18.0.

[0038] In some embodiments, the maleate salt Form I crystal has a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 5.6, 7.0, 8.8, 9.4, 10.2, 10.7, 15.9, 18.0, 20.6, and 22.3.

[0039] In some embodiments, the maleate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 5.6, 7.0, 8.4, 8.8, 9.4, 10.2, 10.7, 11.3, 15.9, 16.8, 18.0, 20.6, 21.5, 22.3, and 23.9.

[0040] In some embodiments, the maleate salt Form I crystal has a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0041] The present disclosure also provides Form I crystalline fumarate of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 6.8, 9.6, 10.5, 17.6, 18.2, and 21.1.

[0042] In some embodiments, the fumarate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 5.7, 6.8, 9.6, 10.5, 16.0, 17.6, 18.2, 19.8, and 21.1.

[0043] In some embodiments, the fumarate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 5.7, 6.8, 8.9, 9.6, 10.5, 11.3, 16.0, 17.6, 18.2, 19.8, 21.1, and 22.2.

[0044] In some embodiments, the fumarate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, as shown in FIG.

[0045] The present disclosure also provides Form II crystalline fumarate of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 7.0, 9.4, 15.0, 17.1, 17.7, and 18.7.

[0046] In some embodiments, the fumarate Form II crystals have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 7.0, 9.4, 10.9, 14.6, 15.0, 17.1, 17.7, 18.7, 19.9, and 23.9.

[0047] In some embodiments, the fumarate salt crystalline Form II has a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0048] The present disclosure also provides a Form III crystalline form of fumarate of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 5.1, 9.6, 10.4, 17.9, 18.5, and 20.5.

[0049] In some embodiments, the fumarate Form III crystals have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 5.1, 6.0, 9.6, 10.4, 17.9, 18.5, 19.4, 20.5, and 23.2.

[0050] In some embodiments, the fumarate Form III crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, with characteristic peaks at 5.1, 6.0, 7.1, 9.6, 10.4, 11.3, 17.9, 18.5, 19.4, 20.5, and 23.2.

[0051] In some embodiments, the fumarate salt crystalline Form III has a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0052] The present disclosure also provides a Form IV crystalline form of fumarate of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 6.2, 10.3, 11.1, 12.5, 21.3, and 22.2.

[0053] In some embodiments, the fumarate Form IV crystals have a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0054] The present disclosure also provides a Form V crystal of a fumarate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 10.5, 17.1, 18.6, 20.1, 21.0, and 23.7.

[0055] In some embodiments, the fumarate Form V crystals have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 5.3, 9.9, 10.5, 11.6, 16.0, 17.1, 18.6, 20.1, 21.0, and 23.7.

[0056] In some embodiments, the fumarate Form V crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 5.3, 6.2, 9.9, 10.5, 11.6, 15.6, 16.0, 17.1, 18.6, 20.1, 21.0, 22.7, 23.2, and 23.7.

[0057] In some embodiments, the fumarate Form V crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, as shown in FIG.

[0058] The present disclosure also provides Form I crystals of L-tartrate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 9.1, 16.0, 17.7, 18.0, 20.0, and 20.7.

[0059] In some embodiments, the L-tartrate salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles with characteristic peaks at 9.1, 9.5, 10.8, 16.0, 17.7, 18.0, 20.0, 20.7, 21.6, and 22.4.

[0060] In some embodiments, the L-tartrate salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 5.7, 9.1, 9.5, 10.8, 16.0, 17.2, 17.7, 18.0, 19.6, 20.0, 20.7, 21.6, 22.4, and 23.9.

[0061] In some embodiments, the L-tartrate salt Form I crystals have a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0062] The present disclosure also provides a Form I crystal of succinate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 9.5, 16.0, 17.6, 18.0, 19.9, 20.7, and 22.3.

[0063] In some embodiments, the succinate salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 9.0, 9.5, 10.3, 16.0, 17.6, 18.0, 19.9, 20.7, 21.5, and 22.3.

[0064] In some embodiments, the succinate salt Form I crystals have a powder X-ray diffraction pattern expressed in diffraction angle 2θ angles having characteristic peaks at 5.6, 6.9, 9.0, 9.5, 10.3, 10.7, 13.7, 16.0, 17.6, 18.0, 19.9, 20.7, 21.5, and 22.3.

[0065] In some embodiments, the succinate salt crystalline form I has a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0066] The present disclosure also provides Form I crystals of the D-malate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has a powder X-ray diffraction pattern, measured at diffraction angles 2θ, having characteristic peaks at 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, and 20.6.

[0067] In some embodiments, the D-malate Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 7.0, 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, 20.0, 20.6, and 22.3.

[0068] In some embodiments, the D-malate Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 5.6, 7.0, 9.0, 9.5, 10.7, 15.9, 17.6, 17.9, 18.2, 20.0, 20.6, 21.5, and 22.3.

[0069] In some embodiments, the D-malate Form I crystals have a powder X-ray diffraction pattern shown in 2θ angles as shown in FIG.

[0070] Furthermore, the presently disclosed compound is a crystalline form of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, wherein the error range of the 2θ angle is ±0.2.

[0071] In another aspect, the present disclosure provides a method for producing a crystallized product of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione by dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in 50% ethanol / ethyl acetate, adding hydrochloric acid solution and stirring, then filtering, followed by adding phosphate buffer and stirring to crystallize the compound. Provided is a method for preparing Form A crystals of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, the method comprising the steps of adding hydrochloride salt of butyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to a phosphate buffer solution and stirring.

[0072] In some embodiments, the phosphate buffer is selected from, but not limited to, sodium dihydrogen phosphate and disodium hydrogen phosphate, and has a pH of 4 to 8.

[0073] The present disclosure also provides a method for producing a compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising: 1) dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in a solvent (1) and adding hydrochloric acid; and 2) stirring the resulting mixture. A method for preparing type I crystals of 2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride salt is provided, wherein the solvent (1) is selected from ethanol / ethyl acetate, methanol, ethanol / water, tetrahydrofuran / ethanol, dichloromethane / ethanol, and methyl tert-butyl ether / ethanol.

