Medicinal salt of tetrahydronaphthalene derivative, crystal form and preparation method

Abstract

The invention relates to a medicinal salt of a tetrahydronaphthalene derivative, a crystal form and a preparation method. Specifically, the invention provides a pharmaceutically acceptable salt, a crystal form and a preparation method of (S)-3-(5-(4-((1-(4-((1R, 2R)-6-hydroxy-2-isobutyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl) phenyl) piperidine-4-yl) methyl) piperazin-1-yl)-1-oxoisoindoline-2-yl) piperidine-2, 6-dione, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

Pharmaceutically acceptable salt, crystal form and preparation method of tetralin derivative

[0001] This application claims the benefit of Chinese patent application No. 2022111977804, filed on September 29, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of pharmaceuticals and relates to a pharmaceutically acceptable salt and crystal form of a tetralin derivative. Background Art

[0003] Protein proteolysis-targeting chimera (PROTAC) is a hybrid bifunctional small molecule compound. Its structure contains two different ligands: one is the E3 ubiquitin ligase ligand, and the other is a ligand that binds to the target protein. The two ligands are connected by a connecting arm. PROTAC forms a target protein-PROTAC-E3 ternary complex by bringing the target protein and the E3 ubiquitin ligase in the cell closer. The E3 ubiquitin ligase then tags the target protein with a ubiquitinated protein tag, initiating a powerful ubiquitination hydrolysis process in the cell, and using the ubiquitin-proteasome pathway to specifically degrade the target protein. Compared with traditional small molecule inhibitors, PROTAC exhibits unique advantages: 1. PROTAC does not require long-term and high-intensity binding to the target protein, and the process of degrading the target protein is similar to a catalytic reaction. It can cyclically bind and degrade the target protein, thereby reducing the systemic exposure of the drug and reducing the occurrence of toxic side effects. 2. After being degraded, the target protein needs to be resynthesized to restore its function. Therefore, degradation of the target protein shows a more efficient and lasting anti-tumor effect than inhibiting its activity, and does not cause drug resistance due to target protein mutations. 3. PROTACs also have therapeutic potential for targets currently considered undruggable, such as transcription factors, scaffold proteins, and regulatory proteins.

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

[0005] On this basis, CRBN ligands are widely used in the preparation of protein degraders, and a series of PROTAC molecules based on CRBN ligands have been developed. PCT / CN2022 / 083597 discloses a new class of tetralin derivatives, among which Compound I, chemically named (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, demonstrates its application as an estrogen receptor degrader in the treatment of estrogen receptor-mediated or dependent diseases.

[0006] The crystalline structure of a pharmaceutically active ingredient often affects the chemical and physical stability of the drug. Different crystallization and storage conditions can lead to changes in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms. Generally speaking, amorphous pharmaceutical products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, difficulty in filtration, caking, and poor flowability. Therefore, research on pharmaceutically acceptable salts and crystalline forms of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 exhibiting excellent biological activity.

[0007] Summary of the Invention

[0008] In one aspect, the present disclosure provides a crystalline Form A of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0009] In some embodiments, the Form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 14.2, 15.3, 16.1, 17.4 and 19.1.

[0010] In other embodiments, the Form A has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 14.2, 15.3, 16.1, 17.4, 19.1, 20.0, 20.9 and 22.3.

[0011] In other embodiments, the Form A has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with 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 other embodiments, the X-ray powder diffraction pattern of the crystal form A expressed in terms of a diffraction angle 2θ is shown in FIG2 .

[0013] Another aspect of the present disclosure provides a pharmaceutically acceptable salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 the group consisting of hydrochloride, maleate, fumarate, L-tartrate, succinate, D-malate, L-malate, sulfate, phosphate and citrate.

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

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

[0016] In an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and fumaric acid is 1:1 or 1:2.

[0019] In an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 an optional embodiment, the chemical ratio of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and sulfuric acid is 1:1 or 1:2.

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

[0026] The present disclosure also provides a compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalene- A method for preparing a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of reacting (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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-malate, sulfate, phosphate and citrate.

[0027] The solvent used for salt formation in the present invention is selected from but not limited to acetonitrile, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, ethanol / ethyl acetate, methanol, ethanol / water, tetrahydrofuran / ethanol, dichloromethane / ethanol, and methyl tert-butyl ether / ethanol.

[0028] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtration, washing or drying.

[0029] On the other hand, the present disclosure also provides a hydrochloride salt form I of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, having characteristic peaks at 13.8, 15.9, 19.0, 20.1 and 22.8.

[0030] In other embodiments, the hydrochloride salt form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6 and 22.8.

[0031] In other embodiments, the hydrochloride salt form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 other embodiments, the X-ray powder diffraction pattern of hydrochloride salt form I expressed in diffraction angle 2θ is shown in FIG3 .

[0033] The present disclosure also provides a hydrochloride salt form II of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 form II has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 form II has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 other embodiments, the X-ray powder diffraction pattern of hydrochloride form I expressed in diffraction angle 2θ is shown in FIG4 .

[0037] The present disclosure also provides a maleate salt form I of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern represented by a diffraction angle of 2θ is shown in FIG5 .