[0074] The present disclosure also provides a method for producing a hydroxybenzoate-based hydroxybenzoate, comprising: 1) dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in a solvent (2) and adding hydrochloric acid; and 2) stirring the resulting mixture. ,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride crystal Form II, wherein the solvent (2) is selected from ethanol / ethyl acetate, methanol, ethanol / water, tetrahydrofuran / ethanol, and dichloromethane / ethanol.

[0075] The present disclosure also provides a method for preparing Form I crystals of maleate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in acetone, adding maleic acid, and stirring.

[0076] The present disclosure also provides a method for preparing Form I crystals of fumarate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in tetrahydrofuran, adding fumaric acid, and stirring.

[0077] The present disclosure also provides a method for preparing Form II crystalline fumarate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in acetonitrile, adding fumaric acid, and stirring.

[0078] The present disclosure also provides a method for preparing Form III crystalline fumarate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in 1,4-dioxane, adding fumaric acid, and stirring.

[0079] The present disclosure also provides a method for preparing Form IV crystalline fumarate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in acetone, adding fumaric acid, and stirring.

[0080] The present disclosure also provides a method for preparing Form I crystals of the L-tartrate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in 1,4-dioxane, adding L-tartaric acid, and stirring.

[0081] The present disclosure also provides a method for preparing Form I crystals of succinate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in 1,4-dioxane, adding succinic acid, and stirring.

[0082] The present disclosure also provides a method for preparing Form I crystals of the D-malate salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in tetrahydrofuran, adding D-malic acid, and stirring.

[0083] In certain embodiments, the methods for preparing the crystalline forms described in the present disclosure also include a crystallization, filtration, washing, or drying step.

[0084] In another aspect, the present disclosure also provides a pharmaceutical composition comprising Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a crystalline form thereof, and optionally a pharmaceutically acceptable excipient.

[0085] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing Form A crystals of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a crystalline form thereof, with a pharmaceutically acceptable excipient.

[0086] The present disclosure also relates to a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or to a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. and (c) use of a pharmaceutically acceptable salt of (a)-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a crystalline form thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for preventing and / or treating a disease state that is treated by degradation of a target protein bound to a target ligand.

[0087] The present disclosure also relates to a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. and (2) use of a pharmaceutically acceptable salt of (2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a crystalline form thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for preventing and / or treating a condition that is treated by binding in the body to a cerebellar protein.

[0088] The condition that may be treated by degradation of a target protein bound to a targeting ligand or by binding in vivo to a cerebellar protein according to the present disclosure is selected from abnormal cell proliferation, tumors, immune disorders, diabetes, cardiovascular disorders, infectious diseases and inflammatory diseases, and optionally the disease is a tumor or an infectious disease.

[0089] The tumors described in the present disclosure are cancers, and optionally, the tumors are selected from, but not limited to, breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, and ovarian masses.

[0090] The infectious diseases referred to in this disclosure are selected from, but are not limited to, viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or infection by HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, pestivirus, rotavirus, or coronavirus.

[0091] The present disclosure also relates to a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or to a Form A crystal of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6- Provided is a pharmaceutically acceptable salt of hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a crystalline form thereof, or the use of said pharmaceutical composition in the preparation for preventing and / or treating an estrogen receptor-mediated or dependent disease or condition.

[0092] The term "2θ or 2θ angle" used in the present disclosure refers to the diffraction angle, where θ is the Bragg angle and is expressed in ° or degrees. The error range of each characteristic peak 2θ is ±0.20 (including rounding to the nearest decimal place), and specifically includes -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0093] In the present disclosure, there is a certain degree of error in the measurement of the chemical composition ratio of the compound and the acid molecule, and generally, ±10% is within a reasonable error range. Depending on the context of use, there is a certain degree of variation in error, and the variation in error does not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%. In the present disclosure, numerical values ​​indicated by "about" are within the above-mentioned reasonable error range.

[0094] "Crystallization" or "crystallization" as referred to in this disclosure includes, but is not limited to, stirred crystallization, slurry crystallization, cooling crystallization, and volatile crystallization.

[0095] "Differential scanning calorimetry or DSC" as used in this disclosure refers to the measurement of temperature and heat flow differences between a sample and a reference during a heating or isothermal process of the sample in order to characterize all physical and chemical changes associated with thermal effects and obtain information on the phase transitions of the sample.

[0096] The drying temperature described in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and drying may be performed under normal pressure or reduced pressure.

[0097] "Pharmaceutically acceptable excipients" as referred to in this disclosure include, but are not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifier that has already been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or domestic animals. [Brief explanation of the drawings]

[0098] [Figure 1] 1 is an XRPD spectrum of amorphous Compound I. [Figure 2] 1 is an XRPD spectrum of crystalline form A of Compound I. [Figure 3] 1 is an XRPD spectrum of the hydrochloride salt form I crystal of Compound I. [Figure 4] 1 is an XRPD spectrum of the hydrochloride salt form II crystal of Compound I. [Figure 5] 1 is an XRPD spectrum of the maleate form I crystal of Compound I. [Figure 6] 1 is an XRPD spectrum of Form I crystals of the fumarate salt of Compound I. [Figure 7] 1 is an XRPD spectrum of crystalline form II of the fumarate salt of Compound I. [Figure 8] 1 is an XRPD spectrum of a fumarate salt of Compound I, Form III crystal. [Figure 9] 1 is an XRPD spectrum of crystalline form IV of the fumarate salt of Compound I. [Figure 10] 1 is an XRPD spectrum of crystalline form V of the fumarate salt of Compound I. [Figure 11] 1 is an XRPD spectrum of Form I crystals of the L-tartrate salt of Compound I. [Figure 12] 1 is an XRPD spectrum of the succinate form I crystal of Compound I. [Figure 13] 1 is an XRPD spectrum of the D-malate form I crystal of Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0099] The present disclosure is further illustrated by the following examples and experimental examples, which are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0100] Test conditions for the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The NMR data are shown in ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0101] For MS measurements, a liquid chromatograph mass spectrometer, Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q 15 Exactive) were used.

[0102] For the HPLC measurements, a high performance liquid chromatograph Agilent 1260DAD (Sunfire C18 150 x 4.6 mm column) and a high performance liquid chromatograph Thermo U3000 (Gimini C18 150 x 4.6 mm column) were used.

[0103] XRPD is a method of detecting powder X-ray diffraction. A BRUKER D8 X-ray diffractometer was used for the measurement. Specific collected information: Cu anode (40 kV, 40 mA), radiation: monochromatic Cu-Ka radiation (l = 1.5418 Å). Scanning method: θ / 2θ, scanning range: 3 to 48o .

[0104] DSC stands for differential scanning calorimetry. A METTLER TOLEDO DSC 3+ differential scanning calorimeter was used for the measurement, with a heating rate of 10°C / min, 25 to 300°C, or 25 to 350°C, and a nitrogen gas purge rate of 50 mL / min.

[0105] TGA is thermogravimetric analysis. A METTLER TOLEDO TGA 2 type thermogravimetric analyzer is used for detection. The heating rate is 10°C / min. The specific temperature range is based on the corresponding spectrum. The nitrogen gas purge rate is 50mL / min.

[0106] DVS stands for dynamic moisture adsorption. Instru- mental Surface Measurement Systems were used, starting from 50% humidity and examining the humidity range of 0% to 95% in 10% increments. The criteria for evaluation were a mass change per gradient (dM / dT) of less than 0.002%, a TMAX of 360 min, and two cycles.

[0107] Known starting materials of the present disclosure may be synthesized by adopting or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0108] In the examples, thin layer chromatography (TLC) was used to monitor the reaction process. The developing solvents used in the reaction, the eluent system of column chromatography used to purify the compounds, and the developing solvent system of thin layer chromatography comprise A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and the volume ratio of the solvents may be adjusted according to the polarity of the compounds, or by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0109] Example 1, Preparation of Compound I (refer to the preparation method of Example 26-1 in the application with application number WO2022206737) [ka] TIFF2025533592000002.tif118168

[0110] Step 1 4-(Dimethoxymethyl)piperidine-1-carboxylic acid benzyl ester 1b 4-Formylpiperidine-1-carboxylic acid benzyl ester 1a (10 g, 40.4 mmol, Shanghai PiDe Pharmaceutical Technology Co., Ltd.) was dissolved in methanol (80 mL), trimethyl orthoformate (40 mL) and p-toluenesulfonic acid monohydrate (385 mg, 2 mmol) were added, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound 1b (12 g), which was used directly in the next reaction without further purification.

[0111] Step 2 4-(Dimethoxymethyl)piperidine 1c Compound 1b (12 g, 40.9 mmol) was dissolved in methanol (100 mL), palladium carbon (1.3 g, 10 wt%) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 1c (6 g). This product was used in the next reaction without further purification.

[0112] Step 3 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one 1e 6-Hydroxy-3,4-dihydronaphthalen-1(2H)-one 1d (8 g, 49.3 mmol, Shanghai PiDe Pharmaceutical Technology Co., Ltd.) and potassium carbonate (10 g, 72.4 mmol) were added to acetonitrile (60 mL), and benzyl bromide (10 g, 58.5 mmol, 7 mL) was added dropwise. The reaction was heated to reflux for 3 h. The reaction was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, affording crude title compound 1e (12 g), which was used directly in the next reaction without further purification. MS m / z (ESI): 253.1 [M+1].

[0113] Step 4 6-(benzyloxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate 1f Compound 1e (8 g, 31.7 mmol) was dissolved in dry tetrahydrofuran (100 mL). The reaction was cooled to -78 °C under an argon atmosphere, and [bis(trimethylsilyl)amino]lithium (1 M, 50.8 mL, 50.8 mmol) was added dropwise. After the addition was complete, the reaction was stirred at -78 °C for 30 minutes. 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (17 g, 47.6 mmol) was added slowly, and the reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the slow addition of water (100 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 1f (10.1 g) in 83% yield. MS m / z (ESI): 385.2 [M+1].

[0114] Step 5 7-(benzyloxy)-4-(4-bromophenyl)-1,2-dihydronaphthalene 1g Compound 1f (32 g, 83.3 mmol), 4-bromophenylboronic acid (20 g, 100 mmol, Shanghai Meryer Chemical Technology Co., Ltd.), tetrakis(triphenylphosphine)palladium (9.62 g, 8.3 mmol), and sodium carbonate (26.47 g, 250 mmol) were added sequentially to 360 mL of a 5:1 mixture of 1,4-dioxane and water and reacted at 80 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1g (14 g) in 43% yield.

[0115] Step 6 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1h Compound 1g (16 g, 40.9 mmol), compound 1c (7.81 g, 49.1 mmol), palladium acetate (1.38 g, 6.1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.9 g, 8.2 mmol), and sodium tert-butoxide (11.79 g, 123 mmol) were added to toluene (350 mL) and reacted at 90 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1h (10.5 g) in 55% yield. MS m / z (ESI): 470.2 [M+1].

[0116] Step 7 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1i Compound 1h (10.5 g, 22.4 mmol) was dissolved in dichloromethane (350 mL) and cooled to −5°C in an ice-salt bath. Pyridinium tribromide (8.58 g, 26.8 mmol) and triethylamine (4.52 g, 44.7 mmol) were added in several portions, and the reaction was allowed to proceed at −5°C for 30 minutes. Saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture. The organic phase was separated, washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using eluent system B to give the title product 1i (5.1 g) in 42% yield. MS m / z (ESI): 550.2 [M+1].

[0117] Step 8 1-(4-(6-(benzyloxy)-2-isobutyl-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1j Under a nitrogen atmosphere, a tetrahydrofuran solution of zinc chloride (1 M, 8.2 mL) was slowly added dropwise to an ice-cooled solution of tert-butylmagnesium chloride (1 M, 7.5 mL, Shanghai Adamas Co., Ltd.). After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. Compound 1i (400 mg, 0.73 mmol) and a tetrahydrofuran solution of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (Ruphos-Pd G3, 90 mg, 0.11 mmol, Jiangsu Aiko Biopharmaceutical Research and Development Co., Ltd.) (2 mL) were added. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. Saturated ammonium chloride solution (10 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (15 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1j (300 g) in 75% yield. MS m / z (ESI): 526.3 [M+1].

[0118] Step 9 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isobutyl-5,6,7,8-tetralin-2-phenol 1k Compound 1j (130 mg, 0.25 mmol) was dissolved in methanol (10 mL), and palladium hydroxide on carbon (100 mg, 20 wt%) was added. The reaction was carried out under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, affording the title compound 1k (90 mg) in an 83% yield. MS m / z (ESI): 438.3 [M+1].