[0041] The present disclosure also provides a crystalline form I of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the fumarate salt crystalline form I expressed in terms of a diffraction angle 2θ is shown in FIG6 .

[0045] The present disclosure also provides a crystalline form II of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 7.0, 9.4, 15.0, 17.1, 17.7 and 18.7.

[0046] In some embodiments, the fumarate salt II crystalline form has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the fumarate salt form II expressed in terms of a diffraction angle 2θ is shown in FIG7 .

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

[0049] In some embodiments, the fumarate salt form III has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 salt form III has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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 X-ray powder diffraction pattern of the fumarate salt form III expressed in terms of a diffraction angle 2θ is shown in FIG8 .

[0052] The present disclosure also provides a crystalline form IV of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, having characteristic peaks at 6.2, 10.3, 11.1, 12.5, 21.3, and 22.2.

[0053] In some embodiments, the X-ray powder diffraction pattern of the fumarate salt form IV expressed in terms of a diffraction angle 2θ is shown in FIG9 .

[0054] The present disclosure also provides a fumarate V crystalline form of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 10.5, 17.1, 18.6, 20.1, 21.0 and 23.7.

[0055] In some embodiments, the fumarate salt crystalline form V has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 salt form V has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the fumarate salt form V, expressed in terms of a diffraction angle 2θ, is shown in FIG10 .

[0058] The present disclosure also provides a crystalline form I of the L-tartrate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the L-tartrate salt form I, expressed as a diffraction angle 2θ, is shown in FIG11 .

[0062] The present disclosure also provides a crystalline form I of the succinate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the succinate salt crystal form I, expressed in terms of a diffraction angle of 2θ, is shown in FIG12 .

[0066] The present disclosure also provides a crystalline form I of the D-malate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 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 salt Form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 salt Form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 X-ray powder diffraction pattern of the D-malate salt form I, expressed as a diffraction angle 2θ, is shown in FIG13 .

[0070] Furthermore, the present invention discloses a crystalline form of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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] On the other hand, the present disclosure provides a method for preparing a crystalline form A of a compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising: adding a crystalline form A of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to the mixture; The method further comprises the steps of dissolving the mixture in 50% ethanol / ethyl acetate, adding a hydrochloric acid solution, stirring, filtering, adding a phosphate buffer solution, and stirring for crystallization, or adding the hydrochloride of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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. In some embodiments, the pH of the phosphate buffer is 4-8.

[0073] The present disclosure also provides a method for preparing a hydrochloride salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in Form I, comprising: 1) reacting compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in Form I. ,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is added to a solvent (1) and dissolved, hydrochloric acid is added, and 2) stirred, 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 preparing a hydrochloride II crystal form of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising: 1) preparing compound (S)-3-(5-(4-((1-(4 -((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is dissolved in a solvent (2), hydrochloric acid is added, and 2) stirred, 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 a maleate crystalline form I of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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-tetrahydronaphthalen-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 a crystalline form of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form of a fumarate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form of an L-tartrate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form I of a succinate salt of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 a crystalline form of D-malate of compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising the steps of dissolving compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 method for preparing the crystalline form described in the present disclosure further comprises the steps of crystallization, filtration, washing or drying.

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

[0085] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystalline form A of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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-tetrahydronaphthalen-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 provides the crystal form A of the aforementioned compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the pharmaceutically acceptable salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or its crystal form, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease treated by degrading a target protein bound to a targeting ligand.

[0087] The present disclosure also provides the crystal form A of the aforementioned compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the pharmaceutically acceptable salt of the compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or its crystal form, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease treated by binding to cerebellin in vivo.

[0088] The diseases treated by degrading the target protein bound to the targeting ligand or by binding to the cerebellum protein in vivo as described in the present invention are selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; optionally, the disease is a tumor or an infectious disease.

[0089] The tumor disclosed herein is cancer; optionally, the tumor is selected from but not limited to breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, and ovarian tumor.

[0090] The infectious diseases disclosed herein are selected from but not limited to viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, trachomavirus, rotavirus, and coronavirus.

[0091] The present disclosure also provides the crystal form A of the aforementioned compound (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a crystal form thereof, or use of the aforementioned pharmaceutical composition in the preparation of a pharmaceutical composition for the treatment and / or prevention of estrogen receptor-mediated or dependent diseases or conditions.

[0092] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -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] The chemical ratios of the compounds and the acid molecules described herein are subject to a certain degree of error. Generally, a range of plus or minus 10% is considered within a reasonable error range. The term "about" is used in a context where the error may vary, but this error may not exceed plus or minus 10%. The error may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%. Numerical values ​​expressed as "about" in this disclosure are within the aforementioned reasonable error range.

[0094] The "crystallization" or "crystallization" described in the present disclosure includes but is not limited to stirring crystallization, slurry crystallization, cooling crystallization and volatile crystallization.

[0095] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

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

[0097] The "pharmaceutically acceptable excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 is the XRPD spectrum of the amorphous form of Compound 1.

[0099] Figure 2 is the XRPD spectrum of Form A of Compound 1.

[0100] Figure 3 is the XRPD spectrum of Compound 1 Hydrochloride Form 1.