[0119] Step 10 (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isobutyl-5,6,7,8-tetralin-2-phenol 1l Compound 1k (90 mg, 0.21 mmol) was separated by chiral preparative chromatography (separation conditions: column: CHIRALPAK IE, 20 mm × 250 mm, 5 μm, mobile phase: A: n-hexane, B: ethanol (+ 20 mmol NH3), A: 85%, B: 15%), flow rate: 20 mL / min. Title compound 1l (31 mg) was obtained. MS m / z (ESI): 438.3 [M+1].

[0120] Step 11 1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidine-4-formaldehyde 1m Compound 1l (35 mg, 0.08 mmol) was dissolved in tetrahydrofuran (2.5 mL), diluted sulfuric acid (2 M, 0.15 mL, 0.3 mmol) was added, and the mixture was heated to 55°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The reaction mixture was concentrated under reduced pressure to remove the solvent, affording the title compound 1m (31 mg) in a 99% yield. MS m / z (ESI): 392.2 [M+1].

[0121] Step 12 (S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-amino-5-oxopentanoic acid tert-butyl ester 1o (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid 1n (40 g, 94 mmol, Shanghai Hanhong Technology Co., Ltd.) and di-tert-butyl dicarbonate (32.83 g, 150 mmol) were added to 1,4-dioxane (300 mL). Under a nitrogen gas atmosphere, the internal temperature was controlled to be lower than 5°C using an ice-water bath, and pyridine (15 mL, 188 mmol) was added dropwise. After the addition was completed, the reaction was carried out in an ice-water bath for 0.5 hours. Ammonium bicarbonate (66.89 g, 282 mmol) was added, and the mixture was warmed to room temperature and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and ethyl acetate (500 mL) was added. The mixture was washed with dilute hydrochloric acid (500 mL x 3) and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, giving the crude title compound 1o (45.3 g), which was used directly in the next reaction without further purification: MS m / z (ESI): 369.1 [M-55].

[0122] Step 13 (S)-4,5-Diamino-5-oxopentanoic acid tert-butyl ester 1p Compound 1o (45.3 g, 94 mmol) and diethylamine (50 mL) were added to dichloromethane (500 mL) and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in methanol (150 mL). Water (5 mL) was added and the mixture was washed with n-heptane (150 mL x 3). The methanol layer was concentrated under reduced pressure to remove the solvent, yielding crude title compound 1p (21.5 g). This product was used directly in the next reaction without purification. MS m / z (ESI): 203.1 [M+1].

[0123] Step 14 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1r Methyl 2-cyano-4-fluorobenzoate 1q (50 g, 0.28 mol, Jiangsu Aikang Bio-Research Development Co., Ltd.), tert-butyl piperazine-1-formate acetate (62.3 g, 0.34 mol), and isopropylethylamine (250 mL, 1.39 mol) were added to tetrahydrofuran (1 L) and reacted at 120 °C for 12 hours. Water (1 L) was added to the reaction mixture, which was then extracted with ethyl acetate (1 L x 3). The combined organic phase was washed with saturated sodium chloride solution (1 L x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, affording crude title compound 1r (89 g). This product was used directly in the next reaction without further purification. MS m / z (ESI): 290.1 ​​[M-55].

[0124] Step 15 4-(3-Formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1s Compound 1r (5 g, 14.5 mmol), pyridine (10.5 mL), glacial acetic acid (6.6 mL), and Raney nickel (2.5 g) were added to water (5 mL) and heated to 70 °C. Sodium hypophosphite (7.5 g) was dissolved in water (15 mL) and added dropwise to the reaction mixture. After the addition was complete, the mixture was reacted at 70 °C for 12 h. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) and water (50 mL) were added. The organic phase was separated, washed with dilute hydrochloric acid (1 M, 50 mL × 3), saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1s (3 g) in 59% yield. MS m / z (ESI): 293.1 [M-55].

[0125] Step 16 (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester 1t Compound 1s (1.3 g, 3.7 mmol) and compound 1p (0.89 g, 4.5 mmol) were added to methanol (10 mL), and the internal temperature was controlled below 5 °C using an ice-water bath. Acetic acid (0.3 mL, 5.6 mmol) and sodium cyanoborohydride (0.46 g, 7.46 mmol) were added dropwise, and the mixture was allowed to react at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The organic phase was separated, washed with saturated citric acid solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1t (0.71 g) in a 38% yield. MS m / z (ESI): 503.2 [M+1].

[0126] Step 17 (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate 1u Compound 1t (5.7 g, 11.4 mmol) and benzenesulfonic acid (3.59 g, 22.7 mmol) were added to acetonitrile (15 mL) and stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was washed with ethyl acetate (100 mL × 3) and dried to give the title compound 1u (5.7 g, yield: 100%). MS m / z (ESI): 329.1 [M+1].

[0127] Step 18 (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 Compound 1u (50 mg, 0.1 mmol) was added to a mixed solvent of dichloromethane and methanol (V / V = 4 / 1, 5 mL), sodium acetate (130 mg, 1.58 mmol) was added, and the mixture was incubated for 10 minutes. Compound 1m (31 mg, 0.08 mmol) was added, and the mixture was incubated for 15 minutes. Sodium triacetoxyborohydride (34 mg, 0.16 mmol) was added, and the mixture was incubated at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (Waters 2767-SQ Detector 2, eluent: 10 mM ammonium bicarbonate, 60% water, 40% acetonitrile) to obtain compound 1 (25 mg) in 45% yield. MS m / z (ESI): 704.4 [M+1]. Powder X-ray diffraction revealed the product to be amorphous, and the powder X-ray diffraction pattern is shown in Figure 1.

[0128] Example 2: Inhibitory effect of Compound I on MCF7 cell proliferation MCF7 cells (TCHu74, cell bank of the Chinese Academy of Sciences' Type Culture Collection Committee) were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded in a 96-well plate at a density of 3,000 cells / well in MEM medium containing 2% fetal bovine serum, with 135 μL of cell suspension in each well, and placed in a cell incubator at 37°C and 5% CO2 for overnight culture. The next day, 15 μL of compounds with different concentrations to be measured prepared in the medium were added to each well, with the final concentrations of the compounds being 9 concentration points diluted in a 4-fold gradient from 1000 nM, and a blank control containing 0.5% DMSO was set up, and then placed in a cell incubator at 37°C and 5% CO2 for 6 days of culture. On the 8th day, the 96-well cell culture plate was taken out, 75 μL of CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added to each well, left at room temperature for 10 minutes, and then the luminescence signal value was read using a multi-label plate reader (PerkinElmer, VICTOR 3), and the IC50 value of the inhibitory activity of the compound was calculated to be 0.59 nM from the compound concentration and the luminescence signal value using the software Graphpad Prism.