[0101] Figure 4 is the XRPD spectrum of Compound I hydrochloride Form II.

[0102] Figure 5 is the XRPD spectrum of Compound 1 maleate salt Form 1.

[0103] Figure 6 is an XRPD spectrum of Compound 1 fumarate salt Form 1.

[0104] Figure 7 is an XRPD spectrum of Compound I fumarate salt Form II.

[0105] Figure 8 is an XRPD spectrum of Compound I fumarate salt Form III.

[0106] Figure 9 is an XRPD spectrum of Compound 1 fumarate IV crystal form.

[0107] Figure 10 is an XRPD spectrum of Compound 1 fumarate Form V.

[0108] Figure 11 is the XRPD spectrum of L-tartrate salt Form I of Compound 1.

[0109] Figure 12 is the XRPD spectrum of Compound 1 Succinate Salt Form 1.

[0110] Figure 13 is the XRPD spectrum of Form I of the D-malate salt of Compound 1. DETAILED DESCRIPTION

[0111] The present disclosure is further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0112] Test conditions of the instruments used in the experiment:

[0113] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0114] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q 15 Exactive).

[0115] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0116] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 3-48°.

[0117] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min, from 25 to 300°C or from 25 to 350°C, and a nitrogen purge rate of 50 mL / min.

[0118] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum, and the nitrogen purge rate was 50 mL / min.

[0119] DVS stands for dynamic moisture sorption: using the Surface Measurement Systems instrument, humidity starts at 50% and the humidity range is 0%-95% with a step of 10%. The judgment standard is that the mass change of each gradient dM / dT is ≤ 0.002%, TMAX is 360min, and there are two cycles.

[0120] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.

[0121] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0122] Example 1. Preparation of Compound I (Refer to the preparation method of Example 26-1 in application No. WO2022206737)

[0123] first step

[0124] Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate 1b

[0125] Benzyl 4-formylpiperidine-1-carboxylate 1a (10 g, 40.4 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in methanol (80 mL), and trimethyl orthoformate (40 mL) and p-toluenesulfonic acid monohydrate (385 mg, 2 mmol) were added. The reaction 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 × 3). The organic phases were combined, washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound 1b (12 g), which was used directly in the next step without purification.

[0126] Step 2

[0127] 4-(Dimethoxymethyl)piperidine 1c

[0128] Compound 1b (12 g, 40.9 mmol) was dissolved in methanol (100 mL), and palladium on carbon (1.3 g, 10 wt%) was added. The reaction was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1c (6 g), which was used directly in the next reaction without purification.

[0129] Step 3

[0130] 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one 1e

[0131] 6-Hydroxy-3,4-dihydronaphthalen-1(2H)-one 1d (8 g, 49.3 mmol, Shanghai Bid 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 under reflux for 3 hours. The reaction solution was filtered through celite, 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 to obtain the crude title compound 1e (12 g). This product was used directly in the next step without purification. MS m / z (ESI): 253.1 [M+1].

[0132] Step 4

[0133] 6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate 1f

[0134] Compound 1e (8 g, 31.7 mmol) was dissolved in dry tetrahydrofuran (100 mL). Under an argon atmosphere, the reaction mixture was cooled to -78°C and lithium (1 M, 50.8 mL, 50.8 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78°C for 30 minutes. 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (17 g, 47.6 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Water (100 mL) was slowly added to quench the reaction mixture. The mixture was extracted with dichloromethane (50 mL x 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 obtain the title compound 1f (10.1 g) in an 83% yield. MS m / z (ESI): 385.2 [M+1].

[0135] Step 5

[0136] 7-(Benzyloxy)-4-(4-bromophenyl)-1,2-dihydronaphthalene 1g

[0137] Compound 1f (32 g, 83.3 mmol), 4-bromophenylboronic acid (20 g, 100 mmol, Shanghai Mairui Chemical Technology Co., Ltd.), tetrakistriphenylphosphine palladium (9.62 g, 8.3 mmol), and sodium carbonate (26.47 g, 250 mmol) were added sequentially to 360 mL of a 1,4-dioxane / water mixture (V / V = 5 / 1) under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and extraction with dichloromethane (200 mL x 3) was performed. The organic phases were combined, washed with saturated sodium chloride solution (200 mL x 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 obtain the title compound 1g (14 g) in a 43% yield.

[0138] Step 6

[0139] 1-(4-(6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1h

[0140] 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 toluene (350 mL) and reacted at 90°C under a nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and extraction with dichloromethane (200 mL x 3) was performed. The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 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 a 55% yield. MS m / z (ESI): 470.2 [M+1].

[0141] Step 7

[0142] 1-(4-(6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1i

[0143] 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 portionwise and the reaction was maintained at -5°C for 30 minutes. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL x 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 obtain the title product 1i (5.1 g) in a 42% yield. MS m / z (ESI): 550.2 [M+1].