[0129] Example 3, Pharmacodynamic Experiment of Compound I 1. Experimental Purpose Evaluate the effect of compound I on inhibiting the growth of MCF-7 (Y537S) transplanted tumors of human breast cancer cells in BEIGE SCID mice.

[0130] 2. Experimental Drugs Compound I. A solution of 2% Tween 80 + 98% PEG-400 was used.

[0131] 3. Experimental Methods and Experimental Materials 3.1. Experimental Animals and Breeding Conditions Experimental animals: Female BEIGE SCID mice purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK (Beijing) 2016-0006), with a body weight of about 19 g at the time of purchase.

[0132] Breeding conditions: They were housed five per cage, regulated with a 12 / 12 hour light / dark cycle, maintained at a temperature of 23±1°C, and kept at a humidity of 50-60%, with free access to water and food.

[0133] 3.2. Animal Grouping After adaptive breeding of BEIGE SCID mice, they were divided into the following groups.

[0134] [Table 1]

[0135] 3.3 Experimental Method: 1.0 × 10 MCF-7 (Y537S) cells in the logarithmic growth phase 7 The tumors were inoculated subcutaneously into the right rib region of female Beige SCID mice at a dose of 200 μL (containing 100 μL of Matrigel) per mouse. After 18 days, the tumor volume of the tumor-bearing mice reached 170 mm 3 When the tumor volume reached the target level, the mice were randomly divided into four groups according to tumor volume and body weight: a vehicle control group, a compound I 5 mpk group, a compound I 15 mpk group, and a compound I 45 mpk group, with 8 mice per group. The day of grouping was designated as D0, and intragastric administration was initiated once a day for a total of 28 days. The 28th day after administration was designated as D0. 28 The tumor volumes of tumor-bearing mice were measured twice a week with a vernier caliper (Table 1).

[0136] 3.4. Data Statistics All data were plotted and statistically analyzed using Excel and GraphPad Prism 8 software.

[0137] The formula for calculating tumor volume (V) is V = 1 / 2 × a × b2, where a and b represent length and width, respectively.

[0138] The relative tumor growth rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where T and C are the tumor volumes of the treatment and control groups at the end of the experiment, and T0 and C0 are the tumor volumes at the start of the experiment.

[0139] Tumor inhibition rate (TGI) (%) = 1 - T / C (%). If TGI (%) exceeds 100%, a specific value cannot be given; only >100% is shown. Tumor regression (%) = [(T0 - T) / T0] × 100 (%).

[0140] 4, results Table 1 shows the data on the therapeutic effect of Compound I on MCF-7 (Y537S) transplanted tumors in BEIGE SCID mice.

[0141] [Table 2]

[0142] 5. Conclusion Compound I was administered 18 days after tumor cell transplantation, and after 28 days of administration once daily, the tumor inhibition rate was 72% in the low-dose 5mpk group, 89% in the medium-dose 15mpk group, and 95% in the high-dose 45mpk group.

[0143] Example 4: Preparation of amorphous compound 5 mg of compound I was weighed and dissolved in a solvent to obtain a product, which was detected by powder X-ray diffraction and showed no obvious characteristic peaks, indicating that the product was amorphous. The XRPD spectrum is shown in Figure 1.

[0144] [Table 3]

[0145] Example 5: Preparation of Compound A Crystals Approximately 24 mg of compound I was weighed and dissolved in 0.7 mL of 50% ethanol / ethyl acetate. Hydrochloric acid solution (2 mol / L, 37 μL) was added, and the reaction solution was slurried for 1 day and centrifuged. 0.2 M phosphate buffer was added to the solid to adjust the pH to 6, and the solid was slurried for 1 day. The solid was centrifuged and dried to obtain the product.

[0146] The product was identified as Compound A type crystals by powder X-ray diffraction. The XRPD spectrum is shown in Figure 2, and its characteristic peak positions are shown in Table 3. The TGA spectrum showed a weight loss of 2.9% before 140°C. The DSC spectrum showed an endothermic peak at 162.58°C.

[0147] [Table 4]

[0148] Example 6: Preparation of Compound Hydrochloride Type I Crystals 48 mg of compound I was weighed and dissolved in 1.4 mL of 50% ethanol / methyl tert-butyl ether. Hydrochloric acid solution (2 mol / L, 74 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0149] Powder X-ray diffraction analysis confirmed that the product was hydrochloride type I crystals. The XRPD spectrum is shown in Figure 3, and its characteristic peak positions are shown in Table 4. Ion chromatography analysis revealed that the chloride ion content was 9.08%. The DSC spectrum showed endothermic peaks at 72.79°C and 248.5°C. The TGA spectrum showed a weight loss of 2.8% between 30°C and 120°C.

[0150] DVS detection showed that the sample's moisture weight gain was approximately 6.3% under normal storage conditions (i.e., 25°C, 60% RH), approximately 7.3% under accelerated storage conditions (i.e., 70% RH), and approximately 8.9% under extreme storage conditions (i.e., 90% RH). Re-measurement of the crystal form after DVS detection showed no conversion of the crystal form.

[0151] [Table 5]

[0152] Example 7: Preparation of Compound Hydrochloride Type I Crystals 48 mg of compound I was weighed, and a solvent and 2 mol / L hydrochloric acid solution were added to obtain a product, which was found to be hydrochloride type I crystals by powder X-ray diffraction.

[0153] [Table 6]

[0154] Example 8: Preparation of Compound Hydrochloride Type I Crystals The hydrochloride type II crystals are heated at a high temperature up to 120°C to obtain a product, which is detected by powder X-ray diffraction to be the hydrochloride type I crystals.