[0144] Step 8

[0145] 1-(4-(6-(Benzyloxy)-2-isobutyl-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 1j

[0146] Under a nitrogen atmosphere, a 1 M zinc chloride tetrahydrofuran solution (8.2 mL) was slowly added dropwise to an ice-cooled tert-butylmagnesium chloride tetrahydrofuran solution (7.5 mL, Shanghai Adamas Co., Ltd.). The mixture was allowed to react at room temperature for 3 hours. Compound 1i (400 mg, 0.73 mmol) and a tetrahydrofuran solution (2 mL) 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 Aikang Biopharmaceutical Research and Development Co., Ltd.) were added dropwise. 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 x 2). The combined organic phases were dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using eluent System B to give the title compound 1j (300 mg) in a 75% yield. MS m / z (ESI): 526.3 [M+1].

[0147] Step 9

[0148] 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isobutyl-5,6,7,8-tetrahydronaphthalen-2-ol 1k

[0149] 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 allowed to proceed at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to afford the title compound 1k (90 mg) in an 83% yield. MS m / z (ESI): 438.3 [M+1].

[0150] Step 10

[0151] (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isobutyl-5,6,7,8-tetrahydronaphthalen-2-ol1l

[0152] 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. The title compound 1l (31 mg) was obtained. MS m / z (ESI): 438.3 [M+1].

[0153] Step 11

[0154] 1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carboxaldehyde 1m

[0155] Compound 1l (35 mg, 0.08 mmol) was dissolved in tetrahydrofuran (2.5 mL), and dilute sulfuric acid (2 M, 0.15 mL, 0.3 mmol) was added. The mixture was heated to 55°C for 1 hour. The reaction mixture was cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted 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, yielding the title compound 1m (31 mg) in a 99% yield. MS m / z (ESI): 392.2 [M+1].

[0156] Step 12

[0157] (S)-tert-Butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-amino-5-oxopentanoate

[0158] (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 atmosphere, the internal temperature was maintained below 5°C in an ice-water bath. Pyridine (15 mL, 188 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react in an ice-water bath for 0.5 hours. Ammonium bicarbonate (66.89 g, 282 mmol) was added, and the mixture was allowed to warm to room temperature and react 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 to obtain the crude title compound 1o (45.3 g), which was used directly in the next reaction without purification. MS m / z(ESI):369.1[M-55].

[0159] Step 13

[0160] (S)-tert-Butyl 4,5-diamino-5-oxopentanoate 1p

[0161] Compound 1o (45.3 g, 94 mmol) and diethylamine (50 mL) were added to dichloromethane (500 mL) and allowed to react 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), added with water (5 mL), and washed with n-heptane (150 mL x 3). The methanol layer was concentrated under reduced pressure to remove the solvent to obtain the crude title compound 1p (21.5 g), which was used directly in the next step without purification. MS m / z (ESI): 203.1 [M+1].

[0162] Step 14

[0163] tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 1r

[0164] Methyl 2-cyano-4-fluorobenzoate 1q (50 g, 0.28 mol, Jiangsu Aikang Biological Research and Development Co., Ltd.), tert-butyl piperazine-1-carboxylate 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 solution, and the mixture was extracted with ethyl acetate (1 L x 3). The organic phases were combined and washed with saturated sodium chloride solution (1 L x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the crude title compound 1r (89 g). This product was used directly in the next step without further purification. MS m / z (ESI): 290.1 ​​[M-55].

[0165] Step 15

[0166] tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 1s

[0167] 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. The mixture was allowed to react 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) and 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 a 59% yield. MS m / z (ESI): 293.1 [M-55].

[0168] Step 16

[0169] (S)-tert-Butyl 4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

[0170] Compound 1s (1.3 g, 3.7 mmol) and compound 1p (0.89 g, 4.5 mmol) were added to methanol (10 mL). The internal temperature was maintained below 5°C in 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 allowed to react at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was added with ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with saturated citric acid solution (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. 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].

[0171] Step 17

[0172] (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate 1u

[0173] 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 x 3) and dried to obtain the title compound 1u (5.7 g, 100% yield). MS m / z (ESI): 329.1 [M+1].

[0174] Step 18

[0175] (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1

[0176] Compound 1u (50 mg, 0.1 mmol) was added to a mixture of dichloromethane and methanol (v / v = 4 / 1, 5 mL). Sodium acetate (130 mg, 1.58 mmol) was added and the mixture was allowed to react for 10 minutes. Compound 1m (31 mg, 0.08 mmol) was then added and allowed to react for 15 minutes. Sodium triacetoxyborohydride (34 mg, 0.16 mmol) was then added and allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by HPLC (Waters 2767-SQ Detector 2, eluent: 10 mM ammonium bicarbonate, 60% water, 40% acetonitrile) to afford compound 1 (25 mg) in a 45% yield. MS m / z (ESI): 704.4 [M+1]. X-ray powder diffraction analysis confirmed the compound to be amorphous. The X-ray powder diffraction spectrum is shown in Figure 1.