[0155] Example 9: Preparation of Compound Hydrochloride Type II Crystals Approximately 48 mg of compound I was weighed and dissolved in 1.4 mL of 50% ethanol / ethyl acetate. Hydrochloric acid solution (2 mol / L, 74 μL) was added, and the reaction solution was slurried for 1 day and centrifuged to obtain the product.

[0156] Powder X-ray diffraction analysis identified the product as hydrochloride type II crystals. The XRPD spectrum is shown in Figure 4, and its characteristic peak positions are shown in Table 6. Ion chromatography analysis revealed a chloride ion content of 8.72%. The DSC spectrum showed endothermic peaks at 66.12°C, 120.27°C, and 248.83°C. The TGA spectrum showed a weight loss of 1.9% between 30°C and 160°C.

[0157] [Table 7]

[0158] Example 10: Preparation of Compound Hydrochloride Type II Crystals 48 mg of Compound I was weighed, and a solvent and 2 mol / L hydrochloric acid solution were added to obtain a product, which was identified as hydrochloride type II crystals by powder X-ray diffraction.

[0159] [Table 8]

[0160] Example 11. Preparation of amorphous compound hydrochloride Approximately 15 mg of compound I was weighed and dissolved in 0.2 ml of 50% ethanol / ethyl acetate. Hydrochloric acid solution (2 mol / L, 11 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0161] Powder X-ray diffraction showed no obvious characteristic peaks, indicating that the product was an amorphous hydrochloride. Ion chromatography revealed that the chloride ion content was 5.66%.

[0162] Example 12: Preparation of Compound Maleate I Crystals Approximately 100 mg of compound I was weighed out and dissolved in 3 mL of acetone, and 18.2 mg of maleic acid was added thereto. The reaction solution was slurried for 1 day to obtain a product.

[0163] Powder X-ray diffraction analysis confirmed that the product was maleate type I crystals. The XRPD spectrum is shown in Figure 5, and its characteristic peak positions are shown in Table 8. Ion chromatography analysis revealed that the maleate ion content was 12.53%. The DSC spectrum showed an endothermic peak at 145.8°C. The TGA spectrum showed a 1% weight loss between 30°C and 90°C and a 12.4% weight loss between 90°C and 190°C.

[0164] [Table 9]

[0165] Example 13: Preparation of Compound Fumarate Type I Crystals Approximately 98 mg of compound I was weighed and dissolved in 3 mL of tetrahydrofuran, 17.1 mg of fumaric acid was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the title product.

[0166] Powder X-ray diffraction analysis confirmed that the product was fumarate type I crystals. The XRPD spectrum is shown in Figure 6, and its characteristic peak positions are shown in Table 9. Ion chromatography analysis revealed that the fumarate ion content was 11.58%. The DSC spectrum showed an endothermic peak at 141.44°C. The TGA spectrum showed a weight loss of 13.6% between 30°C and 160°C.

[0167] [Table 10]

[0168] Example 14: Preparation of Compound Fumarate Type II Crystals Approximately 7.1 mg of compound I was weighed out and dissolved in 0.2 mL of acetonitrile, and 2.3 mg of fumaric acid was added. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0169] Powder X-ray diffraction analysis confirmed that the product was fumarate type II crystals. The XRPD spectrum is shown in Figure 7, and its characteristic peak positions are shown in Table 10. Ion chromatography analysis revealed that the fumarate ion content was 18.78%. The DSC spectrum showed endothermic peaks at 155.97°C and 229.48°C. The TGA spectrum showed a weight loss of 1.3% from 30°C to 100°C and a weight loss of 21.4% from 100°C to 280°C.

[0170] [Table 11]

[0171] Example 15: Preparation of Compound Fumarate III Crystals 100 mg of Compound I was weighed and dissolved in 5 mL of 1,4-dioxane, 16.5 mg of fumaric acid was added, and the mixture was stirred at room temperature for 16 hours, and a solid precipitated and was dried to obtain a product.

[0172] The product was identified as fumarate type III crystals by powder X-ray diffraction, and its XRPD spectrum is shown in FIG. 8, and its characteristic peak positions are shown in Table 11. 1 1 H NMR nuclear magnetic characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0173] [Table 12]

[0174] Example 16: Preparation of fumarate IV crystals 20 mg of compound I was weighed and dissolved in 1 mL of acetone, and 0.2 mL of an acetone solution of fumaric acid (3.3 mg, 28.41 μmol) was added thereto, followed by stirring at room temperature for 2.5 hours. A solid precipitated and was dried to obtain a product.

[0175] The product was identified as fumarate Form IV crystals by powder X-ray diffraction, and its XRPD spectrum is shown in FIG. 9, and its characteristic peak positions are shown in Table 12. 11 H NMR nuclear magnetic characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0176] [Table 13]

[0177] Example 17: Preparation of fumarate type V crystals 100 mg of compound I was weighed and dissolved in 2 mL of 1,4-dioxane, and 0.4 mL of a 1,4-dioxane solution of fumaric acid (16.5 mg, 142.06 μmol) was added thereto, followed by stirring at room temperature for 16 hours. A solid precipitated and was dried to obtain the product.

[0178] The product was identified as fumarate type V crystals by powder X-ray diffraction. The XRPD spectrum is shown in Figure 10, and its characteristic peak positions are shown in Table 13. The DSC spectrum showed endothermic peaks at 142.15°C, 158.14°C, and 232.14°C. The TGA spectrum showed a weight loss of 8.10% from 30°C to 140°C and a weight loss of 1.78% from 140°C to 190°C. 1 1 H NMR nuclear magnetic characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0179] [Table 14]

[0180] Example 18: Preparation of L-tartrate salt type I crystals 100 mg of Compound I was weighed and dissolved in 5 mL of 1,4-dioxane, and L-tartaric acid (21.5 mg, 143.25 μmol) was added thereto, followed by stirring at room temperature for 16 hours. A solid precipitated and was dried to obtain the product.

[0181] The product was identified as L-tartrate salt Form I crystals by powder X-ray diffraction, and its XRPD spectrum is shown in FIG. 11, and its characteristic peak positions are shown in Table 14. 1 H NMR nuclear magnetic characterization: Compound I forms a salt with L-tartaric acid in a 1:1 ratio.

[0182] [Table 15]

[0183] Example 19: Preparation of succinate type I crystals 100 mg of Compound I was weighed and dissolved in 5 mL of 1,4-dioxane, and succinic acid (17 mg, 143.96 μmol) was added thereto, followed by stirring at room temperature for 16 hours. A solid precipitated and was dried to obtain a product.