[0177] Example 2. Inhibitory effect of compound I on MCF7 cell proliferation

[0178] MCF7 cells (TCHu74, Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences) were cultured with MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded at a density of 3,000 cells / well in a 96-well plate using MEM medium containing 2% fetal bovine serum, with 135 μL of cell suspension per well, and cultured overnight in a cell culture incubator at 37°C and 5% CO2. On the second day, 15 μL of the test compound prepared in culture medium at different concentrations was added to each well. The final concentration of the compound was 9 concentration points of 4-fold gradient dilution starting from 1000 nM. A blank control containing 0.5% DMSO was set up, and the cells were cultured in a cell culture incubator at 37°C and 5% CO2 for 6 days. On the eighth day, the 96-well cell culture plate was removed and 75 μL was added to each well. Luminescent Cell Viability Assay (Promega, G7573) was used. After standing at room temperature for 10 minutes, the luminescent signal value was read using a multi-label microplate reader (PerkinElmer, VICTOR 3). The IC50 value of the inhibitory activity of the compound was calculated based on the compound concentration and the luminescent signal value using Graphpad Prism software, and was 0.59 nM.

[0179] Example 3. Pharmacodynamics of Compound I

[0180] 1. Experimental Purpose

[0181] The inhibitory effect of compound I on the growth of human breast cancer cell MCF-7 (Y537S) xenografts in BEIGE SCID mice was evaluated.

[0182] 2. Experimental drugs

[0183] Compound I: A 2% Tween 80 + 98% PEG-400 solution was used.

[0184] 3. Experimental methods and materials

[0185] 3.1 Experimental animals and housing conditions

[0186] Experimental animals: BEIGE SCID female mice were purchased from Beijing Weitonglihua Laboratory Animal Co., Ltd. (License No.: SCXK (Beijing) 2016-0006), weighing approximately 19 g at the time of purchase.

[0187] Rearing conditions: 5 animals / cage, 12 / 12 h light / dark cycle, constant temperature of 23±1°C, humidity of 50 to 60%, free access to food and water.

[0188] 3.2 Animal grouping

[0189] After adaptive feeding, BEIGE SCID mice were divided into the following groups:

[0190] Note: qd means administration once a day; ig means administration by gavage.

[0191] 3.3 Experimental methods:

[0192] MCF-7 (Y537S) cells in the logarithmic growth phase were cultured at a rate of 1.0 × 10 7 200 μL of the solution (containing 100 μL of Matrigel) was inoculated subcutaneously on the right rib of female BEIGE SCID mice. After 18 days, the tumor volume of the tumor-bearing mice reached 170 mm. 3At about 14 days, the mice were randomly divided into 4 groups according to tumor volume and body weight: vehicle control group, compound I 5mpk group, compound I 15mpk group, and compound I 45mpk group, with 8 mice in each group. The day of grouping was set as D0, and oral administration began once a day for a total of 28 days. The 28th day after administration was set as D 28 (Table 1) The tumor volume of tumor-bearing mice was measured with a vernier caliper twice a week.

[0193] 3.4 Data Statistics

[0194] All data were graphed and statistically analyzed using Excel and GraphPad Prism 8 software.

[0195] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b2, where a and b represent length and width, respectively.

[0196] Relative tumor proliferation rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0197] Tumor inhibition rate (TGI) (%) = 1-T / C (%). When TGI (%) exceeds 100%, the specific value will not be displayed and will only be represented as >100%. Tumor regression (%) = [(T0-T) / T0] × 100 (%).

[0198] 4. Results

[0199] The efficacy data of Compound I against MCF-7 (Y537S) xenograft tumors in BEIGE SCID mice are shown in Table 1.

[0200] Table 1 The efficacy of compound I on MCF-7 (Y537S) transplanted tumors in BEIGE SCID mice Note: qd means administration once a day; d means day; ig means oral administration; SEM means standard error.

[0201] 5. Conclusion

[0202] Compound I was administered once a day starting 18 days after tumor cell transplantation. After 28 days of administration, the tumor inhibition rate of the low-dose 5mpk group was 72%, the medium-dose 15mpk group was 89%, and the high-dose 45mpk group was 95%.

[0203] Example 4. Preparation of amorphous compound

[0204] 5 mg of Compound I was weighed and dissolved in a solvent to obtain a product. X-ray powder diffraction analysis revealed no obvious characteristic peaks, indicating that the product was amorphous. The XRPD spectrum is shown in FIG1 .

[0205] Table 2 Preparation of amorphous compound

[0206] Example 5. Preparation of Compound A Crystalline Form

[0207] 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 slurried for 1 day. The solid was centrifuged and dried to obtain the product.

[0208] X-ray powder diffraction analysis identified the product as Compound A. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 3. The TGA spectrum showed a 2.9% weight loss before 140°C. The DSC spectrum showed an endothermic peak at 162.58°C.

[0209] Table 3 Peak positions of compound A crystal form

[0210] Example 6. Preparation of Compound Hydrochloride Form I

[0211] 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. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0212] X-ray powder diffraction analysis identified the product as hydrochloride Form I. The XRPD spectrum is shown in Figure 3, and the locations of its characteristic peaks are shown in Table 4. Ion chromatography analysis revealed a chloride ion content of 9.08%. The DSC spectrum showed endothermic peaks at 72.79°C and 248.5°C. The TGA spectrum revealed a weight loss of 2.8% from 30°C to 120°C.

[0213] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 6.3%. Under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 7.3%. Under extreme conditions (i.e., 90% RH), the moisture gain was approximately 8.9%. Retesting the crystal form after DVS testing revealed no change in form.