[0184] The product was identified as succinate type I crystals by powder X-ray diffraction, and its XRPD spectrum is shown in FIG. 12, and its characteristic peak positions are shown in Table 15. 1 H NMR nuclear magnetic characterization: Compound I forms a salt with L-tartaric acid in a 1:1 ratio.

[0185] [Table 16]

[0186] Example 20: Preparation of D-malate type I crystals 2 g of compound I was weighed and dissolved in 60 mL of tetrahydrofuran. 20 mL of a tetrahydrofuran solution of D-malic acid (381 mg, 2.84 mmol) was added, and the mixture was stirred at room temperature in a dark place for 24 hours to precipitate a solid. The solid was dried in vacuo at 50°C for 16 hours to obtain the product.

[0187] The product was identified as D-malate Form I crystals by powder X-ray diffraction. The XRPD spectrum is shown in Figure 13, and its characteristic peak positions are shown in Table 16. The DSC spectrum showed endothermic peaks at 122.76°C, 142.13°C, and 213.37°C. The TGA spectrum showed a weight loss of 10.11% between 30°C and 140°C.

[0188] [Table 17]

[0189] Example 21: Preparation of amorphous sulfate Approximately 48 mg of compound I was weighed and dissolved in 0.7 mL of 50% ethanol / ethyl acetate. Sulfuric acid solution (2 mol / L, 38 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0190] Powder X-ray diffraction showed no obvious characteristic peaks, indicating that the product was an amorphous sulfate. Ion chromatography revealed that the sulfate ion content was 12.89%. TGA spectrum showed a weight loss of 4.4% between 30°C and 100°C.

[0191] Example 22: Preparation of amorphous phosphate Approximately 48 mg of compound I was weighed and dissolved in 0.7 mL of 50% ethanol / ethyl acetate. A phosphoric acid solution (2 mol / L, 38 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0192] Powder X-ray diffraction showed no obvious characteristic peaks, indicating that the product was amorphous phosphate. Ion chromatography revealed that the phosphate ion content was 13.77%. TGA spectrum showed a weight loss of 1.5% between 30°C and 110°C.

[0193] Example 23: Preparation of amorphous tartrate salt Approximately 28 mg of compound I was weighed and dissolved in 0.4 mL of 50% ethanol / ethyl acetate. Tartaric acid solution (2 mol / L, 21 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0194] Powder X-ray diffraction showed no obvious characteristic peaks, indicating that the product was amorphous tartrate. Ion chromatography revealed that the tartrate ion content was 9.87%. TGA spectrum showed a weight loss of 2.3% between 30°C and 100°C and a weight loss of 1% between 100°C and 180°C.

[0195] Example 24: Preparation of amorphous L-malate salt Approximately 28 mg of compound I was weighed and dissolved in 0.4 mL of 50% ethanol / ethyl acetate. L-malic acid solution (2 mol / L, 21 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0196] Powder X-ray diffraction showed no distinct characteristic peaks, indicating that the product was amorphous L-malate. Ion chromatography revealed a malate ion content of 10.25%. TGA spectra showed a weight loss of 1.6% between 30°C and 90°C and a weight loss of 3.2% between 90°C and 160°C.

[0197] Example 25. Preparation of amorphous citrate salt Approximately 28 mg of compound I was weighed and dissolved in 0.4 mL of 50% ethanol / ethyl acetate. Citric acid solution (0.5 mol / L, 84 μL) was added, and the reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0198] The product is amorphous citrate as determined by powder X-ray diffraction. TGA spectrum showed a weight loss of 2% between 30°C and 100°C.

[0199] Experimental Example 1. Study on the stability of hydrochloride type I crystals due to factors influencing their stability The hydrochloride type I crystals were placed flat in an open state, and the stability of the samples was examined under conditions of light exposure (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). The sampling period was one month.

[0200] [Table 18]

[0201] Conclusion: The hydrochloride type I crystals have good physical and chemical stability when left for one month under conditions other than high temperature and light exposure.

[0202] Experimental Example 2. Study on the long-term accelerated stability of hydrochloride type I crystals The stability of the hydrochloride type I crystals was examined under the conditions of 25°C / 60%RH and 40°C / 75%RH.

[0203] [Table 19]

[0204] Conclusion: The hydrochloride type I crystals have good physical and chemical stability after 2 months storage under long-term accelerated conditions.

Claims

1. The powder X-ray diffraction pattern shown at diffraction angles 2θ is 14.2, 15.3, 16.1, 17.4 and 19.

1. and the powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles is most preferably as shown in FIG. 2 . A type crystal.

2. a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, wherein the pharmaceutically acceptable salt is selected from hydrochloride, maleate, fumarate, L-tartrate, succinate, D-malate, L-malate, sulfate, phosphate, and citrate; Pharmaceutically acceptable salts.

3. a chemical compounding ratio of the (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to an acid of 3:1 to 1:3, preferably 2:1 to 1:2; 3. The pharmaceutically acceptable salt of claim 2.

4. 1. A process for preparing a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of: reacting (hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione with an acid, wherein the acid is selected from hydrochloric acid, maleic acid, fumaric acid, L-tartaric acid, succinic acid, D-malic acid, L-malic acid, sulfuric acid, phosphoric acid, and citric acid; Preparation method.

5. The hydrochloride salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a type I crystal, and the powder X-ray diffraction pattern shown at diffraction angles 2θ is 13.8, 15.9, 19.0, 20.1 and 22. and the powder X-ray diffraction pattern thereof, expressed in terms of diffraction angle 2θ, is as shown in FIG. 3, and preferably has characteristic peaks at 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6 and 22.8, more preferably has characteristic peaks at 10.8, 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6, 22.8, 25.2 and 26.5, and most preferably has characteristic peaks at diffraction angle 2θ as shown in FIG. Hydrochloride type I crystals.

6. The hydrochloride salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a type II crystal, and the powder X-ray diffraction pattern shown at diffraction angles 2θ is characteristic of 13.2, 17.1, 19.7, 20.6, 22.8, and 25.