[0214] Table 4 Hydrochloride I Crystal Peak Position

[0215] Example 7. Preparation of Compound Hydrochloride Form I

[0216] 48 mg of Compound I was weighed, and a solvent and 2 mol / L hydrochloric acid solution were added to obtain a product. X-ray powder diffraction analysis showed that the product was hydrochloride salt form I.

[0217] Table 5 Preparation of Compound Hydrochloride I Crystalline Form

[0218] Example 8. Preparation of Compound Hydrochloride Form I

[0219] The hydrochloride II crystal form is heated to 120° C. to obtain a product, which is detected by X-ray powder diffraction to be the hydrochloride I crystal form.

[0220] Example 9. Preparation of Compound Hydrochloride II Crystalline Form

[0221] About 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.

[0222] X-ray powder diffraction analysis identified the product as hydrochloride Form II. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks 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 revealed a weight loss of 1.9% from 30°C to 160°C.

[0223] Table 6 Hydrochloride II Crystalline Peak Position

[0224] Example 10. Preparation of Compound Hydrochloride II Crystalline Form

[0225] 48 mg of compound I was weighed, and a solvent and 2 mol / L hydrochloric acid solution were added to obtain a product. X-ray powder diffraction analysis showed that the product was hydrochloride II crystal form.

[0226] Table 7 Preparation of Compound Hydrochloride II Crystalline Form

[0227] Example 11. Preparation of amorphous hydrochloride of compound

[0228] About 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. The reaction solution was beaten for 1 day, centrifuged, and dried to obtain the product.

[0229] X-ray powder diffraction analysis showed no obvious characteristic peaks, indicating that the product was amorphous hydrochloride. Ion chromatography analysis showed that the chloride ion content was 5.66%.

[0230] Example 12. Preparation of Compound Maleate Salt Form I

[0231] About 100 mg of compound I was weighed and dissolved in 3 ml of acetone. 18.2 mg of maleic acid was added and the reaction solution was slurried for 1 day to obtain the product.

[0232] X-ray powder diffraction analysis identified the product as maleate salt Form I. The XRPD spectrum is shown in Figure 5, and the locations of its characteristic peaks are shown in Table 8. Ion chromatography analysis revealed a maleate ion content of 12.53%. The DSC spectrum showed an endothermic peak at 145.8°C. The TGA spectrum revealed a weight loss of 1% between 30°C and 90°C, and a weight loss of 12.4% between 90°C and 190°C.

[0233] Table 8 Maleate I Crystalline Peak Position

[0234] Example 13. Preparation of Compound Fumarate I Crystalline Form

[0235] About 98 mg of compound I was weighed and dissolved in 3 ml of tetrahydrofuran. 17.1 mg of fumaric acid was added. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the title product.

[0236] X-ray powder diffraction analysis identified the product as fumarate salt Form I. The XRPD spectrum is shown in Figure 6, and the locations of its characteristic peaks are shown in Table 9. Ion chromatography analysis revealed a fumarate ion content of 11.58%. The DSC spectrum showed an endothermic peak at 141.44°C. The TGA spectrum revealed a weight loss of 13.6% from 30°C to 160°C.

[0237] Table 9 Fumarate I Crystalline Peak Position

[0238] Example 14. Preparation of Compound Fumarate II Crystalline Form

[0239] About 7.1 mg of compound I was weighed and dissolved in 0.2 ml of acetonitrile. 2.3 mg of fumaric acid was added. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0240] X-ray powder diffraction analysis identified the product as fumarate salt Form II. The XRPD spectrum is shown in Figure 7, and the locations of its characteristic peaks are shown in Table 10. Ion chromatography analysis revealed a fumarate ion content of 18.78%. The DSC spectrum showed endothermic peaks at 155.97°C and 229.48°C. The TGA spectrum revealed a weight loss of 1.3% between 30°C and 100°C, and a weight loss of 21.4% between 100°C and 280°C.

[0241] Table 10 Fumarate II Crystalline Form Peak Position

[0242] Example 15. Preparation of Compound Fumarate III Crystalline Form

[0243] 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. A solid was precipitated and dried to obtain the product.

[0244] The product was defined as fumarate III crystalline form by X-ray powder diffraction analysis. The XRPD spectrum is shown in FIG8 , and the positions of its characteristic peaks are shown in Table 11. 1 H NMR characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0245] Table 11 Fumarate III Crystalline Form Peak Position

[0246] Example 16. Preparation of Fumarate IV Crystalline Form

[0247] 20 mg of Compound I was weighed and dissolved in 1 mL of acetone. 0.2 mL of an acetone solution of fumaric acid (3.3 mg, 28.41 μmol) was added. The mixture was stirred at room temperature for 2.5 hours. A solid was precipitated and dried to obtain the product.

[0248] The product was defined as fumarate IV crystalline form by X-ray powder diffraction analysis. The XRPD spectrum is shown in FIG9 , and the positions of its characteristic peaks are shown in Table 12. 1 H NMR characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0249] Table 12 Fumarate IV Crystalline Peak Position

[0250] Example 17. Preparation of Fumarate Crystal Form V

[0251] 100 mg of compound I was weighed and dissolved in 2 mL of 1,4-dioxane. 0.4 mL of a 1,4-dioxane solution of fumaric acid (16.5 mg, 142.06 μmol) was added, and the mixture was stirred at room temperature for 16 hours. A solid precipitated and dried to obtain the product.