0. and preferably has characteristic peaks at 10.4, 13.2, 14.5, 15.1, 17.1, 19.7, 20.6, 22.8, 25.0 and 26.1, more preferably has characteristic peaks at 5.6, 10.4, 13.2, 13.8, 14.5, 15.1, 17.1, 19.7, 20.6, 22.8, 23.3, 25.0 and 26.1, and most preferably has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

4. Hydrochloride type II crystals.

7. The maleate type I crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is shown, and the powder X-ray diffraction pattern shown at diffraction angles 2θ angles is characterized by peaks at 5.6, 8.8, 9.4, 10.2, 10.7 and 18.

0. and preferably has characteristic peaks at 5.6, 7.0, 8.8, 9.4, 10.2, 10.7, 15.9, 18.0, 20.6 and 22.3, more preferably has characteristic peaks at 5.6, 7.0, 8.4, 8.8, 9.4, 10.2, 10.7, 11.3, 15.9, 16.8, 18.0, 20.6, 21.5, 22.3 and 23.9, and most preferably has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

5. Maleate type I crystals.

8. The fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a type I crystal, and the powder X-ray diffraction pattern shown at diffraction angles 2θ is 6.8, 9.6, 10.5, 17.6, 18.2 and 2. and 1.1, preferably 5.7, 6.8, 9.6, 10.5, 16.0, 17.6, 18.2, 19.8 and 21.1, more preferably 5.7, 6.8, 8.9, 9.6, 10.5, 11.3, 16.0, 17.6, 18.2, 19.8, 21.1 and 22.2, and most preferably has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

6. Fumarate Form I crystals.

9. A fumarate type II crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, wherein the powder X-ray diffraction pattern shown at diffraction angles 2θ has characteristic peaks at 7.0, 9.4, 15.0, 17.1, 17.7, and 18.7, preferably has characteristic peaks at 7.0, 9.4, 10.9, 14.6, 15.0, 17.1, 17.7, 18.7, 19.9, and 23.9, and more preferably has a powder X-ray diffraction pattern shown at diffraction angles 2θ as shown in FIG. Fumarate Form II crystals.

10. The fumarate type III crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione has a powder X-ray diffraction pattern shown at diffraction angles 2θ of 5.1, 9.6, 10.4, 17.9, 18.5 and 20.5, preferably having characteristic peaks at 5.1, 6.0, 9.6, 10.4, 17.9, 18.5, 19.4, 20.5 and 23.2, more preferably having characteristic peaks at 5.1, 6.0, 7.1, 9.6, 10.4, 11.3, 17.9, 18.5, 19.4, 20.5 and 23.2, and most preferably having characteristic peaks at diffraction angles 2θ as shown in FIG.

8. Fumarate Form III crystals.

11. A fumarate type IV crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, wherein the powder X-ray diffraction pattern shown at a diffraction angle 2θ has characteristic peaks at 6.2, 10.3, 11.1, 12.5, 21.3, and 22.2, and preferably the powder X-ray diffraction pattern shown at a diffraction angle 2θ is as shown in FIG. 9 . Fumarate type IV crystals.

12. The fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a type V crystal, and the powder X-ray diffraction pattern shown at diffraction angles 2θ is characteristic of 10.5, 17.1, 18.6, 20.1, 21.0, and 23.

7. and the powder X-ray diffraction pattern thereof, expressed in terms of diffraction angle 2θ angles, is most preferably as shown in FIG. 10 . Fumarate type V crystals.

13. The L-tartrate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a type I crystal, and the powder X-ray diffraction pattern shown at diffraction angles 2θ is characteristic of 9.1, 16.0, 17.7, 18.0, 20.0, and 20.

7. and the powder X-ray diffraction pattern thereof, expressed in terms of diffraction angle 2θ angles, is most preferably as shown in FIG. 11 . L-tartrate salt type I crystals.

14. The succinate form I crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is characterized in that the powder X-ray diffraction pattern shown at diffraction angles 2θ is 9.5, 16.0, 17.6, 18.0, 19.9, 20.7, and 22.

3. and preferably has characteristic peaks at 9.0, 9.5, 10.3, 16.0, 17.6, 18.0, 19.9, 20.7, 21.5 and 22.3, more preferably has characteristic peaks at 5.6, 6.9, 9.0, 9.5, 10.3, 10.7, 13.7, 16.0, 17.6, 18.0, 19.9, 20.7, 21.5 and 22.3, and most preferably has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

12. Succinate type I crystals.

15. The D-malate type I crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione has a powder X-ray diffraction pattern shown at diffraction angles 2θ of 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, and 20. and 6, preferably 7.0, 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, 20.0, 20.6 and 22.3, more preferably 5.6, 7.0, 9.0, 9.5, 10.7, 15.9, 17.6, 17.9, 18.2, 20.0, 20.6, 21.5 and 22.3, and most preferably a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles as shown in FIG.

13. D-Malate Form I crystals.

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

2.

16. The crystalline form of any one of claims 1 or 5 to 15.

17. A pharmaceutical composition comprising the following ingredients: i) Type A crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2, or a crystalline form according to any one of claims 5 to 15, ii) one or more pharmaceutically acceptable excipients; Pharmaceutical compositions.

18. A method for preparing a pharmaceutical composition, comprising the steps of: preparing a Type A crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1; mixing a pharmaceutically acceptable salt of 4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form of any one of claims 5 to 15, with a pharmaceutically acceptable excipient; method.

19. The A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2. a pharmaceutically acceptable salt of (methyl)-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form of any one of claims 5 to 15, or the composition of claim 17, in the preparation of a medicament for treating or preventing a condition that is treated by degradation of a target protein bound to a target ligand, use.

20. The A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2.

19. Use of a pharmaceutically acceptable salt of (methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form of any one of claims 5 to 15, or the composition of claim 17, in the preparation of a medicament for treating or preventing a condition that is treated by binding to a cerebellar protein in the body, wherein the condition is preferably abnormal cell proliferation, tumor, immune disease, diabetes, cardiovascular disease, infectious disease and inflammatory disease, more preferably tumor or infectious disease. use.

21. The A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the A-type crystal of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2.

18. The use of a pharmaceutically acceptable salt of (1,2,3,4-tetralin-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form of any one of claims 5 to 15, or the composition of claim 17, in the preparation of a medicament for treating or preventing an estrogen receptor mediated or dependent disease or condition, use.

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