[0252] X-ray powder diffraction analysis identified the product as fumarate form V. The XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks 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 H NMR characterization: Compound I forms a salt with fumaric acid in a 1:1 ratio.

[0253] Table 13 Fumarate V Crystalline Peak Position

[0254] Example 18. Preparation of L-Tartrate Crystal Form I

[0255] 100 mg of compound I was weighed and dissolved in 5 mL of 1,4-dioxane. L-tartaric acid (21.5 mg, 143.25 μmol) was added and stirred at room temperature for 16 hours. A solid precipitated and was dried to obtain the product.

[0256] The product was defined as L-tartrate salt form I by X-ray powder diffraction analysis. The XRPD spectrum is shown in FIG11 , and the positions of its characteristic peaks are shown in Table 14. 1 H NMR characterization: Compound I formed a salt with L-tartaric acid in a 1:1 ratio.

[0257] Table 14 Peak positions of L-tartrate I crystal form

[0258] Example 19. Preparation of Succinate Form I

[0259] 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. The mixture was stirred at room temperature for 16 hours. A solid was precipitated and dried to obtain the product.

[0260] The product was defined as succinate I crystal form by X-ray powder diffraction analysis. The XRPD spectrum is shown in FIG12 , and the positions of its characteristic peaks are shown in Table 15 . 1 H NMR characterization: Compound I formed a salt with L-tartaric acid in a 1:1 ratio.

[0261] Table 15 Succinate I Crystalline Form Peak Position

[0262] Example 20. Preparation of D-malate Form I

[0263] 2 g of compound I was dissolved in 60 mL of tetrahydrofuran, and 20 mL of a tetrahydrofuran solution of D-malic acid (381 mg, 2.84 mmol) was added. The mixture was stirred at room temperature in the dark for 24 hours to precipitate a solid, which was then dried in vacuo at 50° C. for 16 hours to obtain the product.

[0264] X-ray powder diffraction analysis identified the product as D-malate Form I. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks 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% from 30°C to 140°C.

[0265] Table 16 Peak positions of D-malate I crystal form

[0266] Example 21. Preparation of amorphous sulfate

[0267] About 48 mg of compound I was weighed and dissolved in 0.7 ml of 50% ethanol / ethyl acetate. A sulfuric acid solution (2 mol / L, 38 μL) was added. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0268] X-ray powder diffraction analysis revealed no distinct characteristic peaks, indicating the product was an amorphous sulfate salt. Ion chromatography analysis revealed a sulfate ion content of 12.89%. The TGA spectrum showed a weight loss of 4.4% at 30°C-100°C.

[0269] Example 22. Preparation of amorphous phosphate

[0270] About 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. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0271] X-ray powder diffraction analysis revealed no distinct characteristic peaks, indicating the product was an amorphous phosphate. Ion chromatography analysis revealed a phosphate ion content of 13.77%. The TGA spectrum showed a weight loss of 1.5% at 30°C-110°C.

[0272] Example 23. Preparation of amorphous tartrate

[0273] About 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. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0274] X-ray powder diffraction analysis revealed no distinct characteristic peaks, indicating the product was an amorphous tartrate salt. Ion chromatography analysis revealed a tartrate ion content of 9.87%. TGA analysis revealed a 2.3% weight loss between 30°C and 100°C, and a 1% weight loss between 100°C and 180°C.

[0275] Example 24. Preparation of amorphous L-malate

[0276] About 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. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0277] X-ray powder diffraction analysis revealed no distinct characteristic peaks, indicating the product was an amorphous L-malate salt. Ion chromatography analysis revealed a malate ion content of 10.25%. TGA analysis revealed a 1.6% weight loss from 30°C to 90°C and a 3.2% weight loss from 90°C to 160°C.

[0278] Example 25. Preparation of amorphous citrate

[0279] About 28 mg of compound I was weighed and dissolved in 0.4 ml of 50% ethanol / ethyl acetate. A citric acid solution (0.5 mol / L, 84 μL) was added. The reaction solution was slurried for 1 day, centrifuged, and dried to obtain the product.

[0280] X-ray powder diffraction analysis showed that the product was an amorphous citrate salt, and the TGA spectrum showed a 2% weight loss at 30°C-100°C.

[0281] Experimental Example 1. Study on the Stability of Factors Affecting the Hydrochloride Form I

[0282] The hydrochloride salt form I was laid open and the stability of the sample was investigated under light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 1 month.

[0283] Table 17 Factors affecting stability of hydrochloride salt I crystal form

[0284] Conclusion: Except for high temperature and light, the hydrochloride form I has good physical and chemical stability when stored for one month under other conditions.

[0285] Experimental Example 2. Long-term accelerated stability study of hydrochloride form I

[0286] The hydrochloride salt form I was placed under 25°C / 60% RH and 40°C / 75% RH conditions to investigate its stability.

[0287] Table 18 Long-term / accelerated stability of hydrochloride salt form I

[0288] Conclusion: The hydrochloride form I showed good physical and chemical stability under long-term accelerated conditions for 2 months.

Claims

1. A crystalline form A of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ at 14.2, 15.3, 16.1, 17.4 and 19. .1, preferably there are characteristic peaks at 14.2, 15.3, 16.1, 17.4, 19.1, 20.0, 20.9 and 22.3, more preferably there are 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, and most preferably the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 2.

2. A pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 the group consisting of hydrochloride, maleate, fumarate, L-tartrate, succinate, D-malate, L-malate, sulfate, phosphate and citrate.

3. The pharmaceutically acceptable salt according to claim 2, characterized in that The chemical ratio of the (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and the acid is 3:1-1:3, preferably 2:1-1:

2.

4. A method for preparing a pharmaceutically acceptable salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, comprising: a step of reacting (1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-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 citric acid.

5. A crystalline form I of the hydrochloride salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in diffraction angles 2θ of 13.8, 15.9, 19.0, 20.1 The invention further comprises a powder diffraction pattern having characteristic peaks at 13.8, 15.9, 16.9, 17.9, 19.0, 20.1, 20.6 and 22.8, more preferably 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 at a diffraction angle 2θ as shown in FIG3 .

6. A crystalline form II of the hydrochloride salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with peaks at 13.2, 17.1, 19.7, 20.6, 22.8, and 25.

0. Characteristic peaks are preferably present at 10.4, 13.2, 14.5, 15.1, 17.1, 19.7, 20.6, 22.8, 25.0 and 26.1, more preferably 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 the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG4 .

7. A crystalline maleate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, Form I, having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 5.6, 8.8, 9.4, 10.2, 10.7, and 18.

0. 5 .

8. A crystalline form I of a fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ at 6.8, 9.6, 10.5, 17.6, and 18.2 6 , wherein the X-ray powder diffraction pattern is as shown in FIG6 , and ...

9. A crystalline form II fumarate of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, and having characteristic peaks at 7.0, 9.4, 15.0, 17.1, 17.7, and 18.7, preferably having characteristic peaks at 7.0, 9.4, 10.9, 14.6, 15.0, 17.1, 17.7, 18.7, 19.9, and 23.9, more preferably having an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ as shown in Figure 7.

10. A crystalline form III of a fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in diffraction angles 2θ of 5.1, 9.6, 10.4, 17.9, The X-ray powder diffraction pattern is shown in Figure 8, and the X-ray powder diffraction pattern is expressed in terms of diffraction angle 2θ.

11. A crystalline form IV of a fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ degrees, with characteristic peaks at 6.2, 10.3, 11.1, 12.5, 21.3, and 22.

2. Preferably, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ degrees is shown in Figure 9.

12. A crystalline form V of a fumarate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with peaks at 10.5, 17.1, 18.6, 20.1, 21.0, and 23.

7. Characteristic peaks are preferably present at 5.3, 9.9, 10.5, 11.6, 16.0, 17.1, 18.6, 20.1, 21.0 and 23.7, more preferably 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, and most preferably the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 10.

13. (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl) The L-tartrate salt Form I of the (2-methyl)piperazine-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione has an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, and has characteristic peaks at 9.1, 16.0, 17.7, 18.0, 20.0, and 20.7, preferably at 9.1, 9.5, 10.8, 16.0, 17.7, 18.0, 20.0, 20.7, 21.6, and 22.4, more preferably 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, and most preferably, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is shown in Figure 11.

14. A crystalline form I of a succinate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ at 9.5, 16.0, 17.6, 18.0, 19.9, 20.7 and 22.3 There are 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 there are 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 the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 12.

15. A crystalline form I of the D-malate salt of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, having an X-ray powder diffraction pattern expressed in diffraction angles 2θ at 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, and 19.

8. The present invention has characteristic peaks at 7.0, 9.0, 9.5, 10.7, 15.9, 17.9, 18.2, 20.0, 20.6 and 22.3, more preferably 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, and most preferably the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 13.

16. The crystal form according to claim 1, 5-15, wherein The error range of the 2θ angle is ±0.

2.

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

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

19. Crystalline Form A of the (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2. Use of a pharmaceutically acceptable salt of (piperazine-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form according to any one of claims 5 to 15, or the composition according to claim 17 in the preparation of a medicament for treating or preventing a disease treated by degrading a target protein bound to a targeting ligand.

20. The crystalline form A of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the crystalline form A of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 2. -yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form according to any one of claims 5 to 15, or the composition according to claim 17 for preparing a medicament for treating or preventing a disease that is treated by binding to cerebellin in vivo, wherein the disease is preferably abnormal cell proliferation, tumor, immune disease, diabetes, cardiovascular disease, infectious disease and inflammatory disease, more preferably tumor or infectious disease.

21. The crystal form A of (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione according to claim 1, or the crystal form A of (S)-3-(5-(4-((1-(4-((1R,2 Use of a pharmaceutically acceptable salt of (i)-6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or the crystalline form according to any one of claims 5 to 15, or the composition according to claim 17 in the preparation of a medicament for treating or preventing estrogen receptor-mediated or dependent diseases or conditions.

